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There has been considerable controversy about pre- versus postsynaptic expression of memory-related long-term potentiation (LTP), with corresponding disputes about underlying mechanisms. We report here an instance in male mice, in which both types of potentiation are expressed but in separate branches of the same hippocampal afferent. Induction of LTP in the dentate gyrus (DG) branch of the lateral perforant path (LPP) reduces paired-pulse facilitation, is blocked by antagonism of cannabinoid receptor type 1, and is not affected by suppression of postsynaptic actin polymerization. These observations are consistent with presynaptic expression. The opposite pattern of results was obtained in the LPP branch that innervates the distal dendrites of CA3: LTP did not reduce paired-pulse facilitation, was unaffected by the cannabinoid receptor blocker, and required postsynaptic actin filament assembly. Differences in the two LPP termination sites were also noted for frequency facilitation of synaptic responses, an effect that was reproduced in a two-step simulation by small adjustments to vesicle release dynamics. These results indicate that different types of glutamatergic neurons impose different forms of filtering and synaptic plasticity on their afferents. They also suggest that inputs are routed to, and encoded by, different sites within the hippocampus depending upon the pattern of activity arriving over the parent axon.

Xiaosu Guo,1– 4,* Huimin Shi,1,2,* Yuteng Sun,1 Yuan Xing,1– 3 Xin Guo,1– 3 Zhiyuan Shen,1– 3 Mengyi Zheng,1 Yaxin Zhang,1 Yicun Jia,1 Ye Li,1 Junqiang Bao,1,2 Shujuan Tian1– 3 1Department of Neurology, The First Hospital of Hebei Medical University, Shijiazhuang, Hebei, People’s Republic of China; 2Department of Neurology, Hebei Hospital, Xuanwu Hospital, Capital Medical University, Shijiazhuang, Hebei, People’s Republic of China; 3Neuromedical Technology Innovation Center of Hebei Province, Shijiazhuang, Hebei, People’s Republic of China; 4Brain Aging and Cognitive Neuroscience Laboratory of Hebei Province, Shijiazhuang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shujuan Tian; Junqiang Bao, Department of Neurology, The First hospital of Hebei Medical University, Shijiazhuang, Hebei, 050030, People’s Republic of China, Tel +86-0311-87156309, Email 57203005@hebmu.edu.cn; 57903004@hebmu.edu.cnPurpose: To summarize the clinical manifestations, laboratory findings, and magnetic resonance imaging (MRI) characteristics of anti-leucine-rich glioma-inactivated 1 (LGI1) antibody encephalitis (anti-LGI1 antibody encephalitis) and explore the electroencephalogram (EEG) features.Patients and Methods: We retrospectively analyzed the medical history of 16 patients diagnosed with anti-LGI1 antibody encephalitis at the First Hospital of Hebei Medical University from 2021 to 2023. EEGs of patients with anti-LGI1 antibody encephalitis and healthy individuals were analyzed. Based on Video-EEG signal analysis of EEG δ, θ, α, β frequency bands, weighted phase lag index values were calculated to form brain network matrices, studying differences in coherence between brain regions of patients with anti-LGI1 antibody encephalitis and healthy individuals.Results: Patients with anti-LGI1 antibody encephalitis often presented with subacute onset seizures and cognitive decline. Routine test of cerebrospinal fluid was mostly normal. Serum testing revealed hyponatremia in 62.50% of patients, along with positive serum antinuclear antibodies, decreased vitamin B12, and abnormal cytokines such as interleukin-6. Head MRI revealed abnormal lesions related to the disease in seven cases (43.75%), mainly located in the unilateral or bilateral frontal and temporal lobes of the hippocampus. The EEG mainly showed generalized and focal slow waves, sometimes with focal discharges. Brain network functional connectivity analysis found a significant weakening of functional connections in the frontal-temporal lobe in the δ and β frequency bands. Intravenous pulse corticosteroids and intravenous immunoglobulin are first-line immunotherapies for anti-LGI1 antibody-related encephalitis. The disease recovery and cognitive decline improved in most patients.Conclusion: Anti-LGI1 antibody encephalitis is characterized by seizures and cognitive dysfunction. Serum may show abnormalities in immune indicators such as cytokines. Head MRI mainly reveals abnormal signals in the frontal-temporal lobes and the hippocampus. EEG brain network connectivity analysis reveals characteristic weakening of functional connections in the frontal-temporal lobe in the δ and β frequency bands.Keywords: anti-LGI1 antibody encephalitis, epilepsy, electroencephalogram, brain network functional connectivity, immunotherapy

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

Xinyang Nie,1– 3,* Jian Liu,1,2,* Daohan Wang,1,2,* Chuan Li,1,2 Yuxin Teng,1,2 Zhufeng Li,1,2 Yangpu Jia,1,2 Peiyao Wang,1,2 Jingyu Deng,2,3 Weidong Li,1,2 Li Lu1,2 1Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China; 2Tianjin Medical University, Tianjin, People’s Republic of China; 3Department of Gastric Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin’s Clinical Research Center for Cancer, Tianjin, 300060, People’s Republic of China*These authors contributed equally to this workCorrespondence: Li Lu; Weidong Li, Department of General surgery, Tianjin Medical University General Hospital, 154, Anshan Road, Heping District, Tianjin, 300052, People’s Republic of China, Email luli_1989@126.com; tjmughgs_lwd@163.comBackground: Cisplatin (DDP) resistance in gastric cancer (GC) is likely to come from gastric cancer stem cells (GCSC). It is a new idea to study the mechanism of the DDP-resistance in GCSC from miRNA.Materials and Methods: CD44+ GCSCs and CD44- control cells were constructed based on the HGC27 gastric cancer cell line. DDP sensitivities in CD44+ and CD44- cells were detected via CCK-8 assay. The differential expression of miR-21-5p in these cell lines was detected by RT‒qPCR. The expression levels of downstream TGF-β 2, SMAD2 and SMAD3 were determined through RT‒PCR and Western blotting. A luciferase assay was used to detect the relationship between miR-21-5p and TGFB2, and the TCGA database, clinical data from our centre, and vivo experiment were used for validation. Finally, we knocked down miR-21-5p to detect changes in cisplatin resistance in GCSCs and to verify changes in the levels of downstream pathways in GCSCs.Results: CD44+ GCSCs induced cisplatin resistance compared with CD44- cells. miR-21-5p was highly expressed in GCSCs, and the TGF-β 2/SMAD pathway was also highly expressed. TGFB2 was proven to be a downstream target gene of miR-21-5p and had a positive relationship with it in phenotype. After knockdown of miR-21-5p, the TGF-β 2/SMAD pathway was also inhibited, and the resistance of GCSCs to cisplatin was specifically decreased.Conclusion: MiR-21-5p promotes cisplatin resistance in gastric cancer stem cells by regulating the TGF-β 2/SMAD signalling pathway.Keywords: miR-21-5p, cisplatin resistance, GCSCs, TGF-β 2 pathway

Kaixin Wang,1 Lingfei Yang,2 Qingsheng Li,2 Xuan Yang,1 Ziyi Chen,2 Yongyan Zhou,3 Yanjie Jia,1 Zhe Gong1 1Department of Neurology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, People’s Republic of China; 2Academy of Medical Sciences, Zhengzhou University, Zhengzhou, People’s Republic of China; 3Department of Electrocardiogram, Zhoukou Center Hospital, Zhoukou, People’s Republic of ChinaCorrespondence: Yanjie Jia; Zhe Gong, The First Affiliated Hospital of Zhengzhou University, Department of Neurology, Postal FfCode 450052, No. 1 Jianshe East Road, Zhengzhou, People’s Republic of China, Email jiayanjie1971@aliyun.com; gongzhe1415@163.comBackground: Ischemic stroke (IS) is one of the leading causes of death and disability in the world, and alcohol consumption has been gaining attention as an independent risk factor for IS. Blood-brain barrier (BBB) dysfunction and neuroinflammation are the core of cerebral ischemia/reperfusion (I/R) injury, and pericytes play a crucial role in the structure and function. This study is to explore the effects of long-term alcohol consumption on IS and the potential mechanisms of pericytes.Methods: Rat models of long-term alcohol intake followed by transient middle cerebral artery occlusion stroke (EtOH+tMCAO) and cell models of oxygen-glucose deprivation/reoxygenation (OGD/R) with alcohol pre-treatment were constructed.Results: Worsened infarct volume, neurological scores, and BBB disruption were observed in the EtOH+tMCAO group compared with the tMCAO group, and immunofluorescence staining showed increased pericytes NLPR3 inflammasome activation at the ischemic penumbra. In vitro, pericyte mortality and LDH release elevated pre-treated by alcohol after OGD/R, and amplified expression of NLRP3 inflammasome was detected by Western blotting and qPCR. Alcohol pre-treatment activated the TLR4/NF-κB pathway, and transfecting pericytes with TLR4-small interfering RNA (siRNA) to block TLR4 signaling markedly restrained NLRP3 inflammasome over-activation. Injecting TAK-242 in rats alleviated neurological impairment caused by alcohol.Conclusion: Long-term alcohol pre-treatment aggravated ischemic stroke-induced brain damage by activating NLRP3 inflammasome via TLR4/NF-κB signaling pathway in the pericytes.Keywords: cerebral ischemia, chronic ethanol exposure, pericytes, TLR4, NLRP3 inflammasome

