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Xiaoyi Liu,1,* Zhiwei Lin,2,* Yiwen Li,3 Zhiwei Zhong,1 Aiwu Wu,1 Yueting Jiang3 1KingMed School of Laboratory Medicine, Guangzhou Medical University, Guangzhou, People’s Republic of China; 2Department of Clinical Laboratory of the First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Center for Respiratory Medicine, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, Guangzhou, People’s Republic of China; 3Department of Clinical Laboratory, the Key Laboratory of Advanced Interdisciplinary Studies Center, the First Affiliated Hospital of Guangzhou Medical University, National Center for Respiratory Medicine, Guangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Aiwu Wu; Yueting Jiang, Email aiwwu66@163.com; jyting8899@126.comPurpose: The clinical distribution characteristics of nontuberculous mycobacteria (NTM) in general hospital were explored to guide the clinical diagnosis and treatment of NTM infection.Methods: Samples with positive mycobacterium culture in the First Affiliated Hospital of Guangzhou Medical University were collected and identified through PCR. Phenotypic drug sensitivity experiments were conducted on 44 Mycobacteroides abscessus isolated from clinical departments with broth microdilution method, and rrl, rrs and erm (41) genes associated with drug resistance were detected.Results: From September 2020 to July 2023, 314 mycobacterium-positive isolates were separated from patients in the First Affiliated Hospital of Guangzhou Medical University, with 147 (46.8%) NTM isolates were included in our study. The samples were respiratory tract specimens mainly, with 64% bronchoalveolar lavage fluid. Of 144 cases identified, samples were from 133 patients (60 males and 73 females; gender ratio of 0.82:1). NTM was mainly isolated from the people aged 40 and above, especially females (χ2 = 10.688, P = 0.014). M. abscessus (61, 42.36%), M. intracellulare (35, 24.31%) were the two most NTMs in this hospital. Clinical strains of M. abscessus exhibited high resistance to antibiotics, except for cefoxitin (31.8%), linezolid (25.0%), amikacin (0%), and clarithromycin (18.2%). Among 8 strains of M. abscessus with clarithromycin acquired resistance, just 4 strains (50.0%) showed mutations (A2270G, A2271G) in rrl gene, but a new mutation (C2750T) was detected in 1 strain. Among 14 strains of M. abscessus with clarithromycin-induced resistance, 13 (93.0%) strains had T28 erm (41) gene and 1 (7.0%) strain had C28 erm (41) gene.Conclusion: M. avium–intracellulare complex was gradually becoming predominant strain in Guangzhou area. The resistant situation of M. abscessus in general hospital had shown severe. Potential mutation in rrl gene associated with clarithromycin acquired resistance of M. abscessus were found, but drug-resistant mechanism remained unclear.Keywords: nontuberculous mycobacterium, drug resistance, clarithromycin, Mycobacteroides abscessus

Chengran Wang,1,* Yihong Zhang,1,* Weihui Kong,2 Xin’ao Rong,1 Ziming Zhong,1 Lei Jiang,3 Shuhan Chen,1 Chuang Li,1 Fuqiang Zhang,1 Jinlan Jiang1 1Department of Scientific Research Center, China–Japan Union Hospital of Jilin University, Changchun, Jilin Province, People’s Republic of China; 2Department of Stomatology, the First Hospital of Jilin University, Changchun, Jilin Province, People’s Republic of China; 3Department of Geriatric Medicine, Changchun Central Hospital, Changchun, Jilin Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Fuqiang Zhang; Jinlan Jiang, Department of Scientific Research Center, China–Japan Union Hospital of Jilin University, Changchun, Jilin Province, People’s Republic of China, Email zfqzhang@jlu.edu.cn; jiangjinlan@jlu.edu.cnAbstract: Osteosarcoma is the predominant primary malignant bone tumor that poses a significant global health challenge. MicroRNAs (miRNAs) that regulate gene expression are associated with osteosarcoma pathogenesis. Thus, miRNAs are potential therapeutic targets for osteosarcoma. Nanoparticles, widely used for targeted drug delivery, facilitate miRNA-based osteosarcoma treatment. Numerous studies have focused on miRNA delivery using nanoparticles to inhibit the progress of osteosarcoma. Polymer-based, lipid-based, inorganic-based nanoparticles and extracellular vesicles were used to deliver miRNAs for the treatment of osteosarcoma. They can be modified to enhance drug loading and delivery capabilities. Also, miRNA delivery was combined with traditional therapies, for example chemotherapy, to treat osteosarcoma. Consequently, miRNA delivery offers promising therapeutic avenues for osteosarcoma, providing renewed hope for patients. This review emphasizes the studies utilizing nanoparticles for miRNA delivery in osteosarcoma treatment, then introduced and summarized the nanoparticles in detail. And it also discusses the prospects for clinical applications. Keywords: osteosarcoma, MicroRNAs, nanoparticle delivery, molecular targeted therapy

Shuqing Liang, Shuai Li, Zhao Zhong, Qichen Luo, Cai Nie, Donghua Hu, Yalan Li Department of Anesthesiology, The First Affiliated Hospital of Jinan University, Guangzhou, 510630, People’s Republic of ChinaCorrespondence: Yalan Li, Department of Anesthesiology, the First Affiliated Hospital of Jinan University, No. 613 Huangpu West Avenue, Tianhe District, Guangzhou, Guangdong Province, 510630, People’s Republic of China, Tel +86-20-38688779, Email tyalan@jnu.edu.cnPurpose: This study aimed to investigate patients’ expectative pain of spinal anesthesia puncture and anxiety pre-anesthesia, and to examine the effect of lidocaine-prilocaine cream and remimazolam prior to spinal anesthesia puncture on pain relief and anxiety release.Methods: Patients undergoing spinal anesthesia were divided into control, lidocaine-prilocaine cream, and lidocaine-prilocaine cream with remimazolam groups. A questionnaire consisting of The Amsterdam Preoperative Anxiety and Information Scale (APAIS) and patient’s concerns and Visual Analog Scale (VAS) was used to evaluate patient’s anxiety and pain. The primary outcomes were differences in VAS and anxiety scores. Patient’s spinal anesthesia-related concerns, advent events and hemodynamic index were also recorded.Results: The expected spinal anesthesia puncture pain was 5.34± 0.27 and anxiety scores before spinal anesthesia was 10.88 ± 0.64. A statistically significant positive correlation of 31.3% was detected between VAS and APAIS scores (r = 0.313; P=0.003). The VAS score at the time of puncture decreased by 29.7% (3.78± 0.40, P=0.001) in lidocaine-prilocaine cream group and 29.2% (3.75± 0.39, P=0.001) in lidocaine-prilocaine cream with remimazolam group compared with the expected VAS score. Lidocaine-prilocaine cream combined with or without remimazolam reduced the percentage of moderate pain (21.4% and 31.3% vs 50.0%, P=0.0001) and increased mild pain (60.7% vs 59.4% vs 22.7%, P=0.03). Anxiety score in lidocaine-prilocaine cream group was reduced by 2.84 (8.04± 0.76 vs 10.88 ± 0.46, P=0.05) when compared with pre-anesthesia. Concerns about postoperative pain (P=0.03) and fear of the needle or intervention (P=0.000) both decreased post-anesthesia among groups.Conclusion: Approximately half of the patients scheduled for spinal anesthesia experienced a moderate level of preoperative anxiety. The patient’s pain expectation from the spinal anesthesia puncture was moderate, which was higher than the actual pain. Lidocaine-prilocaine cream with or without remimazolam sedative before spinal anesthesia puncture reduced the patient’s pain and anxiety scores after surgery.Keywords: preoperative anxiety, APAIS, spinal anesthesia, lidocaine-prilocaine, remimazolam

Minli Hu,1,* Hao Fang,2,* Yibing Hu,1 Chong Lu,1 Yuan Chen,1 Zhifeng Zhong,3 Hongqi Shi,4 Qunying Wang1 1Department of Gastroenterology, Jinhua Municipal Central Hospital, Jinhua, Zhejiang, People’s Republic of China; 2Department of Traumatology, Jinhua Municipal Central Hospital, Jinhua, Zhejiang, People’s Republic of China; 3Department of Anus & Intestine Surgery, Jinhua Municipal Central Hospital, Jinhua, Zhejiang, People’s Republic of China; 4Department of Pathology, Jinhua Municipal Central Hospital, Jinhua, Zhejiang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qunying Wang, Department of Gastroenterology, Jinhua Municipal Central Hospital, Jinhua, Zhejiang, People’s Republic of China, Email wqy616717@126.comBackground: Allied disorders of Hirschsprung’s disease (ADHD) exhibit symptoms akin to those of Hirschsprung’s disease, primarily characterized by intestinal obstruction, bowel dilatation, and chronic constipation. The occurrence of amyloid complications in patients with ADHD is infrequent. In this report, we present a case of ADHD with intestinal ulcers as the initial gastrointestinal manifestation, and subsequent pathological examination revealed the presence of amyloid deposits in the colonic mucosa.Case Report: A male patient, aged 20, exhibited recurring abdominal distension and intestinal obstruction for a duration of three years. Multiple colonoscopies revealed the presence of recurrent colonic ulcers, with pathological examination indicating the existence of amyloid deposits within the mucosal layer of the colon. Abdominal CT scans suggested colonic dilatation. Following a multidisciplinary consultation, a subtotal resection of the colon was performed, and subsequent postoperative pathology confirmed a decrease and absence of myenteric plexus ganglion cells. Considering the patient’s symptoms and the findings from the postoperative pathology, a diagnosis of ADHD was made. The patient’s symptoms resolved postoperatively and he was discharged from the hospital and followed up for 1 year in stable condition.Conclusion: Our study highlights the potential association between ADHD and the initial presentation of recurrent colonic ulcers, accompanied by amyloid deposition in the intestinal mucosa. This finding suggests a possible pathogenic mechanism for ADHD and offers a novel perspective on its diagnosis.Keywords: allied disorders of Hirschsprung’s disease, colonic ulcer, amyloid, intestinal obstruction, colonoscopy biopsy colonic

