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Zhikang Yu,1,2,* Zifang Shang,1,2,* Qingyan Huang,3 Heming Wu,4 Sandip Patil5,6 1Institute of Basic Medical Sciences, Meizhou People’s Hospital, Meizhou Academy of Medical Sciences, Meizhou, 514031, People’s Republic of China; 2Guangdong Engineering Technological Research Center of Clinical Molecular Diagnosis and Antibody Drugs, Meizhou Academy of Medical Sciences, Meizhou, 514031, People’s Republic of China; 3Institute of Cardiovascular Disease, Meizhou People’s Hospital, Meizhou Academy of Medical Sciences, Meizhou, Guangdong, 514031, People’s Republic of China; 4Meizhou Municipal Engineering and Technology Research Centre for Molecular Diagnostics of Major Genetic Disorders, Meizhou People’s Hospital, Meizhou Academy of Medical Sciences, Meizhou, 514031, People’s Republic of China; 5Department of Hematology and Oncology, Shenzhen Children’s Hospital, Shenzhen, 518038, People’s Republic of China; 6Paediatric Research Institute, Shenzhen Children’s Hospital, Shenzhen, 518038, People’s Republic of China*These authors contributed equally to this workCorrespondence: Heming Wu; Sandip Patil, Email wuheming@mzrmyy.com; sandippatil1309@yahoo.comObjective: The polymorphism of the solute carrier organic anion transporter family member 1B1 (SLCO1B1) gene exerts a marked influence on drug transport, thus playing a pivotal role in personalized drug dosing. This study endeavours to establish a rapid, precise, and straightforward method for detecting SLCO1B1 genetic variants utilizing Duplex Fluorescence Melting Curve Analysis (DFMCA).Methods: Whole blood samples were collected from 54 individuals from Meizhou People’s Hospital (2023.01– 2023.03), with a mean age of 58.90 years (SD = 7.86), including 28 men and 26 women. DNA was extracted from these samples and subjected to PCR amplification targeting two allelic regions. Primers, fluorescent probes, and corresponding allelic target sequences were designed specifically for two common SLCO1B1 polymorphisms (rs2306283 and rs4149056). The functionality of the fluorescent probes in binding to their respective allelic targets was verified using melting curve analysis, enabling the identification of distinct melting temperatures for different genotypes. Subsequently, DFMCA was employed to differentiate genotypes based on the melting temperature shifts of the corresponding fluorescent probes. The sensitivity, accuracy, and consistency of the method were evaluated, with sequencing validation performed on a subset of samples.Results: DFMCA facilitated the concurrent detection and accurate genotyping of both polymorphisms within 2 hours, demonstrating concordance with sequencing results from randomly selected samples. Importantly, stable detection performance was achieved for human genomic DNA at concentrations ≥ 3.125 ng. In a cohort comprising Han Chinese individuals from southern China, the allele frequencies for rs2306283 (A: 28.7%, G: 71.3%) and rs4149056 (T: 88.89%, C: 11.11%) concurred well with previous studies in the Han Chinese population.Conclusion: The SNP typing system utilizing DFMCA technology presents advantages in terms of speed, ease of use, accuracy, and cost-effectiveness, making it a suitable tool.Keywords: SLCO1B1, melting curve analysis, gene polymorphism, drug delivery

Nating Xiong,1 Wendao Han,1 Zhikang Yu2,3 1Department of Blood Transfusion, Meizhou People’s Hospital, Meizhou Academy of Medical Sciences, Meizhou, People’s Republic of China; 2Institute of Basic Medical Sciences, Meizhou People’s Hospital, Meizhou Academy of Medical Sciences, Meizhou, People’s Republic of China; 3Guangdong Engineering Technological Research Center of Clinical Molecular Diagnosis and Antibody Drugs, Meizhou People’s Hospital, Meizhou Academy of Medical Sciences, Meizhou, People’s Republic of ChinaCorrespondence: Zhikang Yu, Institute of Basic Medical Sciences, Meizhou People’s Hospital, Meizhou Academy of Medical Sciences, Meizhou, People’s Republic of China, Email 392244719@qq.comBackground: Lymph node metastasis (LNM) is an important prognostic factor for breast cancer. Inflammatory stimulation can change tumor microenvironment and lead to LNM, but the relationship between LNM and peripheral immunoinflammatory indices has not been clarified in breast cancer.Methods: The clinical information of 1918 patients with breast cancer admitted to Meizhou People’s Hospital from October 2017 to December 2023 were retrospectively analyzed. The relationship of clinicopathological features (age, body mass index (BMI), ABO blood types, family history of cancer, tumor site, disease stage, LNM, distant metastasis, and molecular subtypes) and peripheral immunoinflammatory indices (pan-immune inflammation value (PIV), systemic immune inflammation index (SII), and system inflammation response index (SIRI)) were analyzed.Results: There were 935 (48.7%) patients had no LNM and 983 (51.3%) had LNM. There were statistically significant differences in the distributions of ABO blood groups (p=0.022) and molecular subtypes (p< 0.001) between the two groups. PIV, SII, and SIRI levels in patients with LNM were significantly higher than those without LNM (all p< 0.05). The proportions of LNM in patients with high PIV, SII, and SIRI levels were higher than those with low PIV, SII, and SIRI levels, respectively. Logistic regression analysis showed that non-O blood type (non-O blood type vs O blood type, odds ratio (OR): 1.327, 95% confidence interval (CI): 1.056– 1.667, p=0.015), luminal B subtype (luminal B vs luminal A, OR: 2.939, 95% CI: 2.147– 4.022, p< 0.001), HER2+ subtype (HER2+ vs luminal A, OR: 2.044, 95% CI: 1.388– 3.009, p< 0.001), and high SIRI level (≥ 0.875 vs < 0.875, OR: 1.572, 95% CI: 1.092– 2.265, p=0.015) were independently associated with LNM.Conclusion: Non-O blood type, luminal B and HER2+ subtypes, and high SIRI level (≥ 0.875) have potential role in predicting the status of LNM in breast cancer patients.Keywords: breast cancer, lymph node metastasis, system inflammation response index, ABO blood group

Zhiyuan Yu,1– 3,&ast; Haopeng Liu,4,&ast; Rui Li,1– 3,&ast; Liai Hu,3 Chun Xiao,5 Yunhe Gao,2 Peiyu Li,1– 3 Wenquan Liang,2 Sixin Zhou,2 Xudong Zhao2 1Medical School of Chinese PLA, Beijing, People’s Republic of China; 2Department of General Surgery, The First Medical Center, Chinese PLA General Hospital, Beijing, People’s Republic of China; 3School of Medicine, Nankai University, Tianjin, People’s Republic of China; 4Department of Hepatobiliary Surgery, Zhangqiu District People’s Hospital, Jinan, Shandong Province, People’s Republic of China; 5Department of General Surgery, PLA Rocket Force Characteristic Medical Center, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xudong Zhao; Sixin Zhou, Department of General Surgery, The First Medical Center, Chinese PLA General Hospital, Fuxing Road 28, Haidian District, Beijing, 100853, People’s Republic of China, Email 601489554@qq.com; 35060555@qq.comBackground: The research on lymph node metastasis (LNM) in locally advanced gastric cancer (LAGC) infiltrating the subserous tissue and serous membrane (T3-4a) is significantly inadequate. This study aims to explore the clinicopathological factors related to LNM in stages T3 and T4a LAGC, while also developing predictive nomograms.Methods: After systematic searching and rigorous screening, 1995 T3 and 1244 T4a LAGC cases who underwent surgery without neoadjuvant or perioperative chemotherapy were selected. The risk factors associated with LNM were identified using both univariate and multivariate logistic regression analyses. Subsequently, the independent variables identified through the multivariate analyses were utilized to construct a nomogram.Results: The incidence of LNM in T3 and T4a LAGC was 77.1% (1539/1995) and 83.8% (1043/1244), respectively. The following factors were found to be independently associated with LNM in T3 LAGC: preoperative serum albumin < 41g/L (P=0.007), gastrointestinal obstruction (P< 0.001), tumor location (P=0.040), tumor size > 4cm (P=0.002), mixed (P=0.001) and undifferentiated histological types (P=0.002), presence of lymphovascular invasion (LVI) (P< 0.001) and nerve invasion (P< 0.001). Additionally, in T4a LAGC cases, serum albumin < 39g/L (P=0.004), tumor size > 6cm (P=0.020), mixed (P< 0.001) and undifferentiated histological types (P< 0.001), presence of gastrointestinal hemorrhage (P=0.016), neuroendocrine differentiation (P=0.024), and LVI (P< 0.001) independently influenced the occurrence of LNM.Conclusion: This study identified the risk factors associated with LNM in T3-4a LAGC cases and constructed nomograms, thereby providing valuable guidance for formulating and implementing a multidisciplinary perioperative treatment program.Keywords: locally advanced gastric cancer, lymph node metastasis, clinicopathological factors, nomogram

