Search

Ruidong Ma,* Wei Li,* Qiufeng Peng,* Ao Ren, Ling Zhao, Jiawei Li, Shiqiao Luo Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shiqiao Luo, Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Youyi Road 1st, Yuzhong District, Chongqing, 400016, People’s Republic of China, Tel +86-15002355050, Email 202065@hospital.cqmu.edu.cnPurpose: Prior research has suggested a correlation between gallstones and depressive symptoms, yet the specifics of this relationship remain unclear. This study aims to explore the association between gallstones and depressive symptoms among adults.Patients and Methods: Initially, we conducted a cross-sectional study using data from the National Health and Nutrition Examination Survey (NHANES) 2017 – March 2020. After propensity score matching (PSM) for participants with gallstones and those without gallstones, multivariate logistic regression analysis was used to explore the potential association between gallstones and depressive symptoms. This was followed by Mendelian randomization (MR) analysis to further elucidate the causal relationship between them. Using the genome-wide association study database, we extracted instrumental variables and performed bidirectional univariate and multivariate MR analyses.Results: In the cross-sectional study of NHANES 2017 – March 2020, 835 pairs of participants with comparable characteristics, both with and without gallstones, were identified after PSM. The multivariate adjusted logistic regression analyses revealed a significant association between gallstones and depressive symptoms [fully adjusted model: OR=1.821 (95% CI, 1.181– 2.808), P=0.007]. Subsequent MR analyses further clarified the causal relationship, indicating that genetically determined gallstones significantly increase the risk of developing depressive symptoms [forward univariate MR analysis: OR=1.04 (95% CI, 1.01– 1.06), P=0.002; multivariate MR analysis: OR=1.03 (95% CI, 1.01– 1.05), P=0.009], with no evidence of reverse causation [inverse univariate MR analysis: OR=1.28 (95% CI, 0.90– 1.83), P=0.17].Conclusion: Gallstones are a risk factor for depressive symptoms among adults. Hence, we recommend timely depression screening for patients diagnosed with gallstones, facilitating early detection and effective treatment of depressive symptoms, thus alleviating its impact on both individuals and society.Keywords: depressive symptoms, gallstones, risk factor, causality, genetic analysis, cross-sectional study

Jing Li,1,2,&ast; Ganxiao Chen,1,&ast; Zhanxiong Xie,1 Jiayi Lin,1 Shunxiang Luo,1 Shanghua Xu1 1Department of Cardiology, Affiliated Nanping First Hospital, Fujian Medical University, Nanping, Fujian, People’s Republic of China; 2Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shanghua Xu; Shunxiang Luo, Department of Cardiology, Affiliated Nanping First Hospital of Fujian Medical University, Nanping, Fujian, People’s Republic of China, Email xushanghua@fjmu.edu.cn; luoshunxiang@fjmu.edu.cnPurpose: Flavonoids are naturally occurring compounds with diverse health-promoting properties. The purpose of this study was to explore the associations between dietary flavonoid intake and cardiovascular health in cancer survivors.Patients and Methods: We obtained data from the National Health and Nutrition Examination Survey (NHANES) 2007– 2008, 2009– 2010, and 2017– 2018 cycles. Weighted linear regression and restricted cubic spline (RCS) were used to explore the correlation between dietary flavonoid intake and cardiovascular health (Life’s Essential 8 (LE8) score) in cancer survivors. Then, weighted quantile sum (WQS) regression and quantile-based g-computation (qgcomp) models were performed to assess the mixed effects of the six flavonoid subclasses and to determine the major flavonoid types. Additionally, the protective effect of high flavonoid intake on cardiovascular health was further evaluated in different subgroups, and mediation analysis was used to explore mediating factors.Results: After adjusting for all covariates, compared to those in the first quartile, participants in the fourth quartile of total flavonoids, anthocyanidins, flavonols, flavanones, and flavones intake exhibited increases in LE8 scores of 3.24% (95% CI: 0.45– 6.03, P for trend=0.030), 6.25% (95% CI: 3.14– 9.36, P for trend< 0.001), 3.01% (95% CI: 1.33– 4.69, P for trend= 0.003), 3.23% (95% CI: 0.18– 6.27, P for trend=0.030), and 5.01% (95% CI: 2.42– 7.61, P for trend< 0.001), respectively. Meanwhile, significant non-linear relationships were supported by the RCS models. However, the weighted linear regression and RCS models did not reveal any clear correlations between isoflavone or flavan-3-ol intake and the LE8 score. Regarding mixed effects, anthocyanidin, flavonol, flavanone, and flavone intake were positively related to the LE8 score according to both the WQS and qgcomp models, and anthocyanidin intake was the major contributor.Conclusion: Our study indicated that dietary flavonoid intake is positively associated with cardiovascular health in cancer survivors, among which anthocyanidin intake might provide the most benefit. Keywords: weighted quantile sum, life’s essential 8 score, restricted cubic spline, NHANES

Zhu Y, Cheng M, Yang Z, et al. Drug Des Devel Ther. 2014;8:2449–2462. The authors have advised that figure parts 2E and 4B on pages 2454 and 2456, respectively, are incorrect. An error at the time of figure assembly led to the inadvertent duplication of images in both figures. The correct Figure 2 and 4 are shown below. Figure 2 Continued. Figure 2 Transduction of NK4 cDNA into human MSCs using a lentiviral vector and characterization.Abbreviations: GFP, green fluorescent protein; conc, concentration; HGF, hepatocyte growth factor; ANOVA, analysis of variance; rhHGF, recombinant human hepatocyte growth factor; MOI, multiplicity of infection; Mr, molecular weight; MSCs, mesenchymal stem cells; cDNA, complementary DNA.Notes: The recombinant pGC-FU-GFP-NK4-plasmids, the construction plasmids Helper1.0, and the envelope plasmids Helper2.0 (GeneChem Co., Ltd., Shanghai, People’s Republic of China) were first cotransfected into 293T cells. MSCs were then transduced with Lenti-NK4 (MSCs-NK4) or Lenti-GFP (MSCs-GFP) at varying multiplicity of infection (MOI). (A) Expression of GFP in MSCs observed at day three after Lenti-NK4 infection at MOI of 10, 20, 50, or 100 under fluorescence microscopy, (B) transduction efficiency of Lenti-NK4 in MSCs determined by flow cytometry with an GFP marker which was 87.8% of the enriched GFP-expressing MSC population upon sorting with an MOI of 50, (C) effect of transduction with Lenti-NK4 at different MOIs from 1 to 100 in MSCs on the production of NK4 in the culture medium, (D) effect of time on the production of NK4 in the culture medium after MSCs were transduced with Lenti-NK4 (MOI =50), Lenti-GFP (MOI =50), or not transduced, (E) MSCs-NK4 with increased GFP expression observed at different time points (MOI =50, from Day 1 to Day 3), and (F) Western blot analysis of NK4-GFP fusion protein with a molecular weight of 84 kDa. Recombinant human HGF (Mr =83 kDa) was used as a positive control. *P

Changjin Wang,1,&ast; Bangyuan Yang,1,&ast; Songyuan Luo,1 Shengneng Zheng,2 Yinghao Sun,1 Jiaohua Chen,1 Ruixin Fan,3 Jianfang Luo,1,&ast; Jie Li1,&ast; 1Department of Cardiology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, People’s Republic of China; 2Department of Radiology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, People’s Republic of China; 3Department of Cardiac Surgery, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jie Li; Jianfang Luo, Email leomoku1981@163.com; jianfangluo@sina.comBackground: The relationship between pulmonary hypertension (PH) and outcomes after transcatheter aortic valve replacement (TAVR) has been shown to be unfavorable. The impact of gender on TAVR outcomes remains controversial. There have been no studies evaluating the simultaneous effects of both factors on TAVR outcomes.Methods: We retrospectively analyzed a prospective cohort of patients who underwent TAVR between January 2016 and December 2022. The patients were stratified by gender and the presence of PH. The primary outcome of the study was all-cause mortality. Secondary outcome was a composite of all-cause mortality and heart failure hospitalization.Results: We identified a total of 133 female patients without PH, 179 males without PH, 87 females with PH, and 122 males with PH. The median follow-up period was 18 months. Female patients without PH demonstrated a lower cumulative mortality rate compared to those with male gender and/or PH. Adjusted multivariate Cox proportional hazard analyses revealed that male gender and PH status, either individually or in combination, were independently associated with long-term mortality when compared to female patients without PH. Specifically, females with PH (HR 6.80, 95% confidence interval (CI): 1.49– 31.12, P=0.013), males without PH (HR 6.45, 95% CI: 1.47– 28.22, P=0.013), and males with PH (HR 7.2, 95% CI: 1.63– 31.81, P=0.009) demonstrated significantly higher risk for mortality.Conclusion: Patients who were male or had PH status had a higher risk of mortality. However, there was no synergistic effect between being male and having PH on the prognosis after TAVR.Keywords: transcatheter aortic valve replacement, gender, pulmonary hypertension, outcome

You-Ran Liu,1,&ast; Yan Wang,2,&ast; Juan Chen,3 Shan Luo,2 Xiaomei Ji,1 Huadong Wang,4 Li Zhang1 1School of Nursing, Bengbu Medical University, Bengbu, People’s Republic of China; 2Department of Nursing, Tangshan Vocational & Technical College, Tangshan, People’s Republic of China; 3Department of Acupuncture and Rehabilitation, Hangzhou Hospital of Traditional Chinese Medicine, Hangzhou, People’s Republic of China; 4Department of Respiratory medicine, The First Affiliated Hospital of Bengbu Medical University, Bengbu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Li Zhang, Email 390026566@qq.comPurpose: This study aimed to identify the risk predictors of non-adherence to inhaler therapy and construct a nomogram prediction model for use in Chinese elderly patients with chronic obstructive pulmonary disease (COPD).Patients and Methods: A cross-sectional study was conducted with 305 participants recruited from a tertiary care hospital in Anhui, China. Adherence was analyzed using the Test of Adherence to Inhalers. Potential predictive factors were incorporated based on the social ecological model, and data were collected through a questionnaire method. R version 4.3.3 was utilized to perform the least absolute shrinkage and selection operator regression model and multivariable logistic regression analysis to identify risk factors and establish a nomogram prediction model.Results: The results of the multivariable analysis revealed that medication beliefs, illness perception, the COPD Assessment Test score, smoking status, and education level were significant risk factors for non-adherence to inhaler therapy in elderly COPD patients (all P < 0.05). The nomogram prediction model for non-adherence to inhaler therapy in elderly COPD patients demonstrated a good discriminative ability, with an area under the receiver operating characteristic curve of 0.912. The C-index was 0.922 (95% CI: 0.879 to 0.965), and the Brier value was 0.070, indicating good consistency and calibration. Decision curve analysis indicated that the use of the nomogram would be more beneficial in clinical practice when the threshold probability of non-adherence exceeds 17%.Conclusion: This study identified predictive factors regarding non-adherence among elderly patients with COPD and constructed a predictive nomogram. By utilizing the nomogram model healthcare professionals could swiftly calculate and comprehend the non-compliance level of COPD patients, thus guiding the development of personalized interventions in clinical practice.Keywords: chronic obstructive pulmonary disease, inhaler therapy, nomogram, non-adherence, social ecological model

Shangyu Luo,1 Xueqin Hu,2 Yunjun Hong,1 Yunchun Gao,1 Xianglin Liu,1 Yu Peng,1 Xueqing Tong,3 Xiaobo Zhang,1 Jun Wen1 1Department of Neurology, Changde Hospital, Xiangya School of Medicine, Central South University (The First People’s Hospital of Changde City), Changde City, Hunan Province, People’s Republic of China; 2Department of Neurosurgery, Changde Hospital, Xiangya School of Medicine, Central South University (The First People’s Hospital of Changde City), Changde City, Hunan Province, People’s Republic of China; 3Department of Brain Electrophysiology, Changde Hospital, Xiangya School of Medicine, Central South University (The first People’s hospital of Changde city), Changde City, Hunan Province, People’s Republic of ChinaCorrespondence: Xiaobo Zhang; Jun Wen, Fax +86 0736 7788009 ; +86 0736 7788010, Email 285058041@qq.com; cdwenjun1973@163.comPurpose: Research on post-stroke depression (PSD) following the lifting of coronavirus disease 2019 (COVID-19) restrictions remains sparse. This study aimed to investigate the factors associated with PSD after the easing of COVID-19 restriction measures.Patients and Methods: This cross-sectional study was conducted with 947 stroke patients (cerebral hemorrhage and cerebral infarction) meeting the inclusion criteria. Participants completed a demographic questionnaire and the Patient Health Questionnaire-9 (PHQ-9). Additionally, data were collected on C-reactive protein (CRP), homocysteine (Hcy), modified Rankin Scale (mRS), stroke site, National Institutes of Health Stroke Scale (NIHSS), thyroid-stimulating hormone (TSH), and the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) classification. This study assessed correlations between these indices and PSD.Results: Stroke patients with a PHQ-9 score ≥ 5 were identified as having PSD, with a prevalence rate of 14.15%. No significant correlation was found between previous COVID-19 infection and PSD. However, multiple regression analysis revealed associations between PSD and the following factors: TSH (OR: 0.87, 95% CI: 0.76– 1), CRP levels (OR: 1.01, 95% CI: 1– 1.02), family history of stroke (OR: 4.25, 95% CI: 1.66– 10.88), migraine history (OR: 8.63, 95% CI: 2.49– 29.85), and shorter sleep duration (OR: 0.6, 95% CI: 0.51– 0.71) (all P

Yinping Feng,&ast; Jing Guo, Shuirong Luo, Guangnao Zhou&ast; Department of Tuberculosis, Lishui Hospital of traditional Chinese Medicine Affiliated to Zhejiang University of traditional Chinese Medicine, Lishui, 323000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Guangnao Zhou, Email zgn198615@163.comBackground: Pulmonary tuberculosis (PTB) with tracheobronchial tuberculosis (TBTB) can lead to tracheal stenosis and atelectasis, but the specific risk factors are currently unclear. Therefore, the goal of this retrospective study is to address this issue and help with the early diagnosis of TBTB.Methods: Please include PTB hospitalized in our hospital from January 2021 to October 2023 in the study. After conducting bronchoscopy examinations, the patients were divided into two groups: the PTB group and the PTB&TBTB group. We used the propensity score matching (PSM) to align the baseline data of the two groups of patients, and then performed multiple logistic regression analysis to identify risk factors.Results: 643 patients with PTB were included in the study, 227 of whom (35.30%) were diagnosed with TBTB. A total of 204 pairs of patients were successfully matched using the PSM. After matching, there were no statistically significant differences in basic information between the two groups of patients (P> 0.05). Multivariate logistic regression analysis revealed that disease course ≥ 1 month (OR=1.85, 95% CI: 1.21– 2.83), complicated with diabetes (OR=3.00, 95% CI: 1.91– 4.70), and concomitant pulmonary cavity (OR=3.46, 95% CI: 2.23– 5.36) were risk factors for PTB accompanied by TBTB (all P< 0.05).Conclusion: After adjusting for various influencing factors using PSM, the analysis demonstrated that disease course ≥ 1 month, complicated with diabetes, and concomitant pulmonary cavity are risk factors for PTB combined with TBTB. This emphasizes the significance of improving screening and implementing early intervention measures.Keywords: pulmonary tuberculosis, tracheobronchial tuberculosis, propensity score matching, risk factors

