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DC-DC converters have some inherent characteristics such as high nonlinearity and time-variation, which often result in some difficulties in designing control schemes. An adaptive non-singular terminal sliding mode control method is presented in this paper. Non-singular terminal sliding mode control is used to make the converter reach steady state within a limited time, and an adaptive law is integrated to the non-singular terminal sliding mode control scheme to make the proposed control method have adaptive ability to disturbances, and overcome the limitation on non-singular terminal sliding mode control scheme caused by disturbance boundary value. Simulation results show the validity of this adaptive non-singular terminal sliding mode control approach.

Xin Yang,1,* Lei Fan,2,* Jicheng Huang,2 Yongjun Li1 1Peking University Fifth School of Clinical Medicine, Beijing, People’s Republic of China; 2Breast Center, Department of Thyroid-Breast-Hernia Surgery, Department of General Surgery, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yongjun Li, Email liyongjun4679@126.comBackground: Timely detection of tumor progression in breast cancer (BC) patients is critical for therapeutic management and prognosis. Plasma exosomal miRNAs are potential liquid biopsy markers for monitoring tumor progression, but their roles in BC remain unclear.Methods: In the TCGA database, we first screened for miRNAs significantly associated with BC progression by comparing miRNA expression in para-carcinoma tissues, stage I BC tissues, and stage II–III BC tissues (n = 1026). Cox regression analyses and survival analyses were performed on candidate miRNAs to explore their prognostic value (n = 848). KEGG, GO, and PPI analyses were used to identify enriched pathways associated with cancer. Finally, the potential of candidate miRNAs as liquid biopsy markers was evaluated by sequencing and analyzing plasma exosomal miRNAs from our collection of 45 BC patients (14 in stage I, 31 in stage II–III) and 5 healthy controls, combined with qRT-PCR analysis to assess the correlation of candidate gene expression in plasma exosomes and BC tissues.Results: We found that only miR-203a-3p was progressively elevated with BC progression and was associated with poor prognosis in the TCGA dataset. Its potential target genes were enriched in pathways related to tumor progression, and the downregulation of 48 of these genes was associated with poor prognosis. More importantly, plasma exosomal miR-203a-3p was also found to gradually increase with BC progression, and its expression was positively correlated with miR-203a-3p in BC tissues. This result suggests that plasma exosomal miR-203a-3p may reflect the expression of miR-203a-3p in tumor tissues and serve as a potential liquid biopsy marker for monitoring BC progressions.Conclusion: We found for the first time that elevated miR-203a-3p was associated with BC progression and poor prognosis. Our findings suggested that plasma exosomal miR-203a-3p could hold potential as a liquid biopsy marker for evaluating BC progression in patients.Keywords: plasma exosomal miR-203a-3p, breast cancer, tumor progression, liquid biopsy marker

Qingyang Yu,1,2 Yuanyuan Cui,1 Shuwen Dong,1 Yanqing Ma,1 Yi Xiao,1 Li Fan,1 Shiyuan Liu1 1Department of Radiology, Changzheng Hospital, Navy Military Medical University, Shanghai, 200003, People’s Republic of China; 2Department of Neurosurgery, Changhai Hospital, Navy Military Medical University, Shanghai, 200433, People’s Republic of ChinaCorrespondence: Shiyuan Liu, Department of Radiology, Changzheng Hospital, Navy Military Medical University, 415 Fengyang Road, Shanghai, 200003, People’s Republic of China, Fax +86 2181886012, Email radiology_cz@163.comObjective: Hemifacial spasm (HFS) is a clinical neurosurgical disease, which brain structural alterations caused by HFS remain a topic of debate. We evaluated changes in brain microstructure associated with HFS and observed their relevance to clinical characteristics.Methods: We enrolled 72 participants. T1-weighted structural and diffusion tensor images were collected from all participants using 3.0T magnetic resonance equipment. Voxel-based morphometry (VBM) and tract-based spatial statistics (TBSS) were used to identify changes in gray matter volume (GMV) and disruptions in white matter (WM) integrity. The severity of the spasms was graded using the Cohn scale.Results: VBM analysis revealed that the GMV was significantly reduced in the left Thalamus and increased GMV in the right Cerebellum IV-V of the HFS group. TBSS analysis showed that FA in the left superior longitudinal fasciculus (SLF) of the HFS group was significantly increased. GMV in the thalamus showed a negative correlation with disease duration and Cohn grade, while FA in the left SLF had a positive correlation with both the disease duration and Cohn grade.Conclusion: We identified regions with altered GMV in HFS patients. Additionally, we determined that FA in the left SLF might serve as a significant neural indicator of HFS.Keywords: hemifacial spasm, voxel-based morphometry, diffusion tensor imaging, tract-based spatial statistics, Cohn grading

Mi Tang,1,2,* Liling Xiong,3,* Jianghui Cai,2,4,* Xuejia Gong,2 Li Fan,1 Xiaoyu Zhou,1 Shasha Xing,1 Xiao Yang3 1Chengdu Women’s and Children’s Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 611731, People’s Republic of China; 2School of medicine, University of Electronic Science and Technology of China, Chengdu, People’s Republic of China; 3Obstetrics Department, Chengdu Women’s and Children’s Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 611731, People’s Republic of China; 4Department of Pharmacy, Chengdu Women’s and Children’s Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 611731, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shasha Xing; Xiao Yang, Chengdu Women’s and Children’s Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 611731, People’s Republic of China, Email xingshasha1230@126.com; wcchgcptg@163.comPurpose: Intrahepatic cholestasis of pregnancy (ICP) is a disorder that characterized by maternal pruritus, abnormal liver function, and an elevation in total bile acid concentrations during pregnancy. Immune factors have been recognized as playing a vital role in the mechanism of ICP. However, the underlying mechanisms regulating dysfunctional immune cells and immune genes remain to be fully elucidated.Patients and Methods: Single-cell RNA sequencing and bulk RNA sequencing data of the placenta were downloaded from the SRA database. The AUCell package, Monocle package and SCENIC package were utilized to explored immune cell activity, cell trajectory and transcription factor, respectively. GO, KEGG, and GSEA were employed to explore potential biological mechanisms. Cell-cell communications were further investigated using the CellChat package. RT-PCR, and Western blot were used to verify the gene expression in placenta.Results: In placenta cells, macrophages were found to be significantly increased in ICP. Additionally, macrophages exhibited the highest immune gene score and were divided into four subclusters (MF1-4). Our analysis revealed significant elevations in MF2, associated with LPS response and antigen presentation, and MF4, associated with TNF and cytokine production. MF3 displayed an anti-inflammatory phenotype. MF1, closely related to ribosomes and proteins, exhibited a sharp decrease. Although ICP maintained an anti-inflammatory state, macrophage trajectories showed a gradual progression toward inflammation. Subsequently, we confirmed that cytokine- and chemokine-related signaling pathways were emphasized in macrophages. Within the CXCL signaling pathway, the increased expression of CXCL1 in macrophages can interact with CXCR2 in neutrophils, potentially inducing macrophage infiltration, stimulating neutrophil chemotaxis, and leading to an inflammatory response and cellular damage.Conclusion: In conclusion, we firstly revealed the transcriptional signatures of macrophages in ICP and discovered a tendency toward an inflammatory state. This study also provides new evidence that the CXCL1-CXCR2 axis may play an important role in the pathogenesis of ICP.Keywords: intrahepatic cholestasis of pregnancy, scRNA-Seq, bulk RNA-Seq, immune gene, macrophage

