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Abstract Background The effectiveness of adipose-derived stem cells (ADSCs) in therapy diminishes with age. It has been reported that transcription factors (TFs) play a crucial role in the aging and functionality of stem cells. Nevertheless, there is limited understanding regarding the involvement of TFs in the aging mechanism of ADSCs. Methods RNA sequencing (RNA-seq) was utilized to discern the differentially expressed genes in ADSCs obtained from donors of varying ages. TFs exhibiting significant variations across age groups were identified and subsequently validated. ADSCs were manipulated to exhibit either enhanced expression or reduced levels of HES1 and STAT1 via lentivirus transfection and small interfering RNA (siRNA) techniques. The impact of these genetic alterations on ADSCs’ proliferation, migration, and cellular senescence was assessed using EdU, transwell, and senescence-activated β-galactosidase (SA-β-gal) staining assays. The DNA sequences bound by HES1 were investigated through the CUT & Tag assay. Lastly, the therapeutic efficacy of aged ADSCs with HES1 overexpression was evaluated in skin injury model of male Sprague-Dawley rats. Results 678 genes showed differential expression between ADSCs obtained from young and old donors (Y-ADSCs and O-ADSCs), with 47 of these genes being TFs. Notably, the expression of the TF hairy and enhancer of split 1 (HES1) was notably reduced in ADSCs from old donors. Introducing HES1 overexpression in aged ADSCs resulted in improved cellular function and the suppression of cellular senescence, while reducing HES1 levels in young ADSCs had the opposite effect. Mechanistically, HES1 was found to interact with the promoter region of another TF, signal transducer and activator of transcription 1 (STAT1), to inhibit its transcription. Knocking down STAT1 could fully reverse the negative effects caused by decreased HES1 in ADSCs, leading to a reduction in the secretion of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-8. Ultimately, restoring HES1 expression in aged ADSCs demonstrated enhanced therapeutic potential in promoting skin wound healing. Conclusion HES1 acts as an inhibitor of cellular senescence in the aging progression of ADSCs through the modulation of STAT1 expression, suggesting a promising avenue for rejuvenating senescent ADSCs and improving wound healing.

Yunqing Jiang,1,* Haowen Qi,2,* Mingjuan Wang,1 Kai Chen,3 Chen Chen,1 Haifeng Xie2 1Department of Endodontics, The Affiliated Stomatological Hospital of Nanjing Medical University, State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral Diseases, Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, 210029, People’s Republic of China; 2Department of Prosthodontics, The Affiliated Stomatological Hospital of Nanjing Medical University, State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral Diseases, Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, 210029, People’s Republic of China; 3Collaborative Innovation Center of Atmospheric Environment and Equipment Technology, Jiangsu Key Laboratory of Atmospheric Environment Monitoring and Pollution Control, School of Environmental Science and Engineering, Nanjing University of Information Science and Technology, Nanjing, 210044, People’s Republic of China*These authors contributed equally to this workCorrespondence: Chen Chen, Department of Endodontics, The Affiliated Stomatological Hospital of Nanjing Medical University, State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral Diseases, Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, 210029, People’s Republic of China, Tel +8625 69 593 031, Fax +8625 86 516 414, Email ccchicy@njmu.edu.cn Haifeng Xie Department of Prosthodontics, The Affiliated Stomatological Hospital of Nanjing Medical University, State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral Diseases (Nanjing Medical University), Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, 210029, People’s Republic of China, Tel +8625 69 593 081, Fax +8625 86 516 414, Email hfxie@njmu.edu.cn; xhf-1980@126.comPurpose: Based on nanomedicine strategies, this study employed cucurbit[7]uril (Q[7]) as the macromolecular carrier to synthesize nanocomplex drug delivery system for chlorogenic acid (CGA). The nanocomplex drug delivery system is intended to overcome the unsatisfactory biocompatibility and bioavailability of CGA and realizing its potential role in long-term osteoporosis (OP) medication.Methods: The nanocomplex was synthesized by the reflux stirring method. The chemical structure of the nanocomplex was characterized by Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), X-ray diffraction analysis (XRD), UV-visible spectrophotometry (UV-vis), zeta potential analysis and transmission electronic microscope (TEM). The Cell Counting Kit-8 (CCK-8) assay, Live/Dead staining assay, and cytoskeleton staining were conducted to testify the biocompatibility of the nanocomplex. The release assay, Ferric Reducing Ability of Plasma (Frap) assay and Reactive oxygen species (ROS) staining were implemented to evaluate the release profile of CGA as well as its remaining antioxidative levels.Results: CGA and Q[7] formed hydrogen bonding through an exclusion interaction, with the binding ratio more than 1:1. The nanocomplex had a crystalline and spherical-like structure and improved thermal stability. The nanocomplex demonstrated better biocompatibility than free CGA. The release profile of CGA from the nanocomplex was much steadier, and 70% of CGA was released in 5 days. The CGA released from the nanocomplex maintained its antioxidative properties at high levels and effectively eliminated the accumulated ROS in MC3T3-E1 cells under oxidative stress.Conclusion: Q[7] has been demonstrated to be an ideal nanocarrier for CGA and the nanocomplex delivery system holds the potential for the long-term medication strategy of OP. Keywords: Osteoporosis medication, Chlorogenic acid, Cucurbit[n]uril, Nano drug delivery system, Chemical analysis

JianJiang Pan,1,* XiXuan Cai,1,* JieRu Chen,1 MingYing Xu,1 JingYu Hu,1 YueChun Mao,1 Tao Chen,2 LuSha Li,1 MengQi Jin,1 LiYing Chen1 1Department of General Practice, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310020, People’s Republic of China; 2Department of General Practice, Jianqiao Community Health Service Center, Hangzhou, Zhejiang, 310021, People’s Republic of China*These authors contributed equally to this workCorrespondence: LiYing Chen, Department of General Practice, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, People’s Republic of China, Email 3197020@zju.edu.cnPurpose: Understanding the role of systemic inflammation in the development of Metabolic Syndrome (MetS) is crucial for identifying individuals at a higher risk of this cluster of conditions that increase the risk of heart disease, stroke, and diabetes.Patients and Methods: A retrospective cohort study was conducted with 4,312 participants who were free from MetS at the study’s onset and had high-sensitivity C-reactive protein (hsCRP) levels measured. Latent class trajectory modeling was utilized to identify distinct hsCRP trajectory patterns. Multivariable regression and proportional hazards analyses were employed to evaluate the predictive value of hsCRP trajectories for the development of MetS.Results: During the 1.63-year follow-up period, 1,308 participants developed metabolic syndrome (MetS). Individuals with high hsCRP levels exhibited a significantly increased risk of developing MetS compared to those with low hsCRP levels (HR = 1.062, 95% CI 1.103– 1.113). The hsCRP trajectory analysis identified three distinct groups: low-stable, increasing, and decreasing. The decreasing and increasing hsCRP trajectory groups demonstrated a 1.408-fold (95% CI 1.115– 1.779) and a 1.618-fold (95% CI 1.288– 2.033) increased risk of MetS, respectively.Conclusion: This study suggests that participants with higher baseline hsCRP levels and increasing hsCRP trajectories are associated with a progression toward MetS. Long-term hsCRP trajectories may serve as useful tools for identifying individuals at higher risk of MetS who could benefit from targeted preventive and therapeutic interventions.Keywords: high-sensitivity C-reactive protein, metabolic syndrome, trajectory analysis, retrospective cohort study, risk prediction

Xin Wu,1– 3,* Xinyu Wang,3,* Haiyan Zhang,3,* Hang Chen,3,* Haisheng He,2 Yi Lu,1,2 Zongguang Tai,1 Jianming Chen,3 Wei Wu1,2 1Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, 200443, People’s Republic of China; 2School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery, Ministry of Education, Shanghai, 201203, People’s Republic of China; 3Shanghai Wei Er Lab, Shanghai, 201707, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wei Wu, School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery, Ministry of Education, Shanghai, 201203, People’s Republic of China, Tel/Fax +86-21-64175590, Email wuwei@shmu.edu.cn Zongguang Tai, Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, 200443, People’s Republic of China, Tel/Fax +86-36803155, Email taizongguang@126.comPurpose: The clinical use of paclitaxel (PTX) in cancer treatment is limited by its poor water solubility, significant toxicity, and adverse effects. This study aimed to propose a straightforward and efficient approach to enhance PTX loading and stability, thereby offering insights for targeted therapy against tumors.Patients and Methods: We synthesized a paclitaxel palmitate (PTX-PA) prodrug by conjugating palmitic acid (PA) to PTX and encapsulating it into liposomal vehicles using a nano delivery system. Subsequently, we investigated the in vitro and in vivo performance as well as the underlying mechanisms of PTX-PA liposomes (PTX-PA-L).Results: PTX had a remarkable antitumor effect in vivo and significantly decreased the myelosuppressive toxicity of PTX. Moreover, the introduction of PA increased the lipid solubility of PTX, forming a phospholipid bilayer as a membrane stabilizer, prolonging the circulation time of the drug and indirectly increasing the accumulation of liposomes at the tumor site. Our in vivo imaging experiments demonstrated that PTX-PA-L labeled with DiR has greater stability in vivo than blank liposomes and that PTX-PA-L can target drugs to the tumor site and efficiently release PTX to exert antitumor effects. In a mouse model, the concentration of PTX at the tumor site in the PTX-PA-L group was approximately twofold greater than that of Taxol. However, in a nude mouse model, the concentration of PTX at the tumor site in the PTX-PA-L group was only approximately 0.8-fold greater than that of Taxol. Furthermore, the originally observed favorable pharmacodynamics in normal mice were reversed following immunosuppression. This may be caused by differences in esterase distribution and immunity.Conclusion: This prodrug technology combined with liposomes is a simple and effective therapeutic strategy with promising developmental prospects in tumor-targeted therapy owing to its ability to convert PTX into a long-circulating nano drug with low toxicity, high pharmacodynamics, and good stability in vivo.Keywords: paclitaxel palmitate liposome, prodrug, membrane stabilizer, esterase metabolism, Immunity

Liying Lu,1,2 Mengdan Pang,1,2 Tingting Chen,1,2 Yingying Hu,1,2 Likai Chen,3 Xiaoyue Tao,1,2 Shangqin Chen,1,2 Jianghu Zhu,1,2 Mingchu Fang,1,2 XiaoLing Guo,1,4 Zhenlang Lin1,2,4 1Department of Pediatrics, The Second School of Medicine, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China; 2Key Laboratory of Perinatal Medicine of Wenzhou, the Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China; 3Elson S. Floyd College of Medicine at Washington State University, Spokane, WA, USA; 4Basic Medical Research Center, the Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of ChinaCorrespondence: XiaoLing Guo; Zhenlang Lin, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, 109 Xueyuan West Road, Wenzhou, Zhejiang, 325027, People’s Republic of China, Tel +00-86-138-0668-9800, Fax +86-0577-88002198, Email guoxling@hotmail.com; linzhenlang@hotmail.comIntroduction: Neonatal hypoxic-ischemic encephalopathy (HIE), caused by perinatal asphyxia, is characterized by high morbidity and mortality, but there are still no effective therapeutic drugs. Mitochondrial biogenesis and apoptosis play key roles in the pathogenesis of HIE. Protopine (Pro), an isoquinoline alkaloid, has anti-apoptotic and neuro-protective effects. However, the protective roles of Pro on neonatal hypoxic-ischemic brain injury remain unclear.Methods: In this study, we established a CoCl2-induced PC12 cell model in vitro and a neonatal rat hypoxic-ischemic (HI) brain damage model in vivo to explore the neuro-protective effects of Pro and try to elucidate the potential mechanisms.Results: Our results showed that Pro significantly reduced cerebral infarct volume, alleviated brain edema, inhibited glia activation, improved mitochondrial biogenesis, relieved neuron cell loss, decreased cell apoptosis and reactive oxygen species (ROS) after HI damage. In addition, Pro intervention upregulated the levels of p-AMPK/AMPK and PGC1α as well as the downstream mitochondrial biogenesis related factors, such as nuclear respiratory factor 1 (NRF1) and mitochondrial transcription factor A (TFAM), but the AMPK inhibitor compound c (CC) could significantly reverse these effects of Pro.Discussion: Pro may exert neuroprotective effects on neonatal hypoxic-ischemic brain damage via activation of the AMPK/PGC1α pathway, suggesting that Pro may be a promising therapeutic candidate for HIE, and our study firstly demonstrate the neuro-protective roles of Pro in HIE models.Keywords: neonatal hypoxic-ischemic brain damage, protopine, reactive oxygen species, apoptosis, mitochondrial biogenesis

Haoxiang Wen,1,2,* Ruiming Liang,3,* Xiaofei Liu,4 Yang Yu,1 Shuirong Lin,1 Zimin Song,1 Yihao Huang,1 Xi Yu,1 Shuling Chen,5 Lili Chen,6 Baifeng Qian,1 Jingxian Shen,7 Han Xiao,8 Shunli Shen1 1Center of Hepato-Pancreatico-Biliary Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, People’s Republic of China; 2Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital and Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, Guangdong Province, People’s Republic of China; 3Department of Medical Statistics, Clinical Trials Unit, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, People’s Republic of China; 4Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-senUniversity, Guangzhou, Guangdong Province, People’s Republic of China; 5Precision Medicine Institute, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, People’s Republic of China; 6Department of Pathology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, People’s Republic of China; 7Department of Radiology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong Province, People’s Republic of China; 8Division of Interventional Ultrasound, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shunli Shen, Center of Hepato-Pancreatico-Biliary Surgery, The First Affiliated Hospital of Sun Yat-sen University, No. 58 Zhong-Shan Road2, Guangzhou, Guangdong Province, People’s Republic of China, Email Shenshli@mail.sysu.edu.cn Han Xiao, Division of Interventional Ultrasound, The First Affiliated Hospital of Sun Yat-sen University, No. 58 Zhongshan Road2, Guangzhou, Guang- Dong Province, People’s Republic of China, Email xiaoh69@mail.sysu.edu.cnPurpose: Predicting the pathological response after neoadjuvant conversion therapy for initially unresectable hepatocellular carcinoma (HCC) is essential for surgical decision-making and survival outcomes but remains a challenge. We aimed to develop a radiomics model to predict pathological responses.Methods: We included 203 patients with HCC who underwent hepatectomy after neoadjuvant conversion therapy between 2015 and 2023 and separated them into a training set (100 patients from Center A) and a validation set (103 patients from Center B). Pathological complete response (pCR)-related radiomic features were extracted from the largest tumor layer in the arterial and portal vein phases of the CT. A synthetic minority oversampling technique (SMOTE) was used to balance the minority groups in the training set. The SMOTE radiomics model was constructed using a logistic regression model in the SMOTE training set and its performance was verified in the validation set.Results: The AUC of the preoperative modified response evaluation criteria in solid tumors (mRECIST) assessment for pCR was 0.656 and 0.589 in the training and validation sets, respectively. The SMOTE radiomics model was established based on ten radiomic features and showed good pCR-predictive performance in the SMOTE training set (AUC, 0.889; accuracy, 87.7%) and the validation set (AUC: 0.843, accuracy: 86.4%). The RFS of the radiomics-predicted-pCR group was significantly better than that of the predicted-non-pCR group in the training cohort (P = 0.001, 2-year RFS: 69.5% and 30.1% respectively) and the validation cohort (P = 0.012, 2-year RFS: 65.9% and 38.0% respectively).Conclusion: The SMOTE radiomics model has great potential for predicting pathological response and evaluating RFS in patients with unresectable HCC after neoadjuvant conversion therapy.Keywords: hepatocellular carcinoma, radiomics, pathological complete response, neoadjuvant conversion therapy

