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Haiyan Sun,1,&ast; Siyao Chen,1,&ast; Ayano Nagai,2 Xi Chen,3 Yang Qin,1 Zhiming Wei1 1School of Nursing, Jiangsu Medical College, Yancheng, Jiangsu, People’s Republic of China; 2Social Welfare Corporation Keiseikai Group, Osaka, Japan; 3Department of Nursing, Yancheng NO.1 People’s Hospital, Yancheng, Jiangsu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhiming Wei, School of Nursing, Jiangsu Medical College, NO. 283 South Jiefang Road, Yancheng, Jiangsu, 224005, People’s Republic of China, Tel +8613805104291, Email 4826537@qq.comBackground: In China, spouses of patients with advanced cancer have reported experiencing psychological distress. However, little attention has been paid to the positive psychological health trajectories of these caregivers, particularly regarding their resilience and the factors influencing its development over time.Purpose: To examine the trajectories of resilience in Chinese spousal caregivers over a nine-month post-treatment period and to identify the basic characteristics associated with these trajectory patterns.Methods: This was a longitudinal, observational study conducted in mainland Chinese between January 2022 and May 2024. A total of 306 spouses of patients receiving cancer treatment were recruited from five local hospitals. Data was collected in four waves: within one month of initial treatment, and then at three-, six-, and nine-month intervals post-treatment. Socio-demographic questionnaires, the Connor-Davidson Resilience Scale, and the Beliefs in Chinese Familism Scale were used to collect data. Growth mixture modeling was employed to determine the various trajectories of resilience, followed by logistic regression analysis to examine the associated factors to predict types of trajectories.Results: Growth mixture modeling showed two distinct trajectories of resilience were identified: an increased group (N = 78, 25.5%) and a stable group (N = 228, 74.5%). The increased group began with a low baseline level (intercept = 46.713) and showed a slight increase over time (slope = 7.505, p < 0.001), while the stable group had a moderate baseline level (intercept = 56.565) and remained stable over time (slope = 0.068, p > 0.05). Those in the stable group were more likely to be female, and to have achieved a middle school level of education, a lower family income, and greater Chinese familism at baseline than those in the increased group.Conclusion: Our findings underscore the importance of tracking the trajectories of resilience and predictors of trajectory patterns among spouses caring for patients with advanced cancer within a specific cultural context. Healthcare providers should provide tailored interventions to enhance resilience in spousal caregivers, considering the trajectory patterns of mental health change.Keywords: resilience, spouse, advanced cancer, caregivers, trajectories

Yang Chen,1,&ast; Lijie Sun,1,&ast; Minghui Chen,1,&ast; Hui Zhang,2 Bing Song,3 Hongxiao Wang,3 Aijun Jiang,1,4 Li Zhang,5 Sumei Li,1 Jumei Wang,1 Wei Wang,1 Haoqiang Zhang1 1Department of Endocrinology, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, People’s Republic of China; 2Henan Key Laboratory of Rare Diseases, Endocrinology and Metabolism Center, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, People’s Republic of China; 3Department of Endocrinology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, People’s Republic of China; 4University of Science and Technology of China, Hefei, People’s Republic of China; 5ShuCheng People’s Hospital, Luan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wei Wang; Haoqiang Zhang, Email hfww2001@ustc.edu.cn; drhqzhang@ustc.edu.cnPurpose: Our objective is to investigate the potential involvement of free triiodothyronine (FT3), a key bioactive compound found in thyroid hormones (THs) in the pathogenesis of diabetic peripheral neuropathy (DPN) in patients diagnosed with type 2 diabetes mellitus (T2DM).Patients and Methods: A total of 121 T2DM patients were recruited. And then, they were divided into the control group and the DPN group. Clinical parameters were collected for each patient. Additionally, nerve conduction velocity was tested using neurophysiological methods. Correlation and regression analyses were employed to examine the relationship between the concentrations of FT3 and DPN.Results: Compared to 57 patients without DPN, 64 patients with DPN showed increased HbA1c and low-density lipoprotein cholesterol (LDL-C) levels (P=0.001 and 0.042), as well as decreased concentrations of FT3 (P=0.042). Additionally, FT3 levels are positively associated with the motor and sensory fibers conduction velocity of the Ulnar nerve, as well as the motor conduction velocity of the Tibial nerve, with (R=0.205, P=0.025; R=0.191, P=0.038; R=0.220, p=0.016) or without (R=0.257, P=0.004; R=0.227, P=0.012; R=0.227, p=0.012) adjustment for HbA1c and LDL-C. Furthermore, multiple linear regression analysis suggests that decreased FT3 levels may influence the motor and sensory fibers conduction velocity of the Ulnar nerve (β=0.795, P=0.025 and β=0.909, P=0.038), as well as the motor conduction velocity of the Tibial nerve (β=0.727, P=0.016). Moreover, our study demonstrated that decreased FT3 levels are one of the risk factors for DPN in T2DM patients, as determined by binary logistic regression analysis (OR=0.542, P=0.022).Conclusion: Lower concentrations of FT3 are one of the risk factors for DPN in patients with T2DM. Additionally, decreased FT3 levels may influence peripheral neuropathy, particularly affecting the motor and sensory fibers conduction velocity of the ulnar nerve, as well as the motor fiber conduction velocity of the tibial nerve.Keywords: free triiodothyronine, diabetic peripheral neuropathy, type 2 diabetes mellitus, thyroid hormone, conduction velocity of nerve

