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Xiaoyan Hong,1 Yangrong Huang,1 Wei Lin,1 Yi Zhang,1 Jianyun Lin,1 Shengguo Zhang,2 Fengquan Cai,1 Jie Chen1 1Department of Emergency, Third Affiliated Hospital of Wenzhou Medical University (Rui’an People’s Hospital), Wenzhou, Zhejiang, People’s Republic of China; 2Department of Infection, Third Affiliated Hospital of Wenzhou Medical University (Rui’an People’s Hospital), Wenzhou, Zhejiang, People’s Republic of ChinaCorrespondence: Fengquan Cai; Jie Chen, Department of Emergency, Third Affiliated Hospital of Wenzhou Medical University (Rui’an People’s Hospital), 108 Wansong Road, Wenzhou, 325200, Zhejiang, People’s Republic of China, Tel +86-13967723666 ; +86-13587409966, Email cfqruiyi@163.com; woshichenjie@wmu.edu.cnAbstract: Staphylococcus aureus (S. aureus) infection is readily disseminated, yet the multiple septic arthritis and extensive migratory skin and soft tissue infections it causes are uncommon and challenging to treat. The infection can be life-threatening, with a mortality rate of 15– 31%. Early, targeted antibiotic therapy is critical to improve prognosis. However, routine cultures are time-consuming and have low positivity rates, which may lead to errors in antibiotic regimen selection, depriving patients of optimal treatment. Genetic testing technologies, such as macrogenomic next-generation sequencing (mNGS) and digital polymerase chain reaction (dPCR), are now emerging as powerful tools for early pathogen diagnosis as well as pathogen diagnosis of target detectors with low microbial loads. In this study, we report a 53-year-old man who was admitted to the ICU for treatment of septic shock. The causative agent was targeted earlier as S. aureus by mNGS, and the shock was corrected more quickly with targeted antibiotic medication. However, he later developed multiple septic arthritis and an extensive migratory skin soft tissue infection with persistent fever, and at one point a gram-negative bacterial infection was suspected, and the antibiotic regimen was incorrectly changed. Blood dPCR suggested that the causative organism was still methicillin-sensitive S. aureus (MSSA), with no drug resistance gene detected, and the anti-infective regimen was readjusted, and the patient eventually recovered and was discharged from the hospital. We present this rare case and review related studies to validate the superiority of genetic testing technology in pathogen diagnosis, which deserves further application.Keywords: disseminated Staphylococcus aureus disease, multiple suppurative arthritis, extensive migratory skin and soft tissue infections, digital polymerase chain reaction, next-generation sequencing

Deying Xiao,1,2,* Long Xie,1,* Wenhong Lin,1 Jinhua Fu,1 Lin Deng,1 Qian Zhuang,2,3 Maobai Liu2,3 1Longyan First Affiliated Hospital of Fujian Medical University, Longyan, 364000, People’s Republic of China; 2The School of Pharmacy, Fujian Medical University, Fuzhou, 350004, People’s Republic of China; 3Department of Pharmacy, Fujian Medical University Union Hospital, Fuzhou, 350001, People’s Republic of China*These authors contributed equally to this workCorrespondence: Maobai Liu; Qian Zhuang, Department of Pharmacy, Fujian Medical University Union Hospital, No. 29, Xinquan Road, Antai Street, Gulou District, Fuzhou, 350001, People’s Republic of China, Tel +86-591-83357896, Email liumaobai10@163.com; ZhuangQ0591@163.comBackground: This evaluation aims to provide a reference for clinical decision-making regarding the use of SPN in intensive care unit (ICU) patients. The objective of this study is to evaluate the quality of clinical practice guidelines for the use of supplementary parenteral nutrition (SPN) in ICU patients, both domestically and internationally.Patients and Methods: The quality of clinical practice recommendations for SPN use in ICU patients was assessed using a systematic approach.Results: Five nutrition recommendations in total were included for analysis. The average standardized scores for the recommendations across the six domains of the Appraisal of Guidelines for Research and Evaluation II (AGREE II) are as follows: Scope and purpose scored 87.96%, stakeholder Involvement scored 68.52%, rigour of development scored 73.40%, clarity of presentation scored 84.80%, applicability scored 64.72%, and editorial independence scored 91.10%. In the comprehensive evaluation, two guidelines were rated as grade A recommendations, and three were rated as grade B recommendations. Most guidelines recommended against early use of SPN when energy and protein requirements could not be met solely through enteral nutrition (EN) in ICU patients. The guidelines emphasized achieving target energy levels and discontinuing parenteral nutrition (PN) as soon as the energy requirements were met to prevent overfeeding.Conclusion: This study utilized the AGREE II scale to assess the quality of five nutrition guidelines. All 5 guidelines were deemed acceptable Recommendations include focusing on participants, rigour, and applicability to enhance guideline quality. Clinicians should exercise professional judgment when applying guidelines as they complement training and judgment, rather than replacing them.Keywords: ICU, patients, supplementary parenteral nutrition, clinical practice guidelines, guideline evaluation

Qin Yang,1,2 Xiao Huang,2 Yanhong Lin,1 Ke Chen,1 Qinghua Lu,1 Weinan Lin,1 Xing Wang,2 Yishu Teng,3 Peng Jiang,3 Sandip Patil,3 Yuejie Zheng1 1Department of Respiratory Medicine, Shenzhen Children’s Hospital, Shenzhen, Guangdong Province, People’s Republic of China; 2Department of Sleep Centre, Shenzhen Children’s Hospital, Shenzhen, Guangdong Province, People’s Republic of China; 3Department of Haematology and Oncology, Shenzhen Children’s Hospital, Shenzhen, Guangdong Province, People’s Republic of ChinaCorrespondence: Sandip Patil, Department of Haematology and Oncology, Shenzhen Children’s Hospital, Shenzhen, Guangdong Province, People’s Republic of China, Tel +85-755-82008283, Email sandippatil1309@yahoo.com Yuejie Zheng, Department of Respiratory Medicine, Shenzhen Children’s Hospital, Shenzhen, Guangdong Province, People’s Republic of China, Email shine1990@sina.comBackground: Pediatric obstructive sleep apnea (OSA) is a multifaceted disorder marked by recurrent upper airway obstruction during sleep, often coexisting with various medical conditions. This study, aimed to comprehensively analyze the Multifaceted Landscape of Pediatric Insights into Prevalence, Severity, and Coexisting Conditions. With a sample of 1928 participants, our study sought to determine the prevalence, severity, and associations between OSA and diverse conditions.Methods: Conducted retrospectively from February 2019 to April 2023, the study included pediatric patients. Data were collected through electronic health records, involving clinical assessments, medical histories, and diagnostic tests to establish OSA and coexisting condition diagnoses. Relationships between sleep parameters, apnea types, and severity indices were evaluated.Results: High OSA prevalence was evident across age groups, with severity peaking between 3 to 12 years. Among the participants, coexisting conditions included allergic rhinitis (59.6%), tonsillar hypertrophy (49.7%), adenoid hypertrophy (28.4%), and obesity (15.3%). Analysis revealed intriguing relationships between different sleep parameters and apnea types. Notable associations were observed between Obstructive Apnea (OA) and Central Apnea (CA), and Mixed Apnea (MA) displayed associations with both OA and CA. Hypopnea correlated directly with the Apnea-Hypopnea Index (AHI), reflecting its role in OSA severity.Conclusion: This study provides a comprehensive understanding of the intricate dynamics between pediatric OSA and coexisting conditions. The prevalence of OSA and its coexistence with various conditions underscore the need for comprehensive evaluation and management strategies. By revealing associations between different sleep parameters and apnea types, the study emphasizes the complexity of OSA diagnosis and management. These findings hold the potential to enhance clinical approaches, ultimately leading to improved care and outcomes for affected children.Keywords: pediatric obstructive sleep apnea, coexisting conditions, prevalence, severity, relationships, sleep parameters, management, clinical analysis, comprehensive evaluation, outcomes

Yuhua Wen,1,2,* Lianghe Lu,1,2,* Jie Mei,1,2 Yihong Ling,2,3 Renguo Guan,1,2 Wenping Lin,1,2 Wei Wei,1,2 Rongping Guo1,2 1State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People’s Republic of China; 2Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People’s Republic of China; 3Department of Pathology of Sun Yat-sen University Cancer Center, Guangzhou, 510060, People’s Republic of China*These authors contributed equally to this workCorrespondence: Rongping Guo; Wei Wei, Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, Guangzhou, 510060, People’s Republic of China, Email guorp@sysucc.org.cn; weiwei@sysucc.org.cnBackground: Microvascular invasion (MVI) is a significant pathological feature in hepatocellular carcinoma (HCC), adjuvant hepatic arterial infusion chemotherapy (a-HAIC) and adjuvant transcatheter arterial chemoembolization (a-TACE), are commonly used for HCC patients with MVI. This study aims to evaluate the efficacies of two adjuvant therapies after surgical treatment for HCC, compare them, and identify the significant factors.Methods: Clinical data from two randomized controlled trials involving HCC patients with MVI after surgical treatment were retrospectively reviewed. Propensity score matching (PSM) analysis was performed to balance baseline differences between patients who received a-HAIC or a-TACE, and control groups who underwent hepatectomy alone. Disease-free survival (DFS) and overall survival (OS) rates were compared.Results: In total of 549 patients were collected from two randomized controlled trials. Using the PSM and Kaplan-Meier method, the median DFS of the a-HAIC, a-TACE, and control groups was 63.2, 21.7, and 11.2 months (P

Yunjing Su,1,2 Zhonglian Yan,1 Wenqi Lin,1 Xuelin Liu1 1Faculty of Education, Northeast Normal University, Changchun, Jilin, People’s Republic of China; 2School of Child Welfare, Changchun Humanities and Sciences College, Changchun, Jilin, People’s Republic of ChinaCorrespondence: Yunjing Su, Faculty of Education, Northeast Normal University, No. 5268 Renmin Street, Changchun, Jilin Province, 130024, People’s Republic of China, Email suyj774@nenu.edu.cnPurpose: As an aspect of the lives of private college students in China, interpersonal competence (IC) is important to their socialization and employment competence. This study aimed to investigate the relationship between Chinese private college students’ smartphone addiction (SPA) and IC, the mediating effect of negative emotions (NE), and the moderating effect of psychological resilience (PR).Samples and Methods: Using simple random sampling, 5473 Chinese private college students (male 74.5%, urban household registration 51.6%, served as a student leader 31.5%) were recruited.Results: The results showed that (1) SPA positively predicted IC; (2) NE partially mediated the relationship between SPA and IC; and (3) PR moderated the relationships between SPA and NE, NE and IC, SPA and IC.Conclusion: These findings provide a new perspective to improve Chinese private college students’ socialization and their employment competitiveness.Keywords: Chinese private college students, interpersonal competence, negative emotions, psychological resilience, smartphone addiction

Wu Lin,1,* Yuxiang Yan,2,* Qingling Huang,1 Dali Zheng2 1Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, People’s Republic of China; 2Fujian Key Laboratory of Oral Diseases, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Dali Zheng, Fujian Key Laboratory of Oral Diseases, School and Hospital of Stomatology, Fujian Medical University, 88 Jiao Tong Road, Fuzhou, 350004, People’s Republic of China, Email dalizheng@fjmu.edu.cnAbstract: The p53 tumor suppressor protein plays an important role in physiological and pathological processes. MDM2 and its homolog MDMX are the most important negative regulators of p53. Many studies have shown that MDMX promotes the growth of cancer cells by influencing the regulation of the downstream target gene of tumor suppressor p53. Studies have found that inhibiting the MDMX-p53 interaction can effectively restore the tumor suppressor activity of p53. MDMX has growth-promoting activities without p53 or in the presence of mutant p53. Therefore, it is extremely important to study the function of MDMX in tumorigenesis, progression and prognosis. This article mainly reviews the current research progress and mechanism on MDMX function, summarizes known MDMX inhibitors and provides new ideas for the development of more specific and effective MDMX inhibitors for cancer treatment.Keywords: MDMX, P53, cancer, inhibitors