Guangtian Wang,1,2,* Zhihui Li,3,* Gongchen Wang,4,* Qixu Sun,5 Peng Lin,1 Qian Wang,2 Huishu Zhang,6 Yanyan Wang,7 Tongshuai Zhang,8 Feiyun Cui,9 Zhaohua Zhong1,2 1Teaching Center of Pathogenic Biology, School of Basic Medical Sciences, Harbin Medical University, Harbin, Heilongjiang, 150081, People’s Republic of China; 2Department of Microbiology, School of Basic Medical Sciences, Harbin Medical University, Harbin, Heilongjiang, 150081, People’s Republic of China; 3Department of Neurology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150086, People’s Republic of China; 4Department of Vascular Surgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150086, People’s Republic of China; 5Department of Gastroenterology, Penglai People’s Hospital, Yantai, Shandong, 265600, People’s Republic of China; 6Teaching Center of Biotechnology, School of Basic Medical Sciences, Harbin Medical University, Harbin, Heilongjiang, 150081, People’s Republic of China; 7Teaching Center of Morphology, School of Basic Medical Sciences, Harbin Medical University, Harbin, Heilongjiang, 150081, People’s Republic of China; 8Department of Neurobiology, School of Basic Medical Sciences, Harbin Medical University, Harbin, Heilongjiang, 150081, People’s Republic of China; 9Department of Physiology, School of Basic Medical Sciences, Harbin Medical University, Harbin, Heilongjiang, 150081, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhaohua Zhong; Feiyun Cui, Email zhongzh@hrbmu.edu.cn; feiyun@hrbmu.edu.cnAbstract: Angiogenesis, or the formation of new blood vessels, is a natural defensive mechanism that aids in the restoration of oxygen and nutrition delivery to injured brain tissue after an ischemic stroke. Angiogenesis, by increasing vessel development, may maintain brain perfusion, enabling neuronal survival, brain plasticity, and neurologic recovery. Induction of angiogenesis and the formation of new vessels aid in neurorepair processes such as neurogenesis and synaptogenesis. Advanced nano drug delivery systems hold promise for treatment stroke by facilitating efficient transportation across the the blood-brain barrier and maintaining optimal drug concentrations. Nanoparticle has recently been shown to greatly boost angiogenesis and decrease vascular permeability, as well as improve neuroplasticity and neurological recovery after ischemic stroke. We describe current breakthroughs in the development of nanoparticle-based treatments for better angiogenesis therapy for ischemic stroke employing polymeric nanoparticles, liposomes, inorganic nanoparticles, and biomimetic nanoparticles in this study. We outline new nanoparticles in detail, review the hurdles and strategies for conveying nanoparticle to lesions, and demonstrate the most recent advances in nanoparticle in angiogenesis for stroke treatment. Keywords: angiogenesis, ischemic stroke, nanoparticles, blood brain barrier, neurogenesis, neuroprotection therapy

Yuan Ma,1,2 Li Li,1 Li Yu,1 Wei He,1 Ling Yi,1 Yuxin Tang,1 Jijie Li,1 Zhigang Zhong,3 Meixian Wang,4 Shiyao Huang,5,6 Yiquan Xiong,5,6 Pei Xiao,7 Yuxiang Huang1 1Department of Medical Record Management, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 2Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, Sichuan, People’s Republic of China; 3Department of Prevention, Office of Cancer Prevention and Treatment, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Cancer Hospital Affiliate to University of Electronic Science and Technology of China, Chengdu, Sichuan, People’s Republic of China; 4National Center for Birth Defects Monitoring, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 5Chinese Evidence-Based Medicine Center, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 6NMPA Key Laboratory for Real World Data Research and Evaluation in Hainan, Chengdu, Sichuan, People’s Republic of China; 7Medical Insurance Office, West China Fourth Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of ChinaCorrespondence: Yuxiang Huang, Email 3593213104@qq.comBackground: Uterine leiomyoma (UL) is one of the most common benign tumors in women, and its incidence is gradually increasing in China. The clinical complications of UL have a negative impact on women’s health, and the cost of treatment poses a significant burden on patients. Diagnosis-related groups (DRG) are internationally recognized as advanced healthcare payment management methods that can effectively reduce costs. However, there are variations in the design and grouping rules of DRG policies across different regions. Therefore, this study aims to analyze the factors influencing the hospitalization costs of patients with UL and optimize the design of DRG grouping schemes to provide insights for the development of localized DRG grouping policies.Methods: The Mann–Whitney U-test or the Kruskal–Wallis H-test was employed for univariate analysis, and multiple stepwise linear regression analysis was utilized to identify the primary influencing factors of hospitalization costs for UL. Case combination classification was conducted using the exhaustive chi-square automatic interactive detection (E-CHAID) algorithm within a decision tree framework.Results: Age, occupation, number of hospitalizations, type of medical insurance, Transfer to other departments, length of stay (LOS), type of UL, admission condition, comorbidities and complications, type of primary procedure, other types of surgical procedures, and discharge method had a significant impact on hospitalization costs (P< 0.05). Among them, the type of primary procedure, other types of surgical procedures, and LOS were the main factors influencing hospitalization costs. By incorporating the type of primary procedure, other types of surgical procedures, and LOS into the decision tree model, patients were divided into 11 DRG combinations.Conclusion: Hospitalization costs for UL are mainly related to the type of primary procedure, other types of surgical procedures, and LOS. The DRG case combinations of UL based on E-CHAID algorithm are scientific and reasonable.Keywords: uterine leiomyoma, diagnosis-related groups, decision tree

Xiangli Qing,1,2 Lin Wang,1 Shuangshuang Fang,1 Yanran Ban,1,3 Zhuotai Zhong,1 Weiqi Sun,1 Chenhui Zhang,4 Tao Zhang,1 Yang Yang,1 Wei Wei1 1Department of Gastroenterology, Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing, People’s Republic of China; 2School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, People’s Republic of China; 3Graduate School of Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 4Department of General Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, People’s Republic of ChinaCorrespondence: Wei Wei, Department of Gastroenterology, Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing, People’s Republic of China, Email weiwei3816@mail.cintcm.ac.cnBackground: An unmet medical need for the treatment of inflammatory bowel disease (IBD) exists. A part of antidiabetic drugs had potential effects on IBD in various observational research.Objective: To investigate the potential of antidiabetic drugs on IBD.Methods: We undertook a summary-data-based Mendelian randomization (SMR) using the expression quantitative trait loci (eQTL) expressed in the blood or colon and a two sample Mendelian randomization (TSMR) utilizing single nucleotide polymorphism (SNP) of antidiabetic drug target genes mediated by blood glucose traits. Participants encompassed patients with IBD (25,042 cases/34,915 controls), UC (12,366 cases/33,609 controls), and CD (12,194 cases/28,072 controls). Data on eQTL in the blood or the colon were from the eQTLGen consortium (31,684 individuals) or GTEx Consortium V8, respectively. SMR was performed by SMR software (20,220,322); the primary method for TSMR was inverse-variance weighted (IVW) or Wald ratio through R studio (2023.06.0+421). Sensitivity analyses were carried out.Results: A 1-SD upper expression of the KCNJ11 gene (target gene of sulfonylureas) in the blood reduced the risk of CD (OR per 1-SD = 0.728, 95% CI = 0.586– 0.903, P = 0.004) according to the result of SMR. ABCC8 (target gene of sulfonylureas) expressed in the colon did not affect CD, UC, or IBD. T2D-mediated KCNJ11 has a protective effect on CD (OR = 0.475, 95% CI = 0.297– 0.761, P = 0.002). Gene predicted no relationship between T2D and CD.Conclusion: Sulfonylureas (SUs) may have side effects on CD. This work provides some suggestions for the selection of antidiabetic drugs in patients with CD.Keywords: antidiabetic drugs, inflammatory bowel disease, Mendelian randomization

Yi Yu,1,2,&ast; Zhong Zhong,1,2,&ast; Wenzhuo Yang,1,2 Jianwen Yu,1,2 Jianbo Li,1,2 Xingdi Guo,1,2 Jiasi Chen,3 Haiping Mao,1,2 Zhijian Li1,2 1Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, People’s Republic of China; 2NHC Key Laboratory of Clinical Nephrology (Sun Yat-Sen University) and Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, 510080, People’s Republic of China; 3Department of Nephrology, The First Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510120, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhijian Li, Department of Nephrology, The First Affiliated Hospital, Sun Yat-Sen University, 58th Zhongshan Road II, Guangzhou, 510080, People’s Republic of China, Tel +8620 87335811, Fax +8620 87755766, Email lizhjian@mail.sysu.edu.cnBackground: Neutrophil percentage-to-albumin ratio (NPAR), a new inflammatory marker, has been shown to be associated with poor prognosis in patients with cardiovascular disease. However, limited evidence is available for its role in peritoneal dialysis (PD) patients. Our study aimed at investigating the prognostic value of NPAR for mortality in PD patients.Patients and Methods: This was a single center retrospective cohort study. A total of 1966 PD patients were enrolled in our study from January 2006 to December 2016 and were followed up until December 2021. Patients were stratified into tertiles according to baseline NPAR levels. The associations between NPAR levels with all-cause and cardiovascular mortality were estimated using Cox proportional hazards models. Receiver operating characteristic (ROC) analysis was performed to compare the mortality predictive values of NPAR and other known biomarkers, such as NLR (neutrophil-to-lymphocyte ratio), PLR (platelet-to-lymphocyte ratio), LHR (low-density lipoprotein cholesterol-to-high-density lipoprotein cholesterol ratio) and MLR (monocyte-to-lymphocyte ratio).Results: During a median follow-up of 48.1 months, 503 (25.6%) patients died, in which cardiovascular disease (CVD) death dominated 50.3%. Multivariate Cox regression analysis revealed that the highest NPAR tertile was significantly associated with a higher risk of all-cause and cardiovascular mortality (HR 1.51, 95% CI 1.14– 1.98; HR 1.57, 95% CI 1.07– 2.31; respectively) compared with tertile 1. The AUC values of NPAR were 0.62 (95% CI 0.60– 0.65, P < 0.001) for all-cause mortality and 0.61 (95% CI 0.57– 0.65, P < 0.001) for cardiovascular mortality.Conclusion: Our study showed that higher NPAR levels were independently associated with increased risk of all-cause and cardiovascular mortality in PD patients. Notably, our results demonstrated that NPAR exhibited superior predictive value for mortality compared to NLR, PLR, MLR, and LHR.Keywords: peritoneal dialysis, neutrophil percentage-to-albumin ratio, mortality, inflammation

Jing Yang,1,2,&ast; Jinlu Shang,1,2,&ast; Liuxuan Yang,1,2,&ast; Daiqing Wei,3 Xia Wang,1 Qinmin Deng,2 Zhirong Zhong,4 Yun Ye,1 Meiling Zhou1 1Department of Pharmacy, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China; 2Department of Clinical Pharmacy, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, People’s Republic of China; 3Department of Orthopaedics, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China; 4Department of Pharmaceutical Sciences, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Meiling Zhou, Email meilzhou@163.comAbstract: Honokiol (HNK) is a small-molecule polyphenol that has garnered considerable attention due to its diverse pharmacological properties, including antitumor, anti-inflammatory, anti-bacterial, and anti-obesity effects. However, its clinical application is restricted by challenges such as low solubility, poor bioavailability, and rapid metabolism. To overcome these limitations, researchers have developed a variety of nano-formulations for HNK delivery. These nano-formulations offer advantages such as enhanced solubility, improved bioavailability, extended circulation time, and targeted drug delivery. However, existing reviews of HNK primarily focus on its clinical and pharmacological features, leaving a gap in the comprehensive evaluation of HNK delivery systems based on nanotechnology. This paper aims to bridge this gap by comprehensively reviewing different types of nanomaterials used for HNK delivery over the past 15 years. These materials encompass vesicle delivery systems, nanoparticles, polymer micelles, nanogels, and various other nanocarriers. The paper details various HNK nano-delivery strategies and summarizes their latest applications, development prospects, and future challenges. To compile this review, we conducted an extensive search using keywords such as “honokiol”, “nanotechnology”, and “drug delivery system” on reputable databases, including PubMed, Scopus, and Web of Science, covering the period from 2008 to 2023. Through this search, we identified and selected approximately 90 articles that met our specific criteria. Keywords: honokiol, nanotechnology, drug delivery, targeting, antitumor, bioavailability

