Search

Yuexiang Qin,1,2 Shanhu Yao,3,4 Gaoyuan Wang,5 Ziyuan Xu,6,7 Gangcai Zhu,8 Ying Li,1,2 Pingting Yang,1,2 Jiangang Wang,1,2 Chunbo Zou,5 Changhan Chen7,9 1Department of Health Management Medicine, The Third Xiangya Hospital of Central South University, Changsha, Hunan Province, 410013, People’s Republic of China; 2Hunan Chronic Disease Health Management Medical Research Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan Province, 410013, People’s Republic of China; 3Department of Radiology, The Third Xiangya Hospital, Central South University, Changsha, Hunan Province, 410013, People’s Republic of China; 4Key Laboratory of Medical Information Research, Central South University, Changsha, Hunan Province, 410013, People’s Republic of China; 5Department of Nephrology, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, People’s Republic of China; 6Department of Otolaryngology, Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, Hunan Province, 410008, People’s Republic of China; 7National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China; 8Department of Otolaryngology, Head and Neck Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan Province, 410008, People’s Republic of China; 9National Medical Metabolomics International Collaborative Research Center, Xiangya Hospital, Central South University, Changsha, Hunan Province, 410008, People’s Republic of ChinaCorrespondence: Changhan Chen, National Medical Metabolomics International Collaborative Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, People’s Republic of China, Tel +86-13875974606, Email changhanchen@csu.edu.cnObjective: Inflammation plays a crucial role in the development of metabolic syndrome (MetS). However, the roles of pepsinogens (PGs) and gastrin, known biomarkers linked to gastric inflammation, in MetS and the transition of MetS status are unclear. This research aimed to explore the relationship between MetS, the transition of MetS status, and levels of gastric biomarkers.Methods: This large-scale cross-sectional study included 19162 participants aged 18– 80 years between August 2021 and March 2024. Serum levels of the gastric biomarkers PGI, PGII, and gastrin-17 were analyzed using enzyme-linked immunosorbent assay. In addition, the relationship between transitions of MetS status based on 1032 MetS-negative participants from baseline to the second health exam after 2 years was considered. The association between MetS and the transitions of MetS status and gastric biomarkers was analyzed using logistic regression models.Results: The prevalence of MetS in the study population was 31.4%, with higher rates in males (35.2%) than females (24.6%). Gastrin-17 levels were markedly elevated in participants with MetS, a trend observed in both genders. In the logistic regression analysis, after adjusting for confounding factors, gastrin-17 levels were strongly and positively correlated with MetS in the entire cohort and in males but not in females. Male participants with MetS had lower levels of PGI and PGII than those without MetS, whereas the opposite trend was observed in females. Logistic regression analysis indicated that PGI and PGII were not independently associated with MetS. During the follow-up of 2 years, 199 (19.28%) of the 1032 MetS-negative participants transitioned to MetS-positive status. As compared to the stable MetS-negative subjects, transition from MetS-negative to MetS-positive was associated with higher levels of gastrin-17, especially in males, but not in females.Conclusion: Gastrin-17 is a promising biomarker for MetS, exhibiting potential utility in monitoring the transition of MetS status and revealing gender difference.Keywords: gastric biomarkers, gastrin-17, metabolic syndrome, transition, gender difference

Zhiying Yang,1,* Shun Yao,1,2,* Yichong Xu,1 Xiaoqing Zhang,1,2 Yuan Shi,1,2 Lijun Wang,1,2 Donghong Cui1,2 1Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 2Shanghai Key Laboratory of Psychotic Disorders, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Donghong Cui, Email manyucc@126.comBackground: Schizophrenia is a devastating mental disease with high heritability. A growing number of susceptibility genes associated with schizophrenia, as well as their corresponding SNPs loci, have been revealed by genome-wide association studies. However, using SNPs as predictors of disease and diagnosis remains difficult. Here, we aimed to uncover susceptibility SNPs in a Chinese population and to construct a prediction model for schizophrenia.Methods: A total of 210 participants, including 70 patients with schizophrenia, 70 patients with bipolar disorder, and 70 healthy controls, were enrolled in this study. We estimated 14 SNPs using published risk loci of schizophrenia, and used these SNPs to build a model for predicting schizophrenia via comparison of genotype frequencies and regression. We evaluated the efficacy of the diagnostic model in schizophrenia and control patients using ROC curves and then used the 70 patients with bipolar disorder to evaluate the model’s differential diagnostic efficacy.Results: 5 SNPs were selected to construct the model: rs148415900, rs71428218, rs4666990, rs112222723 and rs1716180. Correlation analysis results suggested that, compared with the risk SNP of 0, the risk SNP of 3 was associated with an increased risk of schizophrenia (OR = 13.00, 95% CI: 2.35– 71.84, p = 0.003). The ROC-AUC of this prediction model for schizophrenia was 0.719 (95% CI: 0.634– 0.804), with the greatest sensitivity and specificity being 60% and 80%, respectively. The ROC-AUC of the model in distinguishing between schizophrenia and bipolar disorder was 0.591 (95% CI: 0.497– 0.686), with the greatest sensitivity and specificity being 60% and 55.7%, respectively.Conclusion: The SNP risk score prediction model had good performance in predicting schizophrenia. To the best of our knowledge, previous studies have not applied SNP-based models to differentiate between cases of schizophrenia and other mental illnesses. It could have several potential clinical applications, including shaping disease diagnosis, treatment, and outcomes.Keywords: schizophrenia, SNP, diagnostic model, bipolar disorder, differential diagnosis

Zuohu Niu,1,&ast; Jialiang Chen,2,&ast; Huijing Wang,3,&ast; Rongrui Wang,3,4 Hongye Peng,3 Shaojie Duan,5 Shukun Yao4 1Department of Infections, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, People’s Republic of China; 2Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China; 3Graduate School, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 4Department of Gastroenterology, China-Japan Friendship Hospital, Beijing, People’s Republic of China; 5Department of Geriatrics, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shaojie Duan, Department of Geriatrics, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang, People’s Republic of China, Email 1782802171@qq.com Shukun Yao, Department of Gastroenterology, China-Japan Friendship Hospital, No. 2 Yinghua East Street, Chaoyang District, Beijing, 100029, People’s Republic of China, Email shukunyao@126.comPurpose: It is unclear how the Chinese Visceral Adiposity Index (cVAI) relates to metabolic dysfunction-associated fatty liver disease (MAFLD) and alanine aminotransferase (ALT) in nonobese individuals. In this study, we evaluated the ability of the cVAI to predict MAFLD and elevated ALT in nonobese participants.Methods: This cross-sectional study recruited 541 nonobese subjects from March 2019 to January 2022 with the age range of 18– 80 years. Hepatic steatosis was diagnosed by ultrasound. Participants were divided into four groups according to cVAI quartiles. To assess the associations between cVAI and MAFLD and elevated ALT, multivariate logistic regression was used. Receiver operating characteristic (ROC) curves were generated to evaluate the ability of the cVAI to predict MAFLD and elevated ALT.Results: Compared to the group with the lowest cVAI, the group with the highest cVAI was positively associated with nonobese MAFLD [16.173 (4.082– 64.073), P < 0.001] and elevated ALT [8.463 (2.859– 25.049), P < 0.001]. The area under the ROC curve (AUC) of the cVAI was greater than that of WC, waist-to-height ratio, or BMI for predicting nonobese MAFLD in the male, female, > 38 and ≤ 38 years old subgroups (P < 0.05), respectively. In addition, the ability of the cVAI to predict MAFLD was better in females, young individuals, and individuals with a higher education level (P < 0.05). The cVAI also had good predictive ability for elevated ALT levels [0.655 (0.602– 0.708)], particularly in females, young people, and highly educated participants. Furthermore, the cVAI was strongly positively correlated with the liver fibrosis score (P < 0.05) and was also a strong indicator of concomitant metabolic syndrome in nonobese MAFLD patients [AUC = 0.688 (0.612– 0.763)].Conclusion: The cVAI was strongly related to nonobese MAFLD and elevated ALT. The cVAI may be a reliable and accessible predictor of nonobese MAFLD and elevated ALT.Keywords: Chinese visceral adiposity index, metabolic dysfunction-associated fatty liver disease, nonobese, Chinese, cross-sectional study

David F Blackburn,1 Shenzhen Yao,2 Jeff G Taylor,1 Qais Alefan,3 Lisa M Lix,4 Dean T Eurich,5 Niteesh K Choudhry6 1College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, Saskatchewan, Canada; 2Public Health Surveillance Unit, Vancouver Coastal Health Authority, Vancouver Coastal Health, Vancouver, British Columbia, Canada; 3Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan; 4Department of Community Health Sciences, Max Rady Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada; 5School of Public Health, University of Alberta, Edmonton, Alberta, Canada; 6Department of Medicine, Brigham and Women’s Hospital/Harvard Medical School, Boston, MA, USACorrespondence: David F Blackburn, Email d.blackburn@usask.caPurpose: To measure the impact of beliefs, expectations, side effects, and their combined effects on the risk for medication nonpersistence.Patients and methods: Using a cross-sectional design, individuals from Saskatchewan, Canada who started a new antihypertensive, cholesterol-lowering, or antihyperglycemic medication were surveyed about risk factors for nonpersistence including: (a) beliefs measured by a composite score of three questions asking about the threat of the condition, importance of the drug, and harm of the drug; (b) incident side effects attributed to treatment; and (c) expectations for side effects before starting treatment. Descriptive statistics and logistic regression models were used to quantify the influence of these risk factors on the outcome of nonpersistence. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated.Results: Among 3,029 respondents, 5.8% (n=177) reported nonpersistence within four months after starting the new drug. After adjustment for numerous covariates representing sociodemographics, health-care providers, medication experiences and beliefs, both negative beliefs (OR: 7.26, 95%CI: 4.98– 10.59) and incident side effects (OR: 8.00, 95%CI: 5.49– 11.68) were associated with the highest odds of nonpersistence with no evidence of interaction. In contrast, expectations for side effects before starting treatment exhibited an important interaction with incident side effects following treatment initiation. Among respondents with incident side effects (n=741, 24.5%), the risk for early nonpersistence was 11.5% if they indicated an expectation for side effects before starting the medication compared to 23.6% if they did not (adjusted OR: 0.38, 95%CI: 0.25– 0.60).Conclusion: Expectations for side effects may be a previously unrecognized but important marker of the probability to persist with treatment. A high percentage of new medication users appeared unprepared for the possibility of side effects from their new medication making them less resilient if side effects occur.Keywords: adherence, persistence, beliefs, attitudes, expectations

Dongping Wan,1,2,&ast; Shihang Cao,1,2,&ast; Xinrui Li,3,4,&ast; Qiang Zan,2 Shuxin Yao,1 Jianbing Ma,1 Lei Shang,1,3 Chao Xu1,3 1Department of Knee Joint Surgery, Honghui Hospital, Xi’an Jiaotong University, Xi’an, People’s Republic of China; 2The First Clinical Medical College, Shaanxi University of Chinese Medicine, Xianyang, People’s Republic of China; 3Department of Health Statistics, Faculty of Preventive Medicine, the Air Force Military Medical University, Xi’an, People’s Republic of China; 4School of Medicine, Northwest University, Xi’an, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Chao Xu; Lei Shang, Email 383697196@qq.com; fmmushanglei@163.comBackground: The High Activity Arthroplasty Score (HAAS) is a validated score that assesses functional outcomes after lower limb arthroplasty, with fewer ceiling effects than other scores. The aim is to translate and cross-culturally adapt the HAAS into a Chinese version (HAAS-C) and to evaluate the psychometric properties of HAAS-C in patients after primary total knee arthroplasty (TKA).Methods: A total of 104 patients diagnosed with knee osteoarthritis who had undergone TKA at least 12 months prior were recruited. A forward and backward translation procedure was performed for developing a culturally acceptable HAAS-C. Internal consistency was assessed using Cronbach’s α, and test-retest reliability was measured using the intraclass correlation coefficient (ICC) within a 10-day interval. Construct validity was assessed by examining the correlations between HAAS-C and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), EuroQoL Group’s five-dimension questionnaire (EQ-5D-5L), and Oxford knee score (OKS).Results: HAAS-C demonstrated adequate Internal consistency reliability, as indicated by Cronbach’s α coefficient of 0.75. Test-retest reliability yielded excellent results, with an ICC value of 0.98. Content validity indices were high, with a scale-level validity index of 0.9 and item-level validity indices greater than or equal to 0.8. HAAS-C showed a strong correlation with WOMAC (r = 0.69), a moderate correlation with EQ-5D-5L (r = 0.43), and OKS (r = 0.53) while exhibiting no floor or ceiling effects.Conclusion: The validated HAAS-C questionnaire is a valid instrument for assessing patients undergoing TKA in mainland China.Keywords: high activity arthroplasty score, total knee arthroplasty, Chinese validation, reliability, validity

