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Yuqing Song,1,2,* Wenjie Lei,1– 3,* Qianqian Huang,1,2 Jiehan Zhang,1,2 Qiao Zhang,4 Lulu Chen,1,2 Huiqing Li,1,2 Li Liu,5 Tianshu Zeng,1,2 Xiang Hu1,2 1Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China; 2Hubei Provincial Clinical Research Center for Diabetes and Metabolic Disorders, Wuhan, 430022, People’s Republic of China; 3People’s Hospital of Luotian County, Huanggang, 438600, People’s Republic of China; 4Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China; 5The People’s Hospital of Maojian, Shiyan, 442000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Tianshu Zeng; Xiang Hu, Email tszeng@126.com; huxiang628@126.comBackground: Functional defects caused by mutations in the insulin receptor (INSR) gene often lead to severe hereditary insulin resistance syndromes, including but not limited to type A insulin resistance syndrome.Method and Result: Here, we report a case of a 12-year-old girl with elevated fasting blood glucose detected by opportunistic testing, associated with severe insulin resistance and hyperandrogenemia. She had axillary hair, acne, clitoral hypertrophy, prominent labia minora hypertrophy and thickened voice with BMI 20.57kg/m2, and ultrasound imaging showed that she had multiple follicles in both ovaries. Insulin was initially administered, but the glycemic control was poor. Accordingly, the prescription was later switched to metformin, maintaining euglycemic blood glucose level. The whole exome sequencing from peripheral blood revealed that the patient carries NM_000208.2:c.1225_1227delTTC (p.Phe409del) heterozygous mutation in the INSR gene. She was tentatively diagnosed as type A insulin resistance syndrome based on her clinical features and heterozygous mutation in the INSR gene.Conclusion: Our results demonstrated that type A insulin resistance syndrome in patients presenting with severe insulin resistance and hyperandrogenemia was associated with a heterozygous variant of c.1225_1227delTTC (p.Phe409del), suggesting that exon sequencing would be beneficial to detect the potential mutations in the INSR gene of these patients for precise diagnosis and intervention in clinical practice.Keywords: insulin receptor gene, heterozygous mutation, severe insulin resistance, hyperandrogenemia, type A insulin resistance syndrome, female

Xiaofang Fu,1,* JiangYing Guo,2,* Xiaofei Gu,1 Liyan Chen,1 Jiangang Ju,1 Huaqiong Huang2 1The First People’s Hospital of Hangzhou Linping District, Zhejiang University School of Medicine Second Affiliated Hospital Linping Hospital, Hangzhou, Zhejiang, People’s Republic of China; 2Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Huaqiong Huang, The Second Affiliated Hospital of Zhejiang University School of Medicine, Shangcheng District, Hangzhou, Zhejiang, 310009, People’s Republic of China, Tel +8615005818703, Email zr_hhq@zju.edu.cn Jiangang Ju, The First People’s Hospital of Hangzhou Linping District, Zhejiang University School of Medicine Second Affiliated Hospital Linping Hospital, Linping District, Hangzhou, Zhejiang, People’s Republic of China, Tel +8615372002070, Email LL0731QQ0516@163.comBackground: Preserved ratio impaired spirometry (PRISm) is considered to be one of the early chronic obstructive pulmonary disease states, and there are few studies on PRISm prevention. We aimed to evaluate the relationship between physical activity and the risk of PRISm.Methods: A cross-sectional study was conducted using data from US adults who participated in the National Health and Nutrition Examination Survey (NHANES) between 2007 and 2012. We examined the association between physical activity and PRISm using multivariable logistic regression models and a restricted cubic spline (RCS) model.Results: Compared to the normal and chronic obstructive pulmonary disease (COPD) groups, the PRISm group had lower levels of physical activity (3537.2 MET-min/week in the normal group vs 3452.1 MET-min/week in the COPD group vs 2841.5 MET-min/week in the PRISm group). Adjusted multivariable regression models revealed that greater physical activity dose (more than 4800 MET-min/week) was associated with lower odds of PRISm (adjusted odds ratio [aOR] = 0.77, 95% confidence interval [95% CI] = 0.61– 0.98; P = 0.031). The RCS curve revealed that there was a significant nonlinear negative dose–response relationship between the level of physical activity and the risk of PRISm (Pnon-linearity