Zhenyu Chen,1,2,&ast; Zhongbing Liu,1,&ast; Shuzao Wang,1,&ast; Cai Cheng,1,&ast; Xiaoduan Sun,1 Zerong Liu,3 Jun Wei,1 Jun Jiang,4,5 Huaqi Lan,1 Meiling Zhou,6 Pei Jing,6 Yan Lin,1 Xiangyu Zhou,7 Zhirong Zhong1,3,8 1Key Laboratory of Medical Electrophysiology, Ministry of Education, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646000, People’s Republic of China; 2The Second People’s Hospital of China Three Gorges University, Yichang, 443000, People’s Republic of China; 3Central Nervous System Drug Key Laboratory of Sichuan Province, Luzhou, Sichuan, 646000, People’s Republic of China; 4Department of General Surgery (Thyroid Surgery), the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, People’s Republic of China; 5Metabolic Vascular Diseases Key Laboratory of Sichuan Province, Luzhou, Sichuan, 646000, People’s Republic of China; 6Department of Pharmacy, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, People’s Republic of China; 7Department of Thyroid and Vascular Surgery, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, People’s Republic of China; 8Key Laboratory of Luzhou City for Aging Medicine, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiangyu Zhou; Zhirong Zhong, Email xiangyuzhou971@vip.126.com; zhongzhirong@126.comBackground: Flurbiprofen axetil (FA) is a non-steroidal anti-inflammatory drug with good analgesic and anti-inflammatory effects. However, it suffers from poor solubility, short circulation time, and off-target binding profile, which significantly limit its clinical application. Here, we loaded FA into stealth lipid microspheres modified with the arginine-glycine-aspartic acid (RGD) peptide (cRGD-FA-SLM), and examined the therapeutic potential of the resulting platform for the treatment of rheumatoid arthritis (RA).Methods: cRGD-FA-SLM was prepared by high pressure homogenization, and its toxicity and uptake by macrophages were examined using cultures of RAW264.7 cells. Hemolysis and hepatotoxicity tests were performed to assess the safety of the developed platform, while its pharmacokinetics, biodistribution, and therapeutic efficacy were investigated in a collagen-induced arthritis rat model.Results: cRGD-FA-SLM showed homogeneous spherical morphology and efficient encapsulation of FA. The developed platform was non-toxic to normal macrophages and was selectively internalized by lipopolysaccharide-activated macrophages in vitro, while it distributed mainly to arthritic joints and significantly prolonged FA in circulation in vivo. cRGD-FA-SLM also significantly reduced the expression of prostaglandin E2 and alleviated joint edema and bone erosion, showing prolonged analgesic effects in arthritic rats.Conclusion: cRGD-FA-SLM shows good inflammation-targeting ability and prolongs drug circulation in vivo, suggesting promise as an anti-inflammatory and analgesic agent for targeted RA treatment.Graphical Abstract: Keywords: flurbiprofen axetil, lipid nanospheres, cRGD, long circulation, rheumatoid arthritis

Dongmei Lu,1 Maidina Abudouaini,1,2 Munire Kerimu,2 Qiuping Leng,1 Hongtao Wu,1 Amar Aynazar,1,2 Zhiwei Zhong1,2 1Center of Pulmonary and Critical Care Medicine, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, People’s Republic of China; 2Department of Public Health, Xinjiang Medical University, Urumqi, People’s Republic of ChinaCorrespondence: Dongmei Lu, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, People’s Republic of China, Tel +18997982968, Email dongmeilu2009@sina.comPurpose: Severe community-acquired pneumonia (SCAP) is the leading cause of death among patients with infectious diseases worldwide. This study aimed to evaluate the effectiveness of metagenomic next-generation sequencing (mNGS) through detecting pathogens in bronchoalveolar lavage fluid (BALF) and identifying risk factors for recovery in SCAP patients.Patients and Methods: This prospective study recruited 158 SCAP patients admitted to respiratory intensive care unit that were randomly divided into control and study groups, with receiving conventional tests and the same conventional tests plus mNGS, respectively. The diagnostic efficiency of mNGS was evaluated by comparing with conventional tests. Furthermore, univariate and multivariate logistic regression analyses were performed to determine the independent risk factors for recovery in SCAP patients, and a nomogram prediction model was established based on these factors.Results: Within the study group, the pathogen detection rate was significantly higher with mNGS than that with conventional tests (84.81% vs 45.57%, P < 0.001), with a positive coincidence rate of 94.44%. Acinetobacter baumannii (21.52%, 17/79), Candida albicans (17.72%, 14/79), and Klebsiella pneumonia (15.19%, 12/79) were the top three common pathogens detected by mNGS. Of note, the improvement rate of patients in the study group was significantly higher than that in the control group. The further analysis revealed that the increased levels of interleukin-6, blood urea nitrogen, procalcitonin, the longer length of hospital stay, and bacterial infection were independent risk factors for recovery of SCAP patients, while mNGS detection status was a protective factor. The predictive model showed a good performance for the modeling and validation sets.Conclusion: Early mNGS exhibited a superior diagnostic efficiency to conventional tests in SCAP patients, which can reduce the risk of death in SCAP patients. Moreover, the clinical factors could also be used for the management and prognosis prediction of SCAP patients.Keywords: severe community-acquired pneumonia, metagenomic next-generation sequencing, pathogen, risk factor

Haoqi Liu,1,2 Ziqiang Yao,1,2 Shuangjiao Shi,1 Feng Zheng,1– 3 Xia Li,1,4 Zhuqing Zhong1,2 1Nursing Department, The Third Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 2Xiangya Nursing School, Central South University, Changsha, People’s Republic of China; 3Cardiology Department, The Third Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 4Endocrinology Department, The Third Xiangya Hospital, Central South University, Changsha, People’s Republic of ChinaCorrespondence: Zhuqing Zhong, Email zhongzhuqing@126.comBackground: Patients with type 2 diabetes have poor medication adherence. Medication literacy is one of the influencing factors of medication adherence among patients with type 2 diabetes. However, the mechanism by which medication literacy affects medication adherence among patients with type 2 diabetes is unclear. The aim of this study was to verify the mediating role of self-efficacy in the relationship between medication literacy and medication adherence.Methods: A total of 402 patients with type 2 diabetes were enrolled in this study. The Chinese versions of the Medication Literacy Scale, the Self-Efficacy for Appropriate Medication Use Scale and the Morisky Medication Adherence Scale-8 were used in the survey. Pearson correlation analysis was used to find correlations among medication literacy, self-efficacy and medication adherence. The PROCESS macro (Version 4.1) with Model 4 for SPSS was used to verify the mediating role of self-efficacy.Results: Twenty-four percent of the participants had poor medication adherence. Self-efficacy and medication literacy (r=0.499, p < 0.01) and medication adherence (r=0.499, p < 0.01) were significantly and positively correlated. Self-efficacy partially mediated the relationship between medication knowledge and medication adherence among patients with type 2 diabetes, accounting for 36.7% of the total effect.Conclusion: Self-efficacy had a partial mediating effect on the relationship between medication literacy and medication adherence among patients with type 2 diabetes. Self-efficacy should be improved through effective measures to increase patients’ confidence in adherence to antihyperglycemic drugs.Keywords: type 2 diabetes, medication literacy, medication adherence, self-efficacy, mediating effect

Kang Huang,1,&ast; Tianyi Ma,1,&ast; Qiang Li,1 Yilei Zhou,2 Ting Qin,1 Zanrui Zhong,1 Shilin Tang,1 Wei Zhang,1 Jianghua Zhong,1 Shijuan Lu1 1Department of Cardiovascular Medicine, Central South University Xiangya School of Medicine Affiliated Haikou Hospital, Haikou, People’s Republic of China; 2Medical College, Jingchu University of Technology, Jingmen, Hubei, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shijuan Lu, Department of Cardiovascular Medicine, Central South University Xiangya School of Medicine Affiliated Haikou Hospital, No. 43, Renmin Avenue, Haidian Island, Haikou, Hainan, 570100, People’s Republic of China, Tel/Fax +86-13005013999, Email lushijuan122@163.comBackground: The pathophysiological mechanism of ischemic stroke is complex. Traditional risk factors cannot fully or only partially explain the occurrence and development of IS. Genetic factors are getting more and more attention. Our study aimed to explore the association between CYP4F2 gene polymorphism and susceptibility to IS.Methods: A total of 1322 volunteers were enrolled to perform an association analysis through SNPStats online software. Using FPRP (false-positive report probability) to detect whether the result is a noteworthy finding. The interaction of SNP-SNP in IS risk was assessed by multi-factor dimensionality reduction. Statistical analysis of this study was mainly completed by SPSS 22.0 software.Results: Mutant allele “A” (OR = 1.24) and genotype “AA” (OR = 1.49) or “GA” (OR = 1.26) of CYP4F2-rs2108622 are risk genetic factors for IS. Rs2108622 is significantly associated with an increased risk of IS among subjects who are females, aging > 60 years old, with BMI ≥ 24 kg/m2, and smoking or drinking volunteers. CYP4F2-rs3093106 and -rs3093105 are associated with susceptibility to IS among smoking, drinking subjects, or IS patients complicated with hypertension.Conclusion: CYP4F2-rs2108622, -rs3093106, and -rs3093105 are associated with an increased risk of IS.Keywords: ischemic stroke, susceptibility, CYP4F2, genetic variants, association analysis

