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Luxun Yang,1,* Haiying Ran,2,* 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*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

Xian He,1,2 Xin Ran,1 Dan Liang,2 Hongxia Fan,3 Yuping Ran1 1Department of Dermatovenereology, West China Hospital, Sichuan University, Chengdu, People’s Republic of China; 2Department of Allergy, Chengdu First People’s Hospital, Chengdu, People’s Republic of China; 3Department of Ultrasonic, West China Hospital, Sichuan University, Chengdu, People’s Republic of ChinaCorrespondence: Yuping Ran, Tel +8618980601697, Email ranyuping@vip.sina.comAbstract: An infantile hemangioma is a congenital benign tumor formed by the proliferation of vascular cells during the embryonic stage. It is more common in the skin but can also occur in the mucous membranes, liver, brain and muscle. Hepatic hemangioma appears to be a benign tumor; however, it may lead to poor outcomes because of severe complications, such as high-output cardiac failure. The main treatment of hepatic hemangioma in infants is oral drugs, such as propranolol and glucocorticoids, but the clinical response is not always satisfactory. We describe a rare case of a 2-month-old boy who presented with infantile cutaneous and hepatic hemangiomas. By using dermoscopy and observations of the abdominal color Doppler ultrasound, after 9 months of oral treatment with itraconazole solution, the infantile cutaneous hemangioma complicated with hepatic hemangioma was eventually cured. There was no liver or kidney function damage during the whole treatment period. Itraconazole oral solution for the treatment of infantile cutaneous hemangioma complicated with hepatic hemangioma showed good efficacy, compliance, and safety in this case.Keywords: infantile hemangioma, cutaneous, hepatic, itraconazole oral solution, dermoscopy, color ultrasonic

Runmin Zhang, Muzhe Li, Huiyun Li, Xun Ran, Fengtian Jin, Qingshan Tan, Zhiwei Chen Department of Orthopaedics, The First Affiliated Hospital of University of South China, Hengyang, People’s Republic of ChinaCorrespondence: Zhiwei Chen, Department of Orthopaedics, The First Affiliated Hospital of University of South China, 69| Chuanshan Road, Hengyang, Hunan, People’s Republic of China, Tel +86-13973409923, Email CZW9915@sina.comAbstract: Inflammation is a common feature of many inflammatory diseases and tumors, and plays a decisive role in their development. Exosomes are extracellular vesicles unleashed by assorted types of cells, and it is widely known that exosomes of different immune cell sources play different functions. Exosome production has recently been reported for immune cells comprising macrophages, T cells, B cells, and dendritic cells (DCs). Immune cell-derived exosomes are involved in a variety of inflammatory responses.Herein, we summarize and review the role of macrophages, T cells, B cells, and dendritic cells (DC) in inflammatory diseases, with a focus on the role of immune cell-derived exosomes in osteoarthritis, rheumatoid arthritis, and the inflammatory tumor microenvironment (TME).These findings are expected to be important for developing new treatments for inflammatory diseases and ameliorating tumor-related inflammation. Keywords: inflammatory diseases, immune cell-derived exosomes, osteoarthritis, rheumatoid arthritis, inflammatory tumor microenvironment

Lihong Chen,1 Yunyi Gao,2 Yan Li,1 Chun Wang,1 Dawei Chen,1 Yun Gao,1 Xingwu Ran1 1Innovation Center for Wound Repair, Diabetic Foot Care Center, Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, 610041, People’s Republic of China; 2Department of Medical Affairs, West China Hospital, Sichuan University, Chengdu, 610041, People’s Republic of ChinaCorrespondence: Xingwu Ran, Innovation Center for Wound Repair, Diabetic Foot Care Center, Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, 37 Guo Xue Lane, Chengdu, 610041, People’s Republic of China, Tel +86 028-85422046, Email ranxingwu@163.comBackground: Obstructive sleep apnea is prevalent in patients with diabetic foot ulcers, while the effect of intermittent hypoxia on wound healing is unclear. The objective of this study was to investigate the effect of severe intermittent hypoxia on wound healing.Methods: C57BL/6 mice were exposed to 5 weeks of severe intermittent hypoxia or normoxia. The wound healing rate were assessed. The gene expression of CD206 and HIF-2α was tested in vivo and in vitro. Inflammatory factors in RAW264.7 macrophages were measured to investigate the effect of intermittent hypoxia on macrophage polarization. The proliferation of HUVECs and HaCaT cells was also assessed after exposure to intermittent hypoxia.Results: Severe intermittent hypoxia decreased wound healing at day 3. The expression of CD206 and HIF-2α was significantly decreased after exposure to severe intermittent hypoxia. In vitro, severe intermittent hypoxia significantly promoted M1 phenotype polarization of RAW264.7 macrophages and increased the expression of proinflammatory factors (IL-1β and TNF-α). Severe intermittent hypoxia also decreased the proliferation of HUVECs cultured in endothelial cell medium and HaCaT cells cultured in high glucose DMEM.Conclusion: Severe intermittent hypoxia could lead to M1 but not M2 macrophage polarization through downregulation of HIF-2α, and then lead to impaired wound healing.Keywords: wound and injuries, intermittent hypoxia, wound healing, inflammation, hypoxia inducible factor