Meng Xiang,1,* Chengzhi Chen,2,* Yuting Chen,1,* Yuhan Zhang,1 Lei Shi,1 Yan Chen,1 Jie Li,2 Bowen Li,1 Bin Zeng,2 H Rosie Xing,1 Jianyu Wang,2 Zhen Zou2 1State Key Laboratory of Ultrasound in Medicine and Engineering, College of Biomedical Engineering, Chongqing Medical University, Chongqing, 400016, People’s Republic of China; 2Molecular Biology Laboratory of Respiratory Disease, Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhen Zou; Jianyu Wang, Email zouzhen@cqmu.edu.cn; 102758@cqmu.edu.cnIntroduction: Inhalation exposure to silica nanoparticles (SiNPs) is frequently inevitable in modern times. Although the impact of SiNPs on the ecological niche of the lungs has been extensively explored, the role and mechanism of SiNPs in the microenvironment of lung tumors remain elusive.Methods: In this investigation, Lewis lung carcinoma (LLC) was implanted into the left lung in situ after 28 days of intratracheal SiNPs injection into the lungs of mice. This study evaluates the effects of SiNPs on the tumor immune microenvironment both in vitro and in vivo. Our findings indicate that SiNPs can suppress lung cancer by modulating the immune microenvironment of tumors.Results: SiNPs treatment promotes macrophage M1 polarization by activating both NF-κB pathway and glycolytic mechanisms. This phenomenon may be associated with lung inflammation and fluctuation in the pre-metastatic and metastatic microenvironments induced by SiNPs exposure in mice. Additionally, we have shown for the first time that SiNPs have an inhibitory effect on lung carcinogenesis and its progression.Conclusion: This study uniquely demonstrates that SiNPs suppress lung cancer by promoting M1 polarization of macrophages in the immune microenvironment of lung tumors. Our findings are critical in exploring the interaction between SiNPs and lung cancer. Keywords: silicon nanoparticles, lung cancer, macrophage polarization, NF-κB, glycolysis

Wenhao Chen,1 Yuanliang Liu,2 Xunwei Deng,3 Bin Li,1 Hao Wang,1 Guoliang Wei,1 Kehui Chen,1 Shen Wang1 1Center for Cardiovascular Diseases, Meizhou People’s Hospital, Meizhou, People’s Republic of China; 2Department of Computer Tomography, Meizhou People’s Hospital, Meizhou, People’s Republic of China; 3Research Experimental Center, Meizhou People’s Hospital, Meizhou, People’s Republic of ChinaCorrespondence: Wenhao Chen, Center for Cardiovascular Diseases, Meizhou People’s Hospital, Meizhou, People’s Republic of China, Email 18319255493@163.comObjective: Cytochrome P450 2C19 (CYP2C19) is a major enzyme involved in the biotransformation and metabolism of various substances. Loss-of-function of the CYP2C19 gene represents downregulation of CYP2C19 enzyme indication limited or no enzymatic function, which may be, in turn, associated with some disease susceptibility. The relationship between CYP2C19 polymorphisms and susceptibility to premature coronary artery disease (PCAD) is not fully understood. This study aimed to assess this relationship.Methods: This study included 635 PCAD patients, and 548 age-matched non-CAD individuals as controls, from November 2019 to August 2023. The CYP2C19 rs4244285 (681G > A, *2) and rs4986893 (636G > A, *3) were genotyped, and the distribution of CYP2C19 polymorphisms between patients and controls and the relationship between CYP2C19 polymorphisms and PCAD risk were analyzed.Results: A total of 442 (37.4%), 543 (45.9%), and 198 (16.7%) individuals had CYP2C19 extensive metabolizer (EM) (*1/*1), intermediate metabolizer (IM) (*1/*2 and *1/*3), and poor metabolizer (PM) (*2/*2, *2/*3, and *3/*3) phenotypes, respectively. CYP2C19 *2/*2 genotype frequency was higher, *1/*1 genotype was lower in PCAD patients than controls. Individuals with CYP2C19 PM phenotype had higher triglyceride (TG) levels than those with CYP2C19 EM or IM phenotypes. Logistic regression analysis showed that body mass index (BMI) ≥ 24.0 kg/m2 (≥ 24.0 kg/m2 vs 18.5– 23.9 kg/m2, odds ratio (OR): 1.326, 95% confidence interval (CI): 1.041– 1.688, p = 0.022), smoking (OR: 1.974, 95% CI: 1.283– 3.306, p = 0.002), hypertension (OR: 1.327, 95% CI: 1.044– 1.687, p = 0.021), diabetes mellitus (OR: 1.390, 95% CI: 1.054– 1.834, p = 0.020), CYP2C19 PM phenotype (PM phenotype vs EM phenotype, OR: 1.701, 95% CI: 1.200– 2.411, p = 0.003), and CYP2C19 IM+PM phenotypes (IM+PM vs EM phenotype, OR: 1.369, 95% CI: 1.077– 1.740, p = 0.010) were associated with PCAD.Conclusion: CYP2C19 PM or IM+PM phenotypes, overweight, smoking, hypertension, and diabetes mellitus were associated with PCAD.Keywords: premature coronary artery disease, cytochrome P450, CYP2C19, loss-of-function

Objective: We present prenatal diagnosis of a 14-Mb 11p11.2-p13 deletion by chromosome microarray analysis (CMA) in a pregnancy with fetal recombinant chromosome 11 syndrome of rec(11)del(11) (p11.2p13)ins(11) (q21p11.2p13) and maternal intrachromosomal insertion of ins(11) (q21p11.2p13). Case Report: A 25-year-old, primigravid woman underwent amniocentesis at 17 weeks of gestation because of a family history of psychiatric disorders in her two brothers and one maternal uncle. Array comparative genomic hybridization (aCGH) analysis of amniocentesis revealed a 14-Mb 11p13p11.2 deletion. The pregnancy was terminated at 19 weeks of gestation, and a 252-g fetus was delivered. Cytogenetic analysis of the parental bloods and cord blood revealed a karyotype of 46,XX,ins(11) (q21p11.2p13) in the mother, 46,XY in the father and 46,XY,rec(11)del(11) (p11.2p13)ins(11) (q21p11.2p13) in the fetus. aCGH analysis on the DNA extracted from cord blood revealed the result of arr 11p13q11.2 (32,697,424–46,712,173) × 1.0 [GRCh37] with a 14-Mb deletion of 11p13-p11.2 encompassing 54 OMIM genes including PHF21A, ALX4, EXT2 and SLC1A2. Polymorphic DNA marker analysis showed a maternal origin of the 11p deletion. The present case had an 11p13-p11.2 deletion encompassing 11p12-p11.3 which is associated with Potocki-Shaffer syndrome (PSS) or chromosome 11p11.2 deletion syndrome. Conclusion: CMA is useful for prenatal detection of fetal genomic imbalance in case of familial intrachromosomal insertion.

There are many ships and ports in Shanghai coastal zones, where disastrous weather occurs frequently. Meteorological disasters often threaten the safety of people’s lives and properties along the coast and in the ports. In the past, the meteorological warnings for Shanghai coastal zones are mainly based on those issued for Yangshan Port by Shanghai Marine Meteorological Centre (SMMC), which are called “unified warnings”. However, there are obvious differences in the time and intensity of meteorological disasters in each region, and the unified warnings cannot meet the needs of the production and operation of the shipping and ports. In 2020, Shanghai coastal zones were divided into five sub-zones, where the meteorological forecast and warnings were carried out separately from July 2020. Based on hourly observational data of the representative stations in Shanghai coastal zones and warning signal data from 2016 to 2022, the gale events are selected to analyse the statistical characteristics of temporal and spatial distribution and evaluate the forecast quality and the economic benefits of the zonal warnings. The results show that: (1) The farther away from the coastline, the more gale days, the higher the wind speed and the longer the duration; the higher the wind speed during the process, the more obvious the difference of wind scale. In particular, the wind scale caused by typhoons can range up to 5 levels. (2) Compared with the “unified warning”, the missing alarm rate (MAR) of gale warnings in each sea area has been reduced significantly, by up to 5%, the false alarm rate (FAR) for the western part of Yangtze River estuary is reduced by more than 8% and the TS score is significantly improved by more than 10%. (3) The advance time of gale warnings has been reduced by more than 3 hours, the maintaining duration has been shortened by more than 16 hours at most, which can reduce the loss of nearly 18 million RMB and improve the production efficiency of the coastal zones of Shanghai greatly. The results of this paper show that refined marine meteorological forecasts and early warnings provide a safety guarantee for marine transportation and port production operations, resulting in significant social and economic benefits and the enhancement of the comprehensive guarantee level of marine meteorological services in Shanghai. In the next step, we will continue to research and develop more refined objective forecast methods adapted to this business, then build a regional shared operational system platform and extend it to the Yangtze River Delta region, so as to promote the high-quality development of shipping meteorological integration in the Yangtze River Delta region.

Zhiyan Dai,1,* Chao Chen,2,3,* Ziyan Zhou,1,2 Mingzhen Zhou,1,2 Zhengyao Xie,1 Ziyao Liu,1 Siyuan Liu,1 Yiqiang Chen,1 Jingjing Li,1 Baorui Liu,2 Jie Shen1,2 1Department of Precision Medicine, Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing, People’s Republic of China; 2Department of Oncology, Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing, People’s Republic of China; 3Department of Oncology, Jinling Hospital, Clinical College of Nanjing Medical University, Nanjing, 21002, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jie Shen, Department of precision medicine, Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing, People’s Republic of China, Email shenjie2008nju@163.com Baorui Liu, Department of Oncology, Nanjing Drum Tower Hospital,Clinical College of Nanjing Medical University, 321 Zhongshan Road, Nanjing, 210008, People’s Republic of China, Email baoruiliu@nju.edu.cnBackground: Immune checkpoint inhibitor (ICI) therapy is a promising treatment for cancer. However, the response rate to ICI therapy in hepatocellular carcinoma (HCC) patients is low (approximately 30%). Thus, an approach to predict whether a patient will benefit from ICI therapy is required. This study aimed to design a classifier based on circulating indicators to identify patients suitable for ICI therapy.Methods: This retrospective study included HCC patients who received immune checkpoint inhibitor therapy between March 2017 and September 2023 at Nanjing Drum Tower Hospital and Jinling Hospital. The levels of the 17 serum biomarkers and baseline patients’ characters were assessed to discern meaningful circulating indicators related with survival benefits using random forest. A prognostic model was then constructed to predict survival of patients after treatment.Results: A total of 369 patients (mean age 56, median follow-up duration 373 days,) were enrolled in this study. Among the 17 circulating biomarkers, 11 were carefully selected to construct a classifier. Receiver operating characteristic (ROC) analysis yielded an area under the curve (AUC) of 0.724. Notably, patients classified into the low-risk group exhibited a more positive prognosis (P = 0.0079; HR, 0.43; 95% CI 0.21– 0.87). To enhance efficacy, we incorporated 11 clinical features. The extended model incorporated 12 circulating indicators and 5 clinical features. The AUC of the refined classifier improved to 0.752. Patients in the low-risk group demonstrated superior overall survival compared with those in the high-risk group (P = 0.026; HR 0.39; 95% CI 0.11– 1.37).Conclusion: Circulating biomarkers are useful in predicting therapeutic outcomes and can help in making clinical decisions regarding the use of ICI therapy.Keywords: hepatocellular carcinoma, predictive model, immunotherapy, machine learning

Yining Li, Yulin Chen, Hui Zhang, Weidong Chen, Yan Pan Department of Nephrology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, People’s Republic of ChinaCorrespondence: Weidong Chen; Yan Pan, Department of Nephrology, The First Affiliated Hospital of Bengbu Medical University, 287 Changhuai Road, Bengbu, People’s Republic of China, Email cwd2012@163.com; py19841205@163.comPurpose: The glucagon-like peptide-1 receptor agonist (GLP-1RA) is a pharmacological agent utilized for the treatment of diabetes, known for its significant reno protective effects. This study aims to investigate the impact of liraglutide, a representative GLP-1RA medication, on early endothelial dysfunction in diabetic rats and elucidate its underlying mechanisms.Methods: The present study employed a high-fat, high-sugar diet in combination with a single intraperitoneal injection of streptozotocin (STZ) to establish an experimental rat model of diabetes. Subsequently, the therapeutic efficacy of liraglutide on renal injury in this model was evaluated using various doses.Results: Compared to the DKD rats, the rats treated with Liraglutide exhibited significant reductions in levels of blood glucose (Glu), serum creatinine (Scr), and blood urea nitrogen (BUN) (P < 0.05). Furthermore, there was a dose-dependent decrease in urinary protein levels, including 24-hour urinary protein excretion rate and microalbuminuria (m-ALB), with higher doses demonstrating more pronounced therapeutic effects (P < 0.05). In addition, treatment with Liraglutide effectively improved glomerular and interstitial damage, and suppressed the expression of CD31, CD34, and VE-cadherin associated with endothelial cell injury (P < 0.05). Furthermore, Liraglutide administration significantly increased nitric oxide (NO) production (P < 0.05). Moreover, Liraglutide treatment resulted in decreased expression of vascular endothelial growth factor (VEGF), Delta-like ligand-4(Dll4), and Notch2 protein in the Notch2 signaling pathway (P < 0.05).Conclusion: The findings indicate that Liraglutide has a substantial effect on decreasing urinary protein excretion and improving vascular microinflammation, thus alleviating endothelial dysfunction in diabetic nephropathy. This observed mechanism can be attributed to the inhibition of the Dll4/Notch2 signaling pathway.Keywords: diabetic kidney disease, Dll4/Notch2 signaling pathway, endothelial dysfunction, liraglutide, VEGF