The globalization of the problem of the formation of bacterial strains poly- and pan-resistant to known antimicrobial drugs creates high risks in the healthcare sector. The threat of a return to the «pre-antibiotic» era dictates the need to search for alternative forms of antibacterial therapy. Phage therapy, based on the use of a natural, widely distributed in the environment, accessible antimicrobial agent, is again becoming relevant. The article highlights the mechanisms of antiviral protection of prokaryotes at various stages of interaction between the virus and the target cell. Revealing the secrets of the confrontation between bacteria and viruses, their co-evolution is necessary to increase the effectiveness of phage therapy and develop modern means of overcoming bacterial resistance to antimicrobial agents.

Hui Peng,1,2,&ast; Qian Jiang,1,&ast; Wenhao Mao,1,3,&ast; Zhonglan Hu,1,&ast; Qi Wang,4 Zhuo Yu,1 Li Zhang,1 Xinyan Wang,5 Chunbo Zhuang,1 Jia Mai,6 Zhiyuan Wang,7 Ting Sun1 1Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, People’s Republic of China; 2Center for Clinical Laboratory, General Hospital of the Yangtze River Shipping Wuhan Brain Hospital, Wuhan, Hubei, 430010, People’s Republic of China; 3Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, People’s Republic of China; 4Department of Pharmacy, Kaifeng Hospital of Traditional Chinese Medicine, Kaifeng, 475000, People’s Republic of China; 5Department of Obstetrics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, People’s Republic of China; 6Department of Laboratory Medicine, West China Second Hospital, Sichuan University, Chengdu, 610041, People’s Republic of China; 7Henan Institute of Advanced Technology, Zhengzhou University, Zhengzhou, 450001, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ting Sun, Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, People’s Republic of China, Email sunting@zzu.edu.cn Zhiyuan Wang, Henan Institute of Advanced Technology, Zhengzhou University, Zhengzhou, 450001, People’s Republic of China, Email wangzhiy@zzu.edu.cnBackground: The hypoxic tumor microenvironment and single mechanisms severely limit the photodynamic therapy (PDT) efficiency of covalent organic framework (COF) nanoparticles in cancer treatment.Purpose: Here, we propose an iron-loaded, hydrophilic 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (DSPE-PEG2000)-modified hollow covalent organic framework (HCOF), Fe-HCOF-PEG2000, for use in hypoxic PDT and ferroptosis therapy owing to its type I and II photodynamic ability and iron nanoparticle loading property.Results: Fe-HCOF-PEG2000 nanoparticles (Fe-HCOFs-PEG2000) with semiconducting polymers and microporous skeletons allow efficient photophysical properties. Moreover, the iron nanoparticles on Fe-HCOF-PEG2000 caused ferroptosis and further enhanced tumor elimination under normoxic and hypoxic conditions. DSPE-PEG2000 endowed Fe-HCOF-PEG2000 with hydrophilicity, allowing it to circulate and accumulate in organs rich in blood supply, especially tumors. 808 nm NIR activated Fe-HCOF-PEG2000 aggregated in tumors and significantly inhibited tumor growth under hypoxia.Conclusion: To our knowledge, Fe-HCOF-PEG2000 is the leading combination of type I/II PDT and ferroptosis. The strong antitumor effects of this nanomaterial suggest prospects for clinical translation as a tumor nanotherapy drug. Keywords: HCOFs, PDT, ROS, hypoxia, ferroptosis, cancer cells

Shuping Song,1,&ast; Jieqiong Liu,2,3,&ast; Wei Su,1 Haitao Yu,4 Binbin Feng,1 Yinshan Wu,1 Feng Guo,1 Zhenwei Yu2 1Intensive Care Unit, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, People’s Republic of China; 2Department of Pharmacy, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, People’s Republic of China; 3Department of Pharmacy, The 903rd Hospital of PLA Joint Logistic Support Force, Hangzhou, People’s Republic of China; 4Department of Clinical Laboratory, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Feng Guo; Zhenwei Yu, Email 3408003@zju.edu.cn; yzw_srrsh@zju.edu.cnBackground: Tigecycline is considered one of the last resorts for treating infections caused by multidrug-resistant bacteria. Continuous renal replacement therapy (CRRT) is widely used in critically ill patients, especially those with acute kidney injury or severe infections. However, pharmacokinetic data for tigecycline in patients receiving CRRT are limited.Methods: This was a single-center prospective clinical study with intensive sampling that included critically ill patients who received tigecycline and CRRT. A population pharmacokinetic (PPK) model was developed and evaluated by goodness-of-fit plots, bootstrap analysis, visual predictive checks, and numerical predictive checks. Pharmacokinetic/pharmacodynamic target attainment and cumulative fraction of response analyses were performed to explore the potential need for dose adjustments of tigecycline in CRRT.Results: In total, 21 patients with 167 concentrations were included. A two-compartment model adequately described the tigecycline concentration–time points, but no covariates were found to adequately explain the viability in the pharmacokinetic parameters of tigecycline. The typical values of CL, Q, V1 and V2 were 4.42 L/h, 34.8 L/h, 30.9 L and 98.7 L, respectively. For most infections, the standard regimen of 50 mg/12 h was deemed appropriate, expect for skin and soft skin tissue infections and community-acquired pneumonia caused by Acinetobacter baumannii and Klebsiella pneumoniae, which required a dosage regimen of 100 mg/12 h or higher.Conclusion: A tigecycline PPK model describing critically ill patients undergoing CRRT was successfully developed. The optimized dosage regimens for various infections are recommended.Keywords: tigecycline, population pharmacokinetics, critically ill, continuous renal replacement therapy

