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Abstract We accurately reconstruct the Local Field Potential time series obtained from anesthetized and awake rats, both before and during CO $$_2$$ 2 euthanasia. We apply the Eigensystem Realization Algorithm to identify an underlying linear dynamical system capable of generating the observed data. Time series exhibiting more intricate dynamics typically lead to systems of higher dimensions, offering a means to assess the complexity of the brain throughout various phases of the experiment. Our results indicate that anesthetized brains possess complexity levels similar to awake brains before CO $$_2$$ 2 administration. This resemblance undergoes significant changes following euthanization, as signals from the awake brain display a more resilient complexity profile, implying a state of heightened neuronal activity or a last fight response during the euthanasia process. In contrast, anesthetized brains seem to enter a more subdued state early on. Our data-driven techniques can likely be applied to a broader range of electrophysiological recording modalities.

Yuan-Qin Du,1,* Bin Yuan,1,* Yi-Xian Ye,1 Feng-ling Zhou,1 Hong Liu,1 Jing-Jing Huang,2 Yan-Fei Wei3,4 1Graduate School, Guangxi University of Traditional Chinese Medicine, Nanning, 530200, People’s Republic of China; 2The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning, 530024, People’s Republic of China; 3Department of Physiology, Guangxi University of Traditional Chinese Medicine, Nanning, 530200, People’s Republic of China; 4Guangxi Key Laboratory of Translational Medicine for Treating High-Incidence Infectious Diseases with Integrative Medicine, Nanning, 530200, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yan-Fei Wei, Department of Physiology, Guangxi University of Traditional Chinese Medicine, No. 13 Wu He Road, Nanning, 530200, People’s Republic of China, Tel/Fax +86-771-4733794, Email weiyanfei@gxtcmu.edu.cnBackground/Aims: Plumbagin (PL) has been shown to effe ctively inhibit autophagy, suppressing invasion and migration of hepatocellular carcinoma (HCC) cells. However, the specific mechanism remains unclear. This study aimed to investigate the effect of PL on tumor growth factor (TGF)-β-induced epithelial-mesenchymal transition (EMT) in HCC.Methods: Huh-7 cells were cultured, and in vivo models of EMT and HCC-associated lung metastasis were developed through tail vein and in situ injections of tumor cells. In vivo imaging and hematoxylin and eosin staining were used to evaluate HCC modeling and lung metastasis. After PL intervention, the expression levels of Snail, vimentin, E-cadherin, and N-cadherin in the liver were evaluated through immunohistochemistry and Western blot. An in vitro TGF-β-induced cell EMT model was used to detect Snail, vimentin, E-cadherin, and N-cadherin mRNA levels through a polymerase chain reaction. Their protein levels were detected by immunofluorescence staining and Western blot.Results: In vivo experiments demonstrated that PL significantly reduced the expression of Snail, vimentin, and N-cadherin, while increasing the expression of E-cadherin at the protein levels, effectively inhibiting HCC and lung metastasis. In vitro experiments confirmed that PL up-regulated epithelial cell markers, down-regulated mesenchymal cell markers, and inhibited EMT levels in HCC cells.Conclusion: PL inhibits Snail expression, up-regulates E-cadherin expression, and down-regulates N-cadherin and vimentin expression, preventing EMT in HCC cells and reducing lung metastasis.Keywords: plumbagin, hepatocellular carcinoma, epithelial-mesenchymal transition, pulmonary metastasis, Snail

Bei Yuan, Shibei Song, Xiao Tang, Zhanqiang Ma Medical Department, The Second People’s Hospital of Guizhou Province (Guizhou Province Mental Health Center), Guizhou, Guiyang, 550001, People’s Republic of ChinaCorrespondence: Zhanqiang Ma, Medical Department, The Second People’s Hospital of Guizhou Province (Guizhou Province Mental Health Center), Guizhou, Guiyang, 550001, People’s Republic of China, Tel +86-13017432067, Email 13017432067@163.comPurpose: This study aims to investigate the impact of multidimensional quality management tools in establishing a medical adverse event management system, with the aim of continuously improving medical quality and safety while ensuring patient well-being.Methods: This study introduces risk management theories, such as the “Gray Rhino Theory”, and employs quality management tools like the Plan-Do-Check-Act (PDCA) cycle, Quality Control Circle (QCC), and Root Cause Analysis (RCA), to provide relevant quality management education and training to employees. This approach facilitates the establishment of a medical adverse event management system that encourages reporting and fosters a blame-free reporting culture, while simultaneously implementing quality management across the entire process. The regular utilization of the QCC facilitates ongoing quality improvement. Furthermore, for sentinel events and patient harm incidents with educational values, the study employs the Incident Decision Tree (IDT) to determine appropriate actions. Additionally, the hospital initiates RCA for system-wide improvements, focusing on areas such as management, institutional processes, and environmental aspects. Moreover, an internal medical quality improvement case competition is organized, with outstanding cases being selected to participate in the multidimensional quality management competition organized by the National Quality Management Alliance.Results: The study reveals a significant improvement in employees’ awareness of adverse events, the percentage of employees reporting adverse events increased significantly from 39.15% in 2019 to 49.77% in 2022, P=0.002. Furthermore, the adverse event reporting rate has risen significantly from 2.78% (2019) to 5.96% (2022), P=0.002. Additionally, each department has been able to utilize QCC or RCA tools for quality improvement, thereby further reinforcing the development of a patient safety culture.Conclusion: Multidimensional quality management tools play a crucial role in establishing a hospital’s adverse event management system, promoting continuous improvement in medical quality, ensuring patient safety, and effectively implementing a culture of patient safety.Keywords: multidimensional quality management tools, adverse events, management system, patient safety

Cong Zhou,1 Hui Zhang,1 Maosuo Xu,1 Yajuan Liu,1 Baoyu Yuan,2 Yong Lin,1 Fang Shen1 1Department of Clinical Laboratory, Shanghai Fifth People’s Hospital, Fudan University, Shanghai, People’s Republic of China; 2Department of Clinical Laboratory, Shanghai Children’s Hospital, Shanghai Jiao Tong University, Shanghai, People’s Republic of ChinaCorrespondence: Fang Shen; Yong Lin, Department of Clinical Laboratory, Shanghai Fifth People’s Hospital, Fudan University, No. 128, Ruili Road, Minhang District, Shanghai, 200240, People’s Republic of China, Tel +86 18021073261 ; +86 18718168695, Email shenfang5th@aliyun.com; linyong7007@163.comBackground: Hypervirulent carbapenem-resistant Klebsiella pneumoniae (hv-CRKP) has recently aroused an extremely severe health challenge and public concern. However, the underlying mechanisms of fitness costs that accompany antibiotic resistance acquisition remain largely unexplored. Here, we report a hv-CRKP-associated fatal infection and reveal a reduction in virulence due to the acquisition of aminoglycoside resistance.Methods: The bacterial identification, antimicrobial susceptibility, hypermucoviscosity, virulence factors, MLST and serotypes were profiled.The clonal homology and plasmid acquisition among hv-CRKP strains were detected by XbaI and S1-PFGE. The virulence potential of the strains was evaluated using Galleria mellonella larvae infection model, serum resistance assay, capsular polysaccharide quantification, and biofilm formation assay. Genomic variations were identified using whole-genome sequencing (WGS).Results: Four K. pneumoniae carbapenemase (KPC)-producing CRKP strains were consecutively isolated from an 86-year-old patient with severe pneumonia. Whole-genome sequencing (WGS) showed that all four hv-CRKP strains belonged to the ST11-KL64 clone. PFGE analysis revealed that the four ST11-KL64 hv-CRKP strains could be grouped into the same PFGE type. Under the pressure of antibiotics, the antimicrobial resistance of the strains increased and the virulence potential decreased. Further sequencing, using the Nanopore platform, was performed on three representative isolates (WYKP586, WYKP589, and WYKP594). Genomic analysis showed that the plasmids of these three strains underwent a large number of breaks and recombination events under antibiotic pressure. We found that as aminoglycoside resistance emerged via acquisition of the rmtB gene, the hypermucoviscosity and virulence of the strains decreased because of internal mutations in the rmpA and rmpA2 genes.Conclusion: This study shows that ST11-KL64 hv-CRKP can further evolve to acquire aminoglycoside resistance accompanied by decreased virulence to adapt to antibiotic pressure in the host.Keywords: hypervirulent carbapenem-resistant Klebsiella pneumoniae, within-host evolution, plasmids, whole-genome sequencing

