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Jian Gao,1 Jiannan Li,2 Zengyou Luo,1 Hongyong Wang,3 Zhiming Ma1 1Department of Gastrointestinal Nutrition and Hernia Surgery, The Second Hospital of Jilin University, Changchun, People’s Republic of China; 2Department of Colorectal and Anal Surgery, The Second Hospital of Jilin University, Changchun, People’s Republic of China; 3Department of Radiotherapy, The Second Hospital of Jilin University, Changchun, People’s Republic of ChinaCorrespondence: Zhiming Ma, Department of Gastrointestinal Nutrition and Hernia Surgery, The Second Hospital of Jilin University, Changchun, People’s Republic of China, Email mazhiming@jlu.edu.cnAbstract: Inflammatory bowel disease (IBD) is a chronic, non-specific inflammatory condition characterized by recurring inflammation of the intestinal mucosa. However, the existing IBD treatments are ineffective and have serious side effects. The etiology of IBD is multifactorial and encompasses immune, genetic, environmental, dietary, and microbial factors. The nanoparticles (NPs) developed based on specific targeting methodologies exhibit great potential as nanotechnology advances. Nanoparticles are defined as particles between 1 and 100 nm in size. Depending on their size and surface functionality, NPs exhibit different properties. A variety of nanoparticle types have been employed as drug carriers for the treatment of inflammatory bowel disease (IBD), with encouraging outcomes observed in experimental models. They increase the bioavailability of drugs and enable targeted drug delivery, promoting localized treatment and thus enhancing efficacy. Nevertheless, numerous challenges persist in the translation from nanomedicine to clinical application, including enhanced formulations and preparation techniques, enhanced drug safety profiles, and so forth. In the future, it will be necessary for scientists and clinicians to collaborate in order to study disease mechanisms, develop new drug delivery strategies, and screen new nanomedicines. Nevertheless, numerous challenges persist in the translation from nanomedicine to clinical application, including enhanced formulations and preparation techniques, enhanced drug safety profiles, and so forth. In the future, it will be necessary for scientists and clinicians to collaborate in order to study disease mechanisms, develop new drug delivery strategies, and screen new nanomedicines.Keywords: nanoparticles, inflammatory bowel diseases, targeted delivery, passive targeting, active targeting, drug delivery system

Jie Cheng,1,* Ya Liu,2,* Guangli Zhang,3 Liping Tan,1 Zhengxiu Luo3 1Department of Emergency, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Rare Diseases in Infection and Immunity, Big Data Engineering Center, Children’s Hospital of Chongqing Medical University, Chongqing, 400014, People’s Republic of China; 2Department of Pediatrics, Chongqing Youyoubaobei Women and Children’s Hospital, Chongqing, 401147, People’s Republic of China; 3Department of Respiratory Medicine, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Rare Diseases in Infection and Immunity, Big Data Engineering Center, Children’s Hospital of Chongqing Medical University, Chongqing, 400014, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhengxiu Luo, Email luozhengxiu816@hospital.cqmu.edu.cnObjective: Mycoplasma pneumoniae (MP) is highly resistant to macrolides in China. However, macrolides still exhibit clinical effectiveness in some macrolide-resistant patients. We tend to explore azithromycin effectiveness in Mycoplasma pneumoniae pneumonia (MPP) children with A2063/2064G mutation.Methods: This retrospective observational cohort study was conducted at the Children’s Hospital of the Chongqing Medical University. Children with macrolide-resistant mutations (A2063/2064G) diagnosed as MPP were retrospectively enrolled. Receiver operating characteristic (ROC) curves and logistic regression analysis were used to evaluate and identify independent risk factors for treatment failure (progress to refractory Mycoplasma pneumoniae pneumonia [RMPP]) in macrolide-unresponsive Mycoplasma pneumoniae pneumonia (MUMPP) children with the A2063/2064G mutation.Results: One hundred fifty-five children were retrospectively enrolled. More than 20% (36/155, 23.23%) of patients experienced defervescence within 3 days of azithromycin treatment. RMPP was diagnosed in 54 patients (54/155, 34.84%) and the incidence of RMPP during hospitalization was 22.72 per 1000 person-days. Logistic regression analysis showed that lactate dehydrogenase (LDH) ≥ 399 (U/L) was an independent risk factor for RMPP (odds ratio [OR] 4.66, 95% confidence interval [CI] 1.31– 17.10, P=0.017). During the year followed, RMPP patients had a significantly higher incidence of bronchiolitis obliterans and bronchiectasis than non-RMPP patients (16.67% vs 1.98%, P=0.001; 9.26% vs 0.00%, P=0.005, respectively).Conclusion: Azithromycin was effective in children with MPP with the A2063/2064G mutation. For MUMPP children with A2063/2064G mutation, children with LDH ≥ 399 (U/L) had significant higher risk for progression to RMPP, and should consider to be treated with alternative antibiotics (eg tetracyclines, and fluoroquinolones).Keywords: azithromycin effectiveness, A2063/2064G mutation, mycoplasma pneumoniae pneumonia, children

Xiaoqing Peng,1– 4,* Yuanyuan Yang,3,4,* Ruirui Hou,1 Longbiao Zhang,1 Can Shen,3 Xiaoyan Yang,3 Zhigang Luo,5 Zongzhi Yin,3,4 Yunxia Cao3,4 1School of Pharmacy, Anhui Medical University, Hefei, People’s Republic of China; 2Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, Hefei, Anhui, People’s Republic of China; 3Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, People’s Republic of China; 4The Key National Health Commission Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei, People’s Republic of China; 5Department of Cardiology, The First Affiliated Hospital of Anhui Medical University, Hefei, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yunxia Cao; Zongzhi Yin, The First Affiliated Hospital of Anhui Medical University, No. 218 Jixi Road, Sushan District, Hefei, Anhui, People’s Republic of China, Email caoyunxia5972@ahmu.edu.cn; yinzongzhi@ahmu.edu.cnAbstract: Mitochondrial carrier homolog 2 (MTCH2) is a member of the solute carrier 25 family, located on the outer mitochondrial membrane. MTCH2 was first identified in 2000. The development in MTCH2 research is rapidly increasing. The most well-known role of MTCH2 is linking to the pro-apoptosis BID to facilitate mitochondrial apoptosis. Genetic variants in MTCH2 have been investigated for their association with metabolic and neurodegenerative diseases, however, no intervention or therapeutic suggestions were provided. Recent studies revealed the physiological and pathological function of MTCH2 in metabolic diseases, neurodegenerative diseases, cancers, embryonic development and reproduction via regulating mitochondrial apoptosis, metabolic shift between glycolysis and oxidative phosphorylation, mitochondrial fusion/fission, epithelial-mesenchymal transition, etc. This review endeavors to assess a total of 131 published articles to summarise the structure and physiological/pathological role of MTCH2, which has not previously been conducted. This review concludes that MTCH2 plays a crucial role in metabolic diseases, neurodegenerative diseases, cancers, embryonic development and reproduction, and the predominant molecular mechanism is regulation of mitochondrial function. This review gives a comprehensive state of current knowledgement on MTCH2, which will promote the therapeutic research of MTCH2. Keywords: Mimp, MTCH2, mitochondrial carrier homolog 2, BID, apoptosis

Yang Li,1 Xue Yan,2 Zhen Luo,1 Xianxian Fu,1 Zhongju Li,1 Qiuzhu Xu,3 Juanjuan Chen,1 Jingmin Yang,2,4,5 Daru Lu4,5 1Department of Nephropathy, Affiliated Haikou Hospital of Xiangya Medical College, Central South University, Hainan, People’s Republic of China; 2Department of Medicine, Shanghai WeHealth Biomedical Technology Co., Ltd., Shanghai, People’s Republic of China; 3Department of Central Supply Service Department, Haikou Orthopedic and Diabetes Hospital, Hainan, People’s Republic of China; 4NHC Key Laboratory of Birth Defects and Reproductive Health (Chongqing Key Laboratory of Birth Defects and Reproductive Health, Chongqing Population and Family Planning, Science and Technology Research Institute), Chongqing, People’s Republic of China; 5State Key Laboratory of Genetic Engineering and MOE Engineering Research Center of Gene Technology, School of Life Sciences, Fudan University, Shanghai, People’s Republic of ChinaCorrespondence: Jingmin Yang; Daru Lu, Email jingmin.yang@we-health.vip; Email drlu@fudan.edu.cnIntroduction: X-linked Alport syndrome (XLAS) is caused by pathogenic variants in COL4A5 which lead to abnormalities of the glomerular basement membrane (GBM) structural and is characterized by progressive kidney disease, hearing loss, and ocular abnormalities. The aim of this study was to identify gene mutations in a Chinese family with XLAS by whole-exome sequencing (WES) and verified the pathogenicity of the mutation in vitro experiments.Case Presentation: A five-generation pedigree with a total of 49 family members originating from Hainan province of China was investigated in this study. The proband was a 23-year-old male who developed microscopic hematuria, proteinuria and end-stage kidney disease (ESKD) at age 17. WES identified a novel splicing mutation c.321+5G>A of COL4A5, which cause exon skip. Further co-segregation analysis confirmed that this mutation exists in relatives who had renal abnormalities using Sanger sequencing. According to American College of Medical Genetics and Genomics guidelines (ACMG), the mutation was determined to be of uncertain significance (VUS). In vitro splicing experiments have shown that the COL4A5 variant induces aberrant mRNA splicing and transcript deletion.Conclusion: We identified a novel intronic COL4A5 pathogenic mutation (c.321+5G>A) in a Chinese XLAS family and described the phenotypes of affected relatives. This study expands the mutation spectrum of COL4A5 gene in XLAS and demonstrates the importance of gene screening for AS.Keywords: Alport syndrome, COL4A5, whole exome sequencing, mRNA splicing, case series

Yanxia He,1,* Zhumei Luo,1,* Haoqing Chen,2,3,* Liqing Ping,2,3 Cheng Huang,2,3 Yan Gao,2,3 Huiqiang Huang2,3 1Department of Oncology, The Third People’s Hospital of Chengdu, Sichuan, People’s Republic of China; 2State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, People’s Republic of China; 3Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Huiqiang Huang; Yan Gao, Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China, Email huanghqsysucc@163.com; gaoyan@sysucc.org.cnBackground: Systemic inflammation, immunity, and nutritional status are closely related to patients’ outcomes in several kinds of cancers. This study aimed to establish a new nomogram based on inflammation-immunity-nutrition score (IINS) to predict the prognosis of extranodal natural killer/T-cell lymphoma (ENKTL) patients.Methods: The clinical data of 435 patients with ENTKL were retrospectively reviewed and randomly assigned to training cohort (n=305) and validation cohort (n=131) at a ratio of 7:3. Cox regression analysis was employed to identify independent prognostic factors and develop a nomogram in the training cohort. Harrell’s concordance index (C-index), calibration curve, receiver operating characteristic (ROC) curve, and decision curve analysis (DCA) curve were employed to assess the performance of the nomogram and compare it with traditional prognostic systems (PINK, IPI, KPI). Internal validation was performed using 1000 bootstrap resamples in the validation cohort. Kaplan-Meier survival analyses were conducted to compare the overall survival (OS) of patients in different risk groups.Results: In the training cohort, in addition to several classic parameters, IINS was identified as an independent prognostic factor significantly associated with the OS of patients. The nomogram established based on the independent prognostic indicators showed superior survival prediction efficacy, with C-index of 0.733 in the training cohort and 0.759 in the validation cohort compared to the PINK (0.636 and 0.737), IPI (0.81 and 0.707), and KPI (0.693 and 0.639) systems. Furthermore, compared with PINK, IPI, and IPI systems, the nomogram showed relatively superior calibration curves and more powerful prognostic discrimination ability in predicting the OS of patients. DCA curves revealed some advantages in terms of clinical applicability of the nomogram compared to the PINK, IPI, and IPI systems.Conclusion: Compared with traditional prognostic systems, the nomogram showed promising prospects for risk stratification in ENKTL patient prognosis, providing new insights into the personalized treatment.Keywords: inflammation-immunity-nutrition score, extranodal natural killer/T-cell lymphoma, nomogram, prognosis, overall survival

Xiaodong Chen,1,* Xiangyuan Wang,1,* Shangqing Huang,1 Wenxuan Luo,1 Zebin Luo,1,* Zipan Chen2,* 1Radiology Imaging Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang City, People’s Republic of China; 2Health Management Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang City, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zipan Chen; Zebin Luo, Email 41881014@qq.com; gdmcfsjd@qq.comObjective: To explore the value of a new model based on CT radiomics in predicting the staging of patients with bronchial asthma (BA).Methods: Patients with BA from 2018 to 2021 were retrospectively analyzed and underwent plain chest CT before treatment. According to the guidelines for the prevention and treatment of BA (2016 edition), they were divided into two groups: acute attack and non-acute attack. The images were processed as follows: using Lung Kit software for image standardization and segmentation, using AK software for image feature extraction, and using R language for data analysis and model construction (training set: test set = 7: 3). The efficacy and clinical effects of the constructed model were evaluated with ROC curve, sensitivity, specificity, calibration curve and decision curve.Results: A total of 112 patients with BA were enrolled, including 80 patients with acute attack (range: 2– 86 years old, mean: 53.89± 17.306 years old, males of 33) and 32 patients with non-acute attack (range: 4– 79 years old, mean: 57.38± 19.223 years old, males of 18). A total of 10 imaging features are finally retained and used to construct model using multi-factor logical regression method. In the training group, the AUC, sensitivity and specificity of the model was 0.881 (95% CI:0.808– 0.955), 0.804 and 0.818, separately; while in the test group, it was 0.792 (95% CI:0.608– 0.976), 0.792 and 0.80, respectively.Conclusion: The model constructed based on radiomics has a good effect on predicting the staging of patients with BA, which provides a new method for clinical diagnosis of staging in BA patients.Keywords: bronchial asthma, BA, Radiomics, computed tomography, CT