Yiwen Zhou,1,&ast; Yuyan Huang,1,&ast; Yingwen Wang,2 Xiaofeng Xu,1 Zhuowen Yu,1 Ying Gu3 1Department of Gastroenterology, Children’s Hospital of Fudan University, National Children’s Medical Center, Shanghai, 201102, People’s Republic of China; 2Centre for Clinical Practice Guideline Production and Evaluation, Children’s Hospital of Fudan University, National Children’s Medical Center, Shanghai, 201102, People’s Republic of China; 3Nursing Department, Children’s Hospital of Fudan University, National Children’s Medical Center, Shanghai, 201102, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ying Gu, Children’s Hospital of Fudan University, National Children’s Medical Center, Shanghai, 201102, People’s Republic of China, Email guying0128@aliyun.com Zhuowen Yu, Department of Gastroenterology, Children’s Hospital of Fudan University, National Children’s Medical Center, Shanghai, 201102, People’s Republic of China, Email yzw100@126.comBackground: The Theoretical Domains Framework (TDF) is among the most extensively utilised foundational frameworks in implementation science. It was developed from 33 psychological theories, with the latest version identifying 14 domains encompassing 84 theoretical constructs. These domains and constructs capture the complexity of factors that affect behaviours, making the framework a valuable tool for designing and implementing interventions within health and social care settings.Objective: To summarise the development, hot topics, and future trends in TDF-related research and provide implementation practitioners with more information on the application of TDF.Methods: We used TDF as the topic and searched the ISI Web of Science Core Collection, identifying 1382 relevant publications. We used analytical tools such as Excel, Tableau, VOSviewer, and Citespace to conduct a bibliometric analysis of the relevant publication.Results: We identified the United Kingdom as the primary contributor, with University College London as the key institution. Susan Michie ranked highest in total citations. The analysis highlighted cancer and stroke as primary clinic medicine-related topics using TDF. Emerging themes encompass abuse, violence, maternal health, antenatal care, patient involvement, and trauma-informed care et al. “Nurse” and “qualitative research” emerged as recent and enduring hotspots, possibly indicating future research trends.Conclusion: This article represents the first attempt to summarise the TDF using bibliometric analysis. We suggest this method can be used to analyse other theoretical frameworks in scientific implementation of its objectivity and quantifiability. Overall, the application scope of TDF is shifting from public health towards more specialised clinical directions, although its application in the field of public health is continuously expanding. In the future, the number of users of TDF is also expected to expand from implementation scientists to professional technical personnel.Keywords: theoretical domains framework, bibliometric analysis, visualization, implementation science

Zijuan Ma,1,&ast; Yunge Fan,1,&ast; Zhijun Yu,1 Wenxuan Wu,1 Xiangting Zhang,1 Huolian Li,1 Shaochen Zhao,2 Yang Li,3 Yuanyuan Li,4 Dongfang Wang,1 Fang Fan1 1Center for Studies of Psychological Application, School of Psychology, and Guangdong Key Laboratory of Mental Health and Cognitive Science, South China Normal University, Guangzhou, People’s Republic of China; 2Research Center for Guangdong-Hong Kong-Macao Policing Model Innovation, China People’s Police University, Guangzhou, People’s Republic of China; 3Department of Educational Psychology, Faculty of Education, The Chinese University of Hong Kong, Hong Kong, People’s Republic of China; 4Guangdong Provincial Hospital of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Dongfang Wang; Fang Fan, School of Psychology, South China Normal University, Shipai Road, Guangzhou, 510631, People’s Republic of China, Email wdfpsyc@126.com; fangfan@scnu.edu.cnPurpose: Although experimental psychopathology using PET, EEG, and fMRI is at the forefront of understanding the underlying mechanisms of sleep inertia, many questions concerning causality remain unanswerable due to ethical constraints and the use of small and heterogeneous samples in experimental methods. There is a pressing need for a novel perspective in a large and relatively homogeneous population to fully capture and elucidate longitudinal processes and dynamic causality that culminate in episodes of sleep inertia over time. Therefore, this study aimed to reveal the causal relationships between symptoms of sleep inertia across its distinct patterns.Patients and Methods: A total of 1636 intern nurses participated in the first survey (94.1% validity rate), then 1277 intern nurses were followed up (82.9% tracing rate). Symptoms of sleep inertia were self-reported using the Sleep Inertia Questionnaire. The cross-lagged panel network models were used to examine unique longitudinal relationships between symptoms of sleep inertia across distinct trajectories.Results: Four distinct trajectories of sleep inertia were established. Additionally, we found differences in those symptoms with the highest influence on other symptoms at the subsequent point across the networks of four trajectories, particularly, “Difficulty in concentrating” in the persistent-high group and “Feeling tense” in the deteriorating groups.Conclusion: The current study highlights changes in sleep inertia based on the long-term course over time. Notably, symptoms of “Difficulty in concentrating” and “Feeling tense” are imperative to address these specific symptoms within subpopulations.Keywords: sleep inertia, change patterns, network structures, intern nurse, shift work

Qichang Gao,1 Yiming Ma,1 Tuo Shao,1 Xiaoxuan Tao,2 Xiansheng Yang,1 Song Li,1 Jiaao Gu,1 Zhange Yu1 1Department of Spinal Surgery, The 1st Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, People’s Republic of China; 2Department of Radiotherapy, The 3st Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, People’s Republic of ChinaCorrespondence: Zhange Yu, Email yuzhange1967@163.comBackground: Progress in research on expression profiles in osteoarthritis (OA) has been limited to individual tissues within the joint, such as the synovium, cartilage, or meniscus. This study aimed to comprehensively analyze the common gene expression characteristics of various structures in OA and construct a diagnostic model.Methods: Three datasets were selected: synovium, meniscus, and knee joint cartilage. Modular clustering and differential analysis of genes were used for further functional analyses and the construction of protein networks. Signature genes with the highest diagnostic potential were identified and verified using external gene datasets. The expression of these genes was validated in clinical samples by Real-time (RT)-qPCR and immunohistochemistry (IHC) staining. This study investigated the status of immune cells in OA by examining their infiltration.Results: The merged OA dataset included 438 DEGs clustered into seven modules using WGCNA. The intersection of these DEGs with WGCNA modules identified 190 genes. Using Least Absolute Shrinkage and Selection Operator (LASSO) and Random Forest algorithms, nine signature genes were identified (CDADC1, PPFIBP1, ENO2, NOM1, SLC25A14, METTL2A, LINC01089, L3HYPDH, NPHP3), each demonstrating substantial diagnostic potential (areas under the curve from 0.701 to 0.925). Furthermore, dysregulation of various immune cells has also been observed.Conclusion: CDADC1, PPFIBP1, ENO2, NOM1, SLC25A14, METTL2A, LINC01089, L3HYPDH, NPHP3 demonstrated significant diagnostic efficacy in OA and are involved in immune cell infiltration.Keywords: osteoarthritis, machine learning, immune cells infiltration, diagnostic model

Danni Yang, Zhao Yu, Xianyou He Center for Studies of Psychological Application, South China Normal University, Guangzhou, People’s Republic of ChinaCorrespondence: Xianyou He, Email xianyouhe@163.comPurpose: The impact of moral beliefs on individuals’ moral judgments, particularly within the framework of contrasting cultural values such as collectivism and individualism, continues to be a subject of interest. This research delves into whether individuals with distinct values display differences in moral beliefs, with a specific focus on selflessness.Methods: Through experiment 1 and 2, we scrutinize the moral judgments of individuals with diverse values concerning pro-social behaviors driven by selflessness and in-group favoritism. Experiment 3 investigates the underlying mechanisms by examining reward expectations.Results: The findings from experiments 1 and 2 indicate that collectivists exhibit significantly higher moral judgment levels for selfless pro-social behaviors compared to individualists, highlighting a disparity in moral beliefs between the two value systems. Experimental 2 also found that collectivists’ moral judgments rose and fell as rescuers’ selflessness increased or decreased. However, individualist moral judgment did not change significantly with behavioral selflessness. The results reveal that collectivists hold higher reward expectations for selfless behavior, which contributes to their heightened moral judgment of selfless behavior.Conclusion: While it may be assumed that collectivists’ moral beliefs would be dominated by in-group preferences, aligning with the conceptual in-group preference of collectivism, this study unexpectedly found evidence of collectivists’ pursuit of selflessness in their moral beliefs. These findings offer initial evidence of distinct patterns of moral beliefs associated with collectivism and individualism, shedding light on potential reasons that lead collectivists to possess stronger moral beliefs about selflessness.Keywords: collectivism, individualism, moral beliefs, pro-social behavior, selflessness