Fengfeng Li,1 Yang Jia,1 Jun Fang,2 Linqiang Gong,3 Yazhou Zhang,4 Shanshan Wei,5 Linlin Wu,6 Pei Jiang5 1Neurosurgery Department, Tengzhou Central People’s Hospital Affiliated to Xuzhou Medical University, Tengzhou, Shandong, 277500, People’s Republic of China; 2Anesthesiology Department, Tengzhou Central People’s Hospital Affiliated to Xuzhou Medical University, Tengzhou, Shandong, 277500, People’s Republic of China; 3Gastroenterology Department, Tengzhou Central People’s Hospital Affiliated to Xuzhou Medical University, Tengzhou, Shandong, 277500, People’s Republic of China; 4Foot and Ankle Surgery Department, Tengzhou Central People’s Hospital Affiliated to Xuzhou Medical University, Tengzhou, Shandong, 277500, People’s Republic of China; 5Translational Pharmaceutical Laboratory, Jining First People’s Hospital, Jining, Shandong, 272000, People’s Republic of China; 6Oncology Department, Tengzhou Central People’s Hospital Affiliated to Xuzhou Medical University, Tengzhou, Shandong, 277500, People’s Republic of ChinaCorrespondence: Linlin Wu, Oncology Department, Tengzhou Central People’s Hospital Affiliated to Xuzhou Medical University, Tengzhou, Shandong, 277500, People’s Republic of China, Tel +86 632-5513457, Email linlinliff@163.com Pei Jiang, Translational Pharmaceutical Laboratory, Jining First People’s Hospital, Jining, Shandong, 272000, People’s Republic of China, Tel +86 537-2106208, Email jiangpeicsu@sina.comBackground: Traumatic brain injury (TBI) is a condition characterized by structural and physiological disruptions in brain function caused by external forces. However, as the highly complex and heterogenous nature of TBI, effective treatments are currently lacking. Mitochondrial open reading frame of the 12S rRNA-c (MOTS-c) has shown notable antinociceptive and anti-inflammatory effects, yet its detailed neuroprotective effects and mode of action remain incompletely understood. This study investigated the neuroprotective effects and the underlying mechanisms of MOTS-c.Methods: Adult male C57BL/6 mice were randomly divided into three groups: control (CON) group, MOTS-c group and TBI group. Enzyme-linked immunosorbent assay (ELISA) kit method was used to measure the expression levels of MOTS-c in different groups. Behavioral tests were conducted to assess the effects of MOTS-c. Then, transcriptomics and metabolomics were performed to search Differentially Expressed Genes (DEGs) and Differentially Expressed Metabolites (DEMs), respectively. Moreover, the integrated transcriptomics and metabolomics analysis were employed using R packages and online Kyoto Encyclopedia of Genes and Genomes (KEGG) database.Results: ELISA kit method showed that TBI resulted in a decrease in the expression of MOTS-c. and peripheral administration of MOTS-c could enter the brain tissue after TBI. Behavioral tests revealed that MOTS-c improved memory, learning, and motor function impairments in TBI mice. Additionally, transcriptomic analysis screened 159 differentially expressed genes. Metabolomic analysis identified 491 metabolites with significant differences. Integrated analysis found 14 KEGG pathways, primarily related to metabolic pathways. Besides, several signaling pathways were enriched, including neuroactive ligand–receptor interaction and retrograde endocannabinoid signaling.Conclusion: TBI reduced the expression of MOTS-c. MOTS-c reduced inflammatory responses, molecular damage, and cell death by down-regulating macrophage migration inhibitory factor (MIF) expression and activating the retrograde endocannabinoid signaling pathway. In addition, MOTS-c alleviated the response to hypoxic stress and enhanced lipid β-oxidation to provide energy for the body following TBI. Overall, our study offered new insights into the neuroprotective mechanisms of MOTS-c in TBI mice.Keywords: MOTS-c, TBI, transcriptomics, metabolomics, neuroprotective

Yatian Jia,1,2 Qian Zhang,1– 3 Yihua Zhang,2 Hui Wang,1,2 Qingmei Niu,1,2 Ruifang Zhu,4 Jia Li,1 Wen Fan,1 Yuexing Zhang2 1Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Tongji Shanxi Hospital, Taiyuan, People’s Republic of China; 2School of Nursing, Shanxi University of Chinese Medicine, Jinzhong, People’s Republic of China; 3School of Nursing/Research Center of Dietary Therapy Technology, Shanxi Medical University, Taiyuan, People’s Republic of China; 4Editorial Office, First Hospital of Shanxi Medical University, Taiyuan, People’s Republic of ChinaCorrespondence: Qian Zhang, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Tongji Shanxi Hospital, Xiaodian District, Taiyuan, Shanxi, People’s Republic of China, Email zhangqian@d.sxmu.edu.cnBackground: Hyperlipidemia has been demonstrated to be an autonomous predictor of numerous cardiovascular and cerebrovascular ailments, and research indicates that polyphenols have preventive and therapeutic effects on hyperlipidemia. Nevertheless, the impact of polyphenol-rich foods on blood lipids and oxidative stress status in patients with hyperlipidemia remains inconclusive.Objective: To examine the impact of polyphenol-rich foods on lipid levels and oxidative stress in individuals with hyperlipidemia.Methods: To retrieve papers published from the establishment of the database through October 9, 2023, eight databases were searched: the Chinese National Knowledge Infrastructure, the China Biomedical Literature Database, the Wanfang Database, the China Science and Technology Journal Database, PubMed, the Cochrane Library, Embase, and the Web of Science. The quality of include studies was assessed using the Cochrane Risk of Bias in Randomized Trials tool, v2.Results: The study involved 13 surveys encompassing 640 patients diagnosed with hyperlipidemia. The scope of the food surveys included 12 commonly consumed food groups and medicinal and food homologous substances. All 13 studies reported the effects of polyphenol-rich foods on blood lipids, with significant improvements observed in blood lipid levels for 9 types of foods. Eight studies examined the impact on oxidative stress, and six foods demonstrated a significant reduction in oxidative stress levels. The observed effects were found to be influenced by factors such as dosage, duration of intervention, and gender.Conclusion: Foods abundant in polyphenols play a crucial role in the prevention and treatment of hyperlipidemia by counteracting oxidative stress and regulating metabolic disorders. The confirmation of certain positive effects by several studies notwithstanding, discrepancies in results arise from various factors, necessitating further large-scale, prospective, well-designed randomized controlled studies to address this issue.Keywords: polyphenols, hyperlipidemia, blood lipids, oxidative stress, systematic review

Yujie Zhao,1 Xiaoyin Xu,1 Anyin Dai,2 Yunxiang Jia,1 Wenxi Wang1 1College of Pharmacy, Zhejiang University of Technology, Hangzhou, People’s Republic of China; 2Department of Pharmacy, The 903rd Hospital of People’s Liberation Army, Hangzhou, People’s Republic of ChinaCorrespondence: Wenxi Wang, College of Pharmacy, Zhejiang University of Technology, 18# Chaowang Road, Hangzhou, Zhejiang, 310014, People’s Republic of China, Tel +86 571 8832 0772, Fax +86 571 8832 0320, Email yjw@zjut.edu.cnPurpose: Curcumin nanocrystals (Cur-NCs) were prepared by hot melt extrusion (HME) technology to improve the dissolution and bioavailability of curcumin (Cur).Methods: Cur-NCs with different drug-carrier ratios were prepared by one-step extrusion process with Eudragit® EPO (EEP) as the carrier. The dispersed size and solid state of Cur in extruded samples were characterized by dynamic light scattering (DLS), scanning electron microscope (SEM), differential scanning calorimetry (DSC), and X-ray diffraction (XRD). The thermal stability of Cur was analyzed by thermogravimetric analysis (TGA) and high performance liquid chromatography (HPLC). Dissolution and pharmacokinetics were studied to evaluate the improvement of dissolution and absorption of Cur by nano-preparation.Results: Cur-NCs with particle sizes in the range of 50~150 nm were successfully prepared by using drug-carrier ratios of 1:1, 2:1 and 4:1, and the crystal form of Cur was Form 1 both before and after HME. The extrudate powders showed very efficient dissolution with the cumulative dissolution percentage of 80% in less than 2 min, and the intrinsic dissolution rates of them were 13.68 ± 1.20 mg/min/cm2, 11.78 ± 0.57 mg/min/cm2 and 4.35 ± 0.20 mg/min/cm2, respectively, whereas that of pure Cur was only 0.04 ± 0.00 mg/min/cm2. The TGA data demonstrated that the degradation temperature of Cur was about 250 °C, while the HPLC results showed Cur was degraded when extruded at the temperature over 150 °C. Pharmacokinetic experiment showed a significant improvement in the absorption of Cur. The Cmax of Cur in the Cur-NC group was 1.68 times that of pure Cur group, and the Cmax and area under the curve (AUC0-∞) of metabolites were 2.79 and 4.07 times compared with pure Cur group.Conclusion: Cur-NCs can be prepared by HME technology in one step, which significantly improves the dissolution and bioavailability of Cur. Such a novel method for preparing insoluble drug nanocrystals has broad application prospects. Keywords: hot melt extrusion technology, curcumin, nanocrystals, dissolution, absorption in vivo

