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Hao Hong,1,* Suya Zhou,2,* Junyao Zheng,3 Haimin Shi,3 Yue Chen,4 Ming Li3 1Department of Intensive Care Unit, The First Affiliated Hospital of Soochow University, Soochow, Suzhou, People’s Republic of China; 2Laboratory Nephrology, Jinshan hospital of Fudan University, Shanghai, People’s Republic of China; 3Laboratory Nephrology, The First Affiliated Hospital of Soochow University, Soochow, Suzhou, People’s Republic of China; 4Laboratory Nephrology, The First People’s Hospital of Kunshan, Soochow, Suzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ming Li, Email 1925924373@qq.comPurpose: The aim of this study was to investigate the changes of different metabolites in the body fluids of non-dialysis patients with chronic kidney disease (CKD) using a metabolomics approach. The goal was to identify early biomarkers of CKD progression through metabolic pathway analysis.Patients and Methods: Plasma samples from 47 patients with stages 1– 4 CKD not requiring dialysis and 30 healthy controls were analyzed by liquid chromatography-mass spectrometry (LC-MS). Using multivariate data analysis, specifically a partially orthogonal least squares discriminant analysis model (OPLS-DA), we investigated metabolic differences between different stages of CKD. The sensitivity and specificity of the analysis were evaluated using the Area Under Curve (AUC) method. Furthermore, the metabolic pathways were analyzed using the Met PA database.Results: Plasma samples from CKD patients and controls were successfully differentiated using an OPLS-DA model. Initially, twenty-five compounds were identified as potential plasma metabolic markers for distinguishing CKD patients from healthy controls. Among these, six compounds (ADMA, D-Ornithine, Kynurenine, Kynurenic acid, 5-Hydroxyindoleacetic acid, and Gluconic acid) were found to be associated with CKD progression It has been found to be associated with the progression of CKD. Changes in metabolic pathways associated with CKD progression include arginine and ornithine metabolism, tryptophan metabolism, and the pentose phosphate pathway.Conclusion: By analyzing the metabolic pathways of different metabolites, we have identified the significant impact of CKD progression. The main metabolic pathways involved are Arginine and Ornithine metabolism, Tryptophan metabolism, and Pentose phosphate pathway. ADMA, D-Ornithine, L-Kynurenine, Kynurenic acid, 5-Hydroxyindoleacetic acid, and Gluconic acid could serve as potential early biomarkers for CKD progression. These findings have important implications for the early intervention and treatment of CKD, as well as for further research into the underlying mechanisms of its pathogenesis.Keywords: arginine and ornithine metabolism, tryptophan metabolism, pentose phosphate pathway, biomarkers

Jun Zheng,1 Xiaohong Pan,2 Yiyun Jiang3 1Department of Rehabilitation, Nanxing Health Service Center, Shangcheng, Hangzhou, Zhejiang, 310000, People’s Republic of China; 2Tuberculosis Care Unit, Hospital of Integrated Traditional Chinese and Western Medicine, Zhejiang, 310003, People’s Republic of China; 3Department of Comprehensive Surgery, Hangzhou Geriatric Hospital, Zhejiang, 310022, People’s Republic of ChinaCorrespondence: Yiyun Jiang, Department of Comprehensive Surgery, Hangzhou Geriatric Hospital, No. 50, Jingxin Road, Hangzhou, Zhejiang, 310022, People’s Republic of China, Tel +8615088664025, Email 458247254@qq.comAbstract: Thrombotic thrombocytopenic purpura is a rare but life-threatening emergency. Tuberculosis can have hematologic complications. However, concurrent tuberculosis and thrombotic thrombocytopenic purpura are extremely rare. In this study, we report a 53-year-old man who was initially treated for pulmonary tuberculosis but later developed weakness and an altered mental status. Laboratory tests revealed evidence of thrombocytopenia, acute renal insufficiency, and microangiopathic hemolytic anemia. Brain imaging identified intracranial hemorrhage. Further testing revealed low ADAMTS13 activity (1.8%) and positive anti-ADAMTS13 antibody, confirming the diagnosis of thrombotic thrombocytopenic purpura. The patient had a full recovery after anti-tuberculosis treatment, plasma exchange, and supportive care. We present this rare case and review previous relevant studies to remind clinicians about the potential connections between tuberculosis and thrombotic thrombocytopenic purpura. In patients with signs of severe thrombocytopenia and microangiopathic hemolysis, necessary diagnostic tests should be performed to eliminate the possibility of thrombotic thrombocytopenic purpura occurring concurrently with tuberculosis.Keywords: Thrombotic thrombocytopenic purpura, tuberculosis, case report, literature review

Hao Hong,1 Junyao Zheng,2 Haimin Shi,2 Suya Zhou,3 Yue Chen,4 Ming Li2 1Department of Intensive Care Unit, The First Affiliated Hospital of Soochow University, Soochow, People’s Republic of China; 2Laboratory Nephrology, The First Affiliated Hospital of Soochow University, Soochow, People’s Republic of China; 3Laboratory Nephrology, Jinshan Hospital of Fudan University, Shanghai, People’s Republic of China; 4Laboratory Nephrology, The First People’s Hospital of Kunshan, Soochow, People’s Republic of ChinaCorrespondence: Ming Li, Email 1925924373@qq.comPurpose: Changes in inflammation, immunity, and nutritional status can promote the development of chronic kidney disease (CKD), and the Naples prognostic score (NPS) reflects changes in these three general clinical parameters. Indoleamine 2.3-dioxygenase (IDO) can block the function of inflammatory cells and inhibit the production of inflammatory cytokines. We examined use of the NPS and IDO activity to predict early-stage CKD.Patients and Methods: Clinical and demographic parameters and the NPS were recorded for 47 CKD patients and 30 healthy controls. A one-way ANOVA or the rank sum test was used to compare variables in the different groups. Spearman or Pearson correlation coefficients were calculated, and logistic regression was used to identify significant factors. Receiver operating characteristic (ROC) analysis was also performed.Results: The NPS had a positive correlation with plasma IDO activity and IDO activity was lowest in controls, and increased with CKD stage. ROC analysis indicated that NPS had an area under the curve (AUC) of 0.779 when comparing controls with all CKD patients. A prediction model for CKD (− 4.847 + [1.234 × NPS] + [6.160 × plasma IDO activity]) demonstrated significant differences between controls and patients with early-stage CKD, and for patients with different stages of CKD. This model had AUC values of 0.885 (control vs CKD1– 4), 0.876 (control vs CKD2), 0.818 (CKD2 vs CKD3), and 0.758 (CKD3 vs CKD4).Conclusion: A prediction model based on the NPS and IDO provided good to excellent predictions of early-stage CKD.Keywords: inflammation, immune, nutrition, score, metabolomic, kynurenine pathway

Li`ao Wang,1 Zhiming Zheng,2 Jia Zheng,2 Guifeng Zhang,3 Zheng Wang4 1Clinical College of Neurology, Neurosurgery and Neurorehabilitation, Tianjin Medical University, Tianjin, 300203, People’s Republic of China; 2Department of Neurosurgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, People’s Republic of China; 3Department of Neurology, Liaocheng People’s Hospital, Liaocheng, 252004, People’s Republic of China; 4Department of Neurosurgery, Liaocheng Traditional Chinese Medicine Hospital, Liaocheng, 252000, People’s Republic of ChinaCorrespondence: Guifeng Zhang, Department of Neurology, Liaocheng People’s Hospital, Liaocheng, 252004, People’s Republic of China, Tel +86 18063513155, Email GFZhangNo.1@gmail.com Zheng Wang, Department of Neurosurgery, Liaocheng Traditional Chinese Medicine Hospital, Liaocheng, 252000, People’s Republic of China, Tel +86 18063560328, Email zhengyimingdao@gmail.comPurpose: Low-grade gliomas (LGG) are common brain tumors with high mortality rates. Cancer cell invasion is a significant factor in tumor metastasis. Novel biomarkers are urgently needed to predict LGG prognosis effectively.Methods: The data for LGG were obtained from the Bioinformatics database. A consensus clustering analysis was performed to identify molecular subtypes linked with invasion in LGG. Differential expression analysis was performed to identify differentially expressed genes (DEGs) between the identified clusters. Enrichment analyses were then conducted to explore the function for DEGs. Prognostic signatures were placed, and their predictive power was assessed. Furthermore, the invasion-related prognostic signature was validated using the CGGA dataset. Subsequently, clinical specimens were procured in order to validate the expression levels of the distinct genes examined in this research, and to further explore the impact of these genes on the glioma cell line LN229 and HS-683.Results: Two invasion-related molecular subtypes of LGG were identified, and we sifted 163 DEGs between them. The enrichment analyses indicated that DEGs are mainly related to pattern specification process. Subsequently, 10 signature genes (IGF2BP2, SRY, CHI3L1, IGF2BP3, MEOX2, ABCC3, HOXC4, OTP, METTL7B, and EMILIN3) were sifted out to construct a risk model. Besides, the survival (OS) in the high-risk group was lower. The performance of the risk model was verified. Furthermore, a highly reliable nomogram was generated. Cellular experiments revealed the ability to promote cell viability, value-addedness, migratory ability, invasive ability, and colony-forming ability of the glioma cell line LN229 and HS-683. The qRT-PCR analysis of clinical glioma samples showed that these 10 genes were expressed at higher levels in high-grade gliomas than in low-grade gliomas, suggesting that these genes are associated with poor prognosis of gliomas.Conclusion: Our study sifted out ten invasion-related biomarkers of LGG, providing a reference for treatments and prognostic prediction in LGG.Keywords: LGG, prognosis, invasion, overall survival, EMILIN3

Hao Hong,1,&ast; Junyao Zheng,2,&ast; Haimin Shi,2 Suya Zhou,3 Yue Chen,4 Ming Li2 1Intensive Care Unit, the First Affiliated Hospital of Soochow University, Soochow, People’s Republic of China; 2Laboratory Nephrology, the First Affiliated Hospital of Soochow University, Soochow, People’s Republic of China; 3Laboratory Nephrology, Jinshan Hospital of Fudan University, Shanghai, People’s Republic of China; 4Laboratory Nephrology, the First People’s Hospital of Kunshan, Soochow, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ming Li, Email 1925924373@qq.comPurpose: We aimed to explore changes in plasma and urine indole lactic acid (ILA) levels and the relationship between inflammation and ILA in chronic kidney disease (CKD) patients and healthy people.Patients and Methods: Forty-seven CKD patients and 30 healthy individuals were included in this study. One-way ANOVA was used for variables with normal distribution and homogeneous variance. A rank-sum test was performed for non-normally distributed variables. Correlation analyses were performed using Pearson’s or Spearman correlation analyses. Independent relationship between patients and CKD was analyzed using ordinal and binary logistic regressions. Receiver operating characteristic (ROC) curve was used.Results: Plasma and urine ILA levels were positively correlated (r = 0.51, P < 0.01). Plasma ILA was positively correlated with BMI, age, creatinine, BUN, triglycerides, and uric acid and negatively correlated with hemoglobin levels. Urine ILA levels were positively correlated with age, creatinine, BUN, and uric acid and negatively correlated with hemoglobin and albumin levels. Ordered logistic regression analysis showed that CKD was significantly correlated with plasma ILA (OR=4.49, P

Lan Hong,1,&ast; Huihui Xu,2,&ast; Jiaqi Zheng,2 Xiujian Lin,2 Lijun Wang,2 Chengjia Zhao,3 Xiaolian Tu,4 Jingjing Zhang,5 Ke Zhao,1,6 Guohua Zhang6,7,&ast; 1Lishui Second People’s Hospital Affiliated to Wenzhou Medical University, Lishui, 323000, People’s Republic of China; 2School of Mental Health, Wenzhou Medical University, Wenzhou, 325035, People’s Republic of China; 3School of Education, Renmin University of China, Beijing, 100872, People’s Republic of China; 4School of Renji, Wenzhou Medical University, Wenzhou, 325035, People’s Republic of China; 5School of Nursing, Wenzhou Medical University, Wenzhou, 325035, People’s Republic of China; 6Zhejiang Provincial Clinical Research Center for Mental Disorders, The Affiliated Wenzhou Kangning Hospital, Wenzhou Medical University, Wenzhou, 325035, People’s Republic of China; 7Institute Of Aging, Key Laboratory Of Alzheimer’s Disease Of Zhejiang Province, Wenzhou Medical University, Wenzhou, 325035, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Guohua Zhang, Zhejiang Provincial Clinical Research Center for Mental Disorders, The Affiliated Wenzhou Kangning Hospital, Wenzhou Medical University, Wenzhou, 325035, People’s Republic of China, Email zghcnu@wmu.edu.cn Ke Zhao, Lishui Second People’s Hospital Affiliated to Wenzhou Medical University, Lishui, 323000, People’s Republic of China, Email cocozk1986@163.comBackground: Bedtime procrastination (BP) has become an important factor affecting individual well-being. This study aimed to assess the stability and changes in BP and examine risk and protective factors.Methods: The study recruited 1423 respondents. Latent profile analysis was used to identify subgroups of BP and latent transition analysis to determine transition probabilities for each subgroup. Logistic regression examined associations between identified classes and related factors.Results: Three subgroups of BP were identified. In terms of stability and changes, the moderate bedtime procrastination group showed the highest stability (66%), followed by the severe bedtime procrastination group (62.4%), and the mild bedtime procrastination group had a 52% probability of switching to moderate bedtime procrastination. In terms of influencing factors, more problematic phone use (PSU) (OR: 1.08; 95% CI = 1.05– 1.12), more depression (OR: 1.17; 95% CI = 1.06– 1.29) and anxiety (OR: 1.16; 95% CI = 1.05– 1.28) are all factors that aggravate the transition from mild to moderate sleep procrastination. Similarly, PSU (OR: 1.15; 95% CI = 1.12– 1.19), anxiety (OR: 1.10; 95% CI = 1.06– 1.14), and depression (OR: 1.10; 95% CI = 1.06– 1.14) increased the risk of severe bedtime procrastination. Self-control emerged as a protective factor against BP.Conclusion: This study identified three subgroups of BP at two time points and the rule of transition for each subgroup. Our findings indicate that BP were relatively stable, with some changes over time. The results also highlight the important function that PSU, depression, anxiety, and self-control can play in preventing and intervening in BP.Keywords: bedtime procrastination, latent profile analysis, latent transition analysis, problematic smartphone use, depression, anxiety, self-control