Yun Han,1,&ast; Jianping Zhu,1,&ast; Jieqiong Liu,2 Ying Zheng,2 Gang Liang,1 Yi Yang,1 Lingyan Yu,3 Zhenwei Yu,1 Gang Han1 1Research Center for Clinical Pharmacy, Sir Run Run Shaw Hospital, School of Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, People’s Republic of China; 2The 903rd Hospital of PLA Joint Logistic Support Force, Hangzhou, People’s Republic of China; 3Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhenwei Yu; Gang Han, Email yzw_srrsh@zju.edu.cn; 3199022@zju.edu.cnIntroduction: Recent studies suggested the potential benefits of extended infusion times to optimize the treatment efficacy of ceftazidime/avibactam, which indicated that the current pharmacokinetic/pharmacodynamic (PK/PD) target may not be sufficient, especially for severe infections. The purpose of this study is to assess the adequacy of dosing strategies and infusion durations of ceftazidime/avibactam when applying higher PK/PD targets.Methods: This study utilized published PK parameters to conduct Monte Carlo simulations. Different dosages including the recommended regimen based on renal function were simulated and evaluated by the probability of target attainment (PTA) and cumulative fraction of response (CFR). Different PK/PD targets were set for ceftazidime and avibactam. MIC distributions from various sources were used to calculate the CFR.Results: Multiple PK/PD targets have been set in this study, All recommended dosage could easily achieve the target of 50%fT ≥ MIC (ceftazidime) and 50%fT ≥ CT=1.0 mg/L (avibactam). However, for severe infection patients with normal renal function and augmented renal clearance at the recommended dosage (2000 mg/500 mg, every 8 hours), the infusion duration needs to be extended to 3 hours and 4 hours to achieve the targets of 100%fT ≥ MIC and 100%fT ≥ CT=1.0 mg/L. Only continuous infusion at higher dosages achieved 100%fT ≥ 4×MIC and 100%fT ≥ CT=4.0 mg/L targets to all currently recommended regimens. According to the varying MIC distributions, higher concentrations are needed for Pseudomonas aeruginosa, with the attainment rates vary across different regions.Conclusion: The current recommended dosing regimen of ceftazidime/avibactam is insufficient for severe infection patients, and continuous infusion is suggested.Keywords: ceftazidime, avibactam, pharmacokinetic/pharmacodynamic, probability of target attainment

Li Zhang,1,2 Zimu Yu,3 Yunfeng Zhang,1 Hengyu Wang,4,5 Juntao Cheng,6 Chao Shi1 1Department of Oncology, Gaoxin Branch Of The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, People’s Republic of China; 2First School of Clinical Medicine, Jiangxi Medical College, Nanchang University, Nanchang, 330031, People’s Republic of China; 3Medical College of Zhengzhou University, Zhengzhou University, Zhengzhou, 450001, People’s Republic of China; 4Queen Mary College, Nanchang University, Nanchang, 330031, People’s Republic of China; 5School of Biological and Biomedical Sciences, Queen Mary University of London, London, UK; 6Peking University First Hospital, Peking University, Beijing, 100034, People’s Republic of ChinaCorrespondence: Chao Shi, The First Affiliated Hospital of Nanchang University, No. 17 Yongwaizheng Street, Donghu District, Nanchang, Jiangxi, 330006, People’s Republic of China, Tel +86 151 7049 8679, Email ndyfy4540@ncu.edu.cnPurpose: Although brain metastasis (BM) from gastric cancer (GC) is relatively uncommon, its incidence has been increasing owing to advancements in treatment modalities. Unfortunately, patients diagnosed with BM from gastric cancer have poor life expectancy. Our study aims to establish a predictive model for brain metastasis in advanced gastric cancer patients, thus enabling the timely diagnosis of brain metastasis.Patients and Methods: The clinicopathological features of a cohort which included 40 GC patients with brain metastasis, 32 of whom from the First Affiliated Hospital of Nanchang University, 2 from Gaoxin Branch of the First Affiliated Hospital of Nanchang University, remaining 6 from Anyang District Hospital, and 80 non-metastatic advanced GC patients from the First Affiliated Hospital of Nanchang University between 2018 and 2022. Data were retrospectively analyzed.Results: Age, tumor size, differentiation, lymph node grade, tumor location, Lauren classification, liver metastasis, carbohydrate antigen 199 (CA199), lactate dehydrogenase (LDH), and human epidermal growth factor receptor 2 (Her-2) were associated with BM. A nomogram integrated with nine risk factors (tumor size, differentiation, lymph node grade, tumor location, Lauren classification, liver metastasis, CA-199, LDH, and Her-2) showed good performance (Area Under Curve 0.95, 95% CI: 0.91– 0.98).Conclusion: We developed and validated a nomogram that achieved individualized prediction of the possibility of BM from GC. This model enables personalized imaging review schedules for timely brain metastasis detection in advanced gastric cancer patients.Keywords: brain metastasis, gastric cancer, nomogram, risk factors

Kaiwu Xu,1 Cailing Xiang,1 Zhige Yu,1 Jia Li,2 Changjun Liu2 1Department of Gastrointestinal Surgery, Hunan Provincial People’s Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, Hunan Province, 410005, People’s Republic of China; 2Department of Hepatobiliary Surgery, Hunan Provincial People’s Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, Hunan Province, 410005, People’s Republic of ChinaCorrespondence: Changjun Liu, Department of Hepatobiliary Surgery, Hunan Provincial People’s Hospital (The First Affiliated Hospital of Hunan Normal University), 61 Jiefang West Road, Changsha, Hunan Province, 410005, People’s Republic of China, Tel +86-0731-83928052, Email liuchangjun712@163.comPurpose: Strategies therapy for hepatocellular carcinoma (HCC) beyond oligometastasis are limited. The optimal sequence of systemic treatment for advanced HCC is not yet clear. Our study aims to evaluate the effectiveness of simultaneous lenvatinib combined PD-1 inhibitor on advanced HCC beyond oligometastasis.Patients and Methods: A total of 232 patients were enrolled in our retrospective study. Patients divided into three groups. (a) Lenvatinib plus simultaneous PD-1 inhibitor (Simultaneous group, n=58); (b) patients received PD-1 inhibitor before the tumor progression with continued lenvatinib administration (Before PD group, n=77); (c) patients received PD-1 inhibitor after the tumor progression (After PD group, n=97). To analyze overall survival (OS) and progression-free survival (PFS) among the three groups.Results: The estimated 6-, 12-, 18- and 24-mon OS for Simultaneous group patients were 100%, 93.1%, 63.4%, 48.3%, whereas the OS rates were 100%, 78%, 36.3%, 23.6% in Before PD group, and 99%, 61.2%, 22.1%, 7.5% in After PD group. The OS rates were obviously improved with the use of simultaneous PD-1 inhibitor among the three groups (P < 0.001). The estimated 3-, 6-, 9- and 12-month PFS rates for patients were 89.6%, 44.8%, 24.6%, 6% in After PD group, 90.9%, 59.7%, 27.3%, 12.4% in Before PD group and 98.3%, 81%, 51.7%, 39.7% in Simultaneous group, respectively. PFS rate was significantly different among the three groups (P < 0.001).Conclusion: Synchronous administration of lenvatinib and PD-1 inhibitors improved survival rate significantly. The synchronous combination could represent a promising strategy in HCC beyond oligometastasis.Keywords: lenvatinib, PD-1 inhibitor, hepatocellular carcinoma beyond oligometastasis, simultaneous, prognosis