Yikuan Du,1,* Xiaolin Cai,2,3,* Bijun Xu,2,3 Yuqing Wu,2,3 Mianhai Chen,2,3 Jinjin Wang,2,3 Bing Yuan,2,3 Weichui Zhang,2,3 Jinfeng Zhu,2,3 Chun Yang2,3 1Central Laboratory, The Tenth Affiliated Hospital of Southern Medical University, Dongguan, 523059, People’s Republic of China; 2Dongguan Key Laboratory of Chronic Inflammatory Diseases, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, 523808, People’s Republic of China; 3Dongguan Key Laboratory of Stem Cell and Regenerative Tissue Engineering, Guangdong Medical University, Dongguan, 523808, People’s Republic of China*These authors contributed equally to this workCorrespondence: Chun Yang, Dongguan Key Laboratory of Chronic Inflammatory Diseases, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, People’s Republic of China, Tel +86 150 1915 9295, Email yangchunangel@163.comBackground: Fascial pathological pain is the main type of chronic pain in older adults today, and studying the relationship between fascia and pain can help in the clinical search for effective treatments. However, in the face of the vast amount of research findings, there is no systematic assessment of the relationship between fascia and pain in a bibliometric analysis. Therefore, the purpose of this study is to analyze studies on fascia and pain using CiteSpace and VOSviewer to identify research hotspots and future directions.Materials and Methods: A total of 744 papers related to fascia and pain from 2013 to 2022 were collected from the core collection database of Web of Science, and the authors, countries, institutions, keyword co-occurrence, keyword clustering, and keyword emergence were analyzed by CiteSpace and VOSviewer to construct a knowledge map.Results: Literature publication has shown an overall upward trend over the past decade, but there have been some fluctuations. Carmelo Pirri, Caterina Fede, and Raffaele De Caro are the top three authors with the most articles. The United States, China, and Spain are major contributors to fascial and pain research. The University of Padua, Universidad Complutense and Harvard Medical School are leading institutions in this field. However, it is noteworthy that the collaboration between authors, countries and institutions is not active. Keyword analysis showed that hot spots and trends in research on fascia and pain focused on hot diseases, major interventions, and mechanism exploration.Conclusion: This analysis identifies the most influential authors, institutions, and countries in the field of fascial and pain research and provides a reference for assessing their academic impact. The analysis of keywords and co-cited literature is useful for analyzing research hotspots and their evolution, as well as for predicting future trends.Keywords: fascia, pain, bibliometrics analysis, knowledge graph, research progress

Fibromyalgia is a chronic, widespread pain disorder that is strongly represented across the affective and cognitive dimensions of pain, given that the underlying pathophysiology of the disorder is yet to be identified. These affective and cognitive deficits are crucial to understanding and treating the fibromyalgia pain experience as a whole but replicating this multidimensionality on a preclinical level is challenging. To understand the underlying mechanisms, animal models are used. In this scoping review, we evaluate the current primary animal models of fibromyalgia regarding their translational relevance within the affective and cognitive pain realms, as well as summarize treatments that have been identified preclinically for attenuating these deficits.

Yulan Chang,1 Shujie Guo,2 Binbin Yuan,3 Huiling Chen,4 Ruxin Jiang5 1Department of Nursing, Henan Vocational College of Nursing, Anyang, Henan, 455001, People’s Republic of China; 2Department of Outpatient, Henan Provincial People’s Hospital, Zhengzhou, Henan, 450003, People’s Republic of China; 3Department of Cardiovascular Surgery, Fuwai Central China Cardiovascular Hospital, Zhengzhou, Henan, 450003, People’s Republic of China; 4Department of Structural Heart Disease, Fuwai Central China Cardiovascular Hospital, Zhengzhou, Henan, 450003, People’s Republic of China; 5Department of Anesthesia and Perioperative Medicine, Henan Provincial People’s Hospital, Zhengzhou, Henan, 450003, People’s Republic of ChinaCorrespondence: Shujie Guo, Department of Outpatient, Henan Provincial People’s Hospital, No. 7 Weiwu Road, Zhengzhou, Henan, 450003, People’s Republic of China, Tel +86 18538298287, Email guosj2022@yeah.netPurpose: The purpose of this study is to understand the risk perception, risk emotions and humanistic care needs of nursing staff during the Novel Coronavirus 2019 (Covid-19) pandemic.Methods: A cross-sectional survey was conducted on the perceived risk, risk emotions and humanistic care needs of 35,068 nurses in 18 cities of the Henan Province, China.We collected a total of 35,188 questionnaires, of which 35,068 were effectively returned, with an effective return rate of 99.7%. The collected data were summarized and statistically analyzed using Excel 97 2003 and IBM SPSS software.Results: Nurses’ risk perceptions and emotions vary during the covid-19 pandemic. In order to provide nurses with targeted psychological intervention to prevent nurses from suffering from unhealthy mental states.The results show that the total score of the nurses’ risk perceptions of Covid-19 was 3.66 ± 0.39, the highest score of nurses’ risk perception part is 5 points, and ≥ 3 points represent high risk and 88.3% of nurses believed that the Covid-19 risk was high. There were significant differences in the nurses’ total perceived risk scores for Covid-19 based on gender, age, prior contact with patients with suspected or confirmed Covid-19 and previous participation in other similar public health emergencies (P < 0.050). Of the nurses included in the study, 44.8% had some level of fear relating to Covid-19 and 35.7% were able to remain calm and objective. There were significant differences in the total scores for risk emotions relating to Covid-19 based on gender, age and prior contact with patients with suspected or confirmed Covid-19 (P < 0.050). Of the nurses included in the study, 84.8% were willing to receive humanistic care and 77.6% of these expected to be provided with humanistic care by institutions in the healthcare sector.Conclusion: Nurses with different basic data have different risk cognition and risk emotions. Different psychological needs should be considered, and targeted multi-sectoral psychological intervention services should be provided to help prevent nurses from developing unhealthy psychological states.Keywords: Covid-19, public health emergencies, risk perception, risk emotion, humanistic care

Haipeng Wang,1,2,&ast; Shichao Zhao,3,&ast; Qian Liu,4 Jinyu Wang,3 Beibei Yuan5 1Centre for Health Management and Policy Research, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China; 2NHC Key Laboratory of Health Economics and Policy Research, Shandong University, Jinan, People’s Republic of China; 3School of Public Administration, Shandong Normal University, Jinan, People’s Republic of China; 4School of Social Development and Public Policy, Beijing Normal University, Beijing, People’s Republic of China; 5China Center for Health Development Studies, Peking University, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Beibei Yuan, China Center for Health Development Studies, Peking University, Box 505, 38 Xue Yuan Road, Haidian District, Beijing, 100191, People’s Republic of China, Email beibeiyuan@bjmu.edu.cnObjective: This study aims to explore the association between financial incentives and job performance of primary care providers (PCPs) from a nationally representative survey in China.Methods: This is a cross-sectional study conducted in six provinces of China in 2019. A sample of 1388 PCPs participated in the survey was selected using a stratified cluster sampling method. A self-administered questionnaire composed of socio-demographic, work-related characteristics, financial incentives received by PCPs and their job performance was used. The association between financial incentives and job performance are analyzed using logistic regression model. The significance level for statistics is set at P < 0.05.Results: The PCPs with higher real income level have lower contextual performance (OR = 0.67, p < 0.01) and learning performance (OR = 0.63, p < 0.01) than those with lower real income level. The PCPs with the expectation of income rising above 50% have lower contextual performance (OR = 0.66, p < 0.05) than those with the expectation of income rising above 20%. The PCPs with preference for monetary income have lower task performance (OR = 0.62, p < 0.01), contextual performance (OR = 0.55, p < 0.01) and learning performance (OR = 0.57, p < 0.01) than those without lower preference for monetary income. The percent of performance-based income has no significant effect on all the three dimensions of job performance.Conclusion: Financial incentive was regarded as the most important motivating factor of PCPs in China, but existing financial incentives received by PCPs could not improve their job performance. The findings can be attributed to the unsatisfying total income level, “intrinsic motivation crowding out” effect, and the poorly designed performance-based salary system for PCPs. Policy attention is called for to continuing efforts and system reform to increase the total income level for PCPs in China, and improve the performance-based salary system to better motivate PCPs and improve their job performance.Keywords: financial incentive, job performance, primary care providers, China

