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Shuang Liang,1 Yan-Jun Liang,1 Zhao Li,2 Yong Wang,1 Xin-Ru Guo,1 Chao-yang Zhang,1 Chun Zhang,1 Jie Wu,1 Xiao-Long Wang,1 Yi-Sha Li,1 Guang-Yan Cai,1 Xiang-Mei Chen1 1Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Nephrology Institute of the Chinese People’s Liberation Army, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease Research, Beijing, People’s Republic of China; 2Haikou People’s Hospital Affiliated to Xiangya School of Medicine, Haikou, People’s Republic of ChinaCorrespondence: Guang-Yan Cai, Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Nephrology Institute of the Chinese People’s Liberation Army, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease Research, Beijing, People’s Republic of China, Tel +86 13601062936, Fax +86 010-68130297, Email caiguangyan@sina.comPurpose: Tacrolimus is recommended by KDIGO Clinical Practice Guidelines as an initial therapy for the treatment of membranous nephropathy (MN). However, little is known about the factors that influence response and recurrence of the disease after tacrolimus therapy, and there are limited data regarding the duration of tacrolimus treatment. Here, we present a real-world retrospective cohort study of 182 MN patients treated with tacrolimus, aiming to assess the efficacy and safety of tacrolimus in the treatment of MN.Patients and Methods: The clinical data of 182 patients with MN treated with tacrolimus and followed up for at least one year were analyzed retrospectively for the efficacy and safety of tacrolimus.Results: The mean follow-up period was 27.3 (19.3– 41.6) months. A total of 154 patients (84.6%) achieved complete or partial remission, and 28 patients (15.4%) did not. Multivariate Cox regression analysis showed that male and higher baseline BMI were independently associated with lower, while higher serum albumin was associated with higher probability of remission. Among the responders, 56 patients (36.4%) relapsed. After adjustments for age and sex, Cox regression analysis revealed that the longer period of full-dose tacrolimus was administered, the lower the incidence of relapse. However, high levels of serum creatinine and proteinuria at the onset of tacrolimus discontinuation were risk factors for relapse. During the treatment of tacrolimus, a decline in renal function (≥ 50% increase in serum creatinine after the onset of tacrolimus treatment) was the most common adverse reaction, observed in 20 (11.0%) patients, followed by elevated blood glucose and infection, but the latter two occurred mostly during treatment with tacrolimus plus corticosteroids.Conclusion: Tacrolimus is effective in the treatment of MN, but the relapse rate is high. Clinical studies with larger sample sizes are needed to further explore the use of tacrolimus in the treatment of membranous nephropathy.Keywords: membranous nephropathy, tacrolimus, response, relapse, safety

Xin Liu,1,* Miao Tang,2,* Tian-Yi He,1 Shuang Zhao,1 Hui-Zhou Li,1 Zhao Li,1 Yue-Xian Guo,3 Xiu-Li Wang1 1Department of Anesthesiology, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050051, People’s Republic of China; 2Department of General Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050000, People’s Republic of China; 3Department of Surgery, The Third Hospital of Hebei Medical University, Shijiazhuang, 050051, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiu-Li Wang, Department of Anesthesiology, The Third Hospital of Hebei Medical University, No. 139 Ziqiang Road, Shijiazhuang, Hebei, 050051, People’s Republic of China, Tel +86-13313019968, Email wangxl311@126.comObjective: This study aimed to investigate the effect of resveratrol (Res) on paclitaxel (PTX)-induced cognitive impairment and elucidate the underlying molecular mechanisms.Methods: Morris Water Maze (MWM) test was used to evaluate the mice’s spatial learning and memory abilities. Western blotting was applied to detect protein expression of receptor-interacting protein (RIP3), mixed lineage kinase domain-like protein (MLKL), silencing information regulator 2 related enzyme 1 (SIRT1), peroxisome proliferator activated receptor coactivator-1 (PGC-1α), NADPH oxidase 2 (NOX2), NOX4, postsynaptic density zone 95 (PSD95), arginase-1 (Arg-1) and inducible nitric oxide synthase (iNOS). Immunofluorescence of RIP3, MLKL, Arg-1, Iba-1 and iNOS was conducted to observe the apoptosis of hippocampal cells and the polarization of microglia. qRT-PCR was performed to detect BDNF mRNA expressions. DHE staining was used to assess the level of oxidative stress response. Golgi-Cox staining and dendritic spine counting were applied to visualize synaptic structural plasticity. Postsynaptic density was performed by transmission electron microscope. ELISA was used to detect the contents of tumour necrosis factor alpha (TNF-α), IL-1β, IL-4, and IL-10.Results: PTX-induced cognitive impairment model was constructed after the application of PTX, represented as longer latency to platform and less platform crossing times over the whole period in PTX group. After Res treatment, the above indicators were reversed, indicating that cognitive function was improved. Moreover, Res reduced neuronal apoptosis and oxidative stress through SIRT1/PGC-1α pathway in mice, manifesting as down-regulated expression of RIP3, MLKL, NOX2 and NOX4. Meanwhile, Res increased the density of dendritic spines and the expression of PSD95 and BDNF, thereby ameliorating the PTX induced synaptic damage. Besides, M2 microglia was in the majority, eliciting the expression of anti-inflammatory cytokines IL-4 and IL-10 after Res treatment in PTX+Res group, while immunofluorescence images results demonstrated an decrease in the proportion of M2 microglia a following SIRT1 inhibitor EX-527.Conclusion: Res improves PTX-induced cognitive impairment in mice by activating SIRT1/PGC-1α pathways to regulate neuronal state and microglia cell polarization.Keywords: resveratrol, paclitaxel, SIRT1/PGC-1α, microglia, M2 polarization

Jun-Jie Zhang,1,* Yu Zhang,2,* Qian Chen,1 Qi-Ning Chen,1 Xin Yang,1 Xiao-Lin Zhu,1 Chun-Yan Hao,3 Hu-Bin Duan1 1Department of Neurosurgery, First Hospital of Shanxi Medical University, Taiyuan, Shanxi, 030001, People’s Republic of China; 2Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, People’s Republic of China; 3Department of Geriatrics, First Hospital of Shanxi Medical University, Taiyuan, Shanxi, 030001, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hu-Bin Duan; Chun-Yan Hao, Tel +8613994201664 ; +8613803494928, Email hubinduan68@163.com; haochunyan68@126.comBackground: Immune microenvironment serves a vital role in glioma progression, and a large number of studies have found that tumor progression can be reduced to some extent by modulating the immune process in tumors.Materials and Methods: ImmuneScore of each sample in CGGA datasets were calculated with Estimate R package, and samples were grouped by median ImmuneScore values for differential analysis to obtain immune microenvironment differential genes. We further conducted survival analysis, ROC curve analysis, independent prognostic analysis, and clinical correlation analysis on glioma sample genes in CGGA to obtain glioma prognostic genes, and then identified their intersection with immune microenvironment DEGs by Venn tool. The GEPIA and UALCAN databases were used to verify the differential expression of intersecting genes in the glioma and normal brain and to identify our target gene. After validation of their prognostic value, we constructed a nomogram to calculate the risk score and to estimate the accuracy of prognostic model. We mined co-expression genes, enriched functions and pathways, and correlations to immune cell infiltration of unigene with an online database. Finally, we verified the differential expression of FCGBP in glioma by immunohistochemical staining.Results: We finally selected Fc fragment of IgG-binding protein (FCGBP) as our study gene. The prognostic values of FCGBP were validated by a series of analyses. Immunohistochemical staining showed that FCGBP expression increased in gliomas and was up-regulated with the progression of glioma grade.Conclusion: As a key unigene in glioma progression, FCGBP contributes to the regulation of immune microenvironment and has the potential to be a prognostic biomarker and immune targets.Keywords: glioma, immune microenvironment, FCGBP, tumor progression, therapeutic target

Yu Zhang,1,* Xue-Li Wang,2,* Jing-Jing Liu,3 Zhen-Yuan Qian,4 Zheng-Yang Pan,5 Ni-Ping Song,5 Hui-Yan Chen,6 Wei Zhang,7 Xin Zhang8 1Cancer Center, Department of Gastroenterology, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, Zhejiang, People’s Republic of China; 2College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, Zhejiang, People’s Republic of China; 3Bengbu Medical College, Bengbu, Anhui, People’s Republic of China; 4General Surgery, Cancer Center, Department of Gastrointestinal and Pancreatic Surgery, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, Zhejiang, People’s Republic of China; 5The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China; 6Clinical Laboratory, Tongxiang First People’s Hospital, Tongxiang, Zhejiang, People’s Republic of China; 7Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China; 8Cancer Center, Department of Pathology, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, Zhejiang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xin Zhang, Cancer Center, Department of Pathology, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), No. 158 Shangtang Road, Hangzhou, Hangzhou, Zhejiang, 310014, People’s Republic of China, Tel +86 13758197690, Fax +86 057185893288, Email zhangxin120189@163.com Wei Zhang, Department of Gastrointestinal surgery, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310005, People’s Republic of China, Email zhangweils1968@163.comPurpose: This study aimed to investigate the expression of inducible T-cell co-stimulator (ICOS) and its ligand (ICOSLG), along with their association with clinicopathological features and influence on the immune profile in colorectal cancer (CRC).Patients and Methods: The Cancer Genome Atlas Colorectal Adenocarcinoma cohorts were used. We also analyzed 131 clinical samples of colon lesions, including precancerous lesions (hyperplastic polyps, low-grade dysplasia, and high-grade dysplasia) and CRC tissues. We conducted immunohistochemical (IHC) assays and multiple IHC (mIHC) of CD4+, Foxp3+ tumor-infiltrating lymphocytes (TILs), and PD-1/PD-L1 immune checkpoints in precancerous lesions and CRC samples from our patient subsets to determine changes and correlations in ICOS and ICOSLG expression during progression through the adenoma–carcinoma pathway.Results: High expression of ICOS and ICOSLG was a significant factor in CRC in multiple analyses and was positively correlated with CD4+/Foxp3+ TIL density and PD-1/PD-L1 expression, which increased with the sequential progression of lesions from precancerous tissues to carcinoma. Multivariable logistic regression analysis suggested that the location and expression level of ICOS/ICOSLG may be involved in precancerous–carcinoma progression. The co-expression status of PD-1 and ICOS/ ICOSLG could stratify patients with colorectal lesions into three groups of low, moderate, and high risk of progression. According to this classification and mIHC assays, we found a strong correlation between increased PD-1+ICOS+ or PD-1+ICOSLG+ co-expression and CRC, which might be deemed an independent factor in carcinogenesis.Conclusion: Increased ICOS/ICOSLG expression may be associated with the progressive formation of Foxp3+ TILs in the immune microenvironment and may further promote the development of the abnormal cytology of colorectal lesions from precancerous neoplasia to CRC. Our findings support the interpretation that enhanced co-expression of PD-1+ICOS+ or PD-1+ICOSLG+ contributes to the immune-active microenvironment of the colorectal adenoma-carcinoma sequence.Keywords: precancerous-carcinoma, immune environment, ICOS/ICOSLG, PD-1/PD-L1, tumor-infiltrating lymphocytes