Fei Zhou,1,2 Liyuan Liu,1,2 Fei Wang,1,2 Lixiang Yu,1,2 Yujuan Xiang,1,2 Chao Zheng,1,2 Shuya Huang,1,2 Zhen Yang,1 Zhigang Yu1,2 1Department of Breast Surgery, The Second Hospital of Shandong University, Jinan, Shandong, 250033, People’s Republic of China; 2Institute of Translational Medicine of Breast Disease Prevention and Treatment, Shandong University, Jinan, Shandong, 250033, People’s Republic of ChinaCorrespondence: Zhigang Yu, Department of Breast Surgery, The Second Hospital of Shandong University, Jinan, Shandong, 250033, People’s Republic of China, Tel +86-531-85875048, Email yzg@medmail.com.cnPurpose: Periductal mastitis (PDM) is a chronic inflammatory lesion of the breast with an unknown etiology, and it is difficult for clinicians to differentiate it from granulomatous lobular mastitis (GLM), although they have different treatment strategies and prognosis. This study aimed to investigate the differences in their clinicopathologic features to inform treatment strategies.Patients and Methods: Between 2011 and 2020, 121 patients diagnosed with PDM and 57 patients with GLM were retrospective analysis. Patient data were extracted on demographics, clinical presentation, pathologic characteristics, treatments and clinical response. Histopathological evaluations were performed on core needle biopsy specimens. Immunohistochemical stains using antibodies against CD3, CD4, CD8, CD20, and CD138 was performed to define immune cell infiltration.Results: PDM patients had a higher median age compared to GLM patients (38 vs 32, p< 0.001). PDM was primarily located in the areolar area, while GLM predominantly affected the peripheral quadrant of the breast (56.20% vs 75.44%, p< 0.001). Histopathologically, more ductal dilatation (90.08% vs 3.51%, p< 0.001), ductal wall thickening (47.93% vs 1.75%, p< 0.001), and ductal rupture (44.63% vs 5.26%, p< 0.001) were observed in PDM. GLM presented with significantly more granuloma (94.74% vs 10.74%, p< 0.001), microabscess (68.42% vs 28.93%, p< 0.001), and lipid vacuole (40.35% vs 8.26%, p< 0.001) formation than PDM. Immunohistochemical analysis revealed a significant presence of CD20+ B lymphocytes in PDM and a higher prevalence of CD8+ T lymphocytes in GLM, indicating differing immune responses. Treatment outcomes varied, with PDM patients responding well to surgery and anti-mycobacterial therapy, while GLM patients showed favorable responses to steroid therapy.Conclusion: PDM is a specific entity with a similar clinical presentation but distinct histopathological features and immune profiles to GLM. Further research is needed to elucidate the pathogenesis and optimize therapeutic approaches for these breast inflammatory conditions.Keywords: etiology, granulomatous lobular mastitis, immunology, pathology, periductal mastitis

Zirui Bian,1,&ast; Tianzhe Bao,2,&ast; Xuequan Sun,3,4 Ning Wang,1 Qian Mu,5 Ting Jiang,6 Zhongxiang Yu,6 Junhang Ding,2 Ting Wang,7 Qihui Zhou2 1Department of Bone, Huangdao District Central Hospital, Qingdao, People’s Republic of China; 2Qingdao Key Laboratory of Materials for Tissue Repair and Rehabilitation, School of Rehabilitation Sciences and Engineering, University of Health and Rehabilitation Sciences, Qingdao, People’s Republic of China; 3Weifang Eye Institute, Weifang Eye Hospital, Zhengda Guangming Eye Group, Weifang, People’s Republic of China; 4Zhengda Guangming International Eye Research Center, Qingdao Zhengda Guangming Eye Hospital, Qingdao University, Qingdao, People’s Republic of China; 5Department of Biomaterials, LongScience Biological (Qingdao) Co, LTD, Qingdao, People’s Republic of China; 6Heart Center, Qingdao Hiser Hospital Affiliated of Qingdao University (Qingdao Traditional Chinese Medicine Hospital), Qingdao University, Qingdao, People’s Republic of China; 7Department of Orthopaedic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qihui Zhou; Junhang Ding, Tel +86-17660670299, Email qihuizhou@uor.edu.cn; dingjunhang@uor.edu.cnIntroduction: The emergence and rapid spread of multidrug-resistant bacteria (MRB) caused by the excessive use of antibiotics and the development of biofilms have been a growing threat to global public health. Nanoparticles as substitutes for antibiotics were proven to possess substantial abilities for tackling MRB infections via new antimicrobial mechanisms. Particularly, carbon dots (CDs) with unique (bio)physicochemical characteristics have been receiving considerable attention in combating MRB by damaging the bacterial wall, binding to DNA or enzymes, inducing hyperthermia locally, or forming reactive oxygen species.Methods: Herein, how the physicochemical features of various CDs affect their antimicrobial capacity is investigated with the assistance of machine learning (ML) tools.Results: The synthetic conditions and intrinsic properties of CDs from 121 samples are initially gathered to form the raw dataset, with Minimum inhibitory concentration (MIC) being the output. Four classification algorithms (KNN, SVM, RF, and XGBoost) are trained and validated with the input data. It is found that the ensemble learning methods turn out to be the best on our data. Also, &epsiv;-poly(L-lysine) CDs (PL-CDs) were developed to validate the practical application ability of the well-trained ML models in a laboratory with two ensemble models managing the prediction.Discussion: Thus, our results demonstrate that ML-based high-throughput theoretical calculation could be used to predict and decode the relationship between CD properties and the anti-bacterial effect, accelerating the development of high-performance nanoparticles and potential clinical translation. Keywords: carbon dots, machine learning, antibacterial, minimum inhibitory concentration, classification algorithms

Xiaochen Chen,1,&ast; Jun Chen,2,&ast; Xue Zhao,2 Rongji Mu,1 Hongsheng Tan,1 Zhangsheng Yu1,3 1Clinical Research Institute & School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 2Clinical Research Center, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 3School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hongsheng Tan, Clinical Research Institute & School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People’s Republic of China, Email tanhs@shsmu.edu.cn Zhangsheng Yu, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 210240, People’s Republic of China, Email yuzhangsheng@sjtu.edu.cnAbstract: The coronavirus disease-2019 pandemic resulted in a major increase in depression and anxiety disorders worldwide, which increased the demand for mental health services. However, clinical interventions for treating mental disorders are currently insufficient to meet this growing demand. There is an urgent need to conduct scientific and standardized clinical research that are consistent with the features of mental disorders in order to deliver more effective and safer therapies in the clinic. Our study aimed to expose the challenges, complexities of study design, ethical issues, sample selection, and efficacy evaluation in clinical research for mental disorders. The reliance on subjective symptom presentation and rating scales for diagnosing mental diseases was discovered, emphasizing the lack of clear biological standards, which hampers the construction of rigorous research criteria. We underlined the possibility of psychotherapy in efficacy evaluation alongside medication treatment, proposing for a multidisciplinary approach comprising psychiatrists, neuroscientists, and statisticians. To comprehend mental disorders progression, we recommend the development of artificial intelligence integrated evaluation tools, the use of precise biomarkers, and the strengthening of longitudinal designs. In addition, we advocate for international collaboration to diversity samples and increase the dependability of findings, with the goal of improving clinical research quality in mental disorders through sample representativeness, accurate medical history gathering, and adherence to ethical principles.Keywords: clinical efficacy assessment, clinical trials, mental health, research design, statistical analysis