Siqi Zhu,1– 3,&ast; Yajun Cui,2,3,&ast; Weidong Zhang,2,3 Yu Ji,2,3 Lingshuang Li,2,3 Shenglei Luo,4 Jing Cui,5,6 Minqi Li2,3 1School of Stomatology, Jinzhou Medical University, Jinzhou, People’s Republic of China; 2Department of Bone Metabolism, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, People’s Republic of China; 3Center of Osteoporosis and Bone Mineral Research, Shandong University, Jinan, People’s Republic of China; 4Department of Oral and Maxillofacial Surgery, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China; 5Department of Oral and Maxillofacial Surgery, Jinan Stomatological Hospital, Jinan, People’s Republic of China; 6Central Laboratory, Jinan Key Laboratory of oral tissue regeneration, Shandong Provincial Health Commission Key Laboratory of Oral Diseases and Tissue Regeneration, Jinan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jing Cui, Department of Oral and Maxillofacial Surgery, Jinan Stomatological Hospital, Jinglv Road 101, Jinan, 250001, People’s Republic of China, Tel +86-0531-86261960, Email 2005cuijing@163.com Minqi Li, Department of Bone Metabolism, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Wenhua West Road 44-1, Jinan, 250012, People’s Republic of China, Tel +86-0531-88382095, Email liminqi@sdu.edu.cnPurpose: Zoledronate (ZA) stands as a highly effective antiresorptive agent known to trigger medication-related osteonecrosis of the jaw (MRONJ). Its clinical dosages primarily encompass those used for oncologic and osteoporosis treatments. While inflammation is recognized as a potential disruptor of mucosal healing processes associated with ZA, prior research has overlooked the influence of varying ZA dosages on tissue adaptability. Therefore, a deeper understanding of the specific mechanisms by which inflammation exacerbates ZA-induced MRONJ, particularly when inflammation acts as a risk factor, remains crucial.Methods: Cell proliferation and migration of human oral keratinocytes (HOK) was analyzed after treatment with different doses of ZA and/or lipopolysaccharide (LPS) to assess their possible effect on mucosal healing of extraction wounds. Mouse periodontitis models were established using LPS, and histological changes in extraction wounds were observed after the administration of oncologic dose ZA. Hematoxylin and eosin (HE) staining and immunofluorescence were used to evaluate mucosal healing.Results: In vitro, LPS did not exacerbate the effects of osteoporosis therapeutic dose of ZA on the proliferation and migration of HOK cells, while aggravated these with the oncologic dose of ZA treatment by inducing mitochondrial dysfunction and oxidative stress via regulating SIRT1 expression. Furthermore, SIRT1 overexpression can alleviate this process. In vivo, local injection of LPS increased the nonunion of mucous membranes in MRONJ and decreased the expression of SIRT1, PGC-1α, and MnSOD.Conclusion: Inflammation aggravates oncologic dose of ZA-induced mitochondrial dysfunction and oxidative stress via a SIRT1-dependent pathway, enhancing the risk of impaired mucosal healing in MRONJ. Our study implies that inflammation becomes a critical risk factor for MRONJ development at higher ZA concentrations. Elucidating the mechanisms of inflammation as a risk factor for mucosal non-healing in MRONJ could inform the development of SIRT1-targeted therapies.Keywords: MRONJ, mucosal healing, inflammation, oxidative stress, mitochondrial dysfunction, SIRT1

Luxun Yang,1,&ast; Haiying Ran,2,&ast; Yaru Yin,1 Jing Liu,1 Binghui Lu,1 Xi Ran,3 Shenglin Luo,1 Weidong Wang,4 Zhangyou Yang,5 Rong Li1 1Institute of Combined Injury, National Key Laboratory of Trauma and Chemical Poisoning, Army Key Laboratory of Nanomedicine, Department of Military Preventive Medicine, Army Medical University, Chongqing, 400038, People’s Republic of China; 2Biomedical Analysis Center, Army Medical University, Chongqing, 400038, People’s Republic of China; 3Department of Medical Laboratory, Xinqiao Hospital, Army Medical University, Chongqing, 400037, People’s Republic of China; 4Department of Radiation Oncology, Sichuan Cancer Hospital, Chengdu, 610041, People’s Republic of China; 5Chongqing Key Laboratory for Pharmaceutical Metabolism Research, Chongqing Pharmacodynamic Evaluation Engineering Technology Research Center, College of Pharmacy, Chongqing Medical University, Chongqing, 400016, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhangyou Yang, Chongqing Medical University, No. 1, Yixueyuan Road, Chongqing, 400016, People’s Republic of China, Email yangzhangyou@cqmu.edu.cn Rong Li, Army Medical University, No. 30, Gaotanyan Street, Chongqing, 400038, People’s Republic of China, Tel +86-13883996627, Fax +8623-68753127, Email lrong361@126.comPurpose: Mitochondrial oxidative stress is an important factor in cell apoptosis. Cerium oxide nanomaterials show great potential for scavenging free radicals and simulating superoxide dismutase (SOD) and catalase (CAT) activities. To solve the problem of poor targeting of cerium oxide nanomaterials, we designed albumin-cerium oxide nanoclusters (TPP-PCNLs) that target the modification of mitochondria with triphenyl phosphate (TPP). TPP-PCNLs are expected to simulate the activity of superoxide dismutase, continuously remove reactive oxygen species, and play a lasting role in radiation protection.Methods: First, cerium dioxide nanoclusters (CNLs), polyethylene glycol cerium dioxide nanoclusters (PCNLs), and TPP-PCNLs were characterized in terms of their morphology and size, ultraviolet spectrum, dispersion stability and cellular uptake, and colocalization Subsequently, the anti-radiation effects of TPP-PCNLs were investigated using in vitro and in vivo experiments including cell viability, apoptosis, comet assays, histopathology, and dose reduction factor (DRF).Results: TPP-PCNLs exhibited good stability and biocompatibility. In vitro experiments indicated that TPP-PCNLs could not only target mitochondria excellently but also regulate reactive oxygen species (ROS)levels in whole cells. More importantly, TPP-PCNLs improved the integrity and functionality of mitochondria in irradiated L-02 cells, thereby indirectly eliminating the continuous damage to nuclear DNA caused by mitochondrial oxidative stress. TPP-PCNLs are mainly targeted to the liver, spleen, and other extramedullary hematopoietic organs with a radiation dose reduction factor of 1.30. In vivo experiments showed that TPP-PCNLs effectively improved the survival rate, weight change, hematopoietic function of irradiated animals. Western blot experiments have confirmed that TPP-PCNLs play a role in radiation protection by regulating the mitochondrial apoptotic pathway.Conclusion: TPP-PCNLs play a radiologically protective role by targeting extramedullary hematopoietic organ-liver cells and mitochondria to continuously clear ROS.Keywords: radioprotective effect, ceria nanoclusters, mitochondria targeting, oxidative stress, superoxide dismutase

Changjin Wang,1,&ast; Xiaolu Hu,1,2,&ast; Songyuan Luo,1,&ast; Yinghao Sun,1 Bangyuan Yang,1 Shengneng Zheng,3 Jiaohua Chen,1 Ming Fu,1 Ruixin Fan,4 Jie Li,1 Jianfang Luo1,2 1Department of Cardiology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, People’s Republic of China; 2School of Medicine South China University of Technology, Guangzhou, People’s Republic of China; 3Department of Radiology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, People’s Republic of China; 4Department of Cardiac Surgery, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jie Li; Jianfang Luo, Department of Cardiology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, &num;96 Dongchuan Road, Yuexiu District, Guangzhou, Guangdong, 510080, People’s Republic of China, Tel +86-20-83827812, Fax +86-20-83875453, Email leomoku1981@163.com; jianfangluo@sina.comPurpose: In mixed aortic valve disease (MAVD), the results of transcatheter aortic valve replacement (TAVR) are conflicting. There is limited data on the outcomes of TAVR in patients with bicuspid aortic valve (BAV) and MAVD. The objective of this study is to compare outcomes after TAVR in BAV patients with MAVD and predominant aortic stenosis (PAS).Patients and Methods: Patients with BAV who underwent TAVR between January 2016 and April 2023 were included. The primary outcome was device success. The secondary endpoints were periprocedural mortality and other complications as defined by the Valve Academic Research Consortium-3 (VARC-3). Propensity score matching was used to minimize potential confounding.Results: A total of 262 patients were included in this study, 83 of whom had MAVD. The median age was 72 years, and 55.7% were male. The baseline comorbidity risk files were comparable between the two groups. Patients with MAVD had more mitral regurgitation, tricuspid regurgitation and pulmonary hypertension, larger annular and left ventricular outflow tract dimensions, and more severe calcification than PAS. In the unmatched population, MAVD patients had similar device success rate (69.9% vs 79.9%, P=0.075) and 30-day mortality (3.6% vs 3.4%, P=1) compared to PAS. Propensity score matching resulted in 66 patient pairs. Device success rate were still comparable in the matched population. Other clinical outcomes, including stroke, bleeding (type 2– 4), major vascular complications, acute kidney injury (stage 2– 4) and permanent pacemaker implantation, were comparable between the two groups. Multivariable logistic regression analysis did not show MAVD to be an independent negative predictor of device success. At one year, survival was similar between patients with MAVD and those with PAS.Conclusion: For the bicuspid valve, patients with MAVD had a more challenging anatomy. MAVD patients associated with comparable 30-day clinical outcomes after TAVR compared to PAS patients in patients with BAV.Keywords: transcatheter aortic valve replacement, mixed aortic valve disease, bicuspid aortic valve, device success, propensity score match

Yinping Feng, Jing Guo, Shuirong Luo, Zunjing Zhang, Zhongda Liu Department of Tuberculosis, Lishui Hospital of Traditional Chinese Medicine Affiliated to Zhejiang University of Traditional Chinese Medicine, Lishui Tuberculosis Clinical Medical Research Center, Lishui, Zhejiang, People’s Republic of ChinaCorrespondence: Zhongda Liu, Email liu_zd0578@126.comObjective: Exploring the risk factors for readmission of elderly patients with pulmonary tuberculosis (PTB) within one month using the propensity score matching(PSM).Methods: A retrospective analysis was conducted on the clinical data of elderly patients with PTB who were admitted to the Tuberculosis Department of Lishui Hospital of Traditional Chinese Medicine from January 2020 to October 2023. The patients were divided into two groups: non-readmission group and readmission group based on whether they were readmitted within one month after discharge. The PSM method was used to match the baseline data of the two groups of patients, and multivariate logistic regression analysis was conducted to explore the risk factors for readmission of elderly patients with PTB within one month after discharge.Results: A total of 1268 hospitalized elderly patients with PTB were included in the study, comprising 977 readmitted patients and 291 newly admitted patients (22.95%). Using the PSM, 288 pairs of patients were successfully matched. Following matching, there were no statistically significant differences between the two groups in terms of gender, age, occupation, body mass index(BMI), past medical history, etc. (all P> 0.05). Multivariate logistic regression analysis indicated that infection, drug-induced liver injury(DILI), acute heart failure(AHF), chronic kidney disease(CKD), and extrapulmonary tuberculosis(EPTB) were all identified as risk factors for readmission of elderly patients with PTB.Conclusion: After controlling for confounding factors through PSM, the study revealed that infection, DILI, AHF, CKD, and EPTB are risk factors for readmission among elderly patients with PTB, highlighting the need for early intervention.Keywords: elderly patients with pulmonary tuberculosis, aged, readmission, propensity score matching, risk factors

Shouyu He,1,&ast; Xiaowen Liu,2,&ast; Shenchang Luo,1 Haidong Li,1 Jikang Min,1 Qian Shi3 1Department of Spine Surgery, First Affiliated Hospital, The First People’s Hospital of Huzhou, Huzhou University, Huzhou, 313000, People’s Republic of China; 2Department of Orthopedic Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, 200003, People’s Republic of China; 3Key Laboratory for Translational Medicine, First Affiliated Hospital, The First People’s Hospital of Huzhou, Huzhou University, Huzhou, 313000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qian Shi, Key Laboratory for Translational Medicine, First Affiliated Hospital, The First People’s Hospital of Huzhou, Huzhou University, Huzhou, 313000, People’s Republic of China, Email 51359@zjhu.edu.cnBackground: Low back pain (LBP) is primarily caused by intervertebral disc degeneration (IVDD). Immune cells penetrating nucleus pulposus (NP) tissues may play an important role in generating IVDD and LBP.Methods: The clinical data from 100 cases of IVDD patients was initially analyzed retrospectively. Subsequently, peripheral blood and NP tissues from 41 IVDD patients were gathered for a validated investigation. Among them, ribosome-removed-RNA sequencing (RNA-seq) was performed on 10 cases of NP tissues of specific classifications (VAS 3 and Pfirrmann 3 were used as the controls, while patients with VAS 6 and Pfirrmann 5 were used as the experimental group). Differentially expressed genes (DEGs) were identified for the subsequent bioinformatics analysis. Further methods to confirm the underlying cause of discogenic LBP included mast cell immunohistochemistry (IHC), 12 cytokine detection, Western blot (WB), and real-time polymerase chain reaction (RT-PCR).Results: Discogenic LBP and IVDD severity are strongly associated, and immunological cell infiltration has been demonstrated to be a significant factor in LBP by bioanalytical research. Tryptase-positive mast cells were found to be significantly more abundant in the VAS 6 NP tissues of IVDD patients than in the VAS 3 NP tissues. It was initially demonstrated that IVDD and LBP were significantly impacted by hemokinin-1 (HK-1), the mast cell-related gene. Furthermore, blood levels of interleukin 12 p70 (IL-12P70) are noticeably elevated and strongly correlated with HK-1, indicating that HK-1 may be involved in the regulation of mast cell activity and IL-12P70 production.Conclusion: The severity of LBP was observed to be positively correlated with the IVDD Pfirrmann grading. Further research indicates that patients with IVDD may experience persistent low back pain due to HK-1 activation of mast cells and the release of the cytokine IL12P70. This work will offer new insights into the diagnosis and treatment of discogenic LBP.Keywords: IVDD, LBP, immune cell infiltration, mast cell, HK-1