Miao-Miao Hua,1 Jia Li,2 Jie Zheng,2 Jing-Jing Wang,2 Chang Liu,2 Yan Zhang,2 Zhi-Feng Zhang,2 Xiao-Li Cao,1,2 Han Shen1,2 1Department of Laboratory Medicine, Nanjing Drum Tower Hospital Clinical College of Jiangsu University, Nanjing, People’s Republic of China; 2Department of Laboratory Medicine, Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital, Nanjing, People’s Republic of ChinaCorrespondence: Xiao-Li Cao; Han Shen, Email cao-xiao-li@163.com; shenhan10366@sina.comObjective: To investigate the clinical and molecular characteristics of Salmonella spp. causing bloodstream infections (BSIs) in our hospital.Methods: We studied 22 clinical Salmonella isolates from BSIs and 16 from non-BSIs, performing antimicrobial susceptibility testing (AST) and whole genome sequencing (WGS). The analysis included serovars, antibiotic resistance genes (ARGs), virulence factors (VFs), sequence types (STs), plasmid replicons, and genetic relationships. We also assessed pathogenicity of the isolates causing BSIs through growth, biofilm formation, and anti-serum killing assays.Results: WGS analysis identified 13 Salmonella serovars, with four responsible for BSIs. S. Enteritidis was the most prevalent serovar, involved in 19 (50.0%) cases. BSIs were caused by 17S. Enteritidis, two S. Typhimurium, two S. Munster and one S. Diguel. Of the 38 isolates, 27 (71.1%) exhibited high resistance to ampicillin, and 24 (63.2%) to ampicillin/sulbactam. Thirty-six types of ARGs were identified, with blaTEM-1B (n = 25, 65.8%) being the most frequent. Ten plasmid replicons were found; the combination of IncFIB(S)-IncFII(S)-IncX1 was the most common in S. Enteritidis (94.7%). Fifteen STs were identified, among which ST11 was the most prevalent and clonally disseminated, primarily responsible for BSIs. A total of 333 different VFs were detected, 177 of which were common across all strains. No significant differences were observed between the BSI and non-BSI isolates in terms of resistance rates, ARGs, plasmid replicons, and VFs, except for seven VFs. No strong pathogenicity was observed in the BSI-causing isolates.Conclusion: BSIs were predominantly caused by clonally disseminated S. Enteritidis ST11, the majority of which carried multiple ARGs, VFs and plasmid replicons. This study provides the first data on clonally disseminated S. Enteritidis ST11 causing BSIs, highlighting the urgent need for enhanced infection control measures.Keywords: Salmonella enteritidis, bloodstream infections, serovars, antibiotic-resistance genes, virulence factors, sequence type

Jianbao Zheng,1,2,&ast; Zepeng Dong,1,&ast; Xianzhen Jin,1 Jing Li,2 Yuanwu Zou,2 Guanghong Bai,2 Qianhong Wu,2 Shenghang Xu,3 Zifeng Wang,3 Xuejun Sun,1 Dingxin Liu,3 Li Guo3 1Department of General Surgery, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710061, People’s Republic of China; 2Tuberculosis Prevention and Treatment Hospital in Shaanxi Province, Xi’an, 710100, People’s Republic of China; 3Center for Plasma Biomedicine, State Key Laboratory of Electrical Insulation and Power Equipment, Xi’an Jiaotong University, Xi’an, 710049, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qianhong Wu; Li Guo, Email 15902969531@126.com; guoli35@mail.xjtu.edu.cnPurpose: This study aimed to investigate the antibacterial effects of plasma-activated saline (PAS) on My-cobacterium tuberculosis (Mtb).Methods: We conducted a growth assay on 3 strains of Mtb and an antibiotic sensitivity test on 4 strains of Mtb. Both tests included groups treated with normal saline (NS), PAS, and hydrochloric acid (HCl). The test of antibiotic sensitivity consisted of parallel tests with two concentrations of bacteria suspension: 10− 2 and 10− 4. The selected antibiotics were rifampicin (RIF), isoniazid (INH), ethambutol (EMB), and streptomycin (SM). The number of bacteria was determined after one month of culture under different conditions. The Kruskal–Wallis test was used to analyze the differences in grouping factors at representative time points.Results: The growth assay indicated that PAS significantly inhibited the growth of 3 strains of Mtb compared with NS and HCl treatment groups. Furthermore, except for the initial observation time point, the remaining three observation time points consistently demonstrate no significant differences between the NS group and the HCl group. The antibiotic sensitivity test of INH, SM, and RIF indicated that PAS could inhibit the growth of antibiotic-resistant Mtb, and the antibiotic sensitivity test of INH and SM with bacterial suspension concentration of 10− 2 and SM with bacterial suspension concentration of 10− 4 showed statistically different results. The antibiotic sensitivity test of EMB indicated that the growth of Mtb in PAS was slower than that in NS and HCl in both antibiotic-resistant and sensitive Mtb, but there was no statistical difference.Conclusion: The study indicates that PAS contains a significant amount of active substances and exhibits high oxidizability and an acidic pH state. The unique physicochemical properties of PAS significantly delayed the growth of Mtb, compared to the NS and the HCl. PAS not only inhibited the growth of drug-sensitive strains but also significantly enhanced the sensitivity of drug-resistant strains to anti-tuberculosis drugs, which may provide a new therapeutic strategy for the treatment of tuberculosis.Keywords: plasma-activated saline, mycobacterium tuberculosis, antibacterial effect, antibiotic sensitivity

Jinjie Gao,1 Jiajia Zheng,2 Hua Zhang,3 Jijun Wang,1 Hongmei Jing1 1Department of Hematology, Lymphoma Research Center, Peking University Third Hospital, Beijing, 100191, People’s Republic of China; 2Department of Laboratory Medicine, Peking University Third Hospital, Beijing, 100191, People’s Republic of China; 3Research Center of Clinical Epidemiology, Peking University Third Hospital, Beijing, 100191, People’s Republic of ChinaCorrespondence: Hongmei Jing, Tel +86-010-82266785, Email hongmeijing@bjmu.edu.cnObjective: We performed a retrospective analysis to investigate the clinical predictors of bacteremia outcome involving Escherichia coli (E. coli) and Klebsiella pneumoniae (K. pneumoniae) after initial empirical antimicrobial therapy among hematological malignancy cases.Methods: This retrospective study was conducted between April 2018 and April 2023. All bloodstream infections (BSIs) caused by E. coli and K. pneumoniae in hospitalized hematological malignancy (HM) patients were identified. Data on patient demographics, clinical characteristics, empirical antimicrobial treatment, outcomes and the antimicrobial susceptibility were collected from medical records. Multivariate analyses were utilized to assess the risk factors for all-cause mortality within 28 days and carbapenem resistance. Optimal cutoffs for continuous predictive variables were evaluated by receiver operating characteristic (ROC) curve analysis.Results: Among 61 individuals diagnosed with bacteremia, 39 cases were caused by E. coli bacteremia, while the remaining 22 were identified as K. pneumoniae bacteremia. Out of these, there were 10 cases of carbapenem-resistant Enterobacteriaceae (CRE) and 12 cases resulted in all-cause mortality within 28 days. Analysis indicated that Pitt score was an independent risk factor for mortality and a cut-off of 2.5 was a reliable predictor with 83.3% sensitivity and 85.7% specificity, respectively. Impaired mental status and elevated body temperature exceeding 38.6°C as well as a procalcitonin (PCT) level over 8.24 ng/mL on the third day (d3) after antimicrobial treatment were identified as independent risk factors for predicting carbapenem resistance.Conclusion: We found that Pitt score with a cut-off of 2.5 was a reliable predictor for mortality within 28 days in HM bacteremia cases. Impaired mental status and elevated temperature exceeding 38.6°C as well as a procalcitonin (PCT) level over 8.24 ng/mL on d3 after antimicrobial treatment were identified as predictive risk factors to carbapenem resistance.Keywords: antimicrobial resistance, mortality, risk factors, initial clinical response

Jing Liu,1,&ast; Zeyi Liang,1,&ast; Maocao Zhongla,2 Hongsheng Wang,3 Xu Sun,4 Juanshan Zheng,1 Xuezhi Ding,1 Feng Yang1 1Key Laboratory of New Animal Drug Project of Gansu Province/Key Laboratory of Veterinary Pharmaceutics Discovery, Lanzhou Institute of Husbandry and Pharmaceutical Sciences of Chinese Academy of Agricultural Science, Lanzhou, People’s Republic of China; 2Gannan Animal Disease Prevention and Control Center, Hezuo, People’s Republic of China; 3Xiangyang Vocational and Technical College, Xiangyang, People’s Republic of China; 4College of Life Sciences and Engineering, Lanzhou University of Technology, Lanzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Feng Yang; Xuezhi Ding, Lanzhou Institute of Husbandry and Pharmaceutical Sciences of Chinese Academy of Agricultural Science, No. 335 Jiangouyan, Qilihe District, Lanzhou, Gansu, 730050, People’s Republic of China, Tel +86-931-2115262, Fax +86-931-2114180, Email yangfeng@caas.cn; dingxuezhi@caas.cnPurpose: This study aimed to investigate the prevalence and genetic characterization of enterococcal isolates (Enterococcus faecalis, Enterococcus faecium and Enterococcus hirae) isolated from clinical bovine mastitis cases in Ningxia, China.Patients and Methods: The enterococci were identified by 16S rRNA amplification and sequencing. Antimicrobial resistance was determined by disc diffusion method. Virulence and antimicrobial resistance genes were detected by PCR assays.Results: Overall, 198 enterococcal isolates were identified from 2897 mastitis samples, including 137 (4.7%) E. faecalis, 50 (1.7%) E. faecium and 11 (0.4%) E. hirae. E. faecalis, E. faecium and E. hirae isolates showed high resistance to tetracycline (92.7%, 68.0%, 90.9%), followed by erythromycin (86.9%, 76.0%, 72.7%). The multidrug-resistant strains of E. faecalis and E. faecium were 29 (21.2%) and 13 (26.0%), respectively. The resistance of E. faecalis, E. faecium and E. hirae isolates to tetracycline is mainly attributed to the presence of tetL (alone or combined with tetM and/or tetK), the erythromycin resistance to ermB (alone or combined with ermC and/or ermA). Moreover, cpd (94.2%), gelE (77.4%), efaAfs (93.4%), and esp (79.6%) were the most common virulence genes in E. faecalis. In E. faecium, except for the gene efaAfs (82.0%), other virulence genes are rarely found. Only two strains of E. hirae carrying asa1 gene were detected.Conclusion: The results of this study can provide a reference for the prevention and treatment of bovine mastitis caused by enterococci.Keywords: bovine mastitis, enterococci, antimicrobial resistance, virulence

Yinfeng Chen,&ast; Xiaying Wang,&ast; Jie Min, Jie Zheng, Xuanli Tang, Xiaoling Zhu, Dongrong Yu, De Jin Department of Nephrology, Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, Zhejiang Province, 310007, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Dongrong Yu; De Jin, Department of Nephrology, Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, Zhejiang Province, 310007, People’s Republic of China, Email yudr68@163.com; 826901274@qq.comPurpose: This study investigated the mechanism of TSF in treating DN through network pharmacology, molecular docking, and experimental validation.Methods: To identify critical active ingredients, targets, and DN genes in TSF, multiple databases were utilized for screening purposes. The drug-compound-target network was constructed using Cytoscape 3.9.1 software for network topological analysis. The protein interaction relationship was analyzed using the String database platform. Metascape database conducted enrichment analysis on the key targets using Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes. The renoprotective effect was evaluated using a mouse model of diabetic nephropathy (db/db mice) that occurred spontaneously. Validation of the associated targets and pathways was performed using Western Blot (WB), Polymerase Chain Reaction (PCR), and Immunohistochemical methods (IHC).Results: The network analysis showed that the TSF pathway network targeted 24 important targets and 149 significant pathways. TSF might have an impact by focusing on essential objectives such as TP53, PTEN, AKT1, BCL2, BCL2L1, PINK-1, PARKIN, LC3B, and NFE2L2, along with various growth-inducing routes. Our findings demonstrated that TSF effectively repaired the structure of mitochondria in db/db mice. TSF greatly enhanced the mRNA levels of PINK-1. WB and IHC findings indicated that TSF had a notable impact on activating the PINK-1/PARKIN signaling pathway in db/db mice, significantly increasing LC3 and NRF2 expression.Conclusion: Our results indicate that TSF effectively addresses DN by activating the PINK-1/PARKIN signaling pathway and enhancing Mitochondrion structure in experimental diabetic nephropathy.Keywords: tangshen formula, diabetes nephropathy, network pharmacology, mitophagy, PINK1/Parkin pathway