Yibin Lin,1,2 Lehua Liu,1 Siyang Lu,1 Linqi Fan,1 Huaqi Hu,1 Xuanyin Wang,1 Jichao Zhu,3 Xinhua Qiang,4 Jie He,5 Hongchang Zhou,1,2,6 Shengwen Shao,1,6 Gaoming Zheng7 1School of Medicine, Huzhou University, Huzhou, 313000, People’s Republic of China; 2Key Laboratory for Precise Prevention and Control of Major Chronic Diseases, Huzhou University, Huzhou, 31300, People’s Republic of China; 3Clinical Laboratory, Huzhou Central Hospital, Huzhou, 313000, People’s Republic of China; 4Clinical Laboratory, First People’s Hospital Affiliated to Huzhou University, Huzhou, 313000, People’s Republic of China; 5Infectious Diseases Department, First People’s Hospital Affiliated to Huzhou University, Huzhou, 313000, People’s Republic of China; 6Key Laboratory of Vector Biology and Pathogen Control of Zhejiang Province, Huzhou University, Huzhou, 313000, People’s Republic of China; 7Clinical Laboratory, Affiliated Hospital of Hangzhou Normal University, Hangzhou, 310015, People’s Republic of ChinaCorrespondence: Gaoming Zheng; Shengwen Shao, Email zheng151031@sina.com; shaoshw@zjhu.edu.cnBackground: Bacillus cereus is a common bacterium found in the environment. Some strains can cause food poisoning, and very few can cause clinically severe infections, leading to death. Here, we characterized the genome sequence of B. cereus LIN78 isolated from teeth with deep caries and compared it with those of 25 other related species.Methods: Third-generation sequencing technology, bacteriological analyses, biochemistry, and mass spectrometry were applied to characterize the drug-resistance genes and virulence factors of B. cereus LIN78.Results: The complete genome sequence of B. cereus Lin78 consists of 5647 genes distributed on a circular chromosome, a 393 kbp plasmid, and 928 pseudogenes (37.4% of whole-genome DNA). The LIN78 genome contains 14 sets of 16s, 23s, and 5s ribosomal RNA operons; 106 tRNA genes, one tmRNA, 12 genomic islands, six prophases, 64 repeats; 37 antibiotic-resistant genes; and 1119 putative virulence genes, including enterotoxins and cytolysins. The B. cereus LIN78 genome carries multiple copies of non-ribosomal polypeptide synthetase (NRPS) and post-translationally modified peptides (RiPPs). Phylogenetic analysis of the 26 B. cereus strains showed that B. cereus LIN78 is evolutionarily closely related to B. thuringiensis ATCC 10792 and B. cereus ATCC 14579.Conclusion: The newly isolated B. cereus carries many virulence genes, including enterotoxins and hemolysins, similar to B. anthracis, and multiple antibiotic resistance genes. These findings suggest that the strain has a potential risk of causing disease. Our studies are vital for further exploration of the evolution of B. cereus, its pathogenic mechanisms, and the control and treatment of bacterial infections.Keywords: bacillus cereus, whole-genome DNA sequencing, virulence factor, drug resistance gene, human teeth

Xu Yang,1,* Jianwei Wu,1,* Longlong Fan,2 Binghua Chen,3 Shiqiang Zhang,4 Wenzhong Zheng1 1Department of Urology, Fujian Medical University Union Hospital, Fuzhou, People’s Republic of China; 2Department of Urology, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, People’s Republic of China; 3Department of Urology, Pingtan Branch of Fujian Medical University Union Hospital, Fuzhou, People’s Republic of China; 4Department of Urology, Kidney and Urology Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wenzhong Zheng, Department of Urology, Fujian Medical University Union Hospital, 29 Xinquan Road, Gulou District, Fuzhou, Fujian Province, 200001, People’s Republic of China, Email wenzhong_zheng@yeah.net Shiqiang Zhang, Department of Urology, Kidney and Urology Center, The Seventh Affiliated Hospital, Sun Yat-sen University, 628, Zhenyuan Road, Guangming Dist, Shenzhen, 518107, People’s Republic of China, Email zhangshq55@mail.sysu.edu.cnBackground: The involvement of cytotoxic CD4+ T cells (CD4+ CTLs) and their potential role in dictating the response to immune checkpoint inhibitors (ICIs) in patients with metastatic renal cell carcinoma (mRCC) remains an unexplored area of research.Methods: Utilizing single-cell RNA sequencing, we analyzed the immunophenotype and expression patterns of CD4+ T lymphocyte subtypes in mRCC patients, followed by preliminary validation via multi-immunofluorescent staining. In addition, we obtained a comprehensive immunotherapy dataset encompassing single-cell RNA sequencing datasets and bulk RNA-seq cohorts from the European Genome-Phenome Archive and ArrayExpress database. Utilizing the CIBERSORTx deconvolution algorithms, we derived a signature score for CD4+ CTLs from the bulk-RNA-seq datasets of the CheckMate 009/025 clinical trials.Results: Single-cell analysis of CD4+ T lymphocytes in mRCC reveals several cancer-specific states, including diverse phenotypes of regulatory T cells. Remarkably, we observe that CD4+ CTLs cells constitute a substantial proportion of all CD4+ T lymphocyte sub-clusters in mRCC patients, highlighting their potential significance in the disease. Furthermore, within mRCC patients, we identify two distinct cytotoxic states of CD4+ T cells: CD4+GZMK+ T cells, which exhibit a weaker cytotoxic potential, and CD4+GZMB+ T cells, which demonstrate robust cytotoxic activity. Both regulatory T cells and CD4+ CTLs originate from proliferating CD4+ T cells within mRCC tissues. Intriguingly, our trajectory analysis indicates that the weakly cytotoxic CD4+GZMK+ T cells differentiate from their more cytotoxic CD4+GZMB+ counterparts. In comparing patients with lower CD4+ CTLs levels to those with higher CD4+ CTLs abundance in the CheckMate 009 and 25 immunotherapy cohorts, the latter group exhibited significantly improved OS and PFS probability.Conclusion: Our study underscores the pivotal role that intratumoral CD4+ CTLs may play in bolstering anti-tumor immunity, suggesting their potential as a promising biomarker for predicting response to ICIs in patients with mRCC.Keywords: single-cell analysis, granzyme K and granzyme B, cytotoxic CD4+ T cells, immune checkpoint inhibitors, renal cell carcinoma