Kang Huang,1 Tianyi Ma,1 Qiang Li,1 Zanrui Zhong,1 Ting Qin,1 Yilei Zhou,2 Wei Zhang,1 Shilin Tang,1 Jianghua Zhong,1 Shijuan Lu1 1Department of Cardiology, Haikou People’s Hospital, Central South University Xiangya School of Medicine Affiliated Haikou Hospital, Haikou, Hainan, 570100, People’s Republic of China; 2Jingchu University of Technology, School of Medicine, Jingmen, Hubei, 448000, People’s Republic of ChinaCorrespondence: Shijuan Lu, Department of Cardiology, Haikou People’s Hospital, Central South University Xiangya School of Medicine Affiliated Haikou Hospital, No. 43, Renmin Avenue, Haidian Island, Haikou, 570100, Hainan, People’s Republic of China, Tel +86-13005013999, Email Lu_shijuan@163.com Jianghua Zhong, Jingchu University of Technology, School of Medicine, No. 33, Xiangshan Avenue, Jingmen, Hubei, 448000, People’s Republic of China, Tel +86-13322003882, Email zhong3882@163.comIntroduction: Ischemic stroke (IS) is a multifactorial and polygenic disease, which is affected by genetic factors. In this study, we explored the role of CYP19A1 single nucleotide polymorphisms (SNPs) in IS in the Chinese population.Methods: 1302 subjects (651 controls and 651 cases) were recruited in this case–control study. Four candidate SNPs (rs28757157 C/T, rs3751592 C/T, rs3751591 G/A, rs59429575 C/T) of CYP19A1 were selected by the 1000 genomes project database. The association between CYP19A1 SNPs and IS risk was assessed using logistic regression analysis with odds ratio (OR) and 95% confidence intervals (CIs). False-positive report probability (FPRP) analysis further verified the positive results. The interaction of SNP-SNP was analyzed by multi-factor dimensionality reduction (MDR) to predict is risk.Results: In the research, CYP19A1 loci (rs28757157 and rs3751591) were associated with the occurrence of IS. The two variants conferred an increased susceptibility to IS in the subjects aged over 60 years old, smokers and drinkers. Rs28757157 was related to the risk of IS in females, non-smokers and subjects with BMI less than 24, while rs59429575 was related to the risk of IS in males and subjects with BMI greater than 24.Conclusion: The study revealed that there is a significant association between CYP19A1 loci (rs28757157 and rs3751591) and IS risk in the Chinese Han population, providing a theoretical basis for further exploring its specific role in the pathogenesis of IS.Keywords: ischemic stroke, risk, CYP19A1, single nucleotide polymorphisms, case-control study, Chinese Han population

Wenli Hui, Wenhua Mu, Cong Zhao, Dan Xue, Zihua Zhong, Yani Fang, Ming Gao, Xiao Li, Shihao Gao, Kaiyue Liu, Kunping Yan College of Life Science, Northwest University, Xi’an City, Shaanxi Province, 710069, People’s Republic of ChinaCorrespondence: Kunping Yan, Email kpyan@nwu.edu.cnIntroduction: A limitation of hemoglobin-based oxygen carriers (HBOCs) as oxygen therapeutics is unpolymerized hemoglobin, which induces vasoconstriction leading to hypertension. The removal of unpolymerized hemoglobin from polymerized hemoglobin (PolyHb) is complex, expensive, and time-consuming.Methods: Herein, we developed a method to completely polymerize hemoglobin almost without unpolymerized hemoglobin. Hemoglobin was adsorbed on the anion-exchange resin Q Sepharose Fast Flow or DEAE Sepharose Fast Flow, and acetal, a crosslinker prepared from glutaraldehyde and ethylene glycol, was employed to polymerize the hemoglobin. The polymerization conditions, including reaction time, pH, resin type, and molar ratios of glutaraldehyde to ethylene glycol and hemoglobin to acetal, were optimized. The blood pressure and blood gas of mice injected with PolyHb were monitored as well.Results: The optimal polymerization condition of PolyHb was when the molar ratio of glutaraldehyde to ethylene glycol was 1:20, and the molar ratio of 10 mg/mL hemoglobin adsorbed on anion-exchange resin to glutaraldehyde was 1:300 for 60 min. Under optimized reactive conditions, hemoglobin was almost completely polymerized, with < 1% hemoglobin remaining unpolymerized, and the molecular weight of PolyHb was more centrally distributed. Furthermore, hypertension was not induced in mice by PolyHb, and there were also no pathological changes observed in arterial oxygen, blood gas, electrolytes, and some metabolic indicators.Conclusion: The findings of this study indicate that the use of solid-phase polymerization and acetal is a highly effective and innovative approach to HBOCs, resulting in the almost completely polymerized hemoglobin. These results offer promising implications for the development of new methods for preparing HBOCs.Graphical Abstract: Keywords: polymerized hemoglobin, glutaraldehyde, acetal, solid-phase adsorption, hemoglobin-based oxygen carriers, HBOCs

Bei Tang, Ze Zhong, Jinping Wu, Jianping Ma, Li Li, Xuzheng Zhong, Dongmei Lin, Jiayuan Hu, Pingan Yu Department of Critical Care Medicine, The First People’s Hospital of Jiande City, Jiande, People’s Republic of ChinaCorrespondence: Ze Zhong, Department of Critical Care Medicine, The First People’s Hospital of Jiande City, Jiande, People’s Republic of China, Tel/Fax +86 571 64096607, Email jdsytbzz@126.comObjective: Involvement of NLR CARD domain containing 4 (NLRC4) in neuroinflammation has been demonstrated. The aim of this study was to ascertain the prognostic role of serum NLRC4 in severe traumatic brain injury (sTBI).Methods: In this prospective cohort study including 140 sTBI patients and 140 controls, serum NLRC4 levels were quantified. Follow-up time was 180 days after trauma and poor prognosis was designated as extended Glasgow outcome scale (GOSE) scores of 1– 4. Severity correlations and prognosis associations were determined under multivariate models.Results: Enhanced serum NLRC4 levels after sTBI, in comparison to controls (median, 0.8 ng/mL versus 0.1 ng/mL; P < 0.001), were independently correlated with Glasgow coma scale (GCS) scores (β, − 0.091; 95% confidence interval (CI), − 0.161— 0.021; P = 0.011), Rotterdam computed tomography (CT) scores (β, 0.136; 95% CI, 0.024– 0.248; P = 0.018), serum C-reactive protein levels (β, 0.016; 95% CI, 0.002– 0.030; P = 0.025) and 180-day GOSE scores (β, − 0.906; 95% CI, − 1.632— 0.180; P = 0.015); and were independently predictive of 180-day death (odds ratio, 4.307; 95% CI, 1.706– 10.879; P = 0.014)), overall survival (hazard ratio, 2.360; 95% CI, 1.118– 4.981; P = 0.040) and poor prognosis (odds ratio, 6.705; 95% CI, 2.889– 15.561; P = 0.016). Under receiver operating characteristic curve, combination of serum NLRC4 levels, GCS scores and Rotterdam CT scores had significantly higher death predictive ability than Rotterdam CT scores (P = 0.040), but not than GCS scores (P = 0.070); and exhibited substantially higher predictive capability for poor prognosis than Rotterdam CT scores (P < 0.001) and GCS scores alone (P = 0.023).Conclusion: There is a dramatical elevation of serum NLRC4 levels after sTBI, which has strong correlation with severity and inflammation, and is significantly associated with long-term death and poor outcome, substantializing serum NLRC4 as an inflammatory, prognostic biomarker in sTBI.Keywords: traumatic brain injury, nucleotide-binding domain leucine-rich repeat-containing protein family caspase activation and recruitment domain-containing protein 4, severity, prognosis, biomarkers, inflammation

Shuliang Chen,1,2,&ast; Qi Li,1,&ast; Xueliang Zou,3 Zhijun Zhong,1 Qian Ouyang,1 Mengmeng Wang,1 Yaxing Luo,1 Dongyuan Yao1 1Neurological Institute of Jiangxi Province and Department of Neurology, Jiangxi Provincial People’s Hospital and The First Affiliated Hospital of Nanchang Medical College, Jiangxi, People’s Republic of China; 2Queen Mary College, Nanchang University, Jiangxi, People’s Republic of China; 3Jiangxi Mental Hospital, Nanchang University, Jiangxi, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Dongyuan Yao, Jiangxi Provincial People’s Hospital, 92 Aiguo Road, Nanchang, Jiangxi, 330006, People’s Republic of China, Tel/Fax +86-791-8689-5077, Email yao9000@gmail.comObjective: To investigate whether continuous positive airway pressure (CPAP) treatment would change EEG activities associated with cyclic alternating pattern (CAP subtype A1, A2, and A3) and non-CAP (NCAP) during non-rapid eye movement sleep stage 3 (N3) in patients with obstructive sleep apnea (OSA).Methods: The effects of CPAP treatment on the percentages of sleep stage N3 occupied by the CAP and NCAP, power of EEG waves in the CAP and NCAP were examined in 18 patients with moderate-to-severe OSA undergoing polysomnographic recordings.Results: Apnea and hypopnea index during sleep stage N3 was positively correlated with ratios of phases A2 and A3 duration to total phase A duration [Phase (A2+A3) /Phase A] and negatively correlated with phase A1/phase A. With CPAP treatment, percentages of sleep stage N3 occupied by total CAPs and subtypes A2 and A3, as well as CAP A2 and CAP A3 indexes were significantly decreased while percentages of sleep stage N3 occupied by NCAP (NCAP/N3) and CAP A1 index were significantly increased. In addition, CPAP treatment significantly decreased percentage of respiratory events associated CAPs and increased percentage of non-respiratory related CAPs. Moreover, absolute and relative delta power was significantly increased during phase A1, unchanged during phase A2 and phase B2, and significantly decreased during phases B1, A3 and B3. The absolute power of faster frequency EEG waves in CAPs showed a general trend of decrease. The absolute and relative power of delta waves with amplitudes ≥ 75 μV, but not < 75 μV, was significantly increased.Conclusion: CPAP treatment improves the sleep quality in OSA patients mainly by increasing delta power and decreasing power of higher frequency waves during phase A1, and decreasing CAP A2 and A3 indexes as well as increasing NCAP/N3 and power of delta waves with amplitudes ≥ 75 μV during NCAP.Keywords: obstructive sleep apnea, continuous positive airway pressure, polysomnographic recordings, non-rapid eye movement sleep, cyclic alternating pattern