Jie Bai,1 Jinxia Zheng,1 Nafei Guo,2 Yueyan Dong,1 Ke Wang,1 Cheng Cheng,3 Hui Jiang,2 Lin Qian4 1Shanghai Key Laboratory of Maternal-Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, People’s Republic of China; 2Nursing Department, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, People’s Republic of China; 3School of Nursing, Fudan University, Shanghai, People’s Republic of China; 4Nursing Department, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of ChinaCorrespondence: Hui Jiang, Nursing Department, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, People’s Republic of China, Tel/Fax +86 21-20261221, Email jianghuitest@163.com Lin Qian, Nursing Department, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China, Email lc699536@126.comPurpose: Receiving assisted reproductive technology is stressful due to its long-lasting process, which might pose negative impacts on clients’ psychological well-being and quality of life. This study was to investigate coping profiles among couples undergoing assisted reproductive technology and examine their associations with psychological distress and quality of life.Methods: This cross-sectional study was conducted at the IVF center of a specialized hospital in Shanghai, China. Of 502 eligible clients completed a structured, online survey of socio-demographic information, Dyadic Coping Inventory, Kessler Psychological Stress Scale, and Fertility quality of life. Coping profiles were identified using latent profile analysis and differences between identified profiles on psychological distress and quality of life were examined using analyses of covariance.Results: A three-profile solution was supported: low dyadic coping group (n = 168, 33.50%), moderate dyadic coping group (n = 241, 48.00%), and high dyadic coping group (n = 93, 18.50%). Significant differences between those groups were found in psychological distress and quality of life.Conclusion: The findings of this study have revealed dyadic coping profiles in clients undergoing assisted reproductive technology, which are differentially associated with psychological distress and quality of life.Keywords: assisted reproductive technology, coping, latent profile analysis, psychological distress, quality of life

Panpan Zi,1,&ast; Ming Fang,2,&ast; Hongfu Yang,1 Jiahao Zheng,3 Ning Ma,1 Qilong Liu1 1Department of Critical Care Medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, People’s Republic of China; 2Institute for Infection Disease Control, Shandong Center for Disease Control and Prevention, Jinan, People’s Republic of China; 3Institute of Animal Quarantine, Chinese Academy of Inspection and Quarantine, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Panpan Zi, Department of Critical Care Medicine, the First Affiliated Hospital of Zhengzhou University, No. 1 Longhu Zhonghuan Road, Jinshui District, Zhengzhou, Henan, People’s Republic of China, Tel +86-0371-66271356, Email zipanda123456@163.comPurpose: The continuous rise in carbapenemase-producing Enterobacteriaceae infections is a major public health concern. However, there is limited information available on New Delhi metallo-β-lactamase-1 (NDM-1) producing Citrobacter koseri. In this study, we isolated a blaNDM-1-carrying C. koseri from a stool sample of an inpatient. Our aim was to investigate the phenotypic and genomic features of this clinically derived carbapenem-resistant C. koseri isolate and to characterize the transmission pattern of the IncFII/IncN plasmid that carries the blaNDM-1 gene.Methods and Results: S1-PFGE, Southern blot and conjugation assay confirmed the presence of blaNDM-1 gene in a conjugative plasmid. C. koseri L2395 and transconjugant L2395-EC600 strains showed similar resistance spectrum. Whole-genome analysis revealed that pL2395_NDM is an IncFII/IncN plasmid with a length of 67,839 bp. Moreover, blaNDM-1 gene was found encoded in the ISKpn19-blaNDM-1-ble-tnpF-dsbD-cutA-ISKpn19 cassette array. Phylogenetic analysis revealed that strain L2395 was close to an IMP-4-bearing C. koseri from Australia.Conclusion: Ongoing surveillance will be essential to control and prevent the spread of carbapenem-resistant Citrobacter spp. in the future.Keywords: Citrobacter koseri, carbapenem-resistant, NDM-1, whole-genome sequencing

Xiaomei Jiang,1,&ast; Xiaohong Jiang,2,&ast; Dongjie Wu,1 Wanzhu Xie,3 Xiong Liu,1 Jintao Zheng4 1Department of Dermatology, Liuzhou Traditional Chinese Medicine Hospital, Liuzhou, 545001, People’s Republic of China; 2Department of Pharmacy, Shantou University Medical College, Shantou, 515041, People’s Republic of China; 3Department of Rehabilitation, Liuzhou Worker’s Hospital, Liuzhou, 545001, People’s Republic of China; 4Department of Biotechnology and Food Engineering, Guangdong Technology Israel Institute of Technology, Shantou, 515063, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jintao Zheng, Department of Biotechnology and Food Engineering, Guangdong Technology Israel Institute of Technology, Shantou, 515063, People’s Republic of China, Tel +86 156 2584 9047, Email jintao.zheng@gtiit.edu.cnBackground: Radiotherapy is a widely used clinical tool for tumor treatment but can cause systemic toxicity if excessive radiation is administered. Although numerous nanoparticles have been developed as radiosensitizers to reduce the required dose of X-ray irradiation, they often have limitations, such as passive reliance on radiation-induced apoptosis in tumors, and little consider the unique tumor microenvironment that contributes radiotherapy resistance.Methods: In this study, we developed and characterized a novel self-assembled nanoparticle containing dysprosium ion and manganese ion (Dy/Mn-P). We systematically investigated the potential of Dy/Mn-P nanoparticles (NPs) as a reactive oxygen species (ROS) amplifier and radiosensitizer to enhance radiation therapy and modulate the tumor microenvironment at the cellular level. Additionally, we evaluated the effect of Dy/Mn-P on the stimulator of interferon genes (STING), an innate immune signaling pathway.Results: Physicochemical analysis demonstrated the prepared Dy/Mn-P NPs exhibited excellent dispersibility and stability, and degraded rapidly at lower pH values. Furthermore, Dy/Mn-P was internalized by cells and exhibited selective toxicity towards tumor cells compared to normal cells. Our findings also revealed that Dy/Mn-P NPs improved the tumor microenvironment and significantly increased ROS generation under ionizing radiation, resulting in a ~70% increase in ROS levels compared to radiation therapy alone. This enhanced ROS generation inhibited ~92% of cell clone formation and greatly contributed to cytoplasmic DNA exposure. Subsequently, the activation of the STING pathway was observed, leading to the secretion of pro-inflammatory immune factors and maturation of dendritic cells (DCs).Conclusion: Our study demonstrates that Dy/Mn-P NPs can potentiate tumor radiotherapy by improving the tumor microenvironment and increasing endogenous ROS levels within the tumor. Furthermore, Dy/Mn-P can amplify the activation of the STING pathway during radiotherapy, thereby triggering an anti-tumor immune response. This novel approach has the potential to expand the application of radiotherapy in tumor treatment.Keywords: radiotherapy, Dy/Mn-P NPs, ROS, tumor microenvironment, STING pathway

Xianqing Hu,1 Yanjun Hu,1 Hai Wang,2 Caicha Yu,3 Jiayong Zheng,2 Hongping Zhang,1 Jianqiong Zheng1 1Department of Obstetrics and Gynecology, The Third Clinical Institute Affiliated to Wenzhou Medical University, Wenzhou People’s Hospital, Wenzhou Maternal and Child Health Care Hospital, Wenzhou, People’s Republic of China; 2Department of Fetal Medicine and Prenatal Diagnosis, The Third Clinical Institute Affiliated to Wenzhou Medical University, Wenzhou People’s Hospital, Wenzhou Maternal and Child Health Care Hospital, Wenzhou, People’s Republic of China; 3Department of Ultrasonography, The Third Clinical Institute Affiliated to Wenzhou Medical University, Wenzhou People’s Hospital, Wenzhou Maternal and Child Health Care Hospital, Wenzhou, People’s Republic of ChinaCorrespondence: Jianqiong Zheng; Hongping Zhang, Email zjq1980120@163.com; 413599343@qq.comObjective: This study aimed to assess the utility of chromosomal microarray analysis (CMA) and noninvasive prenatal testing (NIPT) in detecting clinically significant chromosomal abnormalities among fetuses presenting ultrasonic soft markers (USMs).Methods: A retrospective observational study, spanning from January 1, 2019, to September 30, 2022, enrolled 539 singleton pregnant women with fetal USMs at our center. Of these, 418 cases (77.6%) underwent NIPT, while 121 cases (22.4%) opted for invasive prenatal diagnosis post-appropriate genetic counseling. Cases with high-risk NIPT results proceeded to invasive prenatal diagnosis, where conventional karyotyping and CMA were concurrently performed. Further stratification was done based on the number of USMs, classifying cases into single-USM and multiple-USM groups.Results: Of the 24 cases (4.5%) exhibiting abnormal findings, 17 presented numerical chromosomal abnormalities, 2 featured clinically significant copy number variations (CNVs), 3 showed variants of unknown significance (VOUS), 1 displayed LOH, and 1 exhibited chromosome nine inversion. Notably, 18 cases (75%) theoretically detectable by karyotyping (eg, sizes above 10Mb) and 16 cases (66.7%) detectable by NIPT for five common aneuploidies were identified. Six submicroscopic findings (25%) were exclusively detectable by CMA. The predominant clinically relevant aberrations were observed in the thickened nuchal-translucency (TNT) group (9/35, 25.7%), followed by the multiple soft markers group (3/32, 9.3%). In the NIPT group, the false positive rate was 1.22%, and the false negative rate was 0%.Conclusion: The prevalence of chromosome aneuploidy exceeded that of submicroscopic chromosomal imbalance in pregnant women with fetal USMs. NIPT demonstrated efficacy, particularly for soft markers like echogenic intracardiac focus. However, for those with TNT and multiple soft markers, invasive prenatal diagnosis, including CMA testing, is recommended as the primary investigative approach.Keywords: chromosomal microarray analysis, karyotype, noninvasive prenatal testing, ultrasonic soft markers, prenatal diagnosis

Mengxiao Xie,1,&ast; Jian Liu,2,&ast; Jieyuan Zheng,1 Jingchao Wang,1 Dongsheng Han1,3,4 1Department of Laboratory Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 2Department of Intensive Care Unit, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 3Key Laboratory of Clinical in vitro Diagnostic Techniques of Zhejiang Province, Hangzhou, People’s Republic of China; 4Institute of Laboratory Medicine, Zhejiang University, Hangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Dongsheng Han, Department of Laboratory Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, People’s Republic of China, Email hands@zju.edu.cn; hands1103@163.comObjective: To understand the clinical features, diagnosis and treatment of Lemierre syndrome (LS), a high-risk and low-prevalence infectious disease.Methods: We present the severe LS case that was diagnosed using metagenomic next-generation sequencing (mNGS) in our hospital, and systematically summarized the diagnosis and treatment strategies of patients that reported LS from 2006 to 2022.Results: The 24-year-old patient in our hospital suffered from cranial nerve paralysis, a neurological complication rarely seen in LS cases. The causative agent (Fusobacterium necrophorum, Fn) of this patient was only detected by mNGS tests, and the reads number of Fn detected by plasma mNGS tests was decrease as the patients gradually improved, indicating plasma mNGS is valuable in monitoring treatment efficacy. Although most of the cases retrieved from the literature showed typical symptoms, such as a history of sore throat, septic emboli, and internal jugular vein thrombosis, clinical manifestations were still relatively heterogeneous (eg, diversity of predisposing factors and pathogens, differences in pulmonary imaging features).Conclusion: We summarized the clinical presentation, diagnosis, treatment, and regression of 17 symptomatic cases reported LS to provide clinicians with knowledge about this rare but fatal disease. mNGS assays should be considered as early as possible to identify the responsible pathogens for acute and critically ill patients with suspected infections in order to implement accurate and effective treatment.Keywords: lemierre syndrome, Fusobacterium necrophorum, metagenomic next-generation sequencing, thrombophlebitis, sepsis

Ying Yin,1 Ke Wang,1,2 Yan Xu,2,3 Xin Huang,1 Jinxia Zheng,1 Yuping Fan,1 Jie Bai1 1Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, 200092, People’s Republic of China; 2School of Medicine, Tongji University, Shanghai, 200092, People’s Republic of China; 3School of International Medical Technology, Sanda University, Shanghai, 201206, People’s Republic of ChinaCorrespondence: Ke Wang, Email wangkeyfy@126.comObjective: To analyze the mental health and erectile function status of men using sperm donor during pregnancy after ICSI failure in severe oligoasthenospermia and to provide reference for clinical implementation of more targeted psychological intervention and nursing for this group.Methods: A total of 410 sterile men who received assisted pregnancy treatment in our hospital from December 2020 to December 2022 and met the inclusion and exclusion criteria were collected as the study subjects. Among them, 68 patients with severe oligoasthenospermia who used donor assisted pregnancy after ICSI failure were used as the study group. Sixty-eight patients with severe oligoasthenospermia who continued to receive ICSI assisted pregnancy were matched by propensity score 1:1 as control group. General data questionnaire, self-rating Anxiety Scale (SAS), self-rating Depression Scale (SDS), Chinese version of perceived Stress Scale (CPSS) and International Erectile Function Index Rating Scale (IIEF-5) were used to conduct a cross-sectional investigation to compare the mental health and erectile function status of the two groups.Results: There were statistical differences in age and occupational status between the two groups before PSM (P < 0.05), but there was no statistical significance in social demographic data between the two groups after matching (P > 0.05). The incidence of anxiety, depression, stress and erectile dysfunction (ED) in the study group was higher than that in the control group, and there were statistical differences between the two groups (P < 0.05).Conclusion: The use of donor sperm to assist pregnancy has a great impact on the mental health and erectile function of infertile men. Medical personnel should pay attention to the mental health and erectile function of these men, and formulate targeted measures to help these patients actively cope with infertility, so as to improve the life and marriage quality of this group and improve their mental health status.Keywords: sterile male, supply semen, erectile function, mental health, propensity score

ObjectivesThe majority of patients with respiratory illness are seen in primary care settings. Given COVID-19 is predominantly a respiratory illness, the INTernational ConsoRtium of Primary Care BIg Data Researchers (INTRePID), assessed the pandemic impact on primary care visits for respiratory illnesses.DesignDefinitions for respiratory illness types were agreed on collectively. Monthly visit counts with diagnosis were shared centrally for analysis.SettingPrimary care settings in Argentina, Australia, Canada, China, Norway, Peru, Singapore, Sweden and the United States.ParticipantsOver 38 million patients seen in primary care settings in INTRePID countries before and during the pandemic, from January 1st, 2018, to December 31st, 2021.Main outcome measuresRelative change in the monthly mean number of visits before and after the onset of the pandemic for acute infectious respiratory disease visits including influenza, upper and lower respiratory tract infections and chronic respiratory disease visits including asthma, chronic obstructive pulmonary disease, respiratory allergies, and other respiratory diseases.ResultsINTRePID countries reported a marked decrease in the average monthly visits for respiratory illness. Changes in visits varied from −10.9% [95% confidence interval (CI): −33.1 to +11.3%] in Norway to −79.9% (95% CI: −86.4% to −73.4%) in China for acute infectious respiratory disease visits and − 2.1% (95% CI: −12.1 to +7.8%) in Peru to −59.9% (95% CI: −68.6% to −51.3%) in China for chronic respiratory illness visits. While seasonal variation in allergic respiratory illness continued during the pandemic, there was essentially no spike in influenza illness during the first 2 years of the pandemic.ConclusionThe COVID-19 pandemic had a major impact on primary care visits for respiratory presentations. Primary care continued to provide services for respiratory illness, although there was a decrease in infectious illness during the COVID pandemic. Understanding the role of primary care may provide valuable information for COVID-19 recovery efforts and planning for future global emergencies.