Pingyang Ke,1,&ast; Jing Liu,1,2,&ast; Chengzhi Chen,3,&ast; Sen Luo,3,&ast; Huiwen Gu,3,&ast; Juan Gu,4 Yan Liu,1 Yuanlin Ma,1 Yuan Meng,1 Liqin Hu,1 Xin Tian,1 Fei Xiao1 1Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing, People’s Republic of China; 2Department of Neurology, Chongqing University Three Gorges Hospital, Chongqing, People’s Republic of China; 3Department of Occupational and Environmental Health, School of Public Health and Management, Chongqing Medical University, Chongqing, People’s Republic of China; 4Key Laboratory of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Fei Xiao; Xin Tian, Email feixiao81@126.com; xintian@cqmu.edu.cnBackground: Zinc oxide nanoparticles (ZnO NPs) has been widely used in various fields and has had an important impact on human public health. In addition, it inevitably damages human health, including neurological diseases. Therefore, this study explored the effect of ZnO NPs on epilepsy.Methods: The effect of ZnO NPs on epilepsy was observed by behavioral analysis. TLR4 expression and autophagy related pathways were detected by RNA-seq and Western blot. In addition, the cell types of autophagy were detected by immunofluorescence. Further, the electrophysiological changes of ZnO NPs induced autophagy were detected by whole-cell patch-clamp. Finally, the recovery experiment was carried out by TLR4 inhibitor (TAK-242).Results: We found that ZnO NPs enhanced epilepsy susceptibility and severity. Through RNA-seq analysis and Western blot, it was found that ZnO NPs affected the changes of TLR4 and autophagy related pathways. In addition, we found that ZnO NPs mainly affects autophagy of inhibitory neurons, resulting in excitation/inhibition imbalance. The autophagy and epileptic phenotypes were reversed with TAK-242. In general, ZnO NPs exacerbate epileptic seizures by modulating the TLR4-autophagy axis.Conclusion: ZnO NPs enhanced the susceptibility and severity of epilepsy. Mechanistically, ZnO NPs affected autophagy by changing the expression of TLR4. In particular, the ZnO NPs mainly affected the synaptic function of inhibitory neuron, leading to excitation/inhibition imbalances.Keywords: zinc oxide nanoparticles, epilepsy, excitation/inhibition balance, autophage

Lin Chen,1,&ast; Qini Pan,2,&ast; Xiaohong Li,3 Shuangli Luo,4 Xiao Pan,2 Huiqiao Huang2 1Department of Cardiology, West China Hospital, Sichuan University/West China School of Nursing, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 2Department of nursing, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People’s Republic of China; 3College of Life Sciences, Chongqing Normal University, Chongqing, People’s Republic of China; 4Department of nursing, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guxngxi, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Huiqiao Huang; Xiao Pan, Email huangedugx@126.com; 1910026304@qq.comPurpose: Practitioners in China who implement hospice care services include doctors, nurses, and care workers. These individuals play an important role in the holistic care of patients at the end of life and their families. This study aimed to provide baseline data to develop hospice care services and improve relevant policies by investigating the knowledge and attitudes of hospice care practitioners (HCPs) and analyzing influencing factors.Methods: This cross-sectional descriptive study used stratified sampling and quota sampling. The HCPs were from nursing homes, medical institutions, integrated medical and nursing institutions, and community health service centers in Guangxi Zhuang Autonomous Region. We examined HCPs’ demographic characteristics and scores on a self-designed Chinese scale to measure their knowledge and attitudes(K&A scale). A total of 1821 HCPs completed surveys from May 2022 to July 2022. The data were analyzed using descriptive statistics, univariate analysis and multiple linear regression.Results: The standard score of the K&A scale of 1821 HCPs was 61.62 (SD=9.78), and the individual mean scores of knowledge and attitudes were 76.42 (SD=28.13) and 58.69 (SD=11.31), respectively. The final multiple linear regression analysis indicated that the main factors that influenced the K&A score were monthly income, job satisfaction, and the hospice care-related system (HCS).Conclusion: The HCPs in this study displayed moderate mean scores for knowledge and a less favorable attitude toward hospice care. Monthly income, job satisfaction and the HCS were the common factors that influenced HCPs’ K&A. The results suggest the need to strengthen targeted and professional training for HCPs, increase their welfare and benefits, and improve indigenous policies of hospice care.Keywords: attitudes, hospice care practitioners, hospice care-related system, knowledge

Ye Lin, Shuke Luo, Qiang Lu, Xueke Pan Department of Ophthalmology, The Second People’s Hospital of Foshan, Foshan, Guangdong Province, People’s Republic of ChinaCorrespondence: Shuke Luo, Department of Ophthalmology, The Second People’s Hospital of Foshan, Foshan, Guangdong Province, 528000, People’s Republic of China, Tel +86 13679830510, Email 542377993@qq.comPurpose: To investigate the psychological changes in patients pre and post implantable collamer lens (ICL, EVO) implantation surgery in the posterior chamber.Patients and methods: Self-rating anxiety scale (SAS) and self-rating depression scale (SDS) were used to assess the mental states of 43 patients who underwent ICL implantation surgery performed by the same surgeon between January 2021 and December 2022.Results: Comparing the results before and one week after the operation, there is a significant difference in both the SAS scale (P< 0.05) and the SDS scale (P< 0.05). Similarly, when comparing the pre-operation and one-month post-operation results, there is also a significant difference in both the SAS scale (P< 0.05) and the SDS scale (P< 0.05). However, when comparing the one-week post-operation and one-month post-operation results, there is no significant difference in either the SAS scale (P> 0.05) or the SDS scale (P> 0.05). Moving on to the comparison between the pre-operation results and the national norm level, there is a significant difference in both the SAS scale (P< 0.05) and the SDS scale (P< 0.05). When comparing the one-week post-operation results and the national norm level, there is a significant difference in the SAS scale (P< 0.05). Similarly, when comparing the one-month post-operation results and the national norm level, there is a significant difference in the SAS scale (P< 0.05).Conclusion: After undergoing ICL implantation surgery, patients typically experience a notable decrease in anxiety (SAS) and depression (SDS) scales. These improvements gradually stabilize and enhance during the postoperative recovery period. However, it may require a significant amount of time for patients to fully restore their psychological well-being to levels comparable to the national norm, particularly in terms of anxiety levels.Keywords: implantable collamer lens implantation, myopia, mental state, self-rating anxiety scale, self-rating depression scale

Xing Wang,1,2,&ast; Xiaojing Yang,1,3,&ast; Yiming Zhang,1 Afei Guo,1 Suju Luo,1 Meng Xiao,1 Lu Xue,1 Guohui Zhang,2 Huiping Wang1 1Department of Dermatovenereology, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China; 2Department of Dermatovenereology, Baotou Central Hospital, Baotou City, Inner Mongolia, People’s Republic of China; 3Department of Dermatovenereology, the First Affiliated Hospital of Hebei North University, Zhangjiakou, Hebei, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Huiping Wang; Guohui Zhang, Email huiping1208@163.com; 1259314465@qq.comIntroduction: Skin cutaneous melanoma is becoming more dangerous since it has a poor prognosis and is resistant to treatment. Previous research has shown that lncRNAs and fatty acid metabolism are essential for numerous biological activities. There are no studies on the relationship between fatty acid metabolism-Related lncRNAs and skin cutaneous melanoma.Methods and Results: In order to better understand the prognosis and survival of SKCM patients, we investigated the significance of lncRNAs related to fatty acid metabolism. In this work, we looked at the fatty acid metabolism genes and lncRNAs expression patterns. On the basis of lncRNAs associated with fatty acid metabolism, a nomogram and a prognosis prediction model were created. Based on the profile of lncRNAs associated with fatty acid metabolism, functional and pharmacological sensitivity investigations were also carried out. We also looked at the connection between immunotherapy and the immune response. The findings demonstrated that a risk score model based on 11 essential lncRNAs for fatty acid metabolism may discriminate between the clinical condition of SKCM and more accurately predict prognosis and survival. We conducted quantitative reverse transcription polymerase-chain reaction (RT-PCR) to verify the model.Conclusion: These important lncRNAs further showed a strong association with the tumor immune system, and these important lncRNAs also showed a connection between SKCM and chemotherapeutic treatment sensitivity. Our research strives to provide fresh viewpoints and innovative approaches to the treatment and administration of SKCM.Keywords: skin cutaneous melanoma, lncRNA, fatty acid metabolism, bioinformatics, tumor immune

Hanzhi Wang,1,2,&ast; Siying Qu,2,&ast; Tianshu Zhou,3,&ast; Qunqi Hu,2 Xiaoxuan Zhao,1 Qujia Yang,1,2 Hengyu Chi,2 Shiling Luo,1 Xinyue Li,4 Huanxiao Ke,1,2 Xiaofen He,5 Hongli Zhao1 1Department of Traditional Chinese Medicine (TCM) Gynecology, Hangzhou Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, Hangzhou City, Zhejiang Province, People’s Republic of China; 2Zhejiang Chinese Medical University, Hangzhou City, Zhejiang Province, People’s Republic of China; 3Wenzhou Medical University, Wenzhou City, Zhejiang Province, People’s Republic of China; 4Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou City, Zhejiang Province, People’s Republic of China; 5Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Zhejiang Chinese Medical University, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Hangzhou City, Zhejiang Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiaofen He, Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Zhejiang Chinese Medical University, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Zhejiang Chinese Medical University, 548 Binwen Road, Binjiang District, Hangzhou City, Zhejiang Province, People’s Republic of China, Email zjhxf1986@163.com Hongli Zhao, Department of Traditional Chinese Medicine (TCM) Gynecology, Hangzhou Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, 453 Tiyuchang Road, Xihu District, Hangzhou City, Zhejiang Province, People’s Republic of China, Email z6hl@163.comPurpose: This bibliometric research aims to delineate global publication trends and emerging research interests in the use of acupuncture for breast cancer (BC)-related symptoms treatment over the past three decades. Furthermore, it identifies influential institutions, potential collaborative partners, and future research trends, thereby providing guidance for relevant, novel research directions.Methods: Scientific publications related to acupuncture for BC-related symptoms were gathered from the Web of Science Core Collection (WoSCC) from 1993 to 2023. Four software applications were principally used to analyze the resulting data: the “bibliometrix” package in the R environment (version 4.2.3), VOSviewer, CiteSpace6.1.R6, and the bibliometrics website. These applications were employed to evaluate different parameters.Results: A total of 621 papers on acupuncture in BC-related symptoms treatment were analyzed. The United States, China, and South Korea contributed the most, with Memorial Sloan Kettering Cancer Center, and Columbia University leading institutions. It is interesting to mention that Mao, Jun J. and Molassiotis, A. feature among the top 10 authors and co-cited authors. JAMA is the leading journal, with an ongoing focus on acupuncture’s effectiveness. Keywords show that the initial research focus was mainly on “vasomotor symptoms”, but in recent years there has been a gradual shift towards “pain”, “chemotherapy-induced peripheral neuropathy (CIPN)”, “electroacupuncture”, and “non-specific effects”.Conclusion: Acupuncture has demonstrated a unique value in the process of adjuvant treatment of BC-related symptoms, and has been shown to be effective in reducing pain, eliminating fatigue, and improving quality of life. The study of the mechanisms of acupuncture and the application of electroacupuncture are possible future research priorities in this field. This study offers a deep perspective on acupuncture for BC research, highlighting key points and future trends.Keywords: breast cancer-related symptoms, acupuncture, bibliometric study, cancer pain, CiteSpace, VOSviewer

Guangbin Yu,1 Shuping Luo,1 Cuilian Zhu,1 Li Chen,1 Hao Huang,2 Bin Nie,1,3 Jianhao Gu,4 Jianxin Liu1 1Fifth Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou City, People’s Republic of China; 2First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou City, People’s Republic of China; 3Guangdong Second Traditional Chinese Medicine Hospital, Guangzhou City, People’s Republic of China; 4Clinical Medical College of Acupuncture-Moxibustion and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou City, People’s Republic of ChinaCorrespondence: Bin Nie, Guangdong Second Traditional Chinese Medicine Hospital, Guangzhou City, People’s Republic of China, Tel +86 13826067459, Email niebing26@163.comPurpose: Recent studies have shown that acupuncture may have great potential in the treatment of Bell’s palsy. However, the bibliometric analysis of this field has not been summarized properly. Thus, the purpose of this study is to analyze the hotspot of acupuncture for Bell’s Palsy.Methods: The core collection database of Web of Science was searched for relevant publications from 2000 to 2023, and countries, institutions, authors, keywords, and literature were analyzed and visualized by bibliometric softwareCiteSpace 5.1.R6, Vosviewer, BICOMB, and gCLUTO to explore the scientific achievements, research collaboration networks, research hot spots, and research trends.Results: 229 publications were included in this study. The most cited journal is Journal of Otolaryngology-Head & Neck Surgery; the most prolific country is China; the most prolific author is Li Ying, moreover, the collaboration among scholars is poor; Kyung Hee University is the most prolific institution studying acupuncture for Bell’s Palsy. Reference burst detection indicates that traditional Chinese Medicine philosophy, the role of acupuncture in the prognosis of facial palsy, mechanism of acupuncture to improve facial nerve function, and the use of electroacupuncture are starting to become new research hotspots.Conclusion: The field of acupuncture for Bell’s Palsy has developed rapidly in recent years, and new research trends are mainly: combination with traditional Chinese medicine, the role of acupuncture in the prognosis of facial palsy, mechanism of acupuncture to improve facial nerve function, and the use of electroacupuncture. However, research in this field is still dominated by case reports and clinical trials, and there is a lack of large-scale, multicenter clinical trials and animal experiments there are still many problems in institutional cooperation and experimental design, which requires relevant researchers to strengthen cooperation and improve experimental design.Keywords: acupuncture, Bell’s palsy, CiteSpace, bibliometric analysis, Vosviewer

Wenting Luo,1 Shiyun Tang,2 Xiang Xiao,1 Simin Luo,1 Zixuan Yang,1 Wei Huang,3 Songqi Tang1 1School of Traditional Chinese Medicine, Hainan Medical University, Haikou, Hainan Province, People’s Republic of China; 2Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, People’s Republic of China; 3School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, People’s Republic of ChinaCorrespondence: Wei Huang, School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, 611137, People’s Republic of China, Email gracehw@126.com Songqi Tang, School of Traditional Chinese Medicine, Hainan Medical University, Haikou, Hainan Province, 571199, People’s Republic of China, Tel +86 18689713500, Email tangsongqi@hainmc.edu.cnAbstract: Animal models play a crucial role in studying the pathogenesis of diseases, developing new drugs, identifying disease risk markers, and improving means of prevention and treatment. However, modeling diabetic kidney disease (DKD) has posed a challenge for scientists. Although numerous models have been successfully developed, none of them can encompass all the key characteristics of human DKD. It is essential to choose the appropriate model according to the research needs, as different models develop different phenotypes and have their limitations. This paper provides a comprehensive overview of biochemical and histological phenotypes, modeling mechanisms, advantages and limitations of DKD animal models, in order to update relevant model information and provide insights and references for generating or selecting the appropriate animal models to fit different experimental needs.Keywords: modeling, advanced diabetic kidney disease, diabetic complications, hypertension, atherosclerosis, non-proteinuric diabetic kidney disease