Lu Liu,1 Shuang Yuan,1 Shouheng Yao,1 Wenjiao Cao,1,2 Lihua Wang1 1The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200030, People’s Republic of China; 2Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, 200030, People’s Republic of ChinaCorrespondence: Lihua Wang; Wenjiao Cao, The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, No. 910, Hengshan Road, Xuhui District, Shanghai, 200030, People’s Republic of China, Tel +86-21-18017316018, Fax +86-21-64073896, Email drwanglh0420@163.com; cwj1479@163.comPurpose: Approximately 20% of patients with type I endometrial cancer (EC) of the uterus experience recurrence and metastasis. However, existing data do not provide sufficient evidence for the utility of protein levels as prognostic biomarkers in type I EC. This study aims to determine whether epiplakin1 (EPPK1) and progesterone receptor (PR) play a role in the recurrence and metastasis of type I EC.Methods: Following the Reporting Recommendations for Tumor Marker Prognostic Studies (REMARK) for assessing the quality of biomarker research results, a retrospective analysis was conducted on clinical information and tissue samples of type I EC patients. Protein expression data and clinical data for type I EC were downloaded from The Cancer Proteome Atlas (TCPA) database. We utilized the Kaplan-Meier (K-M) method and Cox proportional hazards regression analyses to evaluate whether epiplakin1 (EPPK1), progesterone receptor (PR) and certain clinical parameters can serve as independent prognostic factors. The Immune Cell Abundance Identifier (ImmuCellAI) and Cancer Immunome Atlas (TCIA) were employed to predict responses to immunotherapy. Immunohistochemistry was carried out to assess the expression of EPPK1 in type I EC.Results: Type I EC patients with high EPPK1 and low PR expression had higher International Federation of Gynecology and Obstetrics (FIGO) stage, recurrence, and metastasis rates. Furthermore, EPPK1 was identified as an independent prognostic factor, and low expression of EPPK1 was predominantly observed in the POLE ultramutated (POLEmut) group, indicating a favorable prognosis. Additionally, the high EPPK1 expression group had a lower Immune Prognostic Score (IPS), suggesting that the high-expression group may not benefit from immune checkpoint inhibitors.Conclusion: High expression of EPPK1 is an independent prognostic factor in type I EC patients with low PR expression. It can identify a subgroup of patients at high risk of recurrence. A more aggressive treatment approach is recommended for these patients.Keywords: type I endometrial cancer, progesterone receptor, epiplakin1, prognostic biomarker, immunotherapy

Saiyu Gao,1– 3 Nanqi Huang,4 Wenmin Huang,5 Yu Lian,5 Huiming Xiao,5 Shuyu Yao5 1Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China; 2National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China; 3Teaching and Research Section of Clinical Nursing, Xiangya Hospital of Central South University, Changsha, Hunan, People’s Republic of China; 4Department of Gastroenterology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China; 5Ocular Emergency and Trauma Department, State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangdong Provincial Clinical Research Center for Ocular Diseases, Guangzhou, People’s Republic of ChinaCorrespondence: Shuyu Yao, Email yaoshuyu@gzzoc.comIntroduction: Position adherence of patients with Pars Plana Vitrectomy with Silicone Oil Tamponade after discharge is of positive significance. However, patients undergoing a day surgery makes the quality of discharge teaching and readiness for hospital discharge is insufficient, which will influence their position adherence at home.Aim: This study aimed to find the correlation of discharge teaching, readiness for hospital discharge, and position adherence in patients who underwent PPV with silicone oil tamponade from the day ward.Methods: This was a cross-sectional survey. One hundred ninety-four patients with day surgery were recruited by convenient sampling from Zhongshan Ophthalmic Center, China. Data were collected using the quality of discharge teaching scale, readiness for hospital discharge scale, and position adherence scale.Results: Patients’ education level, residence, poor postoperative vision, ophthalmic surgery history, and quality of discharge teaching are the main factors of readiness for discharge. Only 41(21%) patients had good position adherence, and education level and readiness for discharge are the main factors of position adherence.Discussion: Discharge teaching improves patients’ knowledge and competence of self-care and helps patients prepare for the transition from hospital to home, and readiness for hospital discharge significantly influences position adherence after discharge and indirectly plays a vital role in postoperative vision recovery and surgical effect.Keywords: discharge teaching, readiness for hospital discharge, position adherence, pars plana vitrectomy with silicone oil tamponade

Miaomiao Sun,1– 3,&ast; Fuquan Wang,1– 3,&ast; Haopeng Li,1– 3 Mengyu Li,1– 3 Yu Wang,1– 3 Chenchen Wang,1– 3 Yan Zhang,1– 3 Dingyu Zhang,1– 4 Jianhua Li,5 Shanglong Yao1– 3 1Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China; 2Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China; 3Key Laboratory of Anesthesiology and Resuscitation (Huazhong University of Science and Technology), Ministry of Education, Wuhan, 430022, People’s Republic of China; 4Wuhan Jinyintan Hospital, Wuhan, 430023, People’s Republic of China; 5Department of Critical Care Medicine, Chongqing University Jiangjin Hospital, Chongqing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shanglong Yao; Jianhua Li, Email yaoshanglong@hust.edu.cn; jianhuali2022@cqu.edu.cnBackground: Sepsis-associated acute kidney injury (SA-AKI) is a common complication in patients with sepsis, triggering high morbidity and mortality. Maresin-1 (MaR1) is a pro-resolution lipid mediator that promotes the resolution of acute inflammation and protects organs from inflammation.Methods: In this study, we established an SA-AKI model using cecal ligation and puncture (CLP) and investigated the effect and mechanism of MaR1. The blood and kidneys were harvested 24 hours after surgery. The blood biochemical/routine indicators, renal function, SA-AKI-related pathophysiological processes, and AMPK/SIRT3 signaling in septic mice were observed by histological staining, immunohistochemical staining, Western blot, qPCR, ELISA and TUNEL Assay.Results: MaR1 treatment alleviated kidney injury in septic mice, reflected in improved pathological changes in renal structure and renal function. MaR1 treatment decreased the levels of serum creatinine (sCr) and blood urea nitrogen (BUN) and the expressions of KIM-1, NGAL and TIMP-2, which were related to kidney injury, while inhibited the expressions of inflammatory factors TNF-α, IL-1β and IL-6. The expression of endoplasmic reticulum stress-related indicators p-PERK/PERK, GRP78, p-EIF2α/EIF2α, ATF4, CHOP, and pyroptosis-related indicators Caspase-1, NLRP3, GSDMD, IL-18, and IL-1β also decreased after MaR1 treatment. The mechanism may be related to the activation of the AMPK/SIRT3 signaling pathway, and an AMPK inhibitor (compound C) partially reverses MaR1’s protective effects in septic mice.Conclusion: Taken together, these findings suggest that MaR1 may partially ameliorate SA-AKI by activating the AMPK/SIRT3 signaling pathway, providing a potential new perspective for research on SA-AKI.Keywords: Maresin-1, pyroptosis, AMPK/SIRT3, endoplasmic reticulum stress, sepsis-associated acute kidney injury, inflammation

Jing Liu,1 Che Wang,2 Yutong Wang,2 Shukun Yao3 1China-Japan Friendship Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People’s Republic of China; 2School of Qi Huang, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 3Department of Gastroenterology, China-Japan Friendship Hospital, Beijing, People’s Republic of ChinaCorrespondence: Shukun Yao, Email shukunyao@126.comIntroduction: Metabolic dysfunction-associated fatty liver disease (MAFLD) is the most common chronic liver disease, which is usually associated with type 2 diabetes mellitus (T2DM) and obesity. However, the incidence of MALFD in non-obese individuals without T2DM is increasing, and the pathogenesis is unclear. Serum uric acid to creatinine ratio (sUA/Cr) can reflect overall metabolic status. This study aims to observe the association between sUA/Cr and MAFLD in non-obese individuals without T2DM.Methods: A total of 21,996 individuals were included in this study. The subjects were divided into four subgroups: non-obese patients without T2DM, obese patients without T2DM, non-obese patients with T2DM, and obese patients with T2DM. Logistic regression analyzed the correlation between sUA/Cr and MAFLD subgroups. Receiver operating characteristics analyzed the predictive value of sUA/Cr for MAFLD subgroups. The stratified analyses by sex and age were performed.Results: Non-obese MAFLD individuals without T2DM had higher sUA/Cr levels than their counterparts. sUA/Cr was significantly correlated positively with MAFLD in non-obese patients. Similar results were observed in both males and females and in populations at all age stages (all p< 0.01). sUA/Cr was capable of discriminating MAFLD in non-obese individuals without T2DM (AUC: 0.667), especially for patients over 60 years old (AUC: 0.704).Conclusion: The sUA/Cr ratio was correlated with MAFLD in non-obese patients without T2DM. The predictive value of sUA/Cr for MAFLD was observed. Hence, the sUA/Cr ratio might be given more concern for the risk of MAFLD in non-obese individuals without T2DM.Keywords: uric acid, creatinine, metabolic dysfunction-associated fatty liver disease, non-obesity, type 2 diabetes mellitus

Jiamin Ma,1– 3,&ast; Fuquan Wang,1,2,&ast; Jingxu Wang,1,2,&ast; Pengcheng Wang,4 Xiaoke Dou,1,2 Shanglong Yao,1,2 Yun Lin1,2 1Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China; 2Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China; 3Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, 201620, People’s Republic of China; 4Department of Anesthesiology, Zhumadian Central Hospital, Zhumadian, 463000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yun Lin, Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277, Jiefang Avenue, Wuhan, Hubei, 430022, People’s Republic of China, Tel/Fax +86 02785351606, Email franklinyun@hust.edu.cnPurpose: This study aims to evaluate the effects of the intraoperative application of low-dose esketamine on postoperative neurocognitive dysfunction (PND) in elderly patients undergoing general anesthesia for gastrointestinal tumors.Methods: Sixty-eight elderly patients were randomly allocated to two groups: the esketamine group (group Es) (0.25 mg/kg loading, 0.125mg/kg/h infusion) and the control group (group C) (received normal saline). The primary outcome was the incidence of delayed neurocognitive recovery (DNR). The secondary outcomes were intraoperative blood loss, the total amount of fluid given during surgery, propofol and remifentanil consumption, cardiovascular adverse events, use of vasoactive drugs, operating and anesthesia time, the number of cases of sufentanil remedial analgesia, the incidence of postoperative delirium (POD), the intraoperative hemodynamics, bispectral index (BIS) value at 0, 1, 2 h after operation and numeric rating scale (NRS) pain scores within 3 d after surgery.Results: The incidence of DNR in group Es (16.13%) was lower than in group C (38.71%) (P < 0.05). The intraoperative remifentanil dosage and the number of cases of dopamine used in group Es were lower than in group C (P < 0.05). Compared with group C, DBP was higher at 3 min after intubation, and MAP was lower at 30 min after extubation in group Es (P

Shengsheng Yao,1,&ast; Bo Zhang,2,&ast; Xiang Fei,3 Mingming Xiao,4 Li Lu,5 Daming Liu,6 Siyuan Zhang,7 Jianchun Cui3 1China Medical University - Department of Thyroid and Breast Surgery, Liaoning Provincial People’s Hospital, Shenyang, Liaoning Province, 110015, People’s Republic of China; 2Department of Science and Education, The 10th Division of Xinjiang Production and Construction Corps, Beitun General Hospital, Beitun City, Xinjiang Province, 831300, People’s Republic of China; 3Department of Thyroid and Breast Surgery, People’s Hospital of China Medical University (Liaoning Provincial People’s Hospital), Shenyang, Liaoning Province, 110015, People’s Republic of China; 4Department of Pathology, People’s Hospital of China Medical University (Liaoning Provincial People’s Hospital), Shenyang, Liaoning Province, 110015, People’s Republic of China; 5Department of Endocrinology, People’s Hospital of China Medical University (Liaoning Provincial People’s Hospital), Shenyang, Liaoning Province, 110015, People’s Republic of China; 6Department of Ultrasound, People’s Hospital of China Medical University (Liaoning Provincial People’s Hospital), Shenyang, Liaoning Province, 110015, People’s Republic of China; 7Department of Thyroid and Breast Surgery, The 10th Division of Xinjiang Production and Construction Corps, Beitun General Hospital, Beitun City, Xinjiang Province, 831300, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jianchun Cui, Department of Thyroid and Breast Surgery, People’s Hospital of China Medical University (Liaoning Provincial People’s Hospital), No. 33 of Wenyi Road, Shenhe District, Shenyang, Liaoning Province, 110015, People’s Republic of China, Tel +86 24 24016014, Fax +86 24 24016014, Email cjc7162003@aliyun.comAbstract: The prevalence of antibody-negative chronic autoimmune thyroiditis (SN-CAT) is increasing. The early diagnosis of SN-CAT can effectively prevent its further development. Thyroid ultrasound can diagnose autoimmune thyroiditis and predict hypothyroidism. Primary hypothyroidism with a hypoechoic pattern suggested by thyroid ultrasound and negative thyroid serum antibodies is the main basis for the diagnosis of SN-CAT. However, for early SN-CAT, only hypoechoic thyroid changes and serological antibodies are currently available. This study explored how to achieve an accurate and early diagnosis of SN-CAT and prevent the development of SN-CAT combined with hypothyroidism. The diagnosis of a hypoechoic thyroid by artificial intelligence is expected to be a breakthrough in the accurate diagnosis of SN-CAT.Keywords: antibody negative, autoimmune thyroiditis, hypothyroidism, hypoechoic thyroid, artificial intelligence, Hashimoto’s disease