Ting He,1,* Kangzhi Chen,1,* Yi Li,1 Zhaohui Luo,1 Mengchuan Luo,2 Huan Yang1 1Department of Neurology, Xiangya Hospital, Central South University, Changsha, 410008, People’s Republic of China; 2Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, 410008, People’s Republic of China*These authors contributed equally to this workCorrespondence: Huan Yang, Department of Neurology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, People’s Republic of China, Email 403850@csu.edu.cnPurpose: To decipher the discrepancies between muscle-specific kinase antibody-positive myasthenia gravis (MuSK-MG) and double-seropositive myasthenia gravis (DSP-MG), and to determine prognostic factors for minimal manifestation status (MMS) achievement in MG patients with MuSK autoantibodies (MuSK-Ab).Patients and Methods: A total of 34 MG patients seropositive for MuSK-Ab were enrolled in this study. The demographic and clinical features were compared between MuSK-MG (n = 28) and DSP-MG (n = 6) patients, and factors affecting MMS induction in all patients with MuSK-Ab were identified using Cox regression analysis.Results: Compared to MuSK-MG patients, those with DSP-MG had similar clinical characteristics, except that they had a lower frequency of bulbar muscle involvement at nadir (50% vs 92.9%; P = 0.029) and higher proportions of comorbidities with diabetes mellitus (33.3% vs 0%; P = 0.027) and thymic abnormalities (33.3% vs 0%; P = 0.027). Higher MG Activities of Daily Living (MG-ADL) scores (HR = 0.16, 95% CI: 0.037– 0.7, P = 0.015) and axial muscle involvement at nadir (HR = 0.39, 95% CI: 0.16– 0.94, P = 0.035) were negative prognostic factors for MMS achievement in patients with MuSK-Ab regardless of acetylcholine receptor antibody (AChR-Ab) positivity. Multivariable Cox regression analysis further established higher MG-ADL scores at the nadir (HR = 0.19, 95% CI: 0.04– 0.94; P = 0.042) as an independent risk factor for MMS achievement.Conclusion: DSP-MG was comparable to MuSK-MG and could be considered a single entity in our cohort. In all MG patients with MuSK-Ab, a higher MG-ADL score at nadir may herald a lower chance of MMS achievement, with no observed potential effect of AChR-Ab presence.Keywords: double-seropositive myasthenia gravis, muscle-specific kinase antibody, acetylcholine receptor antibody, minimal manifestation status, myasthenia gravis activities of daily living

Naigeng Wang,1 Fei Li,2 Jing Du,3 Jianhong Hao,1 Xin Wang,2 Yueru Hou,3 Zhenguo Luo1 1Department of Anesthesiology, Honghui Hospital, Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China; 2Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University, Xi’an, Shaanxi, People’s Republic of China; 3Second Clinical Medical College, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, People’s Republic of ChinaCorrespondence: Zhenguo Luo, Email luozhenguo@stu.xjtu.edu.cnBackground: This study aims to investigate the protective effect of quercetin against global cerebral ischemia‒reperfusion (GCI/R) injury in rats and elucidate the underlying mechanism.Methods: A GCI/R injury rat model was established using a four-vessel occlusion (4-VO) method. An oxygen–glucose deprivation/reoxygenation (OGD/R) injury model was induced in BV2 cells. The extent of injury was assessed by evaluating neurological deficit scores (NDS) and brain water content and conducting behavioral tests. Pathomorphological changes in the prefrontal cortex were examined. Additionally, the study measured the levels of inflammatory cytokines, the degree of microglial activation and polarization, and the protein expression of Toll-like receptor 4 (TLR4) and TIR-domain-containing adaptor inducing interferon-β (TRIF).Results: Quercetin pretreatment significantly ameliorated neurological impairment, improved learning and memory abilities, and reduced anxiety in rats subjected to GCI/R injury. Furthermore, quercetin administration effectively mitigated neuronal injury and brain edema. Notably, it suppressed microglial activation and hindered polarization toward the M1 phenotype. Simultaneously, quercetin downregulated the expression of TLR4 and TRIF proteins and attenuated the release of IL-1β and TNF-α.Conclusion: This study highlights the novel therapeutic potential of quercetin in alleviating GCI/R injury. Quercetin demonstrates its neuroprotective effects by inhibiting neuroinflammation and microglial activation while impeding their transformation into the M1 phenotype through modulation of the TLR4/TRIF pathway.Keywords: quercetin, cerebral ischemia, neuroprotection, neuroinflammation

Beijie Qi,1,* Yuqi Li,2,* Zhen Peng,2 Zhiwen Luo,3 Xingyu Zhang,2 Jiwu Chen,2 Guoqi Li,2 Yaying Sun2 1Department of Orthopedics, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, People’s Republic of China; 2Department of Sports Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 3Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yaying Sun; Guoqi Li, Tel +86 17621642602 ; +86 13816307547, Email yaying.sun@shgh.cn; etherlords@163.comBackground: Acute skeletal muscle injury is common in sports. The injured muscle cannot fully recover due to fibrosis resulting from myofibroblasts. Understanding the origin of fibroblasts is, therefore, important for the development of anti-fibrotic therapies. Accumulating evidence shows that a mechanism called macrophage-myofibroblast transition (MMT) can lead to tissue or organ fibrosis, yet it is still unclear whether MMT exists in skeletal muscle and the exact mechanisms.Methods: Single-cell transcriptome of mice skeletal muscle after acute injury was analyzed with a specific attention on the process of MMT. Cell–cell interaction network, pseudotime trajectory analysis, Gene Ontology (GO), and Kyoto Genome Encyclopedia (KEGG) were conducted. A series of experiments in vivo and in vitro were launched for verification.Results: Single cell transcriptomic analysis indicated that, following acute injury, there were much interactions between macrophages and myofibroblasts. A detailed analysis on macrophages indicated that, CD68+α-SMA+ cells, which represented the status of MMT, mainly appeared at five days post-injury. KEGG/GO analysis underlined the involvement of complement system, within which C3ar1, C1qa, C1qb, and C1qc were up-regulated. Trajectory analysis also confirmed a potential shift from macrophages to myofibroblasts. These findings were verified by histological study in mice skeletal muscle, that there were much MMT cells at five days, declined gradually, and vanished 14 days after trauma, when there was remarkable fibrosis formation within the injured muscle. Moreover, C3a stimulation could directly induce MMT in BMDMs.Conclusion: Fibrosis following acute injury is disastrous to skeletal muscle, but the origin of myofibroblasts remains unclear. We proved that, following acute injury, macrophage-myofibroblast transition happened in skeletal muscle, which may contribute to fibrosis formation. This phenomenon mainly occurred at five days post-injury. The complement system can activate MMT. More evidence is needed to directly support the pro-fibrotic role of MMT in skeletal muscle fibrosis after acute injury.Keywords: skeletal muscle, fibrosis, macrophage-myofibroblast transition, single-cell transcriptomic analysis, complement system

Ju Kuang, Zhihai Luo, Fu Zhou Department of Respiratory and Critical Care Medicine, Affiliated Banan Hospital of Chongqing Medical University, Chongqing, People’s Republic of ChinaCorrespondence: Fu Zhou, Tel +86-17702395630, Email 1163629567@qq.comAbstract: A 66-year-old male patient diagnosed with small-cell lung cancer received chemotherapy and immunotherapy, resulting in successful tumor control. However, the patient subsequently experienced a fever and rapid progression of the pulmonary cavity. Despite sampling bronchoscopic bronchoalveolar lavage fluid for targeted next-generation sequencing (tNGS), the cause remained unidentified. Adding bronchoalveolar lavage fluid to sense metagenomic next-generation sequencing (mNGS) confirmed the infection caused by actinomycetes. The patient’s condition improved after active anti-infection treatment. This case was further analyzed and discussed through a comprehensive literature review, focusing on molecular microbiological diagnosis and treatment processes. The points outlined were as follows: the advancement of molecular microbiology has gradually reduced the challenges associated with diagnosing rare infectious diseases such as pulmonary actinomycosis. Additionally, in immunodeficient individuals, certain infectious diseases with a chronic course may exhibit acute and aggressive characteristics, which is of concern to all colleagues. Currently, tNGS and mNGS are widely employed in clinical settings as practical tools for diagnosing infectious diseases. Notably, these two methods are not substitutes for each other but complement each other.Keywords: pulmonary actinomycosis, lung cancer, targeted next-generation sequencing, metagenomic next-generation sequencing

Ying Zhou,1 Zhixian Luo,1 Mengying Yu,1 Chenyi Zhan,1 Haoli Xu,1 Ru Lin,1 Shuying Bian,1 Yunjun Yang,2,3 Zhenghao Jiang,4 Xinyi Tao,4 Zusen Ye,5 Meihao Wang,1 Dongqin Zhu2 1Department of Radiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of China; 2Department of Nuclear, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of China; 3Key Laboratory of Novel Nuclide Technologies on Precision Diagnosis and Treatment & Clinical Transformation of Wenzhou, Wenzhou, People’s Republic of China; 4The First School of Medicine, Wenzhou Medical University, Wenzhou, People’s Republic of China; 5Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of ChinaCorrespondence: Dongqin Zhu, Department of Nuclear, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, People’s Republic of China, Tel +86 0577 55579667, Email zhudongqin96@163.comObjective: Post-stroke hyperglycemia as a common phenomenon is associated with unfavorable outcomes. Focusing on admission hyperglycemia, other markers of dysglycemia were overlooked. This study aimed to explore the contribution of acute phase blood glucose levels in combination with other radiological signs to the prognostication of functional outcomes in patients with spontaneous intracerebral hemorrhage (sICH).Methods: Consecutive patients with sICH with at least five random plasma glucose measurements and complete radiological data during hospitalization were included. We calculated the average, maximum, minimum, standard deviation, and coefficient of variation of blood glucose levels for each patient. Radiological data, including island, black hole, blend, and satellite signs were collected. Functional outcomes were evaluated using the Barthel index. Unfavorable outcomes were defined as a Barthel index score ≤ 60. Univariate and multivariate analyses were performed to identify independent predictors of unfavorable outcomes.Results: Two hundred and thirty-eight patients (mean age 58.5, 163 men and 75 women) were included, and 71 had a history of diabetes. Unfavorable outcomes occurred in 107 patients (45.0%) at 3 months. Multivariate logistic regression analysis demonstrated that maximum blood glucose levels (odds ratio, 1.256; 95% confidence interval, 1.124‒1.404; p < 0.001) and island sign (odds ratio, 2.701; 95% confidence interval, 1.322‒5.521; p = 0.006) were independent predictors of unfavorable outcomes in the nondiabetic group. Meanwhile, patients without diabetes who experienced hematoma expansion had higher average (p = 0.036) and maximum blood glucose levels (p = 0.014).Interpretation: Maximum blood glucose levels and island sign were independently associated with unfavorable outcomes in patients without diabetes, whereas no glycemic variability indices were associated with unfavorable outcomes. Glucose levels influenced hematoma expansion and functional outcomes, particularly in patients without diabetes with sICH. Thus, clinical management of blood glucose levels should be strengthened for patients with sICH with or without a history of diabetes.Keywords: spontaneous intracerebral hemorrhage, glycemic variability, functional outcomes, island sign, diabetes

Kaiyuan Zhang,1,&ast; Ziyue Luo,1,&ast; Xinchao Zhu,1 Xinyi Yao,1 Dingqi Lu,2 Liying Chen,1 Tao Hong,1 Yating Ren,1 Xinchang Wang3 1Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang Province, 310053, People’s Republic of China; 2First Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang Province, 310053, People’s Republic of China; 3Department of Rheumatology, The Second Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang Province, 310053, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xinchang Wang, The Second Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang Province, People’s Republic of China, Tel +86 13065714635, Email ossani@126.comPurpose: Sjogren’s Syndrome (SS) is a systemic autoimmune disease primarily characterized by dysfunction of the exocrine glands. Research into the etiology and pathogenesis of salivary glands (SG) inflammation of SS is very limited. The aim of this study was to identify potential pyroptosis-related genes in SG inflammation through bioinformatics analysis and validation of the SG in SS.Methods: GSE157159 dataset and GSE159574 dataset were downloaded from Gene Expression Omnibus (GEO). Differentially Expressed Genes (DEGs) analysis was used to screen DEGs from SS and non-SS SG samples. Pyroptosis-related genes were obtained from GeneCards. After intersecting DEGs with pyroptosis-related genes, the pyroptosis-related DEGs in SS were obtained. Subsequently, ClueGO enrichment analysis, Kyoto Encyclopaedia of Genes and Genomes (KEGG) enrichment analysis, Protein-protein Interaction (PPI), and identification and co-expression analysis of hub genes were performed. Subsequently, we collected SG samples from 17 SS patients and 17 non-SS patients and validated the expression of two hub genes (GZMA, GBP1) and characteristic genes (GSDMD) of pyroptosis through immunohistochemistry. The accuracy of hub genes as biomarkers for predicting SS was evaluated by receiver operating characteristic (ROC) curve.Results: 834 DEGs were selected from the GSE157159 dataset, and a total of 39 pyroptosis-related DEGs were obtained. Functional analysis showed that these DEGs were significantly enriched in some inflammatory signaling pathways. Through the intersection of seven algorithms proposed by CytoHubba and validation using the GSE159574 dataset, 11 hub genes were identified, including IL18, AIM2, CCL5, CD274, GBP1, GBP5, GZMA, GZMB, TLR8, TNFS13B, and ICAM1. Finally, the results of immunohistochemistry showed that GSDMD, GZMA and GBP1 were all significantly highly expressed in SG from SS. And ROC analysis showed a high combined diagnostic value of the 3 genes (AUC=0.8858).Conclusion: Our study revealed enhanced levels of pyroptosis in the SS. GZMA and GBP1 were identified as candidate genes for pyroptosis-induced inflammation of the SG in SS, which may be used as biomarkers or potential therapeutic targets for SS.Keywords: Sjogren’s syndrome, pyroptosis, bioinformatics analysis, salivary gland, immunology