Liang Chen,1,* Xiaomei Ying,2,* Haohao Wang,1,* Jiaheng Xie,3,* Qikai Tang,4 Wen Liu1 1Department of Hepatobiliary and Pancreatic Surgery, Conversion Therapy Center for Hepatobiliary and Pancreatic Tumors, First Hospital of Jiaxing, Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, People’s Republic of China; 2Department of General Surgery, Suzhou Hospital of Anhui Medical University, Suzhou, Anhui, People’s Republic of China; 3Department of Plastic and Cosmetic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan Province, 410008, People’s Republic of China; 4Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wen Liu, Department of Hepatobiliary and Pancreatic Surgery, Conversion therapy center for Hepatobiliary and Pancreatic Tumors, First Hospital of Jiaxing, Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, People’s Republic of China, Email nickwen2006@163.comBackground: The role of cellular senescence in the tumor microenvironment of pancreatic cancer (PC) remains unclear, particularly regarding its impact on prognosis and immunotherapy outcomes.Methods: We utilized single-cell sequencing datasets (GSE155698 and GSE154778) for pancreatic cancer from the Gene Expression Omnibus (GEO) database and bulk RNA-seq data from the University of California, Santa Cruz (UCSC) and International Cancer Genome Consortium (ICGC) repositories, creating three patient cohorts: The Cancer Genome Atlas (TCGA) cohort, PAAD-AU cohort, and PAAD-CA cohort. Dimensionality reduction cluster analysis processed the single-cell data, while weighted gene co-expression network analysis (WGCNA) and differential expression gene analysis were applied to bulk RNA-seq data. Prognostic models were developed using Cox proportional hazards (COX) and least absolute shrinkage and selection operator (LASSO) regression, with validation through survival analysis, decision curve analysis, and principal component analysis (PCA). Tumor mutation data were analyzed using the “maftools” package, and the immune microenvironment was assessed with TIMER2 data.Results: We developed a senescence-related (SENR) six-gene prognostic signature for PC, which stratifies patients by risk, with high-risk groups showing poorer prognoses. This model also offers predictive insights into tumor mutations and immune microenvironment characteristics. Caveolin-1 (CAV1) emerged as a significant prognostic biomarker, with functional validation showing its role in promoting cancer cell proliferation and migration, highlighting its potential as a therapeutic target.Conclusion: This study provides a novel senescence-related prognostic tool for PC, enhancing patient stratification for prognosis and immunotherapy, and identifies CAV1 as a key gene with clinical significance for targeted interventions.Keywords: pancreatic cancer, cellular senescence, prognosis, biomarker, immunotherapy