Haotian Wu,1,&ast; Chunxia Li,2,&ast; Song Liu,1 Shuangquan Yao,1 Zhaohui Song,1 Dong Ren,1 Pengcheng Wang1 1Department of Orthopaedic Surgery, The 3rd Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050051, People’s Republic of China; 2Department of Imaging Medicine, General Hospital of Inner Mongolia Autonomous Region, Hohhot, Inner Mongolia, 010017, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Haotian Wu, Department of Orthopaedic Surgery, The 3rd Hospital, Hebei Medical University, No. 139 Ziqiang Road, Shijiazhuang, 050051, People’s Republic of China, Tel +86-311-88603682, Fax +86-311-87023626, Email surgeon_wu@126.comPurpose: Neutrophil lymphocyte ratio (NLR), platelet lymphocyte ratio (PLR), and red blood cell distribution width (RDW) are novel biomarkers to indicate the inflammatory/immune response, and demonstrated to be effective in diagnosis, severity evaluation, and prognosis in a variety of chronic or acute conditions. This study aims to examine whether NLR, PLR and EDW are independently associated with mortality in necrotizing fasciitis (NF).Methods: This study retrospectively enrolled patients diagnosed with NF and based on vitality status during hospitalization or within 30 days after discharge, survival and non-survival groups were defined. For distinctly comparing NLR, PLR, RDW and others, we enrolled the matched healthy controls of the same age and sex as the survivors of NF in a 1:1 ratio, which constituted the healthy control group. Comparisons were made between three groups. Variables tested with a P value < 0.10 were further entered into the multivariate logistic regression model to identify their independent association with mortality.Results: A total of 281 subjects were included, including 127 healthy controls, 127 survivors, and 27 nonsurvivors with NF, respectively, indicating a mortality rate of 17.5%. ROC analysis showed that the optimal cutoff value for NLR, PLR and RDW was 11.1, 196.0 and 15.5%, respectively, and was tested as significant only for the first two (P < 0.001, = 0.004). Multivariate logistic analysis showed that NLR ≥ 11.1 (OR, 2.51) and PLR ≥ 196.0 (OR, 2.09) were independently associated with an increased risk of mortality in NF patients, together with age ((OR, 1.28, for each 10-year increment), comorbid diabetes mellitus (OR, 2.69) and liver disease (OR, 1.86), and elevated creatinine level (OR, 1.21 for each 10 umol/L elevation).Conclusion: Elevated NLR and PLR are significant and independent predictors of mortality and can be considered for use when evaluating patients at risk of mortality.Keywords: necrotizing fasciitis, prognosis, NLR, PLR, RDW

Shunyu Yao,1,2 Suxia Wang,3,&ast; Runxi Yi,1,4,&ast; Liwei Ran,5 Cang Zhang2 1Chinese Traditional Medicine, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 2Department of Dermatology, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, People’s Republic of China; 3Laboratory of Electron Microscopy, Pathological Center, Peking University First Hospital, Beijing, People’s Republic of China; 4Department of Oncology, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, People’s Republic of China; 5Department of Dermatology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Liwei Ran, Department of Dermatology, Beijing Chao-Yang Hospital, Capital Medical University, 8 Gongren Tiyuchang Nanlu, Chaoyang District, Beijing, 100020, People’s Republic of China, Tel +86 010 85231374, Email wlbrlw@163.com Cang Zhang, Department of Dermatology, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, 23 Back Street of Art Gallery, Dongcheng District, Beijing, 100010, People’s Republic of China, Tel +86 13693219292, Email zhangcang@bjzhongyi.comAbstract: An 81-year-old woman presented with purpura, petechiae, ecchymoses, flesh or brown-colored waxy, smooth, papules, warty plaque, nail dystrophy and palmodigital erythematous swelling for more than 6 years. She was diagnosed as multiple myeloma-associated systemic amyloidosis after skin subcutaneous histopathological examinations and relevant examinations such as blood and bone marrow. Systemic amyloidosis is closely related with multiple myeloma (MM). Multiple and pleomorphic skin lesions are not usual among patients with multiple myeloma or systemic amyloidosis.Keywords: multiple myeloma, primary systemic amyloidosis, monoclonal immunoglobulin

Zhiguo Zhang,1,2,&ast; Fangda Fu,1,2,&ast; Yishan Bian,1,2,&ast; Huihao Zhang,1,2 Sai Yao,1,2 Chengcong Zhou,1,2 Yuying Ge,2 Huan Luo,3 Yuying Chen,4 Weifeng Ji,1 Kun Tian,1 Ming Yue,5 Weibin Du,6 Hongting Jin,1 Peijian Tong,1 Chengliang Wu,1,2 Hongfeng Ruan1,2 1Institute of Orthopaedics and Traumatology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, People’s Republic of China; 2The First Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China; 3Department of Pharmacy, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People’s Republic of China; 4The Fourth Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China; 5Department of Physiology, College of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China; 6Research Institute of Orthopedics, The Affiliated Jiangnan Hospital of Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hongfeng Ruan; Chengliang Wu, Institute of Orthopaedics and Traumatology, The First Affiliated Hospital of Zhejiang Chinese Medical University, 548 Binwen Road, Hangzhou, 310053, People’s Republic of China, Fax +86 571 86613684, Email rhf@zcmu.edu.cn; wcl@zcmu.edu.cnBackground: With the rapid growth of the elderly population, the incidence of osteoarthritis (OA) increases annually, which has attracted extensive attention in public health. The roles of dietary intake in controlling joint disorders are perhaps one of the most frequently posed questions by OA patients, while the information about the interaction between dietary intake and OA based on scientific research is limited. α-Chaconine is the richest glycoalkaloid in eggplants such as potatoes. Previous evidence suggests that α-Chaconine is a toxic compound to nervous and digestive systems with potentially severe and fatal consequences for humans and farm animals, but its effect on OA development remains obscure.Objective: To determine whether α-Chaconine deteriorates OA progression through sensory innervation and chondrocyte pyroptosis via regulating nuclear factor-κB (NF-κB) signaling, providing evidence for a possible linkage between α-Chaconine and OA progression.Methods: We established a mouse OA model by destabilization of medial meniscus (DMM) surgery and then intra-articular injection of 20 or 100 μM α-Chaconine into the OA mice for 8 and 12 weeks. The severity of OA progression was evaluated by histological staining and radiographic analyses. The expressions of matrix metabolic indicators, Col2, Mmp3, and Mmp13, as well as pyroptosis-related proteins, Nlrp3, Caspase-1, Gsdmd, IL-1β, IL-18, were determined by immunohistochemistry. And the changes in sensory nerve ingrowth and activity of NF-κB signaling were determined by immunofluorescence.Results: We found that α-Chaconine could exacerbate mouse OA progression, resulting in subchondral sclerosis, osteophyte formation, and higher OARSI scores. Specifically, α-Chaconine could augment cartilage matrix degradation and induce chondrocyte pyroptosis and nerve ingrowth. Mechanistical analysis revealed that α-Chaconine stimulated NF-κB signaling by promoting I-κB α phosphorylation and p65 nuclear translocation.Conclusion: Collectively, our findings raise the possibility that α-Chaconine intake can boost chondrocyte pyroptosis and nerve ingrowth to potentiate OA progression by activating NF-κB signaling.Graphical Abstract: Keywords: α-Chaconine, osteoarthritis, pyroptosis, nerve ingrowth, NF-κB signaling

Zhen Hui,1,&ast; Kelei Guo,2,&ast; Chao Liu,3 Qishuai Ma,3 Weiwei Tian,2 Shujun Yao2 1School of Marxism, Zhaoqing University, Zhaoqing, People’s Republic of China; 2School of Physical Education and Health, Zhaoqing University, Zhaoqing, People’s Republic of China; 3School of Physical Education, Huaibei Normal University, Huaibei, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Kelei Guo; Chao Liu, Email 2021010043@zqu.edu.cn; 827056169@qq.comPurpose: This study examined the relationship between physical exercise (PE) and prosocial behavior (PSB) and constructed a chain mediation model through the mediating effect of physical education learning motivation (PELM) and emotional intelligence (EI).Methods: Through the stratified random sampling, 1053 students (average age = 14 years, SD = 0.96 years) that complied with the requirements were surveyed from Henan Province in China. PE, EI, PELM, and PSB were assessed using standard scales. For data analysis, Pearson’s correlation analysis, structural equation model test, and bias-corrected percentile Bootstrap method were carried out in turn.Results: (1) There was a significant positive correlation between PE and PSB (r = 0.137), and the direct path between PE and PSB was significant (β = 0.09, t = 4.73, p < 0.01); (2) PE can positively predict EI (β= 0.08, t = 5.27, p < 0.01) and PELM (β= 0.04, t = 2.07, p < 0.05), EI can significantly and positively PSB (β= 0.67, t = 22.12, p < 0.01), PELM can significantly and positively predict PSB (β= 0.05, t =2.20, p< 0.05); (3) EI and physical learning motivation play a significant intermediary role between PE and PSB. The mediating effect consists of three indirect effects: PE → EI → PSB (the mediating effect value is 0.055), PE → PELM → PSB (the mediating effect value is 0.002), PE → EI → PELM → PSB (the mediating effect value is 0.002); (4) The chain mediation effect is significant in girls, but not in boys.Conclusion: (1) PE can positively predict PSB. (2) EI and PELM had significant mediating effects between PE and PSB, including single mediating effects of EI and PELM and chain mediating effects of EI-PELM; (3) There are gender differences in the chain mediation effect.Keywords: physical exercise, emotional intelligence, physical education learning motivation, prosocial behavior, junior school students, COVID-19

Yi Guan,1 Nan Liu,1 Yan Yu,1 Qiang Zhou,1,2 Meiyu Chang,1,2 Yongheng Wang,1 Sanqiao Yao1,2 1School of Public Health, North China University of Science and Technology, Tangshan, People’s Republic of China; 2School of Public Health, Xinxiang Medical University, Xinxiang, People’s Republic of ChinaCorrespondence: Sanqiao Yao, Email sanqiaoyao@xxmu.edu.cnPurpose: The objective of this study was to evaluate and compare the histopathological implications of silica nanoparticles (Nano-SiO2) and indium-tin oxide nanoparticles (Nano-ITO), in vivo.Methods: Male Sprague-Dawley rats were exposed to Nano-SiO2 (50 mg/kg) and Nano-ITO (6 mg/kg) by a single intratracheal instillation, respectively. Broncho-alveolar lavage fluid (BALF) and lung tissue were obtained at 7, 14, 28, and 56 days post exposure for analysis of BALF inflammatory factors, total protein, and for lung tissue pathology. Histopathological and ultrastructural change in lungs were investigated by hematoxylin and eosin, Masson’s trichrome, sirius red staining, periodic acid Schiff stain, and transmission electron microscopy. The expression of SP-A, collagen type I and III in lung tissue was determined by immunohistochemistry and ELISA.Results: The rats in both models exhibited obvious collagen fibrosis and the severity of the lung injury increased with time after exposure to respective dosage increased. Several parameters of pulmonary inflammation and fibrosis significantly increased in both groups, which was reflected by increased LDH activity, total proteins, TNF-α, and IL-6 levels in BALF, and confirmed by histopathological examination. The results also showed that the two models exhibited different features. Exposure to Nano-ITO caused persistent chronic lung inflammation, illustrated by the infiltration of a large amount of enlarged and foamy macrophages and neutrophils into the lung parenchyma. In Nano-SiO2 exposed rat lung tissue, granulomatous inflammation was most prominent followed by progressive and massive fibrotic nodules. Compared with the Nano-SiO2 rats, Nano-ITO exposed rats exhibited significantly severe pulmonary alveolar proteinosis (PAP) pathological changes, lower fibrosis, and higher levels of inflammatory biomarkers. However, Nano-SiO2 exposed rats had greater fibrosis pathological changes and more severe granulomas than Nano-ITO exposed rats.Conclusion: This study suggests that the Nano-SiO2-induced model has greater value in research into granulomas and fibrosis, while the Nano-ITO-induced model has greater repeatability in area of PAP.Keywords: silica nanoparticles, indium-tin oxide nanoparticles, silicosis, indium lung disease, pulmonary alveolar proteinosis

Nan Liu,1 Yi Guan,1 Chunling Zhou,2 Yongheng Wang,1 Zhanfei Ma,3 Sanqiao Yao1,4 1School of Public Health, North China University of Science and Technology, Tangshan, 063210, Hebei, People’s Republic of China; 2Baoding Center for Disease Control and Prevention, Baoding, 071030, Hebei, People’s Republic of China; 3Institute of Industrial Hygiene of Ordnance Industry, Xian, 710065, Shanxi, People’s Republic of China; 4XinXiang Medical University, Xinxiang, 453003, Henan, People’s Republic of ChinaCorrespondence: Sanqiao Yao, North China University of Science and Technology, Bohai Avenue 21, Tangshan, 063210, Hebei, People’s Republic of China, Fax +86-315-8805583, Email sanqiaoyao@xxmu.edu.cnPurpose: The main objective of this study was to clarify the biodistribution and in vivo toxicological effects of indium-tin oxide nanoparticles (Nano-ITO) in male rats.Methods: Dose-response (three divided doses) and time-course studies (six exposure durations) were performed to examine Nano‑ITO-induced pulmonary and systemic toxicity. At the end of the experiment, hematology and serum biochemical parameters were determined, and cytokines levels and oxidative stress were analyzed in the bronchoalveolar lavage fluid. In addition, indium biodistribution following Nano‑ITO exposure was determined using inductively coupled plasma mass spectrometer to measure indium concentration in the lung, spleen, brain, liver, kidney, and testis. Rat lung tissues were also harvested for staining with hematoxylin and eosin, periodic acid Schiff stain, Masson’s trichrome, and Sirius red.Results: Relative lung weights were significantly increased in all Nano-ITO-exposed groups. All organs exhibited a statistically significant difference in indium levels. Rat exposure to Nano‑ITO resulted in a dose-response increase in acute systemic inflammation and injury. BALF analysis revealed significantly elevated levels of lung oxidative stress, pulmonary injury, and inflammatory markers across most groups. Serum biochemistry results showed that Nano-ITO could affect the liver and renal functions of rats when exposed for 3 days. Compared with the control group, significant inflammatory responses or pathological changes were observed in the liver, kidney, and testis of rats at different sampling times and three doses examined. Histopathologically, foci of slight-to-severe pulmonary inflammatory response along with acute inflammatory, pulmonary fibrosis and alveolar proteinosis were detected, and the severity of these lesions worsened in a dose- and time-dependent manner.Discussion: These findings provide novel evidence that enhanced progressive massive pulmonary fibrosis, diffuse interstitial fibrosis, and collagen accumulation play a role in the development of pulmonary alveolar proteinosis following Nano-ITO exposure.Keywords: indium-tin oxide nanoparticles, pulmonary fibrosis, pulmonary alveolar proteinosis