Zhiquan Ding1 &ast;, Zhenzhong Zhong1 &ast;, Jun Wang1 &ast;, Run Zhang,2 Jinlian Shao,3 Yulong Li,1 Guiwei Wu,1 Huiru Tu,1 Wen Yuan,4 Haitao Sun,1,5 Qinghua Wang1,3 1Neurosurgery Center, Department of Neurotrauma and Neurocritical Care Medicine, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Zhujiang Hospital, Southern Medical University, Guangzhou, People’s Republic of China; 2Neurosurgery Center, Department of Neuro-oncological Surgery, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Zhujiang Hospital, Southern Medical University, Guangzhou, People’s Republic of China; 3Department of Emergency, Zhujiang Hospital, Southern Medical University, Guangzhou, People’s Republic of China; 4Laboratory Animal Center, Zhujiang Hospital, Southern Medical University, Guangzhou, People’s Republic of China; 5Clinical Biobank Center, Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qinghua Wang; Haitao Sun, Neurosurgery Center, Department of Neurotrauma and Neurocritical Care Medicine, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Zhujiang Hospital, Southern Medical University, Guangzhou, People’s Republic of China, Email wqh1123@126.com; 2009sht@smu.edu.cnBackground: Neuroinflammation plays an important role following intracerebral hemorrhage (ICH). NLRP3 inflammasome-mediated pyroptosis contributes to the mechanism of neuroinflammation. It has been reported that dendritic cell-associated C-type lectin-1 (Dectin-1) activation triggers inflammation in neurological diseases. However, the role of Dectin-1 on NLRP3 inflammasome-mediated pyroptosis after ICH remains unclear. Here, we aimed to explore the effect of Dectin-1 on NLRP3 inflammasome-mediated pyroptosis and neuroinflammation after ICH.Methods: Adult male C57BL/6 mice were used to establish the ICH model. Laminarin, an inhibitor of Dectin-1, was administered for intervention. Expression of Dectin-1 was evaluated by Western blot and immunofluorescence. Brain water content and neurobehavioral function were tested to assess brain edema and neurological performance. Western blot was conducted to evaluate the level of GSDMD-N. ELISA kits were used to measure the levels of IL-1β and IL-18. qRT–PCR and Western blot were performed to evaluate the expressions of NLRP3 inflammasome, IL-1β, and IL-18.Results: The expression of Dectin-1 increased following ICH, and Dectin-1 was expressed on microglia. In addition, inhibition of Dectin-1 by laminarin decreased brain edema and neurological impairment after ICH. Moreover, inhibition of Dectin-1 decreased the expression of pyroptosis-related protein, GSDMD-N, and inflammatory cytokines (IL-1β and IL-18). Mechanistically, Dectin-1 blockade inhibits NLRP3 inflammasome activation, thereby alleviating neuroinflammatory injury by attenuating NLRP3 inflammasome-mediated pyroptosis both in vivo and in vitro.Conclusion: Our study indicates that the inhibition of Dectin-1 alleviates neuroinflammation by attenuating NLRP3 inflammasome-mediated pyroptosis after ICH.Keywords: intracerebral hemorrhage, Dectin-1, NLRP3 inflammasome, pyroptosis, microglia

Li Chen,1,&ast; Maohua Wang,2,&ast; Zhenhua Zhong,3,&ast; Baoxu Liu,1 Wentao Zhang,4 Bin Zhu,4 Cheng Jiao,4 Chenjie Yu,5 Bing Guan4 1Department of Otolaryngology, Head and Neck Surgery, Dalian Medical University, Dalian, 116000, People’s Republic of China; 2Department of Otolaryngology, Head and Neck Surgery, The First People’s Hospital of Foshan, Foshan, 528000, People’s Republic of China; 3Department of Otolaryngology, Head and Neck Surgery, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, 225000, People’s Republic of China; 4Department of Otolaryngology, Head and Neck Surgery, Clinical Medical College, Yangzhou University, Yangzhou, 225001, People’s Republic of China; 5Department of Otolaryngology, Head and Neck Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, Jiangsu Provincial Key Medical Discipline (Laboratory), Nanjing, 210008, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Chenjie Yu, Department of Otolaryngology, Head and Neck Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, Jiangsu Provincial Key Medical Discipline (Laboratory), Nanjing, 210008, People’s Republic of China, Tel/Fax +86-13705168089, Email entphd@163.com Bing Guan, Department of Otolaryngology, Head and Neck Surgery, Clinical Medical College, Yangzhou University, Yangzhou, 225001, People’s Republic of China, Tel/Fax +86-18051063666, Email aliceguan0685@sina.comAbstract: Pharyngocutaneous fistula is the most common complication after total laryngectomy and is difficult to heal. Although conservative treatment and surgical repair are effective, they often take longer and additional trips to the operating room, which undoubtedly increases the financial burden on patients. Especially in combination with diseases such as diabetes and hypertension, which affect the efficacy of surgery. Adding growth factors into the repair material can promote fibroblast proliferation, angiogenesis, and accelerate wound healing. A substantial number of studies have shown that a type of nanoscale extracellular vesicle, called exosomes, facilitates organization repair by promoting blood vessel production, protein polysaccharides, and collagen deposition, thereby representing a new type of cellular therapy. At present, there is little research on the application of exosomes in pharyngocutaneous fistula regeneration after total laryngectomy. In this review, we summarize the biological characteristics of exosomes and their application in biomedical science, and highlight their application prospects in pharyngocutaneous fistula regeneration after total laryngectomy.Keywords: exosomes, extracellular vesicle, head and neck squamous cell carcinoma, pharyngocutaneous fistula, tissue repair and regeneration, bioengineering

Ying Liu,1,&ast; Zhifang Zhong,1,&ast; Zhihong Li,1,&ast; Xin Li,2 Shengkun Zhang,2 Jie Sun,1 Jingfang Zhai,3 Xuekui Liu,4 Min Liu1 1Department of Ultrasound, Xuzhou Central Hospital, Xuzhou, People’s Republic of China; 2Department of Obstetrical and Gynecological, Xuzhou Central hospital, Xuzhou, People’s Republic of China; 3Prenatal Diagnosis Center, Xuzhou Central Hospital, Xuzhou, People’s Republic of China; 4Department of Endocrinology, Xuzhou Central hospital, Xuzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Min Liu, Department of Ultrasound, Xuzhou Central Hospital, Jiefang Road 199#, Xuzhou, 221009, People’s Republic of China, Email 24187358@qq.com Xuekui Liu, Department of Endocrinology, Xuzhou Central Hospital, Jiefang Road 199#, Xuzhou, 221009, People’s Republic of China, Email liuxuekui314@njmu.edu.cnAim: Exposure to famine in early life has been shown to increase the prevalence of non-alcoholic fatty liver disease (NAFLD). Neutrophil-to-lymphocyte ratio (NLR) is a risk factor for developing NAFLD. However, it is not clear that the association between NLR and NAFLD in individuals who were exposed to famine in early life.Methods: To match for age, we selected two group populations from Xuzhou city, China, on two different occasions, 2013 and 2017. The group recruited in 2013 included participants who were born during a period of great famine in China. Participants in the another group recruited in 2017 were born between 1965 and 1968. Clinical characteristics of individuals as well as serology indexes were examined for all participants. Ultrasonography to diagnose NAFLD was performed by trained doctors. A total of 10,574 participants were included in the final analysis.Results: Individuals born during the famine period have a higher NAFLD prevalence than those who had not been exposed to famine and these findings were similar for both sexes (male: 57.6% vs 48.9%, female: 47.6% vs 40.3%). The prevalence of NAFLD according to NLR quartiles in those exposed to famine was 49.5%, 52.7%, 52.9% and 55.5% for Q1, Q2, Q3 and Q4 NLR, respectively, and was higher than that in non-exposed to famine group. After adjusting for age, BMI, and other metabolic variables, the association between NLR and NAFLD disappeared in the non-famine group. The non-linear relationship between NLR and NAFLD was found in those who had been exposed to famine.Conclusion: Individuals who were exposed to famine in early life have a higher prevalence of NAFLD than those who were not exposed. Compared with lower NLR levels, elevated NLR is a risk factor for developing NAFLD. However, there is a non-linear relationship between NLR and the risk of developing NAFLD.Keywords: non-alcoholic fatty liver disease, famine, neutrophil-to-lymphocyte ratio, non-linear relationship

Yifan Wang,1– 3 Shan Wang,1– 3 Liyun Zheng,1– 3 Xiuli Wang,1– 3 Hui Wang,1– 3 Zhenyu Zhong,1– 3 Siqi Liu,1– 3 Xiaodong Zheng,1– 3 Min Gao1– 3 1Department of Dermatology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People’s Republic of China; 2Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, Anhui, People’s Republic of China; 3Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, People’s Republic of ChinaCorrespondence: Min Gao; Xiaodong Zheng, Department of Dermatology, the First Affiliated Hospital of Anhui Medical University, No. 81 Meishan Road, Hefei, Anhui, 230032, People’s Republic of China, Tel/Fax +86-0551-62923042, Email ahhngm@126.com; zhengxiaodong.1234@163.comAbstract: SAPHO (synovitis, acne, pustulosis, hyperostosis, and osteitis) syndrome is a rare disease clinically characterized by a wide range of cutaneous and osteoarticular manifestations. Here, we report a case of SAPHO syndrome with cutis verticis gyrata (CVG) and investigated the genetic causes in the four members of this pedigree. After failure of conventional treatments, a recombinant human TNF-α receptor II:IgG Fc fusion protein (rhTNFR:Fc, YISAIPU®) achieved good control of the disease at the 2-year follow-up. We did not identify any pathogenic mutation in this pedigree. We also summarized the clinical and therapeutic characteristics of 83 patients with SAPHO syndrome through the China National Knowledge Infrastructure (CKNI) database from 2016 to 2021. Patients with acne were young and predominantly male. About 45.8% patients were treated with biological therapies or traditional Chinese medicine (TCM), 84.2% of which showed positive effects against cutaneous and osteoarticular manifestations. We report a case of SAPHO syndrome with CVG that was successfully treated with rhTNFR:Fc. Our results reveal the genetic heterogeneity involved. Biologics and TCM are likely alternative options for the treatment of SAPHO syndrome.Keywords: cutis verticis gyrata, gene mutation, SAPHO syndrome, treatment, whole-exome sequencing

Zhiying Shen,1,2 Zhuqing Zhong,2,3 Jianfei Xie,2,3 Qiuxiang Zhang,2,3 Shougen Li4 1Department of Hematology, Third Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 2Clinical Nursing Safety Management Research Center of Central South University, Third Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 3Department of Nursing, Third Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 4Emergency Department, Third Xiangya Hospital, Central South University, Changsha, People’s Republic of ChinaCorrespondence: Qiuxiang Zhang; Shougen Li, Email nursing_qiuxiangz@163.com; xiaosa20130103@126.comBackground: The COVID-19 pandemic caused by the novel SARS-CoV-2 virus represents an ongoing public health challenge that necessitates a heightened need to understand people’s risk perceptions as well as their information-seeking behavior.Objective: The aim of this study is to explore the impact of different information-seeking behaviors on people’s risk perceptions during the COVID-19 pandemic.Methods: We employed convenience sampling in order to administer questionnaires to 3048 residents in Hunan Province, China. After screening the questionnaires for inclusion in the study, multiple linear regressions were then used to analyze the impact of the characteristics of respondents’ information-seeking behavior on their risk perceptions.Results: From the 3048 distributed 2611 were included. New media (80.20%) was the most frequently used source of information seeking, and traditional media were participants’ most trusted source of COVID-19 information. Statistics of COVID-19 were the type of information most frequently queried by respondents, and approximately 30.0% of them reported that most or all of the COVID-19 information they sought was negative. Approximately one in five respondents reported that they sought COVID-19 information more than 10 times per day. The results of our multivariate linear regression analysis showed that “seeking information from new media ”, “level of trust in new media and local propaganda”, “information content being about protective behaviors and personal related information”, “proportion of negative information”, and “frequency of information seeking” were positively associated, and “seeking information from traditional media” and “level of trust in traditional media” were negatively associated with people’s risk perception of COVID-19.Conclusion: We find that specific types of channels of information acquisition and public trust in these information channels, their informational content, and proportion of negative information, as well as a frequency of information seeking all had an impact on risk perception during COVID-19.Keywords: information seeking behavior, risk perception, COVID-19