Dandan Liu,1,* Mingli Mao,1,* Wenjia Liu,1 Lihua Xie,1 Xiaolin Zhong,1 Wenyu Cao,2 Ling Chen1 1Department of Metabolism and Endocrinology, The First Affiliated Hospital of University of South China, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, People’s Republic of China; 2Clinical Anatomy & Reproductive Medicine Application Institute, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ling Chen, The First Affiliated Hospital of University of South China, Department of Endocrinology and Metabolism, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, People’s Republic of China, Email lingchen-cl@outlook.comAbstract: The transient receptor potential vanilloid 4 channel (TRPV4) is an important member of the TRP superfamily of cation channels. The channel can be activated by different physical and chemical stimuli, such as heat, osmotic, and mechanical stress. It regulates the release of nociceptive peptides (substance P and calcitonin gene-related peptide), and mediates neurogenic inflammation, which indicates the involvement of TRPV4 as a nociceptor. Previous studies show that TRPV4 regulates the contraction of intestinal smooth muscle, mucosal barrier permeability, intestinal ion transport, activation of submucosal enteric neurons, and generation of immune cells. TRPV4 is involved in various pathophysiological activities, and altered TRPV4 expression has been detected in some intestinal diseases (IBD, IBS, intestinal tumors, etc). Evidence indicates that TRPV4 plays a noxious role in intestinal barrier function when the intestine is damaged. This review focuses on the role of the TRPV4 channel in the physiological and pathological functions of the intestine, and evaluates the potential clinical significance to target TRPV4 channel in the treatment of intestinal diseases.Plain Language Summary: TRPV4 is expressed in the intestine and regulates intestinal functions, such as intestinal barrier function, gastrointestinal motility, sensory transduction, and intestinal ion transport. It is upregulated in most intestinal disease models and participates as a negative regulator. TRPV4 inhibition is a potential treatment for intestinal diseases. TRPV4 antagonists also show a positive protective effect on intestinal related diseases. The activation or inhibition of TRPV4 in the treatment of different intestinal diseases has put forward a feasible research direction in the future.Keywords: TRPV4, intestinal diseases, gastrointestinal motility, sensory transduction

Lin Chen,1,* Zhan Zhang,2,* Xueyong Liu1 1Department of Rehabilitation, Shengjing Hospital of China Medical University, Shenyang, People’s Republic of China; 2Department of Orthopedics, Shengjing Hospital of China Medical University, Shenyang, Liaoning, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xueyong Liu, Department of Rehabilitation, Shengjing Hospital of China Medical University, No. 16, Puhe Street, Shenyang, Liaoning, People’s Republic of China, Tel +86 18940112266, Email liusjh@sj-hospital.orgAbstract: Osteoarthritis (OA) is one of the most prevalent degenerative joint diseases, and the knee joint is particularly susceptible to it. It typically affects the entire joint and is marked by the erosion of cartilage integrity, chondrocytopenia, subchondral bone sclerosis and the mild synovial inflammation. Pathological changes in the subchondral bone often serve as initiating factors for joint degeneration. Various predisposing factors, including metabolic disorders, oxidative stress, and abnormal mechanical loading, regulate OA pathogenesis. Of them, mechanical loading is closely associated with the maintenance of the subchondral bone. Disrupted mechanical loading, leading to subchondral bone remodeling, can potentially trigger OA, whereas appropriate loading might ameliorate its progression. Therefore, this narrative review aimed to discuss existing knowledge and explore how mechanical loading mediates changes in the subchondral bone, influencing the development of knee osteoarthritis. Special emphasis is placed on its role and underlying mechanisms in maintaining joint homeostasis.Keywords: mechanical load, bone remodeling, homeostasis, osteogenic differentiation

Linfa Chen,1,2,* Keqi Liao,1,3,* Yutian Zhang,1,3,* Shutao Zheng,1,4 Jiawen He,1,3 Henglei Tang,1,4 Hailing Wu,1,3 Wangtao Zhong,4 Shengnan Li,1,3 You Li1,3 1Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, People’s Republic of China; 2Department of Neurology, Huizhou Third People’s Hospital, Guangzhou Medical University, Huizhou, People’s Republic of China; 3Institute of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, People’s Republic of China; 4Department of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, People’s Republic of China*These authors contributed equally to this workCorrespondence: You Li; Shengnan Li, Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, People’s Republic of China, Email youli805@163.com; 15625102893@163.comBackground: Accumulating evidence suggests that matrix metalloproteinase (MMP) 12 plays a detrimental role in cerebro-cardiovascular diseases, including ischemic stroke (IS). Previous genome-wide association studies (GWAS) correlated the MMP12 rs660599 variant to IS risk in Europeans. However, this association is yet to be elucidated in the Chinese population. This study aims to assess the genetic predisposition of the MMP12 rs660599 G > A variant with regard to IS risk and short-term outcomes in individuals from Southern China.Methods: The Multiplex SNaPshot assay was used to genotype rs660599 in 1035 IS patients and 1061 age-matched healthy controls. Multivariate logistic regression analyses evaluated the effect of the rs660599 G > A polymorphism on IS susceptibility and short-term outcomes.Results: No significant association was found between the rs660599 G > A polymorphism and IS risk, even in dominant and recessive models. However, a relationship between rs660599 genotypes and diabetic status revealed that carriers of the A allele and the GA/AA genotype were more likely to develop IS. The presence of diabetes exacerbated the larger infarct volumes and elevated serum MMP12 levels seen in IS patients with the rs660599 A allele. The A allele of rs660599 and the GA/AA genotype were both correlated to moderate and severe stroke with poor short-term outcomes.Conclusion: The MMP12 rs660599 polymorphism is associated with a higher incidence of IS in people with diabetes and can serve as a biomarker for assessing the severity of IS and its short-term consequences.Keywords: Ischemic Stroke, Matrix Metalloproteinase 12, polymorphism, risk, short-term outcome