Xi Yang,1 Linlin Wen,1 Jinqian Zheng,1 Huijuan Nie,1 Shengli Liu,1 Chengqun Chen,1 Fangying Si,1 Xiaojian Zhang,1,2 Jian Kang,1,2 Shuzhang Du,1 Zhao Yin1 1Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People’s Republic of China; 2Henan Drug Clinical Comprehensive Evaluation Center, Zhengzhou, People’s Republic of ChinaCorrespondence: Zhao Yin; Shuzhang Du, Email yinzhao0601@163.com; dushuzhang911@163.comObjective: The study explores the psychological state and related influences of hospital pharmacists enclosed in extreme work environments in the post-epidemic era, and also explores potential measures to alleviate negative emotions.Methods: An embedded mixed research methodology was used. In the qualitative research phase, semi-structured interviews were carried out with 30 pharmacists consistently confined to their work environments. The data were managed and analyzed using NVivo12 software. In the quantitative research phase, 146 pharmacists with experience in extreme work environments were selected, and the data were collected through questionnaires (GAD-7 and CD-RISC-25) and self-administered questions generated during the qualitative phase. The Shapiro–Wilk test was utilized to assess data normality. Spearman correlation was conducted to evaluate correlations among self-designed questions, resilience, and anxiety.Results: The results from interviews with 30 pharmacists revealed four factors influencing the psychological state of pharmacists in the post-epidemic era: personal factors, interpersonal relationships, environmental factors, and policy and public opinion. Mitigation measures for negative emotions encompass material security, life adjustment, epidemic prevention policy, public opinion information, and organizational management. The results of a quantitative study of 146 pharmacists showed that only 1% had severe anxiety, but the psychological resilience scores were generally low, and 62% had poor psychological resilience, with scores below 73. Simultaneously, it was observed that, except religious beliefs, factors influencing psychological status in extreme work environments were significantly negatively correlated with personal anxiety levels and significantly positively correlated with psychological resilience.Conclusion: Our study holds significance in unraveling the psychological aspects of pharmacists as healthcare workers. It also offers insights into how healthcare organizations respond to the negative emotions experienced by healthcare workers in emergencies or extreme environments.Keywords: mixed study, hospital pharmacists, post-pandemic era, psychological state

Jiayi Yang,&ast; Lihong Chen,&ast; Ruofei Shi, Xiaoqing Zhao, Meng Pan, Jie Zheng Department of Dermatology, School of Medicine, Ruijin Hospital, Shanghai Jiao Tong University, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Meng Pan, Email pm10633@rjh.com.cnBackground: Cytophagic histiocytic panniculitis (CHP) is a rare form of nodular panniculitis characterized by clinical manifestations such as skin erythema, nodules, fever, pancytopenia, liver failure, plasmacytosis, and hepatosplenomegaly. We report a case of CHP that was initially misdiagnosed as subcutaneous panniculitis-like T-cell lymphoma (SPTCL) but achieved complete remission with a favorable prognosis.Methods: A 38-year-old female presented to the dermatology department with a 15-day history of subcutaneous nodules, generalized edema, and continuous fever.Results: The patient was diagnosed as CHP combined with hemophagocytic syndrome by typical clinical manifestations, low value of SUVmax in positron emission tomography/computed tomography (PET/CT), benign differentiated T cells, negative TCR gene rearrangement, pancytopenia, abnormal coagulation, hypertriglyceridemia, decreased NK cell count, impaired liver function, and the presence of hemophagocytic cells observed in bone biopsy smears.Conclusion: In our case, the patient presented with hemophagocytic syndrome with hemodynamic instability, indicating an intensive treatment is needed. The diagnosis of SPTCL necessitates a meticulous process of differential diagnosis, along with the cautious administration of an aggressive chemotherapy regimen. Extended follow-up is imperative to ascertain the long-term outcomes.Keywords: cytophagic histiocytic panniculitis, SPTCL, HLH

Junwei Zheng,1,2 Yan Mi,3 Jinghan Liang,1 Huili Li,1 Peiqi Shao,1 Hong Wen,1 Yun Wang1 1Department of Anesthesiology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Department of Anesthesiology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei Province, People’s Republic of China; 3Department of Anesthesiology, Tumour Hospital, Zhengzhou University, Zhengzhou, Henan Province, People’s Republic of ChinaCorrespondence: Yun Wang; Hong Wen, Department of Anesthesiology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, People’s Republic of China, Tel +86-10-85231330, Fax +86-10-65077808, Email wangyun129@ccmu.edu.cn; wendoctorhong@sina.comPurpose: Total hip arthroplasty (THA) is often associated with moderate to severe pain. The present study compared the efficacy of circum-psoas block (CPB) with supra-inguinal fascia iliaca block (SIFIB) for postoperative analgesia in patients undergoing THA.Patients and Methods: In this randomized trial, sixty-four patients undergoing THA were allocated randomly to the CPB group or SIFIB group with 40 mL of 0.3% ropivacaine. The primary outcome was dynamic pain score at 6 h postoperatively. Secondary outcomes included dynamic pain scores at 12, 24 and 48 h; static pain scores; sensory and motor block; opioid consumption; time to first opioid request; length of hospital stay; patient satisfaction; and adverse events.Results: CPB patients showed significantly lower dynamic pain scores at 6 (3.11 ± 0.66 vs 4.47 ± 0.74, respectively; P = 0.000), 12 (2.52 ± 0.73 vs 3.53 ± 0.85, respectively; P = 0.000) and 24 h (2.30 ± 0.57 vs 2.87 ± 0.71, respectively; P = 0.001) after surgery, as well as lower static pain scores at 6 and 12h (P = 0.001 and P = 0.033 respectively) than SIFIB patients. Lower opioid consumption was observed in the CPB group at 24 and 48 h (P = 0.000, both) than in the SIFIB group. Patients in the CPB group reported improved quadriceps strength at 6 and 12 h (P = 0.000, both), as well as better muscle strength of hip flexion at 6, 12 and 24 h (P = 0.000, P = 0.000 and P = 0.025 respectively). Compared with SIFIB, CPB was associated with increased sensory block coverage at 6, 12 and 24 h (P = 0.000, P = 0.000, and P =0.022, respectively).Conclusion: CPB has a greater potential to alleviate postoperative pain and improve recovery in THA patients than SIFIB.Keywords: total hip arthroplasty, lumbar plexus, sacral plexus, regional anesthesia

BackgroundThe COVID-19 pandemic has reshaped healthcare delivery worldwide.ObjectiveTo explore potential changes in the reasons for visits and modality of care in primary care settings through the International Consortium of Primary Care Big Data Researchers (INTRePID).MethodsWe conducted a cross-sectional, retrospective study from 2018-2021. We examined visit volume, modality, and reasons for visits to primary care in Argentina, Australia, Canada, China, Peru, Norway, Singapore, Sweden, and the USA. The analysis involved a comparison between the pre-pandemic and pandemic periods.ResultsThere were more than 215 million visits from over 38 million patients during the study period in INTRePID primary care settings. Most INTRePID countries experienced a decline in monthly visit rates during the first year of the pandemic, with rate ratios (RR) and 95% confidence intervals (CI) ranging from RR:0.57 (95%CI:0.49-0.66) to RR:0.90 (95%CI:0.83-0.98), except for in Canada (RR:0.99, 95%CI:0.94-1.05) and Norway (RR:1.00, 95%CI:0.92-1.10), where rates remained stable and in Australia where rates increased (RR:1.19, 95%CI:1.11-1.28). Argentina, China, and Singapore had limited or no adoption of virtual care, whereas the remaining INTRePID countries varied in the extent of virtual care utilization. In Peru, virtual visits accounted for 7.34% (95%CI:7.33%-7.35%) of all interactions in the initial year of the pandemic, dipping to 5.22% (95%CI:5.21%-5.23%) in the subsequent year. However, in Canada 75.30% (95%CI:75.20%-75.40%) of the visits in the first year were virtual, decreasing to 62.77% (95%CI:62.66%-62.88%) in the second year. Diabetes, hypertension and/or hyperlipidemia and general health exams were in the top 10 reasons for visits in 2019 for all countries. Anxiety, depression and/or other mental health related reasons were among the top 10 reasons for virtual visits in all countries that had virtual care.ConclusionsThe pandemic resulted in changes in reasons for visits to primary care, with virtual care mitigating visit volume disruptions in many countries.

Renke Chen,1,&ast; Mengxiao Xie,2,&ast; Shenlong Wang,1 Fei Yu,2– 4 Dan Zhang,2– 4 Lingjun Yuan,2 Jieyuan Zheng,2 Jingchao Wang,2 Jieting Zhou,2 Binxiao Li,2 Shufa Zheng,2– 4 Yongsheng Fan,1 Dongsheng Han2– 4 1The First Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China; 2Department of Laboratory Medicine, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 3Key Laboratory of Clinical in vitro Diagnostic Techniques of Zhejiang Province, Hangzhou, People’s Republic of China; 4Institute of Laboratory Medicine, Zhejiang University, Hangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Dongsheng Han, Centre of Clinical Laboratory, First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, 310003, People’s Republic of China, Email hands@zju.edu.cn Yongsheng Fan, School of Basic Medical Sciences, Zhejiang Chinese Medical University, 548 Binwen Road, Hangzhou, 310053, People’s Republic of China, Email fyszjtcm@163.comBackground: Metagenomic next-generation sequencing (mNGS) is a promising tool for improving antimicrobial therapy and infection control decision-making in complex infections. Secondary infection surveillance using mNGS in COVID-19 patients has rarely been reported.Methods: Respiratory pathogen and antibiotic resistance prediction were evaluated by BALF mNGS for 192 hospitalized COVID-19 patients between December 2022 and February 2023.Results: Secondary infection was confirmed in 83.3% (160/192) of the COVID-19 patients, with bacterial infections (45%, 72/160) predominating, followed by mixed bacterial and fungal infections (20%, 32/160), and fungal infections (17.5%, 28/160). The incidence of bacterial or viral secondary infection was significantly higher in patients who were admitted to the ICU, received mechanical ventilation, or developed severe pneumonia (all p< 0.05). Klebsiella pneumoniae (n=30, 8.4%) was the most prevalent pathogen associated with secondary infection followed by Acinetobacter baumannii (n=29, 8.1%), Candida albicans (n=29, 8.1%), Aspergillus fumigatus (n=27, 7.6%), human herpes simplex virus type 1 (n=23, 6.4%), Staphylococcus aureus (n=20, 5.6%) and Pneumocystis jiroveci (n=14, 3.9%). The overall concordance between the resistance genes detected by mNGS and the reported phenotypic resistance in 69 samples containing five clinically important pathogens (ie, K. pneumoniae, A. baumannii, S. aureus, P. aeruginosa and E. coli) that caused secondary infection was 85.5% (59/69).Conclusion: mNGS can detect pathogens causing secondary infection and predict antimicrobial resistance for COVID19 patients. This is crucial for initiating targeted treatment and rapidly detect unsuspected spread of multidrug-resistant pathogens.Keywords: COVID-19, SARS-CoV-2, metagenomic next-generation sequencing, antibiotic resistance

Abstract Macrophages (MΦ) play a role in neonatal etiologies of obstructive cholestasis, however, the role for precise MΦ subsets remains poorly defined. We developed a neonatal murine model of bile duct ligation (BDL) to characterize etiology-specific differences in neonatal cholestatic MΦ polarization. Neonatal BDL surgery was performed on female BALB/c mice at 10 days of life (DOL) with sham laparotomy as controls. Comparison was made to the Rhesus Rotavirus (RRV)-induced murine model of biliary atresia (BA). Evaluation of changes at day 7 after surgery (BDL and sham groups) and murine BA (DOL14) included laboratory data, histology (H&E, anti-CD45 and anti-CK19 staining), flow cytometry of MΦ subsets by MHCII and Ly6c expression, and single cell RNA-sequencing (scRNA-seq) analysis. Neonatal BDL achieved a 90% survival rate; mice had elevated bile acids, bilirubin, and alanine aminotransferase (ALT) versus controls (p