Chenkai Wang,1,2 Zefan Shen,1,2 Yiyang Chen,1,2 Yifan Wang,2 Xuanyi Zhou,2 Xinyi Chen,1 Yuhang Li,2 Pu Zhang,2 Qi Zhang2 1The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China; 2Urology & Nephrology Center, Department of Urology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, 310014, People’s Republic of ChinaCorrespondence: Qi Zhang; Pu Zhang, Email clinic@zju.edu.cn; zhangpuxjtuer@163.comAbstract: A key challenge in cancer treatment is the effective delivery of drugs into deep regions of tumor tissues, which are impermeable due to abnormal vascular network, increased interstitial fluid pressure (IFP), abundant extra cellular matrix (ECM), and heterogeneity of tumor cells. Cyclic peptides have been used for the surface engineering of nanoparticles to enhance the tumor-penetrating efficacy of drugs. Compared with other surface ligands, cyclic peptides are more easily produced by automated chemical synthesis, and they are featured by their higher binding affinity with their targets, tumor selectivity, stability against degradation, and low toxicity. In this review, different types of cyclic peptides, their physicochemical properties and their in vivo pharmacokinetics are introduced. Next, the progress of cyclic peptide-functionalized drug delivery nanodevices is updated, and the mechanism underlying the tumor-penetrating properties of cyclic peptide-functionalized drug delivery nanodevices is discussed.Keywords: cyclic peptide, tumor penetration, drug delivery, nanomaterial functionalization

Yuwei Chen,1,&ast; Zhibo Deng,2,&ast; Jian Chen,1 Jie Lin,1 Jianping Zou,1 Sang Li,1 Yang Sun1 1Department of Gynecology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, Fujian Province, People’s Republic of China; 2Department of Orthopedics, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou, Fujian Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yang Sun, Department of Gynecology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, Fujian, 350014, People’s Republic of China, Email sunyang@fjzlhospital.comBackground: Ovarian cancer (OC) poses a significant health burden with high mortality rates among female reproductive malignancies. Variability in treatment responses underscores the need for reliable prognostic markers to refine risk stratification. PANoptosis, a novel form of programmed cell death, plays pivotal roles in cancer pathogenesis and therapy. However, its prognostic relevance in OC remains unclear.Methods: Utilizing data from The Cancer Genome Atlas (TCGA), we analyzed transcriptomic and clinical signatures of OC patients. Through consensus clustering, we delineated molecular subtypes associated with PANoptosis-related genes (PRGs). We constructed and validated prognostic models using LASSO and Cox regression analyses, corroborated with GEO dataset validation. CIBERSORT assessed immune cell infiltration by risk score, and a predictive algorithm evaluated chemotherapy responses. Additionally, we investigated the biological role of the key gene CXCL13 in OC and its response to immunotherapy.Results: Based on 19 PRGs, we identified two OC subtypes (PAN-Cluster1, PAN-Cluster2). Machine learning-derived risk scores using PAN-Cluster differentially expressed genes emerged as an independent prognostic indicator. Distinct risk groups exhibited varying clinical outcomes, immune profiles, drug sensitivities, and mutational landscapes. Notably, we confirmed CXCL13 as a model key gene and explored its role in OC regulation. In OC cells, suppression of CXCL13 expression enhances cell proliferation and migration, while patients with high CXCL13 expression show an improved response to immunotherapy.Conclusion: We initially identified the molecular subtypes associated with PRGs and established a prognostic model related to PRGs to predict survival and drug response in OC patients. Although further validation is required, these findings offer valuable insights into the development of personalized treatment strategies for OC patients.Keywords: PANoptosis, ovarian cancer, tumor microenvironment, drug sensitivity, prognosis