Yan Wang,1– 4,* He Zhao,2– 4,* Kun Zhao,1– 4,* Huhuifen He,1– 4,* Xinyu Li,5 Jingjing Qiu,2– 4 Limei Cui,2– 4 Liang Chen,2– 4 Wenjing Shang,6,7 Yan Sun2– 4 1The Second Medical College, Binzhou Medical University, Yantai, Shandong, People’s Republic of China; 2Department of Otolaryngology and Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, Shandong, People’s Republic of China; 3Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, Yantai, Shandong, People’s Republic of China; 4Yantai Key Laboratory of Otorhinolaryngologic Diseases, Yantai, Shandong, People’s Republic of China; 5The First Medical College, Binzhou Medical University, Yantai, Shandong, People’s Republic of China; 6Key Laboratory for Genetic Hearing Disorders in Shandong, Binzhou Medical University, Yantai, Shandong, 264003, People’s Republic of China; 7Department of Biochemistry and Molecular Biology, Binzhou Medical University, Yantai, Shandong, 264003, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yan Sun; Wenjing Shang, Email entsunyan@126.com; wenjshang@bzmc.edu.cnIntroduction: Age-related hearing loss (ARHL) is a degenerative condition that involves both peripheral and central auditory system pathologies. There is a close relationship between chronic inflammation and ARHL, but there is currently a lack of in-depth exploration of this relationship, particularly regarding causality.Methods: Using age-appropriate mice for basic experiments to examine changes in central auditory nervous system inflammation, a cohort study was conducted to select relevant clinical data and observe inflammation changes in the elderly population with ARHL. Mendelian randomization was employed to investigate the causal relationship between chronic inflammation and ARHL.Results: Clinical results indicate that CRP levels in the ARHL group are significantly higher than those in the normal group. Chronic inflammation also occurs in the auditory centers. Mendelian randomization studies provide causal evidence that genetic chronic inflammation factors do not increase the risk of ARHL.Discussion: This article provides reliable causal evidence of the relationship between chronic inflammation and ARHL, confirming the accumulation of inflammatory factors in the auditory center, which provides a basis for the prevention and treatment of ARHL and has a good prevention prospect. However, due to the differences of research objects, this study has limitations and needs further research.Keywords: CRP, TNF-α, chronic inflammation, age-related hearing loss, Mendelian randomization