Yuanhang Pan,1,* Di Zhao,1,* Xinbo Zhang,1,* Na Yuan,1 Lei Yang,1 Yuanyuan Jia,2 Yanzhao Guo,3 Ze Chen,1 Zezhi Wang,1 Shuyi Qu,1 Junxiang Bao,4 Yonghong Liu1 1Department of Neurology, Xijing Air Force Medical University, Xi’an, People’s Republic of China; 2Encephalopathy Department No.2, Baoji Hospital of Traditional Chinese Medicine, Baoji, People’s Republic of China; 3Encephalopathy Department No.10, Xi’an Hospital of Traditional Chinese Medicine, Xi’an, People’s Republic of China; 4Department of Aerospace Hygiene, Air Force Medical University, Xi’an, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yonghong Liu, Department of Neurology, Xijing hospital, Air Force Medical University, Xi’an, People’s Republic of China, Tel +86 13991236602, Email liuyhong@fmmu.edu.cn Junxiang Bao, Department of Aerospace Hygiene, Air Force Medical University, Xi’an, People’s Republic of China, Tel +86 02984711241, Email baojunx@fmmu.edu.cnBackground: Excessive daytime sleepiness (EDS) forms a prevalent symptom of obstructive sleep apnea (OSA) and narcolepsy type 1 (NT1), while the latter might always be overlooked. Machine learning (ML) models can enable the early detection of these conditions, which has never been applied for diagnosis of NT1.Objective: The study aimed to develop ML prediction models to help non-sleep specialist clinicians identify high probability of comorbid NT1 in patients with OSA early.Methods: Totally, clinical features of 246 patients with OSA in three sleep centers were collected and analyzed for the development of nine ML models. LASSO regression was used for feature selection. Various metrics such as the area under the receiver operating curve (AUC), calibration curve, and decision curve analysis (DCA) were employed to evaluate and compare the performance of these ML models. Model interpretability was demonstrated by Shapley Additive explanations (SHAP).Results: Based on the analysis of AUC, DCA, and calibration curves, the Gradient Boosting Machine (GBM) model demonstrated superior performance compared to other machine learning (ML) models. The top five features used in the GBM model, ranked by feature importance, were age of onset, total limb movements index, sleep latency, non-REM (Rapid Eye Movement) sleep stage 2 and severity of OSA.Conclusion: The study yielded a simple and feasible screening ML-based model for the early identification of NT1 in patients with OSA, which warrants further verification in more extensive clinical practices.Keywords: obstructive sleep apnea, narcolepsy, machine learning, prediction model, sleep disorder

Liqiong Ding,1,* Fengnan Xu,1,* Binhua Luo,1,* Liyuan Cheng,1 Lingping Huang,2 Yanlong Jia,3 Jieqiong Ding1 1Xianning Medical College, Hubei University of Science and Technology, Xianning, Hubei Province, People’s Republic of China; 2Department of Medical Ultrasound, Xianning Central Hospital, The First Affiliated Hospital of Hubei University of Science and Technology, Xianning, Hubei Province, People’s Republic of China; 3Department of Radiology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, Hubei Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yanlong Jia, Department of Radiology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, Hubei Province, 441021, People’s Republic of China, Tel +86 13669006180, Email yanlongjia@163.com Jieqiong Ding, Xianning Medical College, Hubei University of Science and Technology, Xianning, Hubei Province, 437100, People’s Republic of China, Tel +86 13797244300, Email djq197911@163.comBackground: Medical imaging modalities, such as magnetic resonance imaging (MRI), ultrasound, and fluorescence imaging, have gained widespread acceptance in clinical practice for tumor diagnosis. Each imaging modality has its own unique principles, advantages, and limitations, thus necessitating a multimodal approach for a comprehensive disease understanding of the disease process. To enhance diagnostic precision, physicians frequently integrate data from multiple imaging modalities, driving research advancements in multimodal imaging technology research.Methods: In this study, hematoporphyrin-poly (lactic acid) (HP-PLLA) polymer was prepared via ring-opening polymerization and thoroughly characterized using FT-IR, 1H-NMR, XRD, and TGA. HP-PLLA based nanoparticles encapsulating perfluoropentane (PFP) and salicylic acid were prepared via emulsion-solvent evaporation. Zeta potential and mean diameter were assessed using DLS and TEM. Biocompatibility was evaluated via cell migration, hemolysis, and cytotoxicity assays. Ultrasonic imaging was performed with a dedicated apparatus, while CEST MRI was conducted using a 7.0 T animal scanner.Results: We designed and prepared a novel dual-mode nanoimaging probe SA/PFP@HP-PLLA NPs. PFP enhanced US imaging, while salicylic acid bolstered CEST imaging. With an average size of 74.43 ± 1.12 nm, a polydispersity index of 0.175 ± 0.015, and a surface zeta potential of − 64.1 ± 2.11 mV. These NPs exhibit excellent biocompatibility and stability. Both in vitro and in vivo experiments confirmed the SA/PFP@HP-PLLA NP’s ability to improve tumor characterization and diagnostic precision.Conclusion: The SA/PFP@HP-PLLA NPs demonstrate promising dual-modality imaging capabilities, indicating their potential for preclinical and clinical use as a contrast agent.Keywords: contrast agent, perfluoropentane, salicylic acid, ultrasound imaging, chemical exchange saturation transfer

Fangmin Gong,1 Zhuliu Gong,1 Haimeng Liu,2 Pei Yi,1 Yuhan Jia,3 Jingwen Zhuang,1 Jilin Shu,1 Xincheng Huang,4 Yibo Wu5 1College of Literature and Journalism Communication, Jishou University, Jishou, People’s Republic of China; 2College of Minority Preparatory Education, Jishou University, Zhangjiajie, People’s Republic of China; 3Office of the Party and Administration, Hebei Academy of Fine Arts, Shijiazhuang, People’s Republic of China; 4School of Economics and Management, Beijing Institute of Graphic Communication, Beijing, People’s Republic of China; 5School of Public Health, Peking University, Beijing, People’s Republic of ChinaCorrespondence: Haimeng Liu, Zhangjiajie Campus, Jishou University, Dayongqiao Street, Ziwu Road, Yongding District, Zhangjiajie, Hunan Province, 427000, People’s Republic of China, Tel +86 15074328922, Email Liu.Haimeng@outlook.com Yibo Wu, Peking University School of Public Health, No.38 Xueyuan Road, Haidian District, Beijing, 100191, People’s Republic of China, Tel +86 18810169630, Email bjmuwuyibo@outlook.comPurpose: To explore the relationship between adolescents’ problematic Internet use and loneliness and the mediating roles of social support and family communication.Methods: A questionnaire survey of 2483 adolescents aged 12– 17 years in 148 cities in China was conducted using the Problematic Internet Use Scale, the Collaborative Social Support Scale, the Family Communication Scale, and the Loneliness Scale. The data were statistically analyzed by SPSS 26.0 and validated by AMOS 28.0. Structural equation modelling (SEM) was conducted to test the effects of problematic Internet use on adolescents’ loneliness and the mediating effects of perceptions of social support and family communication.Results: There was a significant positive effect of adolescents’ problematic Internet use on loneliness (B-0.471, P< 0.001), and the mediating effects of perceptual social support (0.003, 0.012) and family communication (0.008, 0.019) were found to play a chain effect between adolescents’ problematic Internet use and loneliness, respectively. Use and feelings of loneliness played a chain mediating role (0.002, 0.006).Conclusion: This study identified the effects of adolescent problematic Internet use on loneliness and its mechanism of action, emphasized the importance of social support and family communication, and provided practical insights for improving family parenting styles and preventing and intervening in adolescent loneliness problems.Keywords: problematic internet use, adolescents, loneliness, perceived social support, family communication

Yu Wang,1,2 Yitong Jia,3 Zheng Wang,4 Guang Feng,3 Yanhui Ma,3 Zhen Fan,3 Miao Liu,3 Kunpeng Feng,3 Tianlong Wang3 1Department of Neurosurgery, Beijing Boai Hospital, China Rehabilitation Research Center, Beijing, People’s Republic of China; 2College of Rehabilitation, Capital Medical University, Beijing, People’s Republic of China; 3Department of Anesthesiology, Xuanwu Hospital, Capital Medical University, Beijing, People’s Republic of China; 4Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing, People’s Republic of ChinaCorrespondence: Tianlong Wang, Department of Anesthesiology, Xuanwu Hospital, Capital Medical University, Beijing, People’s Republic of China, Email w_tl5595@hotmail.comBackground: Neuropathic pain (NP) is recognized as one of the most difficult pain syndromes which lacks a safe, well-tolerated and effective treatment. Pulsed radiofrequency (PRF), a novel and minimally invasive interventions, has been introduced to alleviate various types of NP. Previous studies reported PRF with higher voltage could further improve the treatment efficacy. Therefore, we conducted this systematic review and meta-analysis to determine whether high-voltage PRF is superior to standard-voltage PRF for the treatment of NP patients.Methods: Databases published from the date of inception until 15 March 2022 on PubMed/MEDLINE, EMBASE, Web of Science and the Cochrane Library were searched for RCTs comparing high-voltage PRF and standard-voltage PRF in NP patients. The primary outcome measures were the efficiency rates of NP patients with high-voltage PRF or standard-voltage PRF treatment. Data analysis was conducted using the Review Manager software (RevMan V.5.3).Results: Six RCTs involving 423 patients were included in our meta-analysis. Compared with standard-voltage PRF group, the high-voltage PRF group attained a higher efficiency rate at 1 month (P = 0.04; I2 = 0%), 3 months (P = 0.04; I2 = 0%), 6 months (P = 0.002; I2 = 0%) post-procedure respectively. There was no significant difference in the complications between the two groups.Conclusion: Our study supported that high-voltage PRF attained more satisfactory efficacy than standard-voltage PRF without increased side effects. High-voltage PRF could be a promising, effective, minimally invasive technology for NP patients.Keywords: trigeminal neuralgia, pulsed radiofrequency, high-voltage, standard-voltage, efficacy