Wanchun Cheng,1 Mohammad Mofatteh,2 José Fidel Baizabal-Carvallo,3,4 Shaohuan Lu,1 Ping Su,1 Yimin Chen,5,6 Luoming Li,1 Lizhi Qin,1 Xingmei Zuo,1 Yifeng Lan,7 Yue Huang,8 Zhihui Yu,9 Zirui Luo,10,&ast; Gang Chen10,&ast; 1Department of Neurology and National Stroke Center, The 5th People’s Hospital of Foshan City, Foshan, People’s Republic of China; 2School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, Belfast, UK; 3Parkinson’s Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston, Texas, USA; 4Department of Sciences and Engineering, University of Guanajuato, León, Mexico; 5Department of Neurology and Advanced National Stroke Center, Foshan Sanshui District People’s Hospital, Foshan, People’s Republic of China; 6Neuro International Collaboration (NIC), Foshan, People’s Republic of China; 7Department of Radiology, the 5th People’s Hospital of Foshan City, Foshan, People’s Republic of China; 8Department of Emergency, the 5th People’s Hospital of Foshan City, Foshan, People’s Republic of China; 9Department of Laboratory Medicine, the 5th People’s Hospital of Foshan City, Foshan, People’s Republic of China; 10Dean’s Office, the 5th People’s Hospital of Foshan City, Foshan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zirui Luo; Gang Chen, Dean’s Office, the 5th People’s Hospital of Foshan City, Foshan, Guangdong Province, 528211, People’s Republic of China, Email ziruiluo@126.com; vikingsaga@163.comPurpose: Intravenous thrombolysis has emerged as an effective approach to improve the long-term survival and functional status of patients with ischemic stroke. The aim of this study was to assess the impact of a national stroke project on the door-to-needle-time (DNT).Patients and Methods: The patients were divided into pre-construction and construction periods. Construction Measures were performed during the construction period. The DNT and onset-to-needle time (ONT) were compared in two period groups.Results: After participating in the National Stroke Center Project and effective measurements, the thrombolysis treatment metrics were improved significantly. The DNT (IQR) was shortened from 65.0 (54.5,85.0) minutes in the Pre-Construction period to 40.0 (33.0,53.0) minutes in the Construction period (p < 0.001). Similarly, the ONT was reduced from 157.0 (IQR) (115.0,184.0) minutes to 116.0 (87.8,170.0) minutes (p = 0.035).Conclusion: The DNT time and ONT time can be shortened by National Stroke Center Construction projects. More suitable hospitals should be encouraged to participate as the National Stroke Center.Keywords: acute ischemic stroke, intravenous thrombolysis, door-to-needle time, onset-to-needle time

Ling Yang,1,2,&ast; Liangliang Zhang,3,&ast; Zhu Luo2 1Department of Neurology, West China Hospital, Sichuan University, Chengdu, People’s Republic of China; 2Clinical Trial Center, West China Hospital, Sichuan University, Chengdu, People’s Republic of China; 3Department of Pulmonary and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhu Luo, Clinical Trial Center, West China Hospital, Sichuan University, No. 37 Guoxue Lane, Chengdu, Sichuan, 610044, People’s Republic of China, Tel +86 028 85422707, Email luozhu720@163.comBackground: Pramipexole dihydrochloride extended-release tablet is a novel long-acting form of non-ergot dopamine agonist indicated as one of main therapeutic approaches for Parkinson’s disease. However, pharmacokinetic properties of extended-release pramipexole in healthy Chinese subjects remain unclear.Methods: A single-center, randomized, open-label, two-period crossover, single-dose study was performed to investigate comparative pharmacokinetics and evaluate bioequivalence of 0.375 mg test (Yangtze River Pharmaceutical Group Co., Ltd.) and reference (Trade name: Sifrol®, Boehringer Ingelheim Pharma GmbH & Co. KG) formulations of pramipexole dihydrochloride extended-release tablets in healthy Chinese subjects under fasted and fed states.Results: A total of 56 subjects (28 in each dietary trial) were enrolled and randomized. After single dose of 0.375 mg test and reference formulations under fasted condition, main pharmacokinetics of pramipexole were as follows: peak concentration (Cmax) were 409.33± 95.93 and 413.77± 132.03 pg/mL; plasma area under concentration–time curve from time 0 to last measurable concentration (AUC0-t) were 8801.95± 1966.83 and 8646.37± 2600.49 h&ast;pg/mL; AUC from time 0 to infinity (AUC0-∞) were 9469.03± 1991.61 and 9082.95± 2666.26 h&ast;pg/mL; elimination half-life (t1/2) were 11.98± 3.91 and 9.85± 2.63 h; both time to reach Cmax (Tmax) were about 4.50 h, respectively, for test and reference formulations. The 90% confidence intervals of geometric mean ratios (test/reference) of Cmax, AUC0-t and AUC0-∞ under fasted and fed conditions were all within 80– 125%. Following administration under fed condition, Cmax and Tmax for both test and reference formulations slightly increased and prolonged to 5.0 h, respectively, but AUC approximately remained unchanged compared with dosing under fasted condition. Test and reference formulations showed similar bioequivalence and favorable safety under fasted and fed states.Conclusion: Test and reference formulations of pramipexole dihydrochloride extended-release tablets (0.375 mg) showed similar bioequivalence and well safety and tolerability in healthy Chinese subjects under fasted and fed states, which supports further investigations of test formulation in patients with Parkinson’s disease.Keywords: pramipexole dihydrochloride extended-release tablet, bioequivalence, pharmacokinetics, safety, Parkinson’s disease

Ziyue Luo,1,&ast; Guifang Lu,2,&ast; Qiang Yang,1 Juncan Ding,1 Tianyu Wang,1 Pengfei Hu3 1Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang Province, 310053, People’s Republic of China; 2Department of Rheumatology, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang Province, 310005, People’s Republic of China; 3Department of Cardiology, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang Province, 310005, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Pengfei Hu, Department of Cardiology, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang Province, 310005, People’s Republic of China, Tel +86 15267037741, Email 20064012@zcmu.edu.cnPurpose: The purpose was to identify shared immune cells and co-disease genes in chronic heart failure (HF) and systemic lupus erythematosus (SLE), as well as explore the potential mechanisms of action between HF and SLE.Methods: A collection of peripheral blood mononuclear cells (PBMCs) from ten patients with HF and SLE and ten normal controls (NC) was used for transcriptome sequencing. Differentially expressed genes (DEGs) analysis, enrichment analysis, immune infiltration analysis, weighted gene co-expression network analysis (WGCNA), protein-protein interaction (PPI) analysis, and machine learning were applied for the screening of shared immune cells and co-disease genes in HF and SLE. Gene expression analysis and correlation analysis were used to explore the potential mechanisms of co-disease genes and immune cells in HF and SLE.Results: In this study, it was found that two immune cells, T cells CD4 naïve and Monocytes, displayed similar expression patterns in HF and SLE at the same time. By taking intersection of the above immune cell-associated genes with the DEGs common to both HF and SLE, four immune-associated co-disease genes, CCR7, RNASE2, RNASE3 and CXCL10, were finally identified. CCR7, as one of the four key genes, was significantly down-regulated in HF and SLE, while the rest three key genes were all significantly up-regulated in both diseases.Conclusion: T cells CD4 naïve and Monocytes were first revealed as possible shared immune cells of HF and SLE, and CCR7, RNASE2, RNASE3 and CXCL10 were identified as possible key genes common to HF and SLE as well as potential biomarkers or therapeutic targets for HF and SLE.Graphical Abstract: Keywords: heart failure, systemic lupus erythematosus, immunology, transcriptome sequencing, machine learning

Yueming Zhang,1– 3 Ziyao Guo,1,2 Wen Zhang,3 Qinyuan Li,1,2 Yan Zhao,1,2 Zhili Wang,1,2 Zhengxiu Luo1,2 1Department of Respiratory Medicine, Children’s Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 2National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, People’s Republic of China; 3Department of Respiratory, Xi’an Children’s Hospital, Xi’an, Shaanxi, People’s Republic of ChinaCorrespondence: Zhengxiu Luo, Department of Respiratory Medicine, Children’s Hospital of Chongqing Medical University, Chongqing, People’s Republic of China, Email luozhengxiu816@hospital.cqmu.edu.cnObjective: The objective of this study was to conduct a systematic review and meta-analysis to identify the adverse effects of acute PM2.5 exposure on lung function in children.Design: Systematic review and meta-analysis. Setting, participants and measures: Eligible studies analyzing PM2.5 level and lung function in children were screened out. Effect estimates of PM2.5 measurements were quantified using random effect models. Heterogeneity was investigated with Q-test and I2 statistics. We also conducted meta-regression and sensitivity analysis to explore the sources of heterogeneity, such as different countries and asthmatic status. Subgroup analyses were conducted to determine the effects of acute PM2.5 exposure on children of different asthmatic status and in different countries.Results: A total of 11 studies with 4314 participants from Brazil, China and Japan were included finally. A 10 μg/m3 increase of PM2.5 was associated with a 1.74L/min (95% CI: − 2.68, − 0.90) decrease in peak expiratory flow (PEF). Since the asthmatic status and country could partly explain the heterogeneity, we conducted the subgroup analysis. Children with severe asthma were more susceptible to PM2.5 exposure (− 3.11 L/min per 10 μg/m3 increase, 95% CI − 4.54, − 1.67) than healthy children (− 1.61 L/min per 10 μg/m3 increase, 95% CI − 2.34, − 0.91). In the children of China, PEF decreased by 1.54 L/min (95% CI − 2.33, − 0.75) with a 10 μg/m3 increase in PM2.5 exposure. In the children of Japan, PEF decreased by 2.65 L/min (95% CI − 3.82, − 1.48) with a 10 μg/m3 increase of PM2.5 exposure. In contrast, no statistic association was found between every 10 μg/m3 increase of PM2.5 and lung function in children of Brazil (− 0.38 L/min, 95% CI − 0.91, 0.15).Conclusion: Our results demonstrated that the acute PM2.5 exposure exerted adverse impacts on children’s lung function, and children with severe asthma were more susceptible to the increase of PM2.5 exposure. The impacts of acute PM2.5 exposure varied across different countries.Keywords: particulate matter 2.5, PM2.5, children, peak expiratory flow, PEF, acute exposure, meta-analysis

Ruobing Jiang,1,&ast; Xin Ta,1,&ast; Min Xu,2 Zhihua Luo,3 Yijun Du,4 Xing Zhong,4 Tianrong Pan,4 Xiujing Cao1 1Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, People’s Republic of China; 2Department of Endocrinology, First Affiliated Hospital, Anhui Medical University, Hefei, Anhui, People’s Republic of China; 3Department of Pediatrics, First Affiliated Hospital, Anhui Medical University, Hefei, Anhui, People’s Republic of China; 4Department of Endocrinology, Second Affiliated Hospital, Anhui Medical University, Hefei, Anhui, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiujing Cao, Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, People’s Republic of China, Email xiujing.cao@ahmu.edu.cn Tianrong Pan, Department of Endocrinology, Second Affiliated Hospital, Anhui Medical University, Hefei, Anhui, People’s Republic of China, Email ptr1968@163.comObjective: To investigate the current status of diabetes self-care behavior and the association between depression, self-efficacy and self-care in a sample of Chinese elderly type 2 diabetes mellitus (T2DM) patients.Methods: A cross-sectional study with a convenient sample including 240 elderly T2DM patients collected the data of demographic characteristics, diabetes self-care behavior, self-efficacy and depression status. The difference of self-care behavior in different sample characteristics was compared by independent t-test. The Personal correlation analysis was employed to examine the correlation of study variables. The method of bootstrap was used to analyze mediating role of depression.Results: Only 22.5% of patients reported better diabetes self-care behavior and depression partly mediated the association between self-efficacy and self-care behavior. The significant coefficient of path a (B = − 0.052, p < 0.001) and path b (B = − 0.423, p < 0.05) indicated negative associations of self-efficacy on depression, and depression on self-care behavior. The indirect effect (Path a × b) between self-efficacy and self-care behavior through depression was significant (B = 0.022, p < 0.05), the 95% bias-corrected bootstrap confidence interval was 0.004 to 0.006. Meanwhile, the mediating role of depression was not found significant among the participants reported 60– 74 years old (B = 0.104, p < 0.001). But depression completely mediated this association among the participants reported 75– 89 years old (B = 0.034, p > 0.05).Conclusion: The level of diabetes self-care behavior among the elderly T2DM patients in Dahu community of Anqing city was hardly optimistic. The self-efficacy focused intervention could be encouraged for community and clinicians to improve diabetes self-care behavior. Moreover, the prevalence of depression and T2DM is increasing in younger population. More work is needed to confirm these findings, especially conducting cohort studies on different populations.Keywords: diabetes self-care behavior, the elderly, type 2 diabetes mellitus, diabetes management self-efficacy, depression

Zhen Luo,1 Yansong Li,2 Xiaoqiang Li,1 Ren Liao1 1Department of Anesthesiology, Sichuan University West China Hospital, Chengdu, People’s Republic of China; 2Department of Anesthesiology, Center for Brain Science, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, People’s Republic of ChinaCorrespondence: Xiaoqiang Li, Email 39006900@qq.comObjective: The optimal red blood cell transfusion strategy for children remains unclear. We developed an individualized red blood cell transfusion strategy for children and tested the hypothesis that transfusion guided by this strategy could reduce blood exposure, without increasing perioperative complications in children.Methods: In this randomized controlled clinical trial, 99 children undergoing noncardiac surgeries who had blood loss of more than 20% total blood volume were randomly assigned to an individualized-strategy group using Pediatric Perioperative-Transfusion-Trigger Score or a control group. The amount of transfused red blood cell was counted, and patients were followed up for postoperative complications within 30 days.Results: Twenty-six children (53.1%) in the individualized-strategy group received transfusion perioperatively, as compared with 37 children (74%) in the control group (p < 0.05). During surgery, children in the individualized-strategy group were exposed to fewer transfusions than in the control group (0.87± 1.03 vs 1.33± 1.20 Red-Blood-Cell units per patient, p = 0.02). The incidence of severe complications in the individualized-strategy group had a lower trend compared to the control group (8.2% vs 18%, p = 0.160). No significant difference was found in the other outcomes.Conclusion: This trial proved that red blood cell transfusion guided by the individualized strategy reduced perioperative blood exposure in children, without increasing the incidence of severe complications. This conclusion needs to be reaffirmed by larger-scale, multicenter clinical trials.Keywords: red blood cell, transfusion strategy, perioperative red blood cell transfusion, pediatrics, hemoglobin concentration