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

Lian Chen,1,&ast; Yu-Huan Jiang,2,&ast; Mei-Yong Li,3 Bo Huang,3 Lei Yuan,2 Jin-Hua Wan,2 Ting-Yu Qin,2 Ting-Ting Zeng,2 Qing-Gen Chen2 1Department of Ultrasound Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People’s Republic of China; 2Department of Clinical Laboratory, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People’s Republic of China; 3Department of Clinical Laboratory, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People’s Republic of China&ast;These authors contributed equally to this studyCorrespondence: Qing-Gen Chen, Department of Clinical Laboratory, the First Affiliated Hospital of Nanchang University, Nanchang, 330006, People’s Republic of China, Tel/Fax +86 0791-86319420, Email 272880243@qq.comPurpose: The aim of the present study was to identify more effective laboratory markers to assess the severity of corona virus disease 2019 and predict the progression of the disease by collecting more laboratory markers and variables.Patients and Methods: In this study, most risk factors, including epidemiological characteristics, blood cell counts, cytokines, and infection markers, were collected from 126 patients with COVID-19 to assess their predictive value.Results: The area under curve (AUC) of Albumin (Alb) to fibrinogen (Fib) ratio (AFR) (0.791), Lactate dehydrogenase (LDH) (0.792), myoglobin (MYO) (0.795), C-reactive protein (CRP) (0.801) and lymphocyte count (0.859) were higher than other markers to distinguish severe from non-severe patients in receiver operating characteristic (ROC) analysis. In the univariate logistic regression analysis, thirty-six out of 46 risk factors, including 34 laboratory markers, were significantly associated with increased odds of severe patients. Multivariate logistic regression analysis showed that the CD19+ lymphocyte count, MYO, LDH, and AFR were associated with increased odds of severe disease. Moreover, Lymphocyte count and AFR levels increased, LDH and CRP levels decreased during hospitalization in recovered severe patients, whereas severe lymphocytopenia and continuously increasing LDH levels were observed in deteriorated patients. AFR level increased and CRP level decreased before the disease worsened in the deteriorated patients; however, when the patients deteriorated, AFR decreased and CRP increased significantly.Conclusion: CD19+ lymphocyte count, MYO, LDH, and AFR are independent biomarkers for early identification of severe COVID-19. Lymphocyte count, AFR, LDH, and CRP levels were helpful in predicting the clinical progression of the disease.\. Keywords: Albumin to fibrinogen ratio, C-reactive protein, Lymphocyte, Coronavirus Disease 2019, Inflammation

Guansheng Zeng,1,&ast; Jian Xu,1,&ast; Huadong Zeng,1 Cuilan Wang,1 Lichang Chen,2 Huapeng Yu1 1Department of Pulmonary and Critical Care Medicine, Shenzhen Hospital, Southern Medical University, Shenzhen, People’s Republic of China; 2Department of Pulmonary and Critical Care Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Huapeng Yu, Department of Pulmonary and Critical Care Medicine, Shenzhen Hospital, Southern Medical University, Shenzhen, People’s Republic of China, Email huapengyu1960@163.com Lichang Chen, Department of Pulmonary and Critical Care Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, People’s Republic of China, Email 519744491@qq.comPurpose: To investigate the differential clinical significance of fractional concentration of exhaled nitric oxide measured at a flow rate of 200 mL/s (FENO200) and concentration of nitric oxide in alveolar (CANO) in asthma, chronic obstructive pulmonary disease (COPD) or asthma-COPD Overlap (ACO).Methods: A total of 178 patients were included, with 82 patients in asthma group, 47 patients in COPD group and 49 patients in ACO group. Data for demographic data, spirometry and exhaled nitric oxide were collected for comparative analysis, correlation analysis and discriminant canonical analysis.Results: The values of FENO200 in asthma, COPD and ACO groups were 11.0(7.0– 22.3), 8.0(6.0– 11.0) and 9.0(6.5– 19.5) ppb, respectively. In the asthma group, FENO200 exhibited negative correlations with FEV1/FVC, MMEF and MEF50. No significant correlation was observed between CANO and pulmonary function parameters. In the COPD group, both FENO200 and CANO showed negative correlation with pulmonary function parameters including FVC, FEV1, PEF, MMEF, MEF75, MEF50. In the ACO group, FENO200 demonstrated no significant correlation with pulmonary function parameters, while CANO was correlated with FEV1, PEF, MMEF and MEF50. In COPD group, ΔFEV1 in the bronchodilator test was correlated with FENO200. As for the ACO group, ΔFEV1 was correlated with CANO. In the discriminant canonical analysis, four parameters including gender, age, MEF75 and FENO50 discriminated between the three groups of asthma, COPD and ACO.Conclusion: In asthma, COPD and ACO, FENO200 has demonstrated a robust correlation with CANO. Elevated FENO200 levels are predominantly indicative of pulmonary function impairment in asthma and COPD, whereas elevated CANO levels are mainly correlated with pulmonary function impairment in COPD and ACO. Compared with FENO200 and CANO, FENO50 may have a better discriminatory ability in distinguishing asthma, COPD and ACO.Keywords: FENO200, CANO, ACO, asthma, chronic obstructive pulmonary disease