Min Zhao,1,&ast; Ming-Zhu Gao,1,&ast; Rong-yan Gu,1,&ast; Lei Luo,1 Song-rui Ding,1 Liang He,2 Yue Jia,3 Hong-ping Zhang,3 Hong-ying Yang,3 Gao-feng Li1 1Medical Administration Department, The Third Affiliated Hospital of Kunming Medical University (Yunnan Cancer Hospital, Yunnan Cancer Center), Kunming, Yunnan, People’s Republic of China; 2Medical Laboratory Department, The Third Affiliated Hospital of Kunming Medical University (Yunnan Cancer Hospital, Yunnan Cancer Center), Kunming, Yunnan, People’s Republic of China; 3Gynecological Department, The Third Affiliated Hospital of Kunming Medical University (Yunnan Cancer Hospital, Yunnan Cancer Center), Kunming, Yunnan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hong-ying Yang; Gao-feng Li, Email yanghy913@126.com; ligaofenghl@126.comBackground: Research on the risk factors for cervical cancer in Yunnan Province’s four characteristic ethnic groups (Han, Bai, Dai, and Hani) is lacking.Objective: To study the risk factors of cervical cancer in four ethnic women in Yunnan Province, and to provide evidence for its prevention.Methods: The cervical cancer patients of Han, Bai, Dai and Hani ethnic groups in Yunnan Province who were first diagnosed in the Third Affiliated Hospital of Kunming Medical University (Yunnan Cancer Hospital, Yunnan Cancer Center) from January 2011 to December 2020 were selected as the research objects. The 1:1 matched case-control study method was used, and single factor and conditional logistic regression were used for statistical analysis.Results: HPV types 16, 18 and 58 are mostly related with cervical cancer, the younger the age of the last pregnancy, the more times of pregnancy, childbirth and abortion, especially the younger the first marriage age of Bai and Dai, are the risk factors of cervical cancer; the infection of genital tract bacteria, mycoplasma and chlamydia is closely related to the incidence of cervical cancer in four ethnicities. Multifactorial analysis showed that demographic characteristics and environment/behavior were not included in the influencing factors of cervical cancer; among Han, Bai, Dai and Hani ethnic minorities, contraception (OR=0.29, OR=0.03, OR=0.09, OR=0.16, P< 0.05) was positive factor, HPV infection (OR=64.77, OR=128.71, OR=71.89, OR=40.07, P< 0.01) was a causative factor of cervical cancer.Conclusion: Risk of high parity with cervical cancer could be due to a complex interplay of factors, it is very important to formulate prevention strategies and measures in line with the cervical cancer of Han, Bai, Dai and Hani ethnic groups women in Yunnan Province.Keywords: cervical cancer, risk factors, case-control study, Han, Bai, Dai and Hani ethnic minorities, Yunnan Province

Ji Guo,1– 3 Shengqi Yang,1– 4 Weifeng Zhai,1– 3,5 Yue Xie,1– 4 Zhan Shen,1– 4 Jianpo Zhang,1– 3 Yongwei Jia1– 3,5 1Guanghua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200052, People’s Republic of China; 2Shanghai Guanghua Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai, 200052, People’s Republic of China; 3Institute of Arthritis Research in Integrative Medicine, Shanghai Academy of Traditional Chinese Medicine, Shanghai, 200052, People’s Republic of China; 4Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People’s Republic of China; 5Department of Orthopedics, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai, 201318, People’s Republic of ChinaCorrespondence: Ji Guo; Yongwei Jia, Email 153498661@qq.com; spinejia@163.comBackground: Intervertebral disc degeneration (IVDD) is a pathophysiological process that leads to severe back pain or neurological deficits. The Bushen Huoxue Formula (BSHXF) is a traditional herbal remedy widely used to treat diseases related to IVDD. However, its pharmacological mechanism needs further exploration.Objective: This study aimed to elucidate the mechanisms through which BSHXF treats IVDD-related diseases by integrating metabolomics with network pharmacology.Methods: Network pharmacology was utilized to identify potential targets of BSHXF against IVDD. Additionally, an animal model of needle puncture-induced disc degeneration was established to assess the effect of BSHXF. Mice were randomly assigned to the sham group, model group, and BSHXF group. Various techniques, including PCR, CCK-8 assay, MRI, histological examinations, and immunohistochemical analyses, were employed to evaluate degenerative and oxidative stress conditions in mouse disc tissue and cultured nucleus pulposus (NP) cells. UHPLC-HRMS/MS was used to differential distinct metabolites in the disc tissue from different groups, and MetaboAnalyst 5.0 was employed to enrich the metabolic pathways.Results: Through network pharmacology, 15 core proteins were identified through protein-protein interaction (PPI) network construction. Functional enrichment analysis highlighted the critical role of BSHXF in addressing IVDD by influencing the response to oxidative stress. Furthermore, experimental evidence demonstrated that BSHXF significantly improved the pathological progression of IVDD and increased oxidative stress markers SOD-1 and GPX1, both in the disc degeneration model and cultured NP cells. Metabolomics identified differential metabolites among the three groups, revealing 15 metabolic pathways between the sham and model groups, and 13 metabolic pathways enriched between the model and BSHXF groups.Conclusion: This study, integrating network pharmacology and metabolomics, suggests that BSHXF can alleviate IVDD progression by modulating oxidative stress. Key metabolic pathways associated with BSHXF-mediated reduction of oxidative stress include the citrate cycle, cysteine and methionine metabolism, alanine, aspartate and glutamate metabolism, glycine, serine and threonine metabolism, D-glutamine and D-glutamate metabolism, glutathione metabolism, and tryptophan metabolism. While this research demonstrates the therapeutic potential of BSHXF in reducing oxidative stress levels in IVDD, further research is needed to thoroughly understand its underlying mechanisms.Keywords: metabolomics, network pharmacology, intervertebral disc degeneration, oxidative stress, Bushen Huoxue formula

Pingping Yao,1 Yuying Jia,1 Xuewei Kan,1 Jiaqi Chen,1 Jinliang Xu,1 Huichao Xu,1 Shuyang Shao,1 Bing Ni,2 Jun Tang1 1Department of Dermatology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230000, People’s Republic of China; 2Department of Pathophysiology, Third Military Medical University, Chongqing, 400038, People’s Republic of ChinaCorrespondence: Bing Ni; Jun Tang, Email nibing@tmmu.edu.cn; tangjun0212@ustc.edu.cnBackground: Psoriasis is a common chronic, recurrent, and inflammatory skin disease. Identifying novel and potential biomarkers is valuable in the treatment and diagnosis of psoriasis. The goal of this study was to identify novel key biomarkers of psoriasis and analyze the potential underlying mechanisms.Methods: Psoriasis-related datasets were downloaded from the Gene Expression Omnibus database to screen differential genes in the datasets. Functional and pathway enrichment analyses were performed on the differentially expressed genes (DEGs). Candidate biomarkers for psoriasis were identified from the GSE30999 and GSE6710 datasets using four machine learning algorithms, namely, random forest (RF), least absolute shrinkage and selection operator (LASSO) logistic regression, weighted gene co-expression network analysis (WGCNA), and support vector machine recursive feature elimination (SVM-RFE), and were validated using the GSE41662 dataset. Next, we used CIBERSORT and single-cell RNA analysis to explore the relationship between ADAM23 and immune cells. Finally, we validated the expression of the identified biomarkers expressions in human and mouse experiments.Results: A total of 709 overlapping DEGs were identified, including 426 upregulated and 283 downregulated genes. Enhanced by enrichment analysis, the differentially expressed genes (DEGs) were spatially arranged in relation to immune cell involvement, immune-activating processes, and inflammatory signals. Based on the enrichment analysis, the DEGs were mapped to immune cell involvement, immune-activating processes, and inflammatory signals. Four machine learning strategies and single-cell RNA sequencing analysis showed that ADAM23, a disintegrin and metalloprotease, may be a unique, critical biomarker with high diagnostic accuracy for psoriasis. Based on CIBERSORT analysis, ADAM23 was found to be associated with a variety of immune cells, such as macrophages and mast cells, and it was upregulated in the macrophages of psoriatic lesions in patients and mice.Conclusion: ADAM23 may be a potential biomarker in the diagnosis of psoriasis and may contribute to the pathogenesis by regulating immunological activity in psoriatic lesions.Keywords: psoriasis, machine learning, differential gene analysis, CIBERSORT, ADAM23