Li Zhang,1,* Mupeng Li,1,* Lianlian Fan,1 Fangfang Liu,1 Peiwen Zhang,1 Qian Huang,1 Gang Mai,1 Jianzhong Shentu1,2 1Phase 1 Clinical Trial Center, Deyang People′s Hospital, Deyang, Sichuan, People’s Republic of China; 2Research Center for Clinical Pharmacy, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jianzhong Shentu, Email stjz@zju.edu.cn Gang Mai, Email stdygcp@163.comPurpose: Estradiol valerate (Progynova®) is used as hormone therapy to supplement estrogen deficiency. This study aimed to assess the bioequivalence of an estradiol valerate tablet and its generic form, under fasting and fed conditions.Methods: A randomized, open-label, single-dose, 2-period crossover study was conducted on healthy postmenopausal Chinese female volunteers under fasting and fed conditions. For each period, the subjects received either a 1 mg tablet of estradiol valerate or its generic. Blood samples were collected before dosing and up to 72 hours after administration. Plasma levels of total estrone, estradiol, and unconjugated estrone were quantified using a validated liquid chromatography-tandem mass spectrometry method.Results: A total of 54 volunteers were enrolled in this study. The primary pharmacokinetic parameters, including Cmax, AUC0-t, and AUC0-∞, were similar for the two drugs under both fasting and fed conditions, with 90% confidence intervals for the geometric mean ratios of these parameters, all meeting the bioequivalence criterion of 80– 125%. A total of 48 adverse events (AEs) were reported in the fed study compared with 24 AEs in the fasting study.Conclusion: Estradiol valerate and its generic form were bioequivalent and well tolerated under both fasting and fed conditions.Keywords: bioequivalence, estradiol valerate, postmenopausal, pharmacokinetics, safety

Yuanyuan Su,1,* Ning Lu,2,* Pei Wang,3,* Qian Li,2 Hua Wen,2 Jie Zhang,2 Ling Fan,2 Jie Li,2 Zhaoxiang Yu,4 Manli Cui,2 Mingxin Zhang2 1Department of General Medicine, the People’s Hospital of Yubei District of Chongqing, Chongqing, People’s Republic of China; 2Department of Gastroenterology, the First Affiliated Hospital of Xi’an Medical College, Xi’an, Shaanxi, People’s Republic of China; 3Shaanxi University of Traditional Chinese Medicine, Xianyang, Shaanxi, People’s Republic of China; 4Department of General Surgery, the First Affiliated Hospital of Xi’an Medical College, Xi’an, Shaanxi, People’s Republic of China*These authors contributed equally to this workCorrespondence: Manli Cui, The First Affiliated Hospital of Xi’an Medical University, Xi’an, Shaanxi, Email cuiml1587@163.com; Mingxin Zhang, The First Affiliated Hospital of Xi’an Medical University, Xi’an, Shaanxi, Email zmx3115@xiyi.edu.cn.Objective: This study aims to explore the nexus between students’ psychological well-being and the manifestation of gastrointestinal symptoms (GISs) amid the health lockdown enforced in Xi’an, focusing on the student populace of Xi’an Medical College and Shaanxi University of Traditional Chinese Medicine.Materials and methods: A survey encompassing psychological parameters and GISs was administered to a randomized cohort of 1327 college students drawn from Xi’an Medical College and Shaanxi University of Traditional Chinese Medicine. The survey instrument was developed utilizing the Questionnaire Star platform. Subsequent to data collection, analysis was performed using GraphPad Prism 9 and SPSS 22.0.Results: Comparative analysis revealed statistically significant disparities (P < 0.05) in various GISs between the periods during and preceding the health lockdown, encompassing symptoms such as nausea/vomiting, acid reflux, postprandial fullness/early satiety, anorexia, decreased appetite, bloating, abdominal discomfort, abdominal pain, diarrhea, and constipation. Notably, the mean score for Generalized Anxiety Disorder 7 (GAD-7) was 3.31± 3.92, indicating mild anxiety, while the mean score for Patient Health Questionnaire-2 (PHQ-2) was 1.15± 1.28, suggesting mild depression. Detailed evaluation of anxiety revealed prevalence rates of 34% among respondents, with 34.2% of these individuals reporting concurrent GISs, while among those evaluated for depression (38.8% of the sample), 44.2% reported concurrent GISs. Furthermore, multiple linear regression analysis unveiled a negative correlation between GISs during the health lockdown and lifestyle scores, while positive correlations were observed with GISs preceding the lockdown, anxiety, and depression. The formulated multiple linear regression equation for GISs during the health lockdown is delineated as follows: 14.693– 0.342 life style + 0.725GISs before health lockdown + 0.218anxiety + 0.564 depression.Conclusion: This investigation underscores the substantial impact of anxiety and depression on the student body, accentuating their role in precipitating GISs during health lockdown situations. The psychological well-being of medical students during exigent circumstances such as natural disasters warrants heightened attention, necessitating proactive measures aimed at emotional regulation to mitigate the onset of GISs.Keywords: COVID-19, health lockdown, gastrointestinal symptoms, anxiety, depression

Longfei Fan,1 Zhongqiang Qin,1 Di Wu,1 Yunchuan Yang,2 Yigang Zhang,2 Bo Xie,1 Jingyu Qian,1 Jianzhu Wei,1 Zhaoying Wang,1 Peipei Yang,1 Zhen Qian,1 Mu Yuan,1 Ziyi Zhu,1 Yulin Tan,1 Yi Tan2 1Department of Interventional Radiology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, 233000, People’s Republic of China; 2Department of Hepatobiliary Surgery, The First Affiliated Hospital of Bengbu Medical University, Bengbu, 233000, People’s Republic of ChinaCorrespondence: Yi Tan, Email doctortanyi2007@126.comPurpose: To study the relationship between LARS1 expression and immune infiltration and prognosis in hepatocellular carcinoma (HCC).Patients and Methods: The clinical characteristics together with LARS1 expression levels were obtained from the TCGA database. Immunohistochemistry confirmed LARS1 expression levels in paraneoplastic and tumor tissues. To investigate LARS1-related downstream molecules, a network of protein-protein interactions (PPIs) and the Gene Ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) were built. Furthermore, gene set enrichment analysis (GSEA) was used to analyze the pathways associated with LARS1 expression, whereas Single-sample GSEA (ssGSEA) was applied to perform an association study between immune infiltration and LARS1 gene expression. The TISCH Database and the TISIDB database were used to compare the difference of LARS1 expression in hepatocellular carcinoma and immunomodulators.Results: In comparison to that in normal tissues, the LARS1 expression level was elevated in tumor tissues. LARS1 expression exhibited substantial correlation with AFP, Histologic grade, pathologic stage, Residual tumor, and Vascular invasion in HCC. Higher LARS1 expression in HCC was linked to lower progression-free survival (PFS), disease-specific survival (DSS), and overall survival (OS). According to the GO/KEGG study, the important biological process (neutral lipid metabolic process), cellular component (triglyceride-rich plasma lipoprotein), molecular functions (lipase inhibitor activity), and KEGG pathway (cholesterol metabolism) could be a probable function mechanism in promoting HCC. Various pathways as per GSEA revealed that they were enriched in samples with elevated LARS1 expression. The expression level of LARS1 in malignant tumor cells after immunotherapy was significantly higher than that before immunotherapy. LARS1 was also remarkably linked to the infiltration level and the immunomodulators.Conclusion: LARS1 can be used as a biomarker of HCC, which is associated to immune infiltration of HCC.Keywords: hepatocellular carcinoma, leucyl-tRNA synthetase 1, bioinformatics analysis, biomarker, the cancer genome atlas