Ziyu Guo,1 Yanxiang Gao,2 Enmin Xie,3 Zixiang Ye,1 Yike Li,3 Xuecheng Zhao,2 Nan Shen,1 Jingang Zheng1– 3 1Department of Cardiology, Peking University China-Japan Friendship School of Clinical Medicine, Beijing, People’s Republic of China; 2Department of Cardiology, China-Japan Friendship Hospital, Beijing, People’s Republic of China; 3Graduate School of Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of ChinaCorrespondence: Jingang Zheng, Department of Cardiology, China-Japan Friendship Hospital, Beijing, 100029, People’s Republic of China, Tel +86 18810966781, Email mdjingangzheng@yeah.netPurpose: The pandemic of coronavirus disease 2019 (COVID-19) has highlighted the intricate relationship between underlying conditions and death. We designed this study to determine whether metformin therapy for type 2 diabetes mellitus (T2D) is associated with low in-hospital mortality in patients hospitalized for COVID-19.Materials and Methods: This was a retrospective study including patients with COVID-19 and T2D in Wuhan, from February 4th to April 11th, 2020. Patients were divided into two groups according to metformin exposure. The hazard ratio (HR) of COVID-19-related mortality and invasive mechanical ventilation was estimated using Cox regression.Results: There were 571 T2D patients among the 4330 confirmed COVID-19 patients. Of those patients, 241 received metformin therapy. The in-hospital mortality and invasive mechanical ventilation of metformin group was lower than non-metformin group. In the multivariate model, metformin use was linked to a decreased in-hospital mortality and invasive mechanical ventilation when compared with that of the control group (HR: 0.376 [95% CI 0.154– 0.922]; P = 0.033).Conclusion: Our study indicated that metformin therapy was associated with decreased death risk in COVID-19 patients with T2D.Keywords: COVID-19, diabetes mellitus, metformin, mortality

Xiaochong Li,1,&ast; Bowen Hu,1,&ast; Jiachen Zheng,2,3 Zhiyong Pan,1 Yuxiang Cai,4 Mingjuan Zhao,1 Xiaoqing Jin,2 Zhi-Qiang Li1 1Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, 430071, People’s Republic of China; 2Emergency Center, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, 430071, People’s Republic of China; 3The Second Clinical School, Wuhan University, Wuhan, Hubei, 430071, People’s Republic of China; 4Department of Pathology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, 430071, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiaoqing Jin; Zhi-Qiang Li, Email redjin@whu.edu.cn; lizhiqiang@whu.edu.cnIntroduction: Temozolomide (TMZ) induces intestinal mucosa injury that cannot be fully counteracted by supportive treatment. Probiotics regulate gut microbial composition and the host immune system and may alleviate this side effect. We aimed to investigate the potential and mechanism of Lactobacillus rhamnosus GG (LGG) in relieving intestinal mucosal injury induced by TMZ.Methods: Glioblastoma mice were divided into four groups: CON (control), LGG (109 CFU/mL, treated for 7 days), TMZ (50 mg/kg·d, treated for 5 days), LGG+TMZ (LGG for 7 days and TMZ subsequently for 5 days). Body weight, food intake, and fecal pH were recorded. Intestinal tissue samples were collected 1 day after the end of TMZ treatment. Degree of damage to intestine, expression of IL1β, IL6, TNFα, and IL10 in jejunum were determined. Levels of tight-junction proteins (ZO1, occludin), TLR4, IKKβ, IκBα, and P65 with their phosphorylation in jejunum were measured.Results: Decreases in body weight, food intake, spleen index in the TMZ group were mitigated in the LGG+TMZ group, and the degree of intestinal shortening and damage to jejunum villus were also alleviated. The expression of tight-junction proteins in the LGG+TMZ group was significantly greater than that in the TMZ group. IκBα in intestinal tissue significantly decreased in the TMZ group, phos–IKKβ and phos-P65 increased compared to the CON group, and LGG reversed such changes in IκBα and phos-P65 in the LGG+TMZ group. Intestinal inflammatory cytokines were significantly increased in the TMZ group, but lower in the LGG+TMZ group. Moreover, expression of TLR4 in LGG group was significantly lower than that in the CON group. LGG inhibited the rise of TLR4 after TMZ in the LGG+TMZ group compared to the TMZ group.Conclusion: LGG inhibits the activation of the TLR4–NFκB pathway and alleviates intestinal mucosal inflammation induced by TMZ, thereby protect the jejunum villi and mucosal physical barrier.Keywords: Lactobacillus rhamnosus GG, temozolomide, intestinal mucosal injury, TLR4, NFκB

Songtao Yang,1,2 Jiaoyue Zhang,1,2 Tianshu Zeng,1,2 Juan Zheng,1,2 Jie Min,1,2 Lulu Chen1,2 1Department of Endocrinology, Union Hospital, Huazhong University of Science and Technology Tongji Medical College, Wuhan, Hubei, People’s Republic of China; 2Hubei Provincial Clinical Research Center for Diabetes and Metabolic Disorders, Wuhan, Hubei, People’s Republic of ChinaCorrespondence: Lulu Chen, Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China, Email cheria_chen@126.comBackground: Diabetic retinopathy (DR) remains as the most frequent complication of diabetes, and is the major cause of vision loss for middle-aged to elderly people. With longer life expectancies for people with diabetes, there is a significant rise in diabetic retinopathy worldwide. The treatment of DR is limited; and therefore, our study aimed to investigate the possibilities of circulating exosomal miRNAs in the early screening and prevention of DR; and to explore the function of the exosomal miRNAs in DR.Materials and Methods: Eighteen participants were recruited and divided into two groups: the diabetes mellitus (DM) group and the DR group. We analyzed the expression profile of exosomal miRNAs derived from serum using RNA sequencing. Additionally, we conducted co-culture experiments of RGC-5 and HUVEC cells with DR-derived exosomes to examine the role of highly expressed exosomal miRNA-3976 in DR. Furthermore, we transfected RGC-5 and HUVEC cells with miRNA-3976 to investigate its effects.Results: Among the 1059 miRNAs analyzed, we identified eighteen up-regulated exosomal miRNAs. Treatment with DR-derived exosomes resulted in increased proliferation and reduced apoptosis of RGC-5 cells, and these effects were partially reversed by the miRNA-3976 inhibitor. Moreover, over-expression of miRNA-3976 led to increased apoptosis of RGC-5 cells and indirectly reduced the abundance of NFκB1.Conclusion: Serum-derived exosomal miRNA-3976 has the potential to serve as a biomarker for DR, primarily exerting its effects in the early stages of DR through the regulation of NFκB-associated mechanisms.Keywords: exosomes, miRNAs, diabetes, diabetic retinopathy

Jicheng Jia,1,2 Yongchao Ma,3 Shengnan Xu,1 Jiaqi Zheng,2 Xinli Ma,2 Yuzhen Zhang,2 Weijuan Sun,2 Lizhi Liu2 1Department of Education, The National University of Malaysia, Kuala Lumpur, Malaysia; 2Department of Talent Development and Continuing Education, Shandong Shengli Vocational College, Dongying, Shandong, People’s Republic of China; 3Computer Science, North Dakota State University, Fargo, ND, USACorrespondence: Jicheng Jia, Tel +86 15689138097, Email wabajjc@163.comObjective: This study aimed to investigate the impact of academic self-efficacy on test anxiety among higher vocational students, as well as the role of sense of life meaning, fear of failure, and gender difference in mediating this relationship.Methods: A total of 2231 higher vocational students from Shandong Province were surveyed by means of Academic Self-efficacy Questionnaire, Meaning in Life Questionnaire, and Test Anxiety Scale.Results: There were significant negative correlations among academic self-efficacy, sense of life meaning, and test anxiety. Fear of failure was positively correlated with test anxiety. Sense of life meaning and fear of failure played a mediating role in the relationship between academic self-efficacy and test anxiety. The chain mediating effect was significant only in the female group, not in the male group. In contrast, academic self-efficacy indirectly predicted test anxiety by the independent mediating effect of sense of life meaning or fear of failure in the male group.Conclusion: Academic self-efficacy may influence test anxiety through the independent mediating effect of sense of life meaning, fear of failure, and the chain mediating effect, and there is a gender difference in these effects.Keywords: higher vocational students, academic self-efficacy, sense of life meaning, fear of failure, test anxiety

Min Wang,1,2,&ast; Na Yang,1,2,&ast; Xu Wu,3 Ting Zou,3 Jiahui Zheng,3 Huaijun Zhu,1 Chongbo Zhao,3 Jing Wang3 1Department of Pharmacy, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, People’s Republic of China; 2China Pharmaceutical University Nanjing Drum Tower Hospital, Nanjing, People’s Republic of China; 3College of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Chongbo Zhao; Jing Wang, College of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang, People’s Republic of China, Email 2051077@sntcm.edu.cn; wangjing19890126@126.comBackground: Arisaematis Rhizome (AR) has been used as a damp-drying, phlegm-resolving, wind-expelling, pain-alleviating, and swelling-relieving drug for thousands of years. However, the toxicity limits its clinical applications. Therefore, AR is usually processed (Paozhi in Chinese) prior to clinical use. In this study, the integration of ultra-high performance liquid chromatography-quadrupole/ time-of-flight mass spectrometry-based metabolomics and network analysis was adopted to investigate the metabolic shifts induced by AR and explore the processing mechanism.Materials and Methods: Extracts of crude and processed AR products (1g/kg) were intragastrically administered to rats once daily for four consecutive weeks. The renal function was evaluated by blood urea nitrogen, creatinine, interleukin-1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α), malondialdehyde (MDA), super oxide dismutase (SOD), the ratio of glutathione/glutathione disulfide (GSH/GSSH), glutathione peroxidase (GSH-Px) and histopathological examination. Furthermore, the chemical composition of AR was clarified by ultra-high performance liquid chromatography-quadrupole/ time-of-flight mass spectrometry, after which the integration of metabolomics and network analysis was adopted to investigate the metabolic shifts induced by AR and explore the processing mechanism.Results: Crude AR caused renal damage by stimulating inflammation and oxidative stress, as confirmed by the increased production of IL-1β, TNF-α and MDA, and decreased levels of SOD, GSH/GSSH and GSH-Px. Processing with ginger juice, alumen and bile juice alleviated the damage to kidney. Metabolomics results showed that a total of 35 potential biomarkers enriched in amino acid metabolism, glycerophospholipid metabolism, fatty acid-related pathways, etc. were deduced to be responsible for the nephrotoxicity of AR and the toxicity-reducing effect of processing.Conclusion: This work provided theoretical and data support for the in-depth study of the processing mechanism, showing that processing reduces AR nephrotoxicity through multiple metabolic pathways.Graphical Abstract: Keywords: Arisaematis rhizome, nephrotoxicity, processing, UPLC-Q/TOF-MS, metabolomics

Shan Jiang,1,2 Zhaolei Cui,3 Jianfeng Zheng,1 Qiaoling Wu,1 Haijuan Yu,1 Yiqing You,3 Chaoqiang Zheng,3 Yang Sun1 1Department of Gynecology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, 350014, People’s Republic of China; 2College of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, 350122, People’s Republic of China; 3Laboratory of Biochemistry and Molecular Biology Research, Department of Clinical Laboratory, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, 350014, People’s Republic of ChinaCorrespondence: Yang Sun, Department of Gynecology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, No. 420 Fuma Road, Fuzhou, Fujian, 350014, People’s Republic of China, Email sunyang@fjzlhospital.comBackground: Immunogenic cell death (ICD) can reshape the immune microenvironment of tumors. Driven by stressful pressure, by directly destroying tumor cells and activating the body’s adaptive immunity, ICD acts as a modulator of cell death, enabling the body to generate an anti-tumor immune response that produces a more effective therapeutic effect, while tumor cells are driven to kill. Hence, this research aimed to find and evaluate ICD-related genetic signatures as cervical cancer (CC) prognostic factors.Methods: Data of CC patients from the Tumor Genome Atlas (TCGA) were used as the basis to obtain immunogenic cell-death-related prognostic genes (IPGs) in patients with CC, using the least absolute shrinkage and selection operator and Cox regression screening, and the IPGs scoring system was constructed to classify patients into high- and low-risk groups, with the Gene Expression Omnibus (GEO) dataset as the validation group. Finally, the difference analysis of single-sample gene set enrichment analysis, tumor microenvironment (TME), immune cells, tumor mutational burden, and chemotherapeutic drug sensitivity between the high-risk and low-risk groups was investigated.Results: A prognostic model with four IPGs (PDIA3, CASP8, IL1, and LY96) was developed, and it was found that the group of CC patients with a higher risk score of IPGs expression had a lower survival rate. Single and multifactor Cox regression analysis also showed that this risk score was a reliable predictor of overall survival. In comparison to the low-risk group, the high-risk group had lower TME scores and immune cell infiltration, and gene set variation analysis showed that immune-related pathways were more enriched in the high-risk group.Conclusion: A risk model constructed from four IPGs can independently predict the prognosis of CC patients and recommend more appropriate immunotherapy strategies for patients.Keywords: ICD, cervical cancer, immunity, prognosis, immunotherapy response