Bing Yuan HK Modern Chinese Medicine R&D Center, Kowloon, Hong KongCorrespondence: Bing Yuan, HK Modern Chinese Medicine R&D Center, Room 2, 7/F Kiu Kin Mansion, 566-568 Nathan Road, Kowloon, Hong Kong, Email greenisland@vip.163.comAbstract: The rise of precision medicine has opened up a broad space for the development of modern medicine and has also given practical significance to the concept of personalised medicine. Precision medicine is establishing a personalized disease classification system that differs from the traditional system. However, the research progress of precision medicine in recent years is far from satisfactory: There are few disease types that can be attributed to the abnormality of a single target; the effects of current’precision’ medications are not ideal, and various side effects remain unavoidable. The methodology of precision medicine is still reductionist, and it would not solve the integration problem of clinical treatment but rather would increase the difficulty of integration. Therefore, the precision medicine approach is not a feasible way to build a personalised medicine system. Based on the analysis and demonstration of the scientific limitations of precision medicine and the consistency of traditional Chinese medicine (TCM) and complexity science methods, this paper draws on the concepts and methods of cybernetics and complexity science, and proposes a fresh set of ideas and methods for the development of personalised medicine. The conclusion is as follows: Along the path of precision medicine, ideal personalised medicine cannot be achieved; what people ultimately need is personalised medicine that can achieve holistic integration. On the basis of TCM with the characteristics of holistic integration and personalisation, and according to scientific norms and the principle of evidence, building a theoretical model and state description system grounded in empirical evidence is the best way to establish a personalised medicine system.Keywords: personalised medicine, precision medicine, disease classification, state medicine, holistic medicine

Qiong Zhou,1,2 Yankun Zhu,3 Chun Li,2 Zhiqiang Li,1 Zhe Tang,2 Baohong Yuan,3 Xiaodan Wang,4 Shengqingyu Zhang,1 Xinan Wu1 1School of Public Health, Kunming Medical University, Kunming, People’s Republic of China; 2Department of Endocrinology, Yan’an Hospital Affiliated to Kunming Medical University, Kunming, People’s Republic of China; 3Department of General Surgery, Yan’an Hospital Affiliated to Kunming Medical University, Kunming, People’s Republic of China; 4Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Yan’an Hospital Affiliated to Kunming Medical University, Kunming, People’s Republic of ChinaCorrespondence: Xinan Wu, School of Public Health, Kunming Medical University, Kunming, 650500, People’s Republic of China, Tel +85-13888984762, Fax +86-871-65933614, Email wuxina@kmmu.edu.cnPurpose: Cathepsin L (CTSL) and B (CTSB) were lysosomal proteases, and their expression and activity contribute to the progression of inflammation in obese rodents. Our aim was to investigate CTSB and CTSL expression in omental adipose tissue (AT) of patients with obesity and to correlate CTSB and CTSL expression with proinflammatory cytokines (CCL-2, IL-6 and IL-1β).Patients and Methods: A total of 12 patients without obesity (NOB) and 51 patients with obesity (OB) were involved in this study. Omental AT was collected from all the participants for RNA extraction. Expressions of CTSB, CTSL and proinflammatory cytokines (CCL-2, IL-6 and IL-1β) were qualified with qRT-PCR. BMI (body mass index) and metabolic parameters were measured.Results: The mRNA expression levels of both CTSB and CTSL were upregulated in the OB group (t = 2.693, P < 0.05; t = 2.849, P< 0.01) and were related to TC levels (Std.β=0.443, P< 0.05; Std.β=0.439, P< 0.05). However, only the CTSB level was related to BMI (Std.β=0.261, P< 0.05). In multiple regression analysis, CTSL was independently associated with CCL-2, IL-6 and IL-1β levels (Std.β=0.352– 0.462, P< 0.05).Conclusion: CTSB and CTSL gene expressions were elevated in the omental AT of OB group. CTSL, but not CTSB, was positively correlated with proinflammatory cytokines independently, suggesting that the dysregulation of CTSL may play a significant role in the inflammatory process.Keywords: adipose tissue, cathepsin, cytokines, obesity, inflammation

Huiwen Li,1 Beibei Yuan,2 Yahang Yu,3 Jia Li,4 Qingyue Meng2 1China Population and Development Research Center, Beijing, People’s Republic of China; 2China Center for Health Development Studies, Peking University, Beijing, People’s Republic of China; 3School of Public Health, Peking University, Beijing, People’s Republic of China; 4Department of Health Policy and Management, School of Public Health, Peking University, Beijing, People’s Republic of ChinaCorrespondence: Beibei Yuan, China Center for Health Development Studies, Peking University, 38 Xuan Yuan Road, Haidian District, Beijing, 100191, People’s Republic of China, Tel +86 01 82805703, Fax +86 01 82805695, Email beibeiyuan@bjmu.edu.cnBackground: High turnover intention, as a manifestation of low work motivation, is a crucial barrier to strengthening primary health systems worldwide, including in China. Targeting those being less motivated will be a realistic choice to retain primary health workers. This study translate, adapt, and validate the Work Motivation Scale for Health Workers (WMSHW) scale to directly measure and rate health workers’ motivation composition based on Self-Determination Theory, and assessed how health workers with different levels of motivation being associated with the turnover intention.Methods: The process of translation and cross-cultural adaptation followed the recommendations of international guidelines. Participants include 1341 health workers within 75 primary health institutions from 6 provinces in China. The reliability and validity of the scale was analyzed. Cluster analysis in a person-centered approach and logistic regression analysis was used to understand how different combinations of motivations related to intention to leave.Results: Confirmatory factor analysis indicated that the modified five-factor model had a better fit than the other models in accordance with the original English version. The factor loads were high and ranged from 0.70 to 0.9. Cronbach’s alpha coefficients for five dimensions of the Chinese WMSHW ranged from 0.81 to 0.94, indicating the scale’s high internal consistency. Four distinct clusters of work motivation were found in this study, representing low motivated, highly controlled, highly autonomous and highly motivated primary health workers. Compared with low motivation group, both controlled and autonomous motivation groups were more likely to have lower turnover intention. The negative relationship between motivation and intention to leave became stronger with the level of motivation increasing: highly controlled cluster (OR: 0.47; 95% CI: 0.35– 0.63), highly autonomous (OR: 0.27; 95% CI: 0.18– 0.41) and highly motivated (OR: 0.20; 95% CI: 0.15– 0.27).Conclusion: The Chinese version of WMSHW showed satisfactory reliability and validity and can be used as an instrument for measuring and rating the work motivation of Chinese health workers. The primary health workers were grouped into four motivation levels based on this scale. Both controlled and autonomous motivation could work in reduce the turnover intention, and the influence of autonomous motivation on retaining was stronger.Keywords: work motivation, health worker, self-determination theory, validation, turnover intention

Yulan Chang,1 Shujie Guo,2 Haixin Zhang,3 Binbin Yuan,4 Jun Xu5 1Department of Nursing, Henan Vocational College of Nursing, Anyang, 455001, People’s Republic of China; 2Outpatient Department, Henan Provincial People’s Hospital, Zhengzhou, 450003, People’s Republic of China; 3Department of Nursing, Henan Provincial People’s Hospital, Zhengzhou, 450003, People’s Republic of China; 4Department of Cardiovascular Surgery, Fuwai Huazhong Cardiovascular Hospital, Zhengzhou, 450003, People’s Republic of China; 5Department of Neurology, Henan Provincial People’s Hospital, Zhengzhou, 450003, People’s Republic of ChinaCorrespondence: Shujie Guo, Outpatient Department, Henan Provincial People’s Hospital, No. 7 Weiwu Road, Zhengzhou, Henan, 450003, People’s Republic of China, Tel +86-18538298287, Email shujie_guo116@21cn.comBackground: Novel coronavirus 2019 (COVID-19) infections are highly contagious and have spread worldwide. Healthcare workers must understand the laws and regulations related to major public health emergencies to work effectively within this environment. Through investigation and analysis, a review was conducted to help gain a better understanding of a Level-1 response to public health events and the relevant laws and regulations applicable to medical staff. Based on the results, this study formulated measures for working in the current COVID-19 healthcare context.Methods: A total of 42,490 medical personnel in 18 cities in Henan Province (China) were reviewed and analysed using the convenience sampling method. A questionnaire was employed to address two areas of cognitive status quo (25 items), ie, “general information” and “major public events and rules of the law”.Results: More than 90% of medical staff had a good understanding related to knowledge about prevention and control in the pandemic context, as well as their due diligence and legal responsibility for controlling the pandemic and preventing others from being infected. However, 3.47– 32.61% of medical staff still had a minimal understanding of a Level-1 response to public health events and its relevant laws and regulations.Conclusion: The response to public health events required strengthening at all levels through promotion and education, by implementing an optimised treatment system and establishing an improved legal mechanism for the treatment of major conditions, such as hierarchical, stratified and triaged infectious diseases.Keywords: coronavirus disease 2019, major public health events, laws and regulations, cognitive behaviour