Xiaolan Guo,1 Dansen Wu,1 Xiaoping Chen,2 Jing Lin,1 Jialong Chen,1 Liming Wang,1 Songjing Shi,1 Huobao Yang,1 Ziyi Liu,3 Donghuang Hong1,4 1Department of Critical Care Medicine, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, Fuzhou, Fujian, People’s Republic of China; 2Computer Science and Mathematics, Fujian University of Technology, Fuzhou, Fujian, People’s Republic of China; 3Department of Urology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 4Fujian Provincial Key Laboratory of Critical Care Medicine, Fuzhou, Fujian, People’s Republic of ChinaCorrespondence: Ziyi Liu, Department of Urology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, No. 160, Pujian Road, Pudong District, Shanghai, 200127, People’s Republic of China, Email liu-ziyi@sjtu.edu.cn Donghuang Hong, Department of Critical Care Medicine, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, No. 134, Dongjie Street, Gulou District, Fuzhou, Fujian, 350001, People’s Republic of China, Email hongdh2003@fjmu.edu.cnPurpose: The objective of this study was to identify the risk factors associated with Carbapenem-resistant Enterobacteriaceae (CRE) colonization in intensive care unit (ICU) patients and to develop a predictive risk model for CRE colonization.Patients and Methods: In this study, 121 ICU patients from Fujian Provincial Hospital were enrolled between January 2021 and July 2022. Based on bacterial culture results from rectal and throat swabs, patients were categorized into two groups: CRE-colonized (n = 18) and non-CRE-colonized (n = 103). To address class imbalance, Synthetic Minority Over-sampling Technique (SMOTE) was applied. Statistical analyses including T-tests, Chi-square tests, and Mann–Whitney U-tests were employed to compare differences between the groups. Feature selection was performed using Lasso regression and Random Forest algorithms. A Logistic regression model was then developed to predict CRE colonization risk, and the results were presented in a nomogram.Results: After applying SMOTE, the dataset included 198 CRE-colonized patients and 180 non-CRE-colonized patients, ensuring balanced groups. The two groups were comparable in most clinical characteristics except for diabetes, previous emergency department admission, and abdominal infection. Eight independent risk factors for CRE colonization were identified through Random Forest, Lasso regression, and Logistic regression, including Acute Physiology and Chronic Health Evaluation (APACHE) II score > 16, length of hospital stay > 31 days, female gender, previous carbapenem antibiotic exposure, skin infection, multi-site infection, immunosuppressant exposure, and tracheal intubation. The risk prediction model for CRE colonization demonstrated high accuracy (87.83%), recall rate (89.9%), precision (85.6%), and an AUC value of 0.877. Patients were categorized into low-risk (0– 90 points), medium-risk (91– 160 points), and high-risk (161– 381 points) groups, with corresponding CRE colonization rates of 1.82%, 7.14%, and 58.33%, respectively.Conclusion: This study identified independent risk factors for CRE colonization and developed a predictive model for assessing the risk of CRE colonization.Keywords: carbapenem-resistant Enterobacteriaceae, intensive care unit, colonization, risk factors, risk prediction model

Yongru Chen,1 Chongyue Chen,1 Wei Chen,2,3 Wei Gai,4 Yafeng Zheng,4 Yuxin Guo,4 Zhaoning Wang,1 Yongsong Chen,1 Zhiming Cai1,5,6 1The First Affiliated Hospital of Shantou University, Shantou, Guangdong, People’s Republic of China; 2Department of Urology, Shenzhen Institute of Translational Medicine, Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, International Cancer Center, Shenzhen University School of Medicine, Shenzhen, People’s Republic of China; 3Guangdong Key Laboratory of Systems Biology and Synthetic Biology for Urogenital Tumors, Shenzhen, People’s Republic of China; 4WillingMed Technology (Beijing) Co., Ltd, Beijing, People’s Republic of China; 5BGI Genomics, BGI Shenzhen, Shenzhen, People’s Republic of China; 6Carson International Cancer Center, Shenzhen University, Shenzhen, People’s Republic of ChinaCorrespondence: Zhiming Cai, Carson International Cancer Center of Shenzhen University, No. 1066, Xueyuan Road, Shenzhen, Guangdong Province, People’s Republic of China, Tel +86 136 0253 0322, Email caizhiming2000@163.com Yongsong Chen, The First Affiliated Hospital of Shantou University, No. 57, Changping Road, Shantou, Guangdong Province, People’s Republic of China, Tel +86 0754-88905000, Email yongsongchen@126.comPurpose: This study aimed to evaluate the clinical utility of metagenomic next-generation sequencing (mNGS) in sepsis patients who received early empirical antibiotic treatment.Patients and Methods: A retrospective analysis was conducted on clinical data from sepsis patients diagnosed in the Emergency Intensive Care Unit (EICU) between April 2019 and May 2023. All patients underwent standard conventional microbiological testing. Patients were categorized into either the mNGS group or the control group based on whether they underwent mNGS tests. Baseline variables were matched using propensity scores.Results: Out of 461 sepsis patients screened, 130 were included after propensity matching, with 65 patients in each group. Despite prior antibiotic treatment, 57 cases (87.69%) in the mNGS group had positive mNGS results, exceeding the culture detection rate (52.31%). Besides, a higher proportion of patients in the mNGS group experienced antibiotic adjustments compared to the control group (72.31% vs 53.85%). Mortality rates were also compared based on the duration of antibiotic exposure before mNGS sampling. Patients exposed to antibiotics for less than 24 hours had a lower mortality rate compared to those exposed for over 8 days (22.22% vs 42.86%). COX multivariate analysis identified mNGS testing, underlying diseases, lymphocyte percentage, infection site (respiratory and bloodstream) as independent risk factors for mortality in sepsis patients.Conclusion: With increased antibiotic exposure time, the positive rate of culture testing significantly decreased (44.44% vs 59.52% vs 35.71%, P = 0.031), whereas the positive rate of mNGS remained stable (77.78% vs 88.10% vs 92.86%, P = 0.557). mNGS demonstrated less susceptibility to antibiotic exposure. Early mNGS detection positively impacted the prognosis of sepsis patients.Keywords: metagenomic next-generation sequencing, sepsis, antibiotic management, clinical value, prognosis

Xiang Tang,1,2,&ast; Jinbin Chen,1,2,&ast; Wei Peng,1,2,&ast; Zhoutian Yang,1,2 Li Hu,1,2 Zhiwei Ye,1,2 Yizhen Fu,1,2 Dandan Hu,1,2 Zhongguo Zhou,1,2 Minshan Chen,1,2 Yaojun Zhang,1,2 Jun-Cheng Wang1,2 1State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, People’s Republic of China; 2Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yaojun Zhang; Jun-Cheng Wang, Department of Liver Surgery, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, Guangdong, 510060, People’s Republic of China, Email zhangyuj@sysucc.org.cn; wangjch@sysucc.org.cnObjection: To report the efficacy and safety of triple combination therapy with bevacizumab plus anti-PD-1 (BP1) or anti-PD-L1 inhibitors (BPL) combined with hepatic arterial infusion chemotherapy (HAIC) as a first-line treatment for initially unresectable hepatocellular carcinoma (uHCC).Methods: In this retrospective study, patients with initially uHCC received either BP1-HAIC or BPL-HAIC as first-line treatment. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS), objective response rate (ORR) and disease control rate (DCR).Results: Between January 2020 and December 2022, a total of 136 patients with initially uHCC received triple combination therapy, with 76 in the BP1-HAIC group and 60 in the BPL-HAIC group. The median PFS for the entire cohort was 11.1 months (95% CI, 8.0– 13.7 months), and the median OS was 22.4 months (95% CI, 21.3- not reached). Comparative analysis revealed no significant differences in PFS (HR, 0.91, P = 0.69) or OS (HR, 0.71, P = 0.31) between the BP1-HAIC and BPL-HAIC groups. The ORR was 46.3% per RECIST v1.1 and 66.9% per mRECIST, with a DCR of 83.1% under both criteria. Common adverse events (AEs) included hypoalbuminemia and elevated aspartate/alanine aminotransferase, with 5.1% (7/136) experienced upper gastrointestinal bleeding. Multivariate Cox analysis identified tumor number and BCLC stage as independent prognostic factors for OS, and tumor number for PFS.Conclusion: Triple combination therapy demonstrated significant therapeutic efficacy and tumor response in initially uHCC. No notable differences in outcomes were observed between the BP1-HAIC and BPL-HAIC groups. AEs were manageable in clinical practice.Keywords: hepatocellular carcinoma, immune checkpoint inhibitor, bevacizumab, hepatic arterial infusion chemotherapy, adverse event

Qiong Chen,1,* Yanjin Huang,2,* Xiaomei Chen,3 Limin Xu1 1Department of Intensive Care Medicine, Xiamen Haicang Hospital, Xiamen, Fujian, People’s Republic of China; 2Department of Nursing, Xiamen Haicang Hospital, Xiamen, Fujian, People’s Republic of China; 3Department of Pain, Xiamen Haicang Hospital, Xiamen, Fujian, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qiong Chen, Department of Intensive Care Medicine, Xiamen Haicang Hospital, No. 89 haiyu Road, Haicang District, Xiamen, Fujian, 361026, People’s Republic of China, Tel +86 177 50612461, Email chenqiongfff@163.comPurpose: Post-traumatic stress disorder (PTSD) is a major psychiatric health issue among intensive care unit (ICU) survivors with post-intensive care syndrome (PICS). Although early PTSD intervention has been demonstrated to decrease the risk of progression from acute to chronic PTSD, information on the progression trajectory of short-term PTSD symptoms and modifiable risk factors in PICS patients is limited. This study aimed to explore the clinical progression trajectories of short-term PTSD symptoms and the associated factors in PICS patients by conducting a prospective longitudinal observational study.Patients and Methods: This study was conducted at a tertiary hospital in China. The impact of event scale-revised was used to collect data on the PTSD symptoms of patients at 1, 2, 3, and 4 months post-discharge from the ICU. The latent growth mixture model was used to construct trajectory models for PTSD symptoms and multivariate logistic regression was used to determine the factors associated with the trajectories.Results: A total of 130 ICU survivors with PICS completed the 4-month short-term follow-up. Our results showed that PTSD symptoms in PICS patients manifested as three trajectories, namely, moderate chronic (n = 17, 13.1%), recovery (n = 25, 19.2%), and resilience (n = 88, 67.7%). Compared with the resilience trajectory, age and female were identified as risk factors for the moderate chronic trajectory, while prolonged ICU stay was a risk factor for the recovery trajectory.Conclusion: Our study showed that short-term PTSD symptoms in PICS patients manifested as moderate chronic, recovery, and resilience trajectories. Additionally, our results showed that PTSD screening should be conducted for critically ill patients, especially younger, female, or long-term ICU patients, immediately after their discharge from the ICU.Keywords: post-traumatic stress disorder, latent growth mixture model, longitudinal study, post-intensive care syndrome

Jiamin Yu,1 Yongxia Chen,1 Xiaoyan Pan,1 Ji Chen,1 Zhenhua Mai,1 Yuanli Zhang,1 Xiaoyan Wang,2– 4 Gaosheng Zhou,5 Sayed Adam Bukhari,6 Daqing Ma,6,7 Liehua Deng1 1Department of Critical Care Medicine, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524000, People’s Republic of China; 2Doctoral Scientific Research Center, Lianjiang People’s Hospital, Zhanjiang, 524400, People’s Republic of China; 3Affiliated Lianjiang People’s Hospital, Guangdong Medical University, Zhanjiang, 524400, People’s Republic of China; 4Laboratory of Southern Marine Science and Engineering, Zhanjiang, 524023, People’s Republic of China; 5Department of Critical Care Medicine, The First College of Clinical Medical Science, China Three Gorges University, Yichang Central People’s Hospital, Yichang, Hubei, 443003, People’s Republic of China; 6Division of Anaesthetics, Pain Medicine & Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London, SW10 9NH, UK; 7Perioperative and Systems Medicine Laboratory, The Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, People’s Republic of ChinaCorrespondence: Liehua Deng, Email glinson@126.comPurpose: The early diagnosis of septic cardiomyopathy remains a challenge. The present work aims to evaluate the diagnostic and prognostic value of plasma soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) levels in septic cardiomyopathy when compared with traditional myocardial biomarkers.Methods: In the 143 sepsis enrolled patients, 67 and 76 patients were classified as non-septic cardiomyopathy and septic cardiomyopathy, respectively. Their blood samples were harvested up to 14th day after hospital admission for measurements of sTREM-1 and other biomarkers, such as N-terminal pronatriuretic peptide (NT-proBNP), highly sensitive troponin (TNT-HS), myoglobin (MYO), creatine kinase isoenzyme (CK-MB), etc. All the data were collected at 8:00 a.m. The area under the receiver operating characteristic curve was obtained to assess the diagnostic accuracy of those biomarkers. The Log rank test was utilized to evaluate the prognostic value of sTREM-1 on septic cardiomyopathy.Results: Circulating sTREM-1 showed a high specificity (88.1%) and moderate sensitivity (64.5%) to distinguish patients with septic cardiomyopathy in the 143 septic patients. The diagnostic efficiency of sTREM-1 was higher than inflammatory biomarkers and traditional myocardial markers. Logistic regression revealed that plasma sTREM-1 was an independent predictor of septic cardiomyopathy. Furthermore, in the whole septic cardiomyopathy cohorts, the sTREM-1 levels in the non-survivors were significantly higher than those of survivors during ICU stay. In addition, the left ventricular systolic dysfunction had a high odds ratio (3.968) to predict 90-day mortality in septic patients with cardiomyopathy.Conclusion: High plasma sTREM-1 level may be a diagnostic marker in predicting ICU poor outcome of patients with septic cardiomyopathy.Keywords: sepsis, septic cardiomyopathy, diagnosis, sTREM-1