Ruixian Zhang,1 Sha Luo,1 Nan Wang,1 Hongying Zhang,2 Xuping Wu1 1The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210003, People’s Republic of China; 2Nanjing Center for Disease Control and Prevention Affiliated to Nanjing Medical University, Nanjing, Jiangsu, 210008, People’s Republic of ChinaCorrespondence: Xuping Wu, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210003, People’s Republic of China, Email xuping.wu@njucm.edu.cn Hongying Zhang, Email xiao99now@aliyun.comBackground: Nontuberculous mycobacteria (NTM) are easily misdiagnosed as multidrug-resistant tuberculosis (MDR-TB), and treatment drugs are very limited. The main objective of our study was to evaluate the minimal inhibitory concentration (MIC) in vitro of bedaquiline (BDQ), clofazimine (CFZ), linezolid (LZD), delamanid (DLM), and pretomanid (PA-824) for treatment of M. abscessus and M. intracellulare. Furthermore, we determined whether MAB_1448, MAB_4384, MAB_2299c, MAB_1483, MAB_0540, rplD, rplC, and rrl were related to drug resistance to provide an experimental basis for the use of these five drugs in the treatment of NTM.Methods: We identified sample characteristics of epidemics in 550 patients with suspected NTM infection in Nanjing from 2019 to 2021 using the PCR-reverse spot hybrid method. Furthermore, we evaluated the MIC of BDQ, CFZ, DLM, LZD, and PA-824 against 155 clinical isolates of NTM using the microbroth dilution method. The resistant isolates were sequenced using Sanger sequencing.Results: The top three dominant species of NTM distributed in Nanjing were M. intracellulare, M. avium, and M. abscessus. Notably, the proportion of M. abscessus infections increased. The proportion of M. abscessus increased from 12% in 2019 to 18% in 2021. Demographic analysis showed that female infection rates were substantialy greater than male for M. abscessus (P=0.017, < 0.05). Our results demonstrate that NTM are highly sensitive to bedaquiline and clofazimine in vitro. However, delamanid and pretomanid had little effect on M. abscessus and M. intracellulare. In addition, we found 30– 41 nucleotide deletion mutations and some novel point mutations in the MAB_0540 gene of M. abscessus that are resistant to clofazimine.Conclusion: Bedaquiline, clofazimine, and linezolid were more successful in vitro treatments against M. abscessus and M. intracellulare. The MAB_0540 mutation may be associated with resistance of M. abscessus to clofazimine.Keywords: nontuberculous mycobacteria, minimal inhibitory concentration, gene mutations

JinJian Yao,1,2,&ast; Xiaochun Mao,3,&ast; Qigang Sun,4,&ast; Biao Wu,5 Weiling Yu,6 Yanjing Huang,7 Shuai Luo,1 Jia Zeng,1 Jusheng Lin2 1Department of Emergency, Hainan General Hospital, Haikou, Hainan, People’s Republic of China; 2Institute of Liver and Gastrointestinal Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 3Department of Ophthalmology, Xiangyang Central Hospital Affiliated to Hubei University of Arts and Science, Xiangyang, Hubei, People’s Republic of China; 4Department of Hepatobiliary and Pancreatic Surgery, Hainan General Hospital, Haikou, Hainan, People’s Republic of China; 5Infectious Disease, Hainan General Hospital, Haikou, Hainan, People’s Republic of China; 6Oncology Department, Haikou City People’s Hospital, Haikou, Hainan, People’s Republic of China; 7Oncology Department of Hainan General Hospital, Haikou, Hainan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: JinJian Yao; Jusheng Lin, Email 114715854@qq.com; jslin2005@163.comPurpose: Liver cirrhosis (LC) and hepatocellular carcinoma (HCC) are progressions affected by genetic predispositions, and persistent hepatitis B virus infection also demonstrates genetic susceptibility. All HBV-related outcomes have been compared in parallel to identify risk polymorphism in HBV progression.Methods: The multiple-stage association study filtered and validated the risk SNPs for HBV progression and explored their association with persistent infection, with a total of 8906 subjects in China from three sites. Cox proportional hazards models and Kaplan–Meier Log rank tests were used to determine the time to the progressive event in relation to the risk SNPs.Results: Rs3825214 in TBX5 replicated a specific association with LC and HCC in 4 progression cohorts and was not related to persistent infection, naivety to HBV infection and natural clearance in 3 persistent cohorts. In combined samples, rs3825214 was associated with an increased risk of LC (P< 0.001; OR = 1.98) and HCC (P< 0.001; OR = 1.68). The results of bioinformatics analysis indicated that rs3825214 genotypes change RNA structure and intron excision ratio. In the follow-up of 571 hospital-based persistent HBV infection patients, ninety-three (16.29%) developed LC, and seventy-four (12.96%) progressed to HCC at a median follow-up of 5.1 years. Rs3825214 was associated with HCC and LC events in Cox proportional hazards models (P< 0.001).Conclusion: We identified and confirmed that genetic variants in TBX5 are significantly associated with susceptibility to and the incidence of LC and HCC.Keywords: TBX5, polymorphism, liver cirrhosis, hepatocellular carcinoma, follow-up, hepatitis B virus

Yuehua Li,1 Li Jiang,2 Shengjun Luo,2 Daixing Hu,2 Xin Zhao,2 Guozhi Zhao,2 Wei Tang,2 Yu Guo3 1Department of Urology, University-Town Hospital of Chongqing Medical University, Chongqing, 400000, People’s Republic of China; 2Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400000, People’s Republic of China; 3Department of Urology, Chongqing Traditional Chinese Medicine Hospital, Chongqing, 400000, People’s Republic of ChinaCorrespondence: Yu Guo, Department of Urology, Chongqing Traditional Chinese Medicine Hospital, Chongqing, 400000, People’s Republic of China, Tel/Fax +8623 67665886, Email medicale123@163.comObjective: To investigate the characteristics, pathogens and drug resistance of urinary tract infection (UTI) associated with long-term indwelling double-J stent.Methods: The clinical data of 102 patients with urinary tract infection associated with long-term indwelling double-J stent in University-Town Hospital of Chongqing Medical University and Chongqing Traditional Chinese Medicine Hospital from September 2010 to July 2022 were collected retrospectively, and the difference between etiological characteristics were analyzed. Urine and double-J stent samples of patients were collected for pathogen identification and drug sensitivity test.Results: A total of 102 patients, 39 (38.23%) males and 63 (61.77%) females, aged 24– 72 years, with a median age of 48 years, were included in this study. Urinary calculi (40.20%) and ureteral stricture (24.50%) were the main causes of urinary tract infection associated with long-term indwelling double-J stent. Among the patients with urinary tract infection caused by double-J stent, female patients were higher than male patients (61.77% vs 38.23%). In terms of positive rate of pathogenic bacteria culture, the rate of double-J stent was higher than that of urine (67.65% vs 35.29%). The main pathogenic bacteria in urine were Escherichia coli (30.55%) of Gram negative bacteria, while the main pathogenic bacteria in double-J stent were enterococcus faecalis (27.53%) of Gram positive bacteria. The resistance rate of Gram positive bacteria in double-J stent to vancomycin, ciprofloxacin, meropenem and piperacillin/tazobactam was significantly higher than that in urine (P< 0.05). The resistance rate of Gram negative bacteria in double-J stent to imipenem, cefepime, piperacillin/tazobactam, meropenem and cefoperazone/sulbactam was significantly higher than that in urine (P< 0.05).Conclusion: Double-J stent associated urinary tract infection is more common in women than in men. Escherichia coli and Enterococcus faecalis are the main pathogens, and the pathogens show strong drug resistance.Keywords: double-J stent, biofilm, pathogens, urinary tract infection, drug resistance, drug resistant bacteria, infection

Lujian Zhu,1,&ast; Shengnan Luo,1,&ast; Yin Zhu,2 Shiyue Tang,1 Chenge Li,3 Xiaozhi Jin,4 Faling Wu,4 Huimian Jiang,4 Lina Wu,4 Yejin Xu1 1Department of Infectious Diseases, Jinhua Municipal Central Hospital, Jinhua, People’s Republic of China; 2Department of Infectious Diseases, Taizhou Enze Medical Center (Group), Enze Hospital, Taizhou, People’s Republic of China; 3College of Public Health and Management, Wenzhou Medical University, Wenzhou, People’s Republic of China; 4Department of Infectious Diseases, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yejin Xu, Department of Infectious Diseases, Jinhua Municipal Central Hospital, Jinhua, People’s Republic of China, Email xuyejin-fox@163.comAbstract: Ferroptosis is a recently identified iron-dependent form of intracellular lipid peroxide accumulation-mediated cell death. Different from other types of cell death mechanisms, it exhibits distinct biological and morphological features characterized by the loss of lipid peroxidase repair activity caused by glutathione peroxidase 4, the presence of redox-active iron, and the oxidation of phospholipids-containing polyunsaturated fatty acids. In recent years, studies have shown that ferroptosis plays a key role in various liver diseases such as alcoholic liver injury, non-alcoholic steatohepatitis, liver cirrhosis, and liver cancer. However, the mechanism of ferroptosis and its regulation on chronic liver disease are controversial among different types of cells in the liver. Herein, we summarize the current studies on mechanism of ferroptosis in chronic liver disease, aiming to outline the blueprint of ferroptosis as an effective option for chronic liver disease therapy.Keywords: ferroptosis, iron metabolism, liver disease, oxidative stress, cell death

Si-Yu Chen,1,&ast; Xiang-Quan Kong,1,2,&ast; Ke-Fan Zhang,3,&ast; Shuai Luo,1 Feng Wang,1 Jun-Jie Zhang1,2 1Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, People’s Republic of China; 2Department of Cardiology, Nanjing Heart Centre, Nanjing, People’s Republic of China; 3Department of General Surgery, the Second Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jun-Jie Zhang, Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, No. 68 Changle Road, Nanjing, 210006, People’s Republic of China, Tel/Fax +86-25-52208048, Email jameszll@163.comAbstract: The rising prevalence of cardiovascular disease has become a global health concern. The occurrence of cardiovascular disease is the result of long-term interaction of many risk factors, one of which is diabetes. As a novel anti-diabetic drug, DPP4 inhibitor has been proven to be cardiovascular safe in five recently completed cardiovascular outcome trials. Accumulating studies suggest that DPP4 inhibitor has potential benefits in a variety of cardiovascular diseases, including hypertension, calcified aortic valve disease, coronary atherosclerosis, and heart failure. On the one hand, in addition to improving blood glucose control, DPP4 inhibitor is involved in controlling cardiovascular risk factors. On the other hand, DPP4 inhibitor directly regulates the occurrence and progression of cardiovascular diseases through a variety of mechanisms. In this review, we summarize the recent advances of DPP4 in cardiovascular disease, aiming to discuss DPP4 inhibitor as a potential option for cardiovascular therapy.Keywords: DPP4, DDP4 inhibitor, GLP-1, inflammation, cardiovascular disease

Peng Wang,1,&ast; Shuwen Cheng,1,&ast; Weizheng Song,1 Yaxin Li,2 Jia Liu,1 Qiang Zhao,1 Shuang Luo1 1Department of Neurosurgery, Chengdu Fifth People’s Hospital/Affiliated Chengdu No.5 People’s Hospital of Chengdu University of TCM, Chengdu, People’s Republic of China; 2West China Fourth Hospital/West China School of Public Health, Sichuan University, Chengdu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shuang LuoDepartment of Neurosurgery, Chengdu Fifth People’s Hospital/Affiliated Chengdu No.5 People’s Hospital of Chengdu University of TCM, 33# Mashi Street, Wenjiang, Chengdu, People’s Republic of ChinaTel/Fax +86 28 82726171Email luoshuang2000@126.comBackground and Purpose: The correlation between meteorological parameters and intracerebral hemorrhage (ICH) occurrence is controversial. Our research explored the effect of daily meteorological parameters on ICH risk in a subtropical monsoon basin climate.Methods: We retrospectively analyzed patients with ICH in a teaching hospital. Daily meteorological parameters including temperature (TEM), atmospheric pressure (PRE), relative humidity (RHU), and sunshine duration (SSD) were collected, with the diurnal variation (daily maximum minus minimum) and day-to-day variation (average of the day minus the previous day) calculated to represent their fluctuation. We adopted a time-stratified case-crossover approach and selected conditional logistic regression to explore the effect of meteorological parameters on ICH risk. The influence of monthly mean temperature proceeded via stratified analysis. Air pollutants were gathered as covariates.Results: Our study included 1052 eligible cases with ICH. In a single-factor model, the risk of ICH decreased by 5.9% (P< 0.001) for each 1°C higher of the daily mean TEM, and the risk increased by 2.4% (P=0.002) for each 1hPa higher of the daily mean PRE. Prolongation of daily SSD inhibited the risk of ICH, and OR was 0.959 (P=0.007). The risk was raised by 7.5% (P=0.0496) with a 1°C increment of day-to-day variation of TEM. In a two-factor model, the effect of daily mean TEM or daily SSD on ICH risk was still statistically significant after adjusting another factor. The influence of meteorological parameters on ICH risk continued in cold months but disappeared in warm months after stratified analysis.Conclusion: This research indicates daily TEM and SSD had an inverse correlation to ICH risk in a subtropical monsoon basin climate. They were independent when adjusted by another factor. Daily PRE and day-to-day TEM variation were positively related to ICH risk. The correlation of daily meteorological factors on ICH risk was affected by the monthly thermal background.Keywords: intracerebral hemorrhage, temperature, atmospheric pressure, relative humidity, sunshine duration

Shuyi Li,1 Mengke Niu,2 Wenying Deng,1 Ning Li,1 Chen Wei,1 Chi Zhang,1 Suxia Luo1 1Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, Henan Province, People’s Republic of China; 2Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, People’s Republic of ChinaCorrespondence: Suxia LuoDepartment of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, No. 127 Dongming Road, Zhengzhou, 450008, Henan Province, People’s Republic of ChinaTel +86 371 65587805Email zlyyluosuxia0361@zzu.edu.cnBackground: Primary hepatic neuroendocrine carcinoma (PHNEC) is a rare liver tumor, and there is no clear therapeutic recommendation for patients with advanced PHNEC. This study aims to compare the efficacy of platinum-based chemotherapy (etoposide combined with cisplatin/carboplatin, EP/EC) and transcatheter arterial chemoembolization (TACE) in patients with advanced PHNEC, and to evaluate the relevant prognostic factors.Patients and Methods: The clinical data of 41 patients with advanced PHNEC from June 2014 to October 2019 were retrospectively reviewed.Results: At a median follow-up time of 13.9 months, the median overall survival (OS) was 14.8 months in the EP/EC group and 12.2 months in the TACE group (P = 0.040). The median progression-free survival (PFS) was 4.4 months and 2.7 months in the EP/EC group and the TACE group, respectively (P = 0.005). No significant differences in the overall response rate and disease control rate were observed between the EP/EC group and the TACE group (26.1% vs 11.1%, P = 0.429; 73.9% vs 44.4%, P = 0.055, respectively). A univariate analysis indicated that the Eastern Cooperative Oncology Group performance status (ECOG PS), Ki-67, tumor number, and treatment options were prognostic factors for OS. A multivariate analysis further showed that ECOG PS (P < 0.001), Ki-67 (P = 0.003), and treatment options (P = 0.022) were independent prognostic factors for OS.Conclusion: Ki-67, ECOG PS, and treatment options were the independent prognostic factors for OS in patients with advanced PHNEC. EP/EC may be a better choice for patients with advanced PHNEC.Keywords: chemotherapy, transcatheter arterial chemoembolization, hepatic neuroendocrine carcinoma, prognosis