Baohong Yuan, Danyan Liu, Zunyan Zhu, Yonggang Hao, Kaihua He, Shiyun Deng Department of Anesthesiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of ChinaCorrespondence: Danyan Liu, Tel/Fax +86 23 8901 1069, Email liudanyan0418@163.comPurpose: Ultrasound-guided thoracic paravertebral block (TPVB) has become increasingly popular for postoperative analgesia after thoracic surgery. We designed this prospective, randomized, double-blind, placebo-controlled trial to investigate the effect of TPVB on blood coagulation in patients after thoracoscopic lobectomy.Patients and Methods: Sixty patients scheduled for thoracoscopic lobectomy were randomly allocated to two groups. Patients underwent ultrasound-guided TPVB with 0.33% ropivacaine (T group) or 0.9% saline (C group) at the end of the surgery under general anesthesia. Patient-controlled intravenous analgesia (PCIA) was administered for both group after the surgery. The primary outcome was the thromboelastogram (TEG) parameters before anesthesia (T0), at the end of operation (T1) and in 1 day (T2) and 2 days (T3) after the operation, the second outcomes were the analgesic effect and the amount of intraoperative opioid consumption, operation time, infusion volume, blood loss and urine volume.Results: The visual analog scale (VAS) scores in group T were lower than group C (P < 0.05). In group T, compared with T0, the R value at T1 and T2 is significantly reduced, and the K value at T1 were significantly shortened, the α-angle and MA value at T1 were significantly increased (P < 0.05). In group C, compared with T0, the R value and K value were significantly shortened, the α-angle and MA value were significantly increased at all postoperative time points (P < 0.05). Compared with group C at the same time point, the R and K values of group T were significantly longer, and the α-angle and MA values were significantly reduced at T2 and T3 points, with statistically significant differences (P< 0.05).Conclusion: TPVB is beneficial to improve postoperative hypercoagulability and promote postoperative rehabilitation of patients after thoracoscopic lobectomy.Keywords: paravertebral nerve block, thoracoscopic lobectomy, thrombelastogram, blood coagulation

Cong Zhou,1 Qiang Wu,1 Leqi He,1 Hui Zhang,1 Maosuo Xu,1 Baoyu Yuan,2 Zhi Jin,3 Fang Shen1 1Department of Clinical Laboratory Medicine, Shanghai Fifth People’s Hospital, Fudan University, Shanghai, People’s Republic of China; 2Department of Clinical Laboratory, Shanghai Children’s Hospital, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 3Department of Neurology, Shanghai Fifth People’s Hospital, Fudan University, Shanghai, People’s Republic of ChinaCorrespondence: Fang ShenDepartment of Clinical Laboratory Medicine, Shanghai Fifth People’s Hospital, Fudan University, No. 128, Ruili Road, Minhang District, Shanghai, 200240, People’s Republic of ChinaTel +86 18021073261Email shenfang5th@aliyun.comBackground: The convergence of carbapenem-resistance and hypervirulence in Klebsiella pneumoniae has led to a significant public health challenge. In recent years, there have been more and more reports on carbapenem-resistant hypervirulent Klebsiella pneumoniae (CR-hvKP) isolates.Materials and Methods: Clinical data of patients infected with CR-hvKP from January 2019 to December 2020 in a tertiary hospital were retrospectively evaluated. The number of isolates of Klebsiella pneumoniae, hypermucoviscous Klebsiella pneumoniae (hmKP), carbapenem-resistant hypermucoviscous Klebsiella pneumoniae (CR-hmKP) and carbapenem-resistant hypervirulent Klebsiella pneumoniae (CR-hvKP) collected during the period of 2 years was calculated. The antimicrobial resistance gene, virulence-associated gene, capsular serotype gene and multilocus sequence typing (MLST) of CR-hvKP isolates were detected by PCR.Results: During the study period, a total of 1081 isolates of non-repeat Klebsiella pneumoniae were isolated, including 392 isolates of hypermucoviscous Klebsiella pneumoniae (36.3%), 39 isolates of CR-hmKP (3.6%), and 16 isolates of CR-hvKP (1.5%). About 31.2% (5/16) of CR-hvKP were isolated from 2019, and 68.8% (11/16) of CR-hvKP were isolated from 2020. Among the 16 isolates of CR-hvKP, 13 isolates were ST11 and serotype K64, 1 isolate was ST11 and serotype K47, 1 isolate was ST23 and serotype K1, and 1 isolate was ST86 and serotype K2. The virulence-associated genes entB, fimH, rmpA2, iutA, iucA were present in all of 16 CR-hvKP isolates, followed by mrkD (n=14), rmpA (n=13), aerobactin (n=2), allS (n=1). Sixteen CR-hvKP isolates all carry carbapenemase gene blaKPC-2 and extended-spectrum β-lactamase gene blaSHV. ERIC-PCR DNA fingerprinting results showed that 16 CR-hvKP isolates were highly polymorphic, and there were significant differences in bands among the isolates, presenting a sporadic state.Conclusion: Although CR-hvKP was sporadically distributed, it showed an increasing trend year by year. Therefore, clinical attention should be paid, and necessary measures should be taken to avoid the cloning and transmission of superbacterium CR-hvKP.Keywords: Klebsiella pneumoniae, carbapenem-resistant, hypervirulent, hypermucoviscous, epidemiology

Kai Yuan,1,2 Jin Long Zhang,2 Jie Yu Yan,2 Bing Yuan,1 Jin Xin Fu,2 Yan Wang,2 Xue Dong Sun,3 Yang Guan,2 Feng Duan,2 Mao Qiang Wang1,2 1Medical School of Chinese PLA, Beijing, 100853, People’s Republic of China; 2Department of Interventional Radiology, The Fifth Medical Center, Chinese PLA General Hospital, Beijing, 100853, People’s Republic of China; 3School of Medicine, Nankai University, Tianjin, 300071, People’s Republic of ChinaCorrespondence: Mao Qiang WangDepartment of Interventional Radiology, The Fifth Medical Center, Chinese PLA General Hospital, 28 Fu-Xing Road, Beijing, 100853, People’s Republic of ChinaTel +86 10-66937190Email wangmq@vip.sina.comPurpose: To assess the long-term outcome of performing uterine artery embolization (UAE) using small particles in women with symptomatic adenomyosis (AD).Methods: Twenty-seven consecutive women (median age 42 years, range 29– 53 years) with AD, in eight cases AD combined with fibroids, who underwent UAE between February 2015 and January 2019, were retrospectively analyzed. The embolization was performed using small-sized polyvinyl alcohol particles (100 μm and 300 μm). The patients completed the Uterine Fibroid Symptom and Quality of Life questionnaire at baseline and at a 42-month follow-up (range 24– 71). The junction zone (JZ) thickness and uterine volume were also calculated at baseline and at a three-month follow-up.Results: The total symptom severity score (SSS) decreased from a median of 59 (range 34– 78) at baseline to a median of 9 (range 3– 47) at the end of this study; the health-related quality of life score (HRQOL) increased from a median of 38 (range 23– 49) at baseline to a median of 84 (range 46– 97) at 42 months. Twenty of the 27 patients were asymptomatic. The clinical response of the remaining seven women was little improvement in their symptoms, and one of the seven women underwent a hysterectomy at 35 months. Twenty-six of the 27 (96%) patients had a preserved uterus at the 42-month follow-up. There was no difference after UAE in SSS, HRQOL, junction zone (JZ) thickness, and uterus volume between patients with pure AD and those with AD combined with fibroids (p = 0.729, 0.710, 0.973, and > 0.99). There was no difference in the JZ thickness and uterus volume at baseline between the asymptomatic women and the women with an insufficient response (p = 0.854 and 0.253), and there were no major complications afterwards.Conclusion: From the long-term follow-ups, it could be seen that UAE using small particles is safe and effective in treating AD, especially in preserving the uterus. There is no relationship between the clinical outcomes and the initial presence of AD, with or without fibroids, and the JZ thickness at baseline does not seem to be a predictor for the long-term outcome of UAE.Keywords: adenomyosis, uterine artery embolization, UFS–QoL, interventional radiology