Xiao Ran,1 Dao Wen Wang,2 Zhen Yu,1 Rongxue Wu,3 Qin Zhang4 1Department of Emergency, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, People’s Republic of China; 2The Institute of Hypertension and Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, People’s Republic of China; 3Department of Biological Sciences Division/ Cardiology, University of Chicago, Chicago, IL, 60637, USA; 4Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, People’s Republic of ChinaCorrespondence: Qin Zhang Email qzhang8@tjh.tjmu.cnAim: Tissue kallikrein (TK) exerts protective effects on cardiac cerebrovascular diseases (CCVDs). Changes in TK level in plasma are associated with ischemic stroke and coronary artery disease (CAD); however, a causal correlation could not be established. Therefore, we investigated the association between TK levels and CCVDs in a community-based cross-sectional study in China.Methods: A total of 6043 subjects (4242 men and 1801 women) were enrolled in this community-based cross-sectional study. Then, TK levels were measured using an enzyme-linked immunosorbent assay kit. Multivariate linear regression model and logistic regression were used to assess the correlations between TK levels and CCVDs. Subsequently, the receiver operating characteristic (ROC) curve was drawn to assess the value of TK level in evaluating the risk of ischemic stroke. Finally, the influence of various medications was evaluated on TK levels.Results: The TK level was significantly lower in subjects with ischemic stroke (P < 0.001) and hypertension (P < 0.001) and negatively associated with ischemic stroke (P < 0.001) but not associated with hypertension, coronary heart disease, and diabetes compared to the traditional risk factors. The diagnostic accuracy for ischemic stroke, as quantified by the area under the curve, was 0.892 (95% CI, 0.884– 0.900) for TK level, deeming it as a promising assessment tool. Moreover, no appreciable influence of various drugs therapy was found in TK levels (P = 0.222) except for those taking antilipemic agents.Conclusion: TK is a strong and independent endogenous protective factor against ischemic stroke in the Chinese population and could be a promising biomarker for the risk of ischemic stroke.Keywords: tissue kallikrein, ischemic stroke, cardiac cerebral vascular disease, risk factor

Qin Zhang,1 Juan Tan,1 Li Wan,1 Chao Chen,1 Bin Wu,2 Xijian Ke,1 Rongxue Wu,3 Xiao Ran4 1Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, People’s Republic of China; 2Laboratory of Platelet and Endothelium Biology, Department of Transfusion Medicine, Wuhan Hospital of Traditional Chinese and Western Medicine (Wuhan No.1 Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, People’s Republic of China; 3Department of Biological Sciences Division/ Cardiology, University of Chicago, Chicago, IL, 60637, USA; 4Department of Emergency, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, People’s Republic of ChinaCorrespondence: Xiao Ran Email ranxiao1001@tjh.tjmu.edu.cnAim: Disruption of the blood–brain barrier (BBB) is a critical pathological feature after stroke. Although tissue kallikrein (TK) has used in the treatment of stroke in China, the role of TK in modulating BBB permeability is not clear.Methods: We investigated the effect of different doses of TK on BBB by in vivo assessments of Evans blue (EB) and sodium-fluorescein isothiocyanate (FITC) leakage and in vitro assessments of the integrity of BBB and monolayers of microvascular endothelial cells (BMVECs). The expression of zonula occludens-1 (ZO-1) and bradykinin receptor-mediated signaling in BMVECs was detected.Results: A significant increase in BBB permeability was observed in the mice treated with high dose of TK. However, standard and medium doses of TK could only enable sodium-FITC to enter the brain. The result of in vitro study indicated that high-doses of TK, but not standard and medium-dose of TK, reduced normal BBB integrity accompanied by a decreased expression of zonula occludens-1 (ZO-1), upregulated the mRNA levels of bradykinin 2 receptor (B2R) and endothelial nitric oxide synthase (eNOS) and the abundance of B2R. Moreover, standard-dose of TK exacerbated lipopolysaccharide-induced BBB hyperpermeability, upregulated the mRNA levels of bradykinin 1 receptor (B1R) and inducible nitric oxide synthase (iNOS), increased the abundance of B1R and reduced the abundance of ZO-1; these effects were inhibited by TK inhibitor.Conclusion: TK can disrupt tight junctions and increase normal BBB permeability via B2R-dependent eNOS signaling pathway, aggravate impairment of BBB via B1R-dependent iNOS signaling pathway, and consequently serve as a useful adjunctive treatment for enhancing the efficacy of other neurotherapeutics.Keywords: tissue kallikrein, blood–brain barrier, bradykinin, permeability