Xiang-Ling Liu,&ast; Fa-Jin Lv,&ast; Bin-Jie Fu, Rui-Yu Lin, Wang-Jia Li, Zhi-Gang Chu Department of Radiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhi-Gang Chu, Department of Radiology, The First Affiliated Hospital of Chongqing Medical University, 1&num; Youyi Road, Yuanjiagang, Yuzhong District, Chongqing, 400016, People’s Republic of China, Tel +86 18723032809, Fax +86 23 68811487, Email chuzg0815@163.comPurpose: To investigate the influence factors for the various boundary manifestations of pulmonary non-neoplastic ground glass nodules (GGNs) on computed tomography (CT).Materials and Methods: From January 2015 to March 2022, a total of 280 patients with 318 non-neoplastic GGNs were enrolled. The correlations between degree of inflammatory cell infiltration and relative density (ΔCT) and the boundary manifestations of lesions were evaluated, respectively.Results: Nongranulomatous nodules (283, 89.0%) with fibrous tissue proliferation and/or inflammatory cells as the predominant pathological findings were the most common non-neoplastic GGNs, followed by granulomatous nodules (28, 8.8%). Among nongranulomatous GGNs, cases with more and less/no inflammatory cells were 15 (10.9%) and 122 (89.1%) in 137 well-defined ones with smooth margin, 16 (24.6%) and 49 (75.4%) in 65 well-defined ones with coarse margin, 43 (91.5%) and 4 (8.5%) in 47 ill-defined ones with higher ΔCT (> 151HU), and 4 (11.8%) and 30 (88.2%) in 34 ill-defined ones with lower ΔCT (< 151HU). The proportion of cases with more inflammatory cells in well-defined nodules was similar to that in ill-defined ones with lower ΔCT (P = 0.587) but significantly lower than that in ill-defined ones with higher ΔCT (P < 0.001). Among the granulomatous nodules, ill-defined cases with higher ΔCT (16, 57.1%) were the most common, and they (7/8, 87.5%) frequently had changes during short-term follow-up.Conclusion: Nongranulomatous nodules are the most common non-neoplastic GGNs, their diverse boundary manifestations closely correlate with degree of inflammatory cell infiltration and density difference.Keywords: tomography, X-ray computed, solitary pulmonary nodule, pathology

Yue-Yu Shi,1 Xing-Lei Chen,1 Qian-Xin Chen,1 Yuan-Zhong Yang,2 Meng Zhou,1 Yue-Xiang Ren,3 Lu-Ying Tang,3 Ze-Fang Ren1 1School of Public Health, Sun Yat-sen University, Guangzhou, People’s Republic of China; 2The Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China; 3The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of ChinaCorrespondence: Ze-Fang Ren, School of Public Health, Sun Yat-sen University, 74 Zhongshan 2nd Road, Guangzhou, Guangdong, People’s Republic of China, Tel/Fax +86-20-87332577, Email renzef@mail.sysu.edu.cn Lu-Ying Tang, The Third Affiliated Hospital, Sun Yat-sen University, 600 Tianhe Road, Guangzhou, Guangdong, People’s Republic of China, Tel +86-20-85253000, Fax +86-20-85253336, Email tangly@mail.sysu.edu.cnPurpose: Enolase-1 (ENO1) plays a key role in malignancies. Previous studies on the association between ENO1 expression and breast cancer prognosis had yielded inconsistent results. In the present study, we assessed the prognostic effect of ENO1 in breast cancer using Guangzhou Breast Cancer Study (GZBCS) cohort with full consideration of the potential confounders and the modification effects. The results were further validated in the TCGA-BRCA cohort and explained by tumor immunity.Methods: ENO1 protein expressions were evaluated by immunohistochemistry in tissue microarrays from 961 patients with primary invasive breast cancer. Chi-square tests were used to assess the association of ENO1 levels with the patient’s characteristics. Cox regression models were applied to assess the prognostic effects. The TCGA-BRCA cohort was utilized to validate the results and explore the potential mechanisms. The immune infiltration was determined using the CIBERSORT and ssGSEA algorithms; the correlation between ENO1 expression and the abundance of tumor-infiltrating immune cells (TIICs) and scores of immune-related functions was evaluated by Wilcoxon signed-rank tests and Spearman’s rank test.Results: ENO1 protein expression exerted a protective effect on OS in stage I/II patients (HR=0.58, 95% CI: 0.35– 0.96) but not in stage III patients (HR=1.42, 95% CI: 0.81– 2.49, P interaction=0.04) in GZBCS; consistent results were obtained at mRNA levels in TCGA cohort. Immune infiltration analyses revealed that ENO1 was positively correlated with multiple antitumor TIICs (including M1 macrophages, B cells, CD8 T cells, T helper 2 cells, and NK cells) only in stage I/II but not stage III patients.Conclusion: A higher expression of ENO1 was associated with a better prognosis only in early-stage breast cancer, which may be related to the different effects of ENO1 on immune infiltration, suggesting that ENO1 may be a promising target for precision immunotherapy in breast cancer.Keywords: ENO1, breast cancer, prognosis, tissue microarray, tumor-infiltrating immune cells

Yi Lu,1,&ast; Yi Shi,1,&ast; Qian Wu,1 Xin Sun,1 Wei-Zhen Zhang,1 Xiao-Ling Xu,2 Wei Chen1 1ICU, Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China; 2Shulan International Medical College, Zhejiang Shuren University, Hangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wei Chen, ICU, Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 725 South WanPing Road, Shanghai, 200032, People’s Republic of China, Tel +86-21-64385700-3522, Email cwdoctor@shutcm.edu.cn Xiao-Ling Xu, Shulan International Medical College, Zhejiang Shuren University, 8 Shuren Street, Hangzhou, 310015, People’s Republic of China, Email ziyao1988@zju.edu.cnAbstract: Sepsis, which is a systemic inflammatory response syndrome caused by infection, has high morbidity and mortality. Sepsis-related liver injury is one of the manifestations of sepsis-induced multiple organ syndrome. To date, an increasing number of studies have shown that the hepatic inflammatory response, oxidative stress, microcirculation coagulation dysfunction, and bacterial translocation play extremely vital roles in the occurrence and development of sepsis-related liver injury. In the clinic, sepsis-related liver injury is mainly treated by routine empirical methods on the basis of the primary disease. However, these therapies have some shortcomings, such as serious side effects, short duration of drug effects and lack of specificity. The emergence of drug delivery nanosystems can significantly improve drug bioavailability and reduce toxic side effects. In this paper, we reviewed drug delivery nanosystems designed for the treatment of sepsis-related liver injury according to their mechanisms (hepatic inflammation response, oxidative stress, coagulation dysfunction in the microcirculation, and bacterial translocation). Although much promising progress has been achieved, translation into clinical practice is still difficult. To this end, we also discussed the key issues currently facing this field, including immune system rejection and single treatment modalities. Finally, with the rigorous optimization of nanotechnology and the deepening of research, drug delivery nanosystems have great potential for the treatment of sepsis-related liver injury.Keywords: sepsis, liver-injury, drug delivery nanosystems, inflammatory response, oxidative stress, bacterial translocation

Xiu-Li Xiao,1 Qian-Xue Yang,2 Hui-Zhong Niu,1 Li-Jing Li,1 Zhen-Jing Xie1 1Department of General Surgery I, Children’s Hospital of Hebei Province, Shijiazhaung, 050000, People’s Republic of China; 2Department of Operating Room, Children’s Hospital of Hebei Province, Shijiazhaung, 050000 People’s Republic of ChinaCorrespondence: Xiu-Li Xiao, Department of General Surgery I, Children’s Hospital of Hebei Province, No. 133 Jianhuanan Street, Yuhua District, Shijiazhuang, Hebei, 050000, People’s Republic of China, Tel +86-0311-85911010, Email xxlwwvt7@email.cnObjective: To explore the effective response strategies for infections in infants with short bowel syndrome and solid abdominal tumours, treated with totally implantable venous access ports (TIVAPs).Methods: A total of 210 children who were treated with a TIVAP in our department from 2020 to 2021 were selected for this retrospective study. Eight of these children diagnosed with a catheter-related bloodstream infection were studied in this study; antibiotic lock therapy (ALT) and cluster nursing management were used for treatment, and their effects on the infection outcome were observed.Results: Among the eight children, seven access ports were successfully protected, and one catheter was removed from the right chest wall port due to repeated infection. In this one child, the left side was re-implanted.Conclusion: The use of the ALT combined with cluster-based nursing can better treat infections of TIVAPs, improve the children’s healing time, and has important clinical significance in the prevention of complications from the infection and improving the treatment and nursing of the patients diagnosed with these infections.Keywords: totally implantable venous access port, short bowel syndrome and solid abdominal tumours, catheter-related bloodstream infection, cluster nursing management

Xiao-Lin Wei,1 Qiang-Lin Zeng,2 Min Xie,3 Yong Bao1 1Department of Respirology, Taikang Sichuan Hospital, Chengdu, People’s Republic of China; 2Department of Respiratory and Critical Care Medicine, Affiliated Hospital of Chengdu University School of Clinical Medicine, Chengdu University, Chengdu, People’s Republic of China; 3Department of Respiratory and Critical Care Medicine, West China Hospital of Sichuan University, Chengdu, People’s Republic of ChinaCorrespondence: Yong Bao, Department of Respirology, Taikang Sichuan Hospital, No. 881, Xianghe 1st Street, Huayang Street, Tianfu New District, Sichuan, 610213, People’s Republic of China, Email byong65@163.comObjective: To investigate the distribution and drug resistance of pathogens among hospitalized patients in the respiratory unit during the COVID-19 pandemic, analyze the risk factors of drug resistance, construct a risk prediction model.Methods: This study isolated 791 strains from 489 patients admitted to the Affiliated Hospital of Chengdu University, who were retrospectively enrolled between December 2019 and June 2021. The patients were divided into training and validation sets based on a random number table method (8:2). The baseline information, clinical characteristics, and culture results were collected using an electronic database and WHONET 5.6 software and compared between the two groups. A risk prediction model for drug-resistant bacteria was constructed using multi-factor logistic regression.Results: K. pneumoniae (24.78%), P. aeruginosa (17.19%), A. baumannii (10.37%), and E. coli (10.37%) were the most abundant bacterial isolates. 174 isolates of drug-resistant bacteria were collected, ie, Carbapenem-resistant organism-strains, ESBL-producing strains, methicillin-resistant S. aureus, multi-drug resistance constituting 38.51%, 50.57%, 6.32%, 4.60%, respectively. The nosocomial infection prediction model of drug-resistant bacteria was developed based on the combined use of antimicrobials, pharmacological immunosuppression, PCT> 0.5 ng/mL, CKD stage 4– 5, indwelling catheter, and age > 60 years. The AUC under the ROC curve of the training and validation sets were 0.768 (95% CI: 0.624– 0.817) and 0.753 (95% CI: 0.657– 0.785), respectively. Our model revealed an acceptable prediction demonstrated by a non-significant Hosmer-Lemeshow test (training set, p=0.54; validation set, p=0.88).Conclusion: K. pneumoniae, P. aeruginosa, A. baumannii, and E. coli were the most abundant bacterial isolates. Antimicrobial resistance among the common isolates was high for most routinely used antimicrobials and carbapenems. COVID-19 did not increase the drug resistance pressure of the main strains. The risk prediction model of drug-resistant bacterial infection is expected to improve the prevention and control of antibacterial-resistant bacterial infection in hospital settings.Keywords: COVID-19, respiratory and critical care medicine, drug-resistant bacteria, risk factors, line chart

The mission of HL-2A is to explore the key physical topics relevant to ITER and to the advanced tokamak operation (e.g. the operation of future HL-2M), such as the access of H-mode, energetic particle physics, edge-localized mode (ELM) mitigation/suppression and disruption mitigation. Since the 2016 Fusion Energy Conference, the HL-2A team has focused on the investigations on the following areas: (i) pedestal dynamics and L-H transition, (ii) techniques of ELM control, (iii) turbulence and transport, (iv) energetic particle physics. The HL-2A results demonstrated that the increase of mean shear flow plays a key role in triggering L-I and I-H transitions, while the change of flow is mainly induced by the ion pressure gradient. Both mitigation and suppression of ELMs were realized by laser blow-off seeded impurity (Al, Fe, W). The 30% Ne mixture supersonic molecular beam injection seeding also robustly induced ELM mitigation. The ELMs were mitigated by low-hybrid current drive. The stabilization of m/n = 1/1 ion fishbone activities by electron cyclotron resonance heating was found on the HL-2A. A new m/n = 2/1 ion fishbone activity was observed recently, and the modelling indicated that passing fast ions dominantly contribute to the driving of 2/1 fishbone. The non-linear coupling between the toroidal Alfven eigenmode and tearing mode (TM) led to the generation of a high frequency mode with the toroidal mode number n = 0. The turbulence was modulated by TM when the island width exceeds a threshold and the modulation is localized merely in the inner area of the islands. Meanwhile, turbulence radial spread took place across the island region.