Shao-Xiong Chen, Ri Lin, Jiang-Long Shi, Wei Lin, Xing-Feng Yu, Jia-Yi Chen Department of Critical Care Medicine, Fuqing Hospital Affiliated to Fujian Medical University, Fuqing, Fujian, People’s Republic of ChinaCorrespondence: Jia-Yi Chen; Xing-Feng Yu, Fuqing Hospital Affiliated to Fujian Medical University, Qingrong Road No. 267, Fuqing, Fujian, 350300, People’s Republic of China, Tel +86 139 5912 0913, Email ChenJY199403@163.com; YXF120913@163.comIntroduction: Sepsis is one of the major diseases that seriously threatens human health, and its incidence and in-hospital morbidity and mortality rates remain high. Applying metagenomic next-generation sequencing (mNGS) technology to analyze the differences in pathogenic profiles and clinical factors in patients surviving and dying from sepsis combined with pulmonary infections provides diagnostic value and application for clinical purposes.Methods: Sixty-three BALF samples from patients with sepsis combined with pulmonary infection from Fuqing Hospital Affiliated to Fujian Medical University were collected, and all of them were tested by simultaneous mNGS and conventional microbial combined test (CMT) to compare the pathogenic profiles and clinical indices of patients who survived and died of sepsis combined with pulmonary infection and to further compare the diagnostic differences between mNGS and CMT in patients who survived and died of sepsis combined with pulmonary infection. We analyzed the diagnostic value of mNGS for sepsis combined with pulmonary infection.Results: A total of 141 strains of pathogens were isolated from 63 samples of patients with sepsis combined with pneumonia at suspected infection sites, Klebsiella pneumoniae, Acinetobacter baumannii, and Stenotrophomonas maltophilia are predominant, and higher ApacheII, LAC, P and PT are all risk factors affecting the death of septic patients.Conclusion: Applying the mNGS method to patients with sepsis combined with pneumonia can improve the positive detection rate of pathogenic microorganisms and focus on death-related risk factors such as pathogenic bacteria species as well as clinical laboratory indices, which can guide clinicians to take appropriate measures to treat patients with sepsis and reduce the occurrence of death.Keywords: sepsis, mNGS, clinical diagnosis, death, risk factors

Weiguang Lin,1,2 Yunlong Wang,1,2 Yanxiong Chen1,2 1Department of Urology, Renhui Clinic, Jiangmen, 529099, People’s Republic of China; 2Department of Urology, Renhui Frontline Clinic, Shenzhen, 518038, People’s Republic of ChinaCorrespondence: Yanxiong Chen, Department of Urology, Renhui Clinic, Jiangmen, 529099, People’s Republic of China, Email chenyanxionghbyd@163.comObjective: This study investigates the efficacy of physical therapy in treating chronic prostatitis grounded on the glandular duct blockage theory.Methods: The study includes patients who were diagnosed and treated for chronic prostatitis between November 2022 and July 2023 at Renhui clinic in Jiangmen, Guangdong and Renhui frontline clinic in Shenzhen Guangdong. The recorded data includes the frequency of physical therapies including prostate massages, rectal probe high-frequency vibration treatment, and low-intensity extracorporeal shockwave therapy (Li-ESWT). Post-treatment urine sediment was collected for microscopic examination, and the scores of each patient on the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) and the Premature Ejaculation Diagnostic Tool (PEDT) were recorded pre- and post-treatment in order to calculate the effectiveness rate.Results: The study involved a total of 48 patients, of which 26 were diagnosed with premature ejaculation. On average, each patient received 2.1 prostate massages, underwent 4.1 rectal probe high-frequency vibration treatments, and 8.3 Li-ESWT sessions. Following treatment, the initial microscopic examination of the urine sediment revealed aged white blood cell clusters, prostate calculi clusters, and inactive sperm clusters, all appearing in the shape of glandular tubes. The mean NIH-CPSI scores pre- and post-treatment were 27.2± 6.9 and 18.0± 6.6, respectively, indicating an effectiveness rate of 81.3%. The average PEDT scores pre- and post-treatment were 14.5± 3.5 and 10.5± 4.2, respectively, with an effectiveness rate of 53.8%.Conclusion: Unblocking obstructed glandular ducts might provide a novel therapeutic strategy for treating chronic prostatitis.Keywords: chronic prostatitis, low-intensity extracorporeal shockwave therapy, physical therapy, glandular duct

Wanqing Lin,1,* Hanyu Liang,2,* Huaibin Jiang,3,* Mohd Azrin Mohd Nasir,1,* Huiling Zhou2 1School of Applied Psychology, Social Work & Policy, UUM College of Arts & Sciences, University Utara Malaysia, Sintok, Malaysia; 2School of Medical Humanities, Guizhou Medical University, Guiyang, People’s Republic of China; 3Department of Psychology, Fujian Polytechnic Normal University, Fuqing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Huaibin Jiang; Mohd Azrin Mohd Nasir, Email jianghuaibin@126.com; mohdazrin@uum.edu.myPurpose: Harsh parenting is positively correlated with adolescents’ smartphone addiction, according to a growing corpus of studies. The various mediating processes that could underlie this link, however, are not well understood. Based upon the experiential avoidance model, the current research aimed to identify the relation between harsh parenting and adolescents’ smartphone addiction and the mediating roles of adolescents’ depression and experiential avoidance.Methods: We recruited 456 adolescents (female = 52.6%; Mage = 13.19 years, SD = 0.85) at a public junior high school in China to complete the harsh discipline scale, 90-item Hopkins symptom checklist, acceptance and action questionnaire version II, and smartphone addiction scale short version. SPSS24.0 was used to conduct independent samples t-test, descriptive statistics, Pearson correlation analysis and common method bias test, PROCESS were used to conduct a significance test of the chain mediation effect on the data. Age, gender, and grade were used as con-founders that were controlled in order to make cautious predictions.Results: The results showed that (1) harsh parenting was positively correlated with adolescents’ depression, experiential avoidance, and smartphone addiction; (2) both depression and experiential avoidance fully mediated the link between harsh parenting and smartphone addiction; and (3) depression and experiential avoidance also sequentially mediated the link between harsh parenting and smartphone addiction. These findings have significant implications for the prevention and intervention of adolescents’ smartphone addiction.Conclusion: These findings suggested that harsh parenting may have an indirect impact on smartphone addiction in both a simple way (parallel mediation) and a complicated way (serial mediation). In addition, these studies shed light on smartphone addiction prevention and intervention.Keywords: harsh parenting, depression, experiential avoidance, smartphone addiction, adolescents

Wenqian Lin,1– 3 Yongyong Yang,1– 3 Jun Lin,1– 3 Jianxing Chen,1– 3 Qun Lin1– 3 1Department of Anesthesiology, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, People’s Republic of China; 2Department of Anesthesiology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, People’s Republic of China; 3Anesthesiology Research Institute, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, People’s Republic of ChinaCorrespondence: Qun Lin, Department of Anesthesiology, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, People’s Republic of China, Email linqun008@163.comPurpose: To compare the effect of Dural puncture epidural (DPE) and conventional epidural (EP), in conjunction with programmed intermittent epidural bolus (PIEB) and low-concentration ropivacaine strategy.Methods: After written informed consent was obtained, healthy nulliparous women with singleton pregnancies, vertex presentation at 38– 42 weeks’ gestation, cervical dilation of 3– 5 cm, and a desire for pain relief were randomly assigned to DPE or EP group. Dural matter was puncture with 25G Whitacre needle in DPE group. Analgesia was initiated with 15 mL of 0.1% ropivacaine over 5 minutes and was maintained by PIEB (8 mL of 0.08% ropivacaine with 2 μg/mL fentanyl every 40 min). Primary outcome was the percentage of adequate analgesia, defined as NRPS ≤ 1, at 30 minutes after the initiation of the epidural bolus.Results: Out of 130 enrolled parturients, 127 were included in final analysis (64 in DPE group, 63 in EP group). No significant difference was found in percentage of adequate analgesia at 30 minutes (risk ratio: 1.09; 95% confidence interval: 0.90– 1.31; P = 0.366). At 8, 12, 14, and 16 minutes, percentage of adequate analgesia was higher in DPE group (P = 0.023, 0.027, 0.016 and 0.033, respectively). NPRS scores in DPE group decreased more dramatically within the first 30 min. The incidence of S2 sensory blocks at 20 and 30 min in DPE group was higher (P = 0.010 and 0.006, respectively). There were no differences in patient satisfaction, delivery mode, adverse effects, fetal bradycardia, and Apgar scores at 1 and 5 minutes.Conclusion: The combination of the use of DPE technique with 25G spinal needle and PIEB technique for labor analgesia appears to enhance the quality of labor analgesia by accelerating onset and providing improved sacral blockade, without increasing adverse effects.Keywords: dural puncture epidural, labor analgesia, programmed intermittent bolus, ropivacaine

Xiaoyu Huang,1,2 Ming Zhang,1,3 Lin Chang,1,2 Dali Zheng,2 Wei Lin,4 Yan Feng,1,2 Youguang Lu1,2 1Department of Preventive Dentistry, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, Fujian Province, People’s Republic of China; 2Fujian Key Laboratory of Oral Diseases, School of Stomatology, Fujian Medical University, Fuzhou, Fujian Province, People’s Republic of China; 3Department of Conservative and Endodontic Dentistry, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, Fujian Province, People’s Republic of China; 4College of Chemistry, Fuzhou University, Fuzhou, Fujian Province, People’s Republic of ChinaCorrespondence: Youguang Lu, Tel +86-591-83736429, Fax +86-591-83720599, Email fjlyg63@fjmu.edu.cn; Yan Feng, Tel/Fax +86-591-22862632, Email fengyan@fjmu.edu.cnObjective: The study aims to enhance the anti-caries performance of pit and fissure sealants through the synthesis of novel silver nanocomposites, and to evaluate their mechanical properties and biological safety in vitro and in vivo.Methods: The antibacterial properties of synthetic eggshell/Ag were detected by bacterial inhibition zone, minimum bacteriostatic concentration, fluorescence staining and scanning electron microscopy. The synthetic products were then combined with pit and fissure sealants to prepare specimens, and their effects on mechanical properties, antibacterial properties and cytotoxicity were evaluated. Furthermore, an oral mucosal contact model of golden hamsters was established according to the ISO10933 standard to evaluate local stimulation and systemic effects.Results: The novel nanocomposite eggshell/Ag was confirmed to exhibit strong broad-spectrum antibacterial activity, and that the eggshell/Ag-modified pit and fissure sealant had strong antibacterial properties against common dental caries bacterial biofilms, without any significant change in mechanical properties. The gradient dilution extract showed acceptable cytotoxicity, and in the golden hamster oral contact model, there were no visible abnormalities in local mucosal tissues, blood indices, or liver and kidney histopathology.Conclusions: These findings suggest that eggshell/Ag combined with pit and fissure sealants has strong antibacterial activity and excellent biosafety in vitro and in vivo, making it a promising candidate for clinical applications.Keywords: silver nanocomposites, antibacterial, pit and fissure sealants, biosafety