Shenzhen Yao,1 Lisa Lix,2 Gary Teare,3 Charity Evans,1 David Blackburn1 1College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, Saskatchewan, Canada; 2Department of Community Health Sciences of Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada; 3Program Program Knowledge, Evidence and Innovation, Provincial Population and Public Health, Alberta Health Services, Calgary, Alberta, CanadaCorrespondence: David BlackburnCollege of Pharmacy and Nutrition, University of Saskatchewan, 2A20.01 Health Sciences Building, 107 Wiggins Road, Saskatoon, Saskatchewan, S7N5E5, CanadaTel +1 306 966 2081Fax +1 306 966 6377Email d.blackburn@usask.caPurpose: Age or sex concordance (same sex or same age range) may also be associated with medication adherence but was not fully investigated. We aim to quantify the impact of age and sex concordance on optimal adherence to statin medications.Patients and Methods: A retrospective cohort study was conducted using population-based health administrative data from Saskatchewan, Canada. Participants were individuals newly initiated on statin medications between January 1, 2012, and December 31, 2017. The outcome was optimal adherence (proportion of days covered ≥ 80%) measured at one year after the first statin claim. The independent variables were sex and age concordance (age within five years) between patients and prescribers. The association between adherence outcome and sex/age concordance was analyzed by multivariable logistic regression models using generalized estimating equations controlled by a package of potential confounding factors.Results: Among 51,874 new statin users, 20.6% (n = 10,710) were age concordant with prescriber. The vast majority of age concordance occurred in patients younger than 66 years (88.6%, 9,486/10,710). Sex concordance was observed in 62.8% (n = 32,551) of patients and age-sex combined concordance in 13.2% (n = 6,856). Among patients younger than 66 years (n = 36,641/51,874, 70.6%), age concordance did not have a significant impact on optimal adherence [adjusted OR (aOR) = 1.02, 95% CI 0.97 to 1.07]. Weak association between sex concordance (aOR = 1.05, 95% CI 1.00 to 1.11), and age-sex combined concordance (aOR = 1.05, 95% CI 0.99 to 1.12) was observed.Conclusion: Age and sex concordance were not statistically significant predictors of optimal statin adherence. However, a weak association was detected for sex concordance. Future studies should examine this factor in different health care settings.Keywords: medication adherence, age concordance, sex concordance, statin, observational study, cohort

Huihao Zhang,1,&ast; Sai Yao,1,&ast; Zhiguo Zhang,1,&ast; Chengcong Zhou,1 Fangda Fu,1 Yishan Bian,1 Huan Luo,2 Yan Li,1 Shuxin Yan,1 Yuying Ge,1 Yuying Chen,3 Kunyu Zhan,4 Yanzhi Ge,1 Zuxiang Chen,1 Ming Yue,5 Xiaofeng Li,6 Weibin Du,1,7 Hongting Jin,1 Peijian Tong,1 Hongfeng Ruan,1,8 Chengliang Wu1 1Institute of Orthopaedics and Traumatology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China; 2Department of Pharmacy, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China; 3The Fourth Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China; 4The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China; 5Department of Physiology, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China; 6Department of Orthopedics and Traumatology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China; 7Research Institute of Orthopedics, The Affiliated JiangNan Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China; 8Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hongfeng Ruan; Peijian TongInstitute of Orthopaedics and Traumatology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, People’s Republic of ChinaEmail rhf@zcmu.edu.cn; peijiantongzjtcm@163.comPurpose: To explore the pharmacological mechanisms of Liuwei Dihuang Decoction (LWDHD) against intervertebral disc (IVD) degeneration (IVDD) via network pharmacology analysis combined with experimental validation.Methods: First, active ingredients and related targets of LWDHD, as well as related genes of IVDD, were collected from public databases. The protein–protein interaction (PPI) network, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analyses were performed to predict the core targets and pathways of LWDHD against IVDD. Secondly, the IVDD model of mice treated with LWDHD was selected to validate the major targets predicted by network pharmacology.Results: By searching the intersection of the active ingredient targets and IVDD targets, a total of 110 targets matched the related targets of 30 active ingredients in LWDHD and IVDD were retrieved. PPI network analysis indicated that 17 targets, including Caspase-3, IL-1β, P53, etc., were hub targets. GO and KEGG enrichment analyses showed that the apoptosis pathway was enriched by multiple targets and served as the target for in vivo experimental study validation. The results of animal experiments revealed that LWDHD administration not only restored the decrease in disc height and abnormal degradation of matrix metabolism in IVDD mice but also reversed the high expression of Bax, Caspase-3, IL-1β, P53, and low expression of Bcl-2, thereby inhibiting the apoptosis of IVD tissue and ameliorating the progression of IVDD.Conclusion: Using a comprehensive network pharmacology approach, our findings predicted the active ingredients and potential targets of LWDHD intervention for IVDD, and some major target proteins involved in the predictive signaling pathway were validated experimentally, which gave us a new understanding of the pharmacological mechanism of LWDHD in treating IVDD at the comprehensive level.Keywords: intervertebral disc degeneration, Liuwei Dihuang decoction, network pharmacology, pharmacological mechanisms, apoptosis

Zheng Yan,1 Shuna Yao,1 Yuanyuan Wang,2 Yanyan Liu,1 Zhihua Yao1 1Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China; 2Department of Pathology, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of ChinaCorrespondence: Zhihua Yao; Yanyan LiuDepartment of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, No. 127 Dongming Road, Zhengzhou, Henan, 450008, People’s Republic of ChinaTel/Fax +86 371-65587791Email zlyyyaozhihua1260@zzu.edu.cn; yyliu@zzu.edu.cnAbstract: Primary testicular lymphoma (PTL) is a rare malignancy of testis. Although the multimodality treatment (including orchiectomy, systemic chemotherapy, scrotal radiotherapy, and preventive central nervous system (CNS)-targeted treatment) is widely used to treat PTL, recurrence, especially CNS recurrence, occurred frequently. Patients with relapsed PTL have a dismal prognosis and limited treatment options. In this report, we described the case of a 63-year-old man with early-stage PTL. The patient received the multimodality treatment, but CNS relapse occurred 3 months following the front-line therapy. We gave him a combined chemo-free regimen treatment, including rituximab, ibrutinib, and lenalidomide (RIL), based on the tumor’s gene mutation profile and the patient’s preference. A complete response was achieved after the first cycle of treatment. Whole-brain radiotherapy was delivered as consolidative treatment following three more cycles of RIL. Thereafter, ibrutinib and lenalidomide continued as maintenance treatment. As of the submission of this manuscript, the response has lasted for more than 16 months. Based on the case, we believe chemo-free regimen RIL might be a favorable approach for PTL patients with CNS relapse, especially those frail elderly patients, when alternative treatments are not available.Keywords: primary testicular lymphoma, chemo-free regimen, central nervous system relapse, case report

Yusuke Hanioka,1 Ryo Morita,2 Keiko Yamagami,1 Shuhei Yao,1 Ryota Nakamura,1 Tomoyuki Nakamura,1 Katsushu Shimizu,3 Toshimasa Yamaguchi,3 Hitoshi Goto1 1Department of Internal Medicine, Osaka City General Hospital, Osaka, Japan; 2Department of Infectious Diseases, Osaka City General Hospital, Osaka, Japan; 3Department of Primary Care and Advanced Triage Section, Osaka City General Hospital, Osaka, JapanCorrespondence: Yusuke HaniokaDepartment of Internal Medicine, Osaka City General Hospital, 2-13-22 Miyakojima-Hondori, Miyakojima-ku, Osaka, 534-0021, JapanTel +81-6-6929-1221Fax +81-6-6929-2041Email y-hanioka@med.osakacity-hp.or.jpPurpose: It is important to understand how COVID-19 is affecting general outpatient services, since hospitals see a wide variety of patients. This study aimed to evaluate the incidence and clinical picture of COVID-19 in general outpatient services. Currently, the diagnosis of COVID-19 depends strongly on the results of polymerase chain reaction (PCR) assays. However, since the sensitivity of PCR tests for SARS-CoV-2 is not high enough to assure confidence. On the other hand, the SARS-CoV-2 antibody (Ab) test is highly sensitive after 2 weeks of symptom onset, and might complement the PCR test. Therefore, we measured Ab in addition to PCR to obtain a more accurate clinical profile of COVID-19, which might be helpful in building future practice strategies.Patients: The study patients were those who visited our department for the first time between November 2020 and March 2021 and fulfilled the enrolment criteria.Methods: All patients underwent total SARS-CoV-2 Ab testing, and PCR tests were performed in only some of them; patients were classified according to the performance of PCR tests for comparisons.Results: Ninety-four patients who underwent Ab testing during the study period were eligible for study enrolment, and the PCR test was performed in 40 of them. Only one patient was diagnosed with acute stage COVID-19 based on a positive PCR test. Antibodies were positive in six (6.4%) of the 94 patients. Five of the six Ab-positive patients were negative for PCR, and the test was not performed in the sixth patient. All the six patients had prior symptoms suggestive of infection, and respiratory symptoms were more noticeable than fever. The Ab positivity rate was significantly higher than published data.Conclusion: COVID-19 is not rare in general outpatient services and can be missed based on PCR tests alone. The diagnosis should be made from a comprehensive perspective.Keywords: COVID-19, SARS-CoV-2 antibody, outpatient service, fever

Shifei Yao,1,2 Nanning Luo,1,2 Jiaoyang Liu,1,2 He Zha,1 Yuanhang Ai,1,2 Juan Luo,1,2 Shi Shi,3 Kaifeng Wu1,2 1Department of Laboratory Medicine, Zunyi Medical University Third Affiliated Hospital/The First People’s Hospital of Zunyi, Zunyi, 563000, Guizhou, People’s Republic of China; 2Scientific Research Center, Zunyi Medical University Third Affiliated Hospital/The First People’s Hospital of Zunyi, Zunyi, 563000, Guizhou, People’s Republic of China; 3Department of Laboratory Medicine, The Fourth People’s Hospital of Zunyi, Zunyi, 563000, Guizhou, People’s Republic of ChinaCorrespondence: Kaifeng WuDepartment of Laboratory Medicine/Scientific Research Center, Zunyi Medical University Third Affiliated Hospital/The First People’s Hospital of Zunyi, Zunyi, 563000, Guizhou, People’s Republic of ChinaTel +86 85123116548Email kiphoonwu@126.comBackground: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with the angiocentric inflammation and angiogenesis, yet the molecules involved in this process remain to be determined.Methods: We did a cross-sectional study of a cohort of patients with COVID-19 in Zunyi, China between February 1 and March 30, 2020. Serum concentrations of PGRN were determined by enzyme-linked immunosorbent assay in patients with COVID-19 at hospital admission and at discharge. In parallel, the serum levels of soluble adhesion molecules, vascular cell adhesion molecule-1 (sVCAM-1), intercellular adhesion molecule-1 (sICAM-1), P-selectin (sP-selectin), and E-selectin (sE-selectin) were assayed by a human adhesion molecule multiplex kit. The association between serum PGRN levels and other laboratory test results was analyzed by Spearman correlation analysis.Results: At baseline, the median serum PGRN levels in patients with COVID-19 were 94.8 ng/mL [interquartile range (IQR): 66.6– 119.6 ng/mL], which was significantly elevated compared with those in healthy controls (46.3 ng/mL, IQR: 41.8– 55.6 ng/mL). Moreover, the median serum sVCAM-1 levels were significantly higher in COVID-19 patients (1396.0 ng/mL, IQR: 1019.1– 1774.8 ng/mL) than those in healthy controls (612.4 ng/mL, IQR: 466.4– 689.3 ng/mL). However, the levels of sICAM-1, sP-selectin, and sE-selectin were not significantly elevated in patients with COVID-19 when compared to healthy controls. Further analysis showed that serum PGRN levels were significantly positively associated with sVCAM-1 (r= 0.675, P= 0.008) and inversely with sICAM-1 (r= − 0.609, P= 0.021) and aspartate aminotransferase levels (r= − 0.560, P= 0.037) in patients with COVID-19 at hospital admission. In COVID-19 patients, serum PGRN and sVCAM-1 levels fell significantly after successful treatment.Conclusion: The present study demonstrates elevated serum PGRN and sVCAM-1 levels in patients with COVID-19, which may provide clues as to the mechanisms underlying the pathogenesis of COVID-19. Further studies are warranted to evaluate the potential of PGRN and sVCAM-1 as biomarkers and investigate their role in the pathogenesis of COVID-19.Keywords: COVID-19, PGRN, soluble adhesion molecules, pathogenesis, biomarker