Yanhong Deng,1,&ast; Lishuo Shi,2,&ast; Jianxia Li,1,&ast; Zhipeng Jiang,3,&ast; Chaojun Xie,4 Shuangling Luo,3 Li Ling,5 Hualiang Lin,6 Zongqiu Chen,4 Yunlong Zhao,7 Liang Kang,3 Jun Yuan,4 Weiping Wen8 1Department of Medical Oncology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, Guangzhou, 510655, People’s Republic of China; 2Clinical Research Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, Guangzhou, 510655, People’s Republic of China; 3Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, Guangzhou, 510655, People’s Republic of China; 4Guangzhou Center for Disease Control and Prevention, Guangzhou, Guangdong Province, 510440, People’s Republic of China; 5Department of Medical Statistics, School of Public Health, Sun Yat-sen University, Guangzhou, 510080, People’s Republic of China; 6Department of Epidemiology, School of Public Health, Sun Yat-sen University, Guangzhou, 510080, People’s Republic of China; 7Medical Department, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, Guangzhou, 510655, People’s Republic of China; 8Department of Otolaryngology, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, Guangzhou, 510655, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Weiping WenDepartment of Otolaryngology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, No. 26 Yuan Cun Er Heng Road, Guangzhou, 510655, People’s Republic of ChinaTel +86-20-87333733Email wenwp@mail.sysu.edu.cnJun YuanGuangzhou Center for Disease Control and Prevention, No. 1, Qide Road of Baiyun District, Guangzhou, Guangdong Province, 510440, People’s Republic of ChinaTel +86-20-36052333-1816Email yuanjuncom@163.comBackground: The quarantine in dedicated hotels has become an inevitable safety measure due to the frequent cross-border travel since the outbreak of COVID-19. The aim of the present study was to explore the trends in the psychological status of individuals entering from high-risk areas of COVID-19 coronavirus while quarantining in dedicated hotels.Methods: A total of 591 individuals who isolated in dedicated hotels were recruited between March and June 2020. Participants self-reported mental symptoms [Self-rating Anxiety Scale (SAS) and Self-rating Depression Scale (SDS)] every three days during the quarantine. A mixed-effects linear regression model was used to assess the trends.Results: Participants reporting anxiety and depression symptoms at least one time during quarantine accounted for 4.5% and 18.4%, respectively. Their psychological status was alleviated during some first 9 days, and then it slightly deteriorated, which was suggested by SAS and SDS scores that were negatively correlated with the days of quarantine (T) (adjusted coefficient [β] − 0.81, 95% CI − 1.00 to − 0.62; and β − 0.75, 95% CI − 0.97 to − 0.53, respectively), and were positively correlated with the square of T (β 0.04, 95% CI 0.02 to 0.06; and β 0.04, 95% CI 0.02 to 0.06, respectively). The unemployed and 18∼ 30-year-old participants were prone to greater levels of psychological distress. No significant difference in the trend of mental health was found among different subgroups.Conclusion: The mental health of the people entering Guangzhou from high-risk areas of COVID-19 coronavirus resulted positive during the early period of quarantine in dedicated hotels, after which it deteriorated. The psychological status of individuals should be closely monitored at the beginning and after more than 9 days of quarantine, especially for individuals who are unemployed and 18∼ 30-year-old ones.Keywords: quarantine, dedicated hotels, psychological distress, COVID-19

Shuanghong Luo,1,2 Chuncheng Wu,3 Qiuhong Luo,1,2 Mengdong Ran,4 Yin Liu,5 Fei Lei,6 Xin Chen,7 Zheng Yuan,8 Hanmin Liu,1,2 Chaomin Wan1,2 1Department of Paediatrics, West China Second University Hospital, Sichuan University, Chengdu, People’s Republic of China; 2Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, People’s Republic of China; 3Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, People’s Republic of China; 4Department of Biostatistics, West China Women & Children Union Doctor, Chengdu, People’s Republic of China; 5Research and Development Department, West China Women & Children Union Doctor, Chengdu, People’s Republic of China; 6Medical Information Center, West China Women & Children Union Doctor, Chengdu, People’s Republic of China; 7Child Health Care Department, Nanxin Community Health Service Center, High-Tech Zone, Chengdu, People’s Republic of China; 8Economics School, Southwestern University of Finance and Economics, Chengdu, People’s Republic of ChinaCorrespondence: Chaomin Wan Tel/Fax +86-28-85503185Email wanchaomin@scu.edu.cnAbstract: As an implementation strategy, the actual functional scope of clinical pathway (CPW) can be mastered is the basis for evaluating and improving CPW management, which is very important for bridging the evidence-to-practice gap. Here, we propose and discuss a design and evaluation model for CPWs through some theoretical lenses that may help the designer master the actual functional scope of CPWs and accumulate and refine effective key management steps of a specific disease. We can thus determine the best-optimized design with the largest net benefit that allows definition of the core management steps for a specific disease.Keywords: implementation science, clinical pathway, evidence-based medicine, health technology assessment, public health economics

Siyu Luo,1 Huifeng Zhu,2 Junhui Zhang,3 Dong Wan1 1Department of Emergency & Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 2College of Pharmaceutical Sciences & Chinese Medicine, Southwest University, Chongqing, People’s Republic of China; 3Health Management Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of ChinaCorrespondence: Dong WanDepartment of Emergency & Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People’s Republic of ChinaEmail wandongcqykdx@126.comJunhui ZhangHealth Management Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People’s Republic of ChinaEmail 2275610878@qq.comAbstract: The enteric nervous system (ENS) consists of enteric neurons and enteric glial cells (EGCs) and controls the function of the epithelial barrier. Thus, a novel concept of neuronal–glial–epithelial unit in the gut was put forward by analogy with neuronal–glial–endothelial unit in the brain. The environment in the gastrointestinal (GI) tract is complex as it harbours millions of bacteria, which extensively attach with intestinal epithelium. The cross-talk between the neuronal–glial–endothelial unit and microbiota plays a pivotal role in modulating the epithelial barrier’s permeability, intestinal development and immune response. And evidence shows dysbiosis is the potent risk factor in the pathologic process of Parkinson’s disease (PD) and inflammatory bowel disease (IBD). In this review, we summarize the compelling results in favor of microbiota serving as the key modulator in the neuronal–glial–epithelial unit development and function, with profound effects on intestinal homeostasis.Keywords: neuronal–glial–epithelial unit, microbiome, gut

Shu Luo,1,3 Lina Wang,3 Shuming Li,3 Hongwei Wang,2 Sujing Huang,2 Zhongxia Zhang,2 Ru Wang,2 Hongqiong Guan,3 Yuanhua Huang1,4 1Nanjing Medical University, Nanjing, Jiangsu, 211166, People’s Republic of China; 2Department of Obstetrics, the Second Affiliated Hospital of Hainan Medical University, Haikou, Hainan, 570311, People’s Republic of China; 3College of Second Clinical, Hainan Medical University, Haikou, Hainan, 570311, People’s Republic of China; 4Hainan Medical University, Haikou, Hainan, 571199, People’s Republic of ChinaCorrespondence: Yuanhua HuangNanjing Medical University, No. 101, Longmian Avenue, Nanjing, Jiangsu, 211166, People’s Republic of ChinaTel +86-13036095796Email huangyh4180@hainmc.edu.cnHongqiong GuanCollege of Second Clinical, Hainan Medical University, No. 368, Yehai Avenue, Haikou, Hainan, 570311, People’s Republic of ChinaTel +86-13078900121Email guanhq@163.comBackground: Preeclampsia (PE) is an idiopathic hypertensive disorder of pregnancy and is the leading cause of maternal death, fetal malformation, and premature birth. The purpose of this study is to identify the key molecules and lncRNA-related competitive endogenous (ceRNA) regulatory network in PE.Methods: The differentially expressed mRNAs (DEGs), lncRNAs (DELs), and miRNAs (DEMs) were identified between PE and control using the Deseq R package. In addition, we performed Geno ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) on DEGs and DELs-target genes to explore their function. The ceRNA network was established based on lncRNA-miRNA and miRNA-mRNA interactions and visualized using Cytoscape software. LINCO2532, SLCO4A1-AS1, miR23a-5p, and DYNLRB1 were selected for qRT-PCR assay.Results: Using microarray analysis, we screened 726 DELs (456 upregulated and 370 downregulated), 49 DEMs (37 upregulated and 12 downregulated), and 318 DEGs (230 upregulated and 88 downregulated) between PE patients and control. Based on lncRNA-miRNA pairs and miRNA-mRNA pairs, the ceRNA network was constructed, which contained 16 lncRNA, 1 miRNA (miR-23a-5p), and 1 mRNA (DYNLRB1). LncRNA (LINCO2532 and SLCO4A1-AS1) and DYNLRB1 were downregulated and the expression of miR23a-5p was upregulated in PE patients compared with healthy controls.Conclusion: In this study, the novel ceRNA network was established in the placentas of PE patients. It elucidated the regulatory mechanism of PE, and identified novel PE biomarkers, which have important guiding significance for clinical treatment and further scientific research of PE.Keywords: preeclampsia, lncRNA, miRNA, ceRNA network

Peng Wang,1,&ast; Shuang Luo,1,&ast; Shuwen Cheng,1 Yaxin Li,2 Weizheng Song1 1Department of Neurosurgery, Chengdu Fifth People’s Hospital/Affiliated Chengdu No.5 People’s Hospital of Chengdu University of TCM, Chengdu, People’s Republic of China; 2West China Fourth Hospital/West China School of Public Health, Sichuan University, Chengdu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Weizheng SongDepartment of Neurosurgery, Chengdu Fifth People’s Hospital/Affiliated Chengdu No.5 People’s Hospital of Chengdu University of TCM, Chengdu, 611130, People’s Republic of ChinaTel/Fax +86 28 82726171Email song_cdutcm@126.comBackground and Purpose: The role of antihypertensive medication adherence in reducing the effect of ambient temperature (TEM) on intracerebral hemorrhage (ICH) pathogenesis is unclear. We aimed to study the influence of ambient TEM on the ICH occurrence in hypertensive patients with different medication adherence.Methods: We enrolled consecutive ICH patients with a definite history of hypertension in a teaching hospital over a period of six years. Medication adherence was calculated using the proportion of prescription days covered (PDC) to antihypertensive mediation in the last month before the ICH attack. Optimal medication adherence (OMA) was the PDC > 80%, and non-optimal medication adherence (non-OMA) was ≤ 80%. Daily ambient TEM and its variation were collected as the explanatory variables, and dominant air pollutants were gathered as covariates. We adopted a time-stratified case-crossover approach to minimize individual confounders. Conditional logistic regression was conducted to calculate the odds ratio (OR) of daily ambient TEM on ICH occurrence.Results: We recruited a total of 474 patients in this study. The number of participants with OMA and non-OMA was 249 and 225. Daily mean and max TEM in lag0 to lag2, as well as daily min TEM in lag0 to lag1, were significantly related to ICH onset in all enrolled patients and non-OMA cases. However, only daily TEM in lag0 was meaningfully associated with ICH onset in the OMA cases. The risk of ICH in OMA patients, respectively, changed by 7.9% (OR = 0.921, [0.861, 0.985]) or 6.3% (OR = 0.937, [0.882, 0.995]) when daily mean or max TEM was altered by 1°C in lag0, but the change raised by 10.4% (OR = 0.896, [0.836, 0.960]) or 7.5% (OR = 0.925, [0.868, 0.986]) in non-OMA patients. And the risk varied (OR = 0.933, [0.882, 0.988]) only in non-OMA patients when daily min TEM was altered by 1°C in lag1.Conclusion: Our results indicate that OMA to antihypertensive drugs reduces the influence of ambient TEM on ICH occurrence in hypertensive patients.Keywords: intracerebral hemorrhage, risk, ambient temperature, medication adherence

Yuansong Zhu, Jian Shen, Yuzhou Xue, Zhenxian Xiang, Yi Jiang, Wei Zhou, Suxin Luo Department of Cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of ChinaCorrespondence: Suxin LuoDepartment of Cardiology, The First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuzhong District, Chongqing, 400016, People’s Republic of ChinaTel +86 23 8901 1562Fax +86 23 89011429Email luosuxin0204@163.comObjective: Thyroid hormones are closely related to the cardiovascular system. Our study aimed to explore the impact of admission thyroid-stimulating hormone (TSH) levels on long-term outcomes in patients with acute ST segment elevation myocardial infarction (STEMI) by detailed stratifications of TSH.Methods: Consecutive STEMI patients admitted to our hospital were divided into four groups: Group 1 (TSH < 0.35 mIU/L), Group 2 (TSH 0.35– 1.0 mIU/L), Group 3 (TSH 1.0– 3.5 mIU/L), and Group 4 (TSH > 3.5 mIU/L). The primary endpoint was all-cause mortality during follow-up, and the median follow-up was 2.5 years. Cox proportional hazard regression models were performed to identify the prognostic value of TSH.Results: A total of 1186 patients were included. Group 4 was presented with higher systolic and diastolic blood pressure (all P < 0.001), and Group 1 had more patients complicated by heart failure (Killip class >I, P = 0.014). During follow-up, 138 deaths occurred. Patients in Group 4 had the worst long-term outcomes (P < 0.001). The cumulative survival in Group 4 was remarkably lower (Log rank P < 0.001), whereas the other three groups were comparable (Log rank P = 0.365). Through Cox regression analysis, only TSH > 3.5 mIU/L was identified as an independent risk factor for long-term mortality after STEMI.Conclusion: Only TSH elevation beyond the normal range was associated with worse long-term prognosis in STEMI patients, while high-normal TSH or reduced TSH did not alter long-term prognosis of STEMI patients. TSH > 3.5 mIU/L was an independent risk factor for long-term mortality in STEMI.Keywords: acute myocardial infarction, thyroid hormone, thyroid-stimulating hormone, STEMI, TSH

Ying Liang,1,2 Drolma Yangzom,2 Lhamo Tsokyi,2 Yanping Ning,2 Baiyan Su,3,4 Shuai Luo,4 Bian Ma Cuo,2 Meilang ChuTso,2 Yanling Ding,1 Yahong Chen,1 Yongchang Sun1 1Department of Respiratory and Critical Care Medicine, Peking University Third Hospital, Beijing, 100191, People’s Republic of China; 2Department of Respiratory and Critical Care Medicine, Tibet Autonomous Region People’s Hospital, Lhasa, 850000, People’s Republic of China; 3Radiology Department, Peking Union Medical College Hospital, Beijing, 100730, People’s Republic of China; 4Radiology Department, Tibet Autonomous Region People’s Hospital, Lhasa, 850000, People’s Republic of ChinaCorrespondence: Yongchang SunDepartment of Respiratory and Critical Care Medicine, Peking University Third Hospital, North Garden Road 49, Haidian District, Beijing, People’s Republic of ChinaTel +86 139 1097 9132Fax +86 108 226 6989Email suny@bjmu.edu.cnBackground: COPD at high altitude may have different risk factors and unique clinical and radiological phenotypes. We aimed to investigate the demographic data, clinical and radiological features of COPD patients permanently residing at the Tibet Plateau (≥ 3000 meters above sea level).Methods: We conducted an observational cross-sectional study which consecutively enrolled COPD patients visiting the outpatient of Respiratory Medicine at Tibet Autonomous Region People’s Hospital from January 2018 to March 2021. All patients were Tibetan permanent residents aging ≥ 40 years and met the diagnosis of COPD according to Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines. Data including demographic characteristics, altitude of residence, risk factors, respiratory symptoms, comorbidities and medications, as well as computed tomography (CT) measurements were collected.Results: Eighty-four patients with definite COPD were enrolled for analysis. Their mean age was 64.7 (± 9.1) years. All patients lived at ≥ 3000 m above sea level and 34.5% of them lived at ≥ 4000 m. About 8.3% of the patients were current smokers and 44.0% were ex-smokers. Up to 88.1% of the patients reported long-term exposure to indoor biomass fuels. Most of the patients were classified as having mild-to-moderate (GOLD I: 27.4%; GOLD II: 51.2%) COPD, while 89.3% had a CAT score ≥ 10. Only 36.9% of the patients received regular long-term medications for COPD in the past year, in whom ICS/LABA and oral theophylline were the most common used pharmacological therapy. On CT scanning, the majority of our patients (70.7%) showed no or minimal emphysema, while signs of previous tuberculosis were found in 45.1% of the patients.Conclusion: COPD patients living at the Tibet Plateau had a heavy respiratory symptom burden, but most of them did not receive adequate pharmacological treatment. Indoor biomass fuel exposure and previous tuberculosis were prevalent, while the emphysema phenotype was less common in this population.Keywords: chronic obstructive pulmonary disease, high altitude, phenotype, computed tomography