Guanxiang Huang,1– 3,* Hangjing Gao,1– 3,* Yanlin Chen,1,2 Wenyu Lin,1– 3 Jun Shen,4 Shuxia Xu,5 Dabin Liu,6 Zhihui Wu,7 Xite Lin,1– 3 Tingting Jiang,1– 3 Binhua Dong,1– 3 Pengming Sun1– 3 1Laboratory of Gynecologic Oncology, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, Fujian, 350001, People’s Republic of China; 2Fujian Key Laboratory of Women and Children’s Critical Diseases Research, Fujian Maternity and Child Health Hospital (Fujian Women and Children’s Hospital), Fuzhou, Fujian, 350001, People’s Republic of China; 3Fujian Clinical Research Center for Gynecological Oncology, Fujian Maternity and Child Health Hospital (Fujian Obstetrics and Gynecology Hospital), Fuzhou, Fujian, 350001, People’s Republic of China; 4Fujian Provincial Cervical Disease Diagnosis and Treatment Health Center, Fujian Maternity and Child Health Hospital, Fujian Maternity and Child Health Hospital, Fuzhou, Fujian, 350001, People’s Republic of China; 5Department of Pathology, Fujian Maternity and Child Health Hospital, Fuzhou, Fujian, 350001, People’s Republic of China; 6Department of Gynecology, Fujian Maternity and Child Health Hospital, Fuzhou, Fujian, 350001, People’s Republic of China; 7Department of Clinical Laboratory, Fujian Maternity and Child Health Hospital, Fuzhou, Fujian, 350001, People’s Republic of China*These authors contributed equally to this workCorrespondence: Pengming Sun; Binhua Dong, Laboratory of Gynecologic Oncology, Department of Gynecology, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, Fujian, 350001, People’s Republic of China, Tel +86-591-87558732 ; +86-13599071900, Fax +86-591-87551247, Email fmsun1975@fjmu.edu.cn; sunfemy@hotmail.com; dongbinhua86@fjmu.edu.cn; dbh18-jy@126.comPurpose: The platelet-to-lymphocyte ratio (PLR) is considered correlated with cancer prognosis including cervical cancer, in addition to high-risk papillomavirus (HR-HPV) infection, of which the predictive value in prognosis of high-grade squamous intraepithelial lesions (HSILs) remains unknown. Here, the prognostic predictive value of PLR in HSIL after loop electrosurgical excision procedure (LEEP) was evaluated.Patients and Methods: This study included 335 nonpregnant participants with histopathologically confirmed HSIL and 3- and 5-year follow-ups from the Fujian Cervical Lesions Screening Cohorts (FCLSCs) between September 2016 and September 2018. PLR and other variables were evaluated to identify the factors related to the recurrence/residual cervical intraepithelial neoplasia (CIN)-free survival (RFS), namely, the time from LEEP at baseline to first detection of recurrence/residual CIN or end of follow-up, by logistic and Cox regression.Results: In the Kaplan‒Meier analysis, HR-HPV infection (p=0.049/0.012), higher PLR (p=0.031/0.038), and gland invasion (p=0.047) had a higher risk for recurrence/residual CIN at the 3-/5-year follow-up. The univariate logistic and Cox regression analyses showed significant differences and a higher cumulative risk in patients with HR-HPV infection (OR=3.917, p=0.026; HR=3.996, p=0.020) and higher PLR (OR=2.295, p=0.041; HR=2.161, p=0.030) at the 5-year follow-up. The findings by multivariate Cox regression analysis were similar, indicating a poor prognosis for patients with HR-HPV infection (HR=3.901, p=0.023) and higher PLR (HR=2.082, p=0.038) at the 5-year follow-up. The calibration plot showed a better model fit for RFS at the 3-year follow-up.Conclusion: Preoperative PLR level and HR-HPV infection could be available markers for predicting recurrence/residual disease of HSIL after LEEP. Clinically, combining PLR with HR-HPV tests may provide novel evaluation method and reference for management in post-treatment patients with cervical precancerous lesions.Keywords: systemic inflammatory response, cervical intraepithelial neoplasia, human papillomavirus, HPV, conization, prognosis

Wenkai Chen,1,2,* Wenping Lin,3,* Naichun Yu,1,2,* Linlin Zhang,1,2,* Zuoxing Wu,2 Yongjie Chen,1,2 Zongguang Li,1,2 Fengqing Gong,1,2 Na Li,2 Xiaohui Chen,4 Xu He,3 Yue Wu,5 Xiangchen Zeng,1,2 Yuting Yueh,1,2 Ren Xu,2,4,6,* Guangrong Ji1,2,* 1Department of Orthopedic Surgery, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, People’s Republic of China; 2Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, Xiamen Key Laboratory of Regeneration Medicine, Organ Transplantation Institute of Xiamen University, School of Medicine, Xiamen University, Xiamen, People’s Republic of China; 3Department of Spine Surgery, Shenzhen Pingle Orthopedic Hospital, Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Shenzhen, People’s Republic of China; 4Department of Orthopedic Surgery, The First Affiliated Hospital of Xiamen University, Xiamen, People’s Republic of China; 5Department of Pathology, Zhongshan Hospital, Xiamen University, Xiamen, People’s Republic of China; 6Collaborative Innovation Centre of Regenerative Medicine and Medical BioResource Development and Application Co-Constructed by the Province and Ministry, Guangxi Medical University, Nanning, People’s Republic of China*These authors contributed equally to this workCorrespondence: Guangrong Ji; Ren Xu, Department of Orthopedic Surgery, Xiang’an Hospital of Xiamen University, No. 2000, Xiang’an East Road, Xiang’an District, Xiamen, 361000, People’s Republic of China, Tel +86-15710667257, Fax +86592-2889000, Email jiguangrong@xmu.edu.cn; xuren526@xmu.edu.cnPurpose: To investigate induction of cell death in Osteosarcoma (OS) using the anti-tuberculosis drug, rifampicin, loaded into exosomes.Patients and Methods: BMSC-exosomes were isolated by ultracentrifugation and loaded ultrasonically with rifampicin. Nanoparticle exosome-rifampicin (EXO-RIF) was added to the OS cell-lines, 143B and MG63, in vitro, to observe the growth inhibitory effect. In vivo experiments were conducted by injecting fluorescently labeled EXO-RIF through the tail vein of 143B cell xenograft nude mice and tracking distribution. Therapeutic and toxic side-effects were analyzed systemically.Results: Sonication resulted in encapsulation of rifampicin into exosomes. Exosome treatment accelerated the entry of rifampicin into OS cells and enhanced the actions of rifampicin in inhibiting OS proliferation, migration and invasion. Cell cycle arrest at the G2/M phase was observed. Dynamin-related protein 1 (Drp1) was activated by EXO-RIF and caused mitochondrial lysis and apoptosis. Exosome treatment targeted rifampicin to the site of OS, causing OS apoptosis and improving mouse survival in vivo.Conclusion: The potent Drp1 agonist, rifampicin, induced OS apoptosis and exosome loading, improving OS targeting and mouse survival rates. EXO-RIF is a promising strategy for the treatment of diverse malignancies.Graphical Abstract: Keywords: bone tumor, drug delivery, exosomes, mesenchymal stem cells, survival

Junfeng Chen,* Wei Lin,* Haiting Gu, Kangtai Ying, Tingjian Li, Haiyan Shao Department of Respiration, The First People’s Hospital of Wenling, Wenling, Zhejiang, 317500, People’s Republic of China*These authors contributed equally to this workCorrespondence: Haiyan Shao, Department of Respiration, The First People’s Hospital of Wenling, 333 Chuanan Nan Road, Chengxi Street, Wenling, Zhejiang, 317500, People’s Republic of China, Tel +86 057689668688, Email shaohy_101043@tzc.edu.cnObjective: This study aimed to compare lung function and airway inflammation among cough variant asthma (CVA), chronic cough and classical asthma (CA) and investigate the relationship between these indicators and their possible mechanisms of action in the progression of CVA to CA.Methods: 36 patients with chronic cough, 39 patients with CA, and 57 patients with CVA were included in this study. Pulmonary function tests, bronchial provocation tests and FeNO tests were performed. The patients’ bronchoalveolar lavage fluid (BALF) was collected, the cells in BALF were counted, and the levels of Th1 and Th2 cytokines were detected.Results: The neutrophils, lymphocytes, and eosinophils in BALF in the CA and CVA groups were significantly higher than those in the chronic cough group. Also, they were negatively correlated with FEV1, FVC, and FEV1/FVC and positively correlated with IgE and FeNO. The expression of Th2-related cytokines was increased in CVA and CA patients, and it was positively correlated with FEV1, FVC and FEV1/FVC and negatively correlated with IgE and FeNO, while the results of Th1-related cytokines were the opposite of those for Th2-related cytokines.Conclusion: CVA differs from asthma and chronic cough in terms of Th1/Th2 cytokines and lung function and provides a reference for understanding the disease mechanism of early clinical progression of CVA to CA.Keywords: cough variant asthma, cytokines, pulmonary function, Th1/Th2 balance, cell classified count

Yongxin Yi,1 Jiayang Fang,1 Yunzhu Liu,1 Yidong Gao,1 Weizhi Lin,1 Dongdong Hao,2 Xing Zhang,3,4 Min Zhang1 1Department of Encephalopathy, the Third People’s Hospital Affiliated to Fujian University of Traditional Chinese Medicine, Fuzhou, People’s Republic of China; 2Department of Outpatient, Lanzhou 7th Rest Center for Retired Cadre, Gansu Military Region, Lanzhou, People’s Republic of China; 3Department of Medicine, the State Key Laboratory of Translational Medicine and Innovative Drug Development, Jiangsu Simcere Diagnostics Co., Ltd, Nanjing, People’s Republic of China; 4Department of Medicine, Nanjing Simcere Medical Laboratory Science Co., Ltd, Nanjing, People’s Republic of ChinaCorrespondence: Min Zhang, Department of Encephalopathy, the Third People’s Hospital Affiliated to Fujian University of Traditional Chinese Medicine, Fuzhou, People’s Republic of China, Email minzhang_2018@163.comIntroduction: There is no effective treatment plan for coronavirus disease 2019 (COVID-19). We employed a combination of Chinese and Western medicine treatment for some COVID-19 inpatients.Methods: This study was a prospective cohort study that observed non-critical COVID-19 inpatients. The differences will be observed in the time from admission to two consecutive 2019-nCoV nucleic acid test negatives and the Visual Analog Scale (VAS) score between the two groups.Results: A total of 254 confirmed COVID-19 patients were included in this study. The median time from the admission to two consecutive negative nucleic acid tests was 14 days for the integrated Chinese and Western Medicine (ICWM) group, while the Western Medicine (WM) group was 16 days. Besides, the median VAS score of the ICWM group was 0, which was an average decrease of 2 points compared to the time of admission.Conclusion: For non-critical COVID-19 patients, it was safe and have more benefits to add traditional Chinese medicine decoction based on WM treatment.Keywords: clinical characteristics, COVID-19 inpatients, efficacy, integrated Chinese and Western medicine treatment

Wei Lin,1,2 Wenjun Ren,1,2 Hao Chen,1,2 Yong Wei1,2 1School of Ophthalmology and Optometry, Eye Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of China; 2State Key Laboratory of Optometry, Ophthalmology, and Vision Science, Affiliated Eye Hospital, Wenzhou Medical University, Wenzhou, People’s Republic of ChinaCorrespondence: Yong Wei, School of Ophthalmology and Optometry, Eye Hospital of Wenzhou Medical University, No. 270, Xueyuan West Road, Wenzhou, 325027, People’s Republic of China, Email weiyongdoctor@163.comBackground: To explore the impacts of surgeons’ experience in patients with epiretinal membrane (ERM).Methods: Patients with idiopathic ERM (334 eyes) who underwent PPV and membrane peeling were included in this study. The surgeries were performed by 9 surgeons. Patients were categorized into the experienced group (surgeons who had performed more than 5000 cases of PPV) and the regular group (surgeons who had performed less than 1000 cases of PPV). The patients were also categorized into five groups according to different preoperative best corrected visual acuity (BCVA): 20/100 or worse, 20/70-20/50, 20/40-20/30, 20/25 and 20/20. Impacts of preoperative BCVA, surgeons’ experience, lens status, and internal limiting membrane (ILM) peeling on postoperative BCVA were analyzed.Results: The postoperative BCVA was significantly better at 1 week and 1 month in the experienced group compared to the regular group (p = 0.022 and 0.045, respectively). There were no significant differences in postoperative BCVA at 3 months and 6 months between the two groups (p = 0.268 and 0.233, respectively). Postoperative BCVA at 6 months was similar in the 20/25 group and 20/20 group (p = 0.063); both groups had better BCVA compared to the other three groups. The 20/100 or worse group had the greatest visual improvement among the 5 groups at 6 months.Conclusion: This study suggested that although the experience of surgeons had no significant impact on the final BCVA following PPV and ERM removal, the BCVA during the early postoperative phase appeared to be better in the experienced group.Keywords: surgeons’ experience, epiretinal membrane, pars plana vitrectomy, best corrected visual acuity