Abstract Vascular endothelial growth factor (VEGF)-A induces endothelial hyperpermeability, but the molecular pathways remain incompletely understood. Endothelial nitric oxide synthase (eNOS) regulates acute effects of VEGF-A on permeability of endothelial cells (ECs), but it remains unknown whether and how eNOS regulates late effects of VEGF-A-induced hyperpermeability. Here we show that VEGF-A induces hyperpermeability via eNOS-dependent and eNOS-independent mechanisms at 2 days after VEGF-A stimulation. Silencing of expression of the eNOS gene (NOS3) reduced VEGF-A-induced permeability for dextran (70 kDa) and 766 Da-tracer in human dermal microvascular ECs (HDMVECs), but not in human retinal microvascular ECs (HRECs) and human umbilical vein ECs (HUVECs). However, silencing of NOS3 expression in HRECs increased permeability to dextran, BSA and 766 Da-tracer in the absence of VEGF-A stimulation, suggesting a barrier-protective function of eNOS. We also investigated how silencing of NOS3 expression regulates the expression of permeability-related transcripts, and found that NOS3 silencing downregulates the expression of PLVAP, a molecule associated with trans-endothelial transport via caveolae, in HDMVECs and HUVECs, but not in HRECs. Our findings underscore the complexity of VEGF-A-induced permeability pathways in ECs and the role of eNOS therein, and demonstrate that different pathways are activated depending on the EC phenotype.

Yang Zhao,1 Ruizhe Wang,2 Hebin Li,3 Chong Chen,4 Bowen Zhou,5 Xinying Weng,3 Yidi Hua,6 Yaqi Jia,7 Yajun Wu,8 Ying Li9 1Faculty of Law, Qingdao University, Qingdao, People’s Republic of China; 2HeXie Management Research Center, Xi’an Jiaotong-Liverpool University, Suzhou, People’s Republic of China; 3Department of Social and Behavioural Sciences, City University of Hong Kong, Hong Kong, People’s Republic of China; 4CAS Key Laboratory of Behavioral Science, Institute of Psychology, Chinese Academy of Sciences, Beijing, People’s Republic of China; 5Department of Social Work, Hong Kong Baptist University, Hong Kong, People’s Republic of China; 6School of Humanities and Social Science, The Hong Kong University of Science and Technology, Hong Kong, People’s Republic of China; 7Entrepreneurs College, Xi’an Jiaotong-Liverpool University, Suzhou, People’s Republic of China; 8Department of Applied Psychology, Guangdong University of Foreign Studies, Guangzhou, People’s Republic of China; 9School of Urban Governance and Public Affairs, Suzhou City University, Suzhou, People’s Republic of ChinaCorrespondence: Ying Li, Email yingli.szcityu@gmail.comIntroduction: This longitudinal study aims to investigate the relationship between fear of COVID-19, support-seeking behaviors, and perceived social support among Chinese college students during two distinct periods of the COVID-19 pandemic: the period of strict control (time 1) and the period following a relaxation of restrictions (time 2).Methods: A total of 408 Chinese college students participated in this study. Data collection included demographic information, measures of fear of COVID-19, support-seeking behaviors, and perceived social support.Results: Fear of COVID-19 at time 1 showed a significant positive association with fear of COVID-19 at time 2. The relationship between support-seeking behavior at time 1 and fear of COVID-19 at time 2 was significantly mediated through a chain mediation effect of support-seeking behavior at time 1 and perceived social support at time 2.Discussion: This study contributes to the growing body of evidence on the psychological impacts of the COVID-19 pandemic and underscores the significance of social support in mitigating fear of COVID-19. It calls for a re-evaluation of public health policies considering their potential psychological effects and introduces new opportunities for developing psychosocial interventions.Keywords: fear of COVID-19, social support, Chinese students, COVID-19 policy, longitudinal study

Jie Li,1,2 Yuchen Jia,1,2 Feng Cao,1,2 Gang Wang,3 Fei Li1,2 1Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Clinical Center for Acute Pancreatitis, Capital Medical University, Beijing, People’s Republic of China; 3Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, People’s Republic of ChinaCorrespondence: Fei Li; Gang Wang, Email feili36@ccmu.edu.cn; wgilu79@163.comBackground: Ferroptosis plays an important role in a variety of disease processes and is equally important in pancreatic diseases. However, the role of ferroptosis-related genes (FRGs) in acute pancreatitis (AP) remains unknown, and their specific potential mechanisms still need to be explored extensively.Methods: AP-related gene microarray data were obtained from the GEO database, while FRGs were obtained from the ferroptosis database (FerrDb). Differentially expressed genes (DEGs) were screened by the “limma” package, and GSEA was performed. The corresponding ferroptosis-related differentially expressed genes (FRDEGs) were screened, and GO and KEGG pathway analyses were performed. A PPI network was constructed to identify hub FRDEGs by CytoHubba, MCODE and CTD scores. Transcription factors and miRNAs predicted using the NetworkAnalyst database were used to establish the regulatory network. Immune cell infiltration analysis was performed by the R package “ssGSEA” algorithm. The hub genes were validated by transcriptome sequencing of AP model mice and immunohistochemistry in rats and mice.Results: A total of 82 FRDEGs were screened, and these genes were mainly associated with ferroptosis, hypoxic response, autophagy, mitophagy and immune inflammation. However, we also found that these genes are also jointly involved in other cell death modalities, such as apoptosis and necroptosis. Further analysis obtained 7 hub genes from 82 genes, and single-sample gene set enrichment analysis (ssGSEA) showed that the hub genes are closely associated with the infiltration of specific immune cells and the activation of immune pathways.Conclusion: This study reveals the complex functions and important roles of ferroptosis-related genes in AP and provides gene targets for further studies of AP.Keywords: acute pancreatitis, ferroptosis, mitophagy, autophagy, inflammation

Xiaofei Hao,1,&ast; Yuying Jia,2,&ast; Jie Chen,2 Chuan Zou,1 Cuinan Jiang3 1Department of General Medicine, Chengdu Fifth People’s Hospital, Chengdu, Sichuan, 611130, People’s Republic of China; 2Department of Outpatient, The General Hospital of Western Theater Command, Chengdu, Sichuan, 610083, People’s Republic of China; 3Department of General Surgery, The Third People’s Hospital of Chengdu & The Affiliated Hospital of Southwest Jiaotong University, Chengdu, Sichuan, 610031, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Cuinan Jiang, Department of General Surgery, The Third People’s Hospital of Chengdu & The Affiliated Hospital of Southwest Jiaotong University, Chengdu, Sichuan, 610031, People’s Republic of China, Email 591670443@qq.comBackground: Subthreshold depression (StD) is considered to be the “precursor” stage of major depressive disorder (MDD), which could cause higher risk of suicide, disease burden and functional impairment. There have been various non-pharmacological interventions for StD. However, the comparison of their effectiveness still lacks sufficient evidence. We performed a systematic review and network meta-analysis to evaluate and rank the efficacy of multiple non-pharmacological interventions targeting StD.Methods: We conducted a thorough search across various databases including PubMed, Medline, Embase, Web of Science and PsycINFO from inception to December 2022. All included studies were randomized controlled trials (RCTs) of non-pharmacological interventions for patients with StD compared with control group (CG). Several universal scales for measuring depression severity were used as efficacy outcomes. The surface under the cumulative ranking curve (SUCRA) was used to separately rank each intervention using the “Stata 17.0” software.Results: A total of thirty-six trials were included, involving twenty-eight interventions and 7417 participants. The research found that most non-pharmacological interventions were superior to controls for StD. In each outcome evaluation by different scales for measuring depression, psychotherapy always ranked first in terms of treatment effectiveness, especially Problem-solving Therapy (PST), Behavioral Activation Therapy (BAT), Cognitive Behavioral Therapy (CBT)/Internet-based CBT (I-CBT)/Telephone-based CBT (T-CBT). Since different groups could not be directly compared, the total optimal intervention could not be determined.Conclusion: Here, we show that psychotherapy may be the better choice for the treatment of StD. This study provides some evidence on StD management selection for clinical workers. However, to establish its intervention effect more conclusively, the content, format and operators of psychotherapy still require extensive exploration to conduct more effective, convenient and cost-effective implementation in primary healthcare. Notably, further research is also urgently needed to find the biological and neural mechanisms of StD by examining whether psychotherapy alters neuroplasticity in patients with StD.Keywords: subthreshold depression, non-pharmacological intervention, efficacy, comparison, network meta-analysis, systematic review