Zhengjun Ma,1 Yanmei Zhang,1 Yupu Zhu,2 Minxuan Cui,2 Yutao Liu,2 Yun-You Duan,1 Li Fan,2 Li Zhang1 1Department of Ultrasound Medicine, Tangdu Hospital, Air Force Medical University, Xi’an, People’s Republic of China; 2Department of Pharmaceutical Chemistry and Analysis, School of Pharmacy, Air Force Medical University, Xi’an, People’s Republic of ChinaCorrespondence: Li Fan; Li Zhang, Email xxfanny@fmmu.edu.cn; lilyzhang319_20@hotmail.comIntroduction: Recently, nanobubbles (NBs) have gained significant traction in the field of tumor diagnosis and treatment owing to their distinctive advantages. However, the application of NBs is limited due to their restricted size and singular reflection section, resulting in low ultrasonic reflection.Methods: We synthesized a nano-scale ultrasound contrast agent (IR783-SiO2NPs@NB) by encapsulating SiO2 nanoparticles in an IR783-labeled lipid shell using an improved film hydration method. We characterized its physicochemical properties, examined its microscopic morphology, evaluated its stability and cytotoxicity, and assessed its contrast-enhanced ultrasound imaging capability both in vitro and in vivo.Results: The results show that IR783-SiO2NPs@NB had a “donut-type” composite microstructure, exhibited uniform particle size distribution (637.2 ± 86.4 nm), demonstrated excellent stability (30 min), high biocompatibility, remarkable tumor specific binding efficiency (99.78%), and an exceptional contrast-enhanced ultrasound imaging capability.Conclusion: Our newly developed multiple scattering NBs with tumor targeting capacity have excellent contrast-enhanced imaging capability, and they show relatively long contrast enhancement duration in solid tumors, thus providing a new approach to the structural design of NBs.Keywords: ultrasound contrast agents, nanobubbles, CEUS, scattering cross-section, SiO2 NPs

Di Zhang,1,&ast; Yu Guan,1,&ast; Xiuxiu Zhou,1 Mingzi Zhang,2 Yu Pu,1 Pengchen Gu,2 Yi Xia,1 Yang Lu,2 Jia Chen,2 Wenting Tu,1 Kunyao Huang,2 Jixin Hou,2 Hua Yang,2 Chicheng Fu,2 Qu Fang,2 Chuan He,2 Shiyuan Liu,1 Li Fan1 1Department of Radiology, Second Affiliated Hospital, Naval Medical University, Shanghai, People’s Republic of China; 2Scientific Research Department, Shanghai Aitrox Technology Corporation Limited, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Li Fan; Shiyuan Liu, Department of Radiology, Second Affiliated Hospital, Naval Medical University, 415 Fengyang Road, Shanghai, 200003, People’s Republic of China, Tel +13564684699 ; +13761304518, Fax +86 21 63587668, Email czyxfl@smmu.edu.cn; radiology_cz@163.comPurpose: To develop a novel method for calculating small airway resistance using computational fluid dynamics (CFD) based on CT data and evaluate its value to identify COPD.Patients and Methods: 24 subjects who underwent chest CT scans and pulmonary function tests between August 2020 and December 2020 were enrolled retrospectively. Subjects were divided into three groups: normal (10), high-risk (6), and COPD (8). The airway from the trachea down to the sixth generation of bronchioles was reconstructed by a 3D slicer. The small airway resistance (RSA) and RSA as a percentage of total airway resistance (RSA%) were calculated by CFD combined with airway resistance and FEV1 measured by pulmonary function test. A correlation analysis was conducted between RSA and pulmonary function parameters, including FEV1/FVC, FEV1% predicted, MEF50% predicted, MEF75% predicted and MMEF75/25% predicted.Results: The RSA and RSA% were significantly different among the three groups (p< 0.05) and related to FEV1/FVC (r = − 0.70, p < 0.001; r = − 0.67, p < 0.001), FEV1% predicted (r = − 0.60, p = 0.002; r = − 0.57, p = 0.004), MEF50% predicted (r = − 0.64, p = 0.001; r = − 0.64, p = 0.001), MEF75% predicted (r = − 0.71, p < 0.001; r = − 0.60, p = 0.002) and MMEF 75/25% predicted (r = − 0.64, p = 0.001; r = − 0.64, p = 0.001).Conclusion: Airway CFD is a valuable method for estimating the small airway resistance, where the derived RSA will aid in the early diagnosis of COPD.Keywords: COPD, small airway disease, CT, fluid dynamics

Wenjie Huang,1,2 Ting Luo,1,2 Mengqiu Lan,3 Wenting Zhou,1,2 Ming Zhang,1,2 Lihong Wu,3 Zhenni Lu,3 Li Fan1,2 1Department of Reproductive Medicine, Guangzhou Women and Children’s Medical Center Liuzhou Hospital, Liuzhou, Guangxi, 545616, People’s Republic of China; 2Department of Reproductive Medicine, Liuzhou Maternity and Child Healthcare Hospital, Liuzhou, Guangxi, 545001, People’s Republic of China; 3Clinical Laboratory Science, Liuzhou Municipal Liutie Central Hospital, Liuzhou, Guangxi, 545007, People’s Republic of ChinaCorrespondence: Wenjie Huang, Email a17377552242@163.comPurpose: Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide, characterized by intense lung infiltrations of immune cells (macrophages and monocytes). While existing studies have highlighted the crucial role of the competitive endogenous RNA (ceRNA) regulatory network in COPD development, the complexity and characteristics of the ceRNA network in monocytes remain unexplored.Methods: We downloaded messenger RNA (mRNA), microRNA (miRNA), and long noncoding RNA (lncRNA) microarray data from GSE146560, GSE102915, and GSE71220 in the Gene Expression Omnibus (GEO) database. This data was used to identify differentially expressed mRNAs (DEmRNAs), miRNAs (DEmiRNAs), and lncRNAs (DElncRNAs). Predicted miRNAs that bind to DElncRNAs were intersected with DEmiRNAs, forming a set of intersecting miRNAs. This set was then used to predict potential binding mRNAs, intersected with DEmRNAs, and underwent functional enrichment analysis using R software and the STRING database. The resulting triple regulatory network and hub genes were constructed using Cytoscape. Comparative Toxicomics Database (CTD) was utilized for disease correlation predictions, and ROC curve analysis assessed diagnostic accuracy.Results: Our study identified 5 lncRNAs, 4 miRNAs, and 149 mRNAs as differentially expressed. A lncRNA-miRNA-mRNA regulatory network was constructed, and hub genes were selected through hub analysis. Enrichment analysis highlighted terms related to cell movement and gene expression regulation. We established a LINC00482-has-miR-6088-PRRC2B ceRNA network with diagnostic relevance for COPD. ROC analysis demonstrated the diagnostic value of these genes. Moreover, a positive correlation between LINC00482 and PRRC2B expression was observed in COPD PBMCs. The CTD database indicated their involvement in inflammatory responses.Conclusion: In summary, our study not only identified pivotal hub genes in peripheral blood mononuclear cells (PBMCs) of COPD but also constructed a ceRNA regulatory network. This contributes to understanding the pathophysiological processes of COPD through bioinformatics analysis, expanding our knowledge of COPD, and providing a foundation for potential diagnostic and therapeutic targets for COPD.Keywords: COPD, PBMCs, ceRNA, bioinformatics analysis, PRRC2B, LINC00482