Yi Zhou,1 Xinyu Xiong,1 Zhe Cheng,1 Zekai Chen,1 Shizhen Wu,2 Yan Yu,3 Yujin Liu,4 Guang Chen,1 Lingli Li5 1Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China; 2College of Acupuncture and Bone Injury, Hubei University of Chinese Medicine, Wuhan, 430061, People’s Republic of China; 3Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China; 4Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China; 5Department of Traditional Chinese Medicine, Wuhan Fourth Hospital, Wuhan, 430033, People’s Republic of ChinaCorrespondence: Lingli Li, Department of Traditional Chinese Medicine, Wuhan Fourth Hospital, Wuhan, 430033, People’s Republic of China, Email 379994890@qq.com Guang Chen, Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China, Email guangchen@tjh.tjmu.edu.cnPurpose: Ginseng (Panax ginseng Meyer) is an herbal medicine used in traditional Chinese medicine (TCM), has the effects of treating colitis and other diseases. Ginsenoside Rb1 (GRb1), a major component of ginseng, modulates autoimmunity and metabolism. However, the mechanism underlying GRb1 treatment of ulcerative colitis (UC) has not yet been elucidated. UC is a refractory inflammatory bowel disease (IBD) with a high recurrence rate, and researches on new drugs for UC have been in the spotlight for a long time.Methods: Mice with DSS-induced UC were treated with GRb1 or 0.9% saline for 10 days. Colon tissue of UC mice was collected to detect the levels of intestinal inflammatory cytokines and integrity of the intestinal barrier. RNA-seq and network pharmacology were used to predict the therapeutic targets of GRb1 during UC treatment.Results: GRb1 treatment alleviated intestinal inflammation and improved intestinal barrier dysfunction in UC mice. Specifically, GRb1 downregulated the levels of pro-inflammatory cytokines such as TNF-α and IL-6, while upregulating the level of the anti-inflammatory cytokine IL-10. Additionally, GRb1 treatment increased the levels of tight junction proteins including ZO-1, Occludin, and E-cadherin, which are crucial for maintaining intestinal barrier integrity. Further analyses using RNA-seq and network pharmacology suggested that these effects might involve the regulation of GRb1 in the signal transduction network of VDR, PPARγ, and NF-κB.Conclusion: The study demonstrated that GRb1 effectively alleviated UC by modulating intestinal inflammation and protecting the integrity of the intestinal barrier through the signal transduction network of VDR, PPARγ, and NF-κB.Keywords: ginsenoside Rb1, ulcerative colitis, intestinal barrier, vitamin D receptor, nuclear factor-kappa B

Shengfeng Liu,1,2 Jian Liu,1,2 Xueni Cheng,1 Dahai Fang,1 Xiaolu Chen,1 Xiang Ding,1 Xianheng Zhang,1 Yiming Chen1 1Department of Rheumatology, the First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, Anhui Province, People’s Republic of China; 2Anhui Key Laboratory of Application and Development of Internal Medicine of Modern Chinese Medicine, Anhui University of Chinese Medicine, Hefei, Anhui Province, People’s Republic of ChinaCorrespondence: Jian Liu, Department of Rheumatology, the First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, Anhui Province, People’s Republic of China, Tel +86 13955109537, Email liujianahzy@126.comAbstract: Rheumatoid arthritis (RA) is a chronically progressive autoimmune disease with increasing age-standardized prevalence and incidence of RA worldwide. Its pathological features are persistent synovitis of the joint, accompanied by the release of a large number of inflammatory cytokines and cartilage and bone destruction. RA can lead to progressive joint damage, stiffness and swelling, vascular and bone-related complications, and irreversible disability, which seriously affects patients’ life treatment. Early diagnosis and treatment can enhance the quality of life of RA patients. Platelet-to-lymphocyte ratio (PLR), as a common indicator in routine blood tests, has been proposed as an indicator of systemic inflammation in recent years. Its clinical detection is less invasive, economical, rapid and simple, and has been applied to the clinical evaluation of a variety of diseases. Of note, this indicator is important in assessing disease activity in RA, co-diagnosing RA, detecting subclinical complications, and monitoring responses to anti-inflammatory therapy. Therefore, this review summarizes the relationship between PLR and RA and the relevant mechanisms, further advancing the understanding of the clinical value of PLR.Keywords: platelet-to-lymphocyte ratio, rheumatoid arthritis, inflammatory, blood platelets, lymphocytes

Zhenchao Yuan, Changhua Chen, Kefang Liu, Fengying Chen Department of Clinical Laboratory, People’s Hospital of HuiLi City, Huili, Sichuan Province, 615100, People’s Republic of ChinaCorrespondence: Fengying Chen, Email fengyingchenwork@foxmail.comObjective: Despite the substantial advancements in imaging techniques for the diagnosis and differential diagnosis of acute appendicitis (AA) over recent decades, the specificity and sensitivity of widely utilized laboratory biomarkers in clinical practice remain inadequate.This study aimed to investigate the diagnostic utility of commonly employed blood inflammatory markers for AA.Methods: A total of 399 participants who either sought medical care or underwent health examinations were enrolled in this prospective study. The cohort comprised 200 patients diagnosed with AA (AA group), 100 patients presenting with abdominal pain but without AA (AP group), and 99 healthy individuals undergoing routine health check-ups (HC group). For all subjects, the following biomarkers were measured: plasma neutrophil gelatinase-associated lipocalin (NGAL), white blood cell count (WBC), neutrophil count (NEU), percentage of neutrophils (NEU%), neutrophil-to-lymphocyte ratio (NLR), and C-reactive protein (CRP). The diagnostic performance of the observed indicators, both individually and in combination, was assessed for the diagnosis of AA using Receiver Operating Characteristic (ROC) curves analysis and Delong’s test.Results: The laboratory indicators demonstrated a progressive increase from the HC group to the AP group, and further to the AA group (all p< 0.05). Multifactorial logistic regression analysis identified NEU% and plasma NGAL as significant risk factors for the occurrence of AA. ROC curve analysis and Delong’s test indicated that, in distinguishing the AA group from the HC group, the diagnostic performance of plasma NGAL, CRP, and NLR was equally substantial and superior to that of NEU and WBC. Within the AP group, plasma NGAL and CRP exhibited comparable diagnostic efficacy, outperforming NEU, WBC, and NLR. When differentiating AA in the non-appendicitis group (ie HC group + AP group), NGAL and CRP demonstrated comparable diagnostic efficacy, surpassing that of NEU, white WBC, and NLR. While the integration of multiple diagnostic tests can potentially improve overall diagnostic accuracy, the observed enhancement in the AUC is not statistically significant.Conclusion: NGAL, CRP, WBC, NEU% and NLR were significantly increased in patients with acute abdomen. NGAL and NEU% may function as independent risk factors for predicting the incidence of AA, with NGAL and CRP demonstrating similar and favorable diagnostic performance. While the combined evaluation of these biomarkers may enhance the diagnostic value for AA, the improvement in the area under the curve (AUC) is not substantial.Keywords: neutrophil gelatinase-associated lipocalin, acute appendicitis, biomarkers, diagnostic value

Weiqian Zhang,1,&ast; Shuiying Chen,1,&ast; Zhongyu Bai,1 Menglai Gan,2 Mingwei Chen,2 Ying Zhang,1 Sai Liu,2 Dongjuan Liu1 1Department of Emergency and Oral Medicine, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, Liaoning, People’s Republic of China; 2Department of Dental Materials, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, Liaoning, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Dongjuan Liu, Department of Emergency and Oral Medicine, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, No. 117 Nanjing North Street, Heping District, Shenyang, Liaoning, 110002, People’s Republic of China, Email dongjuanliu@cmu.edu.cn Sai Liu, Department of Dental Materials, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, No. 117 Nanjing North Street, Heping District, Shenyang, Liaoning, 110002, People’s Republic of China, Email liusai@cmu.edu.cnAbstract: Oral squamous cell carcinoma (OSCC) is the most prevalent and deadly malignancy of the head and neck. The standard treatments for OSCC are surgery, radiotherapy, and chemoradiotherapy, which can cause severe cosmetic and functional damage to the oral cavity and impair the patients’ quality of life. Photodynamic therapy (PDT) is a promising alternative that uses light-activated photosensitizers to induce selective phototoxicity and necrosis in the target tissues. PDT has several advantages over conventional treatments, such as minimal invasion, low side effects, high selectivity and preservation of the oral function and appearance. This review explores the principles, mechanisms, and current applications of PDT for OSCC. We address the challenges, such as the depth of light penetration and tissue hypoxia, and underscore the progressive innovations in photosensitizer enhancement, nanotechnological integration, and precision therapy. The exploration of biomarkers for refining patient selection and tailoring individualized treatment regimens is also undertaken. PDT holds promise as a secure and efficacious modality for OSCC management. Nonetheless, additional investigation is imperative to refine treatment protocols and validate sustained therapeutic success. Keywords: oral squamous cell carcinoma, photodynamic therapy, photosensitizers, nanotechnology, biomarkers

Nanxin Chen,1 Xuejie Si,2 Jun Wang,2 Wenjing Chen2 1First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, 250014, People’s Republic of China; 2Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong, 250001, People’s Republic of ChinaCorrespondence: Wenjing Chen, Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong, 250000, People’s Republic of China, Email c13969155126@163.comBackground: The existence of an association between physical activity (PA) and asthma and chronic obstructive pulmonary disease (COPD) has been confirmed in observational studies. Therefore, it is necessary to reveal whether there is a risk-effect relationship between physical activity and asthma and COPD through Mendelian randomization (MR) analysis.Materials and Methods: Univariate Mendelian randomization (UVMR) analyses were performed to examine the associations between moderate to vigorous physical activity (MVPA), vigorous physical activity (VPA), accelerometer-assessed physical activity (AA), and strenuous exercise or other exercise (SSOE) with asthma and COPD. The methods of analysis were dominated by Inverse Variance-Weighted (IVW), Weighted median (WM), and MR-Egger methods. In addition, multivariate Mendelian randomization (MVMR) analyses were performed to correct the effects of four types of physical activity on asthma and COPD. Finally, potential mediating effect relationships were identified through mediation analyses.Results: The results of Univariate Mendelian randomization analysis showed that SSOE could reduce the risk of asthma and COPD(asthma: OR=0.15,95% CI=0.04– 0.58, P=0.006; COPD: OR=0.05, 95% CI=0.01– 0.33, P=0.002). The results of the Multivariate Mendelian randomization analysis showed that SSOE was still able to reduce the risk of asthma and COPD after adjusting for the effects of different types of physical activity(asthma: 95% CI=− 2.77–− 0.31, P=0.014; COPD: 95% CI=− 4.00–− 0.50, P=0.012). Mediation analyses showed that frailty intervened in the causal relationship between physical activity and asthma and chronic obstructive pulmonary disease.Conclusion: SSOE is a protective factor for asthma and COPD in the European population, while frailty plays a mediating role.Keywords: asthma, chronic obstructive pulmonary disease, multivariate Mendelian randomization, mediation analyses, physical activity, univariate Mendelian randomization

Abstract Resistance to gemcitabine in pancreatic ductal adenocarcinoma (PDAC) leads to ineffective chemotherapy and, consequently, delayed treatment, thereby contributing to poor prognosis. Glycolysis is an important intrinsic reason for gemcitabine resistance as it competitively inhibits gemcitabine activity by promoting deoxycytidine triphosphate accumulation in PDAC. However, biomarkers are lacking to determine which patients can benefit significantly from glycolysis inhibition under the treatment of gemcitabine activity, and a comprehensive understanding of the molecular mechanisms that promote glycolysis in PDAC will contribute to the development of a strategy to sensitize gemcitabine chemotherapy. In this study, we aimed to identify a biomarker that can robustly indicate the intrinsic resistance of PDAC to gemcitabine and guide chemotherapy sensitization strategies. After establishing gemcitabine-resistant cell lines in our laboratory and collecting pancreatic cancer and adjacent normal tissues from gemcitabine-treated patients, we observed that circRNA hsa_circ_0008383 (namely cNEK6) was highly expressed in the peripheral blood and tumor tissues of patients and xenografts with gemcitabine-resistant PDAC. cNEK6 enhanced resistance to gemcitabine by promoting glycolysis in PDAC. Specifically, cNEK6 prevented K48 ubiquitination of small ribonucleoprotein peptide A from the BTRC, a ubiquitin E3 ligase; thus, the accumulated SNRPA stopped PP2Ac translation by binding to its G-quadruplexes in 5′ UTR of mRNA. mTORC1 pathway was aberrantly phosphorylated and activated owing to the absence of PP2Ac. The expression level of cNEK6 in the peripheral blood and tumor tissues correlated significantly and positively with the activation of the mTORC1 pathway and degree of glycolysis. Hence, the therapeutic effect of gemcitabine is limited in patients with high cNEK6 levels, and in combination with the mTORC1 inhibitor, rapamycin, can enhance sensitivity to gemcitabine chemotherapy.