Siwei Xing,1,* Xiaohao Ruan,1,* Jingyi Huang,1,* Jiaqi Yan,1 Wenhao Lin,1 Jinlun Huang,1 Jiacheng Liu,1 Da Huang,1 Rong Na,2 Danfeng Xu1 1Department of Urology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 2Division of Urology, Department of Surgery, Queen Mary Hospital, The University of Hong Kong, Hong Kong, People’s Republic of China*These authors contributed equally to this workCorrespondence: Rong Na, Division of Urology, Department of Surgery, Queen Mary Hospital, The University of Hong Kong, 102 Pok Fu Lam Road, Hong Kong, People’s Republic of China, Email narong.hs@gmail.com Da Huang, Department of Urology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, People’s Republic of China, Email huangdasjtu@gmail.comPurpose: To explore the impact of family history (FH) on renal cell carcinoma (RCC) and its pathological subtype clear cell RCC (ccRCC) in a Chinese population; a significant association has previously been determined not only in familial cancer syndrome but also in sporadic cases in western populations.Methods: Consecutive patients with kidney tumors from October 2017 to May 2021 at a tertiary hospital in Shanghai were enrolled in the study. Demographic and clinical information was collected, including age, gender, FH (positive or negative, types of cancers, degree of relatives, etc.), pathological diagnosis, and Fuhrman grades.Results: A positive FH of any cancer was observed in 26.5% of the RCC patients, while only 16.8% patients with benign kidney tumor were found to have a positive FH. A strong correlation was observed between FH of any cancers in first-degree relatives and RCC (odds ratio [OR]=4.60, 95% confidence interval [CI]: 1.95– 10.85, P=5.50× 10− 5) or ccRCC (OR=4.63, 95% CI: 1.95– 11.02, P=9.63× 10− 5). In subgroup analysis, FH of digestive cancers was significantly associated with RCC (OR=4.42, 95% CI: 1.35– 14.51, P=0.005) or ccRCC (OR=4.14, 95% CI: 1.25– 13.75, P=6.84× 10− 4). Similar results were found in multivariate analyses. However, no significant association was observed between FH and age at onset.Conclusion: FH was an independent risk factor for RCC and ccRCC in this Chinese population. FH of any cancer in first-degree relatives and FH of digestive cancers were found to be the most significant risk factors for kidney cancers.Keywords: Chinese population, family history, renal cell carcinoma, risk factor, multivariate regression analysis

Lei Wang,1 Shuying Lv,1,2 Wenjun Lin,1,2 Dingquan Yang1 1Department of Dermatology, China-Japan Friendship Hospital, Beijing, People’s Republic of China; 2School of Clinical Medicine, Beijing University of Chinese Medicine, Beijing, People’s Republic of ChinaCorrespondence: Dingquan Yang, Department of Dermatology, China-Japan Friendship Hospital, Beijing, People’s Republic of China, Tel +86 13901218671, Email ydqlx@163.comAbstract: Linear scleroderma en coup de sabre (LSCS) is a variant of localized scleroderma associated with band-like fibrotic lesions in the frontoparietal area. We report a case of LSCS in a woman who presented with progressive mild hyperchromia on the right side of her forehead, with dermal atrophy and hair and eyebrow loss. After the failure of conservative treatments, the patient responded dramatically to injection of autologous localized concentrated growth factor. After three treatments, the atrophy, stiffness, and angiotelectasis on the affected area had improved. No recurrence was detected 24 months after the last treatment. This is the first study describing the use of autologous concentrated growth factor injection to alleviate clinical symptoms of LSCS. This suggests that concentrated growth factor may be a treatment for LSCS in the clinic.Keywords: concentrated growth factor, linear scleroderma en coup de sabre

Yiyang Zhou,1,* Wei Lin,1,* Tian Rao,1 Jinyu Zheng,2 Tianlei Zhang,1 Min Zhang,1 Zhenlang Lin1 1Department of Pediatrics, The Second School of Medicine, Taizhou Women and Children’s Hospital of Wenzhou Medical University, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, People’s Republic of China; 2Department of Clinical Medicine, Wenzhou Medical University, Wenzhou, 325000, Zhejiang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhenlang Lin, Email lzlprof2020@163.comAbstract: Ferroptosis is a novel regulated cell death characterized by metabolic disorders and iron-dependent oxidative destruction of the lipid bilayer. It is primarily caused by the imbalance of oxidation and anti-oxidation in the body and is precisely regulated by numerous factors and pathways inside and outside the cell. Recent studies have indicated that ferroptosis plays a vital role in the pathophysiological process of multiple systems of the body including the nervous system. Ferroptosis may be closely linked to the occurrence and development of neurodegenerative diseases, strokes, and brain tumors. It may also be involved in the development, maturation, and aging of the nervous system. Therefore, this study aims to investigate ferroptosis’s occurrence and regulatory mechanism and summarize its research progress in the pathogenesis and treatment of neurological diseases. This would allow for novel ideas for basic and clinical research of neurological diseases.Keywords: ferroptosis, iron, lipid peroxidation, molecular mechanism, neurodevelopment, neurological diseases

Libo Wang,1 Gan Li,1 Chang Yuan,1 Yuele Yang,1 Gongxia Ling,1 Jinyu Zheng,1 Yiyang Zhou,1 Tianlei Zhang,1 Wei Lin,2 Zhenlang Lin2 1Department of Clinical Medicine, Wenzhou Medical University, Wenzhou, 325000, Zhejiang, People’s Republic of China; 2Department of Pediatrics, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, People’s Republic of ChinaCorrespondence: Wei Lin; Zhenlang Lin Email linwei1110@163.com; lzlprof2020@163.comAbstract: Coronavirus disease 2019 (COVID-19) has been circulating in many countries around the world, characterized by long incubation period, strong infectivity, strong variability, high population susceptibility and diversified transmission methods. Its causative agent is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Compared with adult patients, the clinical manifestations of COVID-19 in children are often dominated by mild or asymptomatic infections, but children are also important virus carriers and play an important role in the transmission of the virus. In addition, some children will show excessive inflammatory response and experience serious complications such as multisystem inflammatory syndrome in children (MIS-C). At present, the research on COVID-19 in children is still imperfect. This article will review epidemiological characteristics, the mechanism of action, variant characteristics, clinical manifestations, auxiliary examinations and treatment of children with COVID-19, in order to provide help for the diagnosis, treatment and research of children with COVID-19.Keywords: children, COVID-19, mutation, clinical manifestations, treatment

Miao Chen,1,2 Weimin Lin,1 Jianru Yi,1,2 Zhihe Zhao1,2 1State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, People’s Republic of China; 2Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, People’s Republic of ChinaCorrespondence: Jianru Yi; Zhihe Zhao Tel +86-28-85503040; +86-28-85503645Email jianruyi@scu.edu.cn; zhzhao@scu.edu.cnPurpose: Genetic factors in type 2 diabetes (T2D) pathogenesis have been widely explored by the genome-wide association studies (GWAS), identifying a great amount of susceptibility loci. With the development of high-resolution sequencing, the N(6)-methyladenosine (m6A) RNA modification has been proved to be affected by genetic variation. In this study, we identified the T2D-associated m6A-SNPs from T2D GWAS data and explored the underlying mechanism of the pathogenesis of T2D.Methods: We examined the association of m6A-SNPs with T2D among large-scale T2D GWAS summary statistics and further performed multi-omics integrated analysis to explore the potential role of the identified m6A-SNPs in T2D pathogenesis.Results: Among the 15,124 T2D-associated m6A-SNPs, 71 of them reach the genome-wide significant threshold (5.0e-05). The leading SNP rs4993986 (C>G), which is located near the m6A modification site at the 3ʹ end of the HLA-DQB1 transcript, is expected to participate in the pathogenesis of T2D by influencing m6A modification to regulate the HLA-DQB1 expression.Conclusion: The current study has suggested a potential correlation between m6A-SNPs and T2D pathogenesis and also provided new insights into the pathogenic mechanism of the T2D susceptibility loci identified by GWAS.Keywords: type 2 diabetes, single nucleotide polymorphism, epigenetics, m6A, genome-wide association study

Tong Liu,1,* Meng Feng,2,* Zexin Wen,3 Yijie He,1 Wei Lin,2 Min Zhang1 1Department of Medicine, Xizang Minzu University, Xianyang, Shaanxi, People’s Republic of China; 2School of Basic Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, People’s Republic of China; 3Department of Clinical Medicine, Fujian Medical University, Fuzhou, Fujian, People’s Republic of China*These authors contributed equally to this workCorrespondence: Min ZhangDepartment of Medicine, Xizang Minzu University, Xianyang, People’s Republic of ChinaTel +86 2918681997994Email zhangmin-wen@163.comWei LinSchool of Basic Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, People’s Republic of ChinaTel +86 53115098926353Email linw1978@163.comAbstract: Cytokine storm (CS) is a significant cause of death in patients with severe coronavirus pneumonia. Excessive immune–inflammatory reaction, many inflammatory cell infiltration, and extreme increase of proinflammatory cytokines and chemokines lead to acute lung injury and acute respiratory distress syndrome (ARDS). This review compares the characters of cytokine storms and immune responses caused by three highly pathogenic and infectious coronaviruses (HCoVs), including severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome-coronavirus (MERS-CoV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and analyzes the possible mechanisms to guide clinical treatment in the future.Keywords: cytokines, coronavirus pneumonia, cytokine storm, immune evasion, interferon

Lizhi Chen,1,* Yunyun Yang,1,2,* Xuebin Wang,1,* Chenyu Wang,2 Weiwei Lin,3 Zheng Jiao,2,4 Zhuo Wang1 1Department of Pharmacy, Shanghai Changhai Hospital, Naval Medical University, Shanghai, 200433, People’s Republic of China; 2Department of Pharmacy, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200030, People’s Republic of China; 3Department of Pharmacology, The First Affiliated Hospital, Fujian Medical University, Fuzhou, People’s Republic of China; 4Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai, 200040, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zheng JiaoDepartment of Pharmacy, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 Huaihai West Road, Shanghai, 200030, People’s Republic of ChinaTel +86 21 2220 0000 ext 3021Email jiaozhen@online.sh.cnZhuo WangDepartment of Pharmacy, Shanghai Changhai Hospital, Naval Medical University, 168 Changhai Road, Shanghai, 200433, People’s Republic of ChinaTel/Fax +86-21-31162299Email wztgyx223@163.comPurpose: In this study, we aimed to establish a tacrolimus population pharmacokinetic model and better understand the drug-drug interaction between Wuzhi capsule and tacrolimus in Chinese renal transplant recipients.Patients and Methods: We performed a population pharmacokinetic analysis using a non-linear mixed-effects model to determine the suitable Wuzhi capsule dose in combination with tacrolimus. Data on 1378 tacrolimus steady-state concentrations were obtained from 142 patients who received kidney transplant in Changhai Hospital and Huashan Hospital. Demographic characteristics, laboratory tests, genetic polymorphisms, and co-medications were evaluated.Results: The one-compartment model best described data. Our final model identified creatinine clearance rate, hematocrit, Wuzhi capsule dose, CYP3A5*3 genetic polymorphisms, and tacrolimus daily dose as significant covariates for tacrolimus clearance, with the value of 14.4 L h− 1, and the between-subject variability (BSV) was 25.4%. The Wuzhi capsule showed a dose-dependent effect on tacrolimus pharmacokinetics, demonstrating a stronger inhibitory effect than inductive effect.Conclusion: Our model can accurately describe population pharmacokinetics of tacrolimus when combined with different doses of Wuzhi capsule. Additionally, this model can be used for individualizing tacrolimus dose following kidney transplantation.Keywords: renal transplantation, inhibitory effect, one-compartment model, CYP3A5