We show that a class of random all-to-all spin models, realizable in systems of atoms coupled to an optical cavity, gives rise to a rich dynamical phase diagram due to the pairwise separable nature of the couplings. By controlling the experimental parameters, one can tune between integrable and chaotic dynamics on the one hand and between classical and quantum regimes on the other hand. For two special values of a spin-anisotropy parameter, the model exhibits rational Gaudin-type integrability, and it is characterized by an extensive set of spin-bilinear integrals of motion, independent of the spin size. More generically, we find a novel integrable structure with conserved charges that are not purely bilinear. Instead, they develop "dressing tails" of higher-body terms, reminiscent of the dressed local integrals of motion found in many-body localized phases. Surprisingly, this new type of integrable dynamics found in finite-size spin-1/2 systems disappears in the large-S limit, giving way to classical chaos. We identify parameter regimes for characterizing these different dynamical behaviors in realistic experiments, in view of the limitations set by cavity dissipation.

A high precision calibration of the nonlinearity in the energy response of the Daya Bay Reactor Neutrino Experiment's antineutrino detectors is presented in detail. The energy nonlinearity originates from the particle-dependent light yield of the scintillator and charge-dependent electronics response. The nonlinearity model is constrained by γ calibration points from deployed and naturally occurring radioactive sources, the β spectrum from 12B decays, and a direct measurement of the electronics nonlinearity with a new flash analog-to-digital converter readout system. Less than 0.5% uncertainty in the energy nonlinearity calibration is achieved for positrons of kinetic energies greater than 1 MeV.

The precise measurement of the spectrum of protons, the most abundant component of the cosmic radiation, is necessary to understand the source and acceleration of cosmic rays in the Milky Way. This work reports the measurement of the cosmic ray proton fluxes with kinetic energies from 40 GeV to 100 TeV, with 2 1/2 years of data recorded by the DArk Matter Particle Explorer (DAMPE). This is the first time that an experiment directly measures the cosmic ray protons up to ~100 TeV with high statistics. The measured spectrum confirms the spectral hardening at ~300 GeV found by previous experiments and reveals a softening at ~13.6 TeV, with the spectral index changing from ~2.60 to ~2.85. Our result suggests the existence of a new spectral feature of cosmic rays at energies lower than the so-called knee and sheds new light on the origin of Galactic cosmic rays.

This Letter reports the first extraction of individual antineutrino spectra from ^{235}U and ^{239}Pu fission and an improved measurement of the prompt energy spectrum of reactor antineutrinos at Daya Bay. The analysis uses 3.5×10^{6} inverse beta-decay candidates in four near antineutrino detectors in 1958 days. The individual antineutrino spectra of the two dominant isotopes, ^{235}U and ^{239}Pu, are extracted using the evolution of the prompt spectrum as a function of the isotope fission fractions. In the energy window of 4-6 MeV, a 7% (9%) excess of events is observed for the ^{235}U (^{239}Pu) spectrum compared with the normalized Huber-Mueller model prediction. The significance of discrepancy is 4.0σ for ^{235}U spectral shape compared with the Huber-Mueller model prediction. The shape of the measured inverse beta-decay prompt energy spectrum disagrees with the prediction of the Huber-Mueller model at 5.3σ. In the energy range of 4-6 MeV, a maximal local discrepancy of 6.3σ is observed.

We report the first measurements with sub-kiloparsec spatial resolution of strongly inverted gas-phase metallicity gradients in two dwarf galaxies at z ∼ 2. The galaxies have stellar masses ∼109 , specific star formation rate ∼20 Gyr-1, and global metallicity (1/4 solar), assuming the strong-line calibrations of [O iii]/Hβ and [O ii]/Hβ from Maiolino et al. Their radial metallicity gradients are measured to be highly inverted, i.e., 0.122 ± 0.008 and 0.111 ± 0.017 dex kpc-1, which is hitherto unseen at such small masses in similar redshift ranges. From the Hubble Space Telescope observations of the source nebular emission and stellar continuum, we present two-dimensional spatial maps of star formation rate surface density, stellar population age, and gas fraction, which show that our galaxies are currently undergoing rapid mass assembly via disk inside-out growth. More importantly, using a simple chemical evolution model, we find that the gas fractions for different metallicity regions cannot be explained by pure gas accretion. Our spatially resolved analysis based on a more advanced gas regulator model results in a spatial map of net gaseous outflows, triggered by active central starbursts, that potentially play a significant role in shaping the spatial distribution of metallicity by effectively transporting stellar nucleosynthesis yields outwards. The relation between wind mass loading factors and stellar surface densities measured in different regions of our galaxies shows that a single type of wind mechanism, driven by either energy or momentum conservation, cannot explain the entire galaxy. These sources present a unique constraint on the effects of gas flows on the early phase of disk growth from the perspective of spatially resolved chemical evolution within individual systems.

The Asian citrus psyllid (ACP) is a vector of a pathogen associated with greening and thus a major problem in citriculture worldwide. Lures are much needed for improving ACP trapping systems for monitoring populations and surveillance. Previously, we have identified acetic acid as a putative sex pheromone and measured formic acid- and propionic acid-elicited robust electroantennographic responses. We have now thoroughly examined in indoor behavioral assays (4-way olfactometer) and field tests the feasibility of these three semiochemicals as potential lures for trapping ACP. Formic acid, acetic acid, and propionic acid at appropriate doses are male-specific attractants and suitable lures for ACP traps, but they do not act synergistically. An acetic acid-based homemade lure, prepared by impregnating the attractant in a polymer, was active for a day. A newly developed slow-release formulation had equal performance but lasted longer, thus leading to an important improvement in ACP trap capture at low population densities.

This work reports a precise measurement of the reactor antineutrino flux using 2.2 million inverse beta decay (IBD) events collected with the Daya Bay near detectors in 1230 days. The dominant uncertainty on the neutron detection efficiency is reduced by 56% with respect to the previous measurement through a comprehensive neutron calibration and detailed data and simulation analysis. The new average IBD yield is determined to be (5.91±0.09)×10-43 cm2/fission with total uncertainty improved by 29%. The corresponding mean fission fractions from the four main fission isotopes U235, U238, Pu239, and Pu241 are 0.564, 0.076, 0.304, and 0.056, respectively. The ratio of measured to predicted antineutrino yield is found to be 0.952±0.014±0.023 (1.001±0.015±0.027) for the Huber-Mueller (ILL-Vogel) model, where the first and second uncertainty are experimental and theoretical model uncertainty, respectively. This measurement confirms the discrepancy between the world average of reactor antineutrino flux and the Huber-Mueller model.

The precise measurement of the spectrum of protons, the most abundant component of the cosmic radiation, is necessary to understand the source and acceleration of cosmic rays in the Milky Way. This work reports the measurement of the cosmic ray proton fluxes with kinetic energies from 40 GeV to 100 TeV, with 2 1/2 years of data recorded by the DArk Matter Particle Explorer (DAMPE). This is the first time that an experiment directly measures the cosmic ray protons up to ~100 TeV with high statistics. The measured spectrum confirms the spectral hardening at ~300 GeV found by previous experiments and reveals a softening at ~13.6 TeV, with the spectral index changing from ~2.60 to ~2.85. Our result suggests the existence of a new spectral feature of cosmic rays at energies lower than the so-called knee and sheds new light on the origin of Galactic cosmic rays.

This Letter reports the first extraction of individual antineutrino spectra from ^{235}U and ^{239}Pu fission and an improved measurement of the prompt energy spectrum of reactor antineutrinos at Daya Bay. The analysis uses 3.5×10^{6} inverse beta-decay candidates in four near antineutrino detectors in 1958 days. The individual antineutrino spectra of the two dominant isotopes, ^{235}U and ^{239}Pu, are extracted using the evolution of the prompt spectrum as a function of the isotope fission fractions. In the energy window of 4-6 MeV, a 7% (9%) excess of events is observed for the ^{235}U (^{239}Pu) spectrum compared with the normalized Huber-Mueller model prediction. The significance of discrepancy is 4.0σ for ^{235}U spectral shape compared with the Huber-Mueller model prediction. The shape of the measured inverse beta-decay prompt energy spectrum disagrees with the prediction of the Huber-Mueller model at 5.3σ. In the energy range of 4-6 MeV, a maximal local discrepancy of 6.3σ is observed.

Understanding climate-driven impacts on the multivariate global wind-wave climate is paramount to effective offshore/coastal climate adaptation planning. However, the use of single-method ensembles and variations arising from different methodologies has resulted in unquantified uncertainty amongst existing global wave climate projections. Here, assessing the first coherent, community-driven, multi-method ensemble of global wave climate projections, we demonstrate widespread ocean regions with robust changes in annual mean significant wave height and mean wave period of 5–15% and shifts in mean wave direction of 5–15°, under a high-emission scenario. Approximately 50% of the world’s coastline is at risk from wave climate change, with ~40% revealing robust changes in at least two variables. Furthermore, we find that uncertainty in current projections is dominated by climate model-driven uncertainty, and that single-method modelling studies are unable to capture up to ~50% of the total associated uncertainty.

The Daya Bay Collaboration responds to comments posted by S. Parke and R.Zukanovich Funchal regarding our use of Delta(m^2_ee).

Ning Du,1 En-Qiang Mao,2 Zhi-Tao Yang,2 Hong-Ping Qu,3 Xian Qian,4 Ying Shi,5 Xiao-Lan Bian,6 Juan He,6,&ast; Er-Zhen Chen2,&ast; 1National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, People’s Republic of China; 2Emergency Intensive Care Unit, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 3Department of Critical Care Medicine, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 4Department of Pharmacy, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, People’s Republic of China; 5Department of Clinical Pharmacy, Shaoxing Hospital of Traditional Chinese Medicine, Zhejiang, People’s Republic of China; 6Department of Pharmacy, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Er-Zhen Chen, Emergency Intensive Care Unit, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China, Email chenerzhen@hotmail.com Juan He, Department of Pharmacy, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China, Email hejuanwin@126.comPurpose: Infection with carbapenem-resistant Klebsiella pneumoniae (CRKP) is a great challenge. Central nervous system (CNS) infection caused by CRKP is rarely reported, and effective treatment is limited. Thus, this study aimed to assess intrathecal (IT) or intraventricular (IVT) injection of tigecycline for clearing infection with CRKP in CNS.Patients and Methods: Two patients who had intracranial infection with CRKP after craniotomy were treated in our institution and analyzed retrospectively, summarizing their therapeutic schedules.Results: They all had a fever with the positive results of cerebrospinal fluid (CSF) test, and CSF culture showed positive for CPKP, which was sensitive only to tigecycline. In addition, the MIC of polymyxin B was not tested due to the limited laboratory conditions. After IT or IVT injection of tigecycline treatment, the temperature of the patients became normal in 3 days, with normal levels of white blood cells, protein, glucose and chlorine concentrations in the CSF. Crucially, twice CSF cultures also became negative with no clinical symptoms of intracranial infection after IT or IVT injection of tigecycline treatment. Moreover, there were no adverse drug reactions observed.Conclusion: IT or IVT injection of tigecycline may be a bright choice to control intracranial infection with CRKP.Keywords: central nervous system infection, CNS, carbapenem-resistant Klebsiella pneumoniae, CRKP, tigecycline, treatment