Zhenzhen Yu,1 Jianping Niu,1 Chen Wang2 1Department of Neurology, The Second Affiliated Hospital of Xiamen Medical College, Xiamen, Fujian, People’s Republic of China; 2Department of Neurology and Department of Neuroscience, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, People’s Republic of ChinaCorrespondence: Chen Wang, Department of Neurology and Department of Neuroscience, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Zhenhai Road No. 55, Siming District, Xiamen, Fujian, 361000, People’s Republic of China, Email wangchen1986xm@163.com Jianping Niu, Department of Neurology, The Second Affiliated Hospital of Xiamen medical college, Shengguang Road No. 566, Jimei District, Xiamen, Fujian, 361000, People’s Republic of China, Email 549872685@qq.comObjective: This study aims to evaluate the epidemiological features of sexual dysfunction in people aged more than 65 years in parts of China, and to investigate the independent significant risk factors.Methods: According to the population distribution of five communities in Xiamen and Chongqing, we have randomly enrolled 2403 people more than 65 years-of-age. We collected data information through a questionnaire survey. Then demonstrated the current condition of sexual dysfunction in the samples by statistical analysis, and multivariable logistic regression was used to disclose the risk factors of sexual dysfunction in the older adults.Results: According to this study, about 10.48% of the elderly had sexual dysfunctions of different degrees and duration. The proportion of men was about twice that of women (14.5% of males and 7.3% of females). During the course of the disease, 3.19% (43/1344) of women and 3.31% (35/1059) of men had more than 15 years duration of sexual dysfunction. In severity, 5.7% (77/1344) of women and 7.0% (74/1059) of men had very severe sexual dysfunction. There were statistically significant differences in BMI, smoking, drinking history, hypertension, depression incidence or median (p< 0.05). Alcohol consumption history [OR = 1.711, 95% CI: 1.124– 2.604, p = 0.012] and depression [OR = 2.107, 95% CI: 1.109– 4.356, p =0.044] were independent risk factors for sexual dysfunction.Conclusion: The prevalence of sexual dysfunction was low among elderly in the southern part of China. But the course of the disease is long and the degree of the disease is very severe. Elderly with a history of drinking and depression are more prone to sexual dysfunction.Keywords: epidemiology, sexual dysfunction, elderly, prevalence, risk factor

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

Zhe Yu,1– 3 Ruoqi Ding,1– 3 Qiuju Yan,1– 3 Menghan Cheng,1– 3 Teng Li,1– 4 Fei Zheng,5 Lin Zhu,1– 4 Yang Wang,1– 4 Tao Tang,1– 4 En Hu1– 4 1Institute of Integrative Medicine, Department of Integrated Traditional Chinese and Western Medicine, Xiangya Hospital, Central South University, Changsha, 410008, People’s Republic of China; 2NATCM Key Laboratory of TCM Gan, Xiangya Hospital, Central South University, Changsha, 410008, People’s Republic of China; 3Center for Interdisciplinary Research in Traditional Chinese Medicine, Xiangya Hospital, Central South University, Changsha, 410008, People’s Republic of China; 4Xiangya Hospital, Central South University, Nanchang, Jiangxi, 330004, People’s Republic of China; 5The College of Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, 410008, People’s Republic of ChinaCorrespondence: En Hu; Ruoqi Ding, Integrative Medicine, Department of Integrated Traditional Chinese and Western Medicine, Xiangya Hospital, Central South University, Changsha, 410008, People’s Republic of China, Email znxyhe@csu.edu.cn; ruoqi_ding@outlook.comPurpose: Many herbs can promote neurological recovery following traumatic brain injury (TBI). There must lie a shared mechanism behind the common effectiveness. We aimed to explore the key therapeutic targets for TBI based on the common effectiveness of the medicinal plants.Material and methods: The TBI-effective herbs were retrieved from the literature as imputes of network pharmacology. Then, the active ingredients in at least two herbs were screened out as common components. The hub targets of all active compounds were identified through Cytohubba. Next, AutoDock vina was used to rank the common compound-hub target interactions by molecular docking. A highly scored compound-target pair was selected for in vivo validation.Results: We enrolled sixteen TBI-effective medicinal herbs and screened out twenty-one common compounds, such as luteolin. Ten hub targets were recognized according to the topology of the protein-protein interaction network of targets, including epidermal growth factor receptor (EGFR). Molecular docking analysis suggested that luteolin could bind strongly to the active pocket of EGFR. Administration of luteolin or the selective EGFR inhibitor AZD3759 to TBI mice promoted the recovery of body weight and neurological function, reduced astrocyte activation and EGFR expression, decreased chondroitin sulfate proteoglycans deposition, and upregulated GAP43 levels in the cortex. The effects were similar to those when treated with the selective EGFR inhibitor.Conclusion: The common effectiveness-based, common target screening strategy suggests that inhibition of EGFR can be an effective therapy for TBI. This strategy can be applied to discover core targets and therapeutic compounds in other diseases.Keywords: traditional Chinese medicine, medicinal plants, luteolin, AZD3759, epidermal growth factor receptor, astrocyte

Zhao Liu,1,&ast; Ling Wang,2,&ast; Jiabing Sun,1,&ast; Qinghuan Zhang,3 Yue Peng,1 Susu Tang,1 Limei Zhang,4 Xiaobin Li,4,5 Zhijian Yu,1 Tao Zhang6 1Department of Otolaryngology, Zhuhai Hospital Affiliated with Jinan University (Zhuhai People’s Hospital), Zhuhai, People’s Republic of China; 2Department of Obstetrics, Zhuhai Hospital Affiliated with Jinan University (Zhuhai People’s Hospital), Zhuhai, 519000, People’s Republic of China; 3Department of Clinical Laboratory, Zhuhai Hospital Affiliated with Jinan University (Zhuhai People’s Hospital), Zhuhai, 519000, People’s Republic of China; 4Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Hospital Affiliated with Jinan University (Zhuhai People’s Hospital), Zhuhai, People’s Republic of China; 5Zhuhai Precision Medical Center, Zhuhai Hospital Affiliated with Jinan University (Zhuhai People’s Hospital), Zhuhai, People’s Republic of China; 6Department of Otolaryngology, The First Affiliated Hospital of Jinan University, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Tao Zhang; Zhijian Yu, Email 18045681156@163.com; yzjent@163.comObjective: Staphylococcus haemolyticus can cause a series of infections including otitis media (OM), and the oxacillin-resistant S. haemolyticus has become a serious health concern. This study aimed to investigate the genomic characteristics of two strains of oxacillin-resistant and mecA-positive S. haemolyticus isolated from the samples of ear swabs from patients with OM and explore their acquired antibiotic resistance genes (ARGs) and the mobile genetic elements (MGEs).Methods: Two oxacillin-resistant S. haemolyticus strains, isolated from ear swab samples of patients with OM, underwent antimicrobial susceptibility evaluation, followed by whole-genome sequencing. The acquired ARGs and the MGEs carried by the ARGs, harbored by the genomes of two strains of S. haemolyticus were identified.Results: The two strains of oxacillin-resistant S. haemolyticus (strain SH1275 and strain SH9361) both carried the genetic contexts of mecA with high similarity with the SCCmec type V(5C2& 5) subtype c. Surprisingly, the chromosomal aminoglycoside resistance gene aac(6’)-aph(2”) harbored by S. haemolyticus strain SH936 was flanked by two copies of IS 256, forming the IS 256-element (IS 256-GNAT-[aac(6’)-aph(2”)]-IS 256), which was widely present in strains of both Staphylococcus and Enterococcus genus. Furthermore, the two strains of oxacillin-resistant and MDR S. haemolyticus were found to harbor antimicrobial resistance plasmids, including one 26.9-kb plasmid (pSH1275-2) containing msr(A)–mph(C)) and qacA, one mobilizable plasmid pSH1275-3 harboring vga(A)LC, one plasmid (pSH9361-1) carrying erm(C), and one plasmid (pSH9361-2) carrying qacJ.Conclusion: The systematic analysis of whole-genome sequences provided insights into the mobile genetic elements responsible for multi-drug resistance in these two strains of oxacillin-resistant and mecA-positive S. haemolyticus, which will assist clinicians in devising precise, personalized, and clinical therapeutic strategies for treating otitis media caused by multi-drug resistant S. haemolyticus.Keywords: Staphylococcus haemolyticus, ear swabs, mecA, antimicrobial resistance plasmid, whole genome sequence