Yu Pu,&ast; Xiuxiu Zhou,&ast; Di Zhang, Yu Guan, Yi Xia, Shiyuan Liu, Li Fan Department of Radiology, Second Affiliated Hospital of PLA Naval Medical University, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shiyuan Liu; Li Fan, Department of Radiology, Second Affiliated Hospital of Naval Medical University, No. 415 Fengyang Road, Shanghai, 200003, People’s Republic of China, Tel +86 21 81886012 ; +86 21 81886011, Fax +86 21 63587668, Email radiology_cz@163.com; fanli0930@163.comPurpose: To explore the morphological alterations in small pulmonary vessels in populations at high risk for chronic obstructive pulmonary disease (COPD) and smokers based on multiple computed tomography (CT) quantitative parameters.Patients and Methods: A total of 1969 Three Major Chest Diseases Screening Study participants with available demographic data and smoking history who underwent low-dose chest CT from 2018 to 2020 were included. All subjects were divided into normal, high risk for COPD, and COPD groups according to their pulmonary function test (PFT) results. Furthermore, the three groups were further subdivided into never-smokers, current smokers, and former smokers subgroups according to their smoking history. Quantitative parameters, such as the number, area at 6 mm~24 mm subpleura and volume of small pulmonary vessels, were extracted by computer software. Differences in small pulmonary vessel parameters among the groups were compared using two-way ANOVA.Results: The number, area at 6 mm~24 mm subpleura and volume of small pulmonary vessels in the group at high risk for COPD were lower than those in the normal group (P< 0.05). The number, area at 6 mm~24 mm subpleura and volume of small pulmonary vessels in the COPD group were higher than those in the normal group (P< 0.05). The number, area of small pulmonary vessels at 6 mm~12 mm subpleura in current smokers with high risk for COPD were higher than those in former smokers with high risk for COPD (P< 0.05).Conclusion: The number, area, and volume of small pulmonary vessels in populations at high risk for COPD were decreased. Smoking cessation may impede structural changes in small pulmonary vessels in populations at high risk for COPD.Keywords: chronic obstructive pulmonary disease, computed tomography, pulmonary vascular structure, quantitative analysis, smoking

Tao Huang,1,&ast; Yongling Lv,2,&ast; Wei Wang,1 Yunyao Chen,1 Lixin Fan,1 Zhaowei Teng,3 Xianfeng Zhou,2,4 Hexiao Shen,2 Guang Fu1 1Gastrointestinal Surgery, Wuhan Puren Hospital, Wuhan, People’s Republic of China; 2Maintainbiotech. Ltd. (Wuhan), Wuhan, People’s Republic of China; 3Central Laboratory, The Second Affiliated Hospital of Kunming Medical University, Kunming, People’s Republic of China; 4School of Life Sciences and Health Engineering, Hubei University of Technology, Wuhan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hexiao Shen; Guang Fu, Email shenhxmyt@163.com; fuguang71@163.comAbstract: Adverse skin reactions caused by the COVID-19 vaccine have attracted considerable attention. As we all know, the development mechanism of some skin diseases is related to the gut and skin microbiome. A 78-year-old male patient who received the COVID-19 vaccine developed generalized eczema with multiple dense black patches over the body, a widespread rash, erosion, and scabs on his limbs, as well as facial edema. The patient experienced recurrent flare-ups after conventional treatment, but then recovered well without recurrence after undergoing three fecal microbial transplantation (FMT) treatments. This rare case is reported for the first time in this study. This report demonstrates the possible potential of FMT in targeting refractory skin diseases, such as eczema, as well as diseases associated with gut microbiota disturbance after vaccination.Keywords: FMT, eczema, COVID-19 vaccine

Zhe Zhao,1,&ast; Yinghui Gao,2,&ast; Junling Lin,3,&ast; Ruyi Xu,4 Zijun He,5 Libo Zhao,1 Fengfeng Fang,5 Weimeng Cai,6 Kaibin Chen,7 Li Fan,1 Lin Liu6 1Cardiology Department of the Second Medical Center & National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, People’s Republic of China; 2PKU-Upenn Sleep Center, Peking University International Hospital, Beijing, People’s Republic of China; 3Department of Pulmonary and Critical Care Medicine, Beijing Chaoyang Hospital Affiliated to Capital Medical University, Beijing, People’s Republic of China; 4Sixth Medical Center, Chinese PLA General Hospital, Beijing, People’s Republic of China; 5Medical College, Yan’an University, Yan’an, People’s Republic of China; 6Department of Respiratory and Critical Care Medicine of the Second Medical Center & National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, People’s Republic of China; 7Sleep Center, The Affiliated Hospital of Gansu University of Chinese Medicine, Lanzhou City, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Li Fan, Cardiology Department of the Second Medical Center & National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, 28 Fuxing Road, Beijing, 100853, People’s Republic of China, Tel +86 13301100573, Email fl6698@163.com Lin Liu, Department of Respiratory and Critical Care Medicine of the Second Medical Center & National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, 28 Fuxing Road, Beijing, 100853, People’s Republic of China, Tel +86 13263189578, Email liulin715@qq.comIntroduction: Obstructive sleep apnea (OSA) is associated with an increased risk of cardiovascular disease (CVD). Depression is a crucial factor among the various factors that are associated with OSA and CVD.Purpose: This study was conducted with an aim to assess the prognostic significance of depression on the MACE in older patients with OSA.Patients and Methods: 1106 older patients with OSA, without myocardial infarction (MI), history of hospitalization for unstable angina, or heart failure at baseline were enrolled and followed up prospectively. Incidence rates were expressed as cumulative incidence. Cox proportional hazards analysis was used to estimate the risk of all events. The primary outcomes were major adverse cardiovascular events (MACE). Each patient underwent polysomnography (PSG) and GDS-12 scale assessment. Those with an apnea-hypopnea index (AHI) greater than 5 were diagnosed with OSA, while those with a scale score greater than 3 were diagnosed with depression.Results: Among the 1106 older patients with OSA, depression was found in 133(12.0%) patients, 96(8.7%) patients experienced MACE during the follow-up. Depression was associated with a higher cumulative incidence of MACE in older patients with OSA. Multivariate analysis revealed that depression independently increased the risk of MACE (adjusted hazard ratio [aHR] = 2.29; 95% confidence interval [CI]: 1.34– 3.90; P = 0.002). Subgroup analyses showed that male patients (aHR = 2.96; 95% CI: 1.52– 5.77; P = 0.001), overweight-obese individuals (aHR = 2.98; 95% CI: 1.49– 6.00; P = 0.002), and those with moderate-severe OSA (aHR = 2.82; 95% CI: 1.55– 5.14; P = 0.001) and concurrent depression were at a higher risk for MACE.Conclusion: Depression is common in older patients with OSA in the absence of MI, hospitalization for unstable angina, or heart failure, and confers an independent, increased risk of MACE.Keywords: obstructive sleep apnea, OSA, depression, major adverse cardiovascular events, MACE, older adults