Xin-Ying Li,1 Shuang Yao,1 Yang-Ting He,1 Song-Qing Ke,1 Yi-Fei Ma,2 Ping Lu,3 Shao-Fa Nie,1 Shao-Zhong Wei,2 Xin-Jun Liang,3 Li Liu1 1Department of Epidemiology and Biostatistics, The Ministry of Education Key Laboratory of Environment and Health, School of Public Health, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 2Department of Gastrointestinal Oncology Surgery, Hubei Cancer Hospital, The Seventh Clinical School Affiliated of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 3Department of Abdominal Oncology, Hubei Cancer Hospital, The Seventh Clinical School Affiliated of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of ChinaCorrespondence: Li LiuDepartment of Epidemiology and Biostatistics, the Ministry of Education Key Laboratory of Environment and Health, School of Public Health, Huazhong University of Science and Technology, Wuhan, People’s Republic of ChinaTel/Fax +86-27-83693763Email liul2012@hust.edu.cnXin-Jun LiangDepartment of Abdominal Oncology, Hubei Cancer Hospital, The Seventh Clinical School Affiliated of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of ChinaTel/Fax +86-27-87671663Email doctorlxj@163.comPurpose: This study was designed to investigate the prognostic value of the combination of high-sensitivity C-reactive protein, lymphocyte, and albumin in patients with resectable colorectal cancer.Patients and Methods: Seven-hundred-and-nineteen patients who underwent colorectal cancer resection in Hubei Cancer Hospital were included. Inflammation-Immunity-Nutrition score (0– 6) was constructed based on preoperative high-sensitivity C-reactive protein, lymphocyte, and albumin. Time-dependent receiver operating characteristic curve, decision curve, Kaplan-Meier survival curve, Cox regression, and C-index were conducted to detect the prognostic values of inflammation-immunity-nutrition score. The prognostic values of inflammation-immunity-nutrition score in different subgroups by sex, location of tumor, pathologic stage, and KRAS mutation were also explored. The prognostic performance of inflammation-immunity-nutrition score was further compared with that of other traditional prognostic indicators.Results: The median follow-up time was 40 months. High inflammation-immunity-nutrition score (> 2 scores) presented worse survival, with the adjusted hazard ratios (95% confidence intervals) of 3.106 (2.202– 4.380) for overall survival and 2.105 (1.604– 2.764) for disease-free survival. Besides, the associations of high inflammation-immunity-nutrition score with overall survival were even stronger in cases with wild type KRAS, with the adjusted hazard ratios (95% confidence intervals) of 4.018 (2.355– 6.854). Considering the AUCs, C-indices, and hazard ratios estimates, inflammation-immunity-nutrition score presented better prognostic performance than high-sensitivity modified Glasgow prognostic score, high-sensitivity C-reactive protein to albumin ratio, prognostic nutrition index, carcinoembryonic antigen, and carbohydrate antigen 19-9 for overall survival.Conclusion: Inflammation-immunity-nutrition score might serve as a powerful prognostic score in patients with colorectal cancer for overall survival, particularly in patients with wild type KRAS.Keywords: high-sensitivity C-reactive protein, survival, colorectal cancer, inflammation

Chongchong Yu,1,&ast; Chunjie Xu,2,&ast; Yuhong Li,3 Sanqiao Yao,1 Yichun Bai,1 Jizhen Li,1 Lei Wang,4 Weidong Wu,1 Yongbin Wang1 1Department of Epidemiology and Health Statistics, School of Public Health, Xinxiang Medical University, Xinxiang, Henan Province, People’s Republic of China; 2Department of Occupational and Environmental Health, School of Public Health, Capital Medical University, Beijing, 100069, People’s Republic of China; 3National Center for Tuberculosis Control and Prevention, China Center for Disease Control and Prevention, Beijing, People’s Republic of China; 4Center for Musculoskeletal Surgery, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt–Universität Zu Berlin and Berlin Institute of Health, Berlin, Germany&ast;These authors contributed equally to this workCorrespondence: Yongbin WangDepartment of Epidemiology and Health Statistics, School of Public Health, Xinxiang Medical University, Xinxiang, 453000, Henan Province, People’s Republic of ChinaEmail wybwho@163.comObjective: The high morbidity, complex seasonality, and recurring risk of hand-foot-and-mouth disease (HFMD) exert a major burden in China. Forecasting its epidemic trends is greatly instrumental in informing vaccine and targeted interventions. This study sets out to investigate the usefulness of an advanced exponential smoothing state space framework by combining Box-Cox transformations, Fourier representations with time-varying coefficients and autoregressive moving average (ARMA) error correction (TBATS) method to assess the temporal trends of HFMD in China.Methods: Data from January 2009 to December 2019 were drawn, and then they were split into two segments comprising the in-sample training data and out-of-sample testing data to develop and validate the TBATS model, and its fitting and forecasting abilities were compared with the most frequently used seasonal autoregressive integrated moving average (SARIMA) method.Results: Following the modelling procedures of the SARIMA and TBATS methods, the SARIMA (1,0,1)(0,1,1)12 and TBATS (0.024, {1,1}, 0.855, {< 12,4>}) specifications were recognized as being the optimal models, respectively, for the 12-step ahead forecasting, along with the SARIMA (1,0,1)(0,1,1)12 and TBATS (0.062, {1,3}, 0.86, {< 12,4>}) models as being the optimal models, respectively, for the 24-step ahead forecasting. Among them, the optimal TBATS models produced lower error rates in both 12-step and 24-step ahead forecasting aspects compared to the preferred SARIMA models. Descriptive analysis of the data showed a significantly high level and a marked dual seasonal pattern in the HFMD morbidity.Conclusion: The TBATS model has the capacity to outperform the most frequently used SARIMA model in forecasting the HFMD incidence in China, and it can be recommended as a flexible and useful tool in the decision-making process of HFMD prevention and control in China.Keywords: HFMD, morbidity, TBATS, SARIMA, models, time series analysis

Jizhen Li,1 Yuhong Li,2 Ming Ye,3 Sanqiao Yao,1 Chongchong Yu,1 Lei Wang,4 Weidong Wu,1 Yongbin Wang1 1Department of Epidemiology and Health Statistics, School of Public Health, Xinxiang Medical University, Xinxiang, Henan Province, People’s Republic of China; 2National Center for Tuberculosis Control and Prevention, China Center for Disease Control and Prevention, Beijing, People’s Republic of China; 3Preventive Medicine Clinic, Xinxiang Center for Disease Control and Prevention, Xinxiang, Henan Province, People’s Republic of China; 4Center for Musculoskeletal Surgery, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt–Universität Zu Berlin and Berlin Institute of Health, Berlin, GermanyCorrespondence: Yongbin WangDepartment of Epidemiology and Health Statistics, School of Public Health, Xinxiang Medical University, Xinxiang, Henan Province, 453000, People’s Republic of ChinaEmail wybwho@163.comObjective: The purpose of this study is to develop a novel data-driven hybrid model by fusing ensemble empirical mode decomposition (EEMD), seasonal autoregressive integrated moving average (SARIMA), with nonlinear autoregressive artificial neural network (NARNN), called EEMD-ARIMA-NARNN model, to assess and forecast the epidemic patterns of TB in Tibet.Methods: The TB incidence from January 2006 to December 2017 was obtained, and then the time series was partitioned into training subsamples (from January 2006 to December 2016) and testing subsamples (from January to December 2017). Among them, the training set was used to develop the EEMD-SARIMA-NARNN combined model, whereas the testing set was used to validate the forecasting performance of the model. Whilst the forecasting accuracy level of this novel method was compared with the basic SARIMA model, basic NARNN model, error-trend-seasonal (ETS) model, and traditional SARIMA-NARNN mixture model.Results: By comparing the accuracy level of the forecasting measurements including root-mean-square error, mean absolute deviation, mean error rate, mean absolute percentage error, and root-mean-square percentage error, it was shown that the EEMD-SARIMA-NARNN combined method produced lower error rates than the others. The descriptive statistics suggested that TB was a seasonal disease, peaking in late winter and early spring and a trough in autumn and early winter, and the TB epidemic indicated a drastic increase by a factor of 1.7 from 2006 to 2017 in Tibet, with average annual percentage change of 5.8 (95% confidence intervals: 3.5– 8.1).Conclusion: This novel data-driven hybrid method can better consider both linear and nonlinear components in the TB incidence than the others used in this study, which is of great help to estimate and forecast the future epidemic trends of TB in Tibet. Besides, under present trends, strict precautionary measures are required to reduce the spread of TB in Tibet.Keywords: tuberculosis, incidence rate, time series analysis, statistical models, forecasting

Lingxia Niu,1,* Chunlin Yao,1,* Yu Wang,1 Yan Sun,1 Juan Xu,2 Yun Lin,1 Shanglong Yao1 1Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei, People’s Republic of China; 2School of Medicine and Health Management, Tongji Medical College of Huazhong University of Science and Technology, Wuhan 430022, Hubei, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yun Lin; Shanglong YaoDepartment of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277# Jiefang Avenue, Wuhan 430022, Hubei, People’s Republic of ChinaTel +86 13986288403; +86 13886128437Fax +86 27 85726970Email franklinyun@hust.edu.cn; yaoshanglong@hust.edu.cnPurpose: This study examined whether different neuromuscular-blocking agents (NMBAs) work differently on the short-term outcomes of gastric cancer patients in terms of laboratory test results and severity of postoperative illness, and whether the effect is dose-related.Patients and Methods: Data of 1643 adult patients receiving gastric cancer surgery were analyzed by employing generalized linear models (GLMs), to explore the effects of different NMBAs on neutrophil–lymphocyte ratio (NLR), platelet–lymphocyte ratio (PLR), lymphocyte–monocyte ratio (LMR) at postoperative day 1 (POD1), POD3, POD7, and return to intended oncologic therapy (RIOT), among others. We adjusted multiple covariants, including patient-, anesthesia-, and surgical complexity-related risk factors.Results: Without adjusting dosage of NMBAs, POD1NLR, POD1PLR (P < 0.05), POD3NLR, POD7NLR, POD3 lymphocytes, POD7LMR (P < 0.01) in gastric cancer patients administered with benzylisoquinoline NMBAs worsened, and the administration of aminosteroidal NMBAs was associated with less risk of transfer to ICU (P < 0.01); without adjusting the types of NMBAs, the highest dose of NMBAs postponed the RIOT (P < 0.05) and was negatively associated with POD3NLR, POD7NLR and POD7LMR (P < 0.01), and increased risk of postoperative transfer to ICU (P < 0.01). When patients given benzylisoquinolines were re-divided in terms of five equal quintiles, from low to high dose, RIOT was delayed and POD7LMR decreased significantly in the fourth and fifth quintile groups as compared to the first quintile group. A higher risk for postoperative transfer to ICU was found in the fifth quintile group as compared to the first quintile group.Conclusion: Patients with gastric cancer given benzylisoquinoline NMBAs had more unfavorable short-term outcomes, such as more severe inflammation and increased risk of transfer to ICU than their counterparts administered aminosteroidal NMBAs, and the effect of benzylisoquinolines was dose-related. The effect of aminosteroids on short-term outcomes was not dose-related in the dosage range we used.Keywords: neuromuscular-blocking agents, benzylisoquinoline, aminosteroid, short-term postoperative outcomes, gastric cancer surgery

Jinge Zhou,1,* Zekang Xiong,1,* Man Liu,2 Liang Yang,1 Sheng Yao,1 Kaifang Chen,1 Keda Yu,1 Yanzhen Qu,1 Tingfang Sun,1 Xiaodong Guo1 1Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, People’s Republic of China; 2Department of Gastroenterology and Hepatology, Taikang Tongji Hospital, Wuhan 430050, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiaodong Guo; Tingfang Sun Tel +8615327216660; +8613554435801Email xiaodongguo@hust.edu.cn; tingfangsun@163.comIntroduction: Decellularized matrix from porcine small intestinal submucosa (SIS) endows scaffolds with an ECM-like surface, which enhances stem cell self-renewal, proliferation, and differentiation. Mesoporous bioactive glass (MBG) is extensively recognized as an excellent bio-ceramic for fabricating bone grafts.Materials and Methods: In the current study, SIS was doped on an MBG scaffold (MBG/SIS) using polyurethane foam templating and polydopamine chemistry method. To mimic the bony environment of a natural bone matrix, an ECM-inspired delivery system was constructed by coupling the BMP2-related peptide P28 to a heparinized MBG/SIS scaffold (MBG/SIS-H-P28). The release of P28 from MBG/SIS-H-P28 and its effects on the proliferation, viability, and osteogenic differentiation of bone marrow stromal stem cells were investigated in vitro and in vivo.Results: Our research indicated that the novel tissue-derived ECM scaffold MBG/SIS has a hierarchical and interconnected porous architecture, and superior biomechanical properties. MBG/SIS-H-P28 released P28 in a controlled manner, with the long-term release time of 40 d. The results of in vitro experiments showed improvements in cell proliferation, cell viability, alkaline phosphatase activity, and mRNA expression levels of osteogenesis-related genes (Runx-2, OCN, OPN, and ALP) compared to those of MBG/SIS or MBG/SIS-P28 and MBG/SIS-H-P28. The in vivo results demonstrated that MBG/SIS-H-P28 scaffolds evidently increased bone formation in rat calvarial critical-sized defect compared to that in controls.Conclusion: MBG/SIS-H-P28 scaffolds show potential as ideal platforms for delivery of P28 and for providing a bony environment for bone regeneration.Keywords: small intestinal submucosa, mesoporous bioactive glass, microenvironment, osteogenesis, BMP2-related peptide