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

Yu Sun,1 Zhaoyong Li,1 Jiahao Duan,1 Enxu Liu,1 Fei Sun,1 Lei Yang,2 Long Chen,2 Shaofeng Yang2 1Graduate School of Hunan University of Chinese Medicine, Changsha, Hunan, 410208, People’s Republic of China; 2Department of Orthopedics, the First Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, 410007, People’s Republic of ChinaCorrespondence: Shaofeng Yang, Department of Orthopedics, the First Affiliated Hospital of Hunan University of Chinese Medicine, No. 300 Xue-Shi Road, Yuelu District, Changsha, 410007, Hunan, People’s Republic of China, Tel +86 18391076233, Email a18391076233@163.comAbstract: The gut microbiome (GM), often referred to as the second genome of the human body, plays a crucial role in various metabolic processes and mediates the development of numerous diseases. Intervertebral disc degeneration (IDD) is an age-related degenerative spinal disease characterized by the loss of disc height, hydration, and integrity, leading to pain and reduced mobility. Although the pathogenesis of IDD is not fully understood, recent studies suggest that dysbiosis of the gut microbiome may accelerate the progression of IDD through multiple mechanisms. This article begins by discussing the potential relationship between GM dysbiosis and human diseases, followed by a comprehensive review of the regulatory mechanisms of GM in skeletal diseases within the gut-disc axis framework. Furthermore, it explores three potential pathways through which GM dysbiosis may mediate the development of IDD: immunomodulation, bacterial translocation and colonization, and the decomposition and absorption of intestinal metabolites. These pathways can disrupt disc cell homeostasis and promote degenerative changes. Finally, this paper summarizes for the first time the potential therapeutic approaches for delaying IDD by targeting the gut-disc axis, providing new insights into the pathogenesis and regenerative repair strategies for IDD.Keywords: intervertebral disc degeneration, microbiome, inflammation, immunity, metabolism

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

Yaning Gao, Liang Chen, Zhengjun Wen, Huiying Jiang, Jing Feng Respiratory and Critical Care Medicine Department, Beijing Jingmei Group General Hospital, Beijing, People’s Republic of ChinaCorrespondence: Liang Chen, Email huxike000111@sohu.comPurpose: Our aim was to determine the risk factors for multidrug resistance in patients with carbapenem-resistant Klebsiella pneumoniae (CRKP).Methods: The information of 196 patients with Klebsiella pneumoniae infection was collected. The patients were subsequently assigned to the carbapenem-resistant, multidrug-resistant, and non-multidrug-resistant groups. The risk factors for multidrug resistance in CRKP patients were assessed via least absolute shrinkage and selection operator and logistic regression analyses. Moreover, a nomogram was constructed dependent on the identified risk factors, and calibration and decision curves were plotted to detect its accuracy.Results: Length of stay (LOS) [odds ratio (OR) and 95% confidence interval (CI): 4.558 (1.157– 17.961), P = 0.030], intensive care unit (ICU) stay within 30 days [OR and 95% CI: 12.643 (3.780– 42.293), P < 0.001], Glasgow Coma Scale (GCS) score [OR and 95% CI: 13.569 (2.738– 67.236), P = 0.001], fungal infection [OR and 95% CI: 6.398 (1.969– 20.785), P = 0.002], and cardiovascular disease (CVD) [OR and 95% CI: 3.871 (1.293– 11.592), P = 0.016] were identified as risk factors for multidrug resistance in CRKP patients. The concordance index (C-index) of the constructed nomogram was 0.950 (95% CI: 0.945– 0.955). Moreover, decision curve analysis elucidated the nomogram utilization across a wide range of probability thresholds, ranging from 1% to 100%. Finally, internal validation using random data validated the robustness of the predictive model, yielding a C-index of 0.937.Conclusion: The LOS, ICU stay within 30 days, GCS score, fungal infection, and CVD were recognized as risk factors for multidrug resistance in CRKP patients. The constructed nomogram could accurately predict multidrug-resistant CRKP infections in patients.Plain Language Summary: The LOS, ICU stay within 30 days, GCS, fungal infection, and CVD were identified as risk factors for multidrug resistance in CRKP patients.The nomogram constructed in this study had high predictive accuracy.This study provides a reference for the formulation of personalized prevention and therapy strategies.Keywords: Klebsiella pneumoniae, multidrug resistance, carbapenem, prediction model, risk factors