Jitao Liu,1,&ast; Fan Yang,2,&ast; Songyuan Luo,1,&ast; Chenxi Li,3 Weijie Liu,4 Yuan Liu,1 Wenhui Huang,1 Enmin Xie,5 Lyufan Chen,6 Sheng Su,5 Xinyue Yang,6 Qingshan Geng,1 Jianfang Luo1,5 1Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, People’s Republic of China; 2Department of Emergency and Critical Care Medicine, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, People’s Republic of China; 3Department of Cardiac Surgery Intensive Care Unit, Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, People’s Republic of China; 4Center for Information Technology and Statistics, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, People’s Republic of China; 5The Second School of Clinical Medicine, Southern Medical University, Guangzhou, People’s Republic of China; 6School of Medicine, South China University of Technology, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jianfang Luo; Qingshan GengDepartment of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, #106 Zhongshan Second Road, Yuexiu District, Guangzhou, Guangdong, 510080, People’s Republic of ChinaTel +86-20-83827812Fax + 86-20-83875453Email jianfangluo@sina.com; gengqingshan@gdph.org.cnPurpose: The present study aimed to investigate the incidence and predictors of post-operative delirium (POD) in patients with complicated type B aortic dissection (TBAD) undergoing TEVAR with/without concomitant procedures and to assess the association of POD with early and follow-up outcomes.Methods: A retrospective single-center cross-sectional analysis was conducted using a prospectively maintained database from 2010 to 2017. Outcomes were postoperative clinical outcomes, early and follow-up survival.Results: A total of 517 complicated TBAD patients were enrolled. POD was observed in 13.3% (69/517) patients and was associated with increased hospital length of stay (LOS) and hospital costs (P< 0.001 for both). Besides, POD was found to be an independent risk factor for prolonged ICU stay (odds ratio [OR] 4.39, 95% confidence interval [CI] 2.40– 8.01, P< 0.001) and early death (OR 4.42, 95% CI 1.26– 15.54, P= 0.020). Predictors of POD were hybrid procedure (OR 2.17, 95% CI 1.20– 3.92, P= 0.010), the use of benzodiazepine (OR 1.86, 95% CI 1.07– 3.23, P= 0.027) or quinolone (OR 2.35, 95% CI 1.26– 4.38, P= 0.007), creatinine > 2 mg/dL (OR 3.25, 95% CI 1.57– 6.72, P= 0.001) and preoperative blood transfusion (OR 3.31, 95% CI 1.76– 6.21, P< 0.001). After a median follow-up of 73.6 months, POD remained as an independent indicator for follow-up mortality (hazard ratio [HR] 2.40, 95% CI 1.31– 4.38, P= 0.005) after adjusting potential confounders.Conclusion: POD after TEVAR has an incidence of around 13% and could profoundly increase the in-hospital LOS, hospital costs, as well as the early and follow-up mortality. A series of risk factors, including hybrid procedure, the use of benzodiazepine or quinolone, creatinine > 2 mg/dL and preoperative blood transfusion, were identified as independent risk factors for POD. Effective risk-stratification and patient-tailored management strategy should be developed to reduce the incidence of POD.Keywords: type B aortic dissection, thoracic endovascular aortic repair, hybrid procedure, postoperative delirium, predictors, outcomes

Siqi Yan,1 Shaohong Huang,1 Zijing Yang,2 Song Luo,1 Xiaoxia Yang,1 Lidan He,1 Jianbo Li,1 Guoying Que1 1Stomatological Hospital, Southern Medical University, Guangzhou, People’s Republic of China; 2Department of Biostatistics, School of Public Health, Guangdong Provincial Key Laboratory of Tropical Disease Research, Southern Medical University, Guangzhou, People’s Republic of ChinaCorrespondence: Jianbo Li; Guoying QueStomatological Hospital, Southern Medical University, No. 366, South of Jiangnan Avenue, Guangzhou, People’s Republic of ChinaTel +862084413946Email 435264691@qq.com; 2917268593@qq.comPurpose: This study aimed to investigate the new development of caries among preschoolers in northern Guangdong and to assess caries-related factors to distinguish groups with different caries risk levels.Methods: Baseline data were recorded for participants from September to November 2019, and participants were reexamined from September to November 2020. A longitudinal observation of 11,973 preschoolers was conducted. The simplified debris index (DI-S) and decayed-missing-filled tooth (dmft) index values were obtained for each participant.Results: Factors associated with whether caries would occur in the future and one-year increase in dmft (Δdmft) included baseline dmft, baseline DI-S, and baseline age. The risk ratio (RR) of caries occurrence and the number of teeth with new-onset caries were 4.482 (95% confidence interval, 4.056– 4.957) and 2.945 (2.742– 3.165) in the participants with baseline dmft ≥ 3, which were higher than those with baseline dmft =1 or 2. In the baseline caries-free group, whether caries would occur in the future was related to the baseline DI-S (95% confidence interval, 0.022– 0.062). The caries incidence of maxillary central incisors (27.9%) was the highest among teeth of preschoolers without caries at baseline, whereas the caries incidence of mandibular first deciduous molars (42.7%) was the highest among teeth of preschoolers with caries at baseline.Conclusion: Baseline dmft is a good predictor of future caries. Children with baseline caries-free status, baseline dmft > 0, and baseline dmft ≥ 3 should be treated with preventive interventions of different intensities and frequencies. The occurrence of future caries in baseline caries-free participants is related to oral hygiene status. Measures to prevent caries on smooth surfaces, such as topical fluoridation, should be applied to all preschoolers. Preschoolers with caries at baseline may be given priority for pit and fissure sealing.Keywords: preschool children, caries risk, previous caries experience, simplified debris index, oral epidemiology

Maggie E Horn,1 Steven Z George,2 Cai Li,3 Sheng Luo,4 Trevor A Lentz2 1Duke University, Department of Orthopaedic Surgery, Durham, NC, 27701, USA; 2Duke University, Department of Orthopaedic Surgery and Duke Clinical Research Institute, Durham, NC, 27701, USA; 3Yale University, Department of Biostatistics, New Haven, CT, USA; 4Duke University, Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, NC, USACorrespondence: Maggie E HornDuke University, Department of Orthopaedic Surgery, Box 100402, Durham, NC, 27701, USATel +1 9196841365Email maggie.horn@duke.eduRationale: Risk assessment tools can improve clinical decision-making for individuals with musculoskeletal pain, but do not currently exist for predicting reduction of pain intensity as an outcome from physical therapy.Aims and Objective: The objective of this study was to develop a tool that predicts failure to achieve a 50% pain intensity reduction by 1) determining the appropriate statistical model to inform the tool and 2) select the model that considers the tradeoff between clinical feasibility and statistical accuracy.Methods: This was a retrospective, secondary data analysis of the Optimal Screening for Prediction of Referral and Outcome (OSPRO) cohort. Two hundred and seventy-nine individuals seeking physical therapy for neck, shoulder, back, or knee pain who completed 12-month follow-up were included. Two modeling approaches were taken: a longitudinal model included demographics, presence of previous episodes of pain, and regions of pain in addition to baseline and change in OSPRO Yellow Flag scores to 12 months; two comparison models included the same predictors but assessed only baseline and early change (4 weeks) scores. The primary outcome was failure to achieve a 50% reduction in pain intensity score at 12 months. We compared the area under the curve (AUC) to assess the performance of each candidate model and to determine which to inform the Personalized Pain Prediction (P3) risk assessment tool.Results: The baseline only and early change models demonstrated lower accuracy (AUC=0.68 and 0.71, respectively) than the longitudinal model (0.79) but were within an acceptable predictive range. Therefore, both baseline and early change models were used to inform the P3 risk assessment tool.Conclusion: The P3 tool provides physical therapists with a data-driven approach to identify patients who may be at risk for not achieving improvements in pain intensity following physical therapy.Keywords: persistent pain, risk assessment tool, musculoskeletal pain, risk prediction, psychological factors

Hailan Li,1,* Shiyong Luo,2,* Youming Zhang,3 Xiaoyi Xiao,4 Huaping Liu4 1Department of Radiology, Hunan Provincial People’s Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, 410000, Hunan Province, People’s Republic of China; 2Department of Radiology, Wuhan Third Hospital (Tongren Hospital of Wuhan University), Wuhan, 430060, Hubei Province, People’s Republic of China; 3Department of Radiology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan Province, People’s Republic of China; 4Department of Radiology, The Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Huaping LiuDepartment of Radiology, The Third Xiangya Hospital, Central South University, Tongzipo Road 138, Changsha, 410013, Hunan Province, People’s Republic of ChinaTel +86-731-88638888Fax +86-731-84327332Email huaziyiranshuai@126.comPurpose: To evaluate longitudinal computed tomography (CT) features and the predictive value of the initial CT and clinical characteristics for mortality in patients with severe/critical coronavirus disease 2019 (COVID-19) pneumonia.Methods: A retrospective analysis was performed on patients with COVID-19 pneumonia confirmed by laboratory. By excluding mild and common patients, 155 severe/critical patients with definite outcome were finally enrolled. A total of 516 CTs of 147 patients were divided into four stages according to the time after onset (stage 1, 1– 7 days; stage 2, 8– 14 days; stage 3, 15– 21 days, and stage 4, > 21 days). The evolving imaging features between the survival and non-survival groups were compared by using Chi-square, Fisher’s exact test, student’s t-test or Mann–Whitney U-test, as appropriate. The predictive value of clinical and CT features at admission for mortality was analysed through logistic regression analysis. To avoid overfitting caused by CT scores, CT scores were divided into two parts, which were combined with clinical variables, respectively, to construct the models.Results: Ground-glass opacities (GGO) patterns were predominant for stages 1 and 2 for both groups (both P> 0.05). The numbers of consolidation lesions increased in stage 3 in both groups (P=0.857), whereas the linear opacity increased in the survival group but decreased in the non-survival group (P=0.0049). In stage 4, the survival group predominantly presented linear opacity patterns, whereas the non-survival group mainly showed consolidation patterns (P=0.007). Clinical and imaging characteristics correlated with mortality; multivariate analyses revealed age > 71 years, neutrophil count > 6.38 × 109/L, aspartate aminotransferase (AST) > 58 IU/L, and CT score (total lesions score > 17 in model 1, GGO score > 14 and consolidation score > 2 in model 2) as independent risk factors (all P< 0.05). The areas under the curve of the six independent risk factors alone ranged from 0.65 to 0.75 and were 0.87 for model 2, 0.89 for model 1, and 0.92 for the six variables combined. Statistical differences were observed between Kaplan Meier curves of groups separated by cut-off values of these six variables (all P< 0.01).Conclusion: Longitudinal imaging features demonstrated differences between the two groups, which may help determine the patient’s prognosis. The initial CT score combined with age, AST, and neutrophil count is an excellent predictor for mortality in COVID-19 patients.Keywords: COVID-19, SARS-CoV-2, mortality, multivariate combined analysis, chest CT score, risk factors

Shengsheng Lai,1,* Lei Sun,2,* Jialiang Wu,3 Ruili Wei,4 Shiwei Luo,4 Wenshuang Ding,5 Xilong Liu,6 Ruimeng Yang,4 Xin Zhen2 1School of Medical Equipment, Guangdong Food and Drug Vocational College, Guangzhou, Guangdong, 510520, People’s Republic of China; 2School of Biomedical Engineering, Southern Medical University, Guangzhou, Guangdong, 510515, People’s Republic of China; 3Department of Radiology, The University of Hong Kong Shenzhen Hospital, Shenzhen, Guangdong, 518000, People’s Republic of China; 4Department of Radiology, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, 510180, People’s Republic of China; 5Department of Pathology, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, 510180, People’s Republic of China; 6Department of Radiology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ruimeng YangDepartment of Radiology, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, 510180, People’s Republic of ChinaTel +86-20-81048873Email eyruimengyang@scut.edu.cnXin ZhenSchool of Biomedical Engineering, Southern Medical University, Guangzhou, Guangdong, 510515, People’s Republic of ChinaTel +86-20-62789323Email xinzhen@smu.edu.cnObjective: To investigate the predictive performance of different machine learning models for the discrimination of low and high nuclear grade clear cell renal cell carcinoma (ccRCC) by using multiphase computed tomography (CT)-based radiomic features.Materials and Methods: A total of 137 consecutive patients with pathologically proven ccRCC (including 96 low-grade [grade 1 or 2] and 41 high-grade [grade 3 or 4] ccRCC) from January 2011 to January 2019 were enrolled in this retrospective study. Target region of interest (ROI) delineation followed by texture extraction was performed on a representative slice with the largest section of the tumor on the four-phase (unenhanced phase [UP], corticomedullary phase [CMP], nephrographic phase [NP] and excretory phase [EP]) CT images. Fifteen concatenations of the four-phase features were fed into 176 classification models (built with 8 classifiers and 22 feature selection methods), the classification performances of the 2640 resultant discriminative models were compared, and the top-ranked features were analyzed.Results: Image features extracted from the unenhanced phase (UP) CT images demonstrated a dominant classification performance over features from the other three phases. The discriminative model “Bagging + CMIM” achieved the highest classification AUC of 0.75. The top-ranked features from the UP included one shape-based feature and five first-order statistical features.Conclusion: Image features extracted from the UP are more effective than other CT phases in differentiating low and high nuclear grade ccRCC based on machine learning–based classification modeling.Keywords: clear cell renal cell carcinoma, Fuhrman nuclear grade, computed tomography, machine learning, classification