Xu Yin,1 Xiang Zhong,2 Jun Li,1 Ma Le,1 Shiting Shan,1 Chunfu Zhu1 1Department of Hepatobiliary and Pancreatic Surgery, Changzhou No.2 People’s Hospital Affiliated with Nanjing Medical University, Changzhou, Jiangsu, 213000, People’s Republic of China; 2Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu, 226000, People’s Republic of ChinaCorrespondence: Chunfu Zhu, Email zcfmlm@njmu.edu.cnObjective: To explore the value of modified RANSON score in predicting mortality from severe acute pancreatitis (SAP).Methods: In this retrospective study, 461 SAP patients hospitalized from January 2016 to January 2020 were enrolled. AP (acute pancreatitis) patients from our hospital were employed as the training set. In addition, AP patients from the affiliated hospital of Nantong University were set as the validation set. The clinical characteristics of patients were compared between the two sets. The independent risk factors for SAP were determined through logistic regression. Moreover, the risk factors were derived for various prediction models by logistic regression. Multiple methods were adopted to assess the predictive ability of various models.Results: A total of 338 patients were assigned into the training set, while 123 patients were assigned into the validation set. The patients in the training and validation sets showed the consistent distribution trends (P> 0.05). In the training set, significant differences between patients in the non-survival and survival groups were BMI, PCT, platelets (PLT), direct bilirubin (DBil) and RANSON scores (P< 0.05). In further multivariate analysis, BMI, PCT and RANSON score were found as the independent risk factors for the mortality of SAP (OR=1.12, 1.25, 1.28, 95% CI:1.06– 1.19, 1.08– 1.44, 1.12– 1.47, P< 0.05). In the training set and validation set, ROC curve analysis showed that AUC of BMI+RANSON score was 0.778 and 0.789, respectively. In the calibration curve, the fitting degree of RANSON score+BMI and ideal assessment model was 0.975 and 0.854, respectively. The decision curve suggested that the net benefit per patient increased with the lengthening of the RANSON score+ BMI model curve. As revealed by the results of NRI and IDI indicators, RANSON score+BMI was optimized based on RANSON score (P< 0.05).Conclusion: BMI+RANSON was confirmed as a modified model effective in predicting the mortality from SAP.Keywords: SAP, BMI, RANSON score, mortality, model

Hangbin Hu,1,&ast; Yifeng Lou,1,2,&ast; Haiting Feng,3 Jingjing Tao,1 Weixiao Shi,1 Shuangling Ni,4 Qunying Pan,3 Tianxiang Ge,3 Ping Shen,1 Zifeng Zhong,3 Yonghong Xiao,1 Tingting Qu1,3 1State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People’s Republic of China; 2Infectious Disease Department, Sanmen People’s Hospital, Taizhou, Zhejiang, People’s Republic of China; 3Infection Control Department, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People’s Republic of China; 4Infectious Disease Department, Lishui People’s Hospital, Lishui, Zhejiang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Tingting Qu; Yonghong Xiao, Tel +86 571 87236673, Email qutingting@zju.edu.cn; yonghong@163.comObjective: Critical patients in intensive care unit (ICU) are highly susceptible to acquiring carbapenem-resistant Acinetobacter baumannii (CRAB) infection. To investigate the relationship between nosocomial infections and environmental health, we studied the distribution and homology of CRAB isolates from patients and environment and evaluated the effectiveness of infection control measures.Methods: In the 4-month study, we conducted a monthly CRAB screening of the ICU environment prior to disinfection in a Chinese teaching hospital. The ICU underwent routine disinfection procedures twice a day. We collected samples from the environment around the patients before disinfection. Clinical specimens from patients were also screened. The samples obtained were studied for phenotype and homology via antibiotic susceptibility testing, pulsed-field gel electrophoresis (PFGE), and whole-genome sequencing (WGS).Results: Ten specimens were sampled from ICU environments. Five were obtained in May 2020, and sputums from patient a in bed A at this time were cultured for CRAB isolates; in June 2020 another 5 environmental specimens were obtained from the same bed unit for CRAB, and sputums from patient b in bed A at this time were also cultured for CRAB isolates. Following intensive infection control measures, environmental sampling was negative in July and August. These 18 CRAB isolates all carried OXA-66 and OXA-23 genes and showed a similar resistance phenotype. WGS showed a close relationship among specimens from patients’ sputum and their surroundings, but no homology between patients.Conclusion: The analysis of cgMLST and SNPs is more accurate for strain homology analysis. Our data confirm that CRAB isolates spread from patient to environment in ICU; however, contact isolation and disinfection measures are effective in avoiding transmission, highlighting the importance of continued education and surveillance of CRAB. WGS could provide rich information on antimicrobial resistance, which is of great value in scientific research and clinical diagnosis.Keywords: carbapenem-resistant Acinetobacter baumannii, intensive care unit, whole genome sequencing, cgMLST, PFGE

Yu Luo,1,2,&ast; Heming Wu,2,3,&ast; Qingyan Huang,2,3 Hui Rao,2,3 Zhikang Yu,2,3 Zhixiong Zhong2,3 1Department of Gynaecology, Meizhou People’s Hospital (Huangtang Hospital), Meizhou Academy of Medical Sciences, Meizhou, People’s Republic of China; 2Guangdong Provincial Key Laboratory of Precision Medicine and Clinical Translational Research of Hakka Population, Meizhou People’s Hospital (Huangtang Hospital), Meizhou Academy of Medical Sciences, Meizhou, People’s Republic of China; 3Center for Precision Medicine, Meizhou People’s Hospital (Huangtang Hospital), Meizhou Academy of Medical Sciences, Meizhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhikang Yu; Zhixiong Zhong, Center for Precision Medicine, Guangdong Provincial Key Laboratory of Precision Medicine and Clinical Translational Research of Hakka Population, Meizhou People’s Hospital (Huangtang Hospital), Meizhou Academy of Medical Sciences, No. 63 Huangtang Road, Meijiang District, Meizhou, 514031, People’s Republic of China, Tel +753-2131-591, Email yuzhikang01@126.com; zhongzhixiong01@126.comObjective: To investigate the frequencies of BRCA1 and BRCA2 mutations in Chinese Hakka patients with ovarian cancer.Methods: The protein coding regions and exon intron boundary regions of the BRCA gene were sequenced using genomic DNA isolated from the lymphocytes of patients with next-generation sequencing. The patients’ family history and clinical records were collected.Results: A total of 195 patients with ovarian cancer were included in the study, and 52 distinct variants of the BRCA gene were identified. It was found that 64 patients (64/195, 32.8%) had BRCA gene mutations, including 32 patients (50.0%) with BRCA1 mutation, 27 patients (42.2%) with BRCA2 mutation, and 5 patients (7.8%) with both mutations. Furthermore, 22 pathogenic mutations were detected in 26 patients, 2 likely pathogenic variants in 2 patients, 12 variants of uncertain significance in 20 patients, and 16 likely benign variants in 24 patients. The mutations were mainly found to occur in exons 8, 14, and 17 of BRCA1 and exons 10, 11, 14, and 15 of BRCA2. The results showed that the BRCA genes possess different mutation hotspots in different ethnic groups. In addition, recurrent mutations were noted in many patients. BRCA1 c.536 A>T, considered a founder mutation, was identified in 10 patients (15.63%, 10/64), followed by BRCA1 c.2635 G>T (6.25%, 4/64) and BRCA2 c.2566 T>C (6.25%, 4/64).Conclusion: The BRCA1 c.536 A>T could be considered to be a founder mutation in this ovarian cancer population. This recurrent BRCA1 mutation has rarely been observed in other ethnic groups. Our findings are expected to provide valuable data for clinical consultation and for designing individualized treatment for ovarian cancer.Keywords: BRCA gene, ovarian cancer, variants, Hakka population

Mian Shu, Zhengqiang Zhong, Han Ren Business School, Sichuan University, Chengdu, Sichuan, People’s Republic of ChinaCorrespondence: Han RenBusiness School, Sichuan University, No. 24 South Section 1, Yihuan Road, Chengdu, Sichuan, 610064, People’s Republic of China, Email renhan_90_12@126.comPurpose: Drawing on social judgement theory and the self-determination theory, this study aims to test the moderating roles of employees’ extraversion and task performance in the effects of employees’ voice on leaders’ endorsement, as well as the mediating role of leaders’ voice endorsement in the relationship between employees’ voice and creativity, and more importantly, the moderated mediation model.Methods: A total of 250 employees and their direct leaders participated in the two-wave multi-source survey. To examine the hypotheses, we conducted the hierarchical regression and bootstrapping analyses on the basis of Hayes PROCESS Model.Results: Findings revealed that both extraversion and task performance serve as moderators in the effects of employees’ voice on leaders’ voice endorsement. Leaders’ voice endorsement significantly mediates the relationship between employees’ voice and creativity. More importantly, the results indicated that the indirect effect of leaders’ voice endorsement on the association of employees’ voice and creativity is significantly positive only when the employees are extraverted high performers, that is, there is a significant moderated mediation.Conclusion: The present study extends the current literature by exploring the moderated mediation mechanism between employees’ voice, extraversion, task performance, leaders’ voice endorsement, and employees’ creativity. Our findings recommend leaders to be aware of the mediating role of their endorsement of employees’ voice and the moderating roles of employees’ extraversion and performance in linking employees’ voice to their creativity.Keywords: voice endorsement, extraversion, task performance, creativity, moderated mediation

Magnetic reconnection is a fundamental process known to play a crucial role in electron acceleration and heating, however, the mechanism of electron energization during reconnection is still not fully understood. This study introduces a novel electron acceleration mechanism in which electrons can be accelerated by secondary reconnection in the separatrix region. The secondary reconnection occurs in a thin current sheet resulted from the shear of the out‐of‐plane Hall magnetic fields of the primary magnetopause reconnection. It results in the intense electron energy fluxes toward the primary X‐line. This mechanism will likely be an important piece in the puzzle of particle acceleration by reconnection. Plain Language Summary: Magnetic reconnection is a fundamental process that plays a critical role in electron acceleration and heating. The separatrix region of magnetic reconnection, which distinguishes the inflow and outflow regions, is a crucial area in the particle acceleration of the reconnection process. However, previous studies mainly focused on the electron acceleration mechanism in the separatrix region under two‐dimensional reconnection, without considering the influence of the three‐dimensional structures. This paper reports, for the first time, the secondary reconnection occurring in the opposite Hall magnetic field in the three‐dimensional separatrix region of magnetopause primary reconnection. This secondary reconnection can accelerate and heat the inflow electrons of the primary reconnection, which provides important clues on how the particles are accelerated and heated by reconnection. Key Points: Secondary reconnection occurs between Hall magnetic fields in the separatrix region of the primary magnetopause reconnectionIntense electron enthalpy fluxes are injected toward the primary X‐line along the separatrixElectrons are accelerated by the secondary reconnection before being injected into the primary X‐line for further energization [ABSTRACT FROM AUTHOR]