Jin-Tao Huang,&ast; Bin-Yan Zhong,&ast; Nan Jiang,&ast; Wan-Ci Li, Shuai Zhang, Yu Yin, Jun Yang, Jian Shen, Wan-Sheng Wang, Xiao-Li Zhu Department of Interventional Radiology, The First Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiao-Li Zhu, Department of Interventional Radiology, The First Affiliated Hospital of Soochow University, No. 899, Pinghai Road, Suzhou, 215006, People’s Republic of China, Tel/Fax +86 512 67780375, Email zhuxiaoli90@163.comObjective: This study aimed to evaluate the effectiveness and safety of transarterial chemoembolization (TACE) in combination with immune checkpoint inhibitors (ICIs) plus tyrosine kinase inhibitors (TKIs) (TACE+IT) versus ICIs plus TKIs (IT) for advanced hepatocellular carcinoma (HCC).Materials and Methods: Data of consecutive advanced HCC patients receiving TACE+IT or IT between January 2019 and December 2021 were included and were retrospectively analyzed. Propensity score matching (PSM) was performed to reduce bias due to confounding variables. The primary outcome of the study was overall survival (OS). The secondary outcomes were progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and adverse events (AEs), respectively.Results: Sixty-four patients were enrolled in the study, among which 24 and 40 received TACE+IT and IT, respectively. The PSM cohort included 24 patients receiving TACE+IT (TACE+IT group) and 24 patients receiving IT (IT group) alone. During a median follow-up of 23 months, patients in TACE+IT group had significantly longer OS (median, 17.3 vs 11.8 months, P = 0.023), better ORR (41.7% vs 12.5%, P = 0.023) and DCR (79.2% vs 50.0%, P = 0.035) than those in the IT group, whereas a non-significant trend in PFS (median, 7.4 vs 6.7 months, P = 0.23) was observed. According to multivariable cox regression analysis, it was found that treatment modality was the only independent risk factor for OS (HR = 0.404, 95% CI = 0.179– 0.911, P < 0.05). There were no remarkable differences in AEs associated with ICIs and TKIs between the two groups, with the exception of gastrointestinal reaction.Conclusion: TACE combined with ICIs plus TKIs significantly improved OS, ORR, and DCR and showed a relatively longer PFS trend over ICIs combined with TKIs for advanced HCC.Keywords: hepatocellular carcinoma, transarterial chemoembolization, immune checkpoint inhibitors, tyrosine kinase inhibitors

Jia-Li Zhang,1,2,&ast; An-Xin Wang,1,2,&ast; Yang Yang,2,3 Qin Xu,1,2 Xiao-Ling Liao,1,2 Wei-Guo Ma,4 Ning Zhang,2,3 Chun-Xue Wang,2,3,5 Yong-Jun Wang1,2 1Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, People’s Republic of China; 2China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, People’s Republic of China; 3Department of Neuropsychiatry and Behavioral Neurology and Clinical Psychology, Beijing Tiantan Hospital, Capital Medical University, Beijing, People’s Republic of China; 4Beijing Anzhen Hospital, Capital Medical University, Beijing, People’s Republic of China; 5Beijing Institute of Brain Disorders, Collaborative Innovation Center for Brain Disorders, Capital Medical University, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ning Zhang; Chun-Xue Wang, Beijing Tiantan Hospital, 119 South 4th Ring West Road, Beijing, 100070, People’s Republic of China, Emails 827582777@qq.com; snowsen@126.comBackground: Although sleep disorders significantly increase the risk of cognitive impairment, literature is relatively scarce regarding the impact of sleep status on cognitive function in patients with acute ischemic stroke (AIS). We seek to study the association between pre-stroke subjective sleep status and cognitive function at 3 months after stroke.Patients and methods: Data were analyzed for 1,759 AIS patients from the Impairment of Cognition and Sleep after Acute Ischemic Stroke or Transient Ischemic Attack in Chinese Patients Study (ICONS). Pre-stroke subjective sleep status was assessed by the Pittsburgh Sleep Quality Index (PSQI) and Epworth Sleepiness Scale (ESS). Greater sleep fragmentation was defined as waking up in the middle of the night or early morning ≥ 3 times a week. Cognitive function was evaluated using the Montreal Cognitive Assessment (MoCA) at 3 months after stroke. Primary endpoint was the incidence of post-stroke cognitive impairment (PSCI) at 3 months after stroke. The association between subjective sleep status and PSCI was evaluated using multivariable logistic regression.Results: PSCI occurred in 52.1% at 3 months after stroke. Patients with very bad sleep quality before stroke were at increased risk of PSCI (OR, 2.11; 95% CI, 1.11– 4.03; P=0.03). Subgroup analysis found that the association between very bad sleep quality and PSCI was more evident among patients with high school education or above (OR, 5.73; 95% CI, 1.92– 17.10; P for interaction=0.02). In addition, patients with greater sleep fragmentation before stroke were also at higher risk of PSCI (OR, 1.55; 95% CI, 1.20– 2.01; P< 0.01). Similarly, subgroup analysis showed that the risk of PSCI was more pronounced among patients without employment (OR, 2.45; 95% CI, 1.59– 3.77; P for interaction=0.01).Conclusion: Very bad sleep quality and greater sleep fragmentation before stroke were identified as independent risk factors for PSCI at 3 months after stroke.Keywords: subjective sleep status, cognitive impairment, ischemic stroke

Meng-Meng Zheng,1,&ast; Ming-Xing Guo,2,&ast; Li-Min Shang,1,&ast; Jian Zhang,1 Jun Lin,1 Ye Tian,1 Xiang-Li Cui,2,&ast; Yi-Chen Zhu1,&ast; 1Department of Urology, Beijing Friendship Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Department of Pharmacy, Beijing Friendship Hospital, Capital Medical University, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiang-Li Cui, Department of Pharmacy, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong’an Road, Xicheng District, Beijing, 100050, People’s Republic of China, Email xianglicui@ccmu.edu.cn Yi-Chen Zhu, Department of Urology, Capital Medical University, Beijing Friendship Hospital, No. 95 Yong’an Road, Xicheng District, Beijing, 100050, People’s Republic of China, Email zhuyc@ccmu.edu.cnBackground: Carbapenem-resistant Klebsiella pneumoniae (CRKP) infection has proven to be difficult to control and typically presents with devastating effects.Methods: This retrospective study was conducted on the renal recipients at our institution between January 2021 to January 2022. Clinical data was collected to identify factors associated with CRKP infection and clinical outcomes.Results: There were 104 cases out of 186 total renal recipients who presented with at least one infection within 3 months after KT, and 14 cases developed unfavorable clinical outcomes. We identified 16 confirmed CRKP infected cases with the incidence of 8.60%. Possible donor derived infection (DDI) (OR = 6.743; 95% CI: 1.477– 30.786; P = 0.014) were independent risk factors for the occurrence of CRKP infection of renal recipients in our analysis, CRKP infection (OR = 20.723; 95% CI: 3.448– 124.547; P = 0.001) and pneumonia (OR = 28.458; 95% CI: 1.956– 413.984 P = 0.014) were independent risk factors for the occurrence of unfavorable clinical outcomes following KT, and the occurrence of unfavorable clinical outcomes following KT were significantly associated with CRKP infection (r = 0.535; P < 0.001) and antibiotic regimen containing ceftazidime/avibactam (CZA) (r = − 0.655; P = 0.006). The use of CZA was significantly different in the comparison of antibiotic regimens between the CRKP infected renal recipients with unfavorable outcomes and CRKP infected patients with favorable outcomes.Conclusion: It is possible that DDI can lead to CRKP infection, and CRKP infection and pneumonia were closely correlated with poor prognosis. The use of CZA may play a role in avoiding the unfavorable outcomes of CRKP infected recipients.Keywords: kidney transplant, carbapenem-resistant Klebsiella pneumoniae, early infections, risk factors, clinical outcomes

Plague, a highly infectious disease caused by Yersinia pestis, has killed millions of people in history and is still active in the natural foci of the world nowadays. Understanding the spatiotemporal patterns of plague outbreaks in history is critically important, as it may help facilitate the prevention and control for potential future outbreaks. This study's objective was to estimate the effect of the topography, vegetation, climate, and other environmental factors on the Y. pestis ecological niche. A maximum entropy algorithm spatially modelled plague occurrence data from 2004-2018 and the environmental variables to evaluate the contribution of the variables to the distribution of Y. pestis. Our results found that the average minimum temperature in September (-8 °C to +5 °C) and the sheep population density (250 sheep per km2) were influential in characterising the niche. The rim of Qinghai Lake showed more favourable conditions for Y. pestis presence than other areas within the study area. Identifying various factors will assist any future modelling efforts. Our suitability map identifies hotspots and will help public health officials in resource allocation in their quest to abate future plague outbreaks.

De-Han Cai,1 Xiao-Lin Fang2 1Nephrology Department in Jiangxi Provincial People’s Hospital Affiliated to Nanchang Medical College, Nanchang, People’s Republic of China; 2Department II of Respiratory and Critical Care in Jiangxi Provincial People’s Hospital Affiliated to Nanchang Medical College, Nanchang, People’s Republic of ChinaCorrespondence: Xiao-Lin Fang, Department II of Respiratory and Critical Care in Jiangxi Provincial People’s Hospital Affiliated to Nanchang Medical College, Nanchang, People’s Republic of China, Tel +86 13767049980, Email 2301136723@qq.com; lynnfangxialin@163.comBackground: Even with the advent of NGS and PCR diagnostic tools, cases of chest infections caused by Trichomonas are still very rare. Such pathogens are less likely to be considered by clinicians. These cases frequently involve the pleura and lead to pneumothorax, hydropneumothorax, or pyopneumothorax, making the disease severe.Case Presentation: A 69-year-old man diagnosed with cerebral infarction a year ago sought medical attention for right-sided pyopneumothorax and respiratory failure. The pathogen found in the pleural fluid was highly suspected to be Trichomonas tenax (T. tenax). Pleural fluid mNGS confirmed T. tenax and Porphyromonas endodontalis coinfection. Metronidazole combined with piperacillin tazobactam was administered to counteract infection. Simultaneously, closed chest drainage and thoracoscopic release of pleural adhesions were performed. The patient was cured, discharged from the hospital, and was in good condition after six months of follow-up.Conclusion: When chest infections occur in patients with poor oral hygiene and underlying diseases that may lead to aspiration, the identification of Trichomonas infection should be noted. Early confirmation of the diagnosis often requires mNGS and PCR. Metronidazole is essentially effective against Trichomonas, and medical thoracoscopy can be used to manage pleural conditions if necessary.Keywords: pyopneumothorax, Trichomonas tenax, Porphyromonas endodontalis, aspiration, VATS

Xiao-Li Yang,1,&ast; Wen-Yao Xie,2,&ast; Yi-Min Cai,3 Hong-Ying Tang,1 Mei-Yi Tao,3 Zhou-Min Shen,3 Hong-Jiao Chen4 1Department of Liver Surgery, Hunan Provincial People’s Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, 410005, People’s Republic of China; 2Interventional Operating Room, Hunan Provincial People’s Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, 410005, People’s Republic of China; 3Department of Nursing, Hunan Provincial People’s Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, 410005, People’s Republic of China; 4Medical College of Hunan Normal University, Changsha, 410013, People’s Republic of China&ast;These authors contributed equally to this studyCorrespondence: Yi-Min Cai, Nursing department, Hunan Provincial People’s Hospital (The First Affiliated Hospital of Hunan Normal University), No. 61, Jiefang West Road, Changsha, 410005, People’s Republic of China, Tel +86 13787129085, Fax +0731-83928047, Email cyimin2022@163.comPurpose: To understand existing negative emotions in patients with coronary heart disease after percutaneous coronary stent implantation (PCI) and analyse its influencing factors.Methods: Patients with coronary heart disease after PCI in three tertiary hospitals in Changsha City from April to September 2018 were selected as the research subjects. The self-designed general information questionnaire assessed irritability, depression and anxiety (IDA) on a self-rating scale. It was used to examine patients’ existing negative emotions with coronary heart disease after PCI and analyse the influencing factors.Results: 203 questionnaires were distributed, and 202 valid questionnaires were recovered, with an effective recovery rate of 99.5%. The IDA score of patients with coronary heart disease after PCI was 17.01± 7.60 points, the incidence of negative emotions was 63.8%, and the incidences of depression, anxiety and irritability were 39.6%, 8.4% and 15.8%, respectively. Negative emotion was taken as the dependent variable and a patient’s general data, such as lifestyle and disease, as the independent variables. A univariate analysis was conducted to obtain gender, age, educational level, marital status, work status, per capita monthly household income, sleep status, etc. Seven factors were identified as the influencing factors of negative emotions in patients with coronary heart disease after PCI, and the difference was statistically significant (P< 0.05).Conclusion: Most patients with coronary heart disease after PCI tend to exhibit negative emotions such as anxiety and depression. Medical staff should attach great importance to evaluating any negative feelings in this group and take timely targeted intervention measures to prevent and mitigate the occurrence and development of these adverse emotions in patients with coronary heart disease after PCI.Keywords: coronary heart disease, postoperative PCI, negative emotions, influencing factors