Jiao Sun,1,&ast; Lichao Fan,2,&ast; Yanping Zhao,3,&ast; Haoyu Wu,2 Ran Li,2 Yao Tian,2 Moxin Cheng,2 Xin Ma,1 Yingying Ma,1 Xinru Yang,1 Adong Shen,4 Yanhong Yu,1 Yu Chen2 1Tuberculosis Laboratory, Shenyang Tenth People’s Hospital/Shenyang Chest Hospital, Shenyang, People’s Republic of China; 2Department of Tuberculosis, Shenyang Tenth People’s Hospital/Shenyang Chest Hospital, Shenyang, People’s Republic of China; 3School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Special Administrative Region, People’s Republic of China; 4National Clinical Research Center for Respiratory Disease, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yanhong Yu; Yu Chen, Email 438735174@qq.com; yuchensyxk@163.comObjective: Drug-resistant tuberculosis (DR-TB) in children seriously threatens TB control. Information on the epidemiology and characteristics of DR-TB in children in China is limited. We studied data in Shenyang Tenth People’s Hospital to understand the DR-TB epidemiology in children in Shenyang.Design or Methods: We retrospectively analyzed drug resistance testing data of pediatric TB patients between 2017 and 2021, and included 2976 clinically-diagnosed pediatric TB patients. We described the epidemiology of DR-TB and analyzed the trends of DR-TB incidence. The Kappa value was calculated to assess the agreement between MGIT 960 DST and Xpert MTB/RIF for detecting rifampicin resistance. Multivariate logistic regression was used to identify the risk factors for DR-TB in pediatric patients.Results: Of the 2976 TB patients, 1076 were confirmed by MGIT 960 culture and/or Xpert MTB/RIF. Among the 806 patients identified by MGIT 960 culture, 232 cases (28.78%) were DR-TB. Resistance to the six drugs was in the following order: streptomycin (21.09%), isoniazid (9.35%), rifampin (15.01%), levofloxacin (6.20%), ethambutol (4.22%), and amikacin (3.23%). Alarmingly, 12.90% were MDR-TB (104/806), including 28 (3.47%) pre-XDR-TB. Of the 1076 pediatric TB patients, 295 (27.4%) developed DR-TB to any one drug (including 69 rifampicin-resistant cases identified by Xpert MTB/RIF only). No difference was found in the incidence of pediatric DR-TB between 2017 and 2021. Among 376 patients who were positive for both methods, using the MGIT 960 DST results as the gold standard, Xpert MTB/RIF’s sensitivity for detecting rifampicin resistance was 91.38% and its specificity was 94.65%.Conclusion: Between 2017 and 2021, the DR-TB incidence in children remained unchanged in Shenyang. RR-TB, MDR-TB, and even Pre-XDR-TB require attention in children with drug-resistant TB. Xpert MTB/RIF helped to detect more rifampicin-resistant pediatric patients; thus Xpert MTB/RIF should be widely used as an important complementary tool to detect rifampicin-resistant TB in children.Keywords: tuberculosis, drug-resistant, children, rifampicin, Xpert MTB/RIF, drug susceptibility testing

Liyun Xu,1 Lingling Fan,2 Jun Zhu3 1Department of Respiratory Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 200433, People’s Republic of China; 2Department of Obstetrics and Gynecology, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, 200011, People’s Republic of China; 3Department of Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 200433, People’s Republic of ChinaCorrespondence: Jun Zhu, Department of Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 200433, People’s Republic of China, Email rotor121@sina.com Lingling Fan, Department of Obstetrics and Gynecology, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, 200011, People’s Republic of China, Email fanlglg@hotmail.comBackground: Small cell lung cancer (SCLC) is a common subtype of lung cancer, and there is currently no established method for the early identification of SCLC. We prepared a novel rare-earth near-infrared (NIR) downconversion nanoprobe to identify SCLC cells.Methods: The shell precursors Gd-OA and Na-TFA-OA were prepared, and the NaYF4:Nd@NaGdF4-ProGRP antibody probe was obtained after synthesizing downconversion fluorescent nanocrystals. The probe was used for NIR identification of cancer cells and subcutaneous tumors in nude mice. The biotoxicity of the probe to SCLC cells and nude mice was studied.Results: The NaYF4:Nd@NaGdF4-ProGRP antibody probe was successfully prepared, with a size of 44 nm, an NIR emission peak at approximately 1060 nm, and a concentration of 40 μmol/mL. The probe could achieve accurate NIR identification of SCLC cells and subcutaneous tumors in nude mice. Optimal images of the subcutaneous tumor model were obtained approximately 10 minutes after probe injection. There was no significant change in the hematology indices, respiratory rate, or heart rate of nude mice after the probe was injected (all P > 0.05).Conclusion: We have successfully prepared a low-toxicity probe that can identify SCLC cells, which may be useful for the early detection of SCLC. And conduct theoretical exploration for non-invasive identification and identification of some early metastatic lesions without pathological sampling in the future.Keywords: probe, rare-earth, near-infrared, small cell lung cancer

Benjin Xu,1– 3,&ast; Zhuru Hou,2,4,&ast; Ling Liu,1– 3,&ast; Rongrong Yan,3 Jinjing Zhang,3 Jianhong Wei,4 Miao Du,1,2 Yan Xuan,1,2 Lei Fan,2,4 Zhuoxi Li2,4 1Department of Medical Laboratory Science, Fenyang College of Shanxi Medical University, Fenyang, People’s Republic of China; 2Key Laboratory of Lvliang for Clinical Molecular Diagnostics, Fenyang, People’s Republic of China; 3Department of Clinical Laboratory, Fenyang Hospital of Shanxi Province, Fenyang, People’s Republic of China; 4Department of Basic Medicine, Fenyang College of Shanxi Medical University, Fenyang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ling Liu; Benjin Xu, Department of Medical Laboratory Science, Fenyang College of Shanxi Medical University, Fenyang, 032200, People’s Republic of China, Email ll772x@sxmu.edu.cn; bj0726@sxmu.edu.cnObjective: This paper explores the drug resistance, genome and proteome expression characteristics of Salmonella from a food poisoning event.Methods: A multidrug-resistant Salmonella Enteritidis strain, labeled as 27A, was isolated and identified from a food poisoning patient. Antimicrobial susceptibility testing determined the resistance of 27A strain to 14 antibiotics. Then, WGS analysis and comparative genomics analysis were performed on 27A, and the functional annotation of resistance genes, virulence genes were performed based on VFDB, ARDB, COG, CARD, GO, KEGG, and CAZY databases. Meanwhile, based on iTRAQ technology, quantitative proteomic analysis was conducted on 27A to analyze the functions and interactions of differentially expressed proteins related to bacterial resistance and pathogenicity.Results: Strain 27A belonged to ST11 S. Enteritidis and was resistant to levofloxacin, ciprofloxacin, ampicillin, piperacillin, and ampicillin/sulbactam. There were 33 drug resistance genes, 384 virulence genes and 2 plasmid replicon, IncFIB(S) and IncFII(S), annotated by WGS. Proteomic analysis revealed significant changes in virulence and drug proteins, which were mainly involved in bacterial pathogenicity and metabolic processes. PPI prediction showed the relationship between virulence proteins and T3SS proteins, and PagN cooperated with proteins related to T3SS to jointly mediate the invasion of 27A strain on the human body. Phylogenetic analysis indicated that S. Enteritidis has potential transmission in humans, food, and animals.Conclusion: This study comprehensively analyzed the drug resistance and virulence phenotypes of S. Enteritidis 27A using genomic and proteomic approaches. These helps reveal the drug resistance and virulence mechanisms of S. Enteritidis, and provides important information for the source tracing and the prevention of related diseases, which lays a foundation for research on food safety, public health monitoring, and the drug resistance and pathogenicity of S. Enteritidis.Keywords: Salmonella, WGS, quantitative proteomics, resistance, virulence, evolution