Zixiang Pang,&ast; Yangqin Ou,&ast; Jiawei Liang, Shengbin Huang, Jiayi Chen, Shengsheng Huang, Qian Wei, Yuzhen Liu, Hongyuan Qin, Yuanming Chen Department Orthopedics Ward 3 (Spine and Osteopathy Surgery), Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yuanming Chen, Department of Spinal Orthopedics, the Second Affiliated Hospital of Guangxi Medical University, No. 166, University East Road, Nanning, Guangxi, People’s Republic of China, Tel +86 13087712603, Email rkyygk@163.comObjective: The objective of this study aimed to investigate the risk factors for poor wound healing (PWH) after posterior lumbar spinal fusion. Currently, there is limited research on the application of machine learning in analyzing PWH after spinal surgery. Thus, our primary aim is to using machine learning identify these risk factors and construct a clinical risk prediction model.Methods: We retrospectively reviewed 2516 patients who underwent posterior lumbar spinal fusion at Guangxi Medical University’s Second Affiliated Hospital between August 2021 and August 2023. The data was divided into test and validation groups in a 7:3 ratio. In the test group, logistic regression analysis, support vector machine (SVM), random forest (RF), decision tree (DT), XGboost, Naïve Bayes (NB), k-Nearest Neighbor (KNN), and Multi-Layer Perceptron (MLP) were used to identify specific variables. The top six models from the eight machine learning models with the highest area under curve (AUC) values were selected and used to construct a dynamic nomograms model. Model performance was evaluated using receiver operating characteristic (ROC) and calibration curves. The model’s internal performance was then verified in the validation group using ROC and calibration curves.Results: Data from 2516 patients were collected, with 411 eligible cases selected. By combining logistic regression analysis with six machine learning algorithms, this study identified six predictors associated with PWH: subcutaneous lumbar spine index(SLSI), albumin, postoperative glucose, cerebrospinal fluid leakage(CSFL), neutrophil (NEU), and C-reactive protein(CRP). These predictors were used to develop a prediction model, visually represented through a nomogram. The AUC value in the test group was 0.981, and the C-index of the model was 0.986 (95% CI 0.966– 0.995), indicating excellent predictive capability. Calibration curve analysis showed good consistency between nomogram-predicted values and actual measurements.Conclusion: SLSI, albumin, postoperative glucose, CSFL, NEU and CRP were identified as significant risk factors for PWH after posterior lumbar spinal fusion. The developed prediction model exhibited excellent predictive accuracy and usefulness.Keywords: poor wound healing, posterior lumbar spinal fusion, machine learning, dynamic prediction model

Abstract Bone health screening is crucial before and during androgen deprivation therapy (ADT) for prostate cancer, yet changes in bone mineral density during ADT are often overlooked. To improve surveillance rates, we developed an auto-recruit path integrated into the outpatient system, where a pop-up reminder prompts physicians to arrange bone health screenings when ADT is prescribed without a dual-energy x-ray absorptiometry (DXA) screening in the past year. If selected, the system orders DXA and related examinations automatically. We retrospectively reviewed DXA screening rates from 2000 to 2018. During that period, only 286 out of 3,019 patients (9.5%) received DXA screenings. After implementing the auto-recruit system, 251 out of 747 eligible patients (33.6%) were screened from March 2021 to February 2022. Participants using ADT for over a year had worse T-scores and higher osteoporosis rates (34.5% vs. 23.2%) compared to those using ADT for less than a year. Post-screening, there was a significant increase in calcium supplement and bone protective agent use, highlighting improved patient awareness and proactive bone health management. In conclusion, bone health screening for prostate cancer patients on ADT remains an unmet need. The auto-recruit path in the outpatient system effectively increases screening rates and enhances bone health management.

Abstract A proportion of hippocampal CA1 neurons function as place cells from the onset of navigation, which are referred to as early place cells. It is not clear whether this subset of neurons is predisposed to become place cells during early stages, or if all neurons have this potential. Here, we longitudinally imaged the activity of CA1 neurons in developing male rats during navigation with both one-photon and two-photon microscopy. Our results suggested that a largely consistent population of cells functioned as early place cells, demonstrating higher spatial coding abilities across environments and a tendency to form more synchronous cell assemblies. Early place cells were present in both deep and superficial layers of CA1. Cells in the deep layer exhibited greater synchrony than those in the superficial layer during early ages. These results support the theory that an initial cognitive map is primarily shaped by a predetermined set of hippocampal cells.

Jiaxuan He,1,&ast; Peiye Xu,1,&ast; Rongbing Chen,2 Mengyan Chen,3 Beier Wang,4 Yilun Xie,4 Qinsi Yang,5 Da Sun,1 Mingxia Ji3 1Institute of Life Sciences & Biomedical Collaborative Innovation Center of Zhejiang Province, Wenzhou University, Wenzhou, 325035, People’s Republic of China; 2Department of Biomedical Engineering, City University of Hong Kong, Hong Kong, SAR 999077, People’s Republic of China; 3Department of Critical Care Medicine, Yiwu Central Hospital, the Affiliated Yiwu Hospital of Wenzhou Medical University, Yiwu, 322000, People’s Republic of China; 4Department of Hepatobiliary-Pancreatic Surgery, the Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, People’s Republic of China; 5Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, 325000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Mingxia Ji; Da Sun, Email jmx529652@wmu.edu.cn; sunday@wzu.edu.cnAbstract: Sepsis, a severe condition instigated by infections, continues to be a primary global cause of death, typified by systemic inflammation and advancing immune dysfunction. Comprehending the complex pathological processes that underlie sepsis is integral to the creation of efficacious treatments. Despite the inability of animal models to entirely reproduce the clinical intricacies related to sepsis, they are invaluable instruments for the exploration and development of therapeutic approaches. Within this context, the zebrafish model is particularly noteworthy due to its genetic tractability, transparency, and appropriateness for high-throughput screening of genetic mutants and therapeutic compounds. This scholarly review emphasizes the crucial role that the zebrafish disease model plays in enhancing our comprehension of sepsis, by exploring its applications in deciphering immune and inflammatory responses, evaluating the consequences of genetic alterations, and examining novel therapeutic agents. The Insights derived from zebrafish research not only augment our understanding of the underlying mechanisms of sepsis, but also possess considerable potential for the transference of these discoveries into clinical therapies, thus potentially transforming the approach to sepsis management. The objective of this scholarly article is to underscore the importance of zebrafish in the realm of biomedical research pertaining to sepsis, and to delineate forthcoming opportunities for utilizing this model in clinical applications. Keywords: Sepsis, Zebrafish models, Inflammation, Immunology, Drug development