Zebing Luo,1,2,&ast; Baolin Luo,3,&ast; Peiru Wang,4 Jinhua Wu,5 Chujun Chen,6 Zhijun Guo,1 Yiru Wang1 1Nursing Department, Cancer Hospital of Shantou University Medical College, Shantou City, People’s Republic of China; 2Nursing Department, Guangdong Provincial Key Laboratory of Breast Cancer Diagnosis and Treatment, Shantou City, People’s Republic of China; 3Department of Cardiovascular Surgery, Fujian Medical University Union Hospital, Fuzhou City, People’s Republic of China; 4Nursing Department, Shantou Central Hospital, Shantou City, People’s Republic of China; 5Nursing Department, First Affiliated Hospital of Shantou University Medical College, Shantou, People’s Republic of China; 6Mammary Department, Cancer Hospital of Shantou University Medical College, Shantou City, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yiru Wang, Nursing Department, Cancer Hospital of Shantou University Medical College, Shantou City, People’s Republic of China, Tel +8613502972031, Email stwwyyrr@163.com Chujun Chen, Mammary Department, Cancer Hospital of Shantou University Medical College, Shantou City, People’s Republic of China, Tel +86 13531260911, Email 981092602@qq.comObjective: Regular functional exercise can help recover the functions of upper limb for patients with breast cancer. By finding the influencing factors of functional exercise compliance and constructing a predictive model, patients with a poor functional exercise compliance can be better identified. This study aims to find out the factors influencing the functional exercise compliance of patients with breast cancer and build a predictive model based on decision tree.Methods: Convenience sampling was used at two tertiary hospitals in Shantou from August 2020 to March 2021. Data of patients with breast cancer patient was obtained from questionnaires and based on demographics, Constant-Murley Score, Functional Exercise Compliance Scale for Postoperative Breast Cancer Patients, Champion Health Belief Model Scale, Social Support Rating Scale, Disease Perception Questionnaire and Family Care Index Questionnaire. Possible influencing factors of functional exercise compliance were analyzed using correlation analysis as well as univariate and binary logistic regression analysis through SPSS v25, and a CHAID decision tree was used to construct a predictive model on training, validation and test sets via SPSS Modeler v18 at a ratio of 6:2:2. Prediction accuracy, sensitivity, specificity and AUC were used to analyze the efficacy of the predictive model.Results: A total of 227 valid samples were collected, of which 145 were assessed with a poor compliance (63.9%). According to a logistic regression analysis, perceived benefits, time after surgery and self-efficacy were influencing factors. The prediction accuracy, sensitivity, specificity and AUC of the predictive model, based on a CHAID decision tree analysis, were 70.73%, 57.1%, 77.8% and 0.81 respectively.Conclusion: The predictive model, based on a CHAID decision tree analysis, had a moderate predictive efficacy, which could be used as a clinical auxiliary tool for clinical nurses to predict patients’ functional exercise compliance.Keywords: breast cancer, functional exercise, predictive model, decision tree

Shuhui Yang, Zhanmei Zhang, Yulin Liu, Enmei Liu, Zhengxiu Luo Department of Respiratory Disease, Children’s Hospital of Chongqing Medical University/ National Clinical Research Center for Child Health and Disorders/ Ministry of Education Key Laboratory of Child Development and Disorders/ Chongqing Key Laboratory of Pediatrics, Chongqing, People’s Republic of ChinaCorrespondence: Yulin Liu, Email liuyulin817@163.comObjective: To investigate the effects of combined respiratory muscle and exercise training on inspiratory muscle strength, exercise capacity, spirometry measurements, asthma control the quality-of-life in children with asthma.Methods: Fifty children with asthma, who were treated in children’s hospital of Chongqing medical university in Chongqing between May and December 2021, were selected and randomly divided into a rehabilitation group and a control group by using a random number table. The control group was given routine drug treatment and health education while the rehabilitation group received a combination of respiratory muscle and exercise training on the basis of control group.Results: After three months of treatment, the maximum inspiratory pressure, level of asthma control and quality-of-life in the rehabilitation group were significantly improved when compared with those in the control group (P< 0.05); there were no significant differences in the 6-minute walking test and spirometry measurements (P> 0.05). After three months of treatment, all outcome indicators in the rehabilitation group were significantly improved when compared to those before treatment (P< 0.05). The mean value of maximum inspiratory pressure and some indices of spirometry measurements in the control group were significantly improved when compared to those before treatment (P< 0.05).Conclusion: Combining respiratory muscle and exercise training on the basis of the routine drug treatment and health education significantly improved inspiratory muscle strength, the level of asthma control and the quality-of-life in children with asthma. More research is needed to explore its role in asthma in the future.Keywords: training, bronchial asthma, children, respiratory muscles, exercise capacity, spirometry measurements, asthma control level, quality of life

Sun W, Luo Z, Jin J, Cao Z, Ma Y. Int J Chron Obstruct Pulmon Dis. 2021;16:2267–2277. The authors have advised the author list on page 2267 is incorrect. The text “Yingmin Ma2” should read “Yingmin Ma1,2”. The authors apologize for this error.

Ling Yang &ast;, Qi Shen &ast;, Chao Hu, Ying Wang, Xiaohong Zhu, Shiqing Shu, Zhu Luo Clinical Trial Center, National Medical Products Administration Key Laboratory for Clinical Research and Evaluation of Innovative Drugs, West China Hospital Sichuan University, Chengdu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhu Luo, Clinical Trial Center, National Medical Products Administration Key Laboratory for Clinical Research and Evaluation of Innovative Drugs, West China Hospital Sichuan University, No. 37 Guoxue Lane, Chengdu, Sichuan, 610044, People’s Republic of China, Tel +86 28 85422707, Email luozhu720@163.comBackground: Imrecoxib is a novel and moderately selective cyclooxygenase-2 inhibitor with properties of anti-inflammation and alleviating pain, which is widely applied in osteoarthritis patients. The pharmacokinetic data supporting imrecoxib’s rational use in elderly population are not available.Purpose: The study aims to investigate the pharmacokinetics of imrecoxib and its main metabolites and explore the safety of imrecoxib in elderly healthy subjects.Methods: A total of 19 healthy subjects including 10 non-elderly and 9 elderly subjects received single dose of 100 mg imrecoxib under fasting condition. Pharmacokinetics, safety and tolerability profiles were assessed.Results: After oral administration of single dose of 100 mg imrecoxib, it was absorbed into plasma with median time to reach peak concentration (Tmax) around 2 hours. The concentration–time curves of imrecoxib (M0) showed higher interindividual variability in elderly subjects compared with non-elderly subjects. Peak concentration (Cmax) of M0, its hydroxyl metabolite M1 and carboxylated metabolite M2 in plasma increased by 39%, 21% and 17%, and area under concentration–time curve from time 0 to time t (AUC0-t) of M0, M1 and M2 in plasma increased by 34%, 13% and 27%, respectively, in elderly subjects compared with non-elderly subjects. The 90% CIs of geometric mean ratios of Cmax, AUC0-t and AUC0-∞ of M0, M1 and M2 between the two groups were not located within 80– 125%, indicating Cmax, AUC0-t and AUC0-∞ were not completely equivalent between non-elderly and elderly healthy subjects. However, comparison of pharmacokinetic data of M0, M1 and M2 between the two groups showed no significant difference (P> 0.05). Imrecoxib was well tolerated in both non-elderly and elderly healthy subjects, especially with favorable gastrointestinal and cardiovascular safety profiles.Conclusion: Pharmacokinetic and safety profiles of imrecoxib in elderly healthy subjects indicated that no dose adjustment should be required for elderly population.Keywords: cyclooxygenase-2 inhibitor, imrecoxib, pharmacokinetics, safety, elderly

Zhuohui Luo,1 Yongcheng Wang,2 Shuo Pang,1 Shan Gao,1 Ning Liu,1 Xiang Gao,1 Li Zhang,1,3 Xiaolong Qi,1,3 Yajun Yang,2 Lianfeng Zhang1,3 1Key Laboratory of Human Disease Comparative Medicine, National Health Commission of China (NHC), Institute of Laboratory Animal Science, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100021, People’s Republic of China; 2Beijing Key Laboratory of Active Substance Discovery and Drug Ability Evaluation, Institute of Material Medical, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100050, People’s Republic of China; 3Neuroscience Center, Chinese Academy of Medical Sciences, Beijing, 100730, People’s Republic of ChinaCorrespondence: Yajun Yang, Institute of Material Medical, Peking Union Medical College, Chinese Academy of Medical Sciences, Nanwei Road, Xicheng District, Beijing, 100050, People’s Republic of China, Email yangyajun@imm.ac.cn Lianfeng Zhang, Institute of Laboratory Animal Science, Peking Union Medical College, Chinese Academy of Medical Sciences, Panjiayuan Nanli, Chaoyang District, Beijing, 100021, People’s Republic of China, Tel +86 10-87778442, Fax +86 10-67776394, Email zhanglf@cnilas.orgAim: Alzheimer’s disease (AD) is the most common neurodegenerative disease whose patients suffered from cognitive impairments. In our study, a novel 1,2,4-Oxadiazole derivative wyc-7-20 was synthesized, which showed low cytotoxicity and potent neuroprotective effect at the cellular level. Improved cognitive impairments, β-amyloid (Aβ) clearance, and tau pathological phenotypes were detected in transgenic animal models after wyc-7-20 treatment. Reversed expressions in AD-related genes were also detected. The results demonstrated wyc-7-20 was potent in AD therapy.Purpose: The pathological complexity of AD increased difficulties in medical research. To explore a new potential medical treatment for AD, a novel 1,2,4-Oxadiazole derivative (wyc-7-20) was designed, synthesized to explore the application in this study.Materials and Methods: Human neuroblastoma (SH-SY5Y) cells and human hepatocellular carcinoma (HepG2) cells were used to detect median lethal dose (LD50). H2O2 and Aβ1– 42 oligomers (AβOs) were respectively, added into SH-SY5Y cells to detect anti-ROS (reactive oxygen species) and anti-AβOs effects of wyc-7-20. 3×Tg mice were administered with wyc-7-20, and then Y maze test and Morris water maze (MWM) test were applied to detect cognitive improvements. Brain tissue samples were subsequently collected and analyzed using different techniques.Results: wyc-7-20 showed low cytotoxicity and potent neuroprotective effect at the cellular level. Improved cognitive impairments, Aβ clearance, and tau pathological phenotypes were detected in transgenic animal models after wyc-7-20 treatment. Reversed expressions in AD-related genes were also detected.Conclusion: wyc-7-20 was potent in AD therapy.Graphical abstract: Keywords: 1,2,4-oxadiazole, Alzheimer’s disease, animal model, neuroprotective effect

Wei Sun,1 Zhixin Cao,1 Yingmin Ma,2 Jing Wang,1 Liming Zhang,1 Zujin Luo1 1Department of Respiratory and Critical Care Medicine, Beijing Chaoyang Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Department of Respiratory and Critical Care Medicine, Beijing Youan Hospital, Capital Medical University, Beijing, People’s Republic of ChinaCorrespondence: Zujin Luo, Department of Respiratory and Critical Care Medicine, Beijing Chaoyang Hospital, Capital Medical University, Beijing, People’s Republic of China, Email xmjg2002@163.comBackground: Fibrinogen is increasingly being studied as an inflammatory biomarker in chronic obstructive pulmonary disease (COPD), but there are limited data on the role of fibrinogen in assessing the severity of acute exacerbation of COPD (AECOPD). This study aimed to explore whether circulating fibrinogen could be used as a surrogate to measure the severity and predict the prognosis of AECOPD.Methods: A total of 535 AECOPD patients diagnosed at our center from January 2016 to June 2021 were retrospectively enrolled in this study. The electronic medical record of each patient was retrieved to collect data on baseline characteristics and laboratory parameters, as well as the use of noninvasive positive-pressure ventilation (NPPV) and prognosis. Multiple linear regression analysis was used to identify independent factors associated with circulating fibrinogen values. Receiver-operating characteristic curve and multivariate logistic regression analysis were applied to further verify the use of fibrinogen to predict NPPV failure.Results: Compared to patients with fibrinogen < 4 g/L, patients with increased fibrinogen levels (> 4 g/L) tended to have elevated inflammatory response and higher incidence of DVT/PTE, emphysema, pneumonia, and atherosclerosis. In addition, fibrinogen levels in NPPV-failure patients were significantly higher than non-NPPV patients and NPPV-success ones. The presence of emphysema, pneumonia, and history of long-term oxygen therapy and higher CRP levels and leukocyte counts were independent risk factors associated with increased fibrinogen levels in AECOPD. Furthermore, our data indicated that fibrinogen could be considered as a reliable biomarker to predict NPPV failure (AUC, 0.899, 95% CI 0.846– 0.952), with an OR of 7.702 (95% CI 2.984– 19.875; P< 0.001).Conclusion: The level of circulating fibrinogen can be used to measure severity of AECOPD, and among AECOPD patients managed with NPPV, fibrinogen > 3.55 g/L can independently predict NPPV failure.Keywords: COPD, noninvasive positive-pressure ventilation, acute exacerbation, fibrinogen, predictor