Haijun Wan, Bosi Yuan, Kang Jiang, Juan Wei, Xiaoyue Feng, Bo Sun, Fangyu Wang Department of Gastroenterology, General Hospital of Eastern Theater Command, Nanjing City, Jiangsu Province, 210002, People’s Republic of ChinaCorrespondence: Fangyu WangDepartment of Gastroenterology, General Hospital of Eastern Theater Command, No. 305 East Zhongshan Road, Xuanwu District, Nanjing City, Jiangsu Province, 210002, People’s Republic of ChinaEmail fangyuwangnanjing@163.comPurpose: CircRNA CircRIMS has been characterized as an oncogenic circRNA in gastric cancer, while its role in other cancers is unknown. This study aimed to explore the role of CircRIMS in esophageal squamous cell carcinoma (ESCC).Patients and Methods: Tissues collected from 60 ESCC patients were subjected to extractions of total RNA and RT-qPCRs to analyze the differential expression of CircRIMS and miR-613. The 60 ESCC patients were followed up for 5 years to analyze the prognostic value of CircRIMS for ESCC. The interaction between CircRIMS and miR-613 was showed by luciferase activity assay and fluorescence in situ hybridization. The role of CircRIMS in regulating miR-613 expression and methylation was analyzed by overexpression experiments, RT-qPCRs and Western blot assay. The role of CircRIMS and miR-613 in regulating cell proliferation was analyzed using the BrdU assay. ESCC xenograft model was used to demonstrate the role of CircRIMS and miR-613 in vivo.Results: We found that CircRIMS was overexpressed in ESCC and predicted poor survival. In addition, miR-613 was under expressed in ESCC and inversely correlated with CircRIMS. In ESCC cells, CircRIMS overexpression decreased the expression of miR-613 and increased the methylation of miR-613 gene. Cell proliferation assay showed that CircRIMS overexpression reduced the inhibitory effects of miR-613 overexpression on cell proliferation. Animal experience finally illustrated that CircRNA CircRIMS downregulated miR-613 through methylation to promote tumor growth.Conclusion: Therefore, CircRIMS may downregulate miR-613 through methylation to increase cell proliferation in ESCC.Keywords: esophageal squamous cell carcinoma, CircRIMS, miR-613, proliferation, methylation

Bing Yuan HK Modern Chinese Medicine R&D Center, Hong KongCorrespondence: Bing YuanHK Modern Chinese Medicine R&D Center, Room 2, 7/F Kiu Kin Mansion, 566-568 Nathan Road, Kowloon, Hong KongEmail greenisland@vip.163.comAbstract: The rise of precision medicine (PM) has initiated the transition of mainstream medicine from disease-based medicine to personalized medicine, alongside which the US FDA has begun to establish a clinical trial and efficacy evaluation (CTEE) system compatible with personalized medicine based on biological markers. Outside of modern medicine, however, there has always existed a personalized medical system, traditional Chinese medicine (TCM), that is, a personalized medical system built at the organism level with a similar concept and method to today’s complexity science. However, under the current CTEE system, TCM has not usually been shown to be effective. The CTEE system of modern medicine has now begun to embrace personalized medicine at the microlevel. Therefore, there is no reason to continue to reject TCM, which is a type of personalized medicine at the organism level. This paper analyzes and compares the commonality and differences between a personalized medical system based on biomarkers established by PM and a personalized medical system based on syndromes in TCM; the results clearly reveal structural relationships between the two medical systems. On this basis, through rigorous logical reasoning, the feasibility of applying the CTEE method which is used in PM to evaluate the efficacy of TCM treatments is demonstrated. The relationship among biomarkers by which PM describes personalized states and modern medical diseases and the relationship among TCM syndromes and diseases are completely consistent. Because of this consistency, the new CTEE system established by the US FDA to promote the development of PM is fully applicable to the clinical trial and efficacy evaluation of TCM treatment methods. Clinical trials and efficacy evaluations based on this system can scientifically prove the effectiveness of TCM, and TCM is expected to be incorporated into the modern medical system based on scientific norms.Keywords: clinical trials, personalized medicine, precision medicine, efficacy evaluation, holistic medicine, basket trial, umbrella trial, Chinese medicine, TCM

Bocong Yuan,1 Jiannan Li,2 Hairong Zhao,1 Guojun Zeng1 1School of Tourism Management, Sun Yat-Sen University, Guangzhou, People’s Republic of China; 2Institute of Advanced Studies in Humanities and Social Sciences, Beijing Normal University, Beijing, People’s Republic of ChinaCorrespondence: Jiannan LiBeijing Normal University, 19 Xinjiekouwai Street, Haidian District, Beijing, People’s Republic of ChinaEmail 91122020111@bnu.edu.cnGuojun ZengSun Yat-Sen University, 135 West Xingang Road, Haizhu District, Guangzhou, People’s Republic of ChinaEmail zenggj@mail.sysu.edu.cnPurpose: This study examined the roles of population aging and national development level in affecting different phases of novel coronavirus disease development with a view to advancing preparedness and corresponding policy.Methods: Regression analysis was conducted using multisource data from the World Bank and Johns Hopkins COVID-19 Dashboard.Results: Population aging is positively associated with confirmed cases of day-10, day-20, and day-30. The positive association between population aging and death does not emerge until day-20. Countries with a higher proportion of older males face higher risks of death.. Countries with a higher proportion of males aged 70– 74 years are at the highest risk of confirmed cases. National development level is not associated with confirmed cases, but developing countries face significantly higher risks of death of day-10 and day-20.Conclusion: Prevention and control policies for older adults and underdeveloped areas and sex differences need to be studied.Keywords: population aging, sex difference, policy preparedness, national development level, pandemic

Jiannan Li,1 Bocong Yuan,2 Guojun Zeng2 1International School of Business and Finance, Sun Yat-Sen University, Guangzhou, People’s Republic of China; 2School of Tourism Management, Sun Yat-Sen University, Guangzhou, People’s Republic of ChinaCorrespondence: Bocong Yuan; Guojun ZengSchool of Tourism Management, Sun Yat-Sen University, 135 West Xingang Road, Guangzhou, People’s Republic of ChinaEmail yuanbc@mail.sysu.edu.cn; zenggj@mail.sysu.edu.cnBackground: Schools in sub-Saharan Africa respond to the widespread use of tobacco among youth with the tobacco-prohibition policies. This study empirically examined the impact of the strength of campus tobacco-prohibition policies on tobacco use among youth across 20 sub-Saharancountries.Methods: This study used data from the Global School Personnel Survey across 20 sub-Saharan countries during 2005– 2011. Respondents comprised 7,365 school personnel (valid sample size) from Cameroon, Central African Republic, Congo, Eritrea, Ghana, Guinea-Bissau, Lesotho, Malawi, Mauritania, Mauritius, Namibia, Niger, Rwanda, Senegal, Seychelles, Sierra Leone, South Africa, Swaziland, Togo, and Uganda. Considering the potential endogeneity-estimation bias occurring in the normal ordinary least square estimation, instrumental variable estimation was used to ensure the regression results were reliable.Results: The interaction term “tobacco-prohibition policy × policy-enforcement strength” was found to negatively predict perceived seriousness of tobacco use among youth (− 0.0053, 95% CI [-0.0101, -0.0005]; p< 0.05), which indicated that when campus tobacco-prohibition policy and enforcement were both sufficiently strict, the extent to which school personnel felt concerned or anxious about tobacco use among youth in the 20 countries was lowest. A series of identification tests using instrumental variable estimation demonstrated that these regression results were reliable and without endogeneity-estimation bias.Conclusion: This study confirms the effectiveness of the interaction of tobacco-prohibition policy and policy-enforcement strength for alleviating the seriousness of tobacco use among youth in underdeveloped areas. A series of important policy implications are discussed to prevent fast development of tobacco use in this area.Keywords: tobacco-prohibition policy, tobacco use, sub-Saharan African countries, youth