Xiao Ran,1 Qin Zhang,2 Shaoping Li,1 Zhen Yu,1 Li Wan,2 Bin Wu,3 Rongxue Wu,4 Shusheng Li1 1Department of Emergency, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, People’s Republic of China; 2Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, People’s Republic of China; 3Laboratory of Platelet and Endothelium Biology, Department of Transfusion Medicine, Wuhan Hospital of Traditional Chinese and Western Medicine (Wuhan No.1 Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, People’s Republic of China; 4Department of Biological Sciences Division/Cardiology, University of Chicago, Chicago, IL, 60637, USACorrespondence: Qin Zhang Email qzhang8@tjh.tjmu.cnShusheng Li Email Shushengli16@sina.comAim: Sepsis, an acute, life-threatening dysregulated response to infection, affects practically all aspects of endothelial function. Tissue kallikrein (TK) is a key enzyme in the kallikrein–kinin system (KKS) which has been implicated in endothelial permeability. Thus, we aimed to establish a potentially novel association among TK, endothelial permeability, and sepsis demonstrated by clinical investigation and in vitro studies.Methods: We performed a clinical investigation with the participation of a total of 76 controls, 42 systemic inflammatory response syndrome (SIRS) patients, and 150 patients with sepsis, who were followed-up for 28 days. Circulating TK levels were measured with an enzyme-linked immunosorbent assay. Then, the effect of TK on sepsis-induced endothelial hyperpermeability was evaluated by in vitro study.Results: Data showed a gradual increase in TK level among controls and the patients with SIRS, sepsis, and septic shock (0.288± 0.097 mg/l vs 0.335± 0.149 vs 0.495± 0.170 vs 0.531± 0.188 mg/l, respectively, P < 0.001). Further analysis revealed that plasma TK level was positively associated with the severity and mortality of sepsis and negatively associated with event-free survival during 28 days of follow-up (relative risk, 3.333; 95% CI, 2.255– 4.925; p < 0.001). With a septic model of TK and kallistatin in vitro, we found that TK exacerbated sepsis-induced endothelial hyperpermeability by downregulating zonula occluden-1 (ZO-1) and vascular endothelial (VE)-cadherin, and these could be reversed by kallistatin, an inhibitor of TK.Conclusion: TK can be used in the diagnosis of sepsis and assessment of severity and prognosis of disease. Inhibition of TK may be a novel therapeutic target for sepsis through increasing ZO-1 and VE-cadherin, as well as downregulating endothelial permeability.Keywords: tissue kallikrein, sepsis, mortality, endothelial permeability, junction protein

Yunyi Gao,1 Dawei Chen,1 Yan Li,1 Huijiao Chen,2 Xingwu Ran1 1Diabetic Foot Care Center, Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 2Department of Pathology, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of ChinaCorrespondence: Xingwu RanDiabetic Foot Care Center, Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, 37 Guo Xue Lane, Chengdu, Sichuan, 610041, People’s Republic of ChinaTel +86-28-85422362 Email ranxingwu@163.comAbstract: We presented a case of hepatitis B virus (HBV)-related type III cryoglobulinemia vasculitis (CryoVas) characterized by extremity gangrene in a patient with diabetes. The 60-year-old female had a 10-year history of poorly controlled type 2 diabetes mellitus. She complained of sudden onset pain and swelling of toes which quickly progressed to gangrene, with fingers becoming pain and dark violet. The patient was initially misdiagnosed as diabetic foot (DF). Although DF is one of the common chronic complications of diabetes, it rarely involves the hand. What is more, the ischemic manifestations of the extremity were not consistent with the results of the vascular examination and immune system changes. The patient had Raynaud’s phenomenon, arthralgia, and extremity gangrene. Test results showed cryoglobulinemia multiple positive, polyclonal immunoglobulin with rheumatoid factor negative, lower complement 3, leukocytoclastic vasculitis, and HBV infection. HBV-related type III CryoVas was finally diagnosed, and a conservative therapy strategy was given. Six months after treatment with cyclophosphamide, corticosteroid, nucleoside/nucleotide analog therapy, local debridement, and dressing change, she recovered and kept no recurrence by following up for 30 months. To our knowledge, this is the first report of extremity gangrene caused by HBV-related CryoVas in a diabetic patient.Keywords: HBV, type III cryoglobulinemia vasculitis, extremity gangrene, diabetic foot