Zhipeng Wu,1,&ast; Zujin Luo,2,&ast; Zengtao Luo,2 Jingyi Ge,3 Jiawei Jin,4 Zhixin Cao,2 Yingmin Ma1 1Department of Respiratory and Critical Care Medicine, Beijing Youan Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Department of Respiratory and Critical Care Medicine, Beijing Chaoyang Hospital, Capital Medical University, Beijing, People’s Republic of China; 3Department of Respiratory Medicine, Beijing Rehabilitation Hospital, Capital Medical University, Beijing, People’s Republic of China; 4The Clinical Research Center, Beijing Chaoyang Hospital, Capital Medical University, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yingmin Ma, Department of Respiratory and Critical Care Medicine, Beijing Youan Hospital, Capital Medical University, Beijing, People’s Republic of China, Tel +86 10-13501185982, Email mayingmin@ccmu.edu.cnPurpose: The evidence of long-term home noninvasive positive pressure ventilation (LTHNIPPV) in patients with stable hypercapnic chronic obstructive pulmonary disease (COPD) is controversial. In this meta-analysis study, we sought to establish whether a baseline level and reduction in partial pressure of arterial carbon dioxide (PaCO2) were associated with the treatment effect of LTHNIPPV in these patients.Patients and Methods: Six electronic databases were comprehensively searched from January 1980 until June 2020. Randomized clinical trials (RCTs) comparing LTHNIPPV with control treatment were included. Two authors independently extracted data, assessed the study quality, and used the GRADE approach to evaluate evidence quality. The main outcome was mortality.Results: Nineteen studies involving 1482 patients (LTHNIPPV, n = 730; control, n = 752) were included. LTHNIPPV significantly reduced mortality (relative risk [RR] = 0.76; 95% confidence interval [CI]: 0.61– 0.95; p = 0.02; I2 = 14%), the frequency of hospital admissions, PaCO2, and improved partial pressure of oxygen (PaO2) compared to control treatment. LTHNIPPV also relieved dyspnea and improved exercise capacity and health-related quality of life (HRQL) but showed no significant benefit for improving the forced expiratory volume in one second in predicted (FEV1% pred). Subgroup analysis revealed that the baseline level and reduction in PaCO2 were associated with decreased mortality (baseline PaCO2 ≥ 55 mmHg RR = 0.69, P = 0.02; vs baseline PaCO2 < 55 mmHg RR = 0.87, P = 0.32; and higher dPaCO2 RR = 0.42, P < 0.0001; vs lower dPaCO2 RR = 0.91, P = 0.38).Conclusion: LTHNIPPV significantly reduced mortality. The baseline level and reduction in PaCO2 were associated with the treatment effect of LTHNIPPV in patients with stable hypercapnic COPD. Large-scale, multicenter RCTs are needed to confirm our results.Keywords: COPD, long-term home noninvasive positive pressure ventilation, mortality, meta-analysis study, RCTs, stable hypercapnic

Guiqiang Miao,&ast; Zhaohui Li,&ast; Linjian Chen, Wenyong Li, Guobo Lan, Qiyuan Chen, Zhen Luo, Ruijia Liu, Xiaodong Zhao Department of Orthopedics, Foshan Fosun Chancheng Hospital, Foshan, 528010, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiaodong Zhao, Department of Orthopedics, Foshan Fosun Chancheng Hospital, Foshan, 528010, People’s Republic of China, Email CY1002358969@163.comObjective: Bone and bone marrow are the third most frequent sites of metastases from many cancers and are associated with low survival and high morbidity rates. Currently, there are no effective bedside tools to predict the morbidity risk of these patients in general intensive care units (ICUs). The main objective of this study was to establish and validate a nomogram to predict the morbidity risk of patients with bone and bone marrow metastases.Methods: Data on patients with bone and bone marrow metastases were extracted from the Medical Information Mart for Intensive Care III (MIMIC-III) database. The patients were divided into training and validation cohorts. The data were analyzed using univariate and multivariate Cox regression methods. Factors significantly and independently prognostic of survival were used to construct a nomogram predicting 30-day morbidity. The nomogram was validated by various methods, including Harrell’s concordance index (C-index), area under the receiver operating characteristic curve (AUC), calibration curve, integrated discrimination improvement (IDI), net reclassification index (NRI), and decision curve analysis (DCA).Results: The study included 610 patients in the training cohort and 262 in the validation cohort. Multivariate Cox regression analysis showed that temperature, SpO2, Sequential Organ Failure Assessment (SOFA) score, Oxford Acute Severity of Illness Score (OASIS), comorbidities with coagulopathy, white blood cell count, heart rate, and respiratory rate were independent predictors of patient survival. The resulting nomogram had good discriminative ability, as shown by high AUCs, and was well calibrated, as demonstrated by calibration curves. Improvements in NRI and IDI values suggested that the nomogram was superior to the SOFA scoring system. DCA curves revealed that the nomogram showed good value in clinical applications.Conclusion: This prognostic nomogram, based on demographic and laboratory parameters, was predictive of the 30-day morbidity rate in patients with secondary malignant neoplasms of the bone and bone marrow, suggesting its applicability in clinical practice.Keywords: secondary malignant neoplasm of bone and bone barrow, MIMIC-III database, prognosis, nomogram

Guoying Zou,1 Qing Zhu,1 Biqiong Ren,1 Qi Guo,1 Yuanyuan Wu,1 Junyu He,1 Ying Wu,1 Zhihong Luo2 1Department of Clinical Laboratory, The Second People’s Hospital of Hunan Province, Changsha, Hunan, 410007, People’s Republic of China; 2Office of the Party Committee, The Second People’s Hospital of Hunan Province, Changsha, Hunan, 410007, People’s Republic of ChinaCorrespondence: Zhihong Luo, Office of the Party Committee, The Second People’s Hospital of Hunan Province, Furong Middle Road 427, Yuhua District, Changsha, Hunan, 410007, People’s Republic of China, Tel +86 19848029533, Email lzh3068@sina.comPurpose: To determine the levels of serum HDL-associated apolipoproteins (apoM and apoC) and HDL-binding receptor (scavenger receptor BI, SR-BI) in patients with gram-negative bacteria sepsis (G-sepsis) and to evaluate the value of lipoproteins in the diagnosis, severity and prognosis of G-sepsis.Patients and Methods: A total of 128 patients with sepsis, 40 patients with system inflammatory reaction syndrome (SIRS) and 40 healthy subjects were enrolled in the Second People’s Hospital of Hunan Province from September 2019 to September 2020. The levels and the correlation of lipoproteins were detected and dynamically monitored by enzyme-linked adsorption method, ROC curve for the diagnostic, severity and prognostic value of lipoproteins in G-sepsis.Results: The levels of serum HDL-associated lipoproteins in patients with G-sepsis were significantly decreased (P < 0.05), and the ROC curve showed that HDL-C, SR-BI, apoM and apoC had cut-off values of 0.915 mmol/L, 122.100 pg/mL, 102.400 ug/mL and 17.55 mg/mL, respectively, for the diagnosis of G-sepsis, with the sensitivity was 85.56%, 97.78%, 93.33% and 73.03%, and the specificity was 95.0%, 82.50%, 61.54% and 82.50%, respectively. There was a correlation between HDL-associated apolipoproteins. Changes in serum HDL-associated lipoproteins were more obvious in shock group than classic inflammation indicators, such as PCT, IL-6 and CRP. They showed a trend change on day 3, with the levels of SR-BI and apoC changing 2– 3 times, and the sensitivity of HDL-C, SR-BI, apoM and apoC for the diagnosis of G-septic shock were 32.43%, 72.97%, 65.75%, and 43.24%, and specificity of 94.34%, 81.13%, 83.07%, and 86.79%, respectively. The AUC, sensitivity and specificity of apoM combined with SR-BI were improved.Conclusion: HDL-associated lipoproteins were correlated with bacterial-infected types, and serum levels of HDL-associated lipoproteins can be used as potential biomarkers for early diagnosis and progress of G-sepsis. ApoM combined with SR-BI could improve the sensitivity and specificity of prognosis assessment.Keywords: apolipoprotein, high-density lipoprotein, gram-negative sepsis, biomarker, prognosis

Xinlin Xiong,1– 3 Zhenhua Luo,4,5 Haiyan Zhou,3 Zonggang Duan,1 Li Niu,3 Kai Zhang,1 Guangwei Huang,1 Wei Li1,3 1Clinical College, Guizhou Medical University, Guiyang City, Guizhou Province, People’s Republic of China; 2Department of Cardiology, Chengdu University Affiliated Hospital, Chengdu City, Sichuan Province, People’s Republic of China; 3Department of Cardiology, Guizhou Medical University Affiliated Hospital, Guiyang City, Guizhou Province, People’s Republic of China; 4NHC Key Laboratory of Pulmonary Immune-related Diseases, Guizhou Provincial People’s Hospital, Guiyang City, Guizhou Province, People’s Republic of China; 5Department of Central Lab, Guizhou Provincial People’s Hospital, Guiyang City, Guizhou Province, People’s Republic of ChinaCorrespondence: Wei Li, Email liwei249188@sina.comObjective: Little is currently known on the role of T-cell immunoglobulin and ITIM domain (TIGIT) expression in Foxp3+ regulatory T cells (TIGIT+Tregs) in acute coronary syndrome (ACS) patients. The aim of this study was to investigate the role and alterations of TIGIT+Tregs in ACS patients.Methods: We enrolled 117 subjects, including 61 ACS patients, 26 chronic coronary syndrome (CCS) patients, and 30 control subjects without coronary artery disease. The quantification of TIGIT+Tregs was determined by flow cytometry; serum interleukin-6 (IL-6) and transforming growth factor-β (TGF-β) were also measured.Results: TIGIT+Tregs expression was significantly lower in ACS patients compared with CCS and control patients (P< 0.05). The expression of TIGIT+Tregs was comparable in patients with and without traditional risk factors (P> 0.05). Logistic regression analysis revealed that TIGIT+Tregs levels are independent predictors of ACS (P< 0.01). Receiver-operating characteristic (ROC) curve analysis showed the expression levels of TIGIT+Tregs had a discriminative power for ACS (P< 0.01). IL-6 levels were increased (P< 0.01), while TGF-β was decreased in ACS patients compared with CCS and control patients (P< 0.01). Meanwhile, an inverse correlation between IL-6 and TIGIT+Tregs was observed (P< 0.01), while a positive correlation between TGF-β and TIGIT+Tregs was found (P< 0.05).Conclusion: TIGIT+Tregs levels are significantly reduced in ACS, accompanied by upregulated IL-6 and downregulated TGF-β expression. The downregulated TIGIT+Tregs are independent predictors of ACS. These findings suggest that TIGIT+Tregs may have an anti-inflammatory and protective effect on ACS, and its decreased expression may be associated with atherosclerotic plaque destabilization.Keywords: T-cell immunoglobulin and ITIM domain, regulatory T cell, acute coronary syndrome, inflammation

Wei Sun,1,&ast; Zujin Luo,1,&ast; Jiawei Jin,1 Zhixin Cao,1 Yingmin Ma2 1Department of Respiratory and Critical Care Medicine, Beijing Chaoyang Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Department of Respiratory and Critical Care Medicine, Beijing Youan Hospital, Capital Medical University, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yingmin MaDepartment of Respiratory and Critical Care Medicine, Beijing Youan Hospital, Capital Medical University, Beijing, People’s Republic of ChinaTel +86-10-13501185982Email ma.yingmin@163.comPurpose: To determine the effectiveness of neutrophil/lymphocyte ratio (NLR), compared to traditional inflammatory markers, for predicting noninvasive mechanical ventilation (NIMV) failure in acute exacerbation of chronic obstructive pulmonary disease (AECOPD) patients.Patients and Methods: We conducted this retrospective observational study including 212 AECOPD patients who required NIMV during hospitalization from January 2015 to December 2020 in the department of respiratory and critical care medicine of Beijing Chao-Yang Hospital (west campus). We reviewed the medical record to determine if NIMV succeeded or failed for each patient, and compared NLR with traditional markers (leukocyte, C-reactive protein [CRP] and procalcitonin [PCT]) between NIMV failure and NIMV success group. Receiver-operating characteristic (ROC) curve and multivariate logistic regression analysis were used to assess the accuracy of these markers for predicting NIMV failure.Results: A total of 38 (17.9%) patients experienced NIMV failure. NLR was a more sensitive biomarker to predict NIMV failure (AUC, 0.858; 95% CI 0.785– 0.931) than leukocyte counts (AUC, 0.723; 95% CI 0.623– 0.823), CRP (AUC, 0.670; 95% CI 0.567– 0.773) and PCT (AUC, 0.719; 95% CI 0.615– 0.823). There was statistically positive correlation between NLR and leukocytes count (r=0.35, p< 0.001), between NLR and CRP (r=0.258, p< 0.001), between NLR and PCT (r=0.306, p< 0.001). The cutoff value of NLR to predict NIMV failure was 8.9 with sensitivity 0.688, specificity 0.886 and diagnostic accuracy 0.868. NLR> 8.9 (odds ratio, 10.783; 95% CI, 2.069– 56.194; P=0.05) was an independent predictor of NIMV failure in the multivariate logistic regression model.Conclusion: NLR may be an effective marker for predicting NIMV failure in AECOPD patients, and the patients with NLR> 8.9 should be handled with caution since they are at higher risk of NIMV failure and require intubation. Further study with a larger sample size and with more data is necessary to confirm our study.Keywords: COPD, noninvasive mechanical ventilation, neutrophil/lymphocyte ratio, predictor, failure, NIMV, NLR, chronic obstructive pulmonary disease

JinJian Yao,1,&ast; Hangfei Wang,2,&ast; Weiling Yu,3,&ast; Yimin Li,4 Zhiqian Luo,2 Biao Wu,5 Wei Zhang,6 Xiaoran Liu,2 Chuanzhu Lv6,7 1Emergency Center, Hainan General Hospital Affiliated to Hainan Medical University, Haikou, Hainan, People’s Republic of China; 2Department of Emergency, The First Affiliated Hospital of Hainan Medical University, Haikou, Hainan, People’s Republic of China; 3Oncology Department, Haikou City People’s Hospital, Haikou, Hainan, People’s Republic of China; 4Department of General Surgery, Yang Jiang Hospital of Qiongzhong, Qiongzhong, Hainan, People’s Republic of China; 5Department of Infectious Disease, Hainan General Hospital Affiliated to Hainan Medical University, Haikou, Hainan, People’s Republic of China; 6Emergency and Trauma College of Hainan Medical University, Haikou, Hainan, People’s Republic of China; 7Key Laboratory of Emergency and Trauma, Ministry of Education of Hainan Medical University, Haikou, Hainan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiaoran LiuDepartment of Emergency, The First Affiliated Hospital of Hainan Medical University, Haikou, Hainan, People’s Republic of ChinaTel +8613118901829Email liuxiaoran3192@163.comChuanzhu LvKey Laboratory of Emergency and Trauma, Ministry of Education of Hainan Medical University, Haikou, Hainan, People’s Republic of ChinaTel +8617789830771Email lvchuanzhu677@126.comIntroduction: Close contacts of individuals with COVID-19 may directly gain immunity against SARS-CoV-2 despite lacking a detectable infection. This study examined SARS-CoV-2-specific antibodies levels based on gender, age, and exposure source in close contacts of individuals with COVID-19 and compared antibody levels to patients with an asymptomatic or symptomatic COVID-19 infection.Methods: Two patients had confirmed COVID-19 infections at a community hospital in Qiongzhong, Hainan province. Contact tracing identified all individuals in the community who had been exposed to the two patients during the 14 days before their diagnoses. Close contacts quarantined for 14 days, underwent two SARS-CoV-2 tests, and were screened for SARS-CoV-2-specific antibodies at 7 and 12 weeks after the end of quarantine. SARS-CoV-2-specific antibody levels for the close contacts were compared to those for patients with an asymptomatic or symptomatic COVID-19 infection at 7 and 12 weeks after their diagnoses.Results: Contact tracing identified 10,573 individuals in the community, including 360 (3.4%) close contacts. At 7 weeks, 30 (8.33%) close contacts were positive for SARS-CoV-2-specific antibodies (IgG, n = 26 [7.22%]; IgM, n = 4 [1.11%]), which were lower than the proportion of patients with an asymptomatic (IgG, 100% [12/12]) or symptomatic (IgG, 93.6% [44/47]) COVID-19 infection. SARS-CoV-2-specific IgM antibody levels were significantly higher in close contacts who were exposed through a relative compared to a doctor–patient relationship (P = 0.032). SARS-CoV-2-specific IgG antibody levels were significantly higher in close contacts aged < 18 years vs 18– 64 years (P = 0.014). At 12 weeks, SARS-CoV-2-specific IgG antibody levels among close contacts were significantly lower than among patients with an asymptomatic (P = 0.004) or symptomatic COVID-19 infection (P < 0.001).Conclusion: Immune protection conferred by close contact is short term and unlikely to contribute to herd immunity. There remains an unmet public health need for mass vaccination of populations to increase levels of protective antibodies and achieve and maintain herd immunity.Keywords: SARS-CoV-2, COVID-19, antibody, close contact