Haotian Xin,1,2 Beining Yang,1,2 Yulong Jia,1,2 Qunya Qi,1,2 Yu Wang,1,2 Ling Wang,1,2 Xin Chen,1,2 Fang Li,3 Jie Lu,1,2 Nan Chen1,2 1Department of Radiology and Nuclear Medicine, Xuanwu Hospital, Capital Medical University, Beijing, 100053, People’s Republic of China; 2Beijing Key Laboratory of Magnetic Resonance Imaging and Brain Informatics, Beijing, 100053, People’s Republic of China; 3Department of Rehabilitation Medicine, Xuanwu Hospital, Capital Medical University, Beijing, 100053, People’s Republic of ChinaCorrespondence: Nan Chen, Department of Radiology and Nuclear Medicine, Xuanwu Hospital, Capital Medical University, Beijing Key Laboratory of Magnetic Resonance Imaging and Brain Informatics, No. 45 Chang-Chun St, Xicheng District, Beijing, People’s Republic of China, Tel +86 13910784187, Email chenzen8057@sina.comAbstract: Neuropathic pain (NP) is a common and persistent disease that leads to immense suffering and serious social burden. Incomplete understanding of the underlying neural basis makes it difficult to achieve significant breakthroughs in the treatment of NP. We aimed to review the functional and structural brain topological properties in patients with NP and consider how graph measures reveal potential mechanisms and are applied to clinical practice. Related studies were searched in PubMed and Web of Science databases. Topological property changes in patients with NP, including small-worldness, functional separation, integration, and centrality metrics, were reviewed. The findings suggest that NP was characterized by retained but declined small-worldness, indicating an insidious imbalance between network integration and segregation. The global-level measures revealed decreased global and local efficiency in the NP, implying decreased information transfer efficiency for both long- and short-range connections. Altered nodal centrality measures involve various brain regions, mostly those associated with pain, cognition, and emotion. Graph theory is a powerful tool for identifying topological properties of patients with NP. These specific brain changes in patients with NP are very helpful in revealing the potential mechanisms of NP, developing new treatment strategies, and evaluating the efficacy and prognosis of NP.Keywords: neuropathic pain, graph theory, brain network, magnetic resonance imaging

Xiao Chen,&ast; Yuanhe Fan,&ast; Hongliang Tu,&ast; Jie Chen Department of Orthopedics, The First People’s Hospital of Neijiang, Neijiang, Sichuan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiao Chen, Department of Orthopedics, The First People’s Hospital of Neijiang, Neijiang, Sichuan, People’s Republic of China, Email 342918992@qq.comObjective: Postoperative delirium (POD) commonly occurs in elderly individuals following hip fracture surgery, with unclear pathophysiological mechanism. Inflammation is a known factor affecting the onset of delirium. The current work aimed to examine the associations of preoperative immune inflammation-related indicators with POD occurrence in elderly cases following hip fracture surgery.Methods: The current retrospective cohort study included 437 elderly cases administered hip fracture surgery from January 2018 to December 2023. The clinicodemographic data and laboratory findings of all cases were retrospectively analyzed. Immune inflammation-related indicators were assessed, eg, MLR, NLR and PLR, as well as SII and SIRI. The bootstrap method was employed to assign cases at 7:3 to the training (48 and 258 cases in the POD and no-POD groups, respectively) and internal validation (13 and 118 cases in the POD and no-POD groups, respectively) cohorts. Next, LASSO, univariable and multivariable logistic regression analyses were applied to determine risk factors in the training cohort, based on which a nomogram model was built. The obtained nomogram was examined for accuracy by calibration plot analysis. Finally, the nomogram’s clinical value was assessed by decision curve analysis (DCA), followed by internal validation based on the training cohort.Results: Of all 437 cases, 61 developed POD, indicating a POD incidence of 13.96%. LASSO regression and multivariable analyses revealed preoperative SIRI independently predicted POD in the training cohort. The developed nomogram had an area under the curve (AUC) of 0.991 (95% CI 0.983~0.998) in the training cohort versus 0.986 (95% CI 0.966~1.000) in the validation cohort. Calibration curve analysis revealed nomogram-predicted and actual probabilities were in line. DCA demonstrated the novel nomogram could confer net benefits for POD prediction in elderly cases administered hip fracture surgery.Conclusion: The immune inflammation-related indicators SIRI could predict POD in elderly cases following hip fracture surgery.Keywords: postoperative delirium, hip fracture, elderly, immune inflammation related indicators, nomogram

Objective The C4 is the transition point between the upper and lower cervical vertebrae and plays a pivotal role in the middle of the cervical spine. Currently, there are limited reports on large‐scale sample studies regarding C4 anatomy in children, and a scarcity of experience exists in pediatric cervical spine surgery. The current study addresses the dearth of anatomical measurements of the C4 vertebral arch and lateral mass in a substantial sample of children. This study aims to measure the imaging anatomy of the C4 vertebral arch and lateral mass in children under 14 years of age across various age groups, investigate the growth and development of these structures. Methods We measured 12 indicators, including the size (D1, D2, D3, D4, D5, D6, D7, and D8) and angle (A, C, D, and E) of the C4 vertebral arch and lateral mass, in 513 children who underwent cervical CT examinations at our hospital. We employed the aggregate function for statistical analysis, conducted t‐tests for difference statistics, and utilized the least squares method for regression analysis. Results Overall, as age increased, there was a gradual increase in the size of the vertebral arch and lateral mass. Additionally, the medial inclination angle of the vertebral arch decreased, and the lateral mass flattened gradually. The rate of change decreased gradually with age. The mean value of D1 increased from 2.31 mm to 3.88 mm, of D2 from 16.75 mm to 29.2 mm, of D3 from 2.21 mm to 4.92 mm, and of D4 from 7.34 mm to 11.84 mm. Meanwhile, the mean value of D5 increased from 5.2 mm to 9.71 mm, of D6 from 10.19 mm to 16.16 mm, of D7 from 2.53 mm to 5.67 mm, and of D8 from 6.11 mm to 11.45 mm. Angle A ranged from 49.12° to 54.97°, angle C from 15.28° to 19.83°, angle D from 39.91° to 53.7°, and angle E from 18.63° to 28.08°. Conclusion Prior to cervical spine surgery in children, meticulous CT imaging anatomical measurements is essential. The imaging data serves as a reference for posterior C4 internal fixation, aids in designing posterior cervical screws for pediatric patients, and offer morphological anatomical references for posterior cervical spine surgery and screw design in pediatric patients.

Abstract The anterior cingulate cortex (ACC) is one of the critical brain areas for processing noxious information. Previous studies showed that peripheral nerve injury induced broad changes in the ACC, contributing to pain hypersensitivity. The neurons in layer 3 (L3) of the ACC receive the inputs from the mediodorsal thalamus (MD) and form the feedforward inhibition (FFI) microcircuits. The effects of peripheral nerve injury on the MD-driven FFI in L3 of ACC are unknown. In our study, we record the enhanced excitatory synaptic transmissions from the MD to L3 of the ACC in mice with common peroneal nerve ligation, affecting FFI. Chemogenetically activating the MD-to-ACC projections induces pain sensitivity and place aversion in naive mice. Furthermore, chemogenetically inactivating MD-to-ACC projections decreases pain sensitivity and promotes place preference in nerve-injured mice. Our results indicate that the peripheral nerve injury changes the MD-to-ACC projections, contributing to pain hypersensitivity and aversion.

Yan Jiang,1,&ast; Baolin Luo,2,&ast; Wen Lu,1 Yaqin Chen,1 Yanchun Peng,2 Liangwan Chen,3,4 Yanjuan Lin2,3 1School of Nursing, Fujian Medical University, Fuzhou, Fujian, People’s Republic of China; 2Department of Nursing, Fujian Medical University Union Hospital, Fuzhou, Fujian, People’s Republic of China; 3Department of Cardiovascular Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, People’s Republic of China; 4Fujian Provincial Special Reserve Talents Laboratory, Fuzhou, Fujian, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Liangwan Chen, Department of Cardiovascular Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, People’s Republic of China, Email fjxhlwc@163.com Yanjuan Lin, Department of Nursing, Fujian Medical University Union Hospital, Fuzhou, Fujian, People’s Republic of China, Email fjxhyjl@163.comPurpose: The Aggregate Index of Systemic Inflammation (AISI) has emerged as a novel marker for inflammation and prognosis, but its role in patients with acute myocardial infarction has not been studied. Therefore, this study aimed to investigate the impact of different AISI levels on the clinical outcomes of patients with acute myocardial infarction.Patients and Methods: This study was a retrospective study, including 1044 patients with acute myocardial infarction (AMI) who were treated at the Fujian Medical University Affiliated Union Hospital, China from May 2017 to December 2022. The patients were divided into high and low AISI groups based on the median value (Q1 Group, ≤ 416.15, n=522; Q2 Group, ≥ 416.16, n=522), and the differences in baseline characteristics and clinical outcomes between the two groups were analyzed. The primary outcome included major adverse cardiovascular and cerebrovascular events (MACCEs), while the secondary outcomes included contrast-induced nephropathy (CIN) risk and all-cause rehospitalization rate.Results: The findings of the single-factor analysis suggest that a significant association between high AISI levels and the occurrence of MACCEs in AMI patients. After adjusting for confounding factors, the results indicated that compared to Q1, patients in the Q2 group had a higher risk of all-cause mortality [adjusted odds ratio (aOR) 4.64; 95% CI 1.37– 15.72; p=0.032], new-onset atrial fibrillation (aOR 1.75; 95% CI 1.02– 3.00; p=0.047), and CIN (aOR 1.75; 95% CI 1.02– 3.01; p=0.043), with all differences being statistically significant.Conclusion: In the population of AMI patients, an elevated AISI level is significantly associated with an increased risk of cardiovascular death and can serve as an early marker for adverse prognosis.Keywords: acute myocardial infarction, inflammation index, clinical outcomes, MACCEs

Frozen shoulder (FS) manifests as progressively worsening pain and a reduction in shoulder range of motion (ROM). Salvianolic acid B (SaB) is recently expected to be used in the treatment of fibrosis diseases including FS. We firstly demonstrate that SaB can effectively hinder the progression of oxidative stress, inflammation, and pathological fibrosis within the synovial tissue in FS, potentially leading to the reduction or reversal of capsule fibrosis and joint stiffness. For further clinical application, we design and synthesize a novel, superior, antioxidant and antibacterial CSMA-PBA/OD-DA (CPDA) hydrogel for the delivery of SaB. In vitro experiments demonstrate that the CPDA hydrogel exhibits excellent biocompatibility and rheological properties, rendering it suitable for intra-articular injections. Upon injection into the contracted joint cavity of FS model rat, the SaB-CPDA hydrogel accelerate the recovery of ROM and exhibit superior anti-fibrosis effect, presenting the promise for the treatment of FS in vivo.

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal hematopoietic stem cell disease caused by abnormal expression of glycosylphosphatidylinositol (GPI) on the cell membrane due to mutations in the phosphatidylinositol glycan class A(PIGA) gene. It is commonly characterized by intravascular hemolysis, repeated thrombosis, and bone marrow failure, as well as multiple systemic involvement symptoms such as renal dysfunction, pulmonary hypertension, swallowing difficulties, chest pain, abdominal pain, and erectile dysfunction. Due to the rarity of PNH and its strong heterogeneity in clinical manifestations, multidisciplinary collaboration is often required for diagnosis and treatment. Peking Union Medical College Hospital, relying on the rare disease diagnosis and treatment platform, has invited multidisciplinary clinical experts to form a unified opinion on the diagnosis and treatment of PNH, and formulated the Expert Consensus of Multidisciplinary Diagnosis and Treatment for Paroxysmal Nocturnal Hemoglobinuria (2024), with the hope of promoting the standardization of PNH diagnosis and treatment.

Hongmei Xu,1 Ningning Wu,2 Hui Yu,3 Chuanqing Wang,4 Jikui Deng,5 Hongmei Wang,5 Chunzhen Hua,6 Yinghu Chen,6 Xuejun Chen,7 Ting Zhang,8 Hong Zhang,9 Yiping Chen,10 Shifu Wang,11 Qing Cao,12 Huiling Deng,13 Sancheng Cao,14 Jianhua Hao,15 Wei Gao,16 Chunmei Jing2 1Infectious Disease Department, Children’s Hospital of Chongqing Medical University; National Clinical Research Center for Child Health and Disorders; Ministry of Education Key Laboratory of Child Development and Disorders; Chongqing Key Laboratory of Child Rare Diseases in Infection and Immunity, Chongqing, People’s Republic of China; 2Department of Clinical Laboratory, Children’s Hospital of Chongqing Medical University; National Clinical Research Center for Child Health and Disorders; Ministry of Education Key Laboratory of Child Development and Disorders; Chongqing Key Laboratory of Child Rare Diseases in Infection and Immunity, Chongqing, People’s Republic of China; 3Infectious Disease Department, Children’s Hospital of Fudan University, National Children’s Medical Center, Shanghai, People’s Republic of China; 4Department of Clinical Microbiology Laboratory, Nosocomial Infection Control Department, Children’s Hospital of Fudan University, National Children’s Medical Center, Shanghai, People’s Republic of China; 5Infectious Disease Department, Shenzhen Children’s Hospital, Shenzhen, People’s Republic of China; 6Infectious Disease Department, Children’s Hospital of Zhejiang University, Zhejiang, People’s Republic of China; 7Department of Medical Laboratory, Children’s Hospital of Zhejiang University, Zhenjiang, People’s Republic of China; 8Digestive and Infectious Disease Department, Children’s Hospital of Shanghai Jiaotong University, Shanghai, People’s Republic of China; 9Department of Medical Laboratory, Children’s Hospital of Shanghai Jiaotong University, Shanghai, People’s Republic of China; 10Pediatric Infectious Disease Department, Second Affiliated Hospital, and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of China; 11Department of Medical Laboratory, Qilu Children’s Hospital, Shandong University, Shandong, People’s Republic of China; 12Infectious Disease Department, Shanghai Children’s Medical Center, Shanghai, People’s Republic of China; 13Infectious Disease Department, Xi’an Children’s Hospital, Xi’an, People’s Republic of China; 14Department of Medical Laboratory, Xi’an Children’s Hospital, Xi’an, People’s Republic of China; 15Infectious Disease Department, Children’s Hospital of Kaifeng City, Kaifeng, People’s Republic of China; 16Department of Medical Laboratory, Children’s Hospital of Kaifeng City, Kaifeng, People’s Republic of ChinaCorrespondence: Chunmei Jing, Department of Clinical Laboratory, Children’s Hospital of Chongqing Medical University, Chongqing Medical University, No. 136 Zhongshan Er Road, Yu Zhong District, Chongqing, 400014, People’s Republic of China, Email jcm791203@163.comObjective: Aim to investigate the pathogens distribution and drug resistance of gram-negative bacteria causing bloodstream infection (BSIs) in Infectious Disease Surveillance of Pediatric from 2016 to 2022. The prevalence of four important drug resistance phenotypes was studied: difficult-to-treat resistance, fluoroquinolone resistance, carbapenem resistance, and extended-spectrum cephalosporin resistance, and to provide reference basis for preventing and treating BSIs diseases in children.Methods: Strain identification and antimicrobial susceptibility tests were independently performed at each hospital. Data were analyzed using Whonet 5.6 and GraphPad Prism 8 software. The Mann–Whitney U-test was used to examine and compare temporal changes.Results: A total of 39977 BSIs strains were isolated, with 27.1% of the negative bacteria causing BSIs (10824 strains). The highest bacteria detected were E. coli and S. maltophilia in the neonatal and pediatric groups. The detection rate of carbapenem-resistant-K. pneumoniae (CRKPN) in neonate group was 31.4%, significantly increased compared with pediatric group, whose detection rate was 24.7%. The rates of resistance to levofloxacin and trimethoprim/sulfamethoxazole were significantly lower in neonatal groups than pediatric groups in BSIs caused by K. pneumoniae. To imipenem and meropenem were 3.6% and 3.9% among neonatal isolates, which was lower than 4.7% and 5.8 among pediatric BSIs caused by E. coli. Isolated from neonatal BSIs caused by A. baumannii showed lower resistance ratios to all the agents tested than those from pediatric. However, only the prevalence of piperacillin/tazobactam resistance was statistically lower than that in pediatric BSIs caused by P. aeruginosa. The average detection rates of carbapenem resistance, extended-spectrum cephalosporin resistance, and fluoroquinolone resistance for K. pneumoniae and E. coli were 28.1%,41.4%,11.6% and 4.0%,24.3%,31.1%, respectively.Conclusion: The detection rate of gram-negative pathogens showed an increasing trend among the bloodstream infection. The detection rate of CRKPN assumed a downward trend in 2018. There are differences types of pathogens between the neonatal group and the pediatric group, The detection rate of CRKPN in the neonate group was significantly higher than pediatric group. The first average detection rates for carbapenem resistance, extended-spectrum cephalosporin resistance, and fluoroquinolone resistance were obtained for A. baumannii, K. pneumoniae, and Escherichia coli, respectively. Those data showed a high level of antimicrobial resistance, which has posed an urgent threat to Children’s health, suggested that effective monitoring of antimicrobial resistance and antimicrobial stewardship among children in China are required.Keywords: bloodstream infection, pathogenic bacterium, difficult-to-treat resistance, carbapenem resistance, extended-spectrum cephalosporin resistance, fluoroquinolone resistance