Yang Fu, Ying-Chao Yan, Xuan-Liang Ru, Hang-Bo Qu Department of Orthopedics, Affiliated Zhejiang Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of ChinaCorrespondence: Hang-Bo Qu, Department of Orthopedics, Affiliated Zhejiang Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China, Tel +86-153-5571-0890, Email quhb1222@163.comObjective: Chronic low back pain (CLBP) after percutaneous endoscopic transforaminal discectomy (PTED) surgery may be caused by preoperative lumbar microinstability (MI). However, there is a paucity of research on the relationship between lumbar microinstability and chronic low back pain. The purpose of this article is to assess the preoperative radiographic characteristics of patients and evaluate the effects of lumbar microinstability on patient-reported outcomes among single-level lumbar disc herniation (LDH) patients who underwent PTED.Methods: This study retrospectively reviewed the radiographic characteristics of a consecutive series of 127 patients with low back pain and leg pain caused by single-level LDH underwent PTED from August 2018 to March 2021. They were divided into three groups according to the radiographic parameters: the stable group (Group S), the dysfunctional group (Group D), and the microinstability group (Group M). The visual analogue scale (VAS) scores for leg and low back pain and Oswestry Disability Index (ODI) were evaluated preoperatively and postoperatively. Logistic regression analysis was used to identify independent risk factors for CLBP.Results: Compared with Group D and Group S, Group M had the highest ODI scores (P < 0.01) and VAS scores (low back pain) (P < 0.01) after 1 year, while there were no significant differences in the VAS scores for leg pain at different time points after surgery (P > 0.05). In addition, the logistic regression analysis results regarding CLBP revealed that muscle fatty degeneration on MRI (95% CI, 1.20– 8.51, P = 0.02), and facet tropism (95% CI, 1.39 − 11.37, P = 0.01) may be independent risk factors.Conclusion: Patients with lumbar microinstability may have CLBP after PTED, so patients with lumbar microinstability may need to take internal fixation surgery to solve their symptoms.Keywords: chronic low back pain, PTED, microinstability, risk factor

Ting Li,1,&ast; Ling Hu,1,&ast; Xiao-Ling Yin,1 Yi Zou,1 Hai-Yan Fu,1 Hong-Lin Li2 1Department of Endocrinology, The First Hospital of Nanchang (The Third Affiliated Hospital of Nanchang University), Nanchang, Jiangxi, People’s Republic of China; 2Department of Biochemistry, Medical College of Georgia, Augusta, GA, USA&ast;These authors contributed equally to this workCorrespondence: Ling Hu, Department of Endocrinology, The First Hospital of Nanchang (The Third Affiliated Hospital of Nanchang University), No.128 of Xiangshan North Road, Donghu District, Nanchang, Jiangxi, 330008, People’s Republic of China, Tel +86 0791-88862350, Fax +86 0791-6782945, Email ythulingh@163.comObjective: To retrospectively review the clinical data of type 2 diabetes mellitus (T2DM) patients hospitalized in Nanchang, China, summarized the prevalence of osteoporosis (OP) in T2DM patients in this area, and analyzed related influencing factors.Methods: The clinical data of hospitalized patients with T2DM were collected retrospectively. According to the results of bone mineral density test, the subjects were divided into the normal bone mass group, the osteopenia group, and the OP group. Age, gender, educational background, body mass index (BMI), waist-to-hip ratio (WHR), duration of T2DM, glycosylated hemoglobin, serum lipids, and complications of T2DM in the three groups were analyzed and compared.Results: The prevalence of OP in patients with T2DM was 35.77%. There were statistically significant differences in age, gender, BMI, WHR, duration of T2DM, educational background, the level of high-density lipoprotein cholesterol (HDL-C), the prevalence of diabetic retinopathy (DR), and diabetic peripheral neuropathy among the three groups (P < 0.05). Logistic regression analysis showed that increasing age, prolonged duration of T2DM, low BMI, high levels of HDL-C, and complicated DR were risk factors for osteopenia and OP.Conclusion: The prevalence of OP in T2DM was high. Risk factors for abnormal bone mass in T2DM might be females, advanced age, long duration of T2DM, low BMI, high levels of HDL-C, and diabetic microangiopathy.Keywords: type 2 diabetes mellitus, osteoporosis, risk-factors, prevalence

Jie Yang,1,2 Meng-Yu Zhang,1 Yi-Ming Du,2 Xiu-Li Ji,3 Yi-Qing Qu1 1Department of Pulmonary and Critical Care Medicine, Qilu Hospital of Shandong University, Shandong Key Laboratory of Infectious Respiratory Diseases, Jinan, People’s Republic of China; 2Department of Gerontology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, People’s Republic of China; 3Department of Pulmonary Disease, Jinan Traditional Chinese Medicine Hospital, Jinan, People’s Republic of ChinaCorrespondence: Yi-Qing Qu, Department of Pulmonary and Critical Care Medicine, Qilu Hospital of Shandong University; Shandong Key Laboratory of Infectious Respiratory Diseases, Wenhuaxi Road 107#, Jinan, 250012, People’s Republic of China, Tel +86 531 8216 9335, Fax +86 531 8296 7544, Email quyiqing@sdu.edu.cnPurpose: Cellular senescence participates in the occurrence and development of chronic obstructive pulmonary disease (COPD). This study aimed to identify senescence-related hub genes and explore effective diagnostic markers and therapeutic targets for COPD.Methods: The microarray data from the GSE38974 dataset was downloaded from the Gene Expression Omnibus (GEO) database. The overlapping genes between genes from the GSE38974 dataset and CellAge database were considered differentially expressed senescence-related genes (DESRGs). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed using R software. Protein-protein interaction (PPI), miRNA-mRNA network, and competitive endogenous RNA (ceRNA) network were constructed and visualized by Cytoscape software. GSE100281 and GSE103174 datasets were employed to validate the expression and diagnostic value of hub genes. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to measure the mRNA levels of hub genes in peripheral blood mononuclear cells (PBMCs) from COPD and control samples.Results: A total of 23 DESRGs were identified between COPD samples and healthy controls. Enrichment analysis revealed that DESRGs were mainly related to apoptosis and senescence. Moreover, four hub genes and two key clusters were acquired by Cytohubba and MCODE plugin, respectively. CDKN1A and HDAC1 were verified as final hub genes based on GSE100281 and GSE103174 datasets validation. The mRNA expression level of CDKN1A was negatively related to forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC), and HDAC1 expression had the opposite correlation. Finally, an HDAC1-based ceRNA network, including 6 miRNAs and 11 lncRNAs, was constructed.Conclusion: We identified two senescence-related hub genes, CDKN1A and HDAC1, which may be effective biomarkers for COPD diagnosis and treatment. An HDAC1-related ceRNA network was constructed to clarify the role of senescence in COPD pathogenesis.Keywords: chronic obstructive pulmonary disease, senescence, bioinformatics, CDKN1A, HDAC1

Jia-qi Chen,&ast; Jie-ru Chen,&ast; Sheng Wang, Wei Gao, Hai Gu, Xin-lu Yang, Ji-cheng Hu, Xiao-qing Chai, Di Wang Pain Clinic, Department of Anesthesiology, The First Affiliated Hospital of USTC (Anhui Provincial Hospital), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Di Wang; Xiao-qing Chai, Department of Anesthesiology, The First Affiliated Hospital of USTC (Anhui Provincial Hospital), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, People’s Republic of China, Tel/Fax +86-551-62283963 ; +86-551-62283912, Email di.wang@ustc.edu.cn; xiaoqingchai@ustc.edu.cnPurpose: The goal of this study was to evaluate the analgesic efficiency of dexamethasone with ropivacaine in continuous serratus anterior plane block (cSAPB) after video-assisted thoracoscopic surgery (VATS).Patients and Methods: Sixty-six patients who underwent VATS were randomized into two groups. All patients received cSAPB postoperatively, and patients in Group RD received 20 mL of 0.375% ropivacaine plus 0.1 mg/kg dexamethasone followed by an infusion of 0.2% ropivacaine plus 0.02 mg/kg/hour dexamethasone at a rate of 5 mL/h in patient-controlled analgesia (PCA) pump. Patients in Group R received 20 mL of 0.375% ropivacaine with normal saline followed by an infusion of 5 mL/h of 0.2% ropivacaine in PCA pump. Fifty milligrams of tramadol was given as rescue medication when the visual analog scale (VAS) score was ≥ 4 at rest. The primary outcomes were the sum of pressing number within 48 hours postoperatively and the time to the first patient-controlled bolus. The secondary outcomes were VAS scores, the incidence of rescue analgesia, wound infection and nausea/vomiting.Results: Within 48 hours postoperatively, the sum of pressing number was more in Group R (18.33 ± 3.149 vs 16.09 ± 3.292, P = 0.006), and the Log Rank Test showed a significant difference in time to the first patient-controlled bolus (P = 0.006). After the PCA infusion finished, there were significantly lower VAS scores in Group RD at 60 and 72 hours postoperatively (P < 0.001). Additionally, the incidence of rescue analgesia in Group R was significantly more than that in Group RD (P < 0.001). No incision infection was observed in any patient.Conclusion: The cSAPB with ropivacaine plus dexamethasone prolonged the duration of analgesia and motor blockade, reduced pain intensity and rescued analgesia requirements after the end of PCA infusion for patients undergoing VATS, which provide further improvement to continuous perineural block.Keywords: continuous serratus anterior plane block, video-assisted thoracoscopic surgery, dexamethasone, levobupivacaine

Xiao-Ling Li,1,&ast; Hua Liu,2,&ast; Shu-Han Liu,2 Yong Cheng,2,3 Guo-Jun Xie1 1The Third People’s Hospital of Foshan, Foshan, People’s Republic of China; 2Center on Translational Neuroscience, School of Pharmacy, Minzu University of China, Beijing, People’s Republic of China; 3Institute of National Security, Minzu University of China, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yong Cheng, Minzu Unviersity of China, 27 South Zhongguancun Avenue, Beijing, 100081, People’s Republic of China, Email yongcheng@muc.edu.cn Guo-Jun Xie, The Third People’s Hospital of Foshan, 102 South Jinlan Road, Foshan, 528041, People’s Republic of China, Email xiegjfs@163.comIntroduction: Major depression disorder is the most common diagnosed mental illnesses, and it bring a high social and economic burden. However, the current treatment for depression has limitations with side effects. Hence, there is an urgent need to search more effective treatment for major depressive disorder. Brain-derived neurotrophic factor (BDNF) is a neurotrophin that is vital to the survival, growth, and maintenance of neurons.Methods: We administered BDNF into chronic unpredictable mild stress (CUMS)-induced depression mice and assessed the effects of intranasal delivery of BDNF in depression by the tail suspension test, forced swimming test, novelty suppressed feeding test, and open-field test.Results: We find that the intranasal administration of BDNF reversed the depressive-like behaviors in CUMS mice as measured Further analyses suggested that BDNF treatment reduced pro-inflammatory cytokine (IL-6, TNF-α, iNOS and IL-1β) expressions in the hippocampus of CUMS mice. In addition, our results showed that BDNF markedly reduced oxidative stress in the hippocampus and blood of CUMS mice. Moreover, our data suggested that BDNF treatment increased neurogenesis in the hippocampus of CUMS mice.Discussion: Taken together, our results for the first time demonstrated that intranasal delivery of BDNF protein exhibited anti-depressant-like effects in mice, and therefore may represent a new therapeutic strategy for major depressive disorder.Keywords: depression, BDNF, neurogenesis, inflammatory cytokine, oxidative stress