Shuzhong Liu,1,* Xi Zhou,1,* An Song,2 Siyuan Yao,1 Muchuan Wang,1 Tong Niu,1 Chengao Gao,1 Zhen Huo,3 Yong Liu,1,* Yipeng Wang1,* 1Department of Orthopaedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, People’s Republic of China; 2Department of Endocrinology, Key Laboratory of Endocrinology, National Health and Family Planning Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, People’s Republic of China; 3Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yong Liu; Yipeng WangDepartment of Orthopaedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, No. 1 Shuaifuyuan Wangfujing, Beijing 100730, People’s Republic of ChinaEmail liuyong_pumch@163.com; ypwang_pumch@163.comObjective: Metastatic spinal differentiated thyroid carcinoma (MSDTC) is relatively rare in the clinic and often overlooked. The objective of the current study is to analyze the clinical characteristics and prognosis of patients with MSDTC who underwent surgical treatment to determine the prognostic factors that affect survival.Methods: This study retrospectively analyzed the clinical data and postoperative follow-up results of MSDTC patients who underwent spinal surgery at the Orthopedic Department of Peking Union Medical College Hospital from January 2010 to January 2020. Clinical data and survival time were analyzed by Kaplan–Meier analysis.Results: Eleven patients were included, and the average age was 58.3 years (range 37‒74). The average time from the initial surgery to the discovery of spinal metastasis was 42.9 months (range 0‒132), and the average follow-up time was 21.8 months (range 3‒80). Progression was identified in seven patients, and 10 patients (90.9%) died during the follow-up period. Kaplan–Meier analysis showed that extraosseous visceral metastasis (p=0.012), revised Tokuhashi score (p=0.035), Tomita score (p=0.038), and surgical method (p=0.028) were associated with overall survival (OS). In addition, skeletal visceral metastasis (p=0.017), revised Tokuhashi score (p=0.028), Tomita score (p=0.038), and surgical method (p=0.049) were associated with progression-free survival (PFS).Conclusion: Surgical treatment is an effective method for treating MSDTC and leads to pain relief, restored function and increased spinal stability. Based on our single-center experience, extraosseous visceral metastasis, revised Tokuhashi score, Tomita score, and surgical methods may be potential prognostic factors for OS whilst visceral metastasis, revised Tokuhashi score, Tomita score, and surgical methods may be potential prognostic factors for PFS.Keywords: adjuvant therapy, clinical features, differentiated thyroid carcinoma, postoperative survival, prognostic factors, spinal metastasis, surgical treatment

Xinrui Qiao, Jie Yang, Yuli Shang, Shu Deng, Shiyu Yao, Zhe Wang, Yi Guo, Cheng Peng Department of Stomatology, The Second Hospital of Tianjin Medical University, Tianjin, People’s Republic of ChinaCorrespondence: Cheng Peng Department of StomotologyThe Second Hospital of Tianjin Medical University, 23 Pingjiang Road, Hexi District, Tianjin 300211, People’s Republic of ChinaTel +86 139 2007 9346Email peng_cheng2013@163.comBackground: Next generation of coating materials on the surface of implants is designed with a paradigm shift from an inert material to an osteoimmunomodulatory material. Regulating immune response to biomedical implants through influencing the polarization of macrophage has been proven to be an effective strategy.Methods: Through anodization and hydrothermal treatment, magnesium ion incorporated TiO2 nanotube array (MgN) coating was fabricated on the surface of titanium and it is hypothesized that it has osteoimmunomodulatory properties. To verify this assumption, systematic studies were carried out by in vitro and in vivo experiments.Results: Mg ion release behavior results showed that MgN coating was successfully fabricated on the surface of titanium using anodization and hydrothermal technology. Scanning electron microscopy (SEM) images showed the morphology of the MgN coating on the titanium. The expression of inflammation-related genes (IL-6, IL-1β, TNF-α) was downregulated in MgN group compared with TiO2 nanotube (NT) and blank Ti groups, but anti-inflammatory genes (IL-10 and IL-1ra) were remarkably upregulated in the MgN group. The in vitro and in vivo results demonstrated that MgN coating influenced macrophage polarization toward the M2 phenotype compared with NT and blank-Ti groups, which enhanced osteogenic differentiation of rat bone mesenchymal stem cells rBMSCs in conditioned media (CM) generated by macrophages.Conclusion: MgN coating on the titanium endowed the surface with immune-regulatory features and exerted an advantageous effect on osteogenesis, thereby providing excellent strategies for the surface modification of biomedical implants.Keywords: TiO2 nanotube, magnesium ions, osteoimmunomodulation, macrophage

Yongbin Wang,1,* Chunjie Xu,2,* Sanqiao Yao,1 Yingzheng Zhao,1 Yuchun Li,1 Lei Wang,3 Xiangmei Zhao1 1Department of Epidemiology and Health Statistics, School of Public Health, Xinxiang Medical University, Xinxiang, Henan Province, People’s Republic of China; 2Department of Occupational and Environmental Health, School of Public Health, Capital Medical University, Beijing, People’s Republic of China; 3Center for Musculoskeletal Surgery, Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Zu Berlin and Berlin Institute of Health, Berlin, Germany*These authors contributed equally to this workCorrespondence: Yongbin WangDepartment of Epidemiology and Health Statistics, School of Public Health, Xinxiang Medical University, Xinxiang 453000, Henan Province, People’s Republic of ChinaTel +86 373 383 1646Email wybwho@163.comObjective: The aim of this study is to apply the advanced error-trend-seasonal (ETS) framework to forecast the prevalence and mortality series of COVID-19 in the USA, the UK, Russia, and India, and the predictive performance of the ETS framework was compared with the most frequently used autoregressive integrated moving average (ARIMA) model.Materials and Methods: The prevalence and mortality data of COVID-19 in the USA, the UK, Russia, and India between 20 February 2020 and 15 May 2020 were extracted from the WHO website. Then, the data subsamples between 20 February 2020 and 3 May 2020 were treated as the training horizon, and the others were used as the testing horizon to construct the ARIMA models and the ETS models.Results: Based on the model evaluation criteria, the ARIMA (0,2,1) and ETS (M,MD,N), sparse coefficient ARIMA (0,2,(1,6)) and ETS (A,AD,M), ARIMA (1,1,1) and ETS (A,MD,A), together with ARIMA (2,2,1) and ETS (A,M,A) specifications were identified as the preferred ARIMA and ETS models for the prevalence data in the USA, the UK, Russia, and India, respectively; the ARIMA (0,2,1) and ETS (M,A,M), ARIMA (0,2,1) and ETS (M,A,N), ARIMA (0,2,1) and ETS (A,A,N), coupled with ARIMA (0,2,2) and ETS (M,M,N) specifications were selected as the optimal ARIMA and ETS models for the mortality data in these four countries, respectively. Among these best-fitting models, the ETS models produced smaller forecasting error rates than the ARIMA models in all the datasets.Conclusion: The ETS framework can be used to nowcast and forecast the long-term temporal trends of the COVID-19 prevalence and mortality in the USA, the UK, Russia, and India, and which provides a notable performance improvement over the most frequently used ARIMA model. Our findings can aid governments as a reference to prepare for and respond to the COVID-19 pandemic both in restricting the transmission of the disease and in lowering the disease-related deaths in the upcoming days.Keywords: coronavirus disease 2019, outbreak, ARIMA model, ETS model, epidemiological indicators, nowcasting

Gaohong Di,1 Chengkun Xia,1 Shanglong Yao,1 Xiangdong Chen,1 Zhilin Wu,1 Ling Hu,2 Jie Wang1 1Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China; 2Department of Anesthesiology, Tianyou Hospital, Wuhan University of Science and Technology, Wuhan, Hubei, People’s Republic of ChinaCorrespondence: Jie Wang; Chengkun Xia Department of Anesthesiology of Wuhan Union Hospital, No. 1277 Jiefang Avenue, Hankou, Wuhan, Hubei, People’s Republic of ChinaTel/ Fax +86 27-85726834Email gatogiratorio@gmail.com; xiayulong_2001@163.comBackground: The rapid spread of COVID-19 has expanded into a pandemic, for which the main containment strategies to reduce transmission are social distancing and isolation of ill persons. Thousands of medical staff have been infected worldwide. Coronavirus testing kits have been in short supply, and early diagnostic reagents did not have high sensitivity. The aim of this study was to describe the characteristics of patients requiring emergency surgery in a COVID-19 outbreak area.Methods: We assessed medical data regarding all patients who underwent emergency surgery at the main campus of Wuhan Union Hospital from January 23, 2020, to February 15, 2020. We classified patients based on suspicion of COVID-19 infection (suspected vs not suspected) before they were admitted to the operating room. We used descriptive statistics to analyze the data. Outcomes included the incidence of confirmed COVID-19 infection and length of stay, which were followed until March 25, 2020.Results: Among the 88 emergency patients included in this study, the mean age was 37 years. Twenty-five patients presented with abnormalities observed on chest CT scans and 16 presented with fever. The median wait time for surgery was one day. The median preparation time and median time until short orientation memory concentration test (SOMCT) recovery from anesthesia were 44.0 min and 23.0 min, respectively. The median postoperative length of stay was five days. Compared with patients not suspected of COVID-19 infection, six patients were confirmed to be infected with COVID-19 in the suspected group. No health care workers were infected during this study period.Conclusion: Simple identification using temperature screening of patients, respiratory symptoms, and chest CT scans before being admitted for emergency surgery was rapid and effective. Shortened contact times might reduce the risk of infection. Additional investigations with larger samples and improved designs are needed to confirm these observations.Keywords: COVID-19, emergency, cross-infection

Shuzhong Liu,1,* Xi Zhou,1,* An Song,2 Zhen Huo,3 Siyuan Yao,1 Yipeng Wang,1 Yong Liu,1,* Ling-Ya Pan4,* 1Department of Orthopaedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, People’s Republic of China; 2Department of Endocrinology, Key Laboratory of Endocrinology, National Health and Family Planning Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People’s Republic of China; 3Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People’s Republic of China; 4Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yong LiuDepartment of Orthopaedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, No. 1 Shuaifuyuan Wangfujing, Beijing 100730, People’s Republic of China, Email liuyong_pumch@163.comLing-Ya PanDepartment of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, People’s Republic of ChinaEmail panly@pumch.cnObjective: The purpose of this study is to provide key information on the clinical characteristics, surgical treatment, and potential prognostic factors in patients with metastatic spinal gynecologic cancer (MSGC), with a view to their application in clinical practice.Methods: From January 2010 to January 2020, we performed a retrospective analysis of 14 patients with MSGC who underwent surgical treatment in a single center. Surgical treatment was performed on 14 patients, and a total of 14 operations were performed. The survival time of patients after spinal surgery was analyzed by Kaplan–Meier and Cox regression analysis.Results: The average age of patients was 51.9 years (range 25‒70). The average time from initial surgery to the discovery of spinal metastasis was 60.3 months (2‒180), and the average follow-up time was 19.2 months (2‒55). Spinal tumor progression was found in 9 patients, and 12 patients (85.7%) died during follow-up. In univariate analysis, extraosseous visceral metastasis (p = 0.024), revised Tokuhashi stage (p = 0.025), Tomita stage (p = 0.005), and number of spinal lesions (p = 0.038) were associated with overall survival (OS). Extraosseous visceral metastasis (p = 0.026), revised Tokuhashi stage (p = 0.014), Tomita stage (p = 0.001), and gynecological cancer type (p = 0.039) were associated with progression-free survival.Conclusion: Surgical treatment is an effective treatment for MSGC and relieves pain, restores function and rebuilds stability. Based on our single-center experience, extraosseous visceral metastasis, revised Tokuhashi stage, Tomita stage, and gynecological cancer type may be potential prognostic factors for OS.Keywords: clinical prognosis, gynecological cancer, overall survival, progression-free survival, spinal metastasis, surgical treatment