[Objective] This study aimed to investigate the effects of high fat diet and high fat and high fructose diet on uric acid level and liver and kidney function in hyperuricemia (HUA) rats. [Methods] 24 rats were randomly divided into control group, model group, high-fat diet group and high-fat and high-fructose diet group. All rats were fed with the corresponding diets, except the control group, 500 mg/kg potassium oxazinate and 100 mg/kg adenine per day. After 6 weeks, serum biochemical indexes such as uric acid and creatinine were determined, and pathological examination of kidney and liver was performed. [Results] The uric acid content of control group, model group, high-fat diet group and high-fat high-fructose diet group were 118.10, 319.05, 325.71, 456.10 μmol/L, respectively. The levels of uric acid and creatinine in the high-fat diet group were not significantly different from those in the model group, but the kidney injury and liver fat accumulation were more serious. The uric acid in the high-fat and high-fructose group was significantly higher than that in the model group, and the degree of kidney injury and liver fat accumulation was more serious than that in the model group. [Conclusion] High-fat diet cannot further increase the uric acid content of HUA rats, but can aggravate the liver and kidney damage of HUA rats. High-fat and high-fructose diet will further increase the uric acid content of HUA rats, and aggravate kidney injury and liver fat accumulation. Hyperuricemia group should pay attention to control the intake of dietary fat and fructose.

As shale oil exploration and development intensifies， the experimental technologies for shale oil development have been continuously improved while inheriting the experimental technologies and methods of conventional reservoirs and shale gas reservoirs， and a set of experimental technology systems of reservoir physics and flow mechanisms has been initially formed， which provides strong technical support for geological evaluation of shale reservoirs， reservoir engineering optimization design， and enhanced oil recovery. The development status of six experimental technologies in China and abroad， including porosity， permeability， oil-water saturation， wettability， relative permeability， and imbibition， was systematically summarized. In view of the characteristics of continental shale oil， such as low maturity， strong heterogeneity， and well-developed lamina and micro-fractures， the measurement methods and principles， key influencing factors， control conditions of experiments， advantages and disadvantages and technical applicability of experiment methods were analyzed. The main problems， development trends， and research direction of these experimental technologies were put forward. The results show that ① unifying the cleaning agent and cleaning time of rock samples is the key to improving the comparability of different measurement methods of porosity， and nuclear magnetic resonance measurement of porosity is the technological development direction to meet the needs of rapid analysis in mining fields； ② the irregular and multi-directional permeability measurement technology capable of simulating formation pressure changes is the future technological development direction； ③ the alcohol soaking method and two-dimensional nuclear magnetic resonance （T1-T2） method are the technological development direction of the determination of shale oil-water saturation， but they still face the problem of the influence of clay bound water and adsorbed oil on the determination accuracy； ④ the droplet morphology method is one of the future development directions of measurement technology of shale reservoir wettability， which requires further research and unified standards in experimental methods and comprehensive evaluation methods for surface wetting and spontaneous imbibition processes； ⑤ the combination of experimental measurement and numerical method is an effective way to obtain the relative permeability of shale reservoirs， and the micro-oil and water metering， end-effect correction， as well as technologies and methods considering the time-varying pressure are the key directions； ⑥ pressure imbibition measurement method should be used to evaluate imbibition effect and optimize well kill time in elastic development after fracturing. Pressure imbibition measurement methods based on nuclear magnetic resonance T2 spectrum， stratification T2 spectrum， and T1-T2 spectrum will be one of the essential technological development directions.

Abstract The Nab-paclitaxel combined with gemcitabine (AG) regimen is the main chemotherapy regimen for pancreatic cancer, but drug resistance often occurs. Currently, the ability to promote sensitization in drug-resistant cases is an important clinical issue, and the strategy of repurposing conventional drugs is a promising strategy. This study aimed to identify a classic drug that targets chemotherapy resistance’s core signaling pathways and combine it with the AG regimen to enhance chemosensitivity. We also aimed to find reliable predictive biomarkers of drug combination sensitivity. Using RNA sequencing, we found that abnormal PI3K/Akt pathway activation plays a central role in mediating resistance to the AG regimen. Subsequently, through internal and external verification of randomly selected AG-resistant patient-derived organoid (PDO) and PDO xenograft models, we discovered for the first time that the classic anti-inflammatory drug sulindac K-80003, an inhibitor of the PI3K/Akt pathway that we focused on, promoted sensitization in half (14/28) of AG-resistant pancreatic ductal adenocarcinoma cases. Through RNA-sequencing, multiplex immunofluorescent staining, and immunohistochemistry experiments, we identified cFAM124A as a novel biomarker through which sulindac K-80003 promotes AG sensitization. Its role as a sensitization marker is explained via the following mechanism: cFAM124A enhances both the mRNA expression of cathepsin L and the activity of the cathepsin L enzyme. This dual effect stimulates the cleavage of RXRα, leading to large amounts of truncated RXRα, which serves as a direct target of K-80003. Consequently, this process results in the pathological activation of the PI3K/Akt pathway. In summary, our study provides a new treatment strategy and novel biological target for patients with drug-resistant pancreatic cancer.

Structural modularization, lightweight and functional integration are the urgent development directions for next generation high-performance aeroengines. Heat concentration during aeroengine operation would lead to local high temperature, which tremendously negative impacts on aeroengine structural life and performance. Therefore, the design and optimization of radiator structures are significant for the efficiency and reliability of aeroengine. The structural geometry design and layout optimization of radiators is promising to improve the heat dissipation efficiency and reduce aerodynamic loss. The purpose of this study is to investigate the state of the art and perspectives of aeroengine radiator structural design by a comprehensive literature review. The main contents involve the review on the structural design and layout optimization technologies of radiator structures, the analyses of the structural features, design theory and methods of existed radiator structures, the induction of the theory and method of different radiators structural optimization design, and the discussion on the application perspectives of advanced structures in aeroengine radiators, the report on the current challenges and development directions of the design of radiator structures, including smart materials, lattice structures, variable structures, advanced optimization theories and methods, heat dissipation methods and so forth. The efforts of this study are promising to support the high-performance and lightweight design of aeroengine structures besides radiators, and thermal management system.

Zuo Wang,1,2,&ast; Siqi Guo,3,&ast; Chong He,2,4,&ast; Lingling Chen,5 Jinxia Wang,2 Wenbo Xiu,2 Gao Zhang,2 Yang Chen,2 An Li,2 Xiong Zhu,6 Xiao Xiao,2 Ling Yu,3 Fang Lu2,4,7 1Department of Clinical Laboratory, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, People’s Republic of China; 2Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, People’s Republic of China; 3Department of Ophthalmology, Daping Hospital, Army Medical Center, Army Medical University, Chongqing, People’s Republic of China; 4Medico-Engineering Cooperation on Applied Medicine Research Center, University of Electronic Science and Technology of China, Chengdu, People’s Republic of China; 5Department of Immunology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, People’s Republic of China; 6Department of Prenatal Diagnosis, Chengdu Women’s and Children’s Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, People’s Republic of China; 7Health Management Center, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ling Yu; Fang Lu, Email oculistlingyu@hotmail.com; lufangfang@126.comObjective: Evidence suggests that dysbiosis of the gut microbiota plays a pivotal role in the development of glaucoma. This dysbiosis is commonly associated with chronic intestinal inflammation and increased intestinal permeability. However, the understanding of intestinal inflammation and permeability in glaucoma remains insufficient. This study aims to investigate the potential relationship between fecal inflammation and permeability markers and glaucoma.Methods: We recruited 114 glaucoma patients and 75 healthy controls. Levels of fecal lactoferrin (Lf) and alpha-1 antitrypsin (AAT) were quantified using enzyme linked immunosorbent assay (ELISA) to compare both biomarkers between groups and across different severity grades of glaucoma. Logistic regression analysis was used to assess the association between these fecal biomarkers and glaucoma. The severity of glaucoma was assessed based on the mean deviation (MD) in the visual field.Results: In this study, we observed elevated levels of fecal Lf and AAT in glaucoma patients. The proportion of glaucoma patients with abnormal fecal Lf levels (≥ 7.25 μg/g) was significantly higher than that of the controls (p = 0.012). A positive correlation was noted between fecal Lf and AAT (rho = 0.20, p = 0.006). After adjusting for age and sex, multivariable logistic regression analysis indicated that both fecal Lf (OR = 1.11, 95% CI: 1.01– 1.21, p = 0.026) and AAT (OR = 1.01, 95% CI: 1.01– 1.02, p < 0.001) positively correlated with glaucoma. These biomarkers might reflect glaucoma severity, with significant differences in fecal Lf levels observed between moderate and severe stages, but not in the early stage. Furthermore, increasing levels of fecal AAT correlated with greater severity of glaucomatous injury and a larger vertical cup-to-disc ratio (VCDR) (p < 0.05).Conclusion: This study suggests an increase in intestinal inflammation and permeability in glaucoma, further indicating the importance of the ‘gut-retina axis’ in the pathogenesis of the disease and potentially offering new therapeutic avenues.Keywords: fecal lactoferrin, fecal alpha-1 antitrypsin, glaucoma, intestinal inflammation, intestinal permeability, intestinal barrier

Junzi Chen,&ast; Yumin Xiang,&ast; Rong Bao, Yuyi Zheng, Yingxi Fang, Jiajia Feng, Di Wu, Xiaojie Chen Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, School of Pharmaceutical Sciences, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, 310053, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiaojie Chen; Di Wu, Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, School of Pharmaceutical Sciences, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, People’s Republic of China, Email chenxiaojie0902@163.com; wudichem@zju.edu.cnIntroduction: Breast cancer ranks among the most prevalent cancers in women, characterized by significant morbidity, disability, and mortality. Presently, chemotherapy is the principal clinical approach for treating breast cancer; however, it is constrained by limited targeting capability and an inadequate therapeutic index. Photothermal therapy, as a non-invasive approach, offers the potential to be combined with chemotherapy to improve tumor cellular uptake and tissue penetration. In this research, a mesoporous polydopamine-coated gold nanorod nanoplatform, encapsulating doxorubicin (Au@mPDA@DOX), was developed.Methods: This nanoplatform was constructed by surface coating mesoporous polydopamine (mPDA) onto gold nanorods, and doxorubicin (DOX) was encapsulated in Au@mPDA owing to π-π stacking between mPDA and DOX. The dynamic diameter, zeta potential, absorbance, photothermal conversion ability, and drug release behavior were determined. The cellular uptake, cytotoxicity, deep penetration, and anti-tumor effects were subsequently investigated in 4T1 cells. After that, fluorescence imaging, photothermal imaging and pharmacodynamics studies were utilized to evaluate the anti-tumor effects in tumor-bearing mice model.Results: This nanoplatform exhibited high drug loading capacity, excellent photothermal conversion and, importantly, pH/photothermal dual-responsive drug release behavior. The in vitro results revealed enhanced photothermal-facilitated cellular uptake, drug release and tumor penetration of Au@mPDA@DOX under near-infrared irradiation. In vivo studies confirmed that, compared with monotherapy with either chemotherapy or photothermal therapy, the anti-tumor effects of Au@mPDA@DOX are synergistically improved.Conclusion: Together with good biosafety and biocompatibility, the Au@mPDA@DOX nanoplatform provides an alternative method for safe and synergistic treatment of breast cancer. Keywords: breast cancer, synergistic therapy, polydopamine, gold nanorod, chemotherapy