Jiamin Long,1,2,&ast; Jiali Chen,3,&ast; Yue Yuan,4,&ast; Shaozhen Yang,5,&ast; Xinya Xie,1,2 Xuelian Wu,1,2 Yuan Liu,1,2 Jinpeng Guo,2 Yong Chen,1,2 Changjun Wang,1,2 Xiong Liu2 1School of Public Health, China Medical University, Shenyang, 110122, People’s Republic of China; 2Chinese PLA Center for Disease Control and Prevention, Beijing, 100071, People’s Republic of China; 3School of Medicine, NanKai University, Tianjin, 300071, People’s Republic of China; 4Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, People’s Republic of China; 5School of Basic Medical Sciences, Army Medical University (Third Military Medical University), Chongqing, 400038, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiong Liu; Changjun Wang, Chinese PLA Center for Disease Control and Prevention, Beijing, 100071, People’s Republic of China, Email liuxiong714@163.com; science2008@hotmail.comBackground: Klebsiella michiganensis is an emerging human pathogen that causes nosocomial infections. Its prevalence and spread in the environment should not be ignored. This study identified and characterized Klebsiella michiganensis co-harboring blaKPC-2 and TmexCD2-ToprJ2 in hospital wastewater samples.Methods: Twelve K. michiganensis strains were isolated from wastewater samples collected at a tertiary hospital in Beijing, China. The genomic characteristics of K. michiganensis strains were analyzed using whole-genome sequences, providing information on the comparison between the genome of K. michiganensis strains and the reference genome, antibiotic resistance genes (ARGs), virulence genes, secretion systems, and mobile genetic elements (plasmids, insertion sequences [ISs], and prophages).Results: Genome analysis showed that the twelve multi-drug resistant (MDR) strains carried a variety of ARGs and virulence genes, as well as four macromolecular secretion systems (T1SS, T2SS, T5aSS, T5bSS, and T4aP). The genetic environments of both the TmexCD2-ToprJ2 gene cluster and blaKPC-2 gene contained ISs. The plasmids carrying TmexCD2-ToprJ2 gene cluster of nine strains in clade 1 and two strains in clade 2 were annotated as IncR plasmid and rep_cluster_1254 type, respectively. The plasmids carrying blaKPC-2 in 10 strains in clade 1 were identified as IncU, and the plasmids carrying blaKPC-2 in the k11 and k12 strains in clade 2 were IncU and IncX6. The phylogenetic tree and heatmap revealed that the secretion system of type VI (T6SSi) existed in 10 strains in clade 1, and Type IV (T4SS) only existed in the k11 strain in clade 2. In addition, K. michiganensis strains carried 13 plasmids, 14 ISs, and 138 prophages.Conclusion: In this study, the whole genome sequencing demonstrated the diversity of K. michiganensis genome despite 12 K. michiganensis strains from a hospital wastewater, which lays the foundation for further genetic research and drug resistance gene transmission.Keywords: Klebsiella michiganensis, hospital wastewater, whole-genome sequencing, blaKPC-2, TmexCD2-ToprJ2

Jingyi Wang,1,&ast; Wei Zhang,1,&ast; Peige Song,2,&ast; Tingting Wang,3 Ye Yao,1 Yun Chen,4 Haijiang Lin,3 Xiaoqi Yang,1 Xiaoxiao Chen,1,3 Chaowei Fu1 1School of Public Health; NHC Key Laboratory of Health Technology Assessment, Fudan University, Shanghai, People’s Republic of China; 2School of Public Health and the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People’s Republic of China; 3Taizhou City Center for Disease Control and Prevention, Taizhou, Zhejiang Province, People’s Republic of China; 4Yale School of Nursing, Orange, CT, 06477, USA&ast;These authors contributed equally to this workCorrespondence: Chaowei Fu, School of Public Health, NHC Key Laboratory of Health Technology Assessment, Fudan University, Shanghai, 200032, People’s Republic of China, Email fcw@fudan.edu.cn Xiaoxiao Chen, Taizhou City Center for Disease Control and Prevention, Taizhou, Zhejiang Province, 318000, People’s Republic of China, Email tzcdccxx@126.comBackground: COVID-19 threatened global health, however little is known about the long-term courses of loneliness and their effect on mental health in adolescents. This study aimed to explore the trajectories of loneliness among adolescents in Taizhou, Zhejiang Province, China, during the last phase of the pandemic. We also aimed to identify risk factors in each loneliness course and the impact of loneliness on emotional problems, peer problems, hyperactivity and conduct problems.Methods: The study employed multistage cluster sampling to collect four waves of data from 2347 Chinese adolescents (average baseline age of 14.7 years) covering a period of 20 months (October 2021 – May 2023). The UCLA 3-Item Loneliness Scale and the Strengths and Difficulties Questionnaire were utilized to assess loneliness and mental health problems, respectively. Growth mixture modelling was employed to identify latent classes of loneliness trajectories. Associated risk factors were investigated using multinomial logistic regression model. Mixed-effects logistic regression models were constructed to examine the long-term impact of loneliness classes on mental health outcomes.Results: The overall percentage of loneliness increased from 22.9% at baseline to 32.2% at the fourth wave in our sample. Three classes of loneliness were identified: Decreasing Low Loneliness (58.71%), Increasing Medium Loneliness (36.52%), and Increasing High Loneliness (4.77%). Risk factors for poorer loneliness trajectories included lack of physical exercise habits, poorer mental health literacy, medium or low perceived social support, having study difficulties, being female, higher grades, and lower economic status. Loneliness classes were associated with the severity and variability of emotional problems, peer problems, hyperactivity and conduct problems (ORs for the highest loneliness class: 10.24, 4.21, 3.87, 2.68, respectively). Individuals in the higher loneliness classes experienced a significant increase in these mental health problems over time (p < 0.05 for interactions between loneliness classes and time).Conclusion: During the last phase of the pandemic, a large proportion of adolescents in our study endured medium to high levels of loneliness with no signs of improvement. Both unfavorable loneliness trajectories adversely affected internalizing and externalizing problems and displayed an upward trend in these difficulties. Results highlight the importance of tackling loneliness and improving mental health in adolescents.Keywords: adolescents, loneliness, risk factors, internalizing problems, externalizing problems, COVID-19