Bing Yuan,1,* Feng Liao,1,* Zhi-Zhou Shi,2 Yuan Ren,1 Xiao-Li Deng,1 Ting-Ting Yang,1 Deng-Yuan Li,1 Ru-Fang Li,1 Dan-Dan Pu,1 Yu-Jue Wang,1 Yan Tan,1 Zhen Yang,1 Yun-Hui Zhang1 1Department of Pulmonary and Critical Care Medicine, The First People’s Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, People’s Republic of China; 2Medical School, Kunming University of Science and Technology, Kunming, Yunnan, People’s Republic of China*These authors contributed equally to this work.Correspondence: Zhen YangDepartment of Pulmonary and Critical Care Medicine, The First People’s Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, People’s Republic of ChinaEmail 49387127@qq.comYun-Hui ZhangDepartment of Pulmonary and Critical Care Medicine, The First People’s Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, People’s Republic of ChinaEmail yunhuizhang3188@126.comObjective: Lung cancer is the first leading cause of cancer-related deaths both worldwide and in China and threatens human health and quality of life. New drugs and therapeutic methods are urgently needed. Our study evaluated the roles of dihydroartemisinin (DHA) in lung cancer and further explored its underlying mechanisms.Methods: CCK-8, colony formation and trypan blue exclusion assays were used to detect the cell viability, colony formation ability and cell death. qRT-PCR and Western blotting assays were applied to analyze the expressions of key molecules.Results: DHA inhibited the proliferation and colony formation abilities and enhanced the cell death and induced ferroptosis of lung NCI-H23 and XWLC-05 cancer cells. DHA reduced PRIM2 expression and silencing PRIM2 mimicked the inhibitory roles on proliferation and colony formation and promotive roles on cell death and ferroptosis of DHA in lung NCI-H23 and XWLC-05 cancer cells. We further found that DHA treatment and loss of PRIM2 reduced the GSH level and increased the cellular lipid ROS and mitochondrial MDA levels, and further downregulated the expressions of SLC7A11 and β-catenin in lung cancer cells, respectively. Exogenetic overexpression of PRIM2 recovered the inhibitory effects of DHA on proliferation and colony formation in lung NCI-H23 cancer cells, meanwhile loss of PRIM2 sensitizes NCI-H23 cells to DHA therapy. In vivo experiment further showed that DHA treatment significantly suppressed the tumor growth and downregulated PRIM2 and SLC7A11.Conclusion: Our study suggested that DHA inhibited the proliferation, colony formation and enhanced cell death and induced ferroptosis of lung cancer cells by inactivating PRIM2/SLC7A11 axis. Loss of PRIM2 induced ferroptosis might developed to be a novel therapeutic method in lung cancer therapy.Keywords: dihydroartemisinin, lung cancer, proliferation, ferroptosis, PRIM2, SLC7A11

Minxun Lu,1,2 Hongjie Chen,2 Bo Yuan,2 Yong Zhou,1 Li Min,1 Zhanwen Xiao,2 Xiangdong Zhu,2 Chongqi Tu,1 Xingdong Zhang2 1Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, People’s Republic of China; 2National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, People’s Republic of ChinaCorrespondence: Xiangdong ZhuNational Engineering Research Center for Biomaterials, Sichuan University, No. 29 Wangjiang Road, Chengdu 610064, People’s Republic of ChinaTel +86-28-85470770Email zhu_xd1973@scu.edu.cnChongqi TuDepartment of Orthopedics, West China Hospital, Sichuan University, No. 37 Guoxue Street, Chengdu 610041, People’s Republic of ChinaTel +86-28-85422570Email Tuchongqi@yeah.netPurpose: The aim of research is to fabricate nanostructured hydroxyapatite (HA) coatings on the titanium via electrochemical deposition (ED). Additionally, the biological properties of the ED-produced HA (EDHA) coatings with a plate-like nanostructure were evaluated in vitro and in vivo by undertaking comparisons with those prepared by acid/alkali (AA) treatment and by plasma spray-produced HA (PSHA) nanotopography-free coatings.Materials and Methods: Nanoplate-like HA coatings were prepared through ED, and nanotopography-free PSHA coatings were fabricated. The surface morphology, phase composition, roughness, and wettability of these samples were investigated. Furthermore, the growth, proliferation, and osteogenic differentiation of MC3T3-E1 cells cultured on each sample were evaluated via in vitro experiments. Histological assessment and push-out tests for the bone–implant interface were performed to explore the effect of the EDHA coatings on the interfacial osseointegration in vivo.Results: XRD analysis showed that the strongest intensity for the EDHA coatings was at the (002) plane rather than at the regular (211) plane. Relatively higher surface roughness and greater wettability were observed for the EDHA coatings. Cellular experiments revealed that the plate-like nanostructured EDHA coatings not only possessed an ability, similar to that of PSHA coatings, to promote the adhesion and proliferation of MC3T3-E1 cells but also demonstrated significantly enhanced early or intermediate markers of osteogenic differentiation. Significant osseointegration enhancement in the early stage of implantation period and great bonding strength were observed at the interface of bone and EDHA samples. In comparison, relatively weak osseointegration and bonding strength of the bone–implant interface were observed for the AA treatment.Conclusion: The biological performance of the plate-like nanostructured EDHA coating, which was comparable with that of the PSHA, improves early-stage osteogenic differentiation and osseointegration abilities and has great potential for enhancing the initial stability and long-term survival of uncemented or 3D porous titanium implants.Keywords: electrochemical deposition, hydroxyapatite coatings, nanoscale, osteogenic activity, osseointegration

Bo Yuan,1 Rongqing Sun,1 Yuming Du,1 Zhankui Jia,2 Wencheng Yao,2 Jinjian Yang2 1Intensive Care Unit, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province 450052, People’s Republic of China; 2Urinary Surgery Department, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province 450052, People’s Republic of ChinaCorrespondence: Jinjian YangUrinary Surgery Department, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Erqi District, Zhengzhou, Henan Province 450052, People’s Republic of ChinaEmail yangjj_2011@126.comObjective: Long non-coding RNA (lncRNA) cancer susceptibility candidate 9 (CASC9) has been reported to play a vital role in tumorigenesis. This study explored the biological role of CASC9 and its regulation mechanism in bladder cancer (BC).Methods: Gene expression was evaluated using quantitative reverse transcription polymerase chain reaction and Western blot. The functional role of CASC9 in BC was studied using Cell Counting Kit-8, colony formation assay, scratch wound healing assay, transwell invasion assay, and xenograft tumor assay. In addition, the mechanism of CASC9 function in BC was determined using RNA immunoprecipitation assay and chromatin immunoprecipitation assay.Results: CASC9 was upregulated in BC tissues and cell lines, and correlated with the staging and metastasis in BC. Knockdown of CASC9 inhibited the proliferation, migration, and invasion of BC cells. Similarly, silencing of CASC9 inhibited tumor growth in vivo. Signal transducer and activator of transcription 3 (STAT3) was upregulated in BC tissues and cell lines, and positively correlated with CASC9 in BC tissues. Moreover, CASC9 was shown to be regulated by STAT3 in BC cells. Furthermore, CASC9 regulated phosphatase and tensin homolog (PTEN) expression by interacting with enhancer of zeste homolog 2 (EZH2). More significantly, CASC9 silencing-mediated inhibition of BC progression was partly reversed by EZH2 overexpression or PTEN inhibition.Conclusion: Upregulation of CASC9 induced by STAT3 promoted the progression of BC by interacting with EZH2 and affecting the expression of PTEN, representing a novel regulatory mechanism for BC progression.Keywords: bladder cancer, cancer susceptibility candidate 9, signal transducer and activator of transcription 3, phosphatase and tensin homolog, enhancer of zeste homolog 2