Zeyi Liang,&ast; Jiahao Shen,&ast; Jing Liu, Xu Sun, Yayuan Yang, Yanan Lv, Juanshan Zheng, Xiaoqing Mou, Hongsheng Li, Xuezhi Ding, Feng Yang Key Laboratory of New Animal Drug Project of Gansu Province/Key Laboratory of Veterinary Pharmaceutics Discovery, Lanzhou Institute of Husbandry and Pharmaceutical Sciences of Chinese Academy of Agricultural Science, Lanzhou, Gansu, 730050, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Feng Yang; Xuezhi Ding, Lanzhou Institute of Husbandry and Pharmaceutical Sciences of Chinese Academy of Agricultural Science, No. 335 Jiangouyan, Qilihe District, Lanzhou, Gansu, 730050, People’s Republic of China, Tel +86-931-2115262, Fax +86-931-2114180, Email yangfeng@caas.cn; dingxuezhi@caas.cnPurpose: This study aimed to investigate the prevalence and genetic characterization of Serratia marcescens isolates from clinical bovine mastitis in Ningxia Hui Autonomous Region of China.Methods: S. marcescens was identified by the polymerase-chain reaction of 16S rRNA gene and sequencing. Antimicrobial susceptibility was tested by the disk diffusion method. Genes of resistance and virulence were determined by the PCR.Results: Overall, S. marcescens were confirmed from 32 of 2897 (1.1%) mastitis milk samples. These isolates showed high resistance to cefazolin (30/32, 93.8%) and chloramphenicol (28/32, 87.5%). A 12.5% (4/32) of the isolates displayed multidrug resistance (MDR). The most prevalent resistant genes found in S. marcescens were TEM (32/32, 100%) and CTX-M (24/32, 75.0%; CTX-M-15, 14/32, 43.8%; CTX-M-14, 8/32, 25.0%; CTX-M-65, 2/32, 6.3%) for extended-spectrum beta-lactamase, cmlA (28/32, 87.5%) and floR (16/32, 50.0%) for chloramphenicol resistance, SIM-1 (2/32, 6.3%) for carbapenemases, and sdeB (28/32, 87.5%), sdeY (26/32, 81.3%), sdeR (26/32, 81.3%) and sdeD (20/32, 62.5%) for efflux pumps. Moreover, all isolates carried virulence genes flhD, entB, and kpn, and most of them contained mrkD (30/32, 93.8%), ycfM (26/32, 81.3%), bsmB (26/32, 81.3%), pigP (26/32, 81.3%), kfu (24/32, 75.0%) and shlB (24/32, 75.0%).Conclusion: To our knowledge, this is the first report of genetic determinants for antimicrobial resistance and virulence in S. marcescens isolated from bovine mastitis cases in China. These findings are useful for developing strategies for prevention and treatment of bovine mastitis caused by S. marcescens in China.Keywords: Serratia marcescens, bovine mastitis, antimicrobial resistance, virulence

Qian Zhang,1,2 Pan Fu,2 Zhanglei Cao,2 Hua Huang,3 Qinwen Wen,3 Kaizhe Wang,2 Tong Kong,2 Xiudi Wu,3 Jianping Zheng2 1Jiangxi Key Laboratory for Rare Earths Magnetic Materials and Devices, College of Rare Earths, Jiangxi University of Science and Technology, Ganzhou, 341000, People’s Republic of China; 2Cixi Institute of Biomedical Engineering, Ningbo Institute of Materials Technology & Engineering, Chinese Academy of Sciences (CAS), Ningbo, 315300, People’s Republic of China; 3Department of Rheumatology and Immunology, Ningbo First Hospital, Ningbo, 315010, People’s Republic of ChinaCorrespondence: Jianping Zheng; Xiudi Wu, Tel +86– 18091984088 ; +86– 13857826442, Email zhengjianping@nimte.ac.cn; awu1100@aliyun.comPurpose: Methotrexate (MTX) is used as an anchor drug for the treatment of rheumatoid arthritis (RA) and there may be differences in drug action between genotypes. The purpose of this study was to investigate the relationship between clinical efficacy response and disease activity of MTX monotherapy with methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) polymorphisms.Patients and Methods: In the study, a population of 32 patients in East China with early RA fulfilling the diagnostic standards of the American College of Rheumatology (ACR) were enrolled, all of them received MTX monotherapy. Genotyping of patients MTHFR C677T and A1298C, MTRR A66G using tetra-primer ARMS-PCR method and sanger sequencing to verify its accuracy.Results: The distribution of three polymorphic genotypes that were studied is in accordance with the Hardy-Weinberg genetic equilibrium. The patient pathology variables smoke (OR = 0.088, P = 0.037), drink alcohol (OR = 0.039, P = 0.016) and males (OR = 0.088, P = 0.037) were significantly associated with non-response to MTX. Genotype, allele distribution and genetic statistical models were not found to be related to MTX treatment response and disease activity in both the response groups and non-response groups.Conclusion: Our findings suggest that the MTHFR C677T, MTHFR A1298C and MTRR A66G polymorphisms may not predict MTX clinical treatment response and disease activity in patients with early RA. The study revealed that smoke, alcohol, and males were possible influential factors for MTX non-response.Keywords: MTHFR, MTRR, methotrexate, rheumatoid arthritis, DAS28

Wei Sun,1,2,&ast; Songyi Xu,3,&ast; Tianlun Shen,1,3,&ast; Guangyao Li,1 Jingfeng Zhang,2 Chunshu Pan,1,2 Wei Lu,1,2 Xiangrui Liu,1 Jianjun Zheng,2 Jun Ling,1,3 Jihong Sun1 1Department of Radiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 2Department of Radiology, Ningbo No. 2 Hospital, Ningbo, People’s Republic of China; 3MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jihong Sun, Department of Radiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Tel +86 13857176538, Email sunjihong@zju.edu.cn Jianjun Zheng, President of Ningbo No. 2 Hospital, Ningbo, People’s Republic of China, Tel +86 574 83870280, Email zhjjnb2@163.comPurpose: Chemotherapy treatments for cancer are always accompanied by a low concentration of drug delivered in the tumor area and severe side effects including systemic toxicity. Improving the concentration, biocompatibility, and biodegradability of regional chemotherapy drugs is a pressing challenge in the field of materials.Methods: N-Phenyloxycarbonyl-amino acids (NPCs) which exhibit significant tolerance to nucleophiles, such as water and hydroxyl-containing compounds, are promising monomers for the synthesis of polypeptides and polypeptoids. Cell line and mouse models were used to comprehensively explore how to enhance the tumor MRI signal and evaluate the therapeutic effect of Fe@POS-DOX nanoparticles.Results: In this study, poly(3,4-dihydroxy-L-phenylalanine)-b-polysarcosine (PDOPA-b-PSar, simplified as POS) was synthesized by the block copolymerization of DOPA-NPC with Sar-NPC. Fe@POS-DOX nanoparticles were prepared in order to utilize the strong chelation of catechol ligands to iron (III) cations and the hydrophobic interaction between DOX and DOPA block to deliver chemotherapeutics to tumor tissue. The Fe@POS-DOX nanoparticles exhibit high longitudinal relaxivity (r1 = 7.06 mM− 1·s− 1) and act as T1-weighted magnetic resonance (MR) imaging contrast agents. Further, the main focus was improving tumor site-specific bioavailability and achieving therapeutic effects through the biocompatibility and biodegradability of Fe@POS-DOX NPs. The Fe@POS-DOX treatment exhibited excellent antitumor effects.Conclusion: Upon intravenous injection, Fe@POS-DOX delivers DOX specifically to the tumor tissues, as revealed by MR, and leads to the inhibition of tumor growth without overt toxicity to normal tissues, thus displaying considerable potential for use in clinical applications.Graphical Abstract: Keywords: poly (α-amino acid)s, polypeptides, polypeptoids, MRI, chemotherapy, nanoparticles

Even when successfully induced, immunological tolerance to solid organs remains vulnerable to inflammatory insults, which can trigger rejection. In a mouse model of cardiac allograft tolerance in which infection with Listeria monocytogenes (Lm) precipitates rejection of previously accepted grafts, we showed that recipient CD4+ TCR75 cells reactive to a donor MHC class I–derived peptide become hypofunctional if the allograft is accepted for more than 3 weeks. Paradoxically, infection-induced transplant rejection was not associated with transcriptional or functional reinvigoration of TCR75 cells. We hypothesized that there is heterogeneity in the level of dysfunction of different allospecific T cells, depending on duration of their cognate antigen expression. Unlike CD4+ TCR75 cells, CD4+ TEa cells specific for a peptide derived from donor MHC class II, an alloantigen whose expression declines after transplantation but remains inducible in settings of inflammation, retained function in tolerant mice and expanded during Lm-induced rejection. Repeated injections of alloantigens drove hypofunction in TEa cells and rendered grafts resistant to Lm-dependent rejection. Our results uncover a functional heterogeneity in allospecific T cells of distinct specificities after tolerance induction and reveal a strategy to defunctionalize a greater repertoire of allospecific T cells, thereby mitigating a critical vulnerability of tolerance.

Mingxun Wang,1,&ast; Xinfei Yao,2,&ast; Zhiyuan Bo,3,4,&ast; Jiuyi Zheng,3 Haitao Yu,3 Xiaozai Xie,3 Zixia Lin,3 Yi Wang,5 Gang Chen,3,4 Lijun Wu3 1Department of Ultrasonography, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of China; 2The First Clinical College, Wenzhou Medical University, Wenzhou, People’s Republic of China; 3Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of China; 4Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of China; 5Department of Epidemiology and Biostatistics, School of Public Health and Management, Wenzhou Medical University, Wenzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Lijun Wu; Gang Chen, Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Fuxue Road, Wenzhou, Zhejiang, 325035, People’s Republic of China, Tel +86 577 55579-453, Fax +86 577 55579-555, Email wumolijun@163.com; chen.gang@wmu.edu.cnPurpose: The current study aimed to evaluate the synergistic efficacy of lenvatinib and FOLFOX (infusional fluorouracil (FU), folinic acid, and oxaliplatin) in hepatocellular carcinoma (HCC) using patient-derived xenograft (PDX) and PDX-derived organotypic spheroid (XDOTS) models in vivo and in vitro.Methods: PDX and matched XDOTS models originating from three patients with HCC were established. All models were divided into four groups and treated with drugs alone or in combination. Tumor growth in the PDX models was measured and recorded, and angiogenesis and phosphorylation of the vascular endothelial growth factor receptor (VEGFR2), rearranged during transfection (RET), and extracellular signal-regulated kinase (ERK) were detected using immunohistochemistry and Western blot assays. The proliferative ability of XDOTS was evaluated through active staining and immunofluorescence staining, and the effect of the combined medication was evaluated using the Celltiter-Glo luminescent cell viability assay.Results: Three PDX models with genetic characteristics similar to those of the original tumors were successfully established. Combining lenvatinib with FOLFOX led to a higher tumor growth inhibition rate than individual therapies (P < 0.01). Immunohistochemical analysis demonstrated that the combined treatment significantly inhibited the proliferation and angiogenesis of PDX tissues (P < 0.05), and Western blot analysis showed that the combined treatment significantly inhibited the phosphorylation of VEGFR2, RET, and ERK compared with single-agent treatment. Additionally, all three matched XDOTS models were successfully cultured with satisfactory activity and proliferation, and the combined therapies led to better suppression of XDOTS growth compared with individual therapy (P < 0.05).Conclusion: Lenvatinib combined with FOLFOX had a synergistic antitumor effect in HCC PDX and XDOTS models by inhibiting the phosphorylation of VEGFR, RET, and ERK.Keywords: hepatocellular carcinoma, lenvatinib, chemotherapy, patient-derived xenografts, angiogenesis

Lin Zhang,1 Ming Jiang,2 Linghua Wang,1 Jiandi Zheng,1 Weigang Wang2 1Zhejiang Hospital of Integrated Traditional Chinese and Western Medicine, Hangzhou, 310018, People’s Republic of China; 2Department of Statistics and Mathematics, Zhejiang Gongshang University, Hangzhou, 310018, People’s Republic of ChinaCorrespondence: Weigang Wang, Email wangweigang@zjgsu.edu.cnAim: Assess the level of meaning in life of patients with COVID-19, explore the relationship among COVID-19 patients in perceived social support, medical coping modes, psychological resilience and life meaning, and clarify the mediating effect.Methods: Through the convenience sampling method, 144 COVID-19 patients were selected in the year 2021, and surveyed by using general information questionnaire, perceived social support scale (PSSS), medical coping modes questionnaire (MCMQ), meaning in life questionnaire (MLQ) and Connor-Davidson resilience scale (CD-RISC). After the collected data were preprocessed by SPSS, the t-tests, multiple comparison and Pearson coefficient were respectively used for comparative analysis, difference analysis and correlation analysis. Based on the above analysis, the structural equation model of perceived social support, medical coping modes, psychological resilience and meaning in life of COVID-19 patients was established by Amos.Results: COVID-19 patient’s score of meaning in life, perceived social support, medical coping modes and psychological resilience are higher than the medium level. The gender and the place of treatment have significant differences in the meaning of life and perceived social support respectively. The patient’s sense of life meaning it is closely and positively related to the perceived social support, medical coping modes and psychological resilience. Psychological resilience indirectly affects the sense of life meaning through medical coping modes and perceived social support.Conclusion: The life meaning can be improved by strengthening the perceived social support. The high level of perceived social support was conducive to the patient to think about life from a positive perspective. Family, government, enterprise and others should give patients certain care and warmth, make them feel more support from all walks of life. In addition, the life meaning can also be enhanced through the impact of psychological resilience on medical coping modes. So, care-givers can take some proper psychological interventions to patients.Keywords: COVID-19, perceived social support, medical coping modes, psychological resilience, meaning in life, mediation effect