Song Yao,1,* Junwei Yan,2,* Ling Li,1 Dongchun Ma,1 Jie Liu,1 Qing Wang,1 Aimin Wang,1 Fangjin Bao,1 Zekun Zhang,1 Xundi Bao1 1Tuberculosis Prevention and Treatment Institute of Anhui Province (Anhui Chest Hospital), Hefei 230022, Anhui, People’s Republic of China; 2Affiliated Psychological Hospital of Anhui Medical University, Hefei Fourth People’s Hospital, Anhui Metal Health Center, Hefei, People’s Republic of China*These authors contributed equally to this workCorrespondence: Junwei Yan No. 316, Huangshan Road, Hefei 230022, Anhui, People’s Republic of ChinaTel/Fax +86-551-63658250Email 594347807@qq.comBackground: Multidrug-resistant tuberculosis (MDR-TB) is currently a major problem in China. The prevention and treatment work for MDR-TB patients started late in Anhui province. To determine the prevalence of MDR-TB in sputum smear-positive TB patients (SSPTBPs) and analyze the risk factors for MDR-TB in Anhui province, we conducted an investigation of drug resistance among SSPTB outpatients from September 2015 to August 2016.Methods: A stratified cluster-randomized sampling method was used to obtain a representative sample. It was estimated that 2290 new cases and 440 previously treated cases of SSPTBPs needed to be recruited from 40 survey sites. Isolates were tested for resistance to six first-line and second-line anti-TB drugs. Information from patient questionnaire survey was used to identify factors linked to MDR-TB.Results: Finally, a total of 3047 SSPTBPs were recruited from 40 survey sites; of these, 2530 specimens were successfully cultured and had drug susceptibility testing done. The proportions of rifampin resistant (RR)-TB were 11.42% (289/2530, 95% CI: 10.18– 12.66%), 7.64% (163/2133, 95% CI: 6.38– 8.62%) and 31.74% (126/397, 95% CI: 27.38– 36.60%) in all cases, new cases and previously treated cases, respectively, and the proportions of confirmed MDR-TB were 7.63% (193/2530, 95% CI: 6.59– 8.66%), 4.97% (106/2133, 95% CI: 4.05– 5.89%) and 21.91% (87/397, 95% CI: 17.83– 26.00%), respectively. The ofloxacin resistance rate in previously treated SSPTBPs reached 21.66% (95% CI: 17.33– 26.75%). Patients who had received two or more anti-TB treatment courses were significantly associated with MDR-TB compared to patients who have received one anti-TB course.Conclusion: MDR-TB prevalence was high among SSPTBPs in Anhui province, and past anti-TB treatment course was associated with MDR-TB.Keywords: drug resistance, multidrug-resistant, Mycobacterium tuberculosis, tuberculosis

Yongbin Wang,1,* Chunjie Xu,2,* Yuchun Li,1 Weidong Wu,1 Lihui Gui,1 Jingchao Ren,1 Sanqiao Yao1 1Department of Epidemiology and Health Statistics, School of Public Health, Xinxiang Medical University, Xinxiang, Henan, People’s Republic of China; 2Department of Occupational and Environmental Health, School of Public Health, Capital Medical University, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Sanqiao Yao; Yongbin WangDepartment of Epidemiology and Health Statistics, School of Public Health, Xinxiang Medical University, Xinxiang, Henan 453000, People’s Republic of ChinaTel +86 373831646Email 1153483589@qq.com; wybwho@163.comPurpose: Qinghai province has invariably been under an ongoing threat of tuberculosis (TB), which has not only been an obstacle to local development but also hampers the prevention and control process for ending the TB epidemic. Forecasting for future epidemics will serve as the base for early detection and planning resource requirements. Here, we aim to develop an advanced detection technique driven by the recent TB incidence series, by fusing a seasonal autoregressive integrated moving average (SARIMA) with a neural network nonlinear autoregression (NNNAR).Methods: We collected the TB incidence data between January 2004 and December 2016. Subsequently, the subsamples from January 2004 to December 2015 were employed to measure the efficiency of the single SARIMA, NNNAR, and hybrid SARIMA-NNNAR approaches, whereas the hold-out subsamples were used to test their predictive performances. We finally selected the best-performing technique by considering minimum metrics including the mean absolute error, root-mean-squared error, mean absolute percentage error and mean error rate .Results: During 2004– 2016, the reported TB cases totaled 71,080 resulting in the morbidity of 97.624 per 100,000 persons annually in Qinghai province and showed notable peak activities in late winter and early spring. Moreover, the TB incidence rate was surging by 5% per year. According to the above-mentioned criteria, the best-fitting basic and hybrid techniques consisted of SARIMA(2,0,2)(1,1,0)12, NNNAR(7,1,4)12 and SARIMA(2,0,2)(1,1,0)12-NNNAR(3,1,7)12, respectively. Amongst them, the hybrid technique showed superiority in both mimic and predictive parts, with the lowest values of the measured metrics in both the parts. The sensitivity analysis indicated the same results.Conclusion: The best-mimicking SARIMA-NNNAR hybrid model outperforms the best-simulating basic SARIMA and NNNAR models, and has a potential application in forecasting and assessing the TB epidemic trends in Qinghai. Furthermore, faced with the major challenge of the ongoing upsurge in TB incidence in Qinghai, there is an urgent need for formulating specific preventive and control measures.Keywords: tuberculosis, SARIMA model, NNNAR model, hybrid model, forecasting, incidence rate

Yongbin Wang,1,* Chunjie Xu,2,* Jingchao Ren,1 Weidong Wu,1 Xiangmei Zhao,1 Ling Chao,1 Wenjuan Liang,1 Sanqiao Yao1 1Department of Epidemiology and Health Statistics, School of Public Health, Xinxiang Medical University, Xinxiang, Henan, People’s Republic of China; 2Department of Occupational and Environmental Health, School of Public Health, Capital Medical University, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yongbin WangDepartment of Epidemiology and Health Statistics, School of Public Health, Xinxiang Medical University, Xinxiang, Henan 453000, People’s Republic of ChinaTel +86 373 383 1646Email wybwho@163.comObjective: Tuberculosis (TB) is a major public health problem in China, and contriving a long-term forecast is a useful aid for better launching prevention initiatives. Regrettably, such a forecasting method with robust and accurate performance is still lacking. Here, we aim to investigate its potential of the error-trend-seasonal (ETS) framework through a series of comparative experiments to analyze and forecast its secular epidemic seasonality and trends of TB incidence in China.Methods: We collected the TB incidence data from January 1997 to August 2019, and then partitioning the data into eight different training and testing subsamples. Thereafter, we constructed the ETS and seasonal autoregressive integrated moving average (SARIMA) models based on the training subsamples, and multiple performance indices including the mean absolute deviation, mean absolute percentage error, root-mean-squared error, and mean error rate were adopted to assess their simulation and projection effects.Results: In the light of the above performance measures, the ETS models provided a pronounced improvement for the long-term seasonality and trend forecasting in TB incidence rate over the SARIMA models, be it in various training or testing subsets apart from the 48-step ahead forecasting. The descriptive results to the data revealed that TB incidence showed notable seasonal characteristics with predominant peaks of spring and early summer and began to be plunging at on average 3.722% per year since 2008. However, this rate reduced to 2.613% per year since 2015 and furthermore such a trend would be predicted to continue in years ahead.Conclusion: The ETS framework has the ability to conduct long-term forecasting for TB incidence, which may be beneficial for the long-term planning of the TB prevention and control. Additionally, considering the predicted dropping rate of TB morbidity, more particular strategies should be formulated to dramatically accelerate progress towards the goals of the End TB Strategy.Keywords: tuberculosis, incidence, SARIMA, ETS, models, forecasting

Mingli Liu,1–3 Jie Zhang,2 Elwin Hu,4 Huilan Yang,5 Chang Cheng,3 Shuqiao Yao3 1Department of Psychology, Hunan University of Science and Technology, Xiangtan, Hunan 411201, People’s Republic of China; 2State University of New York Buffalo State Department of Sociology, NewYork, NY, USA; 3Medical Psychological Institute, Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, People’s Republic of China; 4School of Psychology, Counselling and Psychotherapy, Cairnmillar Institute, Hawthorn East, VIC, Australia; 5Department of Psychology, University of Western Ontario, London, Ontario N6A 5C2, CanadaCorrespondence: Shuqiao YaoMedical Psychological Institute, Second Xiangya Hospital of Central South University, 139 Middle Renmin Road Changsha, Hunan 410011, People’s Republic of ChinaTel +86 137 8612 0325Email shuqiaoyao@csu.edu.cnMingli LiuDepartment of Psychology, Hunan University of Science and Technology, 2 Taoyuan Road Xiangtan, Hunan 411201, People’s Republic of ChinaTel +86 139 7522 3596Email mlliupsy@163.comBackground and purpose: There are increasing concern about independent associations between physical activity, screen-based sedentary behavior (SSB), and psychological problems, but only a few studies have attempted to explore combined patterns of physical activity and SSB in adolescents and their correlations with psychological problems. This study was aimed at identifying combined patterns of moderate-to-vigorous physical activity (MVPA) and SSB and examining the prevalence of different combined patterns and their correlations with depression, anxiety, and self-injurious behavior among Chinese adolescents.Methods: Junior and senior high school students (N = 13,659; mean age 15.18±1.89) were recruited. Latent class analysis was conducted to identify combined patterns of MVPA and SSB. Associations between subgroups of MVPA and SSB and socio-demographic characteristics were assessed by logistic regression. Their correlation with depression, anxiety, and self-injurious behaviors was assessed by analysis of variance with analysis stratified by gender.Results: Four latent classes were identified: high MVPA/low SSB group (64.7%), low MVPA/low SSB (26.7%), low MVPA/high SSB (4.8%), and low MVPA/moderate SSB (3.9%). Generally, the high MVPA/low SSB class was a relatively healthy group. The low MVPA/high SSB class was at risk of enduring depression, anxiety, and self-injurious behavior, with boys being more at risk than girls.Conclusion: Four latent subgroups of MVPA and SSB were identified in Chinese adolescents. The findings highlight the potential role of concurrent MVPA and SSB, with gender-specific characteristics in the primary prevention of adolescent depression, anxiety, and self-injurious behaviors.Keywords: exercise, internet, media use, subgroups, mental health, suicide

Yanchun Liang,1 Duo Liu,1 Fan Yang,1 Wenwei Pan,1 Feitianzhi Zeng,1 Jinjie Wu,2 Hongyu Xie,2 Jiaying Li,2 Shuzhong Yao1 1Department of Obstetrics and Gynecology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China; 2Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China Purpose: Recent studies have shown that abnormal distribution of pelvic nerves contributes to endometriosis-associated pain. However, the relationship between neurogenesis and pain severity in endometriosis still remains uncertain, which makes it an enigma for both gynecologists as well as neuropathologists. In this study, we tried to explore a special phenomenon, perineural invasion (PNI), in deep infiltrating endometriosis (DIE) and investigated the correlation between PNI- and DIE-associated pain.Patients and methods: The study was conducted in the Department of Obstetrics and Gynecology of the First Affiliated Hospital of Sun Yat-sen University from June 2012 to January 2015. In total, 64 patients with DIE were enrolled. They received laparoscopically surgical resection of endometriotic lesions. The Kruskal–Wallis and Mann–Whitney tests were used for comparisons of enumeration data. Spearman rank correlation was used for linear analysis.Results: Immunohistochemical analysis demonstrated that PNI was commonly found in DIE lesions. Patients were divided into PNI (+) group and PNI (−) group. The visual analog scale scores of dysmenorrhea, dyspareunia, and chronic pelvic pain were higher in PNI (+) group than in PNI (−) group. Also, we found significantly increased density of newly formed nerve fibers as well as microvessels in lesions of PNI (+) group. Further, double immunofluorescence showed a closely spatial nerve–vessel network in the endometriotic lesion of PNI (+) group. More importantly, correlation analysis revealed positive relation between the density of newly formed nerve fibers in the lesion and the density of microvessels in lesions of PNI (+) group.Conclusion: This study suggests that PNI in endometriotic lesions plays an important role in endometriosis-associated pain, mainly through a mechanism named “neuroangiogenesis”. Keywords: perineural invasion, deep infiltrating endometriosis, pain, neuroangiogenesis

Shenglian Yao,1,2 Shukui Yu,3 Zheng Cao,2 Yongdong Yang,2,4 Xing Yu,4 Hai-Quan Mao,5 Lu-Ning Wang,1 Xiaodan Sun,2 Lingyun Zhao,2 Xiumei Wang2 1School of Materials Science and Engineering, University of Science and Technology Beijing, Beijing, China; 2Key Laboratory of Advanced Materials of Ministry of Education, School of Materials Science and Engineering, Tsinghua University, Beijing, China; 3Department of Otolaryngology-Head and Neck Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China; 4Department of Orthopedics, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China; 5Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, MD, USA Background: Designing novel biomaterials that incorporate or mimic the functions of extracellular matrix to deliver precise regulatory signals for tissue regeneration is the focus of current intensive research efforts in tissue engineering and regenerative medicine. Methods and results: To mimic the natural environment of the spinal cord tissue, a three-dimensional hierarchically aligned fibrin hydrogel (AFG) with oriented topography and soft stiffness has been fabricated by electrospinning and a concurrent molecular self-assembling process. In this study, the AFG was implanted into a rat dorsal hemisected spinal cord injury model to bridge the lesion site. Host cells invaded promptly along the aligned fibrin hydrogels to form aligned tissue cables in the first week, and then were followed by axonal regrowth. At 4 weeks after the surgery, neurofilament (NF)-positive staining fibers were detected near the rostral end as well as the middle site of defect, which aligned along the tissue cables. Abundant NF- and GAP-43-positive staining indicated new axon regrowth in the oriented tissue cables, which penetrated throughout the lesion site in 8 weeks. Additionally, the abundant blood vessels marked with RECA-1 had reconstructed within the lesion site at 4 weeks after surgery. Basso-Beattie-Bresnahan scoring showed that the locomotor performance of the AFG group recovered much faster than that of blank control group or the random fibrin hydrogel (RFG) group from 2 weeks after surgery. Furthermore, diffusion tensor imaging tractography of MRI confirmed the optimal axon fiber reconstruction compared with the RFG and control groups. Conclusion: Taken together, our results suggested that the AFG scaffold provided an inductive matrix for accelerating directional host cell invasion, vascular system reconstruction, and axonal regrowth, which could promote and support extensive aligned axonal regrowth and locomotor function recovery. Keywords: spinal cord injury, nerve regrowth, fibrin hydrogel, aligned structure, soft stiffness