Hanbin Zhang,1 Wenrui Lin,2 Dongting Chen,1 Kenie Wang,3 Wei Tu,4 Huiwen Lin,4 Kun Li,4 Shangzhu Ye,5 Tianwang Guan,6 Yuerong Chen4 1Department of Clinical Medicine, The Second Clinical College of Guangzhou Medical University, Guangzhou, People’s Republic of China; 2Department of Clinical Medicine, The Sixth Clinical College of Guangzhou Medical University, Guangzhou, People’s Republic of China; 3The First Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, People’s Republic of China; 4Department of Oncology, Jinshazhou Hospital of Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; 5Department of Ophthalmology and Otorhinolaryngology, Yangjiang Hospital of Traditional Chinese Medicine, Yangjiang, People’s Republic of China; 6Department of Cardiology, Laboratory of Heart Center, Zhujiang Hospital, Southern Medical University, Guangzhou, People’s Republic of ChinaCorrespondence: Tianwang GuanDepartment of Cardiology, Laboratory of Heart Center, Zhujiang Hospital, Southern Medical University, Guangzhou, People’s Republic of ChinaTel +8620-61643888Email guantianwang@163.comYuerong ChenDepartment of Oncology, Jinshazhou Hospital of Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of ChinaTel +8620-81116661Email 604910344@qq.comPurpose: Male breast cancer (MBC) is a rare disease that tends to occur in elderly men. Little is known about the causes of death in MBC because of the small sample size of most studies. This study aimed to investigate the causes of death in MBC patients.Patients and Methods: MBC patient data were obtained from the Surveillance, Epidemiology, and End Results database (1975– 2016). Time trends of MBC mortality in the US population were analyzed using Joinpoint software. We calculated the proportion of each cause of death in the overall cohort and in different patient subgroups. Competing risk models were used to calculate cumulative mortality at different follow-up times. The risk of cardiovascular death (CVD) in MBC patients was compared to that of the age-matched general population by calculating standardized mortality ratio (SMR).Results: In total, 6426 patients were included in the analysis. MBC mortality rate increased between 2004 and 2019 (annual percentage change=1.16, 95% confidence interval [CI]: 0.50, 1.80). There were 1757 patients (27.3%) who died of non-breast cancer causes. CVD was the leading cause of death in patients who were elderly or had localized disease. MBC patients had a 6.58-fold higher risk of CVD than the general population (SMR=6.58, 95% CI: 6.14, 7.05).Conclusion: Non-breast cancer death accounts for the majority of deaths in MBC patients who are elderly or have localized cancer. Compared to the general population, MBC patients have an increased risk of CVD. These results highlight the importance of monitoring cardiovascular comorbidities in MBC patients.Keywords: male breast cancer, cardio-oncology, elderly patients, cause of death, non cancer death, cardiovascular death

Wei Lin,1 Tianlei Zhang,1 Yiyang Zhou,2 Jinyu Zheng,2 Zhenlang Lin1 1Department of Pediatrics, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, People’s Republic of China; 2Wenzhou Medical University, Wenzhou, 325000, Zhejiang, People’s Republic of ChinaCorrespondence: Zhenlang LinDepartment of Pediatrics, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, People’s Republic of ChinaEmail lzlprof2020@163.comAbstract: Fibroblast growth factor 21 (FGF21) regulates many crucial biological processes in human and mammals, particularly metabolic modulation and protective effect after injury. Therefore, determining complex regulatory mechanisms and elucidating the signaling pathway may greatly promote the prevention, diagnosis, and treatment of related injury and metabolic diseases. This review focused on the metabolic modulation and protective effect of FGF21 and summarized the molecular mechanisms and clinical research developments.Keywords: fibroblast growth factor 21, molecular mechanisms, metabolic modulation, protective effect, clinical application

Weihong Lin,* Zuopeng Wang,* Jing Wang, Hanlei Yan, Qilei Han, Wei Yao, Kai Li Department of Pediatric Surgery, Children’s Hospital of Fudan University, National Children’s Medical Center, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Kai LiDepartment of Pediatric Surgery, Children’s Hospital of Fudan University, National Children’s Medical Center, 399 Wan yuan Road, Shanghai, 201102, People’s Republic of ChinaTel +86 21 64931212Fax +86 21 64931211Email likai2727@163.comObjective: The roles of circRNAs in neuroblastoma (NB) are unclear. We used next-generation sequencing to detect the circRNA expression profiles in NB to identify the key circRNAs and analyzed the relationships between the circRNAs and clinical features.Methods: Five paired neuroblastoma tumor and adjacent normal fetal adrenal medulla samples were collected for high-throughput RNA sequencing. Bioinformatics analysis was performed for functional annotation of the host genes of differentially expressed circRNAs. Validation of dysregulated circRNAs was performed by real-time quantitative reverse transcription polymerase chain reaction. The relationships between the key circRNAs and clinical features were analyzed. In addition, overexpression of key circRNAs in an NB cell line, as well as cell proliferation assays, colony formation assays and cell migration assays, was conducted to investigate the biological functions of key circRNAs.Results: A total of 4704 differentially expressed circRNAs were found, including 2462 up-regulated and 2242 down-regulated circRNAs. According to our previous studies, the predicted target circRNAs of miR-21 involved in tumorigenic signaling pathways were selected, including circRNA-TBC1D4, circRNA-NAALAD2 and circRNA-TGFBR3. These circRNAs were associated with clinical features, and the circRNA expression was significantly lower (P < 0.05) in the NB tissues than in normal adrenal tissues. Overexpression of circRNA-TBC1D4 promotes NB cell migration, but not proliferation and colony-formation in vitro.Conclusion: We suggest that circRNA-TBC1D4, circRNA-NAALAD2 and circRNA-TGFBR3 may be cancer suppressor genes, which act by sponging miR-21 in NB. Further investigations are needed to elucidate the underlying mechanism.Keywords: neuroblastoma, circRNA, circRNA-TBC1D4, miR-21

Wenfeng Lin,1,* Chaoming Li,1,2,* Naijin Xu,1,3 Masami Watanabe,1,4 Ruizhi Xue,1 Abai Xu,2 Motoo Araki,1 Ruifen Sun,5 Chunxiao Liu,2 Yasutomo Nasu,1 Peng Huang1,2,6 1Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan; 2Department of Urology, Zhujiang Hospital, Southern Medical University, Guangzhou, People’s Republic of China; 3Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 4Center for Innovative Clinical Medicine, Okayama University Hospital, Okayama, Japan; 5Center for Scientific Research, Yunnan University of Chinese Traditional Medicine, Kunming, People’s Republic of China; 6Okayama Medical Innovation Center, Okayama University, Okayama, Japan*These authors contributed equally to this workCorrespondence: Peng HuangDepartment of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8558, JapanTel + 81-86-235-7997Fax +81-86-235-7884Email huangpeng509@gmail.comPurpose: With the advance of screening techniques, there is a growing number of low-risk or intermediate-risk prostate cancer (PCa) cases, remaining a serious threat to men’s health. To obtain better efficacy, a growing interest has been attracted to develop such emerging treatments as immunotherapy and focal therapy. However, few studies offer guidance on whether and how to combine these modalities against PCa. This study was designed to develop dual-functional nanoparticles (NPs) which combined photothermal therapy (PTT) with immunotherapy and determine the anti-tumor efficacy for PCa treatment.Methods: By a double emulsion technique, the drug nanocarrier, poly(lactic-co-glycolic acid) or PLGA, was applied for co-loading of a fluorescent dye, indocyanine green (ICG) and a toll-like receptor 7/8 (TLR7/8) agonist resiquimod (R848) to synthesize PLGA-ICG-R848 NPs. Next, we determined their characteristic features and evaluated whether they inhibited the cell viability in multiple PCa cell lines. After treatment with PLGA-ICG-R848, the maturation markers of bone marrow-derived dendritic cells (BMDCs) were detected by flow cytometry. By establishing a subcutaneous xenograft model of mouse PCa, we explored both the anti-tumor effect and immune response following the NPs-based laser ablation.Results: With a mean diameter of 157.7 nm, PLGA-ICG-R848 exhibited no cytotoxic effect in PCa cells, but they significantly decreased RM9 cell viability to (3.9± 1.0)% after laser irradiation. Moreover, PLGA-ICG-R848 promoted BMDCs maturation with the significantly elevated proportions of CD11c+CD86+ and CD11c+CD80+ cells. Following PLGA-ICG-R848-based laser ablation in vivo, the decreased bioluminescent signals indicated a significant inhibition of PCa growth, while the ratio of splenic natural killer (NK) cells in PLGA-ICG-R848 was (3.96± 1.88)% compared with (0.99± 0.10)% in PBS group, revealing the enhanced immune response against PCa.Conclusion: The dual-functional PLGA-ICG-R848 NPs under laser irradiation exhibit the anti-tumor efficacy for PCa treatment by combining PTT with immunotherapy.Keywords: prostate cancer, PLGA, indocyanine green, resiquimod, photothermal therapy, immunotherapy

Wenxiang Lin,1,2 Libei Zhao,2 Qian Tan,1,2 Ding Lin1,2 1Department of Ophthalmology, Changsha Aier Eye Hospital, Aier School of Ophthalmology, Central South University, Changsha, People’s Republic of China; 2Department of Ophthalmology, Changsha Aier Eye Hospital, Central South University, Changsha, People’s Republic of ChinaCorrespondence: Ding LinDepartment of Ophthalmology, Changsha Aier Eye Hospital, Aier School of Ophthalmology, Central South University, Changsha, People’s Republic of ChinaTel +86-13787255158Email linding@csu.edu.cnPurpose: Efficacy of norvancomycin (NVCM) through continuous topical ocular instillation drug delivery (CTOIDD) system for treating severe acute bacterial keratitis infection with Staphylococcus aureus was investigated.Methods: Rabbits with bacterial keratitis were treated using CTOIDD with NVCM (n=13), topical NVCM eye drops (n=11), and CTOIDD with saline (n=8). Clinical signs of keratitis in all groups were assessed consecutively for a week. Bacterial quantification of excised corneas was counted on the fourth and eighth days. Histopathologic examinations were performed to assess inflammatory cell infiltration on the eighth day.Results: All signs of bacterial keratitis were alleviated in CTOIDD with NVCM according to criteria, and the CTOIDD-NVCM group had significantly less inflammation than CTOIDD-saline (p< 0.05), and eye drop-NVCM (p< 0.05). Two eyes in the eye drop-NVCM group, four eyes in the CTOIDD-saline group had corneal perforation (CP), while none of the rabbits showed CP in the CTOIDD-NVCM group. Bacterial counts were significantly less in the CTOIDD with NVCM group in comparison to the eye drop-NVCM (p< 0.05), and CTOIDD-saline (p< 0.05) groups. Severe inflammation and marked inflammatory cell infiltration were found in histopathologic examinations in the CTOIDD-saline and eye drop-NVCM groups, while significantly less inflammation was documented in the CTOIDD-NVCM (p< 0.05) group.Conclusion: CTOIDD with NVCM effectively reduced the severity and treated acute bacterial S. aureus keratitis infection in a rabbit model. The presented approach of CTOIDD with NVCM appears to be a promising therapeutic approach for severe acute bacterial keratitis.Keywords: severe acute bacterial keratitis, continuous topical instillation, eye drop, norvancomycin, rabbit eyes

Yiming Zhang,1,2,* Binshen Chen,1,2,* Naijin Xu,3 Peng Xu,1,2 Wenfeng Lin,1– 3 Chunxiao Liu,1,2 Peng Huang1– 3 1Department of Urology, Zhujiang Hospital, Southern Medical University, Guangzhou, People’s Republic of China; 2Guangzhou Key Laboratory of Inflammatory and Immune Diseases, Zhujiang Hospital, Southern Medical University, Guangzhou, People’s Republic of China; 3Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan*These authors contributed equally to this workCorrespondence: Peng Huang; Chunxiao LiuDepartment of Urology, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, People’s Republic of ChinaTel +86-20-62782726Fax +86-20-62782725Email huangpeng509@gmail.com; Liuchx888@hotmail.comBackground: Castration-resistant prostate cancer (CRPC) is still considered incurable, even though the mechanisms of CRPC had been extensively researched. Studies have demonstrated that exosomes in the tumor microenvironment contribute to prostate cancer development and progression. However, the role of exosomes in the process of CRPC progression has not yet been determined.Methods: Co-culturing and exosome treatment assays combined with in vitro and in vivo assays were performed to determine the function of exosomes in the transformation of androgen-dependent prostate cancer (ADPC) cells into androgen-independent cells. Then, the mRNA expression profiles of ADPC cells and ADPC cells co-cultured with androgen-independent prostate cancer (AIPC) cell-derived exosomes were studied using microarrays. After silencing the expression of heme oxygenase-1 (HMOX1), Western blotting, quantitative real-time PCR, immunohistochemistry (IHC) studies, and MTS assay were used to confirm the mechanisms of exosome participation in CRPC progression.Results: The results showed that ADPC cells acquired tolerance for androgen deprivation due to the exosome-mediated communication between cells. AIPC cell-derived exosomes promoted the transformation of ADPC cells into androgen-independent cells in vivo and in vitro. Microarray analysis revealed that HMOX1 in ADPC cells was up-regulated after treatment with AIPC cell-derived exosomes. Further results showed that HMOX1 is overexpressed in human AIPC specimens and protects ADPC cells from androgen deprivation.Conclusions: Our findings revealed that exosomes contribute to CRPC progression via promoting the transition of prostate cancer cells into an androgen-independent growth stage by activating HMOX1.Keywords: prostate cancer, castration resistance, exosomes, heme oxygenase-1