He-xiang Zong, Sheng-qian Xu, Jian-xiong Wang, Yi-ran Chu, Ke-ming Chen, Cong Wang, Wan-qiu Tong, Xi-le Wang Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, People’s Republic of ChinaCorrespondence: Sheng-qian Xu, Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, No. 218, Ji-xi Road, Hefei, Anhui, 230022, People’s Republic of China, Tel +86 551 62922261, Fax +86 551 62923040, Email xsqian-1112@163.comPurpose: Non-steroidal anti-inflammatory drugs (NSAIDs) have generally been viewed as first-line therapy for axial spondyloarthritis (axSpA). Imrecoxib is a selective COX-2 inhibitor developed independently in China. At present, only one single-center RCT trial has shown that imrecoxib is equally effective as celecoxib in treating axSpA. Based on real-world data, our study aims to explore the efficiency of imrecoxib and TNF inhibitor (TNFi) combined with imrecoxib in treating axSpA.Patients and Methods: A total of 163 patients with axSpA who had more than two follow-up records in 6 months and treated with imrecoxib/celecoxib/TNFi combined with imrecoxib/TNFi combined with celecoxib from the First Affiliated Hospital of Anhui Medical University SpA Real World Database (AHSpA) were selected for analysis of our study. The linear mixed model was used to compare efficacy indexes before and after treatment and between different groups, adjust baseline measurement value and follow-up time. The Kaplan–Meier survival analysis was used to identify the differences in cumulative clinical remission rates between groups with different treatment at the follow-up period.Results: Results showed that after treatment ASDAScrp was slightly improved in imrecoxib group and celecoxib group within 6 months (p < 0.05). CRP, ESR, BASDAI, ASDAScrp, BASFI, occiput to wall distance and finger floor distance all significantly improved in TNFi combined with imrecoxib group and TNFi combined with celecoxib group within 6 months (all p < 0.05). According to the Kaplan–Meier survival curve and Log rank test analysis, the clinical remission rate was not significantly different between different treatment during 24-month follow-up (all p > 0.05).Conclusion: ASDAScrp improved slightly within 6 months after treatment with imrecoxib, and TNFi combined with imrecoxib significantly improved multiple effect indexes in axSpA patients. The efficacy of imrecoxib and celecoxib in the treatment of axSpA is equivalent. Also, they have the same efficacy after being combined with TNFi.Keywords: axial spondyloarthritis, imrecoxib, celecoxib, TNF inhibitor

Dao-Fang Ding,1,2,&ast; Yan Xue,3,&ast; Xi-Chen Wu,1,2,&ast; Zhi-Heng Zhu,1,2 Jia-Ying Ding,1,2 Yong-Jia Song,1,2 Xiao-Ling Xu,4 Jian-Guang Xu1,2 1Center of Rehabilitation Medicine, Yueyang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China; 2School of Rehabilitation Science, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China; 3Shanghai Yangzhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Centre), Tongji University, Shanghai, People’s Republic of China; 4Shulan International Medical College, Zhejiang Shuren University, Hangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiao-Ling Xu, Shulan International Medical College, Zhejiang Shuren University, 8 Shuren Street, Hangzhou, 310015, People’s Republic of China, Email ziyao1988@zju.edu.cn Jian-Guang Xu, Center of Rehabilitation Medicine, Yueyang Hospital, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, 200000, People’s Republic of China, Email xjg@shutcm.edu.cnAbstract: Osteoarthritis (OA) is an inflammatory and degenerative joint disease with severe effects on individuals, society, and the economy that affects millions of elderly people around the world. To date, there are no effective treatments for OA; however, there are some treatments that slow or prevent its progression. Polyfunctional nanosystems have many advantages, such as controlled release, targeted therapy and high loading rate, and have been widely used in OA treatment. Previous mechanistic studies have revealed that inflammation and ROS are interrelated, and a large number of studies have demonstrated that ROS play an important role in different types of OA development. In this review article, we summarize third-generation ROS-sensitive nanomaterials that scavenge excessive ROS from chondrocytes and osteoclasts in vivo. We only focus on polymer-based nanoparticles (NPs) and do not review the effects of drug-loaded or heavy metal NPs. Mounting evidence suggests that polyfunctional nanosystems will be a promising therapeutic strategy in OA therapy due to their unique characteristics of being sensitive to changes in the internal environment.Keywords: polyfunctional nanosystems, osteoarthritis, reactive oxygen species, chondrocytes, osteoclasts

Rong-Yun Mai,1,2 Tao Bai,1 Xiao-Ling Luo,2 Guo-Bin Wu1 1Department of Hepatobiliary & Pancreatic Surgery, Guangxi Medical University Cancer Hospital, Nanning, 530021, People’s Republic of China; 2Department of Experimental Research, Guangxi Medical University Cancer Hospital, Nanning, 530021, People’s Republic of ChinaCorrespondence: Guo-Bin Wu; Xiao-Ling Luo, Email wuguobin@gxmu.edu.cn; luoxiaoling67@126.comBackground: Accurate preoperative estimation of liver function reserve is the key to the safety of hepatectomy. Recently, indocyanine green retention test at 15 minutes (ICG-R15) has been widely used to estimate hepatic function reserve in different liver diseases. The purpose of this research was to investigate the clinical value of ICG-R15 in predicting postoperative major complications and severe posthepatectomy liver failure (PHLF) in patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) subjected to hepatectomy.Methods: A total of 354 HBV-associated HCC patients who underwent hepatectomy were enrolled. The Child–Pugh, model for end-stage liver disease (MELD), albumin–bilirubin (ALBI) and ICG-R15 for assessing postoperative complications risk were compared using receiver operating characteristic (ROC) curve and decision curve analysis (DCA).Results: Postoperative major complications developed in 32 patients (9.1%) and severe PHLF developed in 57 (16.1%) patients. Multivariate analyses revealed that ICG-R15 were independent factors for predicting postoperative major complications and severe PHLF. ROC curve analyses and DCA plots showed that the predictive abilities of ICG-R15 for postoperative major complications and severe PHLF risk was significantly greater than Child–Pugh, MELD, and ALBI scores. Similar results were obtained by stratifying different background subgroups. Then, patients were divided into three different risk cohorts, emphasizing the significantly discrepancy between the incidence of postoperative major complications and severe PHLF.Conclusion: Compared with Child–Pugh, MELD and ALBI scores, ICG‐R15 revealed significantly advantages in predicting postoperative major complications and severe PHLF in HBV-related HCC patients subjected to liver resection.Keywords: hepatocellular carcinoma, hepatitis B virus, postoperative major complications, posthepatectomy liver failure, indocyanine green retention test

Qing-Xia Wang,1 Jiao Xue,1 Mei-Jie Shi,2 Yu-Bao Xie,2 Huan-Ming Xiao,2 Sheng Li,2 Ming Lin,2 Xiao-Ling Chi2 1The Second School of Clinical Medicine, Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; 2Department of Hepatology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, People’s Republic of ChinaCorrespondence: Xiao-Ling Chi, Department of Hepatology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, People’s Republic of China, Tel +86+39318398, Fax +86-020-81867705, Email chixiaolingqh@163.comBackground: Metabolic dysfunction-associated fatty liver disease (MAFLD) is a novel proposed concept that is being recognized worldwide. Both chronic hepatitis B (CHB) and MAFLD have been independently attributed to an increased risk of disease development to cirrhosis. However, it is still unclear whether MAFLD is associated with an increased risk of cirrhosis in CHB patients.Aim: This study aimed to analyze the impact of MAFLD on the risk of cirrhosis in CHB patients.Methods: In this retrospective cohort study, consecutive CHB patients with or without MAFLD were enrolled from January 1st, 2007, to May 1st, 2020, in Guangdong Provincial Hospital of Chinese Medicine. Inverse probability treatment weighting (IPTW) was performed to balance the covariates across groups. The weighted Kaplan–Meier analysis and Cox regression analysis were used to compare both groups for the risk of cirrhosis.Results: A total of 1223 CHB patients were included in this study during the median follow-up of 5.25 years; of these patients, 355 were CHB-MAFLD patients. After IPTW, the weighted Kaplan–Meier analysis showed that the weighted cumulative incidence of cirrhosis was significantly higher in patients with MAFLD than that in patients without MAFLD (12.6% versus 7.1%, P=0.015). In the weighted multivariate Cox analysis, coexisting MAFLD was related to an increased risk of cirrhosis [adjusted weighted hazard ratio (HR) 1.790; P =0.020]. Age (> 40 years, adjusted weighted HR, 1.950; P=0.015), diabetes mellitus (adjusted weighted HR, 1.883; P=0.041), non-antiviral treatment (adjusted weighted HR, 2.037; P=0.013), and baseline serum HBV DNA levels (> 2.4 log10 IU/mL, adjusted weighted HR, 1.756; P=0.045) were significant risk factors for cirrhosis.Conclusion: We found that MAFLD was associated with a higher risk of cirrhosis in CHB patients.Keywords: chronic hepatitis B, metabolic dysfunction-associated fatty liver disease, hepatic steatosis, cirrhosis

An-Ran Shen,1 Xiao-Xiao Jin,2 Tao-Tao Tang,1 Yan Ding,2 Xiao-Tao Liu,2 Xin Zhong,1 Yan-Dan Wu,2 Xue-Lian Han,3 Guang-Yu Zhao,3 Chuan-Lai Shen,2 Lin-Li Lv,1 Bi-Cheng Liu1 1Institute of Nephrology, Zhongda Hospital, Medical School of Southeast University, Nanjing, 210009, People’s Republic of China; 2Department of Microbiology and Immunology, Medical School of Southeast University, Nanjing, 210009, People’s Republic of China; 3State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, 100071, People’s Republic of ChinaCorrespondence: Lin-Li Lv; Bi-Cheng Liu, Institute of Nephrology, Zhongda Hospital, Medical School of Southeast University, Nanjing, 210009, People’s Republic of China, Tel +862583272512, Email lvlinli@seu.edu.cn; liubc64@163.comPurpose: Current vaccines for the SARS-CoV-2 virus mainly induce neutralizing antibodies but overlook the T cell responses. This study aims to generate an exosomal vaccine carrying T cell epitope peptides of SARS-CoV-2 for the induction of CD8+ T cell response.Methods: Thirty-one peptides presented by HLA-A0201 molecule were conjugated to the DMPE-PEG-NHS molecules, and mixed with DSPE-PEG to form the peptide-PEG-lipid micelles, then fused with exosomes to generate the exosomal vaccine, followed by purification using size-exclusion chromatography and validation by Western blotting, liquid nuclear magnetic resonance (NMR) test and transmission electron microscopy. Furthermore, the exosomal vaccine was mixed with Poly (I:C) adjuvant and subcutaneously administered for three times into the hybrid mice of HLA-A0201/DR1 transgenic mice with wild-type mice. Then, the epitope-specific T cell responses were detected by ex vivo ELISPOT assay and intracellular cytokine staining.Results: The exosomal vaccine was purified from the Peak 2 fraction of FPLC and injected into the hybrid mice for three times. The IFN-γ spot forming units and the frequencies of IFN-γ+/CD8+ T cells were 10– 82-fold and 13– 65-fold, respectively, higher in the exosomal vaccine group compared to the Poly (I:C) control group, without visible organ toxicity. In comparison with the peptides cocktail vaccine generated in our recent work, the exosomal vaccine induced significantly stronger T cell response.Conclusion: Exosomal vaccine loading T cell epitope peptides of SARS-CoV-2 virus was initially generated without pre-modification for both peptides and exosomes, and elicited robust CD8+ T cell response in HLA-A transgenic mice.Graphical Abstract: Keywords: the severe acute respiratory syndrome coronavirus-2, exosomal vaccine, T cell, epitope, human leukocyte antigen-A