Zhuanbo Luo, Wen Zhang, Lina Chen, Ning Xu Department of Respiratory Disease, Ningbo First Hospital, Zhejiang, People’s Republic of ChinaCorrespondence: Zhuanbo LuoDepartment of Respiratory Disease, Ningbo First Hospital, 59 Liuting Street, Haishu District, Ningbo, Zhejiang, 315010, People’s Republic of ChinaTel +158-6781-3738Email luozhuanbo2929@163.comObjective: Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is the most common cause of hospitalization and death among COPD patients. Clinicians are seeking simple, inexpensive, and easily obtained biomarkers for prognostic evaluation. The aim of this study was to evaluate the association of the neutrophil:lymphocyte ratio (NLR), platelet:lymphocyte ratio (PLR) and lymphocyte:monocyte ratio (LMR) with 28-day mortality and assess the clinical prognostic utility of the NLR, PLR, and LMR in patients with AECOPD.Methods: A retrospective study was conducted from January 2017 to April 2020 at Ningbo First Hospital. Clinical characteristics, NLR, PLR, LMR, serum levels of CRP, and other data were collected. Relationships between the NLR/PLR/LMR and CRP were evaluated with Pearson’s correlation test. Receiver-operating characteristic curves and area under the curve were used to assess the ability of NLR/PLR/LMR to predict 28-day mortality in patients with AECOPD. Optimal cutoff values were determined by the Youden index. Univariate and multivariate logistic regression analysis were used to identify risk factors for 28-day mortality in patients with AECOPD.Results: By reviewing the medical case records, we collected 533 cases diagnosed with AECOPD for analysis. Death had occurred in 48 (9%) patients within 28 days. Univariate analysis identified age, smoking history, FEV1% predicted, neutrophil count, lymphocyte count, NLR, PLR, CRP and blood-urea nitrogen as being associated with increased 28-day mortality. Multivariate analysis demonstrated that elevated NLR and PLR were significantly associated with death at 28 days. Receiver-operating characteristic analysis showed that the NLR had the highest area under the curve (0.801), with optimal cutoff of 6.74, sensitivity of 82.54%, and specificity of 71.38%. At a cutoff of 203.6, the corresponding sensitivity, specificity, and area under the curve of the PLR were 76.86%, 65.27%, and 0.75. The LMR failed to show prognostic significance.Conclusion: Our results indicated that the NLR and PLR were associated with 28-day mortality in patients with AECOPD. These ratios may serve as prognostic biomarkers for short-term mortality in patients hospitalized with AECOPD.Keywords: prognostic value, neutrophil to lymphocyte ratio, platelet to lymphocyte ratio, AECOPD, biomarker

Xiaoling Wang,1 Sandrine Heraud,2 Amelie Thepot,2 Morgan Dos Santos,2 Zhen Luo1 1Infinitus Company Ltd, Guangzhou, People’s Republic of China; 2LabSkin Creations, Edouard Herriot Hospital, Lyon, FranceCorrespondence: Xiaoling Wang Tel +86 13631351533Email Lynn.Wang@infinitus-int.comBackground: Ultraviolet (UV) rays are the major environmental factor that damage skin physiology causing deleterious effects such as oxidation, photoaging and pigmentation. There has been considerable interest in using botanicals to prevent skin damages caused by UV irradiation.Aim: In this study, three plant extracts were tested either individually or combined together (mixture) as well as their corresponding main active compound: pomegranate/punicalagin, osmanthus/verbascoside and olive/hydroxytyrosol. We evaluated the properties of whitening and anti-photoaging of the nutritional mixture using 2D human culture model and a 3D full-thickness pigmented skin model exposed to UVB and UVA.Methods: For exploring skin pigmentation, oxidation and aging, we performed cell viability, tyrosinase activity and melanin content assays as well as histology analysis (Warthin–Starry staining), immunodetection (PMEL, MDA, collagen type I and elastin) and carbonylated proteins analysis by electrophoresis separation.Results: Results showed that the pomegranate extract and the active molecule punicalagin could reduce the tyrosinase activity and melanin content in melanocytes (P < 0.05), which suggested that punicalagin contributed to the whitening properties of the plant extracts mixture. The mixture, pomegranate extract and punicalagin inhibited the melanin production and pre-melanosomal protein (PMEL) expression in the 3D skin pigmented model (P < 0.001). Furthermore, the mixture treatment repaired the expressions of collagen I and elastin decrease by UV exposure (P < 0.01). The mixture also significantly decreased lipid peroxidation (P < 0.001) and carbonylated proteins (P < 0.05) in the skin model compared to the UV-exposed condition.Conclusion: To conclude, the mixture composed of pomegranate, osmanthus and olive extracts protects human skin from UV rays deleterious effects and exhibits antioxidative, anti-aging and skin whitening properties. The mixture might be good candidates for further development as natural antioxidants and skin care products.Keywords: ultraviolet radiation, plants extracts, antioxidation, punicalagin, pigmentation

Yang Liu,1,2,* Yun Wang,1,2,* Jie Wang,2 Kang Chen,2 Lingzi Jin,3 Weiqing Wang,4 Zhengnan Gao,5 Xulei Tang,6 Li Yan,7 Qin Wan,8 Zuojie Luo,9 Guijun Qin,10 Lulu Chen,11 Yiming Mu2 1Graduate School, Chinese PLA General Hospital, Beijing, People’s Republic of China; 2Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, Beijing, People’s Republic of China; 3Department of International Medical Services, Peking Union Medical College Hospital (Xidan Campus), Beijing, People’s Republic of China; 4Shanghai National Research Centre for Endocrine and Metabolic Diseases, State Key Laboratory of Medical Genomics, Shanghai Institute for Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China; 5Department of Endocrinology, Dalian Central Hospital, Dalian, Liaoning, People’s Republic of China; 6Department of Endocrinology, First Hospital of Lanzhou University, Lanzhou, Gansu, People’s Republic of China; 7Department of Endocrinology, Zhongshan University Sun Yat-Sen Memorial Hospital, Guangzhou, Guangdong, People’s Republic of China; 8Department of Endocrinology, Southwest Medical University Affiliated Hospital, Luzhou, Sichuan, People’s Republic of China; 9Department of Endocrinology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People’s Republic of China; 10Department of Endocrinology, First Affiliated Hospital of Zhengzhou University, Zhenzhou, Henan, People’s Republic of China; 11Department of Endocrinology, Wuhan Union Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yiming MuDepartment of Endocrinology, The First Medical Center of Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing, 100853, People’s Republic of ChinaTel +86-10-5549 9001Email muyiming@301hospital.com.cnBackground: Lipid accumulation product (LAP) as a powerful marker of visceral obesity is an independent risk factor of chronic kidney disease. The present study attempted to explore the association between LAP and albuminuria in prediabetic individuals.Methods: We conducted a cross-sectional study and enrolled 26,529 participants with prediabetes over 40 years old with prediabetes from seven provinces in China. LAP was calculated from waist circumference and fasting triglycerides. Elevated albuminuria was defined by urinary albumin-creatinine ratio (uACR) ≥ 30 mg/g. Propensity score matching was applied to reduce bias, comparison between LAP and other traditional visceral obesity indices was performed and multiple logistic regression models were conducted to assess the association between LAP and albuminuria in the prediabetic population.Results: Individuals with uACR ≥ 30 mg/g were older and had higher BP, BMI, WC, TG, fasting insulin, glycohemoglobin and LAP, as well as lower eGFR and HDL level. Multiple logistic regression analysis showed elevated LAP was associated with increased odds of albuminuria (OR [95%CI]Q2 vs Q1 1.09 [0.94, 1.27], OR [95%CI]Q3 vs Q1 1.13 [0.97, 1.31], OR [95%CI]Q4 vs Q1 1.42 [1.21, 1.67], P for trend=0.018), and superior over waist-to-hip ratio or waist-to-height ratio. Stratification indicated that the prediabetic population with higher LAP level and characterized by female gender, middle age, being overweight, and rise in blood pressure were more likely to have increased uACR.Conclusion: Elevated level of LAP was associated with increased albuminuria in the prediabetic population in China.Keywords: albuminuria, lipid accumulation product, prediabetes, visceral obesity

Zhiqiang Luo,1,* Guohua Yu,1,* Wubin Wang,1,* Rui Sun,1 Binbin Zhang,1 Jing Wang,2 Jing Liu,1 Shan Gao,1 Peng Wang,3 Yuanyuan Shi1,4 1School of Life Sciences, Beijing University of Chinese Medicine, Beijing, 102488, People’s Republic of China; 2State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, People’s Republic of China; 3The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, People’s Republic of China; 4Shenzhen Research Institute, Beijing University of Chinese Medicine, Shenzhen, 518118, People’s Republic of China*These authors contributed equally to this workCorrespondence: Peng WangThe First Affiliated Hospital of Guangzhou Medical University, No. 151 Yanjiang Road, Yuexiu District, Guangzhou, 510120, People’s Republic of ChinaEmail mrwp0022@163.comYuanyuan ShiShenzhen Research Institute, Beijing University of Chinese Medicine, No. 16 Lanjingzhong Road, Pingshan District, Shenzhen, 518118, People’s Republic of ChinaTel +86 18565780299Email yshi@bucm.edu.cnIntroduction: Gu-Ben-Ke-Chuan (GBKC) decoction, a well-known prescription composed of seven herbs, has been widely used for treating chronic bronchitis (CB). However, the pharmacological constituents of GBKC and the underlying mechanisms by which these components act on CB remain unclear.Methods: Ultra-high-pressure liquid chromatography coupled with linear ion trap–Orbitrap tandem mass spectrometry (UHPLC-LTQ-Orbitrap) was first employed to rapidly identify compounds from GBKC. Thereafter, network pharmacology and molecular docking analyses were performed to identify the potential active constituents, candidate targets, and major pathways. Finally, the affinities between the key compounds and targets were verified via surface plasmon resonance (SPR) analysis. In addition, the anti-inflammatory effect of GBKC was verified using an LPS-induced inflammatory cell model based on the predicted results.Results: A total of 53 major compounds were identified in the GBKC decoction. After network pharmacology-based virtual screening, 141 major targets and 39 main compounds were identified to be effective in the treatment of CB. The major targets were highly enriched in the tumor necrosis factor (TNF) signaling pathway, suggesting that GBKC could attenuate the inflammatory response in patients with CB. Furthermore, molecular docking results indicated that 20 pairs of components and target proteins relevant to the TNF pathway exhibited notable interactions. Among them, eight compound-target pairs exhibited good affinity as per SPR analysis. In addition, the production of interleukin 6 and TNF-α in LPS-induced MH-S cells was suppressed after GBKC treatment.Conclusion: This study successfully clarified the mechanism of action of GBKC against CB, which demonstrated that the integrated strategy described above is reliable for identifying the active compounds and mechanisms responsible for the pharmacological activities of GBKC decoction.Keywords: Gu-Ben-Ke-Chuan decoction, chronic bronchitis, UHPLC-LTQ-Orbitrap, network pharmacology, surface plasmon resonance

Yaying Sun,* Jinrong Lin,* Zhiwen Luo,* Yuhan Zhang, Jiwu Chen Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jiwu ChenDepartment of Sports Medicine, Huashan Hospital, Fudan University, 12# Middle Wulumuqi Road, Jing’an District, Shanghai, 200040, People’s Republic of ChinaFax +86 21 52888255Email jeevechen@gmail.comPurpose: Disorders with systematic inflammation were prognostic for secondary frozen shoulder (sFS) following rotator cuff repair (RCR); however, how systematic inflammation affects sFS remains unclear. The aim of this study was to observe the effect of pre-operative serum from patients with sFS and the serum from those without on shoulder capsule in mice, and on macrophages and fibroblasts in vitro.Methods: Serum samples of a consecutive cohort of patients for RCR were collected pre-operatively. Three months after RCR, patients who developed sFS (Group S) were identified. Serum samples from gender- and age-matched controls without sFS (group NS) were also picked out. Firstly, the effect of serum on shoulder capsule fibrosis was observed histologically and biomechanically in a mouse model of RCR. Secondly, the roles of the serum on macrophage polarization and fibroblast activation were investigated, and the potentially involved signaling pathways were identified. Finally, inflammation and fibrosis-related cytokines in serum were quantified.Results: In our cohort, all patients had free pre-operative shoulder range of motion. Seven patients developed sFS at 3 months after surgery. Seven matched patients without sFS were selected as control. The inter-group difference of basic characteristics was not significant. Compared to the serum of group NS, the serum of group S significantly induced hypercellularity, capsular thickening, and range of motion deficiency in mice shoulders after RCR. Compared to the serum of group NS, samples of group S significantly promoted M2 polarization of THP-1 human macrophages and the activation of human capsule-derived fibroblasts. Meanwhile, Smad3 and p-Smad3 in macrophages and fibroblasts were significantly up-regulated. On the other hand, levels of inflammation and fibrosis-related cytokines were not significantly different between serum in group S and group NS.Conclusion: Although all patients in this cohort had free range of motion pre-operatively, the pre-operative serum from patients with sFS at 3 months after RCR could act as a trigger of shoulder capsule fibrosis post-operatively. This effect may be related to its promotion on macrophage polarization to M2 phenotype and fibroblast activation.Keywords: rotator cuff, secondary frozen shoulder, serum, macrophage, fibroblast