Meili Xu,1,2 Hongliu Chen,1,2 Jianjing Chen,3 Rongzong Ye,4 Huan Xiao,1,2 Jingwen Li,4 Chaoqian Li1,2 1Department of Emergency, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People’s Republic of China; 2Guangxi University Key Laboratory of Emergency Medicine, Nanning, Guangxi, People’s Republic of China; 3Department of Medical Ultrasound, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People’s Republic of China; 4Guangxi Medical University, Nanning, Guangxi, People’s Republic of ChinaCorrespondence: Chaoqian Li, Department of Emergency, The First Affiliated Hospital of Guangxi Medical University, No. 6 Shuangyong Road, Nanning, Guangxi, 530021, People’s Republic of China, Email lichaoqiangood@163.comObjective: This study aimed to explore the factors influencing pulmonary fibrosis in patients with acute diquat poisoning through logistic regression analysis.Methods: A retrospective analysis was conducted on 68 cases of acute diquat poisoning due to suicidal intent admitted to our hospital from February 2020 to March 2023. Patients were divided into a combined group (28 cases with pulmonary fibrosis) and an acute diquat poisoning group (40 cases without). A healthy control group consisted of 40 individuals. General data were compared among the three groups, and laboratory indicators were analyzed. Single and multiple logistic regression analyses were performed to identify risk factors for pulmonary fibrosis.Results: There were no significant differences in gender, age, BMI, poisoning status, or treatment timing among the groups (P > 0.05). The combined group had significantly higher diquat ingestion dose, SIRS score, SOFA score, and APACHE II score compared to the poisoning group (P < 0.05). In the acute poisoning group, these scores were also higher than in the healthy controls (P < 0.05). Laboratory indicators, including Hb, PLT, ALP, DBil, ALB, BUN, Glu, BNP, and pH, showed no significant differences (P > 0.05). However, WBC, ALT, TBil, DBil, Cr, K+, Tn I, and Lac levels were significantly higher in the combined group compared to the acute poisoning group (P < 0.05). Logistic regression analysis identified factors influencing pulmonary fibrosis as diquat ingestion dose, K+, ALT, PaO2, Lac, and HCO3-.Conclusion: The factors influencing pulmonary fibrosis in acute diquat poisoning include diquat ingestion dose, K+, ALT, PaO2, Lac, and HCO3-. These findings enhance understanding of pulmonary fibrosis pathogenesis and may inform clinical management for affected patients.Keywords: acute diquat poisoning, pulmonary fibrosis, K+, ALT, PaO2