Zhiguo Zhong,1 Yuyun Li,2,3 Yan Chen,2,3 Wen Chen,2 Siyan Li,4 Xiaohua Lv,2 Shiying Luo2 1Traditional Chinese Medicine Department, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524023, People’s Republic of China; 2Department of Pharmacology, School of Pharmacy, Guangdong Key Laboratory for Research and Development of Natural Drugs, Marine Biomedical Research Institute, Guangdong Medical University, Zhanjiang, 524023, People’s Republic of China; 3Institute of Traditional Chinese Medicine and New Pharmacy Development, Guangdong Medical University, Dongguan, 523808, People’s Republic of China; 4School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, People’s Republic of ChinaCorrespondence: Shiying LuoDepartment of Pharmacology, School of Pharmacy, Guangdong Key Laboratory for Research and Development of Natural Drugs, Marine Biomedical Research Institute, Guangdong Medical University, No. 2 East Wenming Road, Xiashan District, Zhanjiang, 524023, Guangdong, People’s Republic of ChinaTel +86 13763058766Fax +86 7592388588Email luosy76@gdmu.edu.cnBackground: Erzhi Pill (EZP), a traditional Chinese medicine (TCM) prescription, has been widely applied to improve bone metabolism and treat osteoporosis (OP) in China. However, its effective constituents and mechanisms remain unclear.Methods: By combining network pharmacology and zebrafish experiments, an integrative method was employed to address this problem. Firstly, the disease targets of OP were collected from two public gene databases. Secondly, the active compounds and drug targets of EZP were obtained from the traditional Chinese medicine systems pharmacology database and analysis platform (TCMSP). Thirdly, a drug-target-disease interaction network was constructed, and the key active components were identified by analyzing the topological characteristics of the network. Finally, these predicted results were tested by zebrafish experiments and compared with those from the literature. Specifically, quercetin as an important representative active component of EZP was applied to wild type and transgenic zebrafish larvae to assess its effects on skull mineralization and osteoplastic differentiation.Results: Our study identified 72 active compounds, 220 targets and 166 signaling pathways probably involved in the prevention and treatment of OP by EZP, wherein quercetin, apigenin, daidzein, luteolin, ursolic acid and kaempferol could be the key compounds, while PI3K-Akt signaling pathway, TNF signaling pathway and IL-17 signaling pathway could be the key signaling pathways. The experiments indicated that quercetin attenuated both the decrease of skull mineralization and the inhibition of skull osteoplastic differentiation in zebrafish larvae trigged by dexamethasone.Conclusion: Our study not only investigated potentially effective constituents and mechanisms of EZP in the prevention and treatment of OP, but also provided a reference for the in-depth research, development and application of TCM.Keywords: Erzhi Pill, osteoporosis, network pharmacology, mechanisms, zebrafish, quercetin

Jie Chen,1 Shiying Luo,1 Ning Li,1 Huimin Li,1 Jinming Han,2 Li Ling1 1Department of Neurology, Affiliated Hospital of Hebei University, Baoding, People’s Republic of China; 2Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, SwedenCorrespondence: Li LingDepartment of Neurology, Affiliated Hospital of Hebei University, Baoding, People’s Republic of ChinaEmail 592201535@qq.comJinming HanDepartment of Clinical Neuroscience, Karolinska Institutet, Stockholm, SwedenEmail jinming.han@ki.seAbstract: CSF1R-related leukoencephalopathy, mainly caused by the mutation of the colony stimulating factor 1 receptor (CSF1R) gene on chromosome 5, is an underestimated neurological disease typically presenting as early-onset cognitive decline and personality changes. Currently, there is no specific treatment for CSF1R-related leukoencephalopathy. Most clinicians failed to recognize this disease during an early disease stage, leading to a high rate of misdiagnosis. Although rare, an increasing amount of CSF1R-related leukoencephalopathy cases have been reported recently. In this study, we first report a 35-year-old woman with CSF1R-related leukoencephalopathy carrying a novel missense mutation c.2463G >C (p.W821C) of CSF1R. An extensive literature research was performed in order to better understand the broader genetic and clinical characteristics of CSF1R-related leukoencephalopathy. A total of 147 patients with CSF1R-related leukoencephalopathy confirmed either by the genetic test or brain biopsy were identified. Among them, 49 patients were sporadic, and the rest of individuals had a family history originating from 46 different families. Our study indicated that the average age of CSF1R-related leukoencephalopathy onset was 41.4 years. Typical clinical symptoms of CSF1R-related leukoencephalopathy include cognitive decline, movement disorders, behavior changes and mental disorders. Genetic studies have reported 93 missense mutations, 13 splicing mutations, 6 deletion/insertion mutations, 1 code shift mutation and 1 nonsense mutation of the CSF1R gene in patients with CSF1R-related leukoencephalopathy. Early genetic detection and brain biopsy would be helpful for a confirmed diagnosis, and more translational studies are needed to combat this devastating disease.Keywords: CSF1R-related leukoencephalopathy, clinical symptoms, CSF1R

Yang Chen,1,* Li Wang,1,* Shi Luo,2 Jun Hu,3 Xing Huang,1 Pei-Wen Li,2 Yi Zhang,1 Chao Wu,1 Bo-Le Tian1 1Department of Pancreatic Surgery, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, People’s Republic of China; 2Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, People’s Republic of China; 3Laboratory of Basic Scientific Research, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Bo-Le TianDepartment of Pancreatic Surgery, West China Hospital of Sichuan University, No. 37 Guo Xue Road, Chengdu, Sichuan Province 610041, People’s Republic of ChinaTel +86 13880683475Fax +86 28-85422475Email tianbolemed@163.comIntroduction: Pancreatic cancer, or pancreatic duct adenocarcinoma (PDAC), remains one of the most lethal cancers and features insidious onset, highly aggressive behavior and early distant metastasis. The dense fibrotic stroma surrounding tumor cells is thought to be a shield to resist the permeation of chemotherapy drugs in the treatment of PDAC. Thus, we synthesized a pancreas-targeting paclitaxel-loaded PEGylated liposome and investigated its antitumor efficacy in the patient-derived orthotopic xenograft (PDOX) nude mouse models of PDAC.Methods: The PTX-loaded PEGylated liposomes were prepared by film dispersion-ultrasonic method and modified by an N,N-dimethyl tertiary amino residue. Morphology characteristics of the PTX-loaded liposomes were observed by transmission electron microscope (TEM). The PDOX models of PDAC were established by orthotopic implantation and imaged by a micro positron emission tomography/computed tomography (PET/CT) imaging system. The in vivo distribution and antitumor study were then carried out to observe the pancreas-targeting accumulation and the antitumor efficacy of the proposed PTX liposomes.Results: PTX loaded well into both modified (PTX-Lip2N) and unmodified (PTX-Lip) PEGylated liposomes with spherical shapes and suitable parameters for the endocytosis process. The PDOX nude mouse models were successfully created in which high 18F-FDG intaking regions were observed by micro-PET/CT. In addition to higher cellular uptakes of PTX-Lip2N by the BxPC-3 cells, the proposed nanoparticle had a notable penetrating ability towards PDAC tumor tissues, and consequently, the antitumor ability of PTX-Lip2N was significantly superior to the unmodified PTX-Lip in vivo PDOX models and even more effective than nab-PTX in restraining tumor growth.Conclusion: The modified pancreas-targeting PTX-loaded PEGylated liposomes provide a promising platform for the treatment of pancreatic cancer.Keywords: pancreas-targeting, tertiary amine, pancreatic duct adenocarcinoma, paclitaxel liposome, antitumor efficacy

Fang Hu,1 Rui Xue,2 Xiaohong Wei,1 Zheng Wang,1 Shunkui Luo,1 Jianghong Lin,1 Zhixiang Yan,3 Liao Sun1 1Department of Endocrinology and Metabolism, The Fifth Affiliated Hospital Sun, Yat-Sen University, Zhuhai, Guangdong, People’s Republic of China; 2Department of Cardio-Thoracic Surgery, Zhuhai Hospital of Integrated Traditional Chinese Western Medicine, NanFang Medical University, Zhuhai, Guangdong, People’s Republic of China; 3Key Laboratory of Biomedical Imaging of Guangdong Province, Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, Guangdong, People’s Republic of ChinaCorrespondence: Zhixiang YanKey Laboratory of Biomedical Imaging of Guangdong Province, Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, Guangdong, People’s Republic of ChinaTel +86 13680373940Fax +86 7562528741Email yanzhx3@mail.sysu.edu.cnLiao SunDepartment of Endocrinology and Metabolism, The Fifth Affiliated Hospital Sun Yat-Sen University, Zhuhai, Guangdong, People’s Republic of ChinaTel/Fax +86 7562528741 Email sunliao@mail.sysu.edu.cnBackground: Increased compensatory intrarenal renin diminishes the efficacy of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) in the treatment of diabetic kidney disease (DKD). Early growth response-1 (Egr1) is a crucial transcriptional factor in the progress of DKD and is a potential transcription factor of intrarenal renin according to bioinformatic analysis. However, whether inhibition of Egr1 can suppress compensatory renin increase in DKD is unclear.Methods: We generated a high-fat diet (HFD)/streptozotocin (STZ)-induced diabetic mouse model. The mice were treated with either enalapril (an ACEI) or enalapril combined with a shEgr1 plasmid, and age-matched DKD mice were used as controls. Urine microalbumin, urinary renin and kidney TGF-β 1 were determined by enzyme-linked immunosorbent assay (ELISA). Hematoxylin and eosin (H&E) and Masson staining were used to determine renal pathological changes. Egr1, renin, TNF-α, and FN were measured by real-time quantitative PCR, Western blot, and immunohistochemistry. The SV40-MES13 murine mesangial cell line was transfected with pENTER-Egr1 plasmid and siEgr1.Results: Our results showed that enalapril increased the renin level of urinary and renal in DKD mice, while shEgr1 attenuated this effect. In addition, enalapril treatment reduced the levels of urinary microalbumin, TNF-α, TGF-β 1 and FN, and alleviated the pathological changes, while shEgr1 strengthened these effects. The protein and mRNA expression of renin in the SV40 MES13 cells was upregulated and downregulated following overexpression and silence of Egr1, respectively.Conclusion: Silence of Egr1 could alleviate renal injury in DKD by downregulating intrarenal renin.Keywords: diabetic kidney disease, early growth response-1, renin-angiotensin system

Ning Li,1,* Xiyang Liu,2,* Yongping Song,2 Suxia Luo,1 Baijun Fang2 1Department of Oncology, Henan Cancer Hospital, Henan Cancer Hospital Affiliated to Zhengzhou University, Zhengzhou University, Zhengzhou, People’s Republic of China; 2Henan Institute of Haematology, Department of Hematology, Henan Cancer Hospital, Henan Cancer Hospital Affiliated to Zhengzhou University, Zhengzhou University, Zhengzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Baijun FangHenan Institute of Haematology, Department of Hematology, Henan Cancer Hospital, Henan Cancer Hospital Affiliated to Zhengzhou University, Zhengzhou University, 127 Dongming Road, Zhengzhou 450008, People’s Republic of ChinaTel +86-371-65587318Fax +86-371-65961505Email bjfdr_sea@163.comObjective: The synchronous presence of multiple myeloma (MM) and other primary malignant tumors (PMTs) were rarely reported. This study aimed to analyze several cases of MM and other PMTs in order to improve clinicians’ understanding of multiple myeloma (MM) with sMPMTs.Methods: This study was a retrospective trial. We retrospectively analyzed six cases of the synchronous presence of MM and other PMTs and reviewed the literature to summarize the clinical features and treatment.Results: The results showed that five cases of immunoglobulin G (IgG) and one case of kappa light chain; D-S stage: six case of stage III; ISS stage: one case of stage I, two cases of stage II, and three cases of stage III; one case each of gastric cancer (pT2N0MO, stage I), breast cancer (pT1bN0M0, stage I), lung cancer (pT1N0M0, stage I), cervical cancer (stage IB2), thyroid cancer (pT1N0M0, stage I), and diffuse large B-cell lymphoma (Ann-Arbor stage II); three of five patients underwent surgery alone, one patient underwent surgery first and then received chemotherapy at the time of pleural metastasis and the other patient only received radiotherapy; two patients were still alive, three died of progression of MM, and one died of lung cancer. The median survival time was 33.5 months (95% CI, 14.17 to 59.5months).Conclusion: The relationship between synchronous MM and other PMTs remains unknown. Clinicians should improve their understanding of MM with sMPMTs by carrying out multidisciplinary collaboration and a patient-oriented approach to optimize treatment and prolong the survival rates of patients.Keywords: multiple myeloma, primary malignant tumors, synchronous multiple primary malignant tumors, clinical features, treatment

Linling Xu, 1, 2 Xiaoxiao Sun, 1, 2 Ying Xia, 1, 2 Shuoming Luo, 1, 2 Jian Lin, 1, 2 Yang Xiao, 1, 2 Yue Liu, 1, 2 Yanfei Wang, 1, 2 Gan Huang, 1, 2 Xia Li, 1, 2 Zhiguo Xie, 1, 2 Zhiguang Zhou 1, 2 1Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China; 2Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, People’s Republic of ChinaCorrespondence: Zhiguang Zhou; Zhiguo Xie Email zhouzhiguang@csu.edu.cn; xiezhiguo@csu.edu.cnPurpose: The purpose of this study was to clarify the association between the NLRC4 gene and the susceptibility and clinical characteristics of type 1 diabetes (T1D) in a Chinese Han population.Patients and Methods: A case-control study was performed in a Chinese Han population including 510 classical T1D patients and 531 healthy controls. rs212704 and rs385076 of the NLRC4 gene were genotyped by MassARRAY. The frequency distributions of alleles and genotypes of polymorphisms in the NLRC4 gene were compared by logistic regression and the chi-square test. The relationships between the polymorphisms of the NLRC4 gene and various clinical characteristics were analyzed by Kruskal–Wallis one-way ANOVA. The statistical power was calculated by Quanto software.Results: 1) rs385076 of the NLRC4 gene was significantly correlated with the onset age of T1D patients and the positive rate of GADA. The relationship between rs212704 and 2-h postprandial C-peptide was statistically significant. 2) There was no significant difference in the frequency distributions of the genotypes and alleles of rs212704 and rs385076 between T1D patients and controls. 3) rs212704 and rs385076 were not correlated with T1D susceptibility under different genetic models.Conclusion: rs212704 was associated with 2-h postprandial C-peptide, while rs385076 of the NLRC4 gene was associated with the onset age and positive rate of GADA in patients with T1D.Keywords: type 1 diabetes, inflammasome, single nucleotide polymorphism