Leilei Fan,1 Xue Ding2 1Department of Cardiovascular, Yellow River Central Hospital, Zhengzhou, 450004, People’s Republic of China; 2Department of Medical, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, 450000, People’s Republic of ChinaCorrespondence: Xue Ding, Department of Medical, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, 450000, People’s Republic of China, Email dingxue1217@sina.comAbstract: Coronavirus disease 2019 is a “Public Health Emergency of International Concern” from 30 January 2020 to 5 May 2023. While battling Coronavirus disease 2019, the Chinese government has actively promoted the collaborative treatment model of Western medicine and traditional Chinese medicine, and clinical and scientific research has applied appropriate and rigorous methodology. Severe acute respiratory syndrome coronavirus 2 infection may damage the cardiovascular system via an unclarified pathogenic mechanism. The National Health Commission of China recommends ‘three formulas and three medicines’ for the treatment of coronavirus disease 2019, which have been shown to be most effective in the treatments. Data from randomized controlled trials of ‘three formulas and three medicines’ suggested that the traditional Chinese medicine is safe and can alleviate the symptoms of cardiac injury. Therefore, we further evaluate the benefits and safety of traditional Chinese medicine treatment for Coronavirus disease 2019 patients with cardiac injury across the care continuum.Keywords: traditional Chinese medicine, coronavirus disease 2019, cardiac injury

Hui Ke,&ast; Xuwei Gui,&ast; Wenwen Sun, Shaojun Zhang, Yan Yang, Zhemin Zhang, Lin Fan Department of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai Clinic and Research Center of Tuberculosis, Shanghai Key Laboratory of Tuberculosis, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Lin Fan; Zhemin Zhang, Email fanlinsj@163.com; zhemindoc@163.comObjective: To evaluate the safety, tolerability, and efficacy of prolonged bedaquiline (Bdq) treatment in patients with multi-drug/rifampin-resistant tuberculosis (MDR/RR-TB).Methods: This prospective cohort study was performed from August 2018 to August 2021. Patients diagnosed with MDR/RR-TB who met the inclusion criteria were prospectively included. Patients were treated with individual regimens of 18– 20 months containing Bdq for six months or a prolonged course of nine or 12 months according to treatment demands, and the efficacy and safety with a different course of Bdq-containing regimens were compared and evaluated.Results: A total of 159 MDR/RR-TB patients were included in the study, including 96 cases with six months of Bdq, 50 cases with nine months of Bdq, and 13 patients with 12 months of Bdq. The treatment success rates were 89.6%, 90%, and 84.6% in Bdq at six months, nine months, and 12 months, respectively, which were not statistically different (P = 0.85). The main adverse events (AEs) were anemia, thrombocytopenia, and liver dysfunction in all patients, with no significant difference among the three groups. Patients who had fewer drugs chosen, disseminated lesions or lesions that were slowly absorbed, and severe cavities were the common reasons for prolonged use of Bdq.Conclusion: Prolonged course use of Bdq from six months to 12 months clinically proved to be safe and efficient, and patients with severe or disseminated lesions had the chance to prolong the use of Bdq for more than six months to achieve optimal treatment outcomes.Keywords: bedaquiline, prolonged course, MDR-TB, RR-TB, safety

Juan Guo,1,&ast; Zhiyu Pan,1,&ast; Lvyuan Fan,1 Yilin Zhong,1 Rui Pang,2 Yubin Su1 1Department of Cell Biology & Institute of Biomedicine, National Engineering Research Center of Genetic Medicine, MOE Key Laboratory of Tumor Molecular Biology, Guangdong Provincial Key Laboratory of Bioengineering Medicine, College of Life Science and Technology, Jinan University, Guangzhou, 510632, People’s Republic of China; 2Guangdong Provincial Key Laboratory of Microbial Safety and Health, State Key Laboratory of Applied Microbiology Southern China, Guangdong Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yubin Su, Email suyb7@jnu.edu.cnBackground: The issue of methicillin-resistant Staphylococcus aureus (MRSA) resistant to many antibiotics and causing serious infectious diseases is a growing healthcare concern.Purpose: In recent years, exogenous administration of metabolites in combination with antibiotics can re-sensitize resistant bacteria to antibiotics; however, their effects vary, and their underlying mechanism of action remains elusive.Methods: We assessed the bactericidal effects of the three amino acids in combination with gentamicin in vitro and in vivo. Subsequently, we explored the role of these amino acids on the metabolomics of MRSA using Liquid chromatography-tandem mass spectrometry (LC-MS/MS). Furthermore, we performed the downstream analyses using MetaboAnalyst and Interactive Pathways Explorer.Results: Exogenous threonine showed the best bactericidal efficacy with gentamicin, followed by glycine, wherein serine had no effect. Amino acid treatments mainly up-regulated the metabolites, increased the amino acid abundance, and significantly activated metabolisms; these effects were consistent with the bactericidal efficacy of the three amino acids. Most amino acids participated in the tricarboxylic acid cycle, and threonine supplementation increased the activities of citrate synthase, isocitrate dehydrogenase and α-ketoglutarate dehydrogenase, whereas glycine increased activities of citrate synthase and α-ketoglutarate dehydrogenase, and serine did not affect the activities of any of the three key enzymes. We identified 24 biomarkers in the three groups, among which glutamic acid and cysteine showed a gradient decrease and increase, respectively. Subsequent analyses revealed that glutamic acid but not cysteine promoted the bactericidal effect of gentamicin synergistically.Conclusion: Threonine has the best synergistic effect in reversing bacterial resistance compared to glycine and serine. We show that different amino acids combined with an antibiotic mainly affect amino acid metabolism and act via different metabolic regulatory mechanisms, which could help develop effective strategies for tackling MRSA infections.Keywords: methicillin-resistant Staphylococcus aureus, metabolomics, gentamicin, amino acid, metabolic regulation