Zhenshan Song,1,&ast; Fa Lin,1,&ast; Yu Chen,1 Tu Li,1 Runting Li,1 Junlin Lu,1 Heze Han,1 Ruinan Li,1 Jun Yang,1 Zhipeng Li,1 Haibin Zhang,1 Kexin Yuan,1 Ke Wang,1 Yunfan Zhou,1 Yitong Jia,1 Xiaolin Chen1– 3 1Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Stroke Center, Beijing Institute for Brain Disorders, Beijing, People’s Republic of China; 3Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiaolin Chen, Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, No. 119 South Fourth Ring West Road, Fengtai District, Beijing, 100070, People’s Republic of China, Email chenxiaolin@bjtth.orgPurpose: Systemic inflammation plays an important role in the pathophysiology and progression of aneurysmal subarachnoid hemorrhage (aSAH). In this study, we aimed to investigate the association between a new biomarker, the inflammatory burden index (IBI) and the prognosis as well as in-hospital complications of aSAH patients.Patients and Methods: We analyzed data from patients with aSAH between January 2019 and September 2022 who were included in the LongTEAM (Long-term Prognosis of Emergency Aneurysmal Subarachnoid Hemorrhage) registry study. The IBI was formulated as C-reactive protein × neutrophils/lymphocytes. The unfavorable functional prognosis was assessed by the modified Rankin Scale (mRS). Receiver operating characteristic (ROC) curve analysis was conducted to determine the optimal cut-off values for IBI to distinguish the unfavorable functional prognosis. Multivariate logistic regression was applied to investigate the association between IBI and in-hospital complications. Propensity score matching was adjusted for imbalances in baseline characteristics to assess the effect of IBI on prognosis.Results: A total of 408 consecutive patients with aSAH enrolled in the study, of which 235 (57.6%) were female patients and the mean age was 55.28 years old. An IBI equal to 138.03 was identified as the best cut-off threshold to distinguish the unfavorable prognosis at 3 months (area under the curve [AUC] [95% CI] 0.637 [0.568– 0.706]). ln IBI was independently associated with 3-month functional prognosis (OR [95% CI] 1.362 [1.148– 1.615]; P< 0.001), pneumonia (OR [95% CI] 1.427 [1.227– 1.659]; P< 0.001) and deep venous thrombosis (DVT). (OR [95% CI] 1.326 [1.124– 1.564]; P=0.001). After propensity score matching (57:57), an increased proportion of patients with IBI ≥ 138.03 had a poor functional prognosis at 3 months and in-hospital complications including developed pneumonia and DVT.Conclusion: In patients with aSAH, high IBI level at admission was associated with unfavorable functional prognosis as well as pneumonia and deep vein thrombosis.Keywords: aneurysmal subarachnoid hemorrhage, inflammatory burden index, functional prognosis, complications

Background: Compared to commonly-used green space indicators from downward-facing satellite imagery, street view-based green space may capture different types of green space and represent how environments are perceived and experienced by people on the ground, which is important to elucidate the underlying mechanisms linking green space and health. Objectives: This study aimed to evaluate machine learning models that can classify the type of vegetation (i.e., tree, low-lying vegetation, grass) from street view images; and to investigate the associations between street green space and socioeconomic (SES) factors, in Los Angeles County, California. Methods: SES variables were obtained from the CalEnviroScreen3.0 dataset. Microsoft Bing Maps images in conjunction with deep learning were used to measure total and types of street view green space, which were compared to normalized difference vegetation index (NDVI) as commonly-used satellite-based green space measure. Generalized linear mixed model was used to examine associations between green space and census tract SES, adjusting for population density and rural/urban status. Results: The accuracy of the deep learning model was high with 92.5% mean intersection over union. NDVI were moderately correlated with total street view-based green space and tree, and weakly correlated with low-lying vegetation and grass. Total and three types of green space showed significant negative associations with neighborhood SES. The percentage of total green space decreased by 2.62 [95% confidence interval (CI): −3.02, −2.21, p < 0.001] with each interquartile range increase in CalEnviroScreen3.0 score. Disadvantaged communities contained approximately 5% less average street green space than other communities. Conclusion: Street view imagery coupled with deep learning approach can accurately and efficiently measure eye-level street green space and distinguish vegetation types. In Los Angeles County, disadvantaged communities had substantively less street green space. Governments and urban planners need to consider the type and visibility of street green space from pedestrian's perspective.

Yan Jia,1,&ast; Ya Liu,1,&ast; Yilin Huang,1,&ast; Jie Wang,1 Hanyue Wang,1 Shu Tan,2 Yuxin Shi,1 Qingxia Wang,3 Jie Peng1 1Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China; 2Department of Emergency, Loudi Central Hospital, Loudi, Hunan, People’s Republic of China; 3Gastrointestinal Endoscopy Center, Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jie Peng, Department of Gastroenterology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan, People’s Republic of China, Tel/Fax +86-731-89753722, Email pengjie2014@csu.edu.cn Qingxia Wang, Gastrointestinal Endoscopy Center, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan, People’s Republic of China, Tel/Fax +86-15874189639, Email 1772509440@qq.comObjective: Infection is a common complication of acute pancreatitis (AP). Klebsiella pneumoniae (KP) is one of the most common pathogens associated with nosocomial infections. Our study focuses on investigating the clinical characteristics and risk factors for death of Klebsiella pneumoniae infections in AP patients, further to quantify the prognosis of the patients, and provide evidence for guiding antibiotic use and improving prognosis.Methods: The data of epidemiology, clinical manifestations and drug resistance rate with K. pneumoniae infections in AP patients from January 1, 2012 to August 30, 2022 were retrospectively collected. Logistic regression model and Cox regression model were, respectively, used to determine the risk factors for carbapenem-resistant Klebsiella pneumoniae (CRKP) acquisition and death. The nomogram prediction model was built by RMS software package to predict the 90-day survival rate.Results: One hundred and twenty-six AP patients combined with K. pneumoniae infections, with a mortality rate of 34.9%. The most common infection sites were pancreas and peri-pancreas (54.8%), followed by lung (20.6%) and blood stream (18.3%). The resistance rate of K. pneumoniae to commonly used antibiotics in clinical practice was high, especially CRKP, which was only sensitive to sulfamethoxazole-trimethoprim (SMZ-TMP) and tigecycline (TGC) (resistance rates were 37.57% and 17.57%, respectively). Independent risk factors for CPKP acquisition were male (OR = 1.655, 95% CI 0.642– 4.265, P = 0.017) and PICC/CVC implantation (OR = 3.157, 95% CI 1.223– 8.147, P = 0.021). Independent risk factors for mortality included carbapenem resistance (HR = 2.556, 95% CI 1.011– 6.462, P = 0.047), hemorrhage (HR = 2.392, 95% CI 1.104– 5.182, P = 0.027), septic shock (HR = 3.022, 95% CI 1.312– 6.959, P = 0.009), age > 60 years (HR = 2.977, 95% CI 1.303– 6.799, P = 0.01), creatinine > 177μmol/L (HR = 2.815, 95% CI 1.075– 7.369, P = 0.035).Conclusion: K. pneumoniae infection has become a serious threat for AP patients, which recommends us more attention and active new strategies seeking.Keywords: Klebsiella pneumoniae, carbapenems, drug resistance, acute pancreatitis, mortality, risk factors, nomogram

Xiaoyu Pan,1,&ast; Huazheng Zhu,2,&ast; Jinglong Du,1 Guangtao Hu,1 Baoru Han,1 Yuanyuan Jia1 1College of Medical Informatics, Chongqing Medical University, Chongqing, People’s Republic of China; 2College of Intelligent Technology and Engineering, Chongqing University of Science and Technology, Chongqing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yuanyuan Jia, Email yyjia@cqu.edu.cnAim: The Coronavirus Disease 2019 (COVID-19) pandemic has increased the public health burden and brought profound disaster to humans. For the particularity of the COVID-19 medical images with blurred boundaries, low contrast and different infection sites, some researchers have improved the accuracy by adding more complexity. Also, they overlook the complexity of lesions, which hinder their ability to capture the relationship between segmentation sites and the background, as well as the edge contours and global context. However, increasing the computational complexity, parameters and inference speed is unfavorable for model transfer from laboratory to clinic. A perfect segmentation network needs to balance the above three factors completely. To solve the above issues, this paper propose a symmetric automatic segmentation framework named MS-DCANet. We introduce Tokenized MLP block, a novel attention scheme that uses a shift-window mechanism to conditionally fuse local and global features to get more continuous boundaries and spatial positioning capabilities. It has greater understanding of irregular lesion contours. MS-DCANet also uses several Dual Channel blocks and a Res-ASPP block to improve the ability to recognize small targets. On multi-modality COVID-19 tasks, MS-DCANet achieved state-of-the-art performance compared with other baselines. It can well trade off the accuracy and complexity. To prove the strong generalization ability of our proposed model, we apply it to other tasks (ISIC 2018 and BAA) and achieve satisfactory results.Patients: The X-ray dataset from Qatar University which contains 3379 cases for light, normal and heavy COVID-19 lung infection. The CT dataset contains the scans of 10 patient cases with COVID-19, a total of 1562 CT axial slices. The BAA dataset is obtained from the hospital and includes 387 original images. The ISIC 2018 dataset is from the International Skin Imaging Collaborative (ISIC) containing 2594 original images.Results: The proposed MS-DCANet achieved evaluation metrics (MIOU) of 73.86, 97.26, 89.54, and 79.54 on the four datasets, respectively, far exceeding other current state-of-the art baselines.Conclusion: The proposed MS-DCANet can help clinicians to automate the diagnosis of COVID-19 patients with different symptoms.Keywords: multi-modality COVID-19 lesion segmentations, laboratory to clinic, multi-scale feature learning, depthwise separable convolution