Teng Ma,1–3,* Jian Cai,4,* Yin-Sheng Zhu,5 Xue-Feng Chu,5 Yong Wang,5 Guo-Ping Shi,5 Zheng-Dong Wang,5 Shun Yao,1–3 Xiao-Feng Wang,1–3 Xiao-Yan Jiang6–8 1Unit of Epidemiology, Ministry of Education Key Laboratory of Contemporary Anthropology, Fudan University, Shanghai, People’s Republic of China; 2State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, People’s Republic of China; 3National Clinical Research Center for Aging and Medicine (Huashan), Huashan Hospital, Fudan University, Shanghai, People’s Republic of China; 4Department of Neurology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 5Rugao People’s Hospital, Rugao, Jiangsu, People’s Republic of China; 6Key Laboratory of Arrhythmias of the Ministry of Education of China, Tongji University School of Medicine, Shanghai, People’s Republic of China; 7Department of Pathology and Pathophysiology, Tongji University School of Medicine, Shanghai, People’s Republic of China; 8Institute of Medical Genetics, Tongji University, Shanghai, People’s Republic of China *These authors contributed equally to this work Background: Risk factors for heart rate-corrected QT interval (QTc) proglongation should be explored to stratify high-risk individuals to aid the prevention of incident cardiovascular events and mortality. The diversity of risk factors for QTc prolongation suggests that use of the frailty index (FI), indicating general health deficits, may be an effective approach, especially in the elderly, to identify the risk of QTc prolongation. Methods: We used the data of 1,780 individuals aged 70–87 years from the Rugao Longevity and Ageing Study (RuLAS), a community-based longitudinal study. The FI was constructed using 20 routine laboratory tests, plus the body mass index and measures of systolic and diastolic blood pressures (FI-Lab). Results: The mean FI-Lab value was 0.24±0.09. The mean heart rate-corrected QT interval (QTc) was 407±38 ms. The prevalence of QTc prolongation was 5.2% in elderly community populations aged 70–87 years. A higher FI-Lab value was associated with a higher risk for QTc prolongation. Each 10% increase in the FI-Lab value increased the odds ratio (OR) by 33% (OR: 1.33; 95% CI: 1.07–1.64). Compared with the lowest quartile, the top quartile FI-Lab score was associated with a 2.50-fold QTc prolongation risk in elderly individuals (95% CI: 1.21–5.19). Conclusion: An FI based on routine laboratory data can identify older adults at increased risk for QTc prolongation. The FI approach may therefore be useful for the risk stratification of QTc prolongation. Keywords: QTc prolongation, frailty, frailty index, Chinese elderly

Tingfang Sun,1,* Man Liu,2,* Sheng Yao,1 Yanhui Ji,1 Lei Shi,3 Kai Tang,1 Zekang Xiong,1 Fan Yang,1 Kaifang Chen,1 Xiaodong Guo1 1Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; 2Department of Gastroenterology and Hepatology, Taikang Tongji Hospital, Wuhan 430050, China; 3State Key Laboratory of Materials Processing and Die & Mould Technology, School of Materials Science and Engineering, Huazhong University of Science and Technology, Wuhan 430074, China *These authors contributed equally to this work Introduction: At present, the treatment of osteoporotic defects poses a great challenge to clinicians, owing to the lower regeneration capacity of the osteoporotic bone as compared with the normal bone. The guided bone regeneration (GBR) technology provides a promising strategy to cure osteoporotic defects using bioactive membranes. The decellularized matrix from the small intestinal submucosa (SIS) has gained popularity for its natural microenvironment, which induces cell response. Materials and methods: In this study, we developed heparinized mineralized SIS loaded with bone morphogenetic protein 2 (BMP2)-related peptide P28 (mSIS/P28) as a novel GBR membrane for guided osteoporotic bone regeneration. These mSIS/P28 membranes were obtained through the mineralization of SIS (mSIS), followed by P28 loading onto heparinized mSIS. The heparinized mSIS membrane was designed to improve the immobilization efficacy and facilitate controlled release of P28. P28 release from mSIS-heparin-P28 and its effects on the proliferation, viability, and osteogenic differentiation of bone marrow stromal stem cells from ovariectomized rats (rBMSCs-OVX) were investigated in vitro. Furthermore, a critical-sized OVX calvarial defect model was used to assess the bone regeneration capability of mSIS-heparin-P28 in vivo. Results: In vitro results showed that P28 release from mSIS-heparin-P28 occurred in a controlled manner, with a long-term release time of 40 days. Moreover, mSIS-heparin-P28 promoted cell proliferation and viability, alkaline phosphatase activity, and mRNA expression of osteogenesis-related genes in rBMSCs-OVX without the addition of extra osteogenic components. In vivo experiments revealed that mSIS-heparin-P28 dramatically stimulated osteoporotic bone regeneration. Conclusion: The heparinized mSIS loaded with P28 may serve as a potential GBR membrane for repairing osteoporotic defects. Keywords: osteoporotic defect, guided bone regeneration, decellularized matrix, heparin, BMP2-related peptide, control release

Yuhao Xu,1,* Shun Yao,2,* Hong Wei,1 Xiaolan Zhu,3 Ming Yu,1 Yuefeng Li2 1Department of Neurology, The Affiliated Hospital of Jiangsu University, Zhenjiang, People’s Republic of China; 2Department of Radiology, The Affiliated Hospital of Jiangsu University, Zhenjiang, People’s Republic of China; 3Department of Central Laboratory, The Fourth Affiliated Hospital of Jiangsu University, Zhenjiang, People’s Republic of China *These authors contributed equally to this work Background: Transient depressive state (TDS) is a transient, negative emotional state caused by certain events or situations. Because of the similarity in depressive symptoms between depression and TDS that arise within 2 weeks of their onset, it is difficult to distinguish TDS from depression. The aims of the present study were to investigate the application value of selected serum indicators in the differential diagnosis of geriatric depression and TDS in the early stage and to provide evidence for treatment.Patients and methods: In this study, a total of 274 elderly patients were divided into the depression group (n=144) and the TDS group (n=130). All participants’ serum samples were collected, and 9 selected serum indicators were analyzed. Afterward, 90 patients with depression and 90 patients with TDS were used to build the diagnostic model. A binary logistic regression analysis was used to establish regression models, and the area under the receiver operating characteristic (ROC) curve was drawn. Finally, another 54 patients with depression and 40 patients with TDS were used to validate our model.Results: For the 9 screening serum indicators, the 3 serum indicators selected to build the regression model were BDNF (P=0.001), IL-1β (P

Lingling Ding,1–3 Jiawei Li,1,2 Rui Huang,1,2 Zhidong Liu,1,2 Chunhua Li,1–3 Shaozi Yao,1,2 Jinyan Wang,1,2 Dongli Qi,1,2 Nan Li,1,2 Jiaxin Pi1,21Tianjin State Key Laboratory of Modern Chinese Medicine, Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, 2Engineering Research Center of Modern Chinese Medicine Discovery and Preparation Technique, Tianjin University of Traditional Chinese Medicine, 3Tianjin International Joint Academy of Biomedicine, Tianjin, People’s Republic of ChinaAbstract: Targeted delivery by the folate ligand is an effective way to enhance an anti-breast carcinoma effect, due to its high affinity for the folate receptor, which is overexpressed in many tumor cells. In this study, we firstly synthesized a folic acid (FA)-targeted and polyethylene glycol (PEG)-modified TiO2 nanocarrier. Then, an FA-PEG-TiO2 nanoparticle (NP) codelivery system loaded with curcumin and salvianolic acid B were prepared by emulsion evaporation–solidification at low temperature. The obtained folate-targeted NPs (FA-NPs) showed more cytotoxicity on MCF7 cells and MDA-MB-231 cells than a nontargeted NP group. Apart from a synergistic anti-breast cancer effect with curcumin, salvianolic acid B protects the cardiovascular system from oxidative injury by the TiO2 nanocarrier. With coumarin 6 as a fluorescent probe to observe cellular uptake of NPs, the results of in vitro cellular uptake demonstrated FA-NPs exhibited higher cellular uptake and accumulation in MCF7 cells and MDA-MB-231 cells than nontargeted NPs. Then, in vivo biodistribution of NPs was further qualitatively and quantitatively confirmed by in vivo imaging. More importantly, the animal study further suggested that FA-NPs had significantly stronger antitumor effects via receptor-mediated targeted delivery. Consequently, FA-PEG-TiO2 NPs loaded with curcumin and salvianolic acid B could be a promising drug-delivery system to treat breast cancer. Keywords: breast cancer, codelivery, curcumin, FA-PEG-TiO2, nanoparticles, salvianolic acid B

Tingfang Yang,1 Shuluan Yao,2 Xianfeng Zhang,3 Yan Guo2 1Department of Pediatrics, Jining No 1 People’s Hospital, Shandong Province, People’s Republic of China; 2Department of Respiratory Medicine, Jining Medical University Affiliated Hospital, Shandong Province, People’s Republic of China; 3Department of Psychiatry, Jining Psychiatric Hospital, Shandong Province, People’s Republic of China Abstract: T-cell acute lymphoblastic leukemia (T-ALL) as a prevalent hematologic malignancy is one of the most common malignant tumors worldwide in children. Andrographolide (Andro), the major active component from Andrographis paniculata, has been shown to possess antitumor activities in several types of cancer cells. However, whether Andro would inhibit T-ALL cell growth remains unclear. In this study, we investigated the cytotoxic effect of Andro on human T-ALL Jurkat cells and explored the mechanisms of cell death. Cell apoptosis was assayed by flow cytometry, and the signaling transduction for Andro was analyzed by Western blotting. The results indicated 10 µg/mL Andro could significantly induce Jurkat cells’ apoptosis, depending on the inhibition of PI3K/AKT pathway. Moreover, Andro-induced apoptosis is enhanced by AKT-selective inhibitor LY294002. ERK- or JNK-selective inhibitors PD98059 and SP600125 had no effect on Andro-induced apoptosis. In addition, p38 inhibitor SB203580 could reverse Andro-induced apoptosis in Jurkat cells. We also found that the protein expression of p-p53 and p-p38 were increased after Andro treatments. The result of an in vivo study also demonstrated Andro’s dose-dependent inhibition in subcutaneous Jurkat xenografts. In conclusion, our findings explained a novel mechanism of drug action by Andro in Jurkat cells and suggested that Andro might be developed into a new candidate therapy for T-ALL patients in the coming days. Keywords: andrographolide, PI3K, AKT, Burkitt lymphoma, Jurkat cell

Ting Yu,1,* Bei Xu,1,* Lili He,2 Shan Xia,3 Yan Chen,1 Jun Zeng,1 Yongmei Liu,1 Shuangzhi Li,1 Xiaoyue Tan,4 Ke Ren,1 Shaohua Yao,1 Xiangrong Song1 1State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, 2College of Chemistry and Environment Protection Engineering, Southwest University for Nationalities, 3Central Laboratory, Science Education Department, Chengdu Normal University, Chengdu, Sichuan, 4Department of Pathology/Collaborative Innovation Center of Biotherapy, Medical School of Nankai University, Tianjin, People’s Republic of China *These authors contributed equally to this work Abstract: Anti-angiogenesis has been proposed as an effective therapeutic strategy for cancer treatment. Pigment epithelium-derived factor (PEDF) is one of the most powerful endogenous anti-angiogenic reagents discovered to date and PEDF gene therapy has been recognized as a promising treatment option for various tumors. There is an urgent need to develop a safe and valid vector for its systemic delivery. Herein, a novel gene delivery system based on the newly synthesized copolymer COOH-PEG-PLGA-COOH (CPPC) was developed in this study, which was probably capable of overcoming the disadvantages of viral vectors and cationic lipids/polymers-based nonviral carriers. PEDF gene loaded CPPC nanoparticles (D-NPs) were fabricated by a modified double-emulsion water-in-oil-in-water (W/O/W) solvent evaporation method. D-NPs with uniform spherical shape had relatively high drug loading (~1.6%), probably because the introduced carboxyl group in poly (D,L-lactide-co-glycolide) terminal enhanced the interaction of copolymer with the PEDF gene complexes. An excellent in vitro antitumor effect was found in both C26 and A549 cells treated by D-NPs, in which PEDF levels were dramatically elevated due to the successful transfection of PEDF gene. D-NPs also showed a strong inhibitory effect on proliferation of human umbilical vein endothelial cells in vitro and inhibited the tumor-induced angiogenesis in vivo by an alginate-encapsulated tumor cell assay. Further in vivo antitumor investigation, carried out in a C26 subcutaneous tumor model by intravenous injection, demonstrated that D-NPs could achieve a significant antitumor activity with sharply reduced microvessel density and significantly promoted tumor cell apoptosis. Additionally, the in vitro hemolysis analysis and in vivo serological and biochemical analysis revealed that D-NPs had no obvious toxicity. All the data indicated that the novel CPPC nanoparticles were ideal vectors for the systemic delivery of PEDF gene and might be widely used as systemic gene vectors. Keywords: pigment epithelium-derived factor gene, nanoparticles based on PLGA derivative, gene delivery, systemic delivery, tumor