Jinchun Liu,1 Zhijun Yu,2,3 Guohua Wang2 1Department of Medicine, Henan Vocational College of Nursing, Anyang, Henan Province, 455000, People’s Republic of China; 2Department of Neurophysiology and Neuropharmacology, Institute of Special Environmental Medicine and Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu, 226019, People’s Republic of China; 3Department of Thoracic Surgery, Nantong Second People’s Hospital, Nantong, Jiangsu, 226001, People’s Republic of ChinaCorrespondence: Guohua Wang, Email wgh036@hotmail.comAbstract: Coronary artery fistulae (CAF) are a rare anomaly characterized by abnormal connections between a coronary artery and a cardiac chamber or a great vessel, with most patients remaining asymptomatic. Despite being predisposed to severe complications like heart failure, patients with CAF infrequently experience severe stenosis in the coronary artery. This study delineates a case involving a 46-year-old male presenting with a fistula bridging the right coronary artery (RCA) and right atrium (RA), manifesting a pronounced 99% stenosis at the right extremity of the coronary artery proximal to the fistula. Concurrently, the individual exhibits six conventional risk factors: age over 40, male gender, hypertension, diabetes, smoking, and hypertriglyceridemia. Following pharmaceutical intervention, the patient was discharged and subjected to extended follow-up. This case highlights the dual processes of “accelerating damage” and “retarding renewal” in the progression of atherosclerosis. Factors such as shear stress, smoking, and hypertension are posited to expedite endothelial cell damage, while aging and diabetes may impede the renewal and repair of these cells. Together with the concept of secondary atherosclerotic plaque healing, this case prompts the introduction of a “Double Endothelial Healings” hypothesis, proposing a potential pathogenetic mechanism for coronary artery atherosclerosis.Keywords: coronary artery fistulae, atherosclerosis, pathogenesis, plaque healing, endothelial injury

Yanping Guo,1 Zhangbin Yu,2 Huiying Tu,2 Biying Zheng,1 Jiamin Li,1 Ying Liu1 1Department of Pediatrics, Peking University Shenzhen Hospital, Shenzhen, Guangdong, People’s Republic of China; 2Department of Neonatology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University, the First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, People’s Republic of ChinaCorrespondence: Yanping Guo; Ying Liu, Tel +86-15919990131 ; +86-13902992158, Email guoyanping1223@163.com; 13902992158@139.comBackground and Objectives: To examine the correlation between the concentration of vitamin D (VD) in venous blood at approximately 4 weeks of age (± 4 weeks of age) and neonatal outcomes in preterm infants (birth weight < 1500 g or gestational age < 32 weeks) in two neonatal intensive care units (NICUs) located in Shenzhen, China.Methods and Study Design: Preterm infants were split into two groups based on their VD concentration at ± 4 weeks of age: VD insufficiency (VDI) group (≤ 20 ng/mL) and VD sufficient (VDS) group (> 20 ng/mL). Binary logistic regression analysis was used to examine relationships between outcomes and VDI.Results: Of 230 infants in total, 119 (51.7%) were assigned to the VDI group and 111 to the VDS group (48.3%). No correlation was found between serum VD at ± 4 weeks of age and gestational age (p> 0.05). The starting point of the two groups for oral VD intake did not differ significantly (p> 0.05). At ± 4 weeks of age, oral VD dose (P< 0.05) was greater in the VDS group. Gestational diabetes mellitus was associated with VDI (OR=1.94, 95% CI 1.01– 3.75, p=0.047) after controlling for this risk. Following correction for gestational age and oral VD dosage at ± 4 weeks old, VDI was also linked to a significant risk of retinopathy of prematurity (OR=2.00, 95% CI 1.08– 3.68, p< 0.027).Conclusion: Preterm newborns (gestational age < 32 weeks or birth age < 1500 g) in NICUs in Shenzhen, China continue to have significantly high VDI. Higher VDI is associated with gestational diabetes mellitus and retinopathy of prematurity.Keywords: very preterm birth, very low birth weight infant, vitamin D, 4 weeks of age, outcome

Reverberation mapping measurements have been used to constrain the relationship between the size of the broad-line region and luminosity of active galactic nuclei (AGN). This R-L relation is used to estimate single-epoch virial black hole masses, and has been proposed to use to standardize AGN to determine cosmological distances. We present reverberation measurements made with Hβ from the 6-yr Australian Dark Energy Survey (OzDES) Reverberation Mapping Program. We successfully recover reverberation lags for eight AGN at 0.12 < z < 0.71, probing higher redshifts than the bulk of Hβ measurements made to date. Our fit to the R-L relation has a slope of α = 0.41 ± 0.03 and an intrinsic scatter of σ = 0.23 ± 0.02 dex. The results from our multi-object spectroscopic survey are consistent with previous measurements made by dedicated source-by-source campaigns, and with the observed dependence on accretion rate. Future surveys, including LSST, TiDES, and SDSS-V, which will be revisiting some of our observed fields, will be able to build on the results of our first-generation multi-object reverberation mapping survey.

Yueliang Chen,1,&ast; Yun Han,2,3,&ast; Feng Guo,1 Zhenwei Yu2,3 1Intensive Care Unit, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China; 2Department of Pharmacy, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China; 3Research Center for Clinical Pharmacy, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Feng Guo; Zhenwei Yu, Email 3408003@zju.edu.cn; yzw_srrsh@zju.edu.cnAbstract: Imipenem is a broad-spectrum antibiotic that has been used in treating severe infections and exhibits a time-dependent PK/PD profile. Its dose should be adjusted based on renal function. However, there is little experience with imipenem dosing in obese adolescent patients with augmented renal clearance (ARC) and history of schizophrenia. This case reported successful dosing of imipenem in an obese adolescent patient with ARC based on therapeutic drug monitoring (TDM) and model-informed precision dosing (MIPD). A 15-year-old male adolescent patient with history of schizophrenia was diagnosed with ventilator-associated pneumonia due to carbapenem-susceptible Klebsiella pneumoniae and received imipenem treatment (0.5 g every 8 hours with a 1-hour infusion). However, the exposure of imipenem was suboptimal due to ARC, and there is no available model for MIPD in this patient. Thus, we utilized prediction error to find a population pharmacokinetic model that fit this patient and ran Maximum a posteriori Bayesian estimation and Monte Carlo simulation based on screened models to predict changes in drug concentrations. The dose of imipenem was adjusted to 0.5 g every 6 hours with a 2-hour infusion, and subsequent TDM revealed that dosing adjustment was accurate and successful. Finally, the patient’s status of infection improved. This study will be beneficial to imipenem dosing in similar cases in the future, thereby improving the safety and effectiveness of imipenem or other antibiotics.Keywords: case report, imipenem, therapeutic drug monitoring, population pharmacokinetic

Staphylococcus aureus has a high level of antibiotic resistance and is a common cause of nosocomial infections, which primarily requires development of new therapeutic strategies.Aim of the study was to investigate the level and spectrum of antibiotic resistance of S. aureus isolates for further isolation of virulent bacteriophages.Material and methods. The study used samples of clinical material obtained on the basis of the City Clinical Hospital No. 3 named after S.M. Kirov (Astrakhan). Bacterial strains isolated from patients were identified on the basis of morphological, cultural, biochemical and molecular genetic characteristics. The determination of the resistance of the isolated cultures was carried out by the disco-diffusion method using standardized commercial discs with antibiotics, in accordance with the guidelines.Results. Evaluation of antibiotic resistance of Staphylococcus aureus isolated during the study of clinical material from patients and analysis of sensitivity level of isolated strains of S. aureus allow us to conclude that all S. aureus isolated from patients are resistant to at least one antibiotic, and most strains are characterized by multidrug resistance to antibiotics.Conclusions. The presence of multi-resistant strains indicates the need to search for new approaches in the treatment of staphylococcal infection and to develop effective means for combination therapy based on virulent staphylococcal bacteriophages.