Luoning Gou,1,* Ming Xiang,2,* Xiao Ran,3,* Fen Wang,1 Shujun Zhang,1 Shusheng Li,3 Kun Dong,1 Xi Chen,1 Yangxin Huang,4 Chengzhen Meng,2 Qian Fan,2 Yan Yang,1 Xuefeng Yu,1 Delin Ma,1 Ping Yin2 1Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 2Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 3Department of Emergency Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 4College of Public Health, University of South Florida, Tampa, Florida, The United States*These authors contributed equally to this workCorrespondence: Ping Yin; Delin MaTongji Medical College, Huazhong University of Science and Technology, 13 Hongkong Road, Wuhan, 430030 Hubei, People’s Republic of ChinaTel + 86-27-83692832Fax +86-27-83692333Email pingyin2000@126.comDelin Ma Email maderine4@163.comPurpose: Recently, a cluster of pneumonia caused by SARS-CoV-2 were identified in Wuhan and spread throughout the world. More information about risk factors for mortality of critically ill patients infected with SARS-CoV-2 remain to be evaluated.Methods: We included adult patients confirmed with SARS-CoV-2 infection who were critically ill and admitted to the intensive care unit (ICU) of Tongji Hospital in Wuhan from Feb 4, 2020 to Feb 20, 2020. Data were collected and compared between patients who died and improved. Logistic regression was used to explore the risk factors for death of SARS-CoV-2-infected critically ill patients.Results: A total of 160 critically ill patients with SARS-CoV-2 infection were included, of which 146 patients with appeared outcomes were included into the final analysis. The random blood glucose, serum sodium and effective plasma osmolarity were higher in deceased patients, especially in patients with diabetes. There were 7 patients with diabetes with hyperosmolar status and all of them were deceased. Multivariable regression revealed that older age (odds ratio 4.28, 95% CI 1.01– 18.20; p = 0.049), higher C-reactive protein (odds ratio 1.01, 1.00– 1.03; p = 0.024), higher interleukin-6 (odds ratio 1.01, 1.00– 1.03; p = 0.0323), and d-dimer greater than 1 μg/mL (odds ratio 1.10, 1.01– 1.20; p = 0.032) at admission were associated with increased odds of death.Conclusion: In conclusion, hyperosmolarity needs more attention and may contribute to mortality in critically ill patients with COVID-19, especially in those with diabetes. Older age, inflammatory response, and thrombosis may be risk factors for death of critically ill patients with SARS-CoV-2 infection.Keywords: SARS-CoV-2, critically ill, hyperosmolarity, diabetes, risk factors, mortality

Zhao-Hua Wang,1,* Chang Shu,2,* Xiao Ran,1 Cui-Hong Xie,1 Lei Zhang2 1Department of Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People’s Republic of China; 2Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People’s Republic of China*These authors contributed equally to this workCorrespondence: Lei ZhangDepartment of Surgery, Tongji Hospital, 1095 Jiefang Avenue, Wuhan 430030, People’s Republic of ChinaTel +86-27-83665312Email zhangl@tjh.tjmu.edu.cnBackground: Coronavirus disease 2019 (COVID-19) is a worldwide pandemic outbreak with a high mortality. Prognostic factors of critically ill patients with COVID-19 have not been fully elucidated yet.Methods: In the present study, 59 patients with COVID-19 from the intensive care unit of the Caidian Branch of Tongji Hospital were enrolled. Epidemiological, demographic, clinical, laboratory, radiological, treatment data, and clinical outcomes were collected. Prognostic factors were statistically defined.Results: Of the 59 patients studied (67.4± 11.3 years), 38 patients were male, 51 had underlying diseases, and 41 patients died during admission. Compared with the survivors, the deceased patients were of older age, had more smoking history, severer fatigue, and diarrhea, a higher incidence of multiple organ injuries, more deteriorative lymphopenia and thrombocytopenia, remarkably impaired cellular immune response, and strengthened cytokine release. Age higher than 70 (OR=2.76, 95% CI=1.45– 5.23), arrhythmia (OR=4.76, 95% CI=1.59– 14.25), and a Sequential Organ Failure Assessment (SOFA) score above 4 (OR=5.16, 95% CI=1.29– 20.55) were identified as risk factors for mortality of patients.Conclusion: Critically ill COVID-19 patients aged higher than 70, arrhythmia, or a SOFA score above 4 have a high risk of mortality, and need prior medical intervention.Keywords: severe acute respiratory coronavirus 2, pneumonia, critically ill, mortality, prognostic factor