Wenhui Liu,1,2 Yiping Liu,1,2 Fang Ma,3 Bao Sun,1,2 Ying Wang,1,2 Jianquan Luo,1,2 Mouze Liu,1,2 Zhiying Luo1,2 1Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 2Institute of Clinical Pharmacy, Central South University, Changsha, People’s Republic of China; 3Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha, People’s Republic of ChinaCorrespondence: Zhiying Luo No. 139, People’s Middle Street, Furong District, Changsha City, Hunan Province 40013, People’s Republic of ChinaTel +86 13787034276Fax +86 0731 85294099Email lzhy199089@csu.edu.cnBackground: Immune checkpoint inhibitors (ICIs) have transformed the treatment landscape for patients with advanced non-small-cell lung cancer (aNSCLC), but immune-related adverse events (irAEs) have been evidenced curtailed the clinical use of them.Purpose: The aim of this study was to research the influences of inflammation-related peripheral blood markers, including neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) levels, on anti-PD-1 inhibitor-induced irAEs.Patients and Methods: A retrospective analysis was conducted of patients treated with PD-1 inhibitors for stage III–IV NSCLC at a single center from 2017 to 2020 were included. Clinical characteristics, peripheral blood markers at the baseline and before subsequent treatment cycles were collected. NLR and PLR were calculated by division of neutrophil and platelet by lymphocyte measured in peripheral blood. The development of irAEs was evaluated and monitored from the therapy start based on CTCAE V4.03.Results: A total of 150 patients were included. Fifty-seven patients had occurred at least one irAEs during follow-up, and mainly grade 1– 2 (73.68%). Pruritus, rash and thyroiditis were the most commonly irAEs. Low NLR, PLR and neutrophil at baseline were significantly associated with the development of severe irAEs (P-values were 0.023, 0.0016 and 0.009). The levels of neutrophil, NLR and PLR also significantly decreased when occurred irAEs compared with baseline (P-values were 0.0069, 0.017 and 1.18E-5, respectively).Conclusion: The levels of NLR, PLR and neutrophil were associated with the increased risk of severe irAEs when baseline levels were low. NLR, PLR, and neutrophil are simple and available biomarkers that can be used to help predict severe adverse effects in NSCLC patients treated with anti-PD-1 inhibitors.Keywords: immune checkpoint inhibitors, NSCLC, irAE, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio

Xu Jia,1,* Ziren Luo,2,* Ying Gao,3 Hua Liu,3 Xinghai Liu,3 Wenli Mai,3 Hong Liu,3 Qian Zheng3 1Department of Pharmacy, Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, People’s Republic of China; 2School of Pharmacy, North Sichuan Medical College, Nanchong 637000, People’s Republic of China; 3Department of Physiology, North Sichuan Medical College, Nanchong 637007, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qian ZhengDepartment of Physiology, North Sichuan Medical College, Nanchong, 637007, People’s Republic of ChinaEmail 373969568@qq.comObjective: The protective effects of epigallocatechin gallate (EGCG) on interleukin-1β (IL-1β)-induced apoptosis were investigated in murine MIN6 pancreatic β-cells. The role of uncoupling protein-3 (UCP3) signaling in this process was also explored.Methods: After treatment with IL-1β and EGCG, cells were collected and analyzed. Cell viability was measured using the CCK8 assay and the function of β-cells was evaluated by analyzing insulin secretion. Detection of mitochondrial function in cells was performed by measuring mitochondrial membrane potential, the concentration of ATP and activity of ROS. Apoptosis was analyzed by Hochest33258 staining and flow cytometry. Expression levels of UCP3 were interrogated using immunohistochemistry, RT-PCR and Western blotting.Results: Compared with the control group, IL-1β treatment (20nM) for 24 h significantly decreased cell viability and insulin secretion, damaged mitochondrial function and increased ROS activity. Results also showed increased apoptosis and a decrease in UCP3 expression levels (p< 0.01). However, treatment with low (1mM) or high (5mM) concentrations of EGCG significantly decreased IL-1β-induced apoptosis (p< 0.01), restored mitochondrial function and subsequently increased UCP3 levels in IL-1β-induced β-cells (p< 0.01).Conclusion: These results suggest that EGCG protects against IL-1β-induced mitochondrial injury and apoptosis in β-cells through the up-regulation of UCP3.Keywords: EGCG, pancreatic β-cells, apoptosis, UCP3

Yu Hei,1 Binhong Teng,2,3 Ziqian Zeng,2,3 Siqi Zhang,3 Qian Li,3 Jijia Pan,3 Zuyuan Luo,3 Chunyang Xiong,1 Shicheng Wei2,3 1Department of Mechanics and Engineering Science, College of Engineering, Peking University, Beijing, People’s Republic of China; 2Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Peking University, Beijing, People’s Republic of China; 3Laboratory of Biomaterials and Regenerative Medicine, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, People’s Republic of ChinaCorrespondence: Chunyang XiongDepartment of Mechanics and Engineering Science, College of Engineering, Peking University, Beijing, People’s Republic of ChinaTel +86 10 62757940Email cyxiong@pku.edu.cnShicheng WeiDepartment of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Peking University, Beijing, People’s Republic of ChinaTel +86 10 82195780Email sc-wei@pku.edu.cnBackground: Immune checkpoint blockades (ICBs) are a promising treatment for cancers such as melanoma by blocking important inhibitory pathways that enable tumor cells to evade immune attack. Programmed death ligand 1 monoclonal antibodies (aPDL1s) can be used as an ICB to significantly enhance the effectiveness of tumor immunotherapy by blocking the PD-1/PD-L1 inhibitory pathway. However, the effectiveness of aPDL1s may be limited by low selectivity in vivo and immunosuppressed tumor microenvironment including hypoxia.Purpose: To overcome the limitations, we develop a multifunctional immunoliposome, called CAT@aPDL1-SSL, with catalase (CAT) encapsulated inside to overcome tumor hypoxia and aPDL1s modified on the surface to enhance immunotherapeutic effects against melanoma.Methods: The multifunctional immunoliposomes (CAT@aPDL1-SSLs) are prepared using the film dispersion/post-insertion method. The efficacy of CAT@aPDL1-SSLs is verified by multiple experiments in vivo and in vitro.Results: The results of this study suggest that the multifunctional immunoliposomes preserve and protect the enzyme activity of CAT and ameliorate tumor hypoxia. Moreover, the enhanced cellular uptake of CAT@aPDL1-SSLs in vitro and their in vivo biodistribution suggest that CAT@aPDL1-SSLs have great targeting ability,resulting in improved delivery and accumulation of immunoliposomes in tumor tissue.Finally, by activating and increasing the infiltration of CD8+ T cells at the tumor site, CAT@aPDL1-SSLs inhibit the growth of tumor and prolong survival time of mice,with low systemic toxicity.Conclusion: In conclusion, the multifunctional immunoliposomes developed and proposed in this study are a promising candidate for melanoma immunotherapy, and could potentially be combined with other cancer therapies like radiotherapy and chemotherapy to produce positive outcomes.Keywords: immunotherapy, programmed death ligand 1 monoclonal antibodies, aPDL1s, tumor hypoxia, melanoma, liposomes

Shida Yan,1,* Yingyi Wang,2,* Xiao Chen,1,* Yefan Zhang,1 Zhen Huang,1 Jianjun Zhao,1 Jianguo Zhou,1 Zhiyu Li,1 Xinyu Bi,1 Zhiwen Luo,1 Jianqiang Cai,1 Hong Zhao1 1Department of Hepatobiliary Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China; 2Department of Medical Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jianqiang Cai; Hong ZhaoDepartment of Hepatobiliary Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17 Panjiayuan Nanli, Chaoyang District, Beijing 100021, People’s Republic of ChinaEmail caijianqiang188@sina.com; zhaohong@cicams.ac.cnPurpose: This study aimed to investigate the clinicopathological features and prognosis of gallbladder neuroendocrine carcinoma (GB-NEC).Patients and Methods: Fifteen patients with GB-NEC and 171 patients with gallbladder adenocarcinoma (GB-ADC) treated in two tertiary medical centers between 2009 and 2015 were included. The clinicopathological features and prognostic risk factors of GB-NEC were analyzed retrospectively. A propensity score matching in a 1:2 ratio was used to compare the prognosis of GB-NEC and GB-ADC.Results: For patients with GB-NEC, the median age of patients was 58.4 years (range 26– 75), with a M:F ratio of 7:8. Based on 2010 WHO classification, ten cases were pathologically confirmed as NECs and five cases as MANECs. For TNM staging, eleven patients were stage III or above; while for Nevin staging, seven patients were stage IV or above. The 1-, 2-, and 3-year overall survival (OS) of GB-NEC were 60.0%, 38.8% and 31.1%, respectively, and the median survival time was 20.4 months. Patients with lymph node metastasis had significantly shorter survival than those without (OS: 10.4 vs 26.0 months, p< 0.05). Accordingly, patients of Nevin stage III had better OS than those of Nevin stage IV (p< 0.05), but other potential risk factors including gender, age, clinical symptoms, TNM stage, histopathologic subtype and treatment showed no significance. After the propensity score matching, the baseline variables had no significant difference between 15 patients with GB-NEC and 30 patients with GB-ADC, survival analysis showed GB-NEC had worse prognosis (3-year overall survival rate: 31.1% vs 63.8%, p< 0.01).Conclusion: Nevin staging helps classify patients of GB-NEC with different prognosis and the lymph node metastasis is a strong negative prognostic factor for OS. The propensity score analysis revealed even with the similar stage and treatment, GB-NEC still had worse OS than GB-ADC.Keywords: gallbladder, neuroendocrine carcinoma, adenocarcinoma, survival, propensity score matching

Zhenghui Luo,1,* Jie Liu,1,* Hai Lin,2 Xi Ren,1 Hao Tian,1 Yi Liang,1 Weiyi Wang,1 Yuan Wang,1 Meifang Yin,1 Yuesheng Huang,1 Jiaping Zhang1 1Department of Plastic Surgery, State Key Laboratory of Trauma, Burns and Combined Injury, Southwest Hospital, The Third Military Medical University (Army Medical University), Chongqing 400038, People’s Republic of China; 2Engineering Research Center in Biomaterials, Sichuan University, Chengdu 610065, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jiaping ZhangDepartment of Plastic Surgery, State Key Laboratory of Trauma, Burns and Combined Injury, Southwest Hospital, The Third Military Medical University (Army Medical University), Chongqing 400038, People’s Republic of ChinaTel +86 23-68754353Email japzhang@aliyun.comBackground: Developing an ideal wound dressing that meets the multiple demands of safe and practical, good biocompatibility, superior mechanical property and excellent antibacterial activity is highly desirable for wound healing. Bacterial cellulose (BC) is one of such promising class of biopolymers since it can control wound exudates and can provide moist environment to a wound resulting in better wound healing. However, the lack of antibacterial activity has limited its application.Methods and Results: We prepared a flexible dressing based on a bacterial cellulose membrane and then modified it by chemical crosslinking to prepare in situ synthesis of nZnO/BCM via a facile and eco-friendly approach. Scanning electron microscopy (SEM) results indicated that nZnO/BCM membranes were characterized by an ideal porous structure (pore size: 30∼ 90 μm), forming a unique string-beaded morphology. The average water vapor transmission of nZnO/BCM was 2856.60 g/m2/day, which improved the moist environment of nZnO/BCM. ATR-FITR further confirmed the stepwise deposition of nano-zinc oxide. Tensile testing indicated that our nanocomposites were flexible, comfortable and resilient. Bacterial suspension assay and plate counting methods demonstrated that 5wt. % nZnO/BCM possessed excellent antibacterial activity against S.aureus and E. coli, while MTT assay demonstrated that they had no measurable cytotoxicity toward mammalian cells. Moreover, skin irritation test and histocompatibility examination supported that 5wt. % nZnO/BCM had no stimulation to skin and had acceptable biocompatibility with little infiltration of the inflammatory cells. Finally, by using a bacteria-infected (S. aureus and E. coli) murine wound model, we found that nZnO/BCM could prevent in vivo bacterial infections and promote wound healing via accelerating the re-epithelialization and wound contraction, and these membranes had no obvious toxicity toward normal tissues.Conclusion: Therefore, the constructed nZnO/BCM has great potential for biomedical applications as an efficient antibacterial wound dressing.Keywords: bacterial cellulose, nano-zinc oxide, in situ synthesis, antibacterial, non-toxicity, wound dressing

Rui Wang, Zhilin Luo, Hong Zhang, Tianhu Wang Department of Respiratory Disease Center, The Third Affiliated Hospital of Chongqing Medical University, Chongqing 401120, People’s Republic of ChinaCorrespondence: Tianhu WangDepartment of Respiratory Disease Center, The Third Affiliated Hospital of Chongqing Medical University, No.1 Shuanghu Road, Yubei District, Chongqing 401120, People’s Republic of ChinaEmail tianhuwang_cmu@163.comBackground: Gefitinib-resistance is a primary obstacle for the treatment of non-small-cell lung cancer (NSCLC). It has been shown that tanshinone IIA (Tan IIA) could induce apoptosis of NSCLC cells. However, the role of combination of gefitinib with Tan IIA on gefitinib-resistance NSCLC cells remains unclear. Thus, this study aimed to investigate the role of combination on the proliferation, apoptosis and invasion of gefitinib-resistance NSCLC cells.Methods: CCK-8, flow cytometric and transwell assays were applied to detect proliferation, apoptosis and invasion in gefitinib-resistance NSCLC cells, respectively. In addition, Western blotting assay was used to detect the expressions of p-EGFR, p-VEGFR2, and p-Akt in HCC827/gefitinib cells.Results: In this study, Tan IIA enhanced the cytotoxic effect of gefitinib in gefitinib-resistance NSCLC cells. In addition, the inhibitory effects of gefitinib on the proliferation, migration and invasion of gefitinib-resistance NSCLC cells were enhanced in the presence of Tan IIA. Moreover, Tan IIA enhanced the pro-apoptotic effect of gefitinib in gefitinib-resistance NSCLC cells via increasing the level of cleaved caspase 3. Meanwhile, Tan IIA enhanced the sensitivity of HCC827/gefitinib cells to gefitinib via downregulation of the VEGFR2/Akt pathway. In vivo experiments further confirmed that combination of gefitinib with Tan IIA inhibited tumor growth in mouse xenograft model of HCC827/gefitinib.Conclusion: We found that Tan IIA could enhance gefitinib sensitivity in gefitinib-resistance NSCLC cells. Therefore, combination of gefitinib with Tan IIA might be considered as a therapeutic approach for the treatment of gefitinib-resistant NSCLC.Keywords: non-small-cell lung cancer, tanshinone IIA, gefitinib-resistance, VEGFR