In September-October 2023 in the Hermitage-Siberia center of the Omsk Region Museum of Fine Arts. M. A. Vrubel hosted the exhibition «Siberian Seasons of the Leningrad Philharmonic. To the 80th anniversary of the 1943 tour»; the project had great public outcry. The exhibition featured unique documents, restored at the St. Petersburg Institute of History of the Russian Academy of Sciences, related to the stay and creative activities of the Philharmonic in the Siberian rear. A conversation with Yu. Z. Kantor, the curator of this museum project, that took place in October 2023, is devoted to its significance and substantive features.

Zhijun Zhang,1,2 Tiehong Yang,2 Jingwei Wang,2 Zhe Yu,2 Youbei Qiao,2 Chaoli Wang,2 Zhenggang Yue,1 Hong Wu2 1School of Pharmacy, Shaanxi University of Chinese Medicine, Xi’an, People’s Republic of China; 2Department of Medicine Chemistry and Pharmaceutical Analysis, School of Pharmacy, Air Force Medical University, Xi’an, People’s Republic of ChinaCorrespondence: Hong Wu, Department of Medicine Chemistry and Pharmaceutical Analysis, School of Pharmacy, Air Force Medical University, Xi’an, People’s Republic of China, Tel/Fax +86 29 84776823, Email wuhong@fmmu.edu.cn Zhenggang Yue, School of Pharmacy, Shaanxi University of Chinese Medicine, Xi’an, People’s Republic of China, Tel +86 18092086211, Email liuxingjian1981@163.comPurpose: The remarkable peroxidase-like activity of single-atom nanozymes (SAzymes) allows them to catalyze the conversion of H2O2 to •OH, rendering them highly promising for antibacterial applications. However, their practical in vivo application is hindered by the near-neutral pH and insufficient H2O2 levels present in physiological systems. This study was aimed at developing a SAzyme-based nanoreactor and investigating its in vivo antibacterial activity.Methods: We developed a hollow mesoporous molybdenum single-atom nanozyme (HMMo-SAzyme) using a controlled chemical etching approach and pyrolysis strategy. The HMMo-SAzyme not only exhibited excellent catalytic activity but also served as an effective nanocarrier. By loading glucose oxidase (GOx) with HMMo-SAzyme and encapsulating it with hyaluronic acid (HA), a nanoreactor (HMMo/GOx@HA) was constructed as glucose-triggered cascade catalyst for combating bacterial infection in vivo.Results: Hyaluronidase (HAase) at the site of infection degraded HA, allowing GOx to convert glucose into gluconic acid and H2O2. An acid environment significantly enhanced the catalytic activity of HMMo-SAzyme to promote the further catalytic conversion of H2O2 to •OH for bacterial elimination. In vitro and in vivo experiments demonstrated that the nanoreactor had excellent antibacterial activity and negligible biological toxicity.Conclusion: This study represents a significant advancement in developing a cascade catalytic system with high efficiency based on hollow mesoporous SAzyme, promising the advancement of biological applications of SAzyme. Keywords: nanozyme, nanocarrier, glucose oxidase, reactive oxygen species, bacterial infection

Yu Z, Chan S, Wang X, et al. Drug Des Devel Ther. 2023;17:993–1006. At the authors request, the Editor and Publisher of the journal Drug Design, Development and Therapy have retracted the published article. Following publication of the article, the authors raised concerns about the duplication of images from Figure 4. Specifically, The images for Figure 4G, HCT116, RUT and 5-FU, have been duplicated. The authors wished to apologize for this error and no longer have confidence in the data and corresponding findings. To maintain academic standards, the authors requested to retract the article and the Editor and Publisher agreed 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”.

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

Hao Qin,1,&ast; Wenjun Wang,2,&ast; Longlong Hu,1 Zuozhong Yu,1 Yang Chen,1 Yuanbin Zhao,1 Yanhui Liao,1 Renqiang Yang1 1Department of Cardiovascular Medicine, the Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, People’s Republic of China; 2Department of Respiratory Diseases, the Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Renqiang Yang, Department of Cardiovascular Medicine, the Second Affiliated Hospital of Nanchang University, 1 Minde Road, Nanchang, Jiangxi, 330006, People’s Republic of China, Tel +86-13979117790, Fax +86-0791-87357375, Email yangrenqiangcn@163.comBackground: Ischemic heart disease is one of the leading causes of death in the world, of which ST-segment elevation myocardial infarction (STEMI) is an important type. Inappropriate activation and accumulation of platelets typically induced thrombosis, which may result in acute vessel occlusion and STEMI. Multiple cytokines have been shown to regulate platelet activation, but the relationship between HMGB2 and platelet activation has not been elucidated.Methods: We collected peripheral blood of STEMI patients and healthy adults, and mass spectrometry analysis of platelet proteins was conducted. The “edgeR” package was used to identify the differentially expressed proteins (DEPs). The Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene ontology (GO) and Gene Set Enrichment Analysis (GSEA) were used to identify the significantly changed pathways. Western blot and ELISA were used to detect the expression of a high mobility group box 2 (HMGB2). Flow cytometric analysis and platelet aggregation rate were performed to evaluate the activation of platelets.Results: We identified ALOX5, HIST1H1B, S100A11, HMGB2, and RPS15A were the top five up-regulated proteins by differential expression analysis. Western blot verified that the relative protein expression of HMGB2 in platelet was significantly higher in STEMI patients compared with control adults, and the results of ELISA indicated that the serum HMGB2 level increased and significantly correlated with neutrophil count in STEMI patients. Further investigation showed that the platelet aggregation induced by ADP, the activation of integrin αIIbβ 3 and CD62P expression on platelet surface were all enhanced by the recombinant HMGB2 (rHMGB2).Conclusion: In conclusion, HMGB2 may be the key molecule to regulate platelet activation in patients with STEMI, which may serve as a potential therapeutic target for STEMI.Keywords: ST-segment elevation myocardial infarction, STEMI, proteomics analysis, platelet, HMGB2

We present the statistical methods that have been developed to analyse the OzDES reverberation mapping sample. To perform this statistical analysis we have created a suite of customizable simulations that mimic the characteristics of each source in the OzDES sample. These characteristics include: the variability in the photometric and spectroscopic light curves, the measurement uncertainties, and the observational cadence. By simulating the sources in the OzDES sample that contain the C iv emission line, we developed a set of criteria that rank the reliability of a recovered time-lag depending on the agreement between different recovery methods, the magnitude of the uncertainties, and the rate at which false positives were found in the simulations. These criteria were applied to simulated light curves and these results used to estimate the quality of the resulting Radius-Luminosity relation. We grade the results using three quality levels (gold, silver, and bronze). The input slope of the R-L relation was recovered within 1σ for each of the three quality samples, with the gold standard having the lowest dispersion with a recovered a R-L relation slope of 0.454 ± 0.016 with an input slope of 0.47. Future work will apply these methods to the entire OzDES sample of 771 AGN.