Zhaolin Li,1,&ast; Qiaojun Zeng,1,&ast; Shuwan Xu,2,&ast; Yuewei Li,1 Tiantian Tang,1 Jianting Shi,1 Xueming Song,1 Wenman He,1 Liang Chen,1 Guirong Liu,1 Boying Gao,3 Jianming Zheng,4 Linjie Huang,1 Ming Chen,1 Shanping Jiang1 1Department of Pulmonary and Critical Care Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China; 2Department of Cardiology, the Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, People’s Republic of China; 3Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China; 4Cardiovascular Medicine Department, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shanping Jiang; Ming Chen, Department of Pulmonary and Critical Care Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Yan-jiang Xi Road 107, Guangzhou, 510120, People’s Republic of China, Tel +86-20-81332441, Email jiangshp@mail.sysu.edu.cn; chenm69@mail.sysu.edu.cnBackground: Although tigecycline is an effective drug against drug-resistant bacteria, it demonstrated a higher all-cause mortality than comparator antibiotics and a high incidence of coagulation disorders which can be accompanied by severe bleeding. At present, a predictive model for tigecycline-related coagulopathy is not readily available, and the prognostic value of coagulopathy in tigecycline-administered patients has not been elucidated. In this paper, we investigate the association between tigecycline-related coagulopathy and in-hospital mortality to develop a nomogram for the prediction of tigecycline-related coagulopathy.Methods: This retrospective cohort study includes 311 adults prescribed with tigecycline from 2018 to 2020. The primary cohort and validation cohort were constructed by dividing the participants in a ratio of 7:3. The endpoint is tigecycline-related coagulopathy, defined as a condition with no abnormality in coagulation prior to tigecycline application but developed the following symptoms upon prescription: activated partial thromboplastin time (APTT) extended by > 10 s than the upper limit of normal (ULN), prothrombin time (PT) prolonged for > 3 s than the ULN or reduced serum level of fibrinogen to < 2.0 g/L. A predictive nomogram based on logistic regression was subsequently constructed.Results: Tigecycline intake for over 7 days, combined other antibiotics, initial PT, initial fibrinogen and estimated glomerular filtration rate (eGFR), are independent prognostic factors of tigecycline-related coagulopathy. The primary and validation cohort each has an area under the receiver operating characteristic curve (AUC) of 0.792 (0.732– 0.851) and 0.730 (0.629– 0.832) for nomogram, respectively. Furthermore, the fitted calibration curve illustrated adequate fit of the model, while the decision curve analysis demonstrated good clinical value. Survival curves showed a high mortality rate among patients with tigecycline-related coagulopathy.Conclusion: This nomogram exhibited helpful clinical value in predicting tigecycline-related coagulopathy that could reduce the high mortality rate of patients prescribed with tigecycline.Keywords: tigecycline, drug-resistant bacteria, coagulopathy, nomogram

Shubing Chen,&ast; Yongyi Peng,&ast; Beilan Shen, Liping Zhong, Zhongping Wu, Jinping Zheng, Yi Gao State Key Laboratory of Respiratory Disease, National Center for Respiratory Medicine, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yi Gao; Jinping Zheng, Email misstall2@163.com; jpzhenggy@163.comPurpose: To develop and internally validate a nomogram for predicting the risk of incorrect inhalation techniques in patients with chronic airway diseases.Methods: A total of 206 patients with chronic airway diseases treated with inhaled medications were recruited in this study. Patients were divided into correct (n=129) and incorrect (n=77) cohorts based on their mastery of inhalation devices, which were assessed by medical professionals. Data were collected on the basis of questionnaires and medical records. The least absolute shrinkage and selection operator method (LASSO) and multivariate logistic regression analyses were conducted to identify the risk factors of incorrect inhalation techniques. Then, calibration curve, Harrell’s C-index, area under the receiver operating characteristic curve (AUC), decision curve analysis (DCA) and bootstrapping validation were applied to assess the apparent performance, clinical validity and internal validation of the predicting model, respectively.Results: Seven risk factors including age, education level, drug cognition, self-evaluation of curative effect, inhalation device use instruction before treatment, post-instruction evaluation and evaluation at return visit were finally determined as the predictors of the nomogram prediction model. The ROC curve obtained by this model showed that the AUC was 0.814, with a sensitivity of 0.78 and specificity of 0.75. In addition, the C-index was 0.814, with a Z value of 10.31 (P< 0.001). It was confirmed to be 0.783 by bootstrapping validation, indicating that the model had good discrimination and calibration. Furthermore, analysis of DCA showed that the nomogram had good clinical validity.Conclusion: The application of the developed nomogram to predict the risk of incorrect inhalation techniques during follow-up visits is feasible.Keywords: inhalation technique, incorrect, chronic airway disease, nomogram, predictors

Zheng J, Shao Y, Jiang Y, et al. Cancer Manag Res. 2019;11:5231–5242. We, the Editors and Publisher of Cancer Management and Therapy, have retracted the following article. Following publication of the article, concerns were raised about the duplication of images from Figures 2, 3 and 4. Specifically, The images for Figure 2A, Control, 30µg/ml, and 90µg/ml have been duplicated with images from Figure 4D, +-0, -+0, -+90 and +-90, respectively. The graph for Figure 3B has been duplicated with the graph for Figure 4G. When approached for an explanation, the authors were cooperative but were unable to provide a sufficient explanation for the image duplication or provide sufficient original data for their study. As verifying the validity of published work is core to the integrity of the scholarly record, we are therefore retracting the article and the authors do not agree with this decision. We have been informed in our decision-making by our editorial policies and COPE guidelines. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as ‘Retracted’.

Huan Hu,&ast; Guangyu Mao,&ast; Jianghong Zheng, Feng Guo Department of Plastic Surgery, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jianghong Zheng; Feng Guo, Department of Plastic Surgery, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 600 Yishan Road, Xuhui District, Shanghai, 200233, People’s Republic of China, Email JianghongZheng2016@126.com; gfasph@163.comBackground: Keloids are fibroproliferative disorders, which seriously affect the quality of life of patients with keloids. Additionally, circRNAs are enriched within exosomes derived from human blood samples, whereas their relationship with keloids remains largely unknown. It has been reported that hsa_circ_0020792 was abnormally upregulated in keloid tissues. However, the role of keloid patient plasma-derived exosomal hsa_circ_0020792 in the formation and development of keloids is not well understood.Methods: Exosomes were isolated from the peripheral blood plasma of the patients with keloids (keloid patient-Exo) and healthy controls (Healthy control-Exo). The hsa_circ_0020792 and miR-193a-5p levels in keloid patient-Exo and healthy control-Exo, as well as in keloid fibroblasts and normal skin fibroblasts (NFs) were evaluated by RT-qPCR.Results: The level of hsa_circ_0020792 was remarkably increased in keloid patient-Exo and keloid fibroblasts compared with that in Healthy control-Exo and NFs, respectively. In addition, keloid patient-Exo obviously enhanced the viability, migration, and extracellular matrix (ECM) synthesis, but reduced the apoptosis of NFs. Moreover, keloid patient-Exo notably promoted the fibrogenesis of NFs, as characterized by enhanced TGF-β signaling, increased expressions of phosphorylated Smad2/3. However, downregulation of hsa_circ_0020792 markedly reversed the promoting effects of keloid patient-Exo on cell growth, migration, and myofibroblast activation and fibrogenesis. Furthermore, downregulation of hsa_circ_0020792 significantly reduced the viability, migration, and fibrogenesis in NFs, whereas these phenomena were reversed by miR-193a-5p inhibitor.Conclusion: Collectively, keloid patient plasma-derived exosomal hsa_circ_0020792 could promote the proliferation, migration, and fibrogenesis of NFs via modulating miR-193a-5p and activating TGF-β 1/Smad2/3 signaling.Keywords: keloid, fibroblasts, exosomes, hsa_circ_0020792, miR-193a-5p

Baijun Li,1 Jie Zheng2 1Institution of Acupuncture-moxibustion and Massage, Shaanxi University of Chinese Medicine, Shaanxi, People’s Republic of China; 2Shaanxi Key Laboratory of Acupuncture and Herbal Medicine, Shaanxi, People’s Republic of ChinaCorrespondence: Jie Zheng, Institution of Acupuncture-moxibustion and Massage, Shaanxi University of Chinese Medicine, Shaanxi, 712046, People’s Republic of China, Tel +86 138 9298 0566, Email 13892980566@163.comBackground: Osteoarthritis(OA) is one of the most common joint diseases, and signaling pathways play an essential role in the occurrence and development of OA, so it is significant to study OA with signaling pathways as an entry point.Purpose: This study aims to visualize and map the knowledge of OA-related signaling pathway research between 2012 and 2022, summarise and analyze the current research status and potential development trends in the domain, and provide a reference for future OA-related research.Methods: Retrieve relevant literature from the Web of Science database and use VOSviwer and CiteSpace software to visualize authors, institutions, country distribution, references, and keywords. The results are interpreted and analyzed in conjunction with the results obtained.Results: According to the search strategy, a total of 4894 articles were published between January 2012 and January 2022; during these ten years, the number of reports increased annually, and the research became further intensive; through this analysis, it was found that China is the most prolific country in this field; The institution with the most articles was Xi’an Jiaotong University from China, and the most prolific author was Tang Chih Hsin; Among the cited references, the reports of Glyn-Jones S and Hunter DJ were ranked first and second respectively. In the keyword analysis, cartilage and expression were the popular keywords; Animal model, akt, and platelet-rich plasma had the highest centrality; Burst analysis revealed pi3k, senescence, Ampk, and exosomes had received more attention in recent years of research.Conclusion: This study analyzes and summarizes the current research status and development trend of relevant signaling pathways in OA from the perspective of bibliometric and visual analysis, which can help researchers to keep track of hot topics and conduct more in-depth exploration of research hotspots and frontier knowledge areas.Keywords: osteoarthritis, signaling pathway, inflammation, articular cartilage, mechanism, CiteSpace, VOSviwer

Junxian Ren,1,&ast; Rongcheng Yu,1,&ast; Jingyan Xue,1 Yiqi Tang,1 Sihui Su,1 Chenxi Liao,1 Quanyi Guo,2 Weimin Guo,3 Jinxuan Zheng1 1Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, 510055, People’s Republic of China; 2Institute of Orthopedics, Chinese PLA General Hospital, Key Laboratory of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, Beijing, 100853, People’s Republic of China; 3Department of Orthopedic Surgery, Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510055, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Weimin Guo, Department of Orthopedic Surgery, Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan 2nd Road, Guangzhou, 510080, People’s Republic of China, Tel +86 20 87755766&num;6236, Email guowm5@mail.sysu.edu.cn Jinxuan Zheng, Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, 56 Lingyuan West Road, Guangzhou, 510055, People’s Republic of China, Tel +86 20 83802802, Email zhengjx27@mail.sysu.edu.cnAbstract: The maintenance of bone homeostasis includes both bone resorption by osteoclasts and bone formation by osteoblasts. These two processes are in dynamic balance to maintain a constant amount of bone for accomplishing its critical functions in daily life. Multiple cell type communications are involved in these two complex and continuous processes. In recent decades, an increasing number of studies have shown that osteogenic and osteoclastic extracellular vesicles play crucial roles in regulating bone homeostasis through paracrine, autosecretory and endocrine signaling. Elucidating the functional roles of extracellular vesicles in the maintenance of bone homeostasis may contribute to the design of new strategies for bone regeneration. Hence, we review the recent understandings of the classification, production process, extraction methods, structure, contents, functions and applications of extracellular vesicles in bone homeostasis. We highlight the contents of various bone-derived extracellular vesicles and their interactions with different cells in the bone microenvironment during bone homeostasis. We also summarize the recent advances in EV-loaded biomaterial scaffolds for bone regeneration and repair.Keywords: bone, homeostasis, metabolism, extracellular vesicles, regeneration

Zhongbin Zhang,1,2,&ast; Jinqing Chen,1,&ast; Linghui Zou,1,&ast; Jing Tang,1 Jiaxin Zheng,1 Meijiao Luo,1 Gang Wang,1 Dan Liang,1,2 Yuyang Li,1 Ben Chen,1 Hongjun Yan,1 Wenya Ding1– 3 1Guangxi University of Chinese Medicine, Nanning, People’s Republic of China; 2Key Laboratory of Common Technology of Chinese Medicine Preparations, Guangxi University of Chinese Medicine, Nanning, People’s Republic of China; 3College of Veterinary Medicine, Northeast Agricultural University, Harbin, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wenya Ding, Guangxi University of Chinese Medicine, Nanning, People’s Republic of China, Tel +86-15045630868, Email DingWenYa666@163.comBackground and Purpose: Infections caused by Staphylococcus aureus (S. aureus) colonization in medical implants are resistant to antibiotics due to the formation of bacterial biofilm internal. Baicalein (BA) has been confirmed as an inhibitor of bacterial biofilm with less pronounced effects owing to its poor solubility and absorption. Studies have found that β-cyclodextrin-grafted chitosan (CD-CS) can improve drug efficiency as a drug carrier. Therefore, this research aims to prepare BA-loaded CD-CS nanoparticles (CD-CS-BA-NPs) for S. aureus biofilm elimination enhancement.Methods: CD-CS-BA-NPs were prepared via the ultrasonic method. The NPs were characterized using the X-ray diffraction (XRD), Thermo gravimetric analyzer (TGA), Transmission electron microscopy (TEM) and Malvern Instrument. The minimum inhibitory concentration (MIC) of the NPs were investigated. The biofilm models in vivo and in vitro were constructed to assess the S. aureus biofilm elimination ability of the NPs. The Confocal laser method (CLSM) and the Live/Dead kit were employed to explore the mechanism of the NPs in promoting biofilm elimination.Results: CD-CS-BA-NPs have an average particle size of 424.5 ± 5.16 nm, a PDI of 0.2 ± 0.02, and a Zeta potential of 46.13 ± 1.62 mV. TEM images revealed that the NPs were spherical with uniform distribution. XRD and TGA analysis verified the formation and the thermal stability of the NPs. The NPs with a MIC of 12.5 ug/mL exhibited a better elimination effect on S. aureus biofilm both in vivo and in vitro. The mechanism study demonstrated that the NPs may permeate into the biofilm more easily, thereby improving the biofilm elimination effect of BA.Conclusion: CD-CS-BA-NPs were successfully prepared with enhanced elimination of S. aureus biofilm, which may serve as a reference for future development of anti-biofilm agents.Graphical Abstract: Keywords: baicalein, β-cyclodextrin-grafted chitosan, nanoparticles, Staphylococcus aureus, biofilm elimination