Xiaoge Li, Jin Wu, Yutong Wu, Zhaoning Duan, Ming Luo, Ling Li, Sijing Li, Ying Jia Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People’s Republic of ChinaCorrespondence: Ying Jia, Email jiaying@hospital.cqmu.edu.cnObjective: To explore the correlation of female vaginal microbiota and immune factors with cervical cancer.Methods: The distribution pattern difference of vaginal microbiota of four groups of women (cervical cancer, HPV-positive CIN, HPV-positive non-CIN, and HPV-negative groups) were compared by microbial 16S rDNA sequencing. The protein chip was used to detect the composition and changes of the immune factors in the four groups.Results: Alpha diversity analysis demonstrated that the diversity of the vaginal microbiota was increased as the disease develops. Among those bacteria abundant in the vaginal microbiota, Lactobacillus, Prevotella, and Gardnerella dominate at the genus level of vaginal flora. Compared with the HPV-negative group, the differentially dominant bacteria, such as Prevotella, Ralstonia, Gardnerella and Sneathia, are enriched in the cervical cancer group. Likewise, Gardnerella, Prevotella, and Sneathia are more in the HPV-positive CIN group, while Gardnerella and Prevotella in the HPV-positive non-CIN group, respectively. In contrast, Lactobacillus and Atopobium are dominant in the HPV-negative group (LDA> 4log10). The concentration of inflammatory immune factors IP-10 and VEGF-A were increased in the cervical cancer group (P < 0.05), compared with other groups.Conclusion: The occurrence of cervical cancer is related to an increase of vaginal microbiota diversity and up-regulation of inflammatory immune factor proteins. The abundance of Lactobacillus was decreased while the one of Prevotella and Gardnerella were increased in the cervical cancer group, compared with other three groups. Moreover, the IP-10 and VEGF-A were also increased in the cervical cancer group. Thus, evaluation of changes in the vaginal microbiota and these two immune factor levels might be a potential non-invasive and simple method to predict cervical cancer. Furthermore, it is significant to adjust and restore the balance of vaginal microbiota and maintain normal immune function in preventing and treating cervical cancer.Keywords: vaginal microbiota, immune factors, cervical cancer, 16S rDNA sequencing, protein chip

Xiaoyang Liu,1 Yan Zhao,1 Zhanglei Mu,1 Yuan Jia,2 Chen Liu,3 Jianzhong Zhang,1 Lin Cai1 1Department of Dermatology, Peking University People’s Hospital, Beijing, People’s Republic of China; 2Department of Rheumatology and Immunology, Peking University People’s Hospital, Beijing, People’s Republic of China; 3Department of Clinical Laboratory, Peking University People’s Hospital, Beijing, People’s Republic of ChinaCorrespondence: Lin Cai, Department of Dermatology, Peking University People’s Hospital, &num; 11. Xizhimen South St, Beijing, 100044, People’s Republic of China, Tel +8610 88325472, Fax +8610 88325474, Email scailin66@hotmail.comBackground: Early screening or timely prediction of psoriatic arthritis (PsA) are crucial. The study aimed to compare the clinical characteristics, cytokines and inflammation index between plaque psoriasis and PsA to explore their values in the early diagnosis of PsA.Methods: This was a case-control study in a single center from January 2021 to February 2023. The differences in clinical characteristics and laboratory examinations between PsA and plaque psoriasis were conducted. Patients with rheumatoid arthritis (RA) were used as a positive control. The correlation between variables were analyzed and multivariable logistic regression were performed by using the 10-fold cross-validation to find independently risk factors of plaque psoriasis that are developing PsA.Results: A total of 109 patients with plaque psoriasis (without joint damage), 47 patients with PsA and 41 patients with RA were enrolled in this study. The study found that the proportion of patients with elevated serum IL-6 levels, as well as the value of platelet to lymphocyte ratio (PLR) and systemic immune-inflammation index (SII), were significantly higher in patients with PsA and early PsA (PsA course ≤ 2 years) compared to those with plaque psoriasis (p< 0.05). After adjusting for age, gender, severity of skin lesions, and comorbidities (diabetes, hypertension, hyperlipidemia, hyperuricemia, and overweight/obesity), the study identified nail psoriasis (OR=4.35, 95% CI 1.67– 11.29, p< 0.002), elevated serum IL-6 (OR=6.78, 95% CI 2.34– 19.67, p< 0.001), and PLR (OR=8.37, 95% CI 2.97– 23.61, p< 0.001) as independent risk factors for PsA. A multivariable logistic regression analysis employing 10-fold cross-validation assessing the predictive association between the diagnosis of early PsA and the combination of IL-6, PLR, and nail psoriasis demonstrated that the area under the curve (AUC) was 0.84 (95% CI 0.77– 0.90) and the F1-score was 0.67 (95% CI 0.54– 0.80).Conclusion: The combination of elevated serum IL-6, PLR, and nail psoriasis can help to predict and screen the early stage of PsA.Keywords: biomarkers, IL-6, PLR, psoriasis, psoriatic arthritis

Jingjing He, Yifei Guo, Yao Zhang, Jiajia Han, Jingwen Chen, Yidi Jia, Zhenxuan Ma, Jingwen Wu, Shenyan Zhang, Fahong Li, Richeng Mao, Jiming Zhang Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, People’s Republic of ChinaCorrespondence: Jiming Zhang; Richeng Mao, Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Room 510, Building 5, 12 Middle Wulumuqi Road, Shanghai, People’s Republic of China, Email jmzhang@fudan.edu.cn; richengmao@gmail.comPurpose: The study aims to evaluate the effectiveness of a tenofovir alafenamide fumarate (TAF) and pegylated interferon alfa (PegIFN-α) regimen compared to a tenofovir disoproxil fumarate (TDF) and PegIFN-α therapy in patients with chronic hepatitis B (CHB).Patients and Methods: Patients who were treated with PegIFN-α in combination with TAF or TDF were retrospectively enrolled. The primary outcome measured was the HBsAg loss rate. The rates of virological response, serological response for HBeAg, and normalization of alanine aminotransferase (ALT) were also calculated. The cumulative incidences of response rates were compared between the two groups using Kaplan–Meier analysis.Results: A total of 114 patients were retrospectively enrolled in the study, with 33 receiving TAF plus PegIFN-α treatment and 81 receiving TDF plus PegIFN-α treatment. The HBsAg loss rate for the TAF plus PegIFN-α group was 15.2% at 24 weeks and 21.2% at 48 weeks, while the TDF plus PegIFN-α group had rates of 7.4% at 24 weeks and 12.3% at 48 weeks (P=0.204 at 24 weeks, P=0.228 at 48 weeks). In subgroup analysis of HBeAg positive patients, the TAF group had a higher HBsAg loss rate of 25% at week 48, compared to 3.8% in the TDF group (P=0.033). According to Kaplan–Meier analysis, the TAF plus PegIFN-α group achieved virological response more quickly than the TDF plus PegIFN-α group (p=0.013). There was no statistical difference in HBeAg serological rate or ALT normalization rate.Conclusion: There was no significant difference in the HBsAg loss between the two groups. However, subgroup analysis revealed that TAF plus PegIFN-α treatment had a higher HBsAg loss rate than TDF plus PegIFN-α treatment in HBeAg-positive patients. Additionally, TAF plus PegIFN-α treatment demonstrated better virological suppression for CHB patients. Therefore, TAF plus PegIFN-α treatment regimen is recommended for CHB patients who aim to achieve functional cure.Keywords: hepatitis B virus infection, tenofovir alafenamide fumarate, tenofovir disoproxil fumarate, interferon, functional cure, combination therapy

BackgroundTo identify genetic associations of quantitative metabolic syndrome (MetS) traits and characterize heterogeneity across ethnic groups.MethodsData was collected from GENetics of Noninsulin dependent Diabetes Mellitus (GENNID), a multiethnic resource of Type 2 diabetic families and included 1520 subjects in 259 African-American, European-American, Japanese-Americans, and Mexican-American families. We focused on eight MetS traits: weight, waist circumference, systolic and diastolic blood pressure, high-density lipoprotein, triglycerides, fasting glucose, and insulin. Using genotyped and imputed data from Illumina's Multiethnic array, we conducted genome-wide association analyses with linear mixed models for all ethnicities, except for the smaller Japanese-American group, where we used additive genetic models with gene-dropping.ResultsFindings included ethnic-specific genetic associations and heterogeneity across ethnicities. Most significant associations were outside our candidate linkage regions and were coincident within a gene or intergenic region, with two exceptions in European-American families: (a) within previously identified linkage region on chromosome 2, two significant GLI2-TFCP2L1 associations with weight, and (b) one chromosome 11 variant near CADM1-LINC00900 with pleiotropic blood pressure effects.ConclusionsThis multiethnic family study found genetic heterogeneity and coincident associations (with one case of pleiotropy), highlighting the importance of including diverse populations in genetic research and illustrating the complex genetic architecture underlying MetS.