Peng Guo,1 Rui Li,2 Tie Hua Piao,3 Chun Lan Wang,3 Xiao Lu Wu,3 Hong Yan Cai3 1College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, Changchun, 130000, People’s Republic of China; 2Graduate School, Beijing University of Chinese Medicine, Beijing, 100000, People’s Republic of China; 3Pulmonology Department, The First Clinical Hospital of Jilin Academy of Traditional Chinese Medicine, Changchun, 130000, People’s Republic of ChinaCorrespondence: Hong Yan Cai, The First Clinical Hospital of Jilin Academy of Traditional Chinese Medicine, Changchun, 130000, People’s Republic of China, Email 774009408@qq.comAbstract: Chronic obstructive pulmonary disease (COPD) includes chronic bronchitis, emphysema, and small airway obstruction. Incompletely reversible airflow limitation, inflammation, excessive mucus secretion and bronchial mucosal epithelial lesions are the main pathological basis of the disease. The prevalence of COPD is increasingly worldwide, which has caused the burden on individuals and society. This paper summarizes the pathogenesis of COPD and clarifies the effect and mechanism of the latest targeted drugs for COPD. Besides, we focus on NOD-like receptor thermal protein domain associated protein 3 inflammasome (NLRP3 inflammasome). NLRP3 can promote production of interleukin-1β (IL-1β) and interleukin-18 (IL-18). NLRP3 is an important factor in the migratory aggregation of macrophages and neutrophils and the generation of oxidative stress. Inhibition of NLRP3 inflammasome indirectly blocks the inflammatory effects of IL-1β and IL-18, which may be regarded as an ideal target for COPD treatment.Keywords: chronic obstructive pulmonary disease, pathogenesis, targeted drugs, NLRP3

Jiao Xue,1 Qing-Xia Wang,1 Huan-Ming Xiao,2 Mei-Jie Shi,2 Yu-Bao Xie,2 Sheng Li,2 Ming Lin,2 Xiao-Ling Chi2 1The Second School of Clinical Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, People’s Republic of China; 2Department of Hepatology, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, 510120, People’s Republic of ChinaCorrespondence: Xiao-Ling Chi, Department of Hepatology, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Dade Road 111, Guangzhou, 510120, People’s Republic of China, Tel +86+39318398, Fax +86-020-81867705, Email chixiaolingqh@163.comPurpose: Both metabolic dysfunction-associated fatty liver disease (MAFLD) and hepatitis B virus (HBV) are risk factors for hepatocellular carcinoma (HCC). Although concurrent MAFLD is common in patients with HBV-related HCC, whether MAFLD increases the risk of poor prognosis in patients with HBV-related HCC remains unclear. This study aimed to investigate the impact of MAFLD on prognosis in patients with HBV-related HCC.Patients and Methods: In this retrospective cohort study, 549 patients with HBV-related HCC were enrolled from January 2010 to April 2020 in Guangdong Provincial Hospital of Chinese Medicine, including 169 patients with MAFLD (MAFLD group) and 380 patients without MAFLD (Non-MAFLD group). Propensity score matching (PSM) analysis was performed to balance the baseline characteristics. Kaplan–Meier survival curves were performed to compare the prognosis between the two matched groups. A multivariate Cox proportional hazards model was used to determine the risk factors for poor prognosis.Results: The median follow-up time for all patients was 20 (interquartile range 8– 40) months. We found concurrent MAFLD was associated with a significantly decreased PFS rate before and after PSM analysis. The 1-year, 2-year, and 3-year PFS rates for the MAFLD and Non-MAFLD groups after PSM were 61.3% and 70.8%, 43.9% and 54.5%, 31.1% and 41.8%, respectively. Cox multivariable analysis showed that concurrent MAFLD was an independent risk factor for poor prognosis (death or progression) (HR = 1.49, P = 0.001). More interestingly, the risk of poor prognosis was significantly higher in the MAFLD subtype with metabolic components ≥ 2 compared to those with metabolic components < 2 (HR = 1.97, P < 0.001).Conclusion: Concurrent MAFLD was associated with a higher risk of poor prognosis in patients with HBV-related HCC, especially MAFLD with metabolic components ≥ 2.Keywords: hepatocellular carcinoma, hepatitis B virus, metabolic dysfunction-associated fatty liver disease, poor prognosis

Xiao-Lan Li,1 Chun-Yan Luan,1 Ying-Jun Fan,2 Xiao-Ying Lin,1 Dong Jiang,1 Mei-Xian Su,3 Gang Wang,4 Xu Yang5 1Department of Dermatology, The Second Affiliated Hospital of Kunming Medical University, Kunming, 650101, People’s Republic of China; 2Department of Rheumatology, The Second Affiliated Hospital of Kunming Medical University, Kunming, 650101, People’s Republic of China; 3Department of Emergency Critical Care Medicine, The Second Affiliated Hospital of Kunming Medical University, Kunming, 650101, People’s Republic of China; 4Department of Intensive Care Unit, The Second Affiliated Hospital of Kunming Medical University, Kunming, 650101, People’s Republic of China; 5Laboratory Bacteria Room, The Second Affiliated Hospital of Kunming Medical University, Kunming, 650101, People’s Republic of ChinaCorrespondence: Xiao-Lan Li, Department of Dermatology, The Second Affiliated Hospital of Kunming Medical University, No. 374 of Dian-Mian Avenue, Wu-Hua District, Kunming, 650101, People’s Republic of China, Tel +86 871 63402212, Fax +86 871 65334416, Email lixiaolan880923@163.comBackground: Purpura fulminans (PF), a rare, life-threatening disorder, is a hematological emergency in which there is skin necrosis, disseminated intravascular coagulation (DIC), and protein C deficiency. In PF, the skin necrosis and DIC are secondary to protein C deficiency. This may progress rapidly to multiorgan failure caused by the thrombotic occlusion of small- and medium-sized blood vessels.Case Report: This article presents the case of a 22-year-old male with fever as well as necrotic and purpuric skin lesions. The ultrasound and computed tomography scans revealed infections in the skin wounds as well as venous microthrombosis and thrombosis in multiple intracranial and pulmonary vessels. The laboratory tests showed signs of sepsis, thrombocytopenia, an abnormal decrease in protein C and antithrombin III, DIC, multiple organ and system failures, gastric varices, and gastrointestinal hemorrhage. The blood, sputum, and secretions under the skin lesions were cultured and were positive for Klebsiella pneumoniae. The results of the high-throughput genetic testing of the pathogenic microorganism DNA were consistent. In addition, human herpesvirus type 5 was detected. The histopathological examination of the skin lesions revealed pathological features consistent with PF. After successful treatment by the departments of Dermatology, Emergency Critical Care Medicine, and the Intensive Care Unit, the patient was discharged after 67 days of hospitalization.Conclusion: Adults with acquired protein C and/or S deficiency states, including certain bacterial and viral infections, who drink alcohol and take varieties of non-steroidal anti-inflammatory analgesics at the same time, may develop acute infectious PF. Clinicians should be aware of this for early diagnosis and treatment.Keywords: acute infectious purpura fulminans, Klebsiella pneumoniae, human herpesvirus type 5, disseminated intravascular coagulation, multiple organ and system failures

Chang Xu,1 Kai Cheng,1 Xiao-Ling Wu,1 Heng Yap Tai,1 Ye-Mao Chai,1 Zhi-Wen Yang,1 Qian-Hui Sun,1 Xing-Hua Qiu,1 Xing-Yue Yang,1 Na Li,1 Yan Tan,2 Shao-Ming Liu,3 Wei Chen4 1College of Acupuncture-Moxibustion and Tuina, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 2School of Life Sciences, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 3Dongfang Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 4Innovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, People’s Republic of ChinaCorrespondence: Na Li, Beijing University of Chinese Medicine, 11 Bei San Huan Dong Lu, Chaoyang District, Beijing, People’s Republic of China, Tel +86 15210722947, Email 201901035@bucm.edu.cnPurpose: We aim to explore expression profiles of genes in SCDH of CPPS model rat relevant to pain and inflammation by RNA-Seq and to investigate the mechanism of anti-inflammatory and analgesic of EA.Methods: Thirty-six SD male rats were randomly divided into three groups (n = 12): sham operation, model, and EA. The rat CPPS model was established by injecting CFA into the ventral lobes of the prostate. The rats in EA group were treated at Guanyuan (CV4), Zhongji (CV3), Sanyinjiao (SP6) and Huiyang (BL35) for a total of 20 times, with a frequency of 2/100Hz. Mechanical allodynia, H&E staining and ELISA were used to detect the changes of pain threshold and tissue inflammation; RNA-Seq technique was used for profiling gene changes in SCDH and qRT-PCR was used for further validation.Results: Persistent mechanical allodynia and severe tissue inflammatory reaction both occurred in CPPS rats. After EA therapy, the pain sensitivity and inflammatory response of CPPS rats decreased significantly. RNA-Seq identified that a total of 46 DEGs were significantly up-regulated and 65 DEGs down-regulated after EA. GO enrichment showed that EA was mainly reflected in the regulation of the immune system by participating in the regulation of leukocyte, neutrophil cellular processes and cytokine metabolism. KEGG enrichment demonstrated that signal transduction and immune system were the most significant pathways. We further identified that the expressions of Pik3r2, Akt1, and Casp9 were significantly up-regulated and Jak2 and Stat3 down-regulated in the PI3K-AKT/JAK-STAT signal pathway.Conclusion: Our study revealed that immune and inflammatory responses are the main biological events that induce chronic pelvic pain in rats, and EA can exert anti-inflammatory and analgesic effects by regulating the expression of related genes on PI3K-AKT/JAK-STAT signal pathway in SCDH. This study provided putative novel targets of EA, which may have anti-inflammatory and analgesic effects of CPPS.Keywords: electroacupuncture therapy, chronic pelvic pain, anti-inflammatory and analgesia, RNA-seq technique, cytokine, spinal cord dorsal horn

Xiao-Wei Fan,1– 4,&ast; Yang Yang,2– 5,&ast; Shuo Wang,2– 5 Yi-Jun Zhang,1– 4 An-Xin Wang,1– 4 Xiao-Ling Liao,1– 4 Wei-Guo Ma,6 Ning Zhang,2– 5 Chun-Xue Wang,2– 5,7 Yong-Jun Wang1– 4 1Department of Neurology, Capital Medical University, Beijing, People’s Republic of China; 2Center of Stroke, Beijing Institute for Brain Disorders, Beijing Tiantan Hospital, Capital Medical University, Beijing, People’s Republic of China; 3China National Clinical Research Center for Neurological Diseases, Beijing, People’s Republic of China; 4Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing Tiantan Hospital, Capital Medical University, Beijing, People’s Republic of China; 5Department of Neuropsychiatry and Behavioral Neurology and Clinical Psychology, Capital Medical University, Beijing, People’s Republic of China; 6Beijing Anzhen Hospital, Capital Medical University, Beijing, People’s Republic of China; 7Beijing Institute of Brain Disorders, Collaborative Innovation Center for Brain Disorders, Capital Medical University, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ning Zhang; Chun-Xue Wang, Beijing Tiantan Hospital, 119 South 4th Ring West Road, Beijing, 100070, People’s Republic of China, Tel +86-15801203052 ; +86-13701193710, Email 827582777@qq.com; snowsen@126.comPurpose: The impact of poor sleep quality after stroke, especially persistent poor sleep quality, on poststroke anxiety and depression is unclear. We seek to investigate the impact of baseline and persistent poor sleep quality on short-term poststroke anxiety and depression.Patients and Methods: Data were analyzed for 1619 patients with acute ischemic stroke from the Impairment of Cognition and Sleep after Acute Ischemic Stroke or Transient Ischemic Attack in Chinese Patients study (ICONS). The sleep quality was assessed at 2 weeks and 3 months using the Pittsburgh Sleep Quality Index scale (PSQI). Poor sleep quality was defined as a PSQI score of > 5, and persistent poor sleep quality was defined as a PSQI score of > 5 at each time point. Patients were divided into three groups according to the quality of sleep: good sleep quality, baseline poor sleep quality and persistent poor sleep quality. Patient Health Questionnaire-9 (PHQ-9), General Anxiety Disorder-7 scale (GAD-7), and Modified Rankin Scale (mRS) at 3 months after stroke were taken as the study outcomes.Results: Persistent poor sleep quality was present in 70.2% of patients after stroke. Compared to those with good sleep quality, patients with baseline poor sleep quality did not show significant differences in disability, anxiety and depression. However, patients with persistent poor sleep were at increased risk of depression (odds ratio, OR 3.04, 95% confidence interval, CI 1.66– 5.57, P < 0.01) and anxiety (OR 3.20, 95% CI 1.42– 7.19, P < 0.01) at 3 months after stroke. Persistent poor sleep quality was not identified as a risk factor for functional disability at 3 months.Conclusion: Patients with persistent poor sleep quality are at added risks for depression and anxiety after stroke.Keywords: sleep quality, depression, anxiety, ischemic stroke