Wanyi Lin,1,2,* Yaping Yang,1,2,* Wenjing Zhong,1,2 Qun Lin,1,2 Nanyan Rao,1– 3 Gehao Liang,1,2 Yun Ling,1,2 Zihao Liu,1,2 Qing Luo,1,2 Zhenluan Tian,1,2 Chang Gong1,2,4 1Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, People’s Republic of China; 2Department of Breast Surgery, Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, People’s Republic of China; 3Department of Oncoplastic and Reconstruction Breast Surgery, Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, People’s Republic of China; 4Bioland Laboratory, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou, 510005, People’s Republic of China*These authors contributed equally to this workCorrespondence: Chang GongDepartment of Breast Surgery, Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 Yanjiang West Road, Guangzhou 510120, People’s Republic of ChinaEmail gchang@mail.sysu.edu.cnBackground: Vacuum drains have been extensively applied to prevent seroma formation after breast surgery. However, the usage of negative suction drainage is mainly determined by surgeon’s experience and preferences. The aim of this study is to prospectively compare the drain effect after breast surgery between the low and high vacuum drains.Methods: This prospectively randomized trial (from January 2018 to June 2019) involved 188 patients who were subjected to modified radical mastectomy (group A, n=128) or immediate breast reconstruction with implants (group B, n=60). In each group, patients were randomized to receive high vacuum drain (pressure=– 98 kPa) or low vacuum drain (pressure=– 12 kPa) after surgery. Days of drain permanence, which means the duration of drainage, was the primary endpoint.Results: According to the comparison of days of drain permanence, the effect of a low vacuum drain is not inferior to a high vacuum drain in group A (pectoral drain, P< 0.001; axillary drain, P< 0.001) or group B (submuscular drain, P=0.002). The complications frequently occurred on patients with high vacuum drain (11.7%), such as seroma formation. The expense of low vacuum drain was significantly lower than high vacuum drain in both groups (P< 0.01).Conclusion: The drain effect of the low vacuum drain is not inferior to a high vacuum drain in both group A and group B. The low vacuum drain was effective, relatively cheap, and did not increase the incidence of complications; it is therefore more recommended after breast surgery.Keywords: breast surgery, days of drain permanence, postoperative drain

Jie Wang,1– 4 Wuji Lin,1– 4 Xu Fang,1– 4 Lei Mo1– 4 1School of Psychology, South China Normal University, Guangzhou 510631, People’s Republic of China; 2Key Laboratory of Brain, Cognition and Education Sciences (South China Normal University), Ministry of Education, Guangzhou 510631, People’s Republic of China; 3Center for Studies of Psychological Application, South China Normal University, Guangzhou 510631, People’s Republic of China; 4Guangdong Key Laboratory of Mental Health and Cognitive Science, South China Normal University, Guangzhou 510631, People’s Republic of ChinaCorrespondence: Lei Mo Email molei@m.scnu.edu.cnBackground: Previous studies of face trustworthiness have often examined isolated face stimulus, ignoring the role of context.Purpose: The current study used mouse-tracking technique and the seven-point Likert scale to examine the effect of emotional visual context on face trustworthiness judgment at the levels of the early evaluation process and final evaluation result.Methods: Experiment 1 used mouse-tracking technique to study the impact of different contexts on the judgment of face trustworthiness at the early evaluation process. Experiment 2 used the seven-point Likert scale to study the effect of different contexts on the judgment of face trustworthiness at the final evaluation result.Results: Experiment 1 found that when faces are embedded in threatening negative contexts, the mouse trajectories are more tortuous for trustworthy responses and straighter for untrustworthy responses than in neutral contexts. When faces are embedded in non-threatening negative contexts, the mouse trajectories are more tortuous for trustworthy responses but did not significantly differ for untrustworthy responses than in neutral contexts. When faces are embedded in positive contexts, the mouse trajectories are straighter for trustworthy responses and more tortuous for untrustworthy responses than in neutral contexts. Experiment 2 found that faces embedded in threatening and non-threatening negative contexts have lower scores and faces embedded in positive contexts have higher scores than in neutral contexts.Conclusion: The results show that the emotional visual context significantly influences the judgment of face trustworthiness both at the levels of the early evaluation process and final evaluation result.Keywords: face processing, trustworthiness, social perception, contextual processing, mouse-tracking

Wenyu Lin,1,2,* Liqing Lin,3,* Binhua Dong,2,4 Lihua Chen,1 Huifang Lei,1,2 Yuqin Gao,1,2 Yaojia Chen,1,2 Pengming Sun1,2,4 1Department of Gynecology, Fujian Maternity and Child Health Hospital, Affiliated Hospital of Fujian Medical University, Fuzhou, People’s Republic of China; 2Fujian Key Laboratory of Women and Children’s Critical Diseases Research, Fujian Maternity and Child Health Hospital, Affiliated Hospital of Fujian Medical University, Fuzhou, 350001, People’s Republic of China; 3Department of Women’s Health Care, Quanzhou Women’s and Children’s Hospital, Quanzhou, 362000, People’s Republic of China; 4Laboratory of Gynecologic Oncology, Department of Gynecology, Fujian Maternity and Child Health Hospital, Affiliated Hospital of Fujian Medical University, Fuzhou, 350001, People’s Republic of China*These authors contributed equally to this workCorrespondence: Pengming SunDirector of Laboratory of Gynecologic Oncology, Fujian Maternity and Child Health Hospital, Affiliated Hospital of Fujian Medical University, No. 18 Daoshan Road, Fuzhou, Fujian 350001, People’s Republic of ChinaEmail sunfemy@hotmail.comBackground: The diagnosis of postpartum pelvic organ prolapse (POP) relies on symptoms combined with pelvic organ prolapse-quantification (POP-Q) and lacks serological indicators. The objective of this study was to assess serum elastin, type I collagen, miRNA-30d, and miRNA-181a in the early postpartum period to identify hematologic predictors of POP.Material and Methods: The study included 1013 42- to 60-day-postpartum women who had delivered at Quanzhou Women’s and Children’s Hospital from October 1, 2016, to October 31, 2017. This study was performed in accordance with the Declaration of Helsinki. The pregnancy and childbirth characteristics and pelvic floor function were evaluated. Forty cases with and without POP were matched, and serum elastin and type I collagen were determined by enzyme-linked immunosorbent assay (ELISA). Reverse-transcription polymerase chain reaction (RT-PCR) was used to detect miRNA-30d and miRNA-181a in 15 pairs.Results: Of the 1013 women recruited, 699 (69.00%) were diagnosed with POP. The mean age was 29.00 years old, and the mean body mass index (BMI) was 22.6 kg/m2. In the univariate analysis, age ≥ 35 years (OR, 1.449; 95% CI, 0.965, 2.298), postpartum BMI ≥ 24 (OR, 4.402; 95% CI, 2.657, 6.148), neonatal weight ≥ 4 kg (OR, 4.832; 95% CI, 1.373, 17.290) and vaginal delivery (OR, 2.751; 95% CI, 1.855, 4.081) were risk factors for postpartum POP. There were no significant differences in the concentrations of serum elastin and type I collagen between the groups (P=0.52; P=0.26). There were significant differences in the concentrations of miRNA-30d and miRNA-181a between the groups (P=0.004; P=0.003).Conclusion: miRNA-30d and miRNA-181a tended to be increased in women with POP and could be potential clinical predictors.Keywords: elastin, miRNA-30d, miRNA-181a, pelvic organ prolapse, type I collagen

Long Hu,1 Wei Lin,2 Tiancheng Xu,1 Dongjie Liang,1 Guangze Xiang,1 Rujie Zheng,1 Changzuan Zhou,1 Qinxue Dai,3 Danyun Jia3 1Department of Cardiovascular Medicine, The Heart Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang, People’s Republic of China; 2Department of Pediatric Intensive Care Unit, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou 325027, Zhejiang, People’s Republic of China; 3Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang, People’s Republic of ChinaCorrespondence: Danyun Jia; Qinxue DaiDepartment of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, Nanbaixiang, Ouhai District, Wenzhou City 325000, Zhejiang Province, People’s Republic of ChinaTel/Fax +86-577-88581162Email 529365150@qq.com; 653091408@qq.comBackground: Admission lactate level has been reported as a useful marker of mortality. In this study, we compared the relative value of different lactate indices to predict survival in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI).Methods: This was a retrospective observational study including consecutive patients with STEMI undergoing primary PCI who admitted to the Coronary Care Unit of the First Affiliated Hospital of Wenzhou Medical University between 2014 and 2017. The predictive value of lactate indices for mortality was compared using receiver operator characteristic (ROC) analysis, and DeLong’s test was used to compare the AUC. We compared the AUC between GRACE score and GRACE score + lactate index.Results: A total of 1080 patients were included. Fifty-nine died in 30 days and 68 died in 180 days. Most lactate indices (Lacadm, Lac24max, Lac24min and Lac24tw) were significantly lower in survivors (all P< 0.001). In Cox proportional hazards model, each lactate index showed as an independent factor of 30-day and 180-day mortality except LacΔ. Kaplan–Meier curves demonstrated that the patients of higher lactate indices group had higher rates of mortality (all P< 0.0001, except LacΔ P=0.0485). In receiver operator characteristic analysis, Lac24max was significantly larger than Lacadm(P< 0.001) while the AUC value for Lacadm was similar to Lac24min and Lac24tw. Lac24tw improved the predictive probability of 30-day mortality (P=0.0415). Lac24max improved the predictive probability of GRACE score for both 30-day and 180-day mortality (P< 0.05).Conclusion: In patients with STEMI undergoing primary PCI, most lactate indices are all associated with 30-day and 180-day mortality except LacΔ. In prediction of both 30-day and 180-day mortality, Lac24max is superior to Lacadm and significantly enhances the ability of risk stratification and prognostic evaluation when adding Lac24max to the GRACE score.Keywords: STEMI, lactate indices, hyperlactatemia, mortality

Wei Lin,1 Danyun Jia,2 Changchang Fu,1 Yihui Zheng,1 Zhenlang Lin1 1Department of Pediatrics, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, People’s Republic of China; 2Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province 325000, People’s Republic of ChinaCorrespondence: Zhenlang Lin Department of PediatricThe Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang, People’s Republic of ChinaEmail lzlprof2020@163.comIntroduction: Electro-acupuncture (EA) can significantly improve inflammatory response, but the specific mechanism is not clear. Limb ischemia-reperfusion (I/R) first produces inflammatory reactions in the lungs. In this study, EA on Zusanli (ST36) and Sanyinjiao (SP6) were used to explore the mechanism of improving tissue inflammation by sciatic nerve disconnection.Material and Methods: A total of 56 male Sprague-Dawley rats were randomly divided into sham group, model group, EA group, SEA group, SNC+EA group, TNC+EA group and PNC+EA group. The sham groups were not given any treatment. Rats in the model group were treated with limb I/R without acupuncture intervention. In the EA group, ST36 and SP6 were given EA treatment for 30min before modeling. No electric current was given in the SEA group, and other operations were the same as those in the EA group. The SNC+EA group, TNC+EA group and PNC+EA group were respectively given sciatic nerve, tibial nerve or peroneal nerve amputation 72h before modeling, and the others were the same as the model group.Results: Compared with the sham group, PaO2 and a/A ratios decreased significantly in the model group (P < 0.05), while PA-aO2, RI, the ratio of wet to dry, lung injury value and inflammatory factor TNF-α, IL-1, IL-6, and MPO increased significantly (P < 0.05). Compared with the model group, PaO2, a/A ratios increased significantly in the EA group (P < 0.05), while PA-aO2, RI, the ratio of wet to dry lung, lung injury value, and TNF-α, IL-1, IL-6, and MPO decreased significantly (P < 0.05). After transection of the sciatic nerve, the protective effect of EA disappeared. However, when the peroneal or tibial nerve was severed, EA continued to maintain the protective effect.Conclusion: EA on ST36 and SP6 can alleviate lung injury caused by limb I/R through the sciatic nerve.Keywords: electro-acupuncture, limb ischemia-reperfusion injury, sciatic nerve