Yu Pan,1,&ast; Lili Cao,2,&ast; Libing Chen,1,&ast; Linjuan Gao,2 Xia Wei,1 Honglei Lin,1 Lei Jiang,1 Yinghui Wang,1,2 Hui Cheng1,2 1Department of Prosthodontics, Institute of Stomatology & Research Center of Dental Esthetics and Biomechanics, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, Fujian, People’s Republic of China; 2Department of Prosthodontics, Fujian Key Laboratory of Oral Diseases & Fujian Provincial Engineering Research Center of Oral Biomaterial & Stomatological Key Laboratory of Fujian College and University, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, Fujian, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yinghui Wang; Hui Cheng, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, Fujian, People’s Republic of China, Email wyh9519@fjmu.edu.cn; ch.fj@fjmu.edu.cnPurpose: The study was intended to compare the surface properties and the bacterial and biofilm adhesion resistance of two potential antibacterial nanometer titanium dioxide (nano-TiO2) coatings on dental titanium (Ti) abutments prepared by atomic layer deposition (ALD) and the anodic oxidation (AO) techniques.Methods: Nano-TiO₂ coatings were developed using ALD and AO techniques and applied to Ti surfaces. The surface properties and the bacterial and biofilm adhesion resistance of these coatings were evaluated against commonly used Ti and Zirconia (ZrO₂) surfaces. The chemical compositions, crystalline forms, surface topography, roughness and hydrophilicity were characterized. The antibacterial performance was assessed by the scanning electron microscope (SEM), the Colony-forming unit (CFU) assay and the 3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide (MTT) assay using in vitro models of Staphylococcus aureus (S. aureus), Streptococcus mutans (S. mutans), and Porphyromonas gingivalis (P. gingivalis) in both single- and mixed-species bacterial compositions.Results: ALD-prepared nano-TiO₂ coatings resulted in a dense, smooth, and less hydrophilic surface with an anatase phase, significantly reducing the adhesion of the three bacteria by over 50%, comparable to ZrO₂. In contrast, AO-prepared coatings led to a less hydrophilic surface, characterized by various nano-sized pores within the oxide film. This alteration, however, had no impact on the adhesion of the three bacteria. The adhesion patterns for mixed-species bacteria were generally consistent with single-species results.Conclusion: ALD-prepared nano-TiO₂ coatings on Ti abutments demonstrated promising antibacterial properties comparable to ZrO₂ surfaces, suggesting potential in preventing peri-implantitis. However, the bacterial and biofilm adhesion resistance of AO-produced nano-TiO₂ coatings was limited. Keywords: atomic layer deposition, anodic oxidation, titanium dioxide, dental abutment, surface properties, antibacterial effect