Jie Jia,1,2 Ji-Qun Yang,3 Ying-Rong Du,3 Yu Xu,2 Deshenyue Kong,1,2 Xiu-Ling Zhang,3 Jun-Hong Mao,1,2 Gui-Fang Hu,3 Kun-Hua Wang,1,2,4 Yi-Qun Kuang1,2 1NHC Key Laboratory of Drug Addiction Medicine, First Affiliated Hospital of Kunming Medical University, Kunming Medical University, Kunming, 650032, People’s Republic of China; 2Scientific Research Laboratory Center, First Affiliated Hospital of Kunming Medical University, Kunming, 650032, People’s Republic of China; 3Third People’s Hospital of Kunming City/Drug Rehabilitation Hospital of Kunming City, Kunming, 650041, People’s Republic of China; 4School of Medicine, Yunnan University, Kunming, 650500, People’s Republic of ChinaCorrespondence: Yi-Qun Kuang; Kun-Hua Wang, NHC Key Laboratory of Drug Addiction Medicine, First Affiliated Hospital of Kunming Medical University, Kunming Medical University, Kunming, 650032, People’s Republic of China, Email yq610433@hotmail.com; wangkunhua1964@126.comBackground: Hypertension is a common complication in injection drug users (IDU), especially a high proportion of resistant hypertension occurs among them. However, the involving mechanisms remain largely unknown.Methods: We here investigated the key signaling moieties in resistant hypertension in drug users. Analyses were performed with high-throughput transcriptomic sequencing data of peripheral blood from individuals with drug-sensitive hypertension (Ctrl-DS), IDU with resistant hypertension (IDU-DR), and IDU with sensitive hypertension (IDU-DS).Results: We showed that 17 and 1 genes in IDU-DS, 48 and 4 genes in IDU-DR were upregulated and downregulated compared Ctrl-DS, and 2 and 4 genes were upregulated and downregulated in IDU-DR compared with IDU-DS, respectively (p ≤ 0.01 and |log2(FC)| ≥ 1). Differentially expressed genes (DEGs) between Ctrl-DS and IDU-DS were mainly involved in Gene ontology terms of immunoglobulin complex and blood microparticle. DEGs between IDU-DS and IDU-DR were mainly involved in immune system process and immunoglobulin complex. DEGs between Ctrl-DS and IDU-DR were mainly involved in immunoglobulin complex, blood microparticle and cytoplasmic vesicle lumen. We identified 2 gene clusters (brown modules, MEbrown; turquoise module, MEturquoise) correlated with IDU-DR and a gene cluster (magenta module, MEmagenta) correlated with IDU-DS by weighted gene co-expression network analysis (WGCNA). Functional analysis demonstrated that pathways of focal adhesion and focalin-1-rich granule lumen were involved in the development of IDU-DR, and the cytosolic large ribosomal subunit may relate to IDU-DR. Further, immune cell infiltration analysis demonstrated that the abundance of dendritic cells (DCs), natural Treg cells (nTreg), and exhausted T cells (Tex) in IDU-DR and IDU-DS, naïve CD8+ T cells in IDU-DS was significantly different compared with that in Ctrl-DS. The abundance of cytotoxic T cells (Tc) was significantly different between IDU-DS and IDU-DR.Conclusion: Our findings indicated a potential function of immunoregulation mechanisms for resistant hypertension.Keywords: drug use, hypertension, treatment-resistant, transcriptome, immunoregulation

Yi-Can Yang,1 Meng-Yu Zhang,1 Jian-Yu Liu,1 Yuan-Yuan Jiang,2 Xiu-Li Ji,3 Yi-Qing Qu2 1Department of Pulmonary and Critical Care Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University; Shandong Key Laboratory of Infectious Respiratory Diseases, Jinan, People’s Republic of China; 2Department of Pulmonary and Critical Care Medicine, Qilu Hospital of Shandong University; Shandong Key Laboratory of Infectious Respiratory Diseases, Jinan, People’s Republic of China; 3Department of Pulmonary Disease, Jinan Traditional Chinese Medicine Hospital, Jinan, People’s Republic of ChinaCorrespondence: Yi-Qing Qu, Department of Pulmonary and Critical Care Medicine, Qilu Hospital, Shandong University, Shandong Key Laboratory of Infectious Respiratory Diseases, Wenhuaxi Road 107#, Jinan, 250012, People’s Republic of China, Tel +86 531 8216 9335, Fax +86 531 8296 7544, Email quyiqing@sdu.edu.cnPurpose: Ferroptosis and immune infiltration are involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). We aim to identify ferroptosis-related hub genes and analyze their association with immune infiltration in COPD through bioinformatics methods.Materials and Methods: The mRNA microarray data of GSE38974 were downloaded from Gene Expression Omnibus to obtain differentially expressed genes (DEGs). The DEGs were intersected with ferroptosis-related genes (FRGs) from FerrDb to obtain differentially expressed FRGs. GO and KEGG enrichment and protein–protein interaction (PPI) analyses of differentially expressed FRGs were conducted in R software and STRING database. The key module and hub genes were screened by Cytoscape software. MiRNAs, transcription factors and signal molecules were predicted in miRNet and NetworkAnalyst. The disease correlation in the Comparative Toxicomics Database (CTD) and the receiver operating characteristic (ROC) curves of hub genes were analyzed. Immune infiltration was evaluated by CIBERSORT algorithm. Spearman correlation analyses were conducted between hub genes and differentially infiltrated immune cells.Results: Fifteen differentially expressed FRGs were identified, which were enriched in some terms involving airway inflammatory responses and structural remodeling. Five hub genes were selected including HIF1A, IL6, PTGS2, CDKN1A and ATM. Inference scores in CTD indicated their association with COPD. Two miRNAs, five transcription factors and one signal molecule were predicted. The combination of hub genes could be a fine diagnostic indicator of COPD (AUC: 0.981, CI: 0.940-1.000). Immune infiltration evaluation showed that monocytes and M0 macrophages were upregulated in COPD lung tissues, while CD8 T cells, activated NK cells, M2 macrophages, resting dendritic cells and resting mast cells were downregulated. The hub genes were significantly associated with differentially infiltrated immune cells.Conclusion: We identified five ferroptosis-related hub genes (HIF1A, IL6, PTGS2, CDKN1A and ATM) in COPD, and found that they may influence the pathogenesis of COPD by regulating ferroptosis and thus affecting infiltrating immune cells.Keywords: COPD, ferroptosis, immune infiltration, bioinformatics

Jiang-Nan Zhang, Xi-Le Zhao Department of Endocrinology, The First Hospital of Fuzhou, Fuzhou, 350009, People’s Republic of ChinaCorrespondence: Jiang-Nan Zhang, Department of Endocrinology, The First Hospital of Fuzhou, No. 190 of DaDao Street, Taijiang District, Fuzhou, 350009, People’s Republic of China, Tel +86 13763892689, Email jiangnanzzhang@163.comObjective: To retrospectively analyze the changes of thyroid function and related factors in critical patients with non-thyroid illness, hoping to find some indicators for the further examination of the thyroid function in the intensive care unit situation.Methods: The clinical data of 52 patients admitted to the ICU of Fuzhou First Hospital in Fujian Province, China, from May 2018 to March 2019 were collected. Patients were allocated into the central hypothyroidism group (CH group, n = 21) and the low T3 syndrome group (LT3S group, n = 31) based on thyroid function. All related medical data were collected, and the correlations between variables were identified using Spearman’s or Pearson’s rank correlation coefficients.Results: The Acute Physiology and Chronic Health Evaluation (APACHE) II score in the CH group and the LT3S group were 20.6 ± 3.6 and 19.3 ± 3.6, respectively, measured within 24 hours following hospital admission. The mean value of thyroid-stimulating hormone (TSH) in the CH group (0.3 ± 0.3 IU/mL) was significantly lower than that in the LT3S group (1.7 ± 0.9 IU/mL), P < 0.001. Fasting plasma glucose (FPG) level in the CH group was significantly higher than that in the LT3S group (10.3 ± 5.0 mmol/L vs 6.8 ± 2.5 mmol/L, P = 0.002).Conclusion: Central hypothyroidism may exist in critically ill patients and may be associated with elevated fasting plasma glucose levels; accordingly, it should be included as part of patient assessment. When FPG is higher than 6.4mmol/L on admission, thyroid function should be actively examined.Keywords: central hypothyroidism, fasting blood glucose, critical illness, thyroid-stimulating hormone

Chu-Yun Cheng,1 Guan-Yin Zeng,1 Tong Wang,1 Yan-Hua Su,1 Feng-Dan Xu,2 Hong Luo,1 Hui-Ting Zhong,1 Xiu-Lan Chen1 1Department of Obstetrics, Dongguan Eighth People’s Hospital (Dongguan Children’s Hospital), Dongguan, Guangdong, 523325, People’s Republic of China; 2Department of Neonatal Clinic, Dongguan Eighth People’s Hospital (Dongguan Children’s Hospital), Dongguan, Guangdong, 523325, People’s Republic of ChinaCorrespondence: Chu-Yun Cheng, Department of Obstetrics, Dongguan Eighth People’s Hospital (Dongguan children’s Hospital), No. 68, West Lake 3rd Road, Shilong Town, Dongguan, Guangdong, 523325, People’s Republic of China, Tel +86 13688988412, Email chChu-Yun@126.comObjective: This study aimed to investigate the ability of serum cholic acid (CA) and lithocholic acid (LCA) in the diagnosis and perinatal prognosis assessment of intrahepatic cholestasis of pregnancy (ICP), and the relationship between both indicators and hypoxia-inducible factor-1α (HIF-1α).Methods: Between March 2020 and March 2021, pregnant women with high levels of total bile acid (TBA) in the late pregnancy with TBA ≥ 10 μmol/L and TBA < 10 μmol/L (control group) were included for the retrospective study. Those with TBA ≥ 10 μmol/L were divided into the ICP group and the asymptomatic hypercholanaemia of pregnancy (AHP) group based on ICP symptoms. The comparison of the bile acid profiles, the receiver operating characteristic (ROC) curve analysis, and Pearson correlation analysis were conducted successively.Results: Nine types of bile acids were significantly higher in ICP and AHP than in the control group, while CA and LCA serum levels in the AHP group were significantly lower than those in the ICP group (P < 0.05). The ROC curve analysis showed that LCA, CA, and LCA+CA were all diagnostic indicators for ICP, and LCA+CA displayed the greatest diagnostic value (area under the curve (AUC), 0.923). Subgroup analysis using the LCA+CA cut-off point (3.28 μmol/L) as the subgroup indicator proved that the incidence of adverse perinatal outcomes and the placental HIF-1α positivity were significantly higher in the high LCA+CA group than in the low LCA+CA group (P < 0.05). Pearson correlation analysis revealed significant positive correlations of HIF-1α expression levels to LCA, CA and LCA+CA (r = 0.473, 0.537, 0.619, respectively. P < 0.05 in all).Conclusion: This study confirmed that CA and LCA have a predictive diagnostic value for ICP in pregnant women, and the combined evaluation is associated with adverse perinatal outcomes, and LCA+CA positively correlates to placental HIF-1α expression levels.Keywords: cholic acid, lithocholic acid, intrahepatic cholestasis of pregnancy, hypoxia-inducible factor-1&#x03B1