Jason D Lickliter, 1 Hui K Gan, 2–4 Mark Voskoboynik, 1, 5, 6 Surein Arulananda, 2–4 Bo Gao, 7 Adnan Nagrial, 7 Peter Grimison, 8 Michelle Harrison, 8 Jianjun Zou, 9 Lianshan Zhang, 9 Stacey Luo, 9 Michael Lahn, 10 Howard Kallender, 11 Andrea Mannucci, 10 Catello Somma, 10 Katherine Woods, 3 Andreas Behren, 3, 4 Pablo Fernandez-Penas, 12 Michael Millward, 13 Tarek Meniawy 13 1Nucleus Network, Melbourne, Victoria, Australia; 2Department of Medicine, University of Melbourne, Heidelberg, Victoria, Australia; 3Olivia Newton-John Cancer Wellness and Research Centre, Austin Hospital, Melbourne, Victoria, Australia; 4Department of Medical Oncology, La Trobe University School of Cancer Medicine, Bundoora, Victoria, Australia; 5Department of Medical Oncology, Alfred Hospital, Melbourne, Victoria, Australia; 6Department of Medical Oncology, Monash University, Central Clinical School, Alfred Campus, Melbourne, Victoria, Australia; 7Blacktown Cancer and Haematology Centre, Blacktown Hospital, University of Sydney, Sydney, New South Wales, Australia; 8Department of Medical Oncology, Chris O’Brien Life House, Camperdown, New South Wales, Australia; 9Jiangsu Hengrui Medicine Co. Ltd, Shanghai, People’s Republic of China; 10Incyte Biosciences International Sarl, Geneva, Switzerland; 11Incyte Corporation, Wilmington, Delaware, USA; 12Department of Dermatology, The University of Sydney, Westmead Hospital, Westmead, New South Wales, Australia; 13Linear Clinical Research, Nedlands, Western Australia, AustraliaCorrespondence: Jason D LickliterNucleus Network, Level 5, Burnet Tower, 89 Commercial Road, Melbourne, Victoria, AustraliaTel +61 3 9076 8900Fax +61 3 9076 8911Email j.lickliter@nucleusnetwork.com.auPurpose: Camrelizumab inhibits PD-1 in non-clinical models and showed typical non-clinical pharmacokinetic (PK) and safety profiles for an IgG4 monoclonal antibody. We report results from the First-in-Human Phase 1 trial of camrelizumab in Australian population.Methods: Camrelizumab was administered to patients with advanced solid tumors who had failed standard therapies. In the dose-escalation phase (n=23), camrelizumab was administered intravenously at 1 mg/kg, 3 mg/kg, 6 mg/kg, and 10 mg/kg every 2 weeks. In dose expansion (n=26), camrelizumab was given at 200 mg or 600 mg every 4 weeks.Results: Two dose-limiting toxicities were observed during dose escalation: transaminase elevation and diarrhea (both grade 3). Overall, treatment-related adverse events were consistent with the expected toxicity profile of immune checkpoint inhibition, with the striking exception of the dose-related development of angiomatous skin lesions characterized as reactive cutaneous capillary endothelial proliferation. The PK profile showed a dose-progressive increase in half-life from 3 days at 1 mg/kg to 7 days at 10 mg/kg. Moreover, receptor occupancy assays showed a PD-1 occupancy of > 50% in most patients out to 28 days post-dose. The objective response rate was 15.2% (95% CI 6.3– 28.9).Conclusion: Camrelizumab has manageable toxicity and encouraging preliminary antitumor activity in advanced solid tumors in Australia.Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT02492789.Keywords: PD-1, monoclonal antibody, first-in-human dose study, cancer, reactive cutaneous capillary endothelial proliferation

Wen-qun Li,1–3,* Jun-yong Wu,1–3,* Da-xiong Xiang,1–3 Shi-lin Luo,1–3 Xiong-bin Hu,1–3 Tian-tian Tang,1–3 Tao-li Sun,4 Xin-yi Liu1–3 1Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha 410011, People’s Republic of China; 2Institution of Clinical Pharmacy, Central South University, Changsha 410011, People’s Republic of China; 3Hunan Provincial Engineering Research Center of Translational Medicine and Innovative Drugs, Changsha 410011, People’s Republic of China; 4Key Laboratory Breeding Base of Hu’nan Oriented Fundamental and Applied Research of Innovative Pharmaceutics, College of Pharmacy, Changsha Medical University, Changsha 410219, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xin-yi LiuDepartment of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, People’s Republic of ChinaTel +86-731-8529-2093Email liuxinyi128@csu.edu.cnBackground: The protective role of puerarin (PUE) against myocardial infarction is closely related to its regulation on mitochondria. However, free PUE can hardly reach the mitochondria of ischemic cardiomyocytes due to the lack of mitochondrial targeting of PUE. Here PUE was loaded into mitochondria-targeted micelles (PUE@TPP/PEG-PE) for precisely delivering PUE into mitochondria with the aim of enhancing the anti-apoptosis effect.Methods: The mitochondriotropic polymer TPP-PEG-PE was synthesized for the preparation of PUE@TPP/PEG-PE micelles modified with triphenylphosphonium (TPP) cation. The physicochemical properties and anti-apoptosis effect of PUE@TPP/PEG-PE micelles were investigated. The coumarin 6 (C6)-labeled TPP/PEG-PE (C6@TPP/PEG-PE) micelles were used to observe the enhanced cellular uptake, mitochondrial targeting and lysosomes escape. Moreover, in vivo and ex vivo biodistribution of lipophilic near-infrared dye 1,1ʹ-dioctadecyl-3,3,3′,3ʹ-tetramethylindotricarbocyanine iodide (DiR)-labeled PUE@TPP/PEG-PE (DiR@TPP/PEG-PE) micelles were detected through fluorescence imaging.Results: The successful synthesis of TPP-PEG-PE conjugate was confirmed. PUE@TPP/PEG-PE micelles had a particle size of 17.1 nm, a zeta potential of −6.2 mV, and a sustained-release behavior. The in vitro results showed that the intracellular uptake of C6@TPP/PEG-PE micelles was significantly enhanced in H9c2 cells. C6@TPP/PEG-PE micelles could deliver C6 to mitochondria and reduce the capture of lysosomes. In addition, compared with the PUE@PEG-PE micelles and free PUE, the PUE@TPP/PEG-PE micelles exerted an enhanced protective effect against isoprenaline-induced H9c2 cell apoptosis, as evident by the decreased percentage of apoptotic cells, Caspase-3 activity, ROS level, Bax expression, and increased Bcl-2 expression. The in vivo detecting results of the targeting effect using DiR probe also indicated that TPP/PEG-PE micelles could accumulate and retain in the ischemic myocardium.Conclusion: The results of this study demonstrate the promising potential of applying PUE@TPP/PEG-PE micelles in mitochondria-targeted drug delivery to achieve maximum therapeutic effects of PUE.Keywords: mitochondrial targeting, anti-apoptosis, ischemic myocardium, TPP

Gang Wang,1 Tian-Mei Si,2 Lingjiang Li3,4 Yiru Fang,5 Chun-Xue Wang,6 Li-Na Wang,7 Kristin Hui Xian Tan,8 Anders Ettrup,9 Hanne-Lise Falgreen Eriksen,9 Si Luo,10 Lan Ge101Beijing An Ding Hospital, Capital Medical University, China National Clinical Research Center for Mental Disorders, Beijing, People’s Republic of China; 2Peking University Sixth Hospital & Peking University Institute of Mental Health, Beijing, 100191, People’s Republic of China; 3Key Laboratory of Mental Health, Ministry of Health (Peking University) &National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing, 100191, People’s Republic of China; 4The Second Xiangya Hospital of Central South University, Changsha, People’s Republic of China; 5Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 6Beijing Tian Tan Hospital, Department of Neuropsychiatry and Behavioral Neurology, Capital Medical University, National Clinical Research Center for Neurological Disease, Beijing, People’s Republic of China; 7Tianjin Anding Hospital, Tianjin, People’s Republic of China; 8Lundbeck Singapore Pte Ltd, Singapore; 9H. Lundbeck A/S, Valby, Denmark; 10Lundbeck China, Beijing, People’s Republic of ChinaObjective: Cognitive symptoms in major depressive disorder (MDD) are common and may negatively impact clinical and functional outcomes. The Prospective Research Observation to Assess Cognition in Treated patients with MDD (PROACT) study aimed to assess the prevalence and course of cognitive symptoms, and their associations with clinical and functional outcomes during 6 months of antidepressant treatment, in a real-world setting among Chinese patients with MDD.Patients and methods: Outpatients (n=598) aged 18–65 years with MDD and a total score ≥17 on the Hamilton Depression Rating Scale – 17 Items (HAM-D17) were observed over 6 months after initiating new antidepressant monotherapy, with follow-up visits at months 1, 2, and 6. Cognitive symptoms were assessed using the Perceived Deficits Questionnaire – Depression (PDQ-D) and cognitive performance using the Digit Symbol Substitution Test (DSST).Results: At baseline, 76.9% of patients had indications of cognitive symptoms (PDQ-D total score ≥21); at month 6, this was reduced, but still present in 32.4%. Across the 6-month study period, patients improved across cognitive, clinical and functional assessments. High levels of cognitive symptoms (PDQ-D) consistently predicted worse clinical outcomes, ie, lower odds for remission and increased odds for relapse, as well as worse patient-reported functional outcomes and lower quality of life. In contrast, cognitive performance (DSST) predicted performance-based functioning but only a few patient-reported functional outcomes (absenteeism and quality of life), and no clinical outcomes. PDQ-D and DSST scores were uncorrelated at baseline.Conclusion: The study highlights the importance of assessing and targeting cognitive symptoms for increasing patients’ chances of recovery and restoring functioning in the treatment of MDD. The results further highlight the relevance of complementary assessment methods to fully capture aspects of cognitive symptoms in patients with depression.Keywords: MDD, antidepressants, cognitive performance, real-world evidence, PDQ-D, DSST

Xianhui Kang,1,2,* Wandong Hong3,*, Kangjie Xie,4 Hongli Tang,1 Jingjing Tang,1 Shan Luo,1 Wujun Geng,1 Danyun Jia11Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, People’s Republic of China; 2Department of Anesthesiology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, People’s Republic of China; 3Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, People’s Republic of China; 4Department of Anesthesiology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, People’s Republic of China*These authors contributed equally to this workPurpose: Episodes of acute emotional or physical stress can have significant adverse effects on the hippocampus. Ginsenoside Rb1, the most predominant ginsenoside present in Panax species, has been reported to show a neuroprotective effect. The purpose of this study was to investigate the influence of ginsenoside Rb1 on plasma corticosterone (CORT) and adrenocorticotropic hormone (ACTH) levels and hippocampal brain-derived neurotrophic factor (BDNF) and tyrosine kinase B (TrkB) levels in rats subjected to acute immobilization stress.Methods: Wistar rats were divided into controls treated with saline only (N), rats exposed to stress only (M), and rats pretreated with Rb1 (40 mg.kg (−1)) thirty minutes prior to stress exposure (R). In the model, animals were restrained in a plastic immobilizer for 2 h of acute immobilization stress at room temperature. ELISA was used to determine plasma levels of CORT and ACTH. The effect of Rb1 pretreatment on the expression of BDNF and TrkB was determined by immunofluorescence, real-time PCR, and Western blotting analysis.Results: The R group showed significantly increased plasma CORT and ACTH levels compared to the N and M groups. Acute stress stimulation suppressed BDNF and TrkB protein and mRNA expression in the hippocampus; otherwise, Rb1 pretreatment reversed the decreases.Conclusion: The results from this study demonstrate that Rb1 pretreatment reverses the decreases in hippocampal BDNF/TrkB and increases the plasma levels of CORT and ACTH, indicating a potential neuroprotective effect of Rb1 against acute stress.Keywords: ginsenoside Rb1, CORT; ACTH, acute immobilization stress, BDNF, TrkB

Jian Xie,1 Shicheng Luo,2 Hongying Mi,3 Yibin Du,4 Guohong Bao,1 Jing Zhou,1 Yumei Xi,1 Cichun Li51Department of Traditional Chinese Medicine and Anorectum, The First People’s Hospital of Yunnan Province, Kunming 650000, People’s Republic of China; 2Department of General Surgery, The First People’s Hospital of Yunnan Province, Kunming 650000, People’s Republic of China; 3Department of Pediatrics, First People’s Hospital of Yunnan Province, Kunming 650000, People’s Republic of China; 4Department of Geriatrics, The First Affiliated Hospital of Yunnan College of Traditional Chinese Medicine, Kunming 650000, People’s Republic of China; 5Department of Traditional Chinese Medicine and Anorectum, The Second Affiliated Hospital of Kunming Medical University, Kunming 650000, People’s Republic of ChinaBackground: Rectal polyps is a major risk factor for rectal cancer. There is a need to explore a panel of preventive measures, as well as reliable biomarkers for screening of rectal polyps.Patients and methods: We conducted a case control study which aimed to explore the effects of regular consumption of ginsenoside Rg3, profiling of selected cytokines, and development of rectal polyps in a Chinese population.Results: Significantly higher levels of IL-4, MIP-1β, FasL, TGF-β1, and RANTES were detected in rectal polyp cases. Further, we found significant dose-response relationships between quartile-categorized levels of IL-4, MIP-1β, FasL, and TGF-β1, and risk of rectal polyps. The strongest associations for IL-4, MIP-1β, FasL, and TGF-β1 were observed for the highest quartile vs the lowest quartile with an OR of 1.78, 2.70, 1.49, and 2.36, respectively. Compared with non-Rg3 consumers, regular Rg3 consumers had a significantly lower risk of rectal polyps (OR =0.71; 95% CI: 0.55–0.92; P=0.009). We also found that Rg3 consumers had significantly lower levels of IL-4, MIP-1β, FasL, and TGF-β1 than non-Rg3 consumers, in both rectal polyp cases and healthy controls.Conclusion: These results indicate that regular consumption of Rg3 might prevent the occurrence of rectal polyps through decreasing the serum level of selected cytokines, including IL-4, MIP-1β, FasL, and TGF-β1. Further clinical trials and prospective cohort studies with larger sample sizes are warranted to validate the anti-inflammatory activity and the anti-tumorigenic role of Rg3.Keywords: cytokine, Rg3, rectal polyps, IL-4, MIP-1β, FasL, TGF-β1

Shaoguang Li, Shaohong Luo, Hao Chen, Yanjie Zheng, Liqing Lin, Hong Yao, Xinhua LinDepartment of Pharmaceutical Analysis, Faculty of Pharmacy, Fujian Medical University, Fuzhou 350122, People’s Republic of ChinaPurpose: Discovering new antimyocardial ischemia drug candidates that are highly efficient, have low toxicity, and originate from natural products is a popular trend for new cardiovascular drug development at present. The ethanol extract of Livistona chinensis leaves showed a favorable antioxidant activity in our preliminary screening test. This study aims to screen out antioxidants from the herb leaves further and evaluate their efficacy in acute myocardial ischemia treatment at the cellular level.Materials and methods: Guided with online 1, 1-diphenyl-2-picrylhydrazyl (DPPH)–high-performance liquid chromatography (HPLC) screening, antioxidants were first separated and isolated from the ethanol extract of L. chinensis leaves by preparative-HPLC. Subsequently, offline DPPH approach was used to validate the free radical scavenging activity of the components. Ultimately, the resulting antioxidants were evaluated against the hypoxia/reoxygenation (H/R)-, H2O2-, or adriamycin (ADM)-induced injury in H9c2 cells to verify their cardioprotective effects in vitro.Results: Five antioxidant ingredients, namely, orientin, isoorientin, vitexin, isovitexin, and tricin, were quickly distinguished and isolated from L. chinensis leaves. The IC50 values of these ingredients were further examined by offline DPPH assay, as follows: 15.51±0.22, 6.64±0.38, 11.86±0.24, 8.89±0.66, and 31.86±0.24 μg/mL, respectively. Out of these ingredients, isoorientin showed the strongest antioxidation, which was equivalent to that of the positive control drug (vitamin C, IC50: 6.99±0.62 μg/mL). Using H/R-, H2O2-, and ADM-induced H9c2 cell injury models, the five ingredients had different extents of cardioprotective effects in vitro. In particular, isoorientin showed the strongest protection. All the five ingredients also showed insignificant cytotoxic effect to normal H9c2 cells.Conclusion: The ethanol extract of L. chinensis leaves contained five antioxidants with low cardiac cytotoxicity. Isoorientin possessed the strongest antioxidation, which can predominantly account for the myocardial protection effects within the extract.Keywords: effect-directed analysis, antioxidant, protective effects, flavone, H9c2 cell