Zenghua Deng,1,2,&ast; Kanghua Huang,3,&ast; Dongfang Liu,1 Nan Luo,1,2 Tingting Liu,1 Long Han,1 Dexiao Du,1 Dongbo Lian,1,2 Zhaohui Zhong,4 Jirun Peng1,2 1Department of Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, 100038, People’s Republic of China; 2Ninth School of Clinical Medicine, Peking University, Beijing, 100038, People’s Republic of China; 3Department of Radiation Oncology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, People’s Republic of China; 4Department of General Surgery, Peking University People’s Hospital, Beijing, 100044, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jirun Peng; Zhaohui Zhong Email pengjr@medmail.com.cn; pengjr@bjsjth.cn; zhongzhaohui@pkuph.edu.cnBackground: Hepatocellular carcinoma (HCC) is the most common subtype of primary liver cancer, which causes ∼ 800,000 deaths annually world-wide. Immune checkpoint inhibitor (ICI) has reformed cancer therapy and achieved unprecedented results in various malignancies, including HCC. However, the response rate of immunotherapy is very low in HCC. Considereing the complicated and unique immune status in liver, we hypothesize that critical molecules will affect prognosis and correlate with immune context in the tumor microenvironment of HCC.Methods: Using Kaplan–Meier plotter, GEPIA2 and Integrative Molecular Database of Hepatocellular Carcinoma (HCCDB), survival genes and their prognostic value were estimated in HCC. Based on Tumor Immune Estimation Resource (TIMER), association between survival genes and immune infiltration was examined in HCC. FunRich and STRING were used to analyze gene ontology and protein–protein interaction (PPI) Network, qRT-PCR was used to measure mRNA level of candidates; and a Cell Counting Kit-8 was used to measure proliferation of HCC cell line.Results: Using multiple databases, we identified 36 key prognostic genes highly expressed in HCC and associated with poor survival of patients. Meanwhile, the 36 gene signatures correlated with immune infiltration in HCC. Moreover, these genes were significantly associated with exhausted T cells and polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) in HCC. Among the 36 key genes, SKA3, SGOL2, SPINDOC, TEDC2, TMCO3 and NUP205 were highly expressed in tumor samples compared with adjacent normal tissues in our HCC cohort (n=22). Additionally, proliferation of SMMC7721 cell line was inhibited when it interfered with SiRNA of each gene.Conclusion: The 36 genes may serve as potential prognostic biomarkers and molecular targets to ameliorate tumor immune microenvironment (TIME) in HCC and therefore represent a novel avenue for individualized immunotherapy in HCC.Keywords: HCC, prognosis, immune infiltrates, exhausted T cell, MDSC

Yudong Ning,1 Hong Yang,2 Sheng Qin,2 Bangrong Cao,3 Zuxian Zhong,4 Chuanshi He,5 Guiquan Zhu6 1Department of Head and Neck Surgery, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, People’s Republic of China; 2Department of Pathology, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, People’s Republic of China; 3Radiation Oncology Key Laboratory of Sichuan Province, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, People’s Republic of China; 4Department of Head and Neck Radiotherapy, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, People’s Republic of China; 5Sichuan Key Laboratory of Radiation Oncology, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610041, People’s Republic of China; 6Department of Head and Neck Oncology, West China Hospital of Stomatology, State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Sichuan University, Chengdu, 610041, People’s Republic of ChinaCorrespondence: Guiquan ZhuDepartment of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, No. 14, Section 3, Renmin South Road, Chengdu, Sichuan, 610041, People’s Republic of ChinaEmail zhugq@scu.edu.cnObjective: We aimed to identify new prognostic factors of oral squamous cell carcinoma (OSCC) among platelet-related parameters, establish a survival prediction model to predict the survival status of OSCC patients, and analyze the therapeutic effect of neoadjuvant chemotherapy on OSCC patients on the basis of real-world data.Materials and Methods: The real-world data of patients with OSCC confirmed by pathologic examination at Cancer Hospital from January 2011 to January 2015 and May 2017 to January 2020 were collected. We analyzed clinicopathologic factors using a Cox regression analysis, the Kaplan-Meier method, and propensity score matching (PSM).Results: The multivariate Cox regression analysis of not only validated the traditional prognostic factors such as tumor site, neural invasion, poor differentiation, and tumor-node-metastasis (TNM) stage but also identified a new prognostic factor, preoperative mean platelet volume (MPV) for overall survival (OS, HR, 0.47; 95% CI: 0.25– 0.89, P = 0.020). A nomogram was created to predict the probability of 3-year and 5-year OS. We found that neoadjuvant chemotherapy improved OS in patients with OSCC.Conclusion: Preoperative MPV, being associated with female, neoadjuvant chemotherapy, and advanced stage (Stage III and IV), may be a new prognostic factor for OS of patients with OSCC. The nomograms provided useful prediction for OS in OSCC patients. Neoadjuvant chemotherapy may improve the OS of patients with OSCC.Keywords: oral squamous cell carcinoma, overall survival, nomogram, mean platelet volume, neoadjuvant chemotherapy, induction chemotherapy

Zhanwang Xiang,1,&ast; Zhihui Zhong,2,&ast; Luwen Mu,1 Guohong Li,3 Churen Zhou,1 Haofan Wang,1 Mingsheng Huang1 1Interventional Radiology Program, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, People’s Republic of China; Guangdong Provincial Key Lab of Biomedical Imaging, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, 519000, People’s Republic of China; 2Department of Minimally Invasive Intervention, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, People’s Republic of China; 3Department of Radiology, Guangdong Second Provincial General Hospital, Guangdong Provincial Emergency Hospital, Guangzhou, 510000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Mingsheng Huang; Haofan WangInterventional Radiology Program, The Third Affiliated Hospital, Sun Yat-sen University, 600 Tianhe Road, Guangzhou, 510630, People’s Republic of China; Guangdong Provincial Key Lab of Biomedical Imaging, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, 519000, People’s Republic of ChinaEmail huangmsh@mail.sysu.edu.cn; wanghaof@mail.sysu.edu.cnPurpose: To further evaluate the efficacy and safety of computed tomography (CT)-guided iodine 125 (125I) brachytherapy to treat locally advanced non-small cell lung cancer (NSCLC) after progression of concurrent radiochemotherapy (CCRT).Methods: This study obtained written consent from all patients and was approved by our institution. From January 2006 to June 2018, 210 NSCLC patients (progression of first-line CCRT) were retrospectively recruited and then divided into two groups. A total of 116 patients were given CT-guided 125I brachytherapy and second-line chemotherapy (group A), and 94 were treated with second-line chemotherapy alone (group B).Results: In group A, local response rate (LRR) within 3 years was significantly better (P< 0.05). Mean survival time [progression-free survival time (PFST) and overall survival (OS)] was 15.1± 1.4 months and 21.2± 1.6 months in group A compared with 10.0± 1.4 months and 16.2± 1.7 months in group B (PFST: P< 0.01, HR=1.472, 95% CI 1.097– 1.975; OS: P = 0.036, HR=1.342, 95% CI 1.005– 1.791). Tumor size and No. of first cycle chemotherapy were independent factors that affected survival, ≤ 3cm largest tumor diameter and more than 4 first cycles of chemotherapy showed longer PFST and OS (P< 0.05). Tumor-related clinical symptoms were relieved in group A (P< 0.01). No serious complications occurred in the two groups.Conclusion: 125I brachytherapy is effective and safe in locally advanced NSCLC after progression of CCRT.Keywords: 125I, brachytherapy, NSCLC, concurrent radiochemotherapy, efficacy, safety

Jia Ouyang,1 Yu Jiang,2 Chao Deng,2 Zhiyuan Zhong,2 Qing Lan1 1Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, People’s Republic of China; 2Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, and State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, 215123, People’s Republic of ChinaCorrespondence: Zhiyuan Zhong; Qing Lan Tel/Fax +86-512-65880098Email szlq006@163.com; zyzhong@suda.edu.cnPurpose: Glioblastoma multiforme (GBM) poorly responds to chemotherapy owing to the existence of blood-brain barriers (BBB). It has been a long desire to develop BBB-permeable vehicles to facilitate drug targeting to GBM.Method and Results: Here, we report that doxorubicin hydrochloride loaded in ApoE peptide-functionalized reduction-sensitive polymersomes (ApoE-PS-DOX) induces potent therapy of orthotopic U-87 MG model in nude mice. ApoE-PS-DOX with varying amount of ApoE (10∼ 30 mol%) all had stable DOX loading and small sizes (< 90 nm). As revealed by flow cytometry, confocal microscopy, apoptosis and MTT assays, ApoE-PS-DOX with 20 mol.% ApoE induced the best cellular uptake and inhibitory effect to U-87 MG cells, which were much better than the non-targeted PS-DOX and liposomal doxorubicin (Lipo-DOX) used in the clinic. ApoE-PS-DOX revealed a pharmacokinetic profile comparable to PS-DOX but induced considerably better growth inhibition of orthotopically xenografted U-87 MG tumors in nude mice than PS-DOX and Lipo-DOX, leading to significant survival benefits with a median survival time of 44 days, which was almost doubled relative to the phosphate-buffered saline (PBS) group. Moreover, in contrast to mice treated with Lipo-DOX and PS-DOX, ApoE-PS-DOX group exhibited little body weight loss, signifying that ApoE-PS-DOX not only has low side effects but also can effectively inhibit glioblastoma invasion.Conclusion: This ApoE-docked multifunctional polymersomal doxorubicin induces potent and safe chemotherapy of orthotopic U-87 MG model in nude mice offering an alternative treatment modality for GBM.Keywords: apolipoprotein E, polymersomes, doxorubicin, brain tumor, blood-brain barrier