Linmei Xiao,1,&ast; Jingjing Ma,2,&ast; Ruidong Chen,2,3,&ast; Jie Chen,4 Qiang Wang,5 Nana Tang,2 Xiaojing Zhao,2 Hongjie Zhang,2 Chunhua Jiao2 1Department of Liver Disease, Wuxi No.5 People’s Hospital Affiliated to Jiangnan University, Wuxi, People’s Republic of China; 2Department of Gastroenterology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, Jiangsu Province, People’s Republic of China; 3Department of Gastroenterology, The Second Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China; 4Northern Jiangsu People’s Hospital/Northern Jiangsu People’s Hospital of Jiangsu Province, Yangzhou, Jiangsu Province, People’s Republic of China; 5Jiangsu Shengze Hospital, Suzhou, Jiangsu Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Chunhua Jiao; Hongjie Zhang, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu Province, 210029, People’s Republic of China, Tel +86 13913928581, Email jch0409@163.com; hjzhang06@163.comPurpose: Cytomegalovirus (CMV) infection exacerbates intestinal inflammation in ulcerative colitis (UC) patients, yet the effect of CMV infection on UC relapse has not been fully elucidated. This study aimed to investigate the impact of CMV infection on UC relapse and identify associated risk factors.Patients and Methods: This multicenter retrospective cohort study included UC patients who visited research centers from January 2016 to December 2020. Univariate and multivariate Cox regression analyses were conducted to explore risk factors for UC relapse. Propensity score matching was used to balance the differences in the clinical characteristics between the groups.Results: A total of 298 UC patients participated in this study, including 19 with CMV colitis, 37 with CMV viremia, and 242 CMV-negative patients. The 2-year cumulative recurrence rate was higher in patients with CMV colitis than that in CMV-negative patients (84.21% vs 51.65%, p = 0.01). Univariate and multivariate Cox regression analyses confirmed that fecal calprotectin ≥ 250 μg/g, Montreal classification E3, CMV colitis, duration > 48 months, and serum albumin < 30 g/L were independent risk factors for UC relapse at 2 years, whereas the use of biologics for induction of remission was identified as an independent protective factor.Conclusion: Our study suggests that the risk of relapse increases among UC patients with CMV colitis over two years. Risk factors for UC relapse at 2 years include fecal calprotectin ≥ 250 μg/g, Montreal classification E3, CMV colitis, UC duration > 48 months, and albumin < 30 g/L, whereas the use of biologics during induction is a protective factor.Plain Language Summary: Patients with ulcerative colitis and cytomegalovirus colitis are at a higher risk of relapse over a 2-year period than those who are CMV negative. Additionally, we identified several risk factors for UC relapse at 2 years, including fecal calprotectin ≥ 250 μg/g, Montreal classification E3, CMV colitis, duration of UC ≥ 48 months, and albumin < 30 g/L, whereas the administration of biologics during remission induction contributed to reducing UC relapse.Keywords: Ulcerative colitis, cytomegalovirus colitis, relapse, risk factors

Yong Chen,1 Yan-Juan Chen,1 Jian-Feng Luo,2 Mang He,1 Si-Jin Zhao,3 Shi-Dan Tian,1 Yong-Qiao Zhang,3 Xiao-Long Chen,3 Chuan-Jie Yang,3 Yu-Zhuo Luo,3 Kutty Selva Nandakumar,4 Mei Tian1 1Department of Rheumatology and Immunology, Affiliated Hospital of Zunyi Medical University, Zunyi, People’s Republic of China; 2Department of Biostatistics, School of Public Health, Fudan University, Shanghai, People’s Republic of China; 3The First School of Clinical Medicine, Zunyi Medical University, Zunyi, People’s Republic of China; 4Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, SwedenCorrespondence: Mei Tian, Department of Rheumatology and Immunology, Affiliated Hospital of Zunyi Medical University, 149 Dalian Road, Huichuan District, Zunyi City, Guizhou Province, 563000, People’s Republic of China, Email 348820517@qq.com Kutty Selva Nandakumar, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, 17177, Sweden, Email ksnandakumar@outlook.comPurpose: The quality of life (QoL) of elderly patients with rheumatoid arthritis (RA) in Zunyi China based on health parameters has not been previously analyzed. This study compares the 36-Item Short Form Health Survey (SF-36) scores and prevailing health complications between < 60y and ≥ 60y patients with RA. Data from 1166 patients with RA who visited the rheumatology department of Zunyi Medical University Hospital were followed up and retrospectively analyzed.Patients and Methods: Data from 1166 patients with RA who visited the rheumatology department of Zunyi Medical University Hospital (2021.1– 2022.8) were followed up and retrospectively analyzed.Results: Twenty cases passed away at 61.55 ± 8.11y, which was 6.75 years less than the local average age of death. Elderly patients with RA reported lower recovery levels, and their levels of inflammatory markers such as Immunoglobulin M-rheumatoid factor (IgM-RF), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) levels were significantly higher than those of younger patients during their past one-year observation period. The SF-36 results indicated that eight items of QoL in the elderly patients were all significantly inferior to < 60y patients, while the complications of interstitial lung disease (ILD), latent tuberculosis infection (LTBI) and, lung and herpes zoster infections were significantly higher.Conclusion: Elderly patients had a higher disease activity along with poor QoL, more health-related complications, and susceptibility to infections. Our study emphasizes the imperative need for optimization of RA treatment modalities in the elderly to alleviate their sufferings.Keywords: elderly rheumatoid arthritis, SF-36 scores, clinical characteristics, treatment outcomes