Xi Fu,1 Pin Liu,1 Dingyun Zhao,2 Bo Yuan,1 Zhanwen Xiao,1 Yong Zhou,2 Xiao Yang,1 Xiangdong Zhu,1 Chongqi Tu,2 Xingdong Zhang1 1National Engineering Research Center for Biomaterials, Sichuan University, Chengdu 610064, People’s Republic of China; 2Department of Orthopaedics, West China Hospital of Sichuan University, Chengdu 610041, People’s Republic of ChinaCorrespondence: Xiangdong ZhuNational Engineering Research Center for Biomaterials, Sichuan University, No. 29 Wangjiang Road, Chengdu 610064, People’s Republic of ChinaTel +86 28 8547 0770Email zhu_xd1973@scu.edu.cnChongqi TuDepartment of Orthopaedics, West China Hospital of Sichuan University, No. 37 Guo Xue Xiang, Chengdu 610041, People’s Republic of ChinaTel +86 28 8542 2570Email tcqbonetumor@163.comBackground: Angiogenic and osteogenic activities are two major problems with biomedical titanium (Ti) and other orthopedic implants used to repair large bone defects.Purpose: The aim of this study is to prepare hydroxyapatite (HA) coatings on the surface of Ti by using electrochemical deposition (ED), and to evaluate the effects of nanotopography and silicon (Si) doping on the angiogenic and osteogenic activities of the coating in vitro.Materials and Methods: HA coating and Si-doped HA (HS) coatings with varying nanotopographies were fabricated using two ED modes, ie, the pulsive current (PC) and cyclic voltammetry (CV) methods. The coatings were characterized through scanning electron microscope (SEM), X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), X-ray photoelectron spectrometer (XPS), and atomic force microscopy (AFM), and their in vitro bioactivity and protein adsorption were assessed. Using MC3T3-E1 pre-osteoblasts and HUVECs as cell models, the osteogenic and angiogenic capabilities of the coatings were evaluated through in vitro cellular experiments.Results: By controlling Si content in ∼ 0.8 wt.%, the coatings resulting from the PC mode (HA-PC and HS-PC) and CV mode (HA-CV and HS-CV) had nanosheet and nanorod topographies, respectively. At lower crystallinity, higher ionic dissolution, smaller contact angle, higher surface roughness, and more negative zeta potential, the HS and PC samples exhibited quicker apatite deposition and higher BSA adsorption capacity. The in vitro cell study showed that Si doping was more favorable for enhancing the viability of the MC3T3-E1 cells, but nanosheet coating increased the area for cell spreading. Of the four coatings, HS-PC with Si doping and nanosheet topography exhibited the best effect in terms of up-regulating the expressions of the osteogenic genes (ALP, Col-I, OSX, OPN and OCN) in the MC3T3-E1 cells. Moreover, all leach liquors of the surface-coated Ti disks promoted the growth of the HUVECs, and the HS samples played a more significant role in promoting cell migration and tube formation than the HA samples. Of the four leach liquors, only the two HS samples up-regulated NO content and expressions of the angiogenesis-related genes (VEGF, bFGF and eNOS) in the HUVECs, and the HS-PC yielded a better effect.Conclusion: The results show that Si doping while regulating the topography of the coating can help enhance the bone regeneration and vascularization of HA-coated Ti implants.Keywords: electrochemical deposition, hydroxyapatite, silicon, coating, morphology, MC3T3-E1 cells, HUVECs

Baoying Yuan,1,* Feifei Li,2,* Youbao Li,3 Yuhan Chen4 1Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China; 2The First Class Ward 2, The First Affiliated Hospital of Jinan University, Guangzhou, People’s Republic of China; 3Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China; 4Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yuhan Chen Email cspnr1@126.comObjective: The tumor microenvironment plays a key role in regulating tumor progression. This research aimed to develop the biomarker related to tumor microenvironment in clear cell renal cell carcinoma (ccRCC).Methods: The ESTIMATE algorithm was used to evaluate the immune score of ccRCC cases from The Cancer Genome Atlas (TCGA). Differentially expressed genes between high and low immune scores were identified and a 13-gene signature was constructed by the LASSO Cox regression model to predict overall survival (OS) for ccRCC cases in TCGA or International Cancer Genome Consortium (ICGC) project. The immune cell fractions were calculated by the TIMER algorithm. Cell viability and gene expression were determined by CCK-8 and qRT-PCR, respectively.Results: The OS of patients with high immune scores was worse than that of patients with low immune scores. The OS between ccRCC patients from TCGA or ICGC cohort in high- and low-risk groups stratified by the gene signature was significantly different. Subgroup analysis also showed a robust prognostic ability of the gene signature. Multivariate Cox regression analysis demonstrated that this gene signature was an independent prognostic factor. The nomogram that integrated the gene signature and three clinicopathological risk factors had a favorably predictive ability in predicting 3, 5 and 10 year survival. Moreover, the high-risk group had a significantly higher abundance of B cell, T cell, CD4, neutrophil and DC infiltration. Among 13 genes, X-C motif chemokine receptor1 (XCR1) was upregulated in ccRCC cells and exerted an inhibitory effect on cell proliferation.Conclusion: This study constructs a 13-gene signature as a novel prognostic marker to predict the survival of ccRCC patients and XCR1 may serve as a therapeutic target.Keywords: clear cell renal cell carcinoma, tumor microenvironment, immune, gene signature, XCR1

The nucleus accumbens (NAc) is a subcortical brain structure known primarily for its roles in pleasure, reward, and addiction. Despite less focus on the NAc in pain research, it also plays a large role in the mediation of pain and is effective as a source of analgesia. Evidence for this involvement lies in the NAc’s cortical connections, functions, pharmacology, and therapeutic targeting. The NAc projects to and receives information from notable pain structures, such as the prefrontal cortex, anterior cingulate cortex, periaqueductal gray, habenula, thalamus, etc. Additionally, the NAc and other pain-modulating structures share functions involving opioid regulation and motivational and emotional processing, which each work beyond simply the rewarding experience of pain offset. Pharmacologically speaking, the NAc responds heavily to painful stimuli, due to its high density of μ opioid receptors and the activation of several different neurotransmitter systems in the NAc, such as opioids, dopamine, calcitonin gene-related peptide, γ-aminobutyric acid, glutamate, and substance P, each of which have been shown to elicit analgesic effects. In both preclinical and clinical models, deep brain stimulation of the NAc has elicited successful analgesia. The multi-functional NAc is important in motivational behavior, and the motivation for avoiding pain is just as important to survival as the motivation for seeking pleasure. It is possible, then, that the NAc must be involved in both pleasure and pain in order to help determine the motivational salience of positive and negative events.

Yajie Wang,1,2,* Wei Liu,3,4,* Bo Yuan,1,2 Xuebo Yin,3 Yiming Li,1 Zongjin Li,1 Jianlin Cui,1 Xiaoyong Yuan,2 Yuhao Li1,5 1Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, Nankai University School of Medicine, Tianjin 300071, People’s Republic of China; 2Tianjin Eye Hospital, Tianjin Key Laboratory of Ophthalmology and Visual Science, Nankai University Eye Hospital, Tianjin 300020, People’s Republic of China; 3State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Biosensing and Molecular Recognition, Nankai University College of Chemistry, Tianjin 300071, People’s Republic of China; 4Tianjin University School of Science, Tianjin 300072, People’s Republic of China; 5Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Tianjin 300192, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yuhao LiTianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, Nankai University School of Medicine, 94 Weijin Road, Tianjin 300071, People’s Republic of ChinaTel +86 22 2350 2554Email liyuhao@nankai.edu.cnXiaoyong YuanTianjin Eye Hospital, Tianjin Key Laboratory of Ophthalmology and Visual Science, 4 Gansu Road, Tianjin 300020, People’s Republic of ChinaTel +86 22 2731 3336Email yuanxy_cn@hotmail.comBackground: Photoreceptor degeneration is one of the most refractory oculopathy in the world, leading to vision loss in severe cases. Methyprednisolone is one of the most commonly prescribed medications for the treatment of retinal degenerative diseases, either by oral administration or repeated intraocular injections. However, the efficacy was unsatisfactory due to its systemic or local side effects and short retention time within the retina.Methods: Nanoscale zirconium-porphyrin metal-organic framework (NPMOF) was synthesized and characterized. The biotoxicity and imaging capability of NPMOF were evaluated using zebrafish embryos and larvae. NPMOF was then used as a skeleton and loaded with methylprednisolone (MPS) to prepare a novel kind of nanoparticle, MPS-NPMOF. Photoreceptor degeneration was induced by high-intensity light exposure in adult zebrafish. MPS-NPMOF was delivered to the injured retina by intraocular injection. The photoreceptor regeneration and its underlying mechanism were explored by immunohistochemistry, quantitative real-time polymerase chain reaction and behavioral test.Results: NPMOF not only had low biotoxicity but also emitted bright fluorescence. Following a single MPS-NPMOF intraocular injection, the injured retina exhibited the faster photoreceptor regeneration with better visual function by promoting the cell proliferation.Conclusion: NPMOF is an ideal carrier and could be applied in tracking and delivering medications. By intraocular injection, the novel drug delivery system, MPS-NPMOF, accomplishes the sustained release of drug and plays a therapeutic role in photoreceptor degeneration.Keywords: nanoscale zirconium-porphyrin metal-organic framework, photoreceptor, degeneration, methylprednisolone, drug delivery