Manzhao Ouyang,1,2,* Zhentao Luo,1,* Jinhao Wu,1,* Weijie Zhang,1 Shibin Tang,1 Yan Lu,1 Weixian Hu,2,3 Xueqing Yao2,3 1Department of Gastrointestinal Surgery, Shunde Hospital, Southern Medical University, Foshan, Guangdong Province 528308, People’s Republic of China; 2Department of General Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510000, People’s Republic of China; 3Department of General Surgery, The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong Province 510080, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xueqing YaoDepartment of General Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, No.106 Zhongshaner Road, Guangzhou, Guangdong 510000, People’s Republic of ChinaTel +86 7 572 231 8566Fax +86 7 572 222 3899Email yjb9211@21cn.comBackground: This retrospective study compared the outcomes of laparoscopic complete mesocolic excision (CME) guided by superior mesenteric artery with laparoscopic conventional radical resection (CRR) performed for right-sided colon cancer.Methods: Patients with right-sided colon cancer underwent CME (n=107; January 2011 to December 2015) or CRR (n=60; January 2008 to December 2010).Results: The 2 groups were comparable regarding age, gender, body mass index, maximum tumor diameter, and tumor stage. In the CME group, the distances between the tumor and the high vascular tie (HVT; 12.6 cm), and between the closest bowel wall and HVT (10.4±0.9 cm) was significantly greater than that of the CRR group (11.5 cm and 9.3±1.0 cm, respectively; P0.05).Conclusion: CME for right-sided colon cancer guided by superior mesenteric artery has similar short-term outcomes, higher lymph node yield, and higher 3-year overall survival compared with CRR.Keywords: laparoscopy, right-sided colon cancer, complete mesocolic excision

Zhenqin Luo, Peiguo Cao Oncology Department, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, People’s Republic of ChinaCorrespondence: Peiguo CaoOncology Department, The Third Xiangya Hospital of Central South University, 138 Tongzipo Road, Yuelu District, Changsha, Hunan 410013, People’s Republic of ChinaEmail csucaopeiguo@126.comBackground: Hepatoblastoma is the most common liver malignancy in children. The long noncoding RNA (IncRNA) PVT1 plays oncogenic roles in human cancers; however, its regulation and function in hepatoblastoma remain poorly understood.Purpose: This study was designed to investigate the regulation and function of PVT1 in hepatoblastoma. Methods: PVT1 expression was compared between human hepatoblastoma tissues and adjacent non-tumor tissues, and then analyzed using Kaplan-Meier method. The proliferation of hepatoblastoma cells was determined by BrdU incorporation assay. The tumor xenograft model was used to assess tumor proliferation in vivo. The gene expression level was measured by qRT-pCR, Western blot and immunohistochemistry analyses.Results: Compared with normal counterparts, PVT1 is upregulated in human hepatoblastoma tissues as well as in hepatoblastoma cell lines. Additionally, PVT1 promotes the proliferation of hepatoblastoma cells in vitro and accelerates tumor growth in xenograft model in vivo. Mechanistically, PVT1 promotes the activation of the signal transducer and activator of transcription 3 (STAT3), which leads to the transcriptional activation of downstream targets involved in cell cycle progression, and moreover,STAT3 inhibition with the selective inhibitor stattic abolishes PVT1 pro-proliferative role in hepatoblastoma cells.Conclusion: PVT1 promotes hepatoblastoma cell proliferation through activating STAT3-induced cell cycle progression, which may implicate PVT1 as a potential therapeutic target for hepatoblastoma treatment.Keywords: long noncoding RNA, PVT1, hepatoblastoma, proliferation, STAT3

Lili Wu,1 Xuemei Huang,2 Yaqi Kuang,2 Zengmiao Xing,2 Xiujun Deng,2 Zuojie Luo21Department of Integrated Medicine, The Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi 530021, People’s Republic of China; 2Department of Endocrinology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, People’s Republic of ChinaObjective: Thapsigargin (TG) is a natural product that exists in most parts of the plant Thapsia garganica L. and possesses potential anticancer activities against variety tumor cell lines. TG induces endoplasmic reticulum (ER) stress and apoptosis by inhibiting cancer growth. However, the antineoplastic effect of TG in human adrenocortical carcinoma (ACC) cells is still unknown.Methods: In this study, two human ACC cell lines including SW-13 and NCI-H295R were employed to explore the potential role of TG in ACC. A mouse xenograft model of SW-13 cells was established to verify the role of TG in vivo. The cell viability was tested using Cell Counting Kit-8 and Transwell assays. Flow cytometry and Hoechst 33,258 staining were employed to analyze cell apoptosis. RT-qPCR and Western blot (WB) were performed to explore the underlying mechanism of TG-induced apoptosis in ACC cells.Results: The results indicated that TG dose-dependently inhibited proliferation, migration and invasion in human ACC cells. TG significantly increased the mitochondrial rate of apoptosis and ER stress activity in ACC cells and suppressed ACC xenograft growth in vivo. In addition, the expression of Jun N-terminal kinase (JNK) signaling-related genes and proteins was upregulated by the treatment with TG.Conclusion: Our findings suggest that TG inhibits the viability of ACC cells by inducing apoptosis through the activation of JNK signaling. Thus, TG is expected to be a potential candidate for the treatment of ACC.Keywords: thapsigargin, adrenocortical carcinoma, apoptosis, Jun N-terminal kinase signaling, endoplasmic reticulum ER stress

Kun Liu,1 Jingchun Zeng,2 Wenya Pei,3 Siyu Chen,1 Zhenke Luo,1 Liming Lu,4 Guohua Lin21The First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou 510405, People’s Republic of China; 2Department of Acupuncture, The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou 510405, People’s Republic of China; 3Department of Acupuncture, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510405, People’s Republic of China; 4Clinical Research and Data Center, Medical College of Acu-Moxi and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou 510405, People’s Republic of ChinaBackground: This study evaluates the reporting quality of randomized controlled trials (RCTs) on acupuncture use for the treatment of postherpetic neuralgia and explores related factors.Methods: The following six databases PubMed, Embase, Cochrane Library, VIP, CNKI, and SinoMed, were systematically searched from their inception to December 2018. RCTs using acupuncture as an intervention for postherpetic neuralgia were selected and incorporated in this study. The reporting quality was assessed based on the CONSORT statement and the STRICTA guidelines. Regression analyses were also conducted on pre-specified study characteristics searching for factors associated with reporting quality.Results: A total of 137 RCTs were included in this study. The CONSORT based median OQS was 12 (minimum 3, maximum 29). Of the items comprised in the statement, ten were sufficiently reported (reported in over 70% of trials). The remaining fifty-five items were poorly reported (reported by fewer than 5% of trials). The STRICTA based median OQS was 9 (minimum 2, maximum 15). The results showed that eight of the comprised items were well reported (reported in over 70% of trials), and only three were incompletely reported (reported in fewer than 20% of trials). Based on the CONSORT statement related analysis, a post-2010 publication (β coefficient 2.394, 95% confidence interval [CI] 1.168–3.620) and funding (β coefficient 4.456, 95% CI: 3.009–5.903) represented independent and significant predictors of a high overall reporting quality. However, only a funding source (β coefficient 1.305, 95% CI 0.219–2.391) was associated with an increased OQS based on STRICTA analysis.Conclusion: The findings indicated that RCTs on acupuncture for PHN generally had a sub-optimal reporting quality, a situation that improved for those published after 2010 or with funding sources. Therefore, rigorous adherence to the CONSORT statement and the STRICTA guidelines should be emphasized in future studies.Keywords: randomized controlled trials, acupuncture, postherpetic neuralgia, CONSORT, STRICTA

Yanqing Li,1 Yan Jiao,2 Zhuo Fu,3 Zhangping Luo,4 Jing Su,1 Yang Li11Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, People’s Republic of China; 2Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun, Jilin 130021, People’s Republic of China; 3Department of Hand and Foot Surgery, The First Hospital of Jilin University, Changchun, Jilin 130021, People’s Republic of China; 4Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, People’s Republic of ChinaPurpose: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the clinic all over the world, which has become a public health challenge. The T/N/M staging system plays a core role in HCC prognosis. However, it cannot precisely stratify the risk of HCC prognosis. MiR-454-3p plays an important role in the progression of tumors. Therefore, we need to develop more reliable prognostic markers for HCC patients which can focus on miR-454-3p.Methods: We used Chi-square and Fisher exact tests to assess correlations between miR-454-3p expression and clinical parameters in liver cancer patients from The Cancer Genome Atlas database (TCGA). Then, Cox regression analysis, Kaplan-Meier curve, and log-rank test were used to compare the difference of survival between the high-expression group and low-expression group, and P value was included. Finally, we used TCGA data set to carry out gene enrichment analysis.Results: In this research, the expression of miR-454-3p increased in HCC and was associated with patient survival, G3/G4 staging, III/IV staging and T staging. Higher miR-454-3p expressed patients had shorter survival time. Besides, mitotic spindle, G2M checkpoint, and E2F targets were differentially enriched in miR-454-3p high-expression phenotype by Gene set enrichment analysis.Conclusion: Overexpression of miR-454-3p may be a significant and independent predictor of poor prognosis in HCC patients.Keywords: miR-454-3p, hepatocellular carcinoma (HCC), prognosis, predictor

Zhuang Luo,1,* Tingting Zhu,2,* Wei Luo,3,* Yuanyuan Lv,1 Liyan Zhang,1 Chu Wang,1 Min Li,1 Wenjuan Wu,4 Shaoqing Shi1 1Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, People’s Republic of China; 2Department of Dermatology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, People’s Republic of China; 3Department of Respiratory Medicine, The People’s Hospital of Leshan, Leshan, Sichuan 640000, People’s Republic of China; 4Department of Dermatology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, People’s Republic of China *These authors contributed equally to this work Background: Metformin, a first-line antidiabetic drug, has recently been reported with anticancer activities in various cancers; however, the underlying mechanisms remain elusive. The aim of the present study was to investigate the role of cellular FADD-like IL-1β-converting enzyme (FLICE)-inhibitory protein large (c-FLIPL) in metformin-induced anticancer activity in non-small cell lung cancer (NSCLC) in vitro. Materials and methods: Cell viability was measured by MTT assay. Quantitative real-time PCR was carried out to detect the level of mRNA of related genes. The expression of related proteins was detected by Western blot. siRNA was used to silence the expression of targeted proteins. Results: Metformin significantly suppressed proliferation of both A549 and H460 cells in a dose-dependent manner. Mechanistic studies suggested that metformin killed NSCLC cells by inducing apoptotic cell death. Moreover, metformin greatly inhibited c-FLIPL expression and then promoted its degradation. Furthermore, metformin significantly activated Adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK) and its downstream glycogen synthase kinase 3beta (GSK-3β), block the expression of AMPK, and GSK-3β with siRNA partially reversed metformin-induced cytotoxicity and restored the expression of c-FLIPL in lung cancer cells. Metformin also suppressed the activity of AMPK downstream protein kinase A (PKA), PKA activators, both 8-Br-cAMP and forskolin, greatly increased c-FLIPL expression in NSCLC cells. Conclusion: This study provided evidence that metformin killed NSCLC cells through AMPK/PKA/GSK-3β axis-mediated c-FLIPL degradation. Keywords: non-small cell lung cancer, c-FLIPL, AMPK, GSK-3β, PKA

Minggu Zhu,1,* Qicai Wang,2,* Zhaowen Luo,1 Kelong Liu,2 Zhiqiao Zhang1 1Department of Internal Medicine, The Affiliated Chencun Hospital of Shunde Hospital, Southern Medical University, Shunde District, Guangdong, China; 2Department of General Surgery, The Affiliated Chencun Hospital of Shunde Hospital, Southern Medical University, Shunde District, Guangdong, China *These authors contributed equally to this work Background: As a serious challenge for public health, the prognosis of gastric cancer patients is still poor. The current study aimed to develop and validate a prognostic signature to predict the overall survival of gastric cancer patients.Patients and methods: The dataset in the present study was obtained from The Cancer Genome Atlas database. The present study finally included 343 gastric cancer patients with information on long non-coding RNA (lncRNA) expression and overall survival.Results: A prognostic model named Eleven-lncRNA signature was constructed according to the expression values of eleven prognostic lncRNA predictors identified by univariate and multivariate Cox regression model. According to time-dependent receiver operating characteristic curves, the Harrell’s concordance indexes of Eleven-lncRNA signature were 0.764 (95% CI 0.720–0.808), 0.776 (95% CI 0.732–0.820), and 0.807 (95% CI 0.763–0.851) for 1-year overall survival, 3-year overall survival, and 5-year overall survival respectively in the model group. In the validation group, the Harrell’s concordance indexes of Eleven-lncRNA signature were 0.748 (95% CI 0.704–0.792), 0.794 (95% CI 0.750–0.838), and 0.798 (95% CI 0.754–0.842) for 1-year overall survival, 3-year overall survival, and 5-year overall survival respectively. The gastric cancer patients (n=343) in the model group could be stratified into low-risk group (n=171) and high-risk group (n=172) according to the median of Eleven-lncRNA signature score. Kaplan–Meier survival curves showed that the mortality rate in the high-risk group was significantly poorer than that in the low-risk group (P