Objective To compare the therapeutic efficacy of robot-assisted laparoscopic radical prostatectomy versus conventional laparoscopic radical prostatectomy, and analyze the factors influencing treatment outcomes. Methods A retrospective cohort study was conducted on 719 patients (total cohort) who underwent radical prostatectomy in our department from June 2002 to October 2023. According to different surgical methods, they were divided into robot-assisted laparoscopic radical prostatectomy group (robotic group, n=409) and conventional laparoscopic radical prostatectomy group (conventional group, n=310). Clinical characteristics, biochemical recurrence rates, and recovery of urinary continence at 1, 3, 6, and 12 months postoperatively, as well as sexual function recovery at 6 and 12 months after surgery, were compared between the 2 groups. Additionally, the factors influencing biochemical recurrence and urinary continence recovery were analyzed across the entire cohort. Results In the cohort, the robot group demonstrated significantly larger proportions of pathological high T stages (≥pT3, P < 0.01), increased positive lymph node rate (P < 0.01), and greater number of dissected lymph nodes (P < 0.01) than the conventional group. There were no statistical differences between the 2 groups in terms of Gleason score, biochemical recurrence rate, or incidence and type of complications. The robot group exhibited significantly higher rates of urinary continence recovery at 1 (P=0.004), 3 (P < 0.01), 6 (P=0.002) and 12 months (P=0.004) postoperatively. But no obvious difference was seen in the score of International Index of Erectile Function-5 (IIEF-5) between the 2 groups at 6 and 12 months. Across the entire cohort, pathological high T stage (≥pT3, P < 0.01), high Gleason score (>7, P=0.036), fewer lymph nodes dissected (≤10, P < 0.01), and positive lymph nodes (P=0.046) were independent risk factors for biochemical recurrence. Additionally, the surgical method, specifically robot-assisted laparoscopic radical prostatectomy, was identified as a significant factor influencing urinary continence recovery at 12 months postoperatively (P=0.005). Conclusion Compared to conventional laparoscopic radical prostatectomy, robot-assisted laparoscopic radical prostatectomy shows certain effect on reducing biochemical recurrence rate and enhancing recovery of urinary continence in prostate cancer patients at 1, 3, 6 and 12 months postoperatively.

Abstract Background Despite remarkable achievements in applying chimeric antigen receptor (CAR)-T cells to treat hematological malignancies, they remain much less effective against solid tumors, facing several challenges affecting their clinical use. We previously showed that multichain DNAX-activating protein (DAP) CAR structures could enhance the safety and efficacy of CAR-T cells when used against solid tumors. In particular, mesothelin (MSLN)-targeted CAR-T cell therapy has therapeutic potential in MSLN-positive solid tumors, including ovarian cancer and mesothelioma. Methods In vitro cell killing assays and xenograft model were utilized to determine the anti-tumor efficacy of MSLN targeting DAP-CAR-T cells and other CAR-T cells. ELISA and flow cytometry analysis were used to assess the cytokine secretion capacity and proliferation ability. Eight patients with MSLN expression were enrolled to evaluate the safety and efficacy of MSLN-DAP CAR-T cell therapy. Single-cell sequencing was performed to explore the dynamics of immune cells in patients during treatment and to identify the transcriptomic signatures associated with efficacy and toxicity. Results We found that multichain DAP-CAR formed by combining a natural killer cell immunoglobulin-like receptor truncator and DAP12 exhibited better cytotoxicity and tumor-killing capacity than other natural killer cell-activated receptors associated with DAP12, DAP10, or CD3Z. The safety and efficacy of MSLN-DAP CAR-T cell therapy in patients with ovarian cancer and mesothelioma were evaluated in a single-arm, open-label clinical trial (ChiCTR2100046544); two patients achieved partial response, while four patients had a stable disease status. Furthermore, single-cell sequencing analysis indicated that KT032 CAR-T cell infusion could recruit more immune cells and temporarily remodel the TME. Conclusions Our study highlights the safety and therapeutic efficacy of multiple-chain DAP-CAR-T cell therapy targeting MSLN to treat patients with ovarian cancer and mesothelioma. Trial registration ChiCTR.org.cn, ChiCTR2100046544 . May 21, 2021.

Ani Zhao,1,&ast; Yanchun Peng,2,&ast; Baolin Luo,2 Yaqin Chen,1 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 Province, 350001, People’s Republic of China; 3Department of Cardiovascular Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, 350001, People’s Republic of China; 4Key Laboratory of Cardio-Thoracic Surgery (Fujian Medical University) Fujian Province University, Fuzhou, Fujian Province, 350001, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Liangwan Chen; Yanjuan Lin, Email fjxhlwc@163.com; fjxhyjl@163.comPurpose: Acute Type A aortic dissection (ATAAD) is a rare and life-threatening aortic disease. This study was aimed at the potential of the D-dimer to platelet count ratio (DPR) as a prognostic indicator of ATAAD.Patients and Methods: This study retrospectively analyzed ATAAD patients who were admitted to the Department of Cardiac Surgery, Fujian Medical University Union Hospital from January 2022 to April 2023. Patients were divided into survival (n = 173) and death (n = 24) groups based on whether death occurred. The primary outcome was death, and the secondary outcome was adverse hospitalization, including new postoperative arrhythmias, acute renal insufficiency, acute liver insufficiency, pleural effusion, length of ICU stay, mechanical ventilation length, and length of stay. The logistic regression model was used to analyze the relationship between DPR and in-hospital death, and the receiver operating characteristic curve (ROC) was drawn to analyze the predictive value of DPR for in-hospital death of ATAAD patients.Results: Of the 197 patients included, 24 died, and the in-hospital mortality rate was 12.2%. There was a significant difference in diastolic blood pressure (P < 0.05). In terms of laboratory indexes, total bilirubin, direct bilirubin, indirect bilirubin, D-dimer, red blood cell volume distribution width, and DPR in the death group were higher than those in the survival group, with statistical significance (P < 0.05). Operation duration, hospital stay, ICU stay, mechanical ventilation time, and acute renal insufficiency in the death group were higher than those in the survival group (P < 0.05). Univariate analysis and multivariate analysis showed that DPR > 0.0305 ug/mL was an independent risk factor for death in ATAAD patients.Conclusion: Increased DPR is independently associated with in-hospital death in patients with ATAAD.Keywords: acute type A aortic dissection, death, D-dimer/platelet ratio, prognosis