Jie Bai,1 Jinxia Zheng,1 Yueyan Dong,1 Ke Wang,1 Cheng Cheng,2 Hui Jiang3 1Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, 200092, People’s Republic of China; 2School of Nursing, Fudan University, Shanghai, 200032, People’s Republic of China; 3Nursing Department, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, 200092, People’s Republic of ChinaCorrespondence: Hui Jiang, Nursing Department, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, 200092, People’s Republic of China, Tel +86 021-20261221, Fax +86 021-20261221, Email jianghuitest@163.comPurpose: Infertile clients undergoing assisted reproductive technology (ART) are exposed to a stressful situation and evidence has highlighted the importance of dyadic coping in reducing stress, yet little is known about the associations between psychological distress, dyadic coping, and quality of life in this population.Patients and Methods: A cross-sectional study was conducted at a tertiary hospital in Shanghai, China. A structured questionnaire was administered online to assess psychological distress, dyadic coping, and fertility quality of life. Sociodemographic information was collected. Descriptive statistics, Pearson correlation, and stepwise regression models were used to analyze the data.Results: Of 715 infertile males and females who completed the survey. Results showed that there was a negative association between psychological distress and quality of life. The use of positive dyadic coping was associated with better quality of life, whereas negative dyadic coping might contribute to worse quality of life. Moreover, males reported having a better quality of life in contrast to females.Conclusion: The findings of this study highlighted the significant associations between particular dyadic coping and quality of life in clients undergoing ART. Healthcare professionals should recognize the significance of dyadic coping in the context of ART and consider improving clients’ quality of life through coping-oriented interventions.Keywords: adaptation, infertility, psychological distress, reproductive techniques

Yun Li &ast;, Junfeng Lin &ast;, Zihui Wang &ast;, Zhufeng Wang, Lunfang Tan, Shuyi Liu, Jinhai Huang, Yi Gao, Jinping Zheng National Clinical Research Center for Respiratory Disease, State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yi Gao; Jinping Zheng, National Clinical Research Center for Respiratory Disease, State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, 151 Yanjiang Road, Yuexiu District, Guangzhou, 510120, People’s Republic of China, Tel +86 20 83062869, Fax +86 20 83062729, Email misstall2@163.com; jpzhenggy@163.comBackground: In the 2021 ERS/ATS interpretive strategies for routine lung function tests, a positive bronchodilator response (BDR) was updated as a change of > 10% relative to the predicted value in forced expiratory volume in 1 second (FEV1) or forced vital capacity (FVC). We aimed to explore the differences between the 2005 and 2021 ERS/ATS criteria applied to patients with asthma as well as chronic obstructive pulmonary disease (COPD).Methods: BDR test data about asthma patients aged 6– 80 years and COPD patients aged 18– 80 years were derived from the National Respiratory Medicine Center, First Affiliated Hospital of Guangzhou Medical University, from January 2017 to March 2022. BDR results defined by the 2005 and 2021 ERS/ATS criteria were named 2005-BDR and 2021-BDR, respectively. We compared differences between 2005-BDR and 2021-BDR and analyzed the trend in the proportion of positive BDR (BDR+) with the level of airflow obstruction.Results: A total of 4457 patients with asthma and 7764 patients with COPD were included in the analysis. The percentages of 2005-BDR+ and 2021-BDR+ were 63.32% and 52.84% for asthma, 30.92% and 22.94% for COPD, respectively. Of patients with 2005-BDR+, 81.86% for asthma and 70.18% for COPD showed 2021-BDR+ results, and these patients had higher FEV1%pred, FVC%pred (all P< 0.05). Whichever BDR criterion was adopted, the proportion of BDR+ had an upward linear trend with the increased degree of airflow obstruction in COPD, but exhibited an approximate inverted U-shaped curve in asthma. In COPD, the proportion of BDRFEV1 was negatively associated with the degree of airflow obstruction, while BDRFVC was positively associated (all P< 0.05).Conclusion: Compared with 2005-BDR+, the proportion of 2021-BDR+ reduced markedly in patients with asthma and COPD, but their trends with the degree of airflow obstruction did not change. Patients with consistent BDR+ had higher initial FEV1%pred and FVC%pred.Keywords: pulmonary function test, bronchodilator responsiveness testing, asthma, chronic obstructive pulmonary disease, European Respiratory Society, ERS, American Thoracic Society, ATS

Ping Yang,1,2 Chao Liu,3 Zhenchao Wu,2 Jiajia Zheng,4 Juan Yi,1 Nan Wu,2 Zhangli Wu,1,2 Ming Lu,2,3 Liyan Cui,4,&ast; Ning Shen1– 3,&ast; 1Institute of Medical Technology, Peking University Health Science Center, Beijing, People’s Republic of China; 2Department of Pulmonary and Critical Care Medicine, Peking University Third Hospital, Beijing, People’s Republic of China; 3Department of Infectious Diseases, Peking University Third Hospital, Beijing, People’s Republic of China; 4Department of Laboratory Medicine, Peking University Third Hospital, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Liyan Cui; Ning Shen, Email cliyan@163.com; shenningputh@163.comPurpose: This study aimed to identify the clinical outcomes, microbiological features and risk factors for difficult-to-treat resistance (DTR) Klebsiella pneumoniae (Kp) infection.Materials and Methods: A retrospective study was conducted at Peking University Third Hospital from January 2020 to March 2021. DTR was defined as resistance to ≥ 1 carbapenem, ≥ 1 extended-spectrum cephalosporin, and ≥ 1 fluoroquinolone. Hypervirulent Kp (HvKp) was defined as peg-344-, iroB-, iucA-, rmpA-, or rmpA2-positive. Clinical data were collected. Antimicrobial susceptibility testing and string tests were performed to determine resistance and hypermucoviscosity phenotype. Whole genome sequencing was performed to analyze the sequence type (ST), capsular serotypes, resistance and virulence genes. Risk factors for 30-day mortality were analyzed.Results: Fifty DTR-Kp (50.0%) strains were identified among 100 patients. Compared to non-DTR-Kp group, a significant number of patients with DTR-Kp infection experienced ICU admission (44.0% versus 10.0%, P< 0.001) and mechanical ventilation after Kp detection (26.0% versus 10.0%, P=0.037). Notably, the percentage of hvKp among the DTR-Kp isolates increased consistently over the 15 months evaluated. Most DTR-Kp strains belonged to ST11 (82.0%), followed by ST15 (12.0%), ST86 (2.0%), ST996 (2.0%), and ST3157 (2.0%). DTR-Kp isolates possessed various resistance genes, such as blaKPC-2, blaTEM-1D and fosA3 (90.0%, 80.0% and 72.0%, respectively). Importantly, the yersiniabactin genes were significantly clustered in DTR group (48/50, 96.0%). The 30-day mortality was significantly higher in patients with DTR-Kp infection than non-DTR-Kp group (38.0% versus 8.2%, P=0.001). DTR-Kp infection (odds ratio [OR] = 4.196) was an independent risk factor for the 30-day mortality of Kp-infected patients. Additionally, cerebrovascular disease (OR = 2.780) and Charlson comorbidity index (OR= 1.584) were independent risk factors for DTR-Kp infections.Conclusion: DTR-hvKp is rapidly emerging. The DTR-Kp strains harbored various resistance genes and high rates of yersiniabactin siderophore genes. DTR-Kp infection was an independent risk factor for mortality, suggesting that enhanced awareness essential.Keywords: Klebsiella pneumoniae, difficult-to-treat resistance, mortality, risk factor

Guohua Lin,1,&ast; Jiaqi Zheng,1,&ast; Pou Kuan Tang,1 Yu Zheng,1 Hao Hu,1,2 Carolina Oi Lam Ung1,2 1Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao SAR, People’s Republic of China; 2Department of Public Health and Medicinal Administration, Faculty of Health Sciences, University of Macau, Taipa, Macao SAR, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Carolina Oi Lam Ung, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao SAR, People’s Republic of China, Email carolinaung@um.edu.moPurpose: This review aimed to summarize empirical evidence about pharmacist-led interventions for chronic obstructive pulmonary disease (COPD) patients in hospital settings and to identify the components of a logic model (including input, interventions, output, outcome and contextual factors) to inform the development of hospital pharmacist’s role in COPD management.Methods: A systematic review of literature retrieved from four English databases (PubMed, Web of Science, Scopus, ScienceDirect) and one Chinese database (CNKI) were conducted to identify eligible studies published from inception to March 2022. Studies concerning pharmacist and COPD were identified to screen for randomized controlled studies that focused on pharmacist interventions for COPD at the hospital setting.Results: Twenty-nine studies were included in this review. The components of interventions identified were categorized according to the six service domains in the International Pharmaceutical Federation’s Basel Statements, and mainly concerned prescribing, preparation, administration and monitoring but not procurement and training. Extended interventions were also identified including life guidance, psychological counseling, and respiratory function exercise. The most common outputs reported were improvement in medication adherence, rational drug use, level of knowledge, and inhalation technique. The clinical outcomes (symptomatic control, lung function, rates of hospital readmission, length of hospital stay, and adverse drug adverse reactions), humanistic outcomes (quality of life and patient satisfaction), and economic outcomes (drug costs, hospitalization costs, antibiotic costs, and direct costs) were reported only in some studies. The contextual factors mainly included geographical factors, education level of patients, socio-economic factors, and no-smoking policy.Conclusion: The evidence for hospital pharmacists’ interventions in improving COPD patients’ outcome is growing. However, considering the challenges of COPD management, hospital pharmacists should further leverage the advantages of cross-sector and multi-disciplinary collaboration in order to provide more comprehensive support to better address the needs of their patients.Keywords: chronic obstructive pulmonary disease, hospital pharmacist, systematic review, intervention, output, outcome, logic model

Lingling Lu,1,&ast; Jiaolong Zheng,1,2,&ast; Bang Liu,1,&ast; Haicong Wu,1,2 Jiaofeng Huang,1 Liqing Wu,2 Dongliang Li1,2 1Fuzong Clinical Medical College of Fujian Medical University, The 900th Hospital, Fuzhou, People’s Republic of China; 2Department of Hepatobiliary Disease, The 900th Hospital of Joint Logistics Support Force, Fuzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Dongliang Li, Fuzong Clinical Medical College of Fujian Medical University, The 900th Hospital of the People’s Liberation Army Joint Logistics Support Force, No. 156 Xierhuan Road, Fuzhou, Fujian, 350025, People’s Republic of China, Tel/Fax +86 591 22859128, Email ldliang900@163.comPurpose: The 7-methylguanosine (m7G)-related genes were used to identify the clinical severity and prognosis of patients with coronavirus disease 2019 (COVID-19) and to identify possible therapeutic targets.Patients and Methods: The GSE157103 dataset provides the transcriptional spectrum and clinical information required to analyze the expression of m7G-related genes and the disease subtypes. R language was applied for immune infiltration analysis, functional enrichment analysis, and nomogram model construction.Results: Most m7G-related genes were up-regulated in COVID-19 and were closely related to immune cell infiltration. Disease subtypes were grouped using a clustering algorithm. It was found that the m7G-cluster B was associated with higher immune infiltration, lower mechanical ventilation, lower intensive care unit (ICU) status, higher ventilator-free days, and lower m7G scores. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that differentially expressed genes (DEGs) between m7G-cluster A and B were enriched in viral infection and immune-related aspects, including COVID-19 infection; Th17, Th1, and Th2 cell differentiation, and human T-cell leukemia virus 1 infection. Finally, through machine learning, six disease characteristic genes, NUDT4B, IFIT5, LARP1, EIF4E, LSM1, and NUDT4, were screened and used to develop a nomogram model to estimate disease risk.Conclusion: The expression of most m7G genes was higher in COVID-19 patients compared with that in non-COVID-19 patients. The m7G-cluster B showed higher immune infiltration and milder symptoms. The predictive nomogram based on the six m7G genes can be used to accurately assess risk.Keywords: COVID-19, 7-methylguanosine, SARS-CoV-2, nomogram, risk, immune cells

Ming Hu,1,&ast; Pan Ding,1,&ast; Jinfang Ma,2 Nan Yang,1 Jinping Zheng,2 Naitong Zhou1 1West China School of Pharmacy Sichuan University, Chengdu, People’s Republic of China; 2State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Naitong Zhou, West China School of Pharmacy Sichuan University, No. 17, 3rd Section, Renmin South Road, Chengdu, 610041, People’s Republic of China, Tel +86-13881962880, Fax +86-28-85501387, Email zhou-2316@163.com Jinping Zheng, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, 151 Yanjiang Road, Guangzhou, 510120, People’s Republic of China, Tel +86 20 8306 2869, Fax +86 20 8306 2729, Email jpzhenggy@163.comIntroduction: Traditional Chinese medicine (TCM) is becoming increasingly important as it provides further options for treating many diseases worldwide. The TCM “Yupingfeng” has been used in China for over 800 years, and its clinical efficacy and safety for COPD treatment have been proven in previous studies. The objective of this study was to compare the long-term cost-effectiveness of Yupingfeng granules and the current conventional treatment for COPD patients in China.Methods: A Markov model was constructed from the perspective of the Chinese healthcare system using TreeAge Pro 2011. The model cycle length was 12 months, and the cycle time was set to 10 years. Data from a randomized controlled trial were used to generate the number of acute exacerbations, COPD assessment test (CAT) score and actual medication used. The state transition probabilities, costs and quality-adjusted life years (QALYs) were derived from available sources. A threshold of 72,447 yuan per QALY gained was used as a cost-effectiveness criterion. One-way and probabilistic sensitivity analyses were conducted to verify the model. In addition, the cost-effectiveness of a 35-year cycle was evaluated as a scenario analysis.Results: In the basic-case analysis, the ICER of adding Yupingfeng granules to the current conventional treatment drugs was ¥ 2123.04 per QALY, which was less than the threshold (one-time per capita GDP).Sensitivity analyses showed the results to be robust. Probabilistic sensitivity analysis showed that the probability of the ICER being less than the one-time per capita GDP threshold was 100%. In the scenario analysis, the incremental cost-effectiveness was ¥ 12,051.27 per QALY which was also under the one-time per capita GDP.Conclusion: By reducing the number of acute exacerbations of COPD, thereby correspondingly reducing the follow-up treatment cost, Yupingfeng granules combined with conventional treatment were found to provide a cost-effective therapeutic strategy for COPD.Keywords: Yupingfeng granule, traditional Chinese medicine, COPD, Markov model, cost-effectiveness analysis