Wenting Tu,1,&ast; Taohu Zhou,1,2,&ast; Xiuxiu Zhou,1,&ast; Yanqing Ma,3 Shaofeng Duan,4 Yun Wang,1 Xiang Wang,1 Tian Liu,1 HanXiao Zhang,5 Yan Feng,1 Wenjun Huang,2 Xinang Jiang,1 Yi Xiao,1 Shiyuan Liu,1 Li Fan1 1Department of Radiology, Second Affiliated Hospital of Naval Medical University, Shanghai, 200003, People’s Republic of China; 2School of Medical Imaging, Weifang Medical University, Weifang, Shandong, 261053, People’s Republic of China; 3Department of Radiology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital of Hangzhou Medical College, Hangzhou, Zhejiang, 310000, People’s Republic of China; 4GE Healthcare, Precision Health Institution, Shanghai, 210000, People’s Republic of China; 5School of Medical Imaging, Xuzhou Medical University, Xuzhou, Jiangsu, 221018, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shiyuan Liu; Li Fan, Department of Radiology, Second Affiliated Hospital, Naval Medical University, No. 415 Fengyang Road, Shanghai, 200003, People’s Republic of China, Tel +86 21 81886012 ; +86 21 81886018, Fax +86 21 63587668, Email cjr.liushiyuan@vip.163.com; fanli0930@163.comPurpose: This study aimed to screen out computed tomography (CT) morphological features and clinical characteristics of patients with lung cancer to identify chronic obstructive pulmonary disease (COPD). Further, we aimed to develop and validate different diagnostic nomograms for predicting whether lung cancer is comorbid with COPD.Patients and Methods: This retrospective study examined data from 498 patients with lung cancer (280 with COPD, 218 without COPD; 349 in training cohort, 149 in validation cohort) from two centers. Five clinical characteristics and 20 CT morphological features were evaluated. Differences in all variables were assessed between COPD and non-COPD groups. Models were developed using multivariable logistic regression to identify COPD, including clinical, imaging, and combined nomograms. Receiver operating characteristic curves were used to evaluate and compare the performance of nomograms.Results: Age, sex, interface, bronchus cutoff sign, spine-like process, and spiculation sign were independent predictors of COPD in patients with lung cancer. In the training and validation cohorts, the clinical nomogram showed good performance to predict COPD in lung cancer patients (areas under the curves [AUCs] of 0.807 [95% CI, 0.761– 0.854] and 0.753 [95% CI, 0.674– 0.832]); while the imaging nomogram showed slightly better performance (AUCs of 0.814 [95% CI, 0.770– 0.858] and 0.780 [95% CI, 0.705– 0.856]). For the combined nomogram generated with clinical and imaging features, the performance was further improved (AUC=0.863 [95% CI, 0.824– 0.903], 0.811 [95% CI, 0.742– 0.880] in the training and validation cohort). At 60% risk threshold, there were more true negative predictions (48 vs 44) and higher accuracy (73.15% vs 71.14%) for the combined nomogram compared with the clinical nomogram in the validation cohort.Conclusion: The combined nomogram developed with clinical and imaging features outperformed clinical and imaging nomograms; this provides a convenient method to detect COPD in patients with lung cancer using one-stop CT scanning.Keywords: chronic obstructive pulmonary disease, lung cancer, computed tomography, chest imaging, nomogram

Hao Wang,1 Jun Guo,1 Yujie Zhang,2 Jin Fang,2 Shaobo Qiu,3 Yanwei He,4 Lijie Fan,4 Xulu Lei2 1Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, People’s Republic of China; 2Department of Preventive Care Center, Beijing Fengtai Hospital of Integrated Chinese and Western Medicine, Beijing, People’s Republic of China; 3Department of Neurology, Beijing Fengtai Hospital of Integrated Chinese and Western Medicine, Beijing, People’s Republic of China; 4Department of Functional Section, Beijing Fengtai Hospital of Integrated Chinese and Western Medicine, Beijing, People’s Republic of ChinaCorrespondence: Xulu Lei, Department of Preventive Care Center, Beijing Fengtai Hospital of Integrated Chinese and Western Medicine, Beijing, People’s Republic of China, Email lxl2524@126.comBackground: In China, acupuncture has been widely used in treating cerebrovascular diseases since time immemorial. Scalp acupuncture using the long-stay method is a traditional acupuncture treatment. However, previous studies have concluded that the clinical efficacy of scalp acupuncture for the treatment of stroke remains uncertain. In addition, no randomized controlled trials have been conducted on scalp acupuncture using the long-stay method. This study aimed to evaluate the efficacy and safety of the long-stay method of scalp acupuncture for limb movement dysfunction in patients after acute ischemic stroke (AIS).Methods: Seventy-two patients with acute strokes were randomly divided into treatment and control groups. The control group received conventional acupuncture with a half-hour needle stay each time, whereas the treatment group underwent scalp needling using a long retention method, with each retention of needles lasting 24 hours. Both groups received acupuncture treatment for 2 weeks and were followed up for 6 months. Cerebrovascular reserve (CVR), breath-holding index (BHI), pulsatility index (PI), Fugl–Meyer, and Barthel index (BI) were assessed at baseline, week 1, week 2, and during follow-up.Results: Compared with the baseline, both groups showed a significant improvement in CVR, Fugl–Meyer, BI, PI, and BHI (P < 0.05). Compared with the control group, the treatment group showed more significant improvements in Fugl–Meyer scores, BI, CVR, PI, and BHI (P < 0.05). Correlation analysis showed that Fugl–Meyer and BI scores increased significantly with CVR recovery over the course of treatment.Conclusion: Scalp acupuncture with the long-stay method can improve neurological deficits and the ability to perform daily activities among AIS patients, which may be related to the improvement of CVR function in patients.Keywords: scalp acupuncture, stroke, motor dysfunction, cerebrovascular reserve

Xinru Xiao,1,2 Wei Cai,1 Ziqi Ding,1 Yujia Shi,1 Liang Fan,1 Qian Zhang1,3 1Department of Respiratory and Critical Care Medicine, The Affiliated Changzhou Second People’s Hospital of Nanjing Medical University, Changzhou, People’s Republic of China; 2Department of the Second Clinical College, Dalian Medical University, Dalian, People’s Republic of China; 3Changzhou Medical Center, Nanjing Medical University, Changzhou, People’s Republic of ChinaCorrespondence: Qian Zhang, Tel +86-519-81087391, Fax +86-519-88115560, Email qianzhang@njmu.edu.cnBackground: Chronic obstructive pulmonary disease (COPD) often associated with cigarette smoking. However, increasing evidence suggests that non-smoking COPD is much higher than previously thought. This study aims to identify a nonsmoking COPD biomarker and examined its value in diagnosis and prediction of acute exacerbation.Methods: A total of 35 stable COPD patients, 70 acute exacerbation chronic obstructive pulmonary disease (AECOPD) patients and 35 healthy control subjects were included. Plasma α 2 macroglobulin (A2M) and matrix metalloproteinase-9 (MMP-9) levels were measured using the enzyme-linked immunosorbent assay (ELISA) method on all participants. Their association with clinical characteristics and lung function parameters were determined by regression analysis. Receiver operating characteristic (ROC) curve was used to determine the diagnostic sensitivity and specificity. Correlation coefficients were evaluated using Pearson’s correlation.Results: Plasma A2M concentration was decreased and MMP-9 concentration, MMP-9/A2M ratio were elevated in stable COPD patients compared with control groups. And MMP-9 expression was significantly higher in AECOPD patients. A2M level was increased in AECOPD patients with infection compared with those without. In addition, there was no statistical difference in A2M levels between smokers and nonsmokers COPD or healthy control subjects. Furthermore, A2M, MMP-9 and MMP-9/A2M were correlated with forced expiratory volume in one second (FEV1)%, FEV1/ forced vital capacity (FVC), CAT and mMRC score in COPD patients, but had no correlation with fraction of exhaled nitric oxide (FeNO) and concentration of alveolar nitric oxide (CaNO).Conclusion: A2M is altered in peripheral blood of COPD patients and correlated with severity and infection. Moreover, there was no significant correlation between the change in A2M and smoking, FeNO and CaNO, suggesting A2M may reflect the overall rather than local inflammation in COPD patients and serve as a potential biomarker for nonsmoking COPD patients.Keywords: chronic obstructive pulmonary disease, α 2 macroglobulin, matrix metalloproteinase-9