Liying Zhang,1,* Xinhua Chen,2,* Haili Wang,1 Haipeng Huang,1 Mengyuan Li,1 Lin Yao,1 Shiqi Ma,1 Zhen Zhong,1 Hongmei Yang,3 Hongfeng Wang4 1School of Acupuncture and Massage, Changchun University of Chinese Medicine, Changchun, Jilin, 130117, People’s Republic of China; 2Department of Acupuncture and Moxibustion, Affiliated Hospital of Changchun University of Chinese Medicine, Changchun, Jilin, 130021, People’s Republic of China; 3Jilin Ginseng Academy, Changchun University of Chinese Medicine, Jilin, 130117, People’s Republic of China; 4Northeast Asia Institute of Chinese Medicine, Changchun University of Chinese Medicine, Jilin, 130117, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hongmei Yang; Hongfeng WangJilin Ginseng Academy, Changchun University of Chinese Medicine, 1035 Boshuo Road, Changchun, Jilin, 130117, People’s Republic of ChinaTel/Fax +86 431 86763992Email yanghm@mit.eduHongfeng WangNortheast Asia Institute of Chinese Medicine, Changchun University of Chinese Medicine, 1035 Boshuo Road, Changchun, Jilin, 130117, People’s Republic of ChinaTel/Fax +86 431 89912521Email ccwhf@126.comIntroduction: Traditional Chinese acupuncture has been demonstrated to be beneficial for treatment of type 2 diabetes mellitus (T2DM). The mechanism of acupuncture on T2DM is crucial for their biological activity as well as their usefulness as tools in biology and medicine. However, its mechanism is poorly understood.Methods: In an effort to explore the mechanism, eight db/db mice (a type of spontaneous T2DM mouse) were treated with adjusting internal organs and dredging channel electroacupuncture (AODCEA) for 2 weeks. Another eight db/db mice were fed as T2DM group (T2DMG), and eight db/m mice were set as normal control group (NCG). Lipopolysaccharide (LPS), interleukin-6 (IL-6), and diabetes-related indicators, such as fasting blood glucose (FBG) and triglyceride (TG), were detected by enzyme-linked immune sorbent assay (ELISA). The V4 region of 16S rRNA gene was analyzed by Illumina sequencing to evaluate the effect of AODCEA on intestinal flora. The amount of short-chain fatty acids (SCFAs) in the feces were determined by gas chromatography-mass spectrometry (GC-MS).Results: Our results indicate that AODCEA treatment can reduce diabetes-related indicators. We observed the increased probiotics such as Blautia and Lactobacillus and decreased opportunist pathogens (Alistipes, Helicobacter, Prevotella) by AODCEA interventions. Importantly, the total amount of SCFAs in the feces of T2DM mice was promoted by AODCEA. Finally, obviously alleviated systemic inflammation was exhibited through AODCEA treatment by detection of lipopolysaccharide (LPS) and interleukin-6 (IL-6) in serum.Conclusion: AODCEA can reshape the structure of intestinal flora, which can increase intestinal SCFAs, affect the circulating LPS level, and reduce the inflammatory response.Keywords: gut microbiota, acupuncture, Type 2 diabetes mellitus, short-chain fatty acids, inflammation, insulin resistance

Tiantian Liang,1,* Rongtao Zhang,1,* Xianbin Liu,1,* Qian Ding,1 Siqiong Wu,1 Chunhong Li,2 Yan Lin,2 Yun Ye,1 Zhirong Zhong,2 Meiling Zhou1 1Department of Pharmacy, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, People’s Republic of China; 2Department of Pharmaceutical Sciences, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Meiling ZhouDepartment of Pharmacy, The Affiliated Hospital of Southwest Medical University, No. 25, Taiping Street, Luzhou, Sichuan, 646000, People’s Republic of ChinaEmail meilzhou@163.comZhirong ZhongDepartment of Pharmaceutical, Sciences School of Pharmacy, Southwest Medical University, No. 319 Zhongshan Road Jiangyang District, Luzhou, Sichuan, 646000, People’s Republic of ChinaEmail zhongzhirong@126.comAbstract: Macrophages have been extensively used in the development of drug delivery systems, as they can prolong the circulation and release of drugs, extend their half-life, increase their stability and targeting ability, and reduce immunogenicity. Moreover, they have good biocompatibility and degradability and offer abundant surface receptors for targeted delivery of a wide variety of drugs. Macrophage-mediated drug delivery systems can be prepared by loading drugs or drug-loaded nanoparticles into macrophages, macrophage membranes or macrophage-derived vesicles. Although such systems can be used to treat inflammation, cancer, HIV infection and other diseases, they require further research and optimization since they have been assembled from diverse sources and therefore can have quite different physical and chemical properties. Moreover, potential cell-drug interactions can limit their application, and the biological activity of membrane proteins might be lost during membrane extraction and storage. In this review, we summarize the recent advances in this field and discuss the preparation of macrophage-mediated drug delivery systems, their advantages over other delivery systems, their potential applications and future lines of research.Keywords: macrophage, macrophage membranes, drug delivery systems, inflammation, tumor, biomimetic

Zhiguo Zhong,1 Yuyun Li,2,3 Yan Chen,2,3 Wen Chen,2 Siyan Li,4 Xiaohua Lv,2 Shiying Luo2 1Traditional Chinese Medicine Department, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524023, People’s Republic of China; 2Department of Pharmacology, School of Pharmacy, Guangdong Key Laboratory for Research and Development of Natural Drugs, Marine Biomedical Research Institute, Guangdong Medical University, Zhanjiang, 524023, People’s Republic of China; 3Institute of Traditional Chinese Medicine and New Pharmacy Development, Guangdong Medical University, Dongguan, 523808, People’s Republic of China; 4School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, People’s Republic of ChinaCorrespondence: Shiying LuoDepartment of Pharmacology, School of Pharmacy, Guangdong Key Laboratory for Research and Development of Natural Drugs, Marine Biomedical Research Institute, Guangdong Medical University, No. 2 East Wenming Road, Xiashan District, Zhanjiang, 524023, Guangdong, People’s Republic of ChinaTel +86 13763058766Fax +86 7592388588Email luosy76@gdmu.edu.cnBackground: Erzhi Pill (EZP), a traditional Chinese medicine (TCM) prescription, has been widely applied to improve bone metabolism and treat osteoporosis (OP) in China. However, its effective constituents and mechanisms remain unclear.Methods: By combining network pharmacology and zebrafish experiments, an integrative method was employed to address this problem. Firstly, the disease targets of OP were collected from two public gene databases. Secondly, the active compounds and drug targets of EZP were obtained from the traditional Chinese medicine systems pharmacology database and analysis platform (TCMSP). Thirdly, a drug-target-disease interaction network was constructed, and the key active components were identified by analyzing the topological characteristics of the network. Finally, these predicted results were tested by zebrafish experiments and compared with those from the literature. Specifically, quercetin as an important representative active component of EZP was applied to wild type and transgenic zebrafish larvae to assess its effects on skull mineralization and osteoplastic differentiation.Results: Our study identified 72 active compounds, 220 targets and 166 signaling pathways probably involved in the prevention and treatment of OP by EZP, wherein quercetin, apigenin, daidzein, luteolin, ursolic acid and kaempferol could be the key compounds, while PI3K-Akt signaling pathway, TNF signaling pathway and IL-17 signaling pathway could be the key signaling pathways. The experiments indicated that quercetin attenuated both the decrease of skull mineralization and the inhibition of skull osteoplastic differentiation in zebrafish larvae trigged by dexamethasone.Conclusion: Our study not only investigated potentially effective constituents and mechanisms of EZP in the prevention and treatment of OP, but also provided a reference for the in-depth research, development and application of TCM.Keywords: Erzhi Pill, osteoporosis, network pharmacology, mechanisms, zebrafish, quercetin

Jihua Feng,* Jielong Pang,* Dan He,* Zimeng Wu, Qian Li, Pan Ji, Cuiying He, Zhimei Zhong, Hongyuan Li, Jianfeng Zhang Department of Emergency Medicine, The Second Affiliated Hospital of Guangxi Medical University, Nanning 530007, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jianfeng ZhangDepartment of Emergency Medicine, The Second Affiliated Hospital of Guangxi Medical University, Nanning 530007, People’s Republic of ChinaEmail drzhangjf@163.comPurpose: Early diagnosis of sepsis-induced acute respiratory distress syndrome (ARDS) is critical for effective treatment. We aimed to identify early stage biomarkers.Materials and Methods: Differentially expressed genes were identified in whole blood samples from patients with sepsis or ARDS based on the Gene Expression Omnibus (GEO) datasets GSE32707, GSE54514 and GSE10361. Functional enrichment analysis explored the biological characteristics of differentially expressed genes. Genes with high functional connectivity based on a protein-protein interaction network were marked as hub genes, which were validated using the GEO dataset GSE76293, and a gene set variation analysis index (GSVA) was assigned. Diagnostic and predictive ability of the hub genes were assessed by receiver operating characteristic (ROC) curve analysis. DNA methylation levels of hub genes were quantified using the GEO dataset GSE67530.Results: Forty-one differentially expressed genes were shared between sepsis-specific and ARDS-specific datasets. MAP2K2 and IRF7 functional activity was highly connected in sepsis-induced ARDS. Hub genes included RETN, MVP, DEFA4, CTSG, AZU1, FMNL1, RBBP7, POLD4, RIN3, IRF7. ROC curve analysis of the hub gene GSVA index showed good diagnostic ability in sepsis or ARDS. Among genes related to sepsis-induced ARDS, 17 were differentially methylated. Principal component analysis and heatmaps indicated that gene methylation patterns differed significantly between ARDS patients and controls.Conclusion: We identified a genetic profile specific to early-stage sepsis-induced ARDS. The abnormal expression of these genes may be caused by hypomethylation, which may serve as a biomarker for early diagnosis of ARDS.Keywords: acute respiratory distress syndrome, ARDS, sepsis-induced ARDS, hub genes, methylation, gene set variation analysis

Ying Liu,1,* Xiaojie Li,1,* Shuwen Xiao,1 Xinyi Liu,1 Xuanming Chen,1 Qiyue Xia,1 Song Lei,2 Hongxia Li,1 Zhihui Zhong,3 Kai Xiao1 1National Chengdu Center for Safety Evaluation of Drugs and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, People’s Republic of China; 2Department of Pathology, West China Hospital, Sichuan University, Chengdu 610041, People’s Republic of China; 3Laboratory of Non-Human Primate Disease Model Research, West China Hospital, Sichuan University, Chengdu 610041, People’s Republic of China*These authors contributed equally to this workCorrespondence: Kai Xiao Tel +86-28-83326313Email xiaokaikaixiao@scu.edu.cnBackground: Gold nanoparticles (AuNPs) have shown great promise in various biomedical applications, but their effects on male reproductive function remain to be ascertained. The aim of this study was to investigate the uptake, cytotoxicity and testosterone production inhibition of AuNPs in mouse Leydig cells, as well as their accumulation in the testes of male mice and their effects on male reproductive function.Results: AuNPs (5 nm) were able to be internalized into the endosomes/lysosomes of TM3 Leydig cells, induce the formation of autophagosomes, increase the production of reactive oxygen species (ROS), and disrupt the cell cycle in S phase, resulting in concentration-dependent cytotoxicity and DNA damage. Interestingly, AuNPs significantly reduced testosterone production in TM3 cells by inhibiting the expression of 17α-hydroxylase, an important enzyme in androgen synthesis. After repeated intravenous injection, AuNPs gradually accumulated and retained in the testes of male BALB/c mice in a dose-dependent manner. One week after withdrawal, the level of plasma testosterone in the 0.5 mg/kg AuNPs group was significantly reduced compared to that in the PBS control group, accompanied by the decreased expression of 17α-hydroxylase in the testes. In addition, AuNPs treatment significantly increased the rate of epididymal sperm malformation, but without affecting fertility.Conclusion: Our results suggest that AuNPs can accumulate in the testes and reduce testosterone production in Leydig cells by down-regulating the expression of 17α-hydroxylase, thus affecting the quality of epididymal sperm.Keywords: gold nanoparticles, Leydig cells, testosterone, reproductive toxicity, fertility