Wenbin Guo,1,&ast; Lin Sun,1,&ast; Huijun Yue,1,&ast; Xueqin Guo,1 Lin Chen,1 Jinhong Zhang,1 Zhuqi Chen,1 Yiming Wang,1 Jiao Wang,2 Wenbin Lei1 1Otorhinolaryngology Hospital, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, 510080, People’s Republic of China; 2School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong, 510080, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jiao Wang, School of Public Health, Sun Yat-sen University, Guangzhou, 510080, Guangdong, People’s Republic of China, Email wangj836@mail.sysu.edu.cn Wenbin Lei, Otorhinolaryngology Hospital, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, Guangdong, People’s Republic of China, Email leiwb@mail.sysu.edu.cnPurpose: Clinical studies focusing on the association between the gut microbiota and obstructive sleep apnea (OSA) are limited. This study aimed to explore the relationship between intermittent hypoxia and the composition of gut microbiota in adults by analyzing the differences in the characteristics and functional distribution of gut microbiota between patients with different severities of OSA and healthy individuals.Patients and Methods: A cohort of 113 individuals from the First Affiliated Hospital of Sun Yat-sen University underwent overnight polysomnography from July 2019 to August 2021. The individuals included 16 healthy controls and 97 patients with OSA, categorized by the apnea-hypopnea index into mild, moderate, and severe groups. Fecal samples were analyzed using high-throughput sequencing of the 16S rRNA V3–V4 region to assess gut microbiota composition and function. Correlation analysis was used to evaluate the association between clinical indicators and microbiota markers.Results: In patients with OSA, the gut microbiota diversity and the abundance of specific microbes that produce short-chain fatty acids decreased (P< 0.05). The phyla Verrucomicrobia and Candidatus Saccharibacteria, genera Gemmiger and Faecalibacterium, and the species Gemmiger formicilis exhibited decreasing abundance with increasing OSA severity. Correlation analysis revealed a robust association between the proportion of total sleep time, characterized by nighttime blood oxygen saturation below 90%, and the alterations in the gut microbiota, demonstrating that elevated levels of desaturation are correlated with pronounced microbiota dysbiosis (P< 0.05).Conclusion: Compared to the control group, the intermittent hypoxia exhibited by patients with OSA may be related to alterations in the composition and structure of the gut microbiota. Our results demonstrate the importance of monitoring hypoxia indicators in future clinical practice.Keywords: obstructive sleep apnea, gut microbiota, 16S rRNA, intermittent hypoxia

Dong Wu,1,&ast; Bingyu Long,1,&ast; Bangxiao Huang,1,&ast; Xiaomei Zhong,1 Xiaoer Chen,1 Xiaoping Shen,1 Qiu Huang,1 Wenchao Zhang,1 Jiayuan Wu,2 Min Chen,1 Dongming Li,1 Bin Wu,1 Dong Lv,3 Dan Huang,1 Xuanna Zhao1 1Department of Respiratory and Critical Care Medicine, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, People’s Republic of China; 2Department of Clinical Research, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, People’s Republic of China; 3Department of Psychiatry, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xuanna Zhao; Dan Huang, Department of Respiratory and Critical Care Medicine, Affiliated Hospital of Guangdong Medical University, No. 57, South of Renmin Road, Zhanjiang, Guangdong, 524013, People’s Republic of China, Email 792665234@qq.com; 287538250@qq.comBackground: Education and living environment are related to mental health. But the independent and combined effects of them on mental health among patients with chronic obstructive pulmonary disease (COPD) are uncertain.Methods: The independent and combined effects of education and living environment on mental health were assessed by binary logistic regression in 1064 COPD patients. Additive interaction was assessed with the relative excess risk ratio (RERI), attribution percentage (AP), and synergy index (SI).Results: Our results shown that low education level and urban living environment were independently associated with higher risks for anxiety (odds ratio [OR]: 1.56, 95% confidence interval [CI] 1.06– 2.29 and OR:2.15, 95% CI 1.51– 2.05) or depression (OR:1.62, 95% CI 1.17– 2.27 and OR: 2.01, 95% CI 1.46– 2.75) among COPD patients. The combination effect of them was also associated with higher risks for anxiety (OR: 7.90, 95% CI 3.83– 16.29, P < 0.001) or depression (OR: 11.79, 95% CI 5.77– 24.10, P < 0.001) among these patients. Furthermore, we observed strong synergistic additive interactions between them for anxiety (SI: 11.57, 95% CI 1.41– 95.27; RERI: 6.31, 95% CI 1.60– 11.01; AP: 0.8, 95% CI 0.66– 0.94) and depression (SI: 31.31, 95% CI 1.59– 617.04; RERI: 10.44, 95% CI 2.66– 18.23; AP: 0.89, 95% CI 0.8– 0.97).Conclusion: Low education levels and living in urban areas had an independent and synergistic effects on mental health among COPD patients.Keywords: anxiety, China, COPD, depression, education, living environment

Colorectal cancer (CRC) is a common malignant tumor of digestive tract with an increasing incidence and mortality worldwide, and most patients have lost the opportunity of surgical treatment once diagnosed. With the continuous development of precision targeted therapy, anti-angiogenesis targeted drugs have achieved good therapeutic effect in the treatment of advanced CRC. Regorafenib is a multi-target oral tyrosine kinase inhibitor, which can improve the tumor immune microenvironment by regulating tumor-associated macrophage, vascular endothelial growth factor receptor, and has a synergistic effect with immunotherapy. This article reviews the progress of basic and clinical research on regorafenib in the field of CRC.

Suwen Huang,1,&ast; Wei Xie,1,2,&ast; Yufan Gao,1,3,&ast; Yining Jin,1,3 Yilin Chen,1,2 Guoliang Zhou,1,2 Feng Chen,1,2 Qiaoqiao Jin,1,2 Zihao Wu,1,2 Lingsheng Wang,1,2 Chao Chen,4 Yiyun Weng,1 Guangyong Chen5 1Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China; 2The First School of Medicine, School of Information and Engineering, Wenzhou Medical University, Wenzhou, People’s Republic of China; 3The Second School of Medicine, Wenzhou Medical University, Wenzhou, People’s Republic of China; 4Department of Nutriology, The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China; 5Department of Neurology, The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Guangyong Chen, Department of Neurology, The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of China, Email gychen@wmu.edu.cn Yiyun Weng, Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China, Email wengyiyun2012@126.comBackground and Purpose: The dynamic systemic inflammation level and stroke-associated infection (SAI) are related to the prognosis of acute ischemic stroke (AIS). We aimed to explore whether the systemic inflammatory response index (SIRI), systemic immune inflammation index (SII), and their dynamic changes possess predictability for SAI and long-term prognosis.Methods: A total of 1804 AIS patients without intravenous thrombolysis in two hospitals were included. We explored the relationship between SIRI, SII, and their dynamic changes and outcomes by constructing clusters. The mediating effects of SAI between prognosis and systemic inflammation were further evaluated.Results: Each SD increase in the concentration of SIRI exhibited a significant correlation with the risk of poor functional outcome, mortality, and functional dependency. Through K-means clustering analysis, patients with dramatically elevated or decreased systemic inflammation levels of SIRI (OR: 2.293, 95% CI: 1.279– 4.109) and SII (OR: 3.165, 95% CI: 1.627– 6.156) within 7 days had a higher risk of functional outcome. Through mediation analysis, SAI mediated the association between systemic inflammation and poor prognosis (SIRI: 33.73%, SII: 16.01%).Conclusion: Dramatically changing dynamics of SIRI and SII were significantly associated with a higher risk of poor prognosis in AIS patients. SAI mediated the association between systemic inflammation and prognosis at 1 year.Keywords: AIS, inflammation, SAI, mediation analysis, clustering analysis

Liling Chen,1 Cunqing Zheng,1 Honglin Luan,2 Xinyuan Chen3 1Department of Clinical Laboratory, Wenzhou Seventh People’s Hospital, Wenzhou, Zhejiang Province, People’s Republic of China; 2Department of Psychiatry, Wenzhou Seventh People’s Hospital, Wenzhou, Zhejiang Province, People’s Republic of China; 3Department of Clinical Laboratory, Wenzhou Central Hospital, Wenzhou, Zhejiang Province, People’s Republic of ChinaCorrespondence: Xinyuan Chen, Department of Clinical Laboratory, Wenzhou Central Hospital, Bailidonglu Street, Lucheng District, Wenzhou, 325000, People’s Republic of China, Tel +8615858805715, Fax +86057788070190, Email 742846523@qq.comPurpose: This study aimed to assess High-density Lipoprotein (HDL)-based Inflammatory Indices and lipid profile changes in antipsychotic-naive first-episode schizophrenia (AN-FES) patients, chronic schizophrenia (CS) patients, and explore the clinical and predictive value of these parameters for schizophrenia.Patients and Methods: The study cohort included 52 AN-FES patients, 46 CS patients, and 52 healthy controls (HCs), with an average age of 24 years. Upon admission, patients underwent complete blood count and lipid profile analyses. Various ratios were calculated, including neutrophil-to-HDL (NHR), monocyte-to-HDL (MHR), lymphocyte-to-HDL (LHR), and platelet-to-HDL (PHR), as well as lipid ratios like triglycerides/HDL, non-HDL/HDL, total cholesterol/HDL, and low-density lipoprotein/HDL. For the AN-FES group, these evaluations were repeated after two months of treatment with atypical antipsychotics. Statistical analyses included correlation analysis, Receiver Operating Characteristic (ROC) curve analysis, and univariate and multivariate regression.Results: Compared to HCs, CS patients exhibited significantly higher MHR and NHR values, while AN-FES patients showed elevated levels of PHR, MHR, and NHR. No significant differences were observed in LHR or lipid ratios across the three groups. In the AN-FES cohort, MHR correlated positively with neutrophil counts, and NHR with monocyte counts. Additionally, white blood cell counts were positively associated with both MHR and NHR. Following treatment, NHR levels decreased, whereas TG/HDL ratios increased, with MHR and PHR remaining elevated. ROC analysis highlighted NHR as the most diagnostically valuable parameter (AUC = 0.799), with 86.5% specificity at an optimal cutoff of 3.534, outperforming MHR and PHR. Regression analyses recognized NHR (OR=2.225) as an independent risk factor for schizophrenia, even after adjusting for confounders.Conclusion: HDL-based inflammatory indices, particularly NHR, may serve as valuable diagnostic and prognostic markers in young adults with schizophrenia, even though significant alterations in lipid ratios were not observed in this demographic.Keywords: neutrophil-to-HDL ratio, NHR, monocyte-to-HDL ratio, MHR, platelet-to-HDL ratio, PHR, lipid ratios, schizophrenia, inflammatory indices

Dan Yao,1 Jiefeng Jiang,1 Qianyun Zhou,1 Caiyun Feng,1 Jianping Chu,2 Zhiyan Chen,1 Jie Yang,1 Jinying Xia,3 Yujia Chen1 1Department of Endocrinology, Xiangshan Hospital of TCM Medical and Health Group, Xiangshan, Ningbo, People’s Republic of China; 2Department of Endocrinology, Ningbo First Hospital, Ningbo, People’s Republic of China; 3Department of Endocrinology, Ningbo No. 2 Hospital, Ningbo, People’s Republic of ChinaCorrespondence: Jiefeng Jiang, Department of Endocrinology, Xiangshan Hospital of TCM Medical and Health Group, Ningbo, 315799, People’s Republic of China, Tel +86-13606781301,, Email xszyyjjf@126.com Dan Yao, Department of Endocrinology, Xiangshan Hospital of TCM Medical and Health Group, Xiangshan, Ningbo, 315799, People’s Republic of China, Tel +86-13777191528, Email 3299048@qq.comAbstract: In recent years, there have been hundreds of reports on insulin autoimmune syndrome (IAS) globally; however, fewer than a hundred patients have undergone genetic testing. Our objective is to examine the background of IAS and the variations in drugs that trigger it among patients who have been genetically tested, aiming to deepen our understanding of this condition. HLA Analysis of 68 cases showed that DR4 is predominant, especially in individuals of East Asian descent, notably in DRB1 &ast;0406. Methimazole was the primary drug associated with IAS in these populations, while in Caucasian individuals, the emphasis was on DRB1 &ast;0403, with lipoic acid being the common inducer. The key factor determining disease risk is the combination of chromosomal allele variations, with HLA class II allele DR4 positive patients showing a strong association with DQA1 &ast;0301/DQB1 &ast;0302.Keywords: insulin autoimmune syndrome, HLA, methimazole, α-lipoic acid

Longqing Xia,1 Mengmeng Yang,1 Nan Zang,1– 4 Jia Song,1– 4 Jun Chen,1– 4 Huiqing Hu,1 Kewei Wang,1 Yingyue Xiang,1 Jingwen Yang,1 Liming Wang,1 Ying Zou,1 Xiaoyu Lv,1 Xinguo Hou,1– 4 Li Chen1– 4 1Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 250012, People’s Republic of China; 2Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, 250012, People’s Republic of China; 3Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, 250012, People’s Republic of China; 4Jinan Clinical Research Center for Endocrine and Metabolic Disease, Jinan, 250012, People’s Republic of ChinaCorrespondence: Li Chen, Department of Endocrinology, Qilu Hospital of Shandong University, Shandong, People’s Republic of China, Email chenli3@email.sdu.edu.cnBackground: The depletion of β cell mass is widely recognized as a significant contributor to the progression of type 2 diabetes mellitus (T2DM). Exosomes derived from mesenchymal stem cells (MSC-EXOs) hold promise as cell-free therapies for treating T2DM. However, the precise effects and mechanisms through which MSC-EXO affects β cell function remain incompletely understood, and the limited ability of MSC-EXO to target β cells and the short blood circulation time hampers its therapeutic effectiveness.Methods: The effects of MSC-EXO were investigated in T2DM mice induced by a high-fat diet combined with STZ. Additionally, the high glucose-stimulated INS-1 cell line was used to investigate the potential mechanism of MSC-EXO. Michael addition reaction-mediated chemical coupling was used to modify the surface of the exosome membrane with a β-cell-targeting aptamer and polyethylene glycol (PEG). The β-cell targeting and blood circulation time were evaluated, and whether this modification enhanced the islet-protective effect of MSC-EXO was further analyzed.Results: We observed that the therapeutic effects of MSC-EXO on T2DM manifested through the reduction of random blood glucose levels, enhancement of glucose and insulin tolerance, and increased insulin secretion. These effects were achieved by augmenting β cell mass via inhibiting nuclear factor erythroid 2–related factor 2 (NRF2)-mediated ferroptosis. Mechanistically, MSC-EXOs play a role in the NRF2-mediated anti-ferroptosis mechanism by transporting active proteins that are abundant in the AKT and ERK pathways. Moreover, compared to MSC-EXOs, aptamer- and PEG-modified exosomes (Apt-EXOs) were more effective in islet protection through PEG-mediated cycle prolongation and aptamer-mediated β-cell targeting.Conclusion: MSC-EXO suppresses NRF2-mediated ferroptosis by delivering bioactive proteins to regulate the AKT/ERK signaling pathway, thereby improving the function and quantity of β cells. Additionally, Apt-EXO may serve as a novel drug carrier for islet-targeted therapy.Keywords: exosome, type 2 diabetes mellitus, β-cell-targeting, polyethylene glycol modification, ferroptosis