Haoyu Zhao,1,&ast; Yachao Jia,1,&ast; Feng Wang,1 Yimin Chai,1 Chunfu Zhang,2 Jia Xu,1 Qinglin Kang1 1Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Department of Orthopedic Surgery, Shanghai, People’s Republic of China; 2Shanghai Jiao Tong University, School of Biomedical Engineering, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jia Xu; Qinglin Kang, Email xujia0117@126.com; orthokang@163.comIntroduction: Large bone abnormalities are commonly treated using distraction osteogenesis (DO), but it is not suitable for a long-term application; therefore, there is an urgent need for adjuvant therapy that can accelerate bone repair.Methods: We have synthesized mesoporous silica-coated magnetic nanoparticles doped with cobalt ions (Co-MMSNs) and assessed their capacity to quicken bone regrowth in a mouse model of DO. Furthermore, local injection of the Co-MMSNs significantly accelerated bone healing in DO, as demonstrated by X-ray imaging, micro-CT, mechanical tests, histological evaluation, and immunochemical analysis.Results: In vitro, the Co-MMSNs exhibited good biocompatibility and induced angiogenic gene expression and osteogenic development in bone mesenchymal stem cells. And the Co-MMSNs can promote bone regeneration in a rat DO model.Discussion: This study demonstrated the significant potential of Co-MMSNs to shorten the DO treatment duration and effectively reduce the incidence of complications.Keywords: mesoporous silica-coated magnetic nanoparticles, mesenchymal stem cells, large bone defects, distraction osteogenesis, bone regeneration

Fanghui Li,1,2,&ast; Dongze Li,1,&ast; Jing Yu,1 Yu Jia,3 Jirui Wen,4 Wentao Li,2 Yao Tong,2 Jiang Wu,4 Zhi Wan,1 Yu Cao,1 Qing Zhang,2 Rui Zeng1,2 1Department of Emergency Medicine, Laboratory of Emergency Medicine, West China Hospital, Sichuan University, Chengdu, People’s Republic of China; 2Department of Cardiology, West China Hospital, Sichuan University, Chengdu, People’s Republic of China; 3Department of General Practice and National Clinical Research Center for Geriatrics, International Medical Center, West China Hospital, Sichuan University, Chengdu, People’s Republic of China; 4Deep Underground Space Medical Center, West China Hospital, Sichuan University, Chengdu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Rui Zeng; Qing Zhang, Department of Cardiology, West China Hospital, Sichuan University, 37 Guoxue Road, Chengdu, Sichuan, 610041, People’s Republic of China, Tel +86-28-85423248, Fax +86-28-85582944, Email zengrui_0524@126.com; qzhang2000cn@163.comBackground: The plasma lipidome profile is likely to improve risk stratification in patients with acute coronary syndrome (ACS) and predict cardiovascular events for secondary disease prevention. Ceramides are involved in the initiation or acceleration of several key pathophysiological processes in atherosclerosis. This study evaluated whether plasma ceramide levels at admission was associated with one-year mortality in patients with ACS.Methods: In total, 826 patients with ACS from a prospective multicenter study for early evaluation of acute chest pain were enrolled. High-performance liquid chromatography with tandem mass spectrometry (LC/MS) was used to measure the plasma levels of eleven ceramides (C16–C26). The primary outcome was all-cause mortality, and the secondary outcome was cardiac mortality during the one-year follow-up. The relationship between the ceramide levels and mortality was evaluated by Cox regression analysis. The receiver operating characteristic (ROC) curve was established to evaluate discrimination of ceramides.Results: Eighty-eight (10.7%) patients died after a 12-month follow-up. Five ceramides (C16:0, C18:0, C20:0, C24:1 and C24:2) and their ratios to Cer(d18:1/24:0) were independently associated with the risk of all-cause death and cardiac death. Combining the Global Registry of Acute Coronary Events (GRACE) score with ceramides and their ratios to Cer(d18:1/24:0) had areas under ROC curves ranging from 0.778– 0.804 (P< 0.001) for all-cause mortality, which was greater than that of the GRACE score alone.Conclusion: Measurements of long-chain ceramides and very-long-chain ceramides may help in identifying a high risk of mortality beyond traditional assessment tools in patients with ACS.Trial Registration: clinicaltrials.gov, identifier: NCT04122573.Keywords: ceramide, acute coronary syndrome, mortality, high-performance liquid chromatography with tandem mass spectrometry

Lujia Hu,1,2,&ast; Chen Chen,1,&ast; Junli Zhu,1 Yao Zhang,3 Yun Chen,4,5 Yufei Jia6 1School of Public Health, Capital Medical University & Research Center for Capital Health Management and Policy, Beijing, People’s Republic of China; 2Department of Basic Health Care, Tianjin Hedong District Health Commission, Tianjin, People’s Republic of China; 3Department of Human Resources, Beijing Tongren Hospital, Capital Medical University, Beijing, People’s Republic of China; 4The National Clinical Research Center for Mental Disorders & Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing, People’s Republic of China; 5Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, People’s Republic of China; 6Department of Human Resources, Beijing Shijitan Hospital, Capital Medical University, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Junli Zhu, School of Public Health, Capital Medical University & Research Center for Capital Health Management and Policy, No. 10, Xitoutiao, Youanmen Wai, Fengtai District, Beijing, 100069, People’s Republic of China, Tel +86 18701515093, Fax +86 01083911578, Email smallying@126.comBackground: In China, physicians have long faced long working hours, high stress levels, and tensions between physicians and patients, which can lead to negative behaviors. Understanding physicians’ expectations and requirements of the hospital and increasing satisfaction with their psychological contract can help improve physician motivation and stabilize the hospital team.Aim: The study aims to analyze the relationship between physicians’ psychological contract violations and different behavioral choices, encourage hospitals to conclude a balanced psychological contract with physicians, and provide governance and intervention strategies for hospital human resource management.Methods: Stratified cluster sampling was used to select 321 physicians from four public hospitals in Beijing for questionnaire surveys. Descriptive statistical analysis, t-test, ANOVA, correlation analysis, and regression models were performed using Stata 15.0 and SPSS 26.0 to analyze the relationship between psychological contract violations, physicians’ EVLN behaviors and organizational justice.Results: Psychological contract violation had a positive effect on exit behavior and neglect behavior, and a negative effect on voice behavior and loyalty behavior. Organizational justice plays a mediating role between psychological contract violation and physicians’ exit, voice and loyalty behaviors.Conclusion: Psychological contract violation can drive negative behavior among physicians, and organizational justice can play a mediating role in this. Public hospitals should establish a healthy psychological contract with physicians and place a premium on organizational justice to promote constructive behaviors and prevent destructive behaviors. This study constructs a more complete theoretical framework to explain physicians’ behavior, and further dynamic tracking investigations are necessary because the evolution of physicians’ behavior is a dynamic and long-term process.Keywords: tertiary public hospitals, physicians, psychological contract violation, EVLN, China, mediation effect

Jinpeng Li,1,&ast; Yuntao Jia,1,&ast; Changdong Shao,2,&ast; Yuanming Li,3 Jinlong Song1 1Intervention Ward 1, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, People’s Republic of China; 2Qixia Hospital of Traditional Chinese Medicine Hospital, Qixia, Shandong, People’s Republic of China; 3Laizhou Hospital of Traditional Chinese Medicine, Laizhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jinpeng Li, Intervention Ward 1, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, 250117, People’s Republic of China, Tel +86 531 67626412, Fax +86 531 67626411, Email Ljpxxx308@126.comPurpose: This study aimed to evaluate the safety and efficacy of a combination of programmed death-1 (PD-1) inhibitor and regorafenib as second-line treatment for advanced hepatocellular carcinoma (HCC).Patients and Methods: We retrospectively analyzed the data of 38 patients with unresectable HCC who were treated with PD-1 inhibitor in combination with regorafenib as a second⁃line therapy as well as the data of 32 patients treated with regorafenib only therapy as a control. The clinical data, previous treatment strategies, follow-up imaging results, and adverse events during follow-ups were recorded. The mRECIST Criteria were used to evaluate the treatment outcome of intrahepatic lesions, and the Kaplan–Meier method was used to evaluate survival time.Results: Up to the last follow-up, the rego-PD-1 group had higher objective response rate (39.5% vs 15.6%, P = 0.028), longer progression-free survival (median 5.9 vs 4.6 months; P = 0.044), and better overall survival (OS) (median 14.5 vs 9.5 months; P = 0.041) than the regorafenib only group. Among the 38 patients in rego-PD-1 group, 1 patient (2.7%) achieved complete response, 14 patients (36.8%) achieved partial response, 14 patients (36.8%) achieved stable disease, and 9 patients (23.7%) achieved progressive disease. Among the 32 patients in regorafenib alone, 5 (15.6%) achieved partial response, 12 (37.5%) achieved stable disease, and 15 (46.9%) achieved progressive disease. Regorafenib alone, Child–Pugh B, and tumors > 3 were independent prognostic factors for poor OS. The difference in the incidence of grade 3/4 adverse events between the two groups was not statistically significant (36.8% vs 28.1%; P = 0.439). Grade ≥ 3 treatment-related adverse events included hypertension and diarrhea.Conclusion: PD-1 inhibitor combined with regorafenib is a promising regimen in treating patients with unresectable HCC owing to its safety and effectiveness as well as low incidence of serious adverse events with its use.Keywords: hepatocellular carcinoma, immune checkpoint inhibitor, regorafenib, anti-PD-1 antibody, second-line treatment, overall survival