Libei Zhao, Manqiang Peng, Wenxiang Lin, Qian Tan, Muhammad Ahmad Khan, Ding Lin Department of Ophthalmology, Changsha Aier Eye Hospital, Aier School of Ophthalmology, Central South University, Changsha, People’s Republic of ChinaCorrespondence: Ding LinDepartment of Ophthalmology, Changsha Aier Eye Hospital, Aier School of Ophthalmology, Central South University, No. 388, Section 2, Furong Middle Road, Changsha City, Hunan Province 410005, People’s Republic of ChinaTel +86 13787255158Email linding@csu.edu.cnPurpose: To explore the feasibility of cyclophosphamide (CP) via a sub-Tenon micro-perfusion system (SMS) in rabbits, and assess its therapeutic efficacy in severe ocular inflammation.Materials and Methods: Distribution and pharmacokinetics of CP were evaluated in vivo, and the concentrations of CP in plasma, vitreous humor, and retina/choroid were quantitated by ultra-high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) at different time points. After induction of severe experimental uveitis, rabbits were divided into three groups (n=8 in each): the SMS group, subconjunctival injection (SI) group, and control group. Clinical inflammatory score was assessed in rabbits. Electroretinography and histopathology were performed on post-treatment day 8. Statistical analyses were performed using Mann–Whitney and Kruskal–Wallis tests. P-value less than 0.05 was considered significant.Results: The concentrations of CP in vitreous humor and retina/choroid in the SMS group were significantly higher than that of the SI group at 3, 6, 10, and 24 hours (P< 0.01), while plasmatic CP concentrations were comparable at all time points in the SMS group and SI group (P> 0.05). The SMS group showed significantly less inflammation compared to the control group and SI group. Furthermore, the restoration of retinal structure and function were more obvious in the SMS group compared with conventional SI application.Conclusion: Sub-Tenon micro-perfusion of CP exhibited satisfied therapeutic efficacy in rabbits with severe ocular inflammation and may provide a promising alternative for controlling ocular inflammatory disease and immune-mediated ocular diseases.Keywords: cyclophosphamide, sub-Tenon drug delivery, ocular inflammation, treatment, rabbit

Qiaoyu Zhang,1,* Binhua Dong,1,* Lihua Chen,1 Tingting Lin,2 Yao Tong,1 Wenyu Lin,1 Haifeng Lin,1 Yuqin Gao,1 Fen Lin,1 Pengming Sun1,3 1Laboratory of Gynecologic Oncology, Fujian Provincial Maternity and Children’s Health Hospital, Affiliated Hospital of Fujian Medical University, Fuzhou, People’s Republic of China; 2Department of Gynecology, The First Affiliated Hospital of Xiamen University, Xiamen, People’s Republic of China; 3Department of Gynecology, Fujian Provincial Maternity and Children’s Health Hospital, Affiliated Hospital of Fujian Medical University, Fuzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Pengming SunLaboratory of Gynecologic Oncology, Fujian Provincial Maternity and Children’s Hospital, Affiliated Hospital of Fujian Medical University, Fuzhou, People’s Republic of ChinaTel +86 591 8755 8732Fax +86 591 8755 1247Email sunfemy@hotmail.comObjective: To assess the clinical value of the PCR-reverse dot blot human papillomavirus genotyping test during follow-up of patients with CIN grade 2 or worse (CIN 2+).Methods: Four hundred patients with CIN 2+ receiving treatment from January 2008 to January 2017 were included in our study. Postoperative follow-up procedures comprised HPV examination and cervical cytology every 3– 6 months for the first 2 years and then followed up every 6– 12 months. A pathology examination was performed when there was a positive funding for HPV 16/18 or an abnormal ThinPrep cytology test (TCT) with or without positive for HR-HPV according to the American Society for Coloscopy and Cervical Pathology (ASCCP) guidelines.Results: The median follow-up period was 27.10± 12.47 months (ranging from 3 to 50 months). During follow-up, 12.00% (48/400) of the women developed residual/recurrent disease. The highest risk in CIN 2+ and CIN 3+ residual/recurrence was HPV-16/-18 (hazard ratio (HR)=12.898, 95% CI= 6.849– 24.289; HR= 20.726, 95% CI= 9.64– 44.562, respectively). Among the different follow-up methods, type-specific (TP) HR-HPV persistent infection showed the highest cumulative incidence risk (CIR) (84.62%, 95% CI=73.29– 95.94) and HR (5.38, 95% CI= 2.596– 11.149) during the 4-year follow-up period. At the CIN 2+ and CIN 3+ endpoints, TP-HPV testing had relatively high sensitivity (84.62%, 95% CI=73.29– 95.94 and 89.28%, 95% CI= 77.83– 100.00, respectively) and specificity (78.07%, 95% CI= 72.70– 83.44 and 75.73%, 95% CI= 70.30– 81.17, respectively). However, at the CIN 2+/CIN 3+ endpoint, TCT follow-up had a sensitivity of 60.42%/62.16% (95% CI=46.58– 72.25/46.54– 77.79) and specificity of 90.18%/88.72% (95% CI=86.95– 93.41/85.35– 92.10).Conclusion: TP HR-HPV follow-up can provide a reliable and sensitive clinical reference for CIN 2+ postoperative patients.Keywords: papillomavirus, genotype, cell biology, histology, postoperative

Juan Xu, 1,* Wenping Lin, 2,* Yanmin Chen, 3 Fang He 3 1Institute of Hygiene, Zhejiang Academy of Medical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang 310013, People’s Republic of China; 2Centers for Disease Control and Prevention of Ningbo, Ningbo, Zhejiang 315010, People’s Republic of China; 3Department of Clinical Laboratory, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014, People’s Republic of China*These authors contributed equally to this workCorrespondence: Fang He Tel/Fax +86-571-8821-5596Email hetrue@163.comPurpose: Imipenemase (IMP), an Ambler class B metallo-β-lactamase, is an important carbapenemase that confers resistance to almost all β-lactams. In this study, we characterized the genomic feature of an IMP-4-producing Klebsiella pneumoniae ST1873 strain, a rare sequence type (ST) isolated from an infant with a bloodstream infection in China.Patients and Methods: K. pneumoniae strain, BKP19, was collected from a bloodstream infection in an infant who was hospitalized at the department of paediatrics. The whole genome sequence of the strain was sequenced using the Illumina NovaSeq 6000 platform and long-read MinION sequencer. Multilocus sequence typing, antimicrobial resistance gene identification, plasmid and phylogenetic relationship analysis of the strain were analysed by various bioinformatics approaches.Results: K. pneumoniae BKP19 was resistant to multiple antimicrobials, including carbapenems. Eleven antimicrobial resistance genes corresponding to beta-lactam resistance, quinolone resistance, phenicol resistance and fosfomycin resistance could be identified in the genome. The carbapenem resistance gene blaIMP-4 was located in an IS26-associated class 1 integron of an IncN-type plasmid with 39,033 bp (pIMP-4-BKP19). Sequence alignment revealed that pIMP-4-BKP19 is closely related to the common plasmid carrying IMP-4 in K. pneumoniae (pIMP-HZ1-like plasmid) but is smaller, lacking the quinolone resistance gene qnrS1 and multiple tra gene orthologs. Conjugation experiment revealed that pIMP-4-BKP19 is a non-conjugative plasmid. According to in silico MLST analysis, K. pneumoniae strain BKP19 belongs to a sporadic clone ST1873.Conclusion: In summary, our study reports the first genome sequence of a K. pneumoniae ST1873 strain harbouring the class B β-lactamase blaIMP-4 in an IncN-type plasmid recovered from an infant with a bloodstream infection in China. Considering the global emergence of IMP-4 carbapenemase, more attention must be paid to prevent its future prevalence.Keywords: Klebsiella pneumoniae, blaIMP-4, IncN plasmid, ST1873, bloodstream infection

Wenxiang Lin,1,2 Libei Zhao,1,2 Xuetao Huang,3 Qian Tan,1,2 Manqiang Peng,1,2 Muhammad Ahmad Khan,1,2 Ding Lin1,2 1Aier School of Ophthalmology, Central South University, Changsha, People’s Republic of China; 2Department of Ophthalmology, Changsha Aier Eye Hospital, Changsha, People’s Republic of China; 3Department of Ophthalmology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People’s Republic of ChinaCorrespondence: Ding LinDepartment of Ophthalmology, Changsha Aier Eye Hospital, Aier School of Ophthalmology, Central South University, Changsha, People’s Republic of ChinaTel +86-13787255158Email linding@csu.edu.cnBackground: The aim of this study was to compare the distribution characteristics and ocular pharmacokinetics of norvancomycin (NVCM) in ocular tissues of the anterior segment between continuous topical ocular instillation and hourly administration of eye drop in rabbits.Methods: Sixty rabbits were randomly divided into two groups: continuous topical ocular instillation drug delivery (CTOIDD) group and eye drop (control) group. In the CTOIDD group, NVCM solution (50 mg/mL) was perfused to the ocular surface using the CTOIDD system at 2 mL/h up to 10 h and the same solution was administered at one drop (50 μL) per hour for 10 h in the control group. Animals (N=6 per time-point per group) were humanely killed at 2, 4, 6, 10, and 24 h to analyze their ocular tissues and plasma. The concentrations of NVCM in the conjunctiva, cornea, aqueous humour, iris, ciliary body and plasma were measured by HPLC with photodiode array detector. The pharmacokinetic parameters were calculated by Kinetica 5.1.Results: The highest concentrations of NVCM for the CTOIDD group and control group were 2105.45± 919.89 μg/g and 97.18± 43.14 μg/g in cornea, 3033.92± 1061.95 μg/g and 806.99± 563.02 μg/g in conjunctiva, 1570.19± 402.87 μg/g and 46.93± 23.46 μg/g in iris, 181.94± 47.11 μg/g and 15.38± 4.00 μg/g in ciliary body, 29.78± 4.90 μg/mL and 3.20± 1.48 μg/mL in aqueous humour, and 26.89± 5.57 μg/mL and 1.90± 1.87 μg/mL in plasma, respectively. The mean NVCM levels significantly increased at all time-points in cornea, iris, and ciliary body (p< 0.05) in the CTOIDD group. The AUC0– 24 values in the CTOIDD group were 27,543.70 μg·h/g in cornea, 32,514.48 μg·h/g in conjunctiva, 8631.05 μg·h/g in iris, 2194.36 μg·h/g in ciliary body and 343.9 μg·h/mL in aqueous humour, which were higher than for the eye drop group in all tissues.Conclusion: Since continuous instillation of NVCM with CTOIDD could reach significantly higher concentrations and was sustained for a longer period compared with hourly administration of eye drop, CTOIDD administered NVCM could be a possible method to treat bacterial keratitis.Keywords: topical drug delivery, ocular tissue, anterior segment, area under the curve, rabbit eye

Hua-Xing Zhang, 1, 2 Yong Shen, 3 Jia Chen, 2 Long Zhang, 2 Wei Lin 1 1Department of Graduate School, Graduate School of Hebei Medical University, Shijiazhuang, Hebei 050000, People’s Republic of China; 2Department of Orthopedics, Hebei General Hospital, Shijiazhuang, Hebei 050000, People’s Republic of China; 3Department of Spine Surgery, The Third Affiliated Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, People’s Republic of ChinaCorrespondence: Yong ShenDepartment of Spine Surgery, The Third Affiliated Hospital of Hebei Medical University, No. 139, Ziqiang Road, Xinhua District, Shijiazhuang, Hebei, Province 050000, People’s Republic of ChinaTel +86- 18533112820Fax +86-0311-85988832Email shenyonghbgh2018@126.comPurpose: To determine the risk factors for pulmonary complications after minimally invasive surgery in elderly patients with vertebral compression fractures (VCFs).Methods: A total of 233 elderly patients (age ≥ 65 years) with VCFs, who underwent percutaneous vertebroplasty (PVP) or percutaneous kyphoplasty (PKP) surgery at Hebei General Hospital from January 2011 to December 2016, were retrospectively analyzed. Risk factors and the effects of the model were determined by univariate logistic regression analyses and the receiver operating characteristic (ROC) curve, respectively. A risk assessment scale was established based on the risk factors, as well as physiological and surgical scores for mortality and morbidity. The risk assessment scale prospectively evaluated risk factors of pulmonary complications after minimally invasive surgery for elderly patients with VCFs from January to June 2017.Results: 27 patients were diagnosed with pulmonary complications (27/233, 11.59%). There were statistically significant differences between patients with and without pulmonary complications in terms of age, body mass index (BMI), smoking, cardiovascular diseases and old fractures between patients with and without pulmonary complications (P < 0.05). Logistic regression analysis showed that smoking, cardiovascular diseases and old fractures were risk factors (P < 0.05) and area under the curve was 0.738 (95% confidence intervals (CI): 0.648– 0.828). 53 elderly patients with VCFs were assessed, 5 of them occurred pulmonary complications. Areas under the curve of preoperative and total risk assessment values were all 0.925.Conclusion: Significant risk factors of pulmonary complications were BMI, cardiovascular diseases and old fractures for patients aged 65 years or elderly with VCFs after minimally invasive surgery. The risk assessment scale gained high accuracy.Keywords: vertebral compression fractures, pulmonary complications, risk factors, elderly patients