Tian-quan Yang,1,* Min Chen,1,* Yong-qiang Wang,1 Wei Xu,1 Yong Han,1 Jin Xu,1 Yong-jun Xiang,1 Bin Yuan,1 Hang-zhou Wang,1 You-xin Zhou2 1Department of Neurosurgery, Children’s Hospital of Soochow University, 2Department of Neurosurgery and Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China *These authors contributed equally to this work Abstract: Glioma is one of the most common types of adult primary brain tumors, and the underlying molecular mechanisms still remain unclear. Nuclear factor-kappa B1 (NF-κB1) is involved in a variety of malignancies and is widely expressed in malignant tumors. However, the expression of NF-κB1 in different grades of glioma, the correlation between NF-κB1 and Bcl-2 expressions in gliomas, and the research between NF-κB1 and early apoptosis of glioma cells have not been reported so far. In this study, the expression level of NF-κB1 in 31 human glioma tissues and six nonneoplastic brain tissues was determined using quantitative real-time polymerase chain reaction. Results showed that the expression of NF-κB1 in human glioma ­tissues and glioma cell lines, SHG44 and U87, was significantly higher compared to noncancerous brain tissues and that the expression increased with increasing degrees of tumor malignancy. Similar results were demonstrated with the expression of Bcl-2 in the same human glioma specimens. Flow cytometry results showed that inhibition of NF-κB1 expression significantly promoted apoptosis of SHG44 and U87 in human glioma cells. Western blot analysis further confirmed decreased expression of Bcl-2 protein after inhibition of NF-κB1 protein expression. Taken together, NF-κB1 overexpression inhibits early apoptosis of glioma cells and high expression of NF-κB1 promotes the expression of antiapoptotic gene Bcl-2. Therefore, our study results provide a theoretical basis for antiapoptotic mechanism of tumor cells in association with NF-κB1. Keywords: NF-κB1, Bcl-2, glioma, apoptosis

Dong Wu,1,* Yalian Yuan,1,* Zhixiu Lin,2,* Tianwen Lai,1 Min Chen,1 Wen Li,1 Quanchao Lv,1 Binfan Yuan,1 Dongmin Li,1 Bin Wu1 1Department of Respiratory, Institute of Respiratory Diseases, 2Department of Pharmacy, The Affiliated Hospital of Guangdong Medical University, Zhanjiang, People’s Republic of China *These authors contributed equally to this work Abstract: Etiological evidence demonstrates that there is a significant association between cigarette smoking and chronic airway inflammatory disease. Abnormal expression of placental growth factor (PlGF) has been reported in COPD, and its downstream signaling molecules have been reported to contribute to the pathogenesis of airway epithelial cell apoptosis and emphysema. However, the signaling mechanisms underlying cigarette smoke extract (CSE)-induced PlGF expression in airway microenvironment remain unclear. Herein, we investigated the effects of reactive oxygen species (ROS)-dependent activation of the mitogen-activated protein kinase (MAPK) (extracellular signal-regulated kinase1/2 [ERK-1/2])/early growth response-1 (Egr-1) pathway on CSE-induced PlGF upregulation in human bronchial epithelium (HBE). The data obtained with quantitative reverse transcription polymerase chain reaction, Western blot, enzyme-linked immunosorbent assay (ELISA) and immunofluorescence staining analyses showed that CSE-induced Egr-1 activation was mainly mediated through production of ROS and activation of the MAPK (ERK-1/2) cascade. The binding of Egr-1 to the PlGF promoter was corroborated by an ELISA-based DNA binding activity assay. These results demonstrate that ROS activation of the MAPK (ERK-1/2)/Egr-1 pathway is a main player in the regulatory mechanism for CSE-induced PlGF production and that the use of an antioxidant could partly abolish these effects. Understanding the mechanisms of PlGF upregulation by CSE in the airway microenvironment may provide rational therapeutic interventions for cigarette smoking-related airway inflammatory diseases. Keywords: cigarette smoke, reactive oxygen species, airway epithelium, placental growth factor, extracellular signal-regulated kinase1/2, early growth response-1

Bo Yuan, Thomas J Webster, Amit K Roy Chemical Engineering Department, College of Engineering, Northeastern University, Boston, MA, USA Abstract: It is a widely accepted fact that environmental factors affect cells by modulating the components of subcellular compartments and altering metabolic enzymes. Factors (such as oxidative stress and heat-shock-induced proteins and heat shock factors, which upregulate stress-response related genes to protect affected cells) are commonly altered during changes in environmental conditions. Studies by our group and others have shown that nanoparticles (NPs) are able to efficiently attenuate oxidative stress by penetrating into specific tissues or organs. Such findings warrant further investigation on the effects of NPs on heat-shock-induced stress, specifically in cells in the presence or absence (pretreated) of NPs. Here, we examined the cytoprotective effects of two different NPs (cerium and selenium) on heat-induced cell death for a model cell using dermal fibroblasts. We report for the first time that both ceria and selenium NPs (at 500 µg/mL) possess stress-relieving behavior on fibroblasts undergoing heat shock. Such results indicate the need to further develop these NPs as a novel treatment for heat shock. Keywords: ceria, heat shock, nanotechnology, cell death, nanomedicine, protective

Varicella zoster virus (VZV) infects the face and can result in chronic, debilitating pain. The mechanism for this pain is unknown and current treatment is often not effective, thus investigations into the pain pathway become vital. Pain itself is multidimensional, consisting of sensory and affective experiences. One of the primary brain substrates for transmitting sensory signals in the face is the ventral posterior medial/posterior lateral thalamus (VPM/VPL). In addition, the anterior cingulate cortex (ACC) has been shown to be vital in the affective experience of pain, so investigating both of these areas in freely behaving animals was completed to address the role of the brain in VZV-induced pain. Our lab has developed a place escape avoidance paradigm (PEAP) to measure VZV-induced affective pain in the orofacial region of the rat. Using this assay as a measure of the affective pain experience a significant response was observed after VZV injection into the whisker pad and after VZV infusion into the trigeminal ganglion. Local field potentials (LFPs) are the summed electrical current from a group of neurons. LFP in both the VPM/VPL and ACC was attenuated in VZV injected rats after inhibition of neuronal activity. This inhibition of VPM/VPL neurons was accomplished using a designer receptor exclusively activated by a designer drug (DREADD). Immunostaining showed that cells within the VPM/VPL expressed thalamic glutamatergic vesicle transporter-2, NeuN and DREADD suggesting inhibition occurred primarily in excitable neurons. From these results we conclude: (1) that VZV associated pain does not involve a mechanism exclusive to the peripheral nerve terminals, and (2) can be controlled, in part, by excitatory neurons within the VPM/VPL that potentially modulate the affective experience by altering activity in the ACC.

The α2 single phase interdiffusion in Ti3Al-Nb ternary system was studied at temperatures of 1323, 1373 and 1423 K. The interdiffusion coefficients were calculated by the method of Dayananda. The average ternary interdiffusion coeffcients were determined in the mid of the diffusion zone, and the trace diffusion coefficients can be estimitaed in the limit cX→0. The obtained main interdiffusion coeffcients is little smaller than privious reported and the diffusion activation energy of Nb calculated by the trace diffusion coefficients is 299.29 kJmol-1 accoding to the Arrhenius equation. These results can provide a theoretical basis for the mechanisms of Nb improving the oxidation resistance of Ti3Al.

1. This study focused on the relationship between MITF mRNA expression and plumage colour in quail and the effect of promoter methylation on the expression of MITF mRNA. 2. The CDS region of MITF mRNA was cloned by RT-PCR, followed by DNA sequencing. The RT-qPCR method was used to analyse the expression levels of MITF mRNA in dorsal skin tissue in Korean quail and Beijing white quail. The promoter region of the MITF gene was cloned, and the CpG island was predicted by the CpGplot program. The methylation levels of the CpG island were analysed using BS-PCR technology. 3. Quail MITF mRNA contains a 1,476 bp complete ORF, which encodes a 492 amino acid residue protein. The MITF protein has no signal peptide or transmembrane region. The expression of MITF mRNA in dorsal tissue of Korean quail was significantly higher than that in Beijing white quail (p < 0.01). Abundant cis-elements and a 346 bp CpG island were found in the promoter region of the MITF gene. The average methylation level of the CpG island was 22 (22%) in Korean quail, and 46 (30%) in Beijing white quail (p < 0.05). 4. The hypermethylation of the MITF gene promoter region in Beijing white quail resulted in a decrease in expression level, which was related to white feather colour. [ABSTRACT FROM AUTHOR]

Fibromyalgia is a chronic, widespread pain disorder that is strongly represented across the affective and cognitive dimensions of pain, given that the underlying pathophysiology of the disorder is yet to be identified. These affective and cognitive deficits are crucial to understanding and treating the fibromyalgia pain experience as a whole but replicating this multidimensionality on a preclinical level is challenging. To understand the underlying mechanisms, animal models are used. In this scoping review, we evaluate the current primary animal models of fibromyalgia regarding their translational relevance within the affective and cognitive pain realms, as well as summarize treatments that have been identified preclinically for attenuating these deficits. [ABSTRACT FROM AUTHOR]