Zhengwen Feng,1 Hui Li,1 Xiaolei Chen,1 Tiancheng Zhang,2 Yanxiang Chen,3 Shuang Shao,1,&ast; Juan Du1,&ast; 1School of General Practice and Continuing Education, Capital Medical University, Beijing, People’s Republic of China; 2Department of General Practice, Dahongmen Community Health Service Center, Beijing, Fengtai District, People’s Republic of China; 3Department of general practice, Changying Community Health Service Center, Beijing, Chaoyang District, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Juan Du; Shuang Shao, School of General Practice and Continuing Education, Capital Medical University, 10 You’ Anmen Outer West 1 st Street, Beijing, 100069, People’s Republic of China, Email cuckoo@ccmu.edu.cn; shaoshuang@ccmu.edu.cnPurpose: Our study aimed to explore the current status of patient participation in medication safety from the perspectives of general practitioners (GPs), pharmacists, and outpatients in Beijing, China.Patients and Methods: A qualitative study using semi-structured in-depth individual interviews with GPs, pharmacists, and outpatients. Subjects were identified by purposive sampling until code saturation. Semi-structured qualitative interviews were conducted with GPs, pharmacists, and patients from community health service centers in three urban districts of Beijing, China. The interviews were transcribed verbatim and the text was analysed using thematic analysis techniques including familiarising with data, generating initial codes, searching for themes, reviewing themes, defining and naming themes, and producing the report.Results: A total of eight GPs, seven pharmacists, and 18 outpatients were interviewed. Data analysis led to the generation of five key themes: (1) mutual trust between patient and GP, (2) communication with healthcare professionals, (3) acquisition of knowledge about medication safety, (4) implementation of medication self-management at home, and (5) different attitudes toward participation in medication decisions. Patients participated in medication safety in multiple ways. However, insufficient knowledge about medication safety, lack of awareness of the patient’s role in ensuring medication safety, shortage of consultation lengths, and being misled by some information were problems with patient participation in medication safety.Conclusion: This exploratory study contributes to our initial understanding of patient participation in medication safety. There were still many issues and barriers in the process of patient participation. Appropriate policies and measures, such as providing various forms of patient education, ensuring sufficient physician-patient communication, giving full play to the role of pharmacists, and making judicious use of digital health tools should be taken to improve medication safety by fully utilising the role of patients.Plain Language Summary: Medication safety is a significant concern around the world. Patient participation in the medication process is effective in reducing the incidence of medication errors and improving medication safety. However, the role of outpatients with chronic conditions in ensuring medication safety is often neglected. This study aims to explore the perspectives and experiences of GPs, pharmacists, and outpatients by qualitative interviews in Beijing, China. The study involved a series of interviews with eight GPs, seven pharmacists, and 18 outpatients living with noncommunicable diseases. The interview revealed five themes: (1) mutual trust between patient and GP, (2) communication with healthcare professionals, (3) acquisition of knowledge about medication safety, (4) implementation of medication self-management at home, and (5) different attitudes toward participation in medication decisions. The findings might help propose suggestions for patient participation in medication safety. Integrating these findings into future studies can help healthcare professionals formulate interventions and better support patients in participating in the medication process.Keywords: medication safety, patient participation, patient safety, qualitative study, noncommunicable disease, community health service centers

Objective To analyze the changes in fertility trends of seasonally and calendar adjusted fertility rate (SAFR) in different countries before and after the COVID-19 pandemic outbreak and investigate the influence factors. Methods Monthly SAFR data of 28 countries during January 2012 and December 2022 were collected in the Human Fertility Database (HFD). The node of December 2020 (9-month delay in gestation from the start of the March 2020 outbreak) was used as the point of division for comparison between the pre- (2012.1-2020.11) and post-pandemic (2020.12-2022.12) periods. Interrupted time series was used to analyze whether fertility rate trends (short-term fluctuations and long-term trends) changed before and after the pandemic in each country. Wilcoxon test was employed to analyze whether pre-pandemic fertility rate, GDP per capita, public health and social measures (PHSM) and unemployment rate were associated with the changes in fertility trends. Results Nineteen out of the 28 countries experienced a short-term decline in fertility rate after the pandemic, which subsequently rebounded. With respect to long-term trends, 2 countries shifted from a declining trend to an increasing trend, 8 countries shifted from an increasing trend to a declining trend, and 6 countries had their SAFR unchanged. The SAFR decline was mainly observed in some of the countries of Central Europe and the Western Mediterranean, while its increase was mainly in Northern and Western Europe. Pre-pandemic SAFR was lower in the countries with no short-term fluctuations in SAFR than those with short-term fluctuations (P=0.041). The countries with declining rate of SAFR had significantly lower pre-pandemic SAFR (P=0.005) and GDP per capita (P=0.027) than the countries with increasing rate of SAFR. No association was found between short-term fluctuations or long-term trends in fertility rate and the PHSM severity index or unemployment rate. Conclusion The COVID-19 pandemic has had varying short- and long-term impacts on SAFR in 28 countries, with the countries with relatively low economic levels and pre-pandemic SAFRs more vulnerable to further blows. The longer-term impacts of the COVID-19 pandemic on the populations of each country deserve further attention. X

Fei Chen,1,2 Rujun Chen,3,&ast; Jiangfeng Zhou,1,2,&ast; Weiyi Xu,1,2,&ast; Jiahui Zhou,1,4 Xianxian Chen,1,5 Xiaohua Gong,1 Zimiao Chen1 1Department of Endocrinology and Metabology, The First Affiliated Hospital of Wenzhou Medical University, Zhejiang, People’s Republic of China; 2Wenzhou Medical University, Zhejiang, People’s Republic of China; 3Department of Burn, 906 Hospital of the Joint Logistics Team, PLA, Wenzhou, People’s Republic of China; 4Department of Internal Medicine, The First People’s Hospital of Longwan District, Wenzhou, People’s Republic of China; 5Department of Internal Medicine, The People’s hospital of Pingyang, Wenzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiaohua Gong; Zimiao Chen, Department of Endocrinology and Metabology, The First Affiliated Hospital of Wenzhou Medical University, Zhejiang, People’s Republic of China, Email gxh1204@163.com; zimiaochen@163.comBackground: Thyroid hormone levels are associated with the distribution of body components in humans.Objective: This study aimed to investigate the associations between thyroid hormone (TH) levels, central sensitivity to THs, and body composition in overweight and obese patients with euthyroid type 2 diabetes mellitus (T2DM).Methods: This cross-sectional study included 1215 euthyroid T2DM patients (721 men and 494 women) aged 20– 80 years. The thyroid hormone sensitivity indices included the thyroid feedback quartile-based index (TFQI), thyrotroph T3 resistance index (TT3RI), thyrotroph T4 resistance index (TT4RI), and thyroid-stimulating hormone index (TSHI). The appendicular fat ratio, trunk fat ratio, android fat ratio, gynoid fat ratio, and appendicular skeletal muscle mass (ASM) were measured via dual-energy X-ray absorptiometry.Results: The data revealed a greater proportion of subjects with impaired central sensitivity to THs in the obese group. TFQIFT4 and TFQIFT3 levels were positively correlated with the upper limb fat ratio, lower limb fat ratio, gynoid fat ratio, and total fat ratio. TSHI was positively correlated with body mass index (BMI), upper limb fat ratio, lower limb fat ratio, trunk fat ratio, android fat ratio, gynoid fat ratio, total fat ratio, and appendicular skeletal muscle mass index (ASMI) in women. In men, TSHI was only positively correlated with upper limb fat ratio, lower limb fat ratio, and total fat ratio. Logistic regression analysis indicated that TT3RI and TFQIFT3 were independently and positively associated with central obesity and low muscle mass in overweight and obese men. No significant differences were found among the women.Conclusion: THs central sensitivity is related to the body composition of euthyroid T2DM patients. Specifically, high levels of TT3RI and TFQIFT3 are associated with central obesity and low muscle mass in T2DM men with overweight and obesity.Keywords: thyroid hormones central sensitivity, euthyroid, body components, muscle mass, fat ratio, obese

Yang Xi,1,&ast; Yu-Qin Deng,1,2,&ast; Han-Da Li,1 Wo-Er Jiao,1 Jin Chen,2 Jian-Jun Chen,3 Ze-Zhang Tao1,2 1Department of Otolaryngology, Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China; 2Institute of Otolaryngology, Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China; 3Department of Otorhinolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ze-Zhang Tao, Department of Otolaryngology, Head and Neck Surgery Renmin Hospital of Wuhan University, 238 Jie-Fang Road, Wuhan, 430060, Hubei, People’s Republic of China, Tel +86 13907141892, Fax +86 27 88043958, Email taozezhang696@163.com Jian-Jun Chen, Department of Otorhinolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Jianghan District, Wuhan, 430060, Hubei, People’s Republic of China, Tel +86 13659851719, +86 27 85726300, Email ylly80331@163.comPurpose: Up to now, there is no generally accepted biomarker to indicate the clinical response of immunotherapy. This study mainly analyzed the correlation between eosinophil cationic protein-myeloperoxidase (ECP-MPO) test papers and other immunotherapy indices in subcutaneous immunotherapy of dust mites and to explore whether the test paper can be used as an auxiliary index to quickly evaluate the efficacy of immunotherapy.Patients and methods: This study included 53 participants who received subcutaneous immunotherapy at the allergy clinic of Renmin Hospital of Wuhan University and 28 control participants. Six visits were conducted during a prospective study over one year. The results of the ECP-MPO test paper, nasal secretion eosinophil smear and count, nasal secretion ECP concentration, and clinical symptom scores were collected during five follow-up visits after the start of subcutaneous immunotherapy. Th1/Th2/Th17 cytokines, chemokines, IgE, IgG4 against dust mite components, and ECP concentrations were detected in the serum of participants at baseline, six months, and one year after subcutaneous immunotherapy.Results: The ECP test paper is not only easy to operate, but also can effectively and quickly detect the concentrations of ECP in the nasal secretion and diagnose allergic rhinitis. Symptom score is an important index for evaluating clinical immune efficacy, during subcutaneous immunotherapy, the ECP test paper showed a positive correlation with the symptom score. Simultaneously, during immunotherapy, the changes in the chromogenic grading of the test paper were synchronized with the changes in inflammatory cytokines and eosinophilic chemokines in Th2 cells of serum dust mite IgE. The sIgG4 against dust mites weakly negatively correlated with the concentration of ECP in nasal secretions and the color classification of the ECP test paper.Conclusion: The ECP-MPO test paper has a certain correlation with subcutaneous immunotherapy markers of allergic rhinitis, indicating that the ECP test paper may become an auxiliary biomarker to replace other complex laboratory tests.Keywords: dust mites, ECP-MPO test paper, subcutaneous immunotherapy, allergic rhinitis

Dongdong Chen,1,2,&ast; Surong Qian,3,&ast; Wenjun Qian,3 Miao Wu,3 Xinlong Wang,3 Haitao Shen,1 Xianming Long,4 Ming Ye,1 Yan Gong,3 Gang Chen1 1Department of Neurosurgery& Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215006, People’s Republic of China; 2Department of Neurosurgery, The Affiliated Hospital of Jiang Nan University, Wuxi, Jiangsu, 214000, People’s Republic of China; 3Department of Rehabilitation Medicine, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital Rehabilitation Medical Center, Gusu School, Suzhou, Jiangsu, 215000, People’s Republic of China; 4Department of Rheumatology, the First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215006, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yan Gong; Ming Ye, Email gongyan200605@126.com; yeming@suda.edu.cnBackground: Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive neuromodulation technique that shows promise for the treatment of Parkinson’s disease (PD). However, there is still limited understanding of the optimal stimulation frequencies and whether rTMS can alleviate PD symptoms by regulating the CaMKII-CREB-BMAL1 pathway.Methods: A PD mouse model was induced intraperitoneally with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and treated with 1 Hz, 5 Hz, and 10 Hz rTMS. The neurological function, survival of dopaminergic neurons, and protein levels of Tyrosine hydroxylase (TH), α-synuclein(α-syn), and brain-derived neurotrophic factor (BDNF) in the striatum were measured to determine the optimal stimulation frequencies of rTMS treatment in PD mice. The levels of melatonin, cortisol, and the circadian rhythm of Brain and muscle ARNT-like 1 (BMAL1) in PD model mice were detected after optimal frequency rTMS treatment. Additionally, KN-93 and Bmal1siRNA interventions were used to verify that rTMS could alleviate PD symptoms by regulating the CaMKII-CREB-BMAL1 pathway.Results: Administration of 10 Hz rTMS significantly improved neurological function, increased the protein levels of TH and BDNF, and inhibited abnormal aggregation of a-syn. Furthermore, administration of 10 Hz rTMS regulated the secretion profile of cortisol and melatonin and reversed the circadian arrhythmia of BMAL1 expression. After the KN-93 intervention, the MPTP+rTMS+KN-93 group exhibited decreased levels of P- Ca2+/calmodulin-dependent protein kinase II (CaMKII)/CaMKII, P-cAMP-response-element-binding protein (CREB)/CREB, BMALI, and TH. After Bmal1siRNA intervention, the protein levels of BMAL1 and TH were significantly reduced in the MPTP+10 Hz+ Bmal1siRNA group. At the same time, there were no significant changes in the proportions of P-CaMKIIα/CaMKIIα and P-CREB/CREB expression levels. Finally, immunohistochemical analysis showed that the number of TH-positive neurons was high in the MPTP+10 Hz group, but decreased significantly after KN-93 and Bmal1siRNA interventions.Conclusion: Treatment with 10 Hz rTMS alleviated MPTP-induced PD symptoms by regulating the CaMKII-CREB-BMAL1 pathway. This study provides a comprehensive perspective of the therapeutic mechanisms of rTMS in PD.Keywords: Parkinson’s disease, transcranial magnetic stimulation, brain and muscle ARNT-like 1, Ca2+/calmodulin-dependent protein kinase II, cAMP-response-element-binding protein