Shuying Lv,1,2 Lei Wang,2 Xiaohui Zou,3 Zihan Wang,1 Baoquan Qu,1,2 Wenjun Lin,1,2 Dingquan Yang2 1School of Clinical Medicine, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 2Department of Dermatology, China-Japan Friendship Hospital, Beijing, People’s Republic of China; 3Laboratory of Clinical Microbiology and Infection, Department of Pulmonary and Critical Care Medicine, China–Japan Friendship Hospital, Beijing, People’s Republic of ChinaCorrespondence: Dingquan YangDepartment of Dermatology, China-Japan Friendship Hospital, Beijing, People’s Republic of ChinaTel +86 13901218671Email ydqlx@163.comAbstract: As the number of COVID-19 cases increasing, more and more patients are concerning about alopecia, a sequela after SARS-CoV-2 infection. We here report a case of a 38-year-old woman with a typical acute telogen effluvium (ATE) after recovery from COVID-19.Keywords: COVID-19, SARS-CoV-2, acute telogen effluvium, alopecia

Jingyi Ye,1,* Huiyi Wu,1,* Chuanli Huang,1 Wanting Lin,2 Caifeng Zhang,1 Bei Huang,2 Banyi Lu,2 Hongyu Xu,2 Xiaoling Li,3 Xiaoying Long1,41Department of Pharmaceutics, School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, People’s Republic of China; 2Department of Pharmacy of Chinese Materia Medica, School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, People’s Republic of China; 3Department of Pharmaceutics and Medicinal Chemistry, Thomas J. Long School of Pharmacy & Health Sciences, University of the Pacific, Stockton, CA 95211, USA; 4Department of Oral Delivery, Guangdong Engineering and Technology Research Center of Topical Precise Drug Delivery System, Guangdong Pharmaceutical University, Guangzhou 510006, People’s Republic of China*These authors contributed equally to this workPurpose: The objective of this study was to compare the in vitro Fick’s first law, in vitro lipolysis, and in vivo rat assays for oral absorption of Biopharmaceutical Classification Systems Class II (BCS II) drugs in self-nanoemulsifying drug delivery system (SNEDDS), and studied drugs and oils properties effects on the absorption.Methods: The transport abilities of griseofulvin (GRI), phenytoin (PHE), indomethacin (IND), and ketoprofen (KET) in saturated water solutions and SNEDDS were investigated using the in vitro Madin-Darby canine kidney cell model. GRI and cinnarizine (CIN) in medium-chain triglycerides (MCT)-SNEDDS and long-chain triglycerides (LCT)-SNEDDS were administered in the in vivo SD rat and in vitro lipolysis models to compare the oral absorption and the distribution behaviors in GIT and build an in vitro-in vivo correlation (IVIVC).Results: In the cell model, the solubility of GRI, PHE, IND, and KET increased 6–8 fold by SNEDDS, but their permeability were only 18%, 4%, 8%, and 33% of those of their saturated water solutions, respectively. However, in vivo absorption of GRI-SNEDDS was twice that of the GRI suspension and those of CIN-SNEDDS were 15–21 fold those of the CIN suspension. In the lipolysis model, the GRI% in aqueous and pellet phases of MCT were similar to that in LCT. In contrast, the CIN% in the aqueous and pellet phases were decreased but that of the lipid phase increased. In addition, an IVIVC was found between the CIN% in the lipid phase and in vivo relative oral bioavailability (Fr).Conclusion: The in vitro cell model was still a suitable tool to study drug properties effects on biofilm transport and SNEDDS absorption mechanisms. The in vitro lipolysis model provided superior oral absorption simulation of SNEDDS and helped to build correlation with in vivo rats. The oral drug absorption was affected by drug and oil properties in SNEDDS.Keywords: SNEDDS, MDCK cell model, in vivo rat model, in vitro lipolysis, in vitro-in vivo correlation

Yanxia Sun,*,1,2 Xiaolan Lai,*,3 Yue Yu,1,2 Jieyu Li,2,4 Lei Cao,3 Wansong Lin,2,4 Chuanzhong Huang,2,4 Jinrong Liao,2,4 Wei Chen,1,2 Chao Li,5 Chunkang Yang,6 Mingan Ying,6 Qiang Chen,3 Yunbin Ye2,41School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, Fujian Province, People’s Republic of China; 2Laboratory of Immuno-Oncology, Fujian Provincial Cancer Hospital, Fuzhou 350014, Fujian Province, People’s Republic of China; 3Department of Medical Oncology, Union Hospital of Fujian Medical University, Fuzhou 350001, Fujian Province, People’s Republic of China; 4Fujian Key Laboratory of Translational Cancer Medicine, Fuzhou 350014, Fujian Province, People’s Republic of China; 5Department of Pathology, Fujian Provincial Cancer Hospital, Fuzhou 350014, Fujian Province, People’s Republic of China; 6Department of Abdominal Surgery, Fujian Provincial Cancer Hospital, Fuzhou 350014, Fujian Province, People’s Republic of China*These authors contributed equally to this workBackground: Inhibitor of DNA binding 1 (Id1) is upregulated in multiple cancers, and Id1overexpression correlates with cancer aggressiveness and poor clinical outcomes in cancer patients. However, its roles in cancer stem-like cells (CSCs) and epithelial-mesenchymal transition (EMT) are still elusive.Purpose: This study aimed to examine the role of Id1 on the mediation of CRC stemness and explore the underlying mechanisms.Methods: Id1 and CD133 expression was detected by qPCR assay and immunohistochemistry (IHC) in normal mucosal and primary colorectal cancer (CRC) specimens. Id1 was stably knocked down (KD) in human CRC cell lines. Spheres forming assay and tumorigenic assay were performed to evaluate self-renewal capacity and tumor initiation. Expression of CSC- and EMT-related markers and TCF/LEF activity were assessed in HCT116 cells after Id1 KD.Results: qPCR assay showed higher Id1 and CD133 expression in CRC specimens than in normal mucosal specimens (P

Ying Huang, Weiji Lin, Zhe Chen, Yu Wang, Yao Huang, Shenghao TuInstitute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of ChinaObjectives: This study evaluated the correlation between tumor necrosis factor alpha inhibitor (TNF-I) and interstitial lung disease (ILD) in rheumatoid arthritis (RA). We aimed to raise awareness and consummate therapy by summarizing the characteristics of the adverse events of ILD.Methods: A comprehensive search of the PubMed, Embase, Ovid, Cochrane, China National Knowledge Infrastructure, and Wanfang databases was performed from inception to November 2018. Statistical analysis of demographic characteristics, clinical features, and relative risks was performed using Microsoft Excel 2007 and SPSS version 20.0.Results: A total of 7 eligible articles and another 28 case reports were enrolled. The 7 cohort studies demonstrated the tendency that ILD cases might not benefit from TNF-I therapy. TNF-I might be associated with ILD adverse events. The case reports further confirmed these findings, as most (87.5%) of the cases showed that TNF-1 was harmful to patients with ILD and even resulted in a 35% mortality rate. Further investigation revealed that ILD adverse events tended to appear in female patients with a long RA history (p

Wenshan Lin,*,1 Hong-Yan Li,*,2 Shujun Lin,1 Tianbiao Zhou11Department of Nephrology, The Second Affiliated Hospital of Shantou University Medical College, Shantou, People’s Republic of China; 2Department of Nephrology, Huadu District People’s Hospital of Guangzhou, Southern Medical University, Guangzhou, People’s Republic of China*These authors contributed equally to this workBackground: As one of the therapeutic drugs for idiopathic membranous nephropathy (IMN), tacrolimus (TAC) has not been fully vindicated for its efficacy and tolerability. A meta-analysis was performed to detect the efficacy and safety of TAC plus glucocorticoid vs cyclophosphamide (CTX) plus glucocorticoid in therapy of patients with IMN.Methods: A literature search with a pre-defined search strategy was conducted using English databases (PubMed, EMBASE, ClinicalKey and the Cochrane Library) and Chinese databases (China National Knowledge International, Wanfang, Chinese Scientific Journal Database (VIP)) from inception to Nov 19, 2018. Any high-quality randomized controlled trials (RCTs) comparing the effectiveness or safety of TAC with CTX in IMN patients were included. Data were extracted by two authors independently and analyzed using RevMan 5.3.Results: Four randomized controlled studies were included. In this analysis, we did not find that the statistically significant difference between TAC and CTX groups on 6-month and 12-month treatment complete remission (CR) was evident (6-month: OR=1.53, 95% CI: 0.85–2.76, P=0.15; 12-month: OR=2.17, 95% CI: 0.56–8.44, P=0.27). But TAC had better 6-month total remission (TR; total CR plus partial remission [PR]) than CTX (6-month: OR=2.62, 95% CI: 1.38–4.96, P=0.003; 12-month: OR=1.74, 95% CI: 0.29–10.48, P=0.54), and got a lower proteinuria after 6-month treatment (OR=−0.80, 95% CI: −1.53 to −0.07, P=0.03). TAC had a lower incidence rate on leucopenia than CTX, but had a tendency towards higher blood creatinine. In the meantime, tremor in TAC group was higher than that in CTX group. The differences on other adverse effects such as gastrointestinal syndrome, infection, herpes zoster, hypertension, liver function disorder and hyperglycemia were also analyzed. However, none of them were statistically significant.Conclusion: TAC treatment could get high value of TR and had low value of proteinuria level when compared with those in CTX on 6-month treatment in therapy of patients with IMN.Keywords: tacrolimus, idiopathic membranous nephropathy, complete remission, CR, total remission, TR, meta-analysis

Shujun Lin,1 Hong-Yan Li,2 Tianbiao Zhou,1 Wenshan Lin11Department of Nephrology, The Second Affiliated Hospital of Shantou University Medical College, Shantou 515041, People’s Republic of China; 2Department of Nephrology, Huadu District People’s Hospital of Guangzhou, Southern Medical University, Guangzhou 510800, People’s Republic of ChinaIntroduction: The efficacy of cyclosporine A (CsA) in the treatment of idiopathic membranous nephropathy (IMN) is unclear. This meta-analysis was conducted to assess the efficacy and the safety of CsA in the treatment of IMN in Asians.Methods: We searched the Pubmed, China Biomedical Database, CNKI, Wanfang Data, VIP, and EMBASE (November 30, 2018) systematically to identify the appropriate randomized controlled trials (RCTs) reporting the efficacy and the safety of CsA and glucocorticoid (GC) treatment vs other immunosuppressants and GC on patients with IMN in Asian populations.Results: The CsA treated group entered complete remission (CR) faster (3 months) than a cyclophosphamide (CTX) group. While the CsA group lower inefficacy rates and higher total remission (TR, CR, or partial remission) than the CTX group in the total treatment (3 months, 6 months, and 12 months), it had a higher relapse rate. As for the CsA group vs the tacrolimus (TAC) group, the TAC had a significant effect in increasing the CR and the TR, with decreased no remission. With the therapeutic regimens of CsA+GC vs CTX+GC, the CsA exhibited better efficacy in lowering the proteinuria levels only at 12 months, not at 3 months or 6 months. Severe events like leucopenia, hemorrhagic cystitis, and alopecia were observed in the CTX group. Gingival hyperplasia, hirsutism, and elevated blood pressure were reported only in the CsA group. Gastrointestinal syndrome, liver function lesion, happened more frequently in the CTX group, and elevated uric acid was more common in the CsA group.Conclusions: In brief, the CsA has better efficacy than the CTX group in the Asian population, with mild adverse effects but higher relapse rates in short-term treatment.Keywords: idiopathic membranous nephropathy, cyclosporine A, cyclophosphamide, mycophenolate mofetil, tacrolimus