Zhenkang Liang,&ast; Zehong Chen,&ast; Chaowei Zhang, Cui Chen, Wende Yang, Yuxuan Zhang, Hongbo Wei Department of Gastrointestinal Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hongbo Wei, Department of Gastrointestinal Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Tianhe Road 600, Guangzhou, 510630, People’s Republic of China, Tel +86-020-85253000, Email weihb@mail.sysu.edu.cnPurpose: Erectile dysfunction (ED) frequently arises as a complication of pelvic surgeries, including rectal and prostate surgery, and has no definitive cure. This study explored whether mitochondria-rich microvesicles (MVs) can be used to treat ED stemming from cavernous nerve injury (CNI) and investigated its potential mechanisms.Methods: We isolated MVs and mitochondria (MT) from PC12. The apoptosis rate, mitochondrial membrane potential (MMP), reactive oxygen species (ROS), mitochondrial derived reactive oxygen species (mtROS), iron content, malondialdehyde (MDA) content and endogenous antioxidant system activity of corpus cavernosum smooth muscle cells (CCSMCs) cultured with MVs and MT were detected in vitro. In vivo, twenty-four male Sprague Dawley rats were randomly divided into four groups: sham operation group and CNI group were injected with PBS, MVs and MT respectively. After fourteen days of treatment, the erectile function was measured and penile tissues were collected for histological analysis. Subsequently, inhibition of mitochondria in MV was performed to explore the mechanism of the rescue experiment.Results: The CCSMCs, PC12-MVs and PC12-MT were successfully isolated and identified. After MVs culture, apoptosis rate, ROS, mtROS, iron content and MDA content of CCSMCs were significantly decreased, while MMP and the activities of endogenous antioxidant system were increased. MVs transplantation can significantly restore erectile function and smooth muscle content in CNIED rats. The rescue experiment suggested that MVs exerted the above therapeutic effect by transferring mitochondria within it.Conclusion: MVs transplantation significantly improve erectile function in CNI ED rats. MVs may play a role in anti-OS and anti-ferroptosis at the transplant site through efficient transfer of mitochondria, providing a potential treatment vehicle for CNI ED.Keywords: cavernous nerve injury, erectile dysfunction, microvesicles, oxidative stress, ferroptosis

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,&ast; Haowen Qi,2,&ast; 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&ast;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,&ast; XiXuan Cai,1,&ast; 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&ast;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,&ast; Xinyu Wang,3,&ast; Haiyan Zhang,3,&ast; Hang Chen,3,&ast; 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&ast;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,&ast; Ruiming Liang,3,&ast; 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&ast;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,&ast; Chengzhi Chen,2,&ast; Yuting Chen,1,&ast; 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&ast;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, &ast;2) and rs4986893 (636G > A, &ast;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) (&ast;1/&ast;1), intermediate metabolizer (IM) (&ast;1/&ast;2 and &ast;1/&ast;3), and poor metabolizer (PM) (&ast;2/&ast;2, &ast;2/&ast;3, and &ast;3/&ast;3) phenotypes, respectively. CYP2C19 &ast;2/&ast;2 genotype frequency was higher, &ast;1/&ast;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.

Fe–Fe3P adhesive premixed powders were prepared by using hyperbranched polyester as the binders. The microstructure of the powders was observed by scanning electron microscope. The effect of hyperbranched polyester binder content (mass fraction) on the properties of the Fe−Fe3P powder mixture and the sintered products was studied. The results show that the proportion of small particle size powders with particle size ≤10 μm (mostly Fe3P powders) in the bonded mixed powders accounts for 0.65% of the total number of powder particles, which is significantly lower than that of the un-bonded mixed powders (5.93%). Hyperbranched polyester can successfully bond the Fe3P powders to the iron powder surface, which is beneficial to improve the uniformity of phosphorus in the mixed powders and prevent segregation. The Fe–Fe3P bonded mixed powders with 0.10% terminal hydroxyl hyperbranched polyester show the best powder fluidity and loose packing density. The pressing pressure of the Fe–Fe3P green billets with the same density increases with the increase of the mass fraction of hyperbranched polyester. The addition of hyperbranched polyester binder can reduce the size change rate of the sintered body before and after sintering, improve the transverse fracture strength of the sintered body, and maintain good bonding property in the actual production process.

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,&ast; Chao Chen,2,3,&ast; 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&ast;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