Jun Zhang,1,* Feng Zhou,2,* Xiaoxiang Ge,3 Xu Ran,4 Yeping Li,4 Si Chen,5 Xiaotong Dai,5 Dafang Chen,5 Baoguo Jiang6 1Department of Neurology, Peking University People’s Hospital, Beijing, China; 2Department of Data Science, Tsinghua University, Beijing, China; 3Office of Academic Affairs, Army Military Medical University, Chongqing, China; 4Department of Research and Development, Chongqing Hospital Management Limited Company (Doctor-Patient Experience Research Base, National Health and Family Planning Commission of the People’s Republic of China), Chongqing, China; 5Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China; 6Department of Orthopedics, Peking University People’s Hospital, Beijing, China *These authors contributed equally to this work Background and aims: Patient satisfaction is one of the important ways to measure the results of treatment and the quality of medical services. The purpose of the present study was to verify the reliability and validity of the indicator system for evaluating satisfaction of outpatients and inpatients in Chinese hospitals.Methods: The study was based on the satisfaction questionnaire program of the national doctor–patient experience research center with data from 99,802 outpatients and 229,215 inpatients, collected in China between 2016 and 2017. We adopted exploratory factor analysis for validity analysis and the method of split-half reliability and Cronbach’s α coefficient for reliability analysis.Results: In the validity analysis of the indicator system for outpatients, the factor loading was between 0.438 and 0.919, and the reliability was excellent. In the validity analysis of the indicator system for nonsurgical inpatients, the factor loading of the secondary indicators was between 0.417 and 0.75, and the reliability was excellent. In the validity analysis of the indicator system for surgical inpatients satisfaction, the factor loading of the secondary indicators range was 0.391–0.751, and the reliability was excellent.Conclusion: The indicator systems for evaluating satisfaction of outpatients, surgical inpatients and nonsurgical inpatients all have excellent reliability and good validity. They can be widely used for an outpatient and inpatient satisfaction questionnaire in Chinese hospitals. Keywords: patient satisfaction questionnaire, reliability, validity, evaluation

Huanli Luo, Yanan He, Fu Jin, Dingyi Yang, Xianfeng Liu, Xueqi Ran, Ying Wang Department of Radiation Oncology, Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, Chongqing, 400030, China Introduction: Accurate delineation of targets and organs at risk (OAR) is required to ensure treatment efficacy and minimize risk of normal tissue toxicity with radiotherapy. Therefore, we evaluated the impacts of computed tomography (CT) slice thickness and reconstruction methods on the volume and dose evaluations of targets and OAR. Patients and methods: Eleven CT datasets from patients with thoracic cancer were included. 3D images with a slice thickness of 2 mm (2–CT) were created automatically. Images of other slice thickness (4–CT, 6–CT, 8–CT, 10–CT) were reconstructed manually by the selected 2D images using two methods; internal tumor information and external CT Reference markers. Structures and plans on 2–CT images, as a reference data, were copied to the reconstructed images. Results: The maximum error of volume was 84.6% for the smallest target in 10–CT, and the maximum error (≥20 cm3) was 10.1%, 14.8% for the two reconstruction methods, internal tumor information and external CT Reference, respectively. Changes in conformity index for a target of

Xiongwen Ran, Kai Yang Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China Abstract: Head and neck cancer (HNC) is a common malignant tumor, but traditional therapeutic methods have unsatisfactory curative effects and many complications occur. Hence, there is an urgent need to develop therapeutic methods that can elicit curative effects as well as low toxic and few side effects. With the development of cancer molecular biology and immunology, targeted therapy for immune checkpoints of programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) has shown enormous development prospects for HNC treatment. Groundbreaking progress has been achieved in the treatment of recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). This review describes current treatment by PD-1- and PD-L1-targeted drugs for HNC. Keywords: head and neck cancer, squamous cell carcinoma, programmed cell death 1, programmed cell death ligand 1, immunotherapy, immune checkpoint

Anomaly detection is one of the many challenging areas in cybersecurity. The anomaly can occur in many forms, such as fraudulent credit card transactions, network intrusions, and anomalous imageries or documents. One of the most common challenges in anomaly detection is the obscurity of the normal state and the lack of anomalous samples. Traditionally, this problem is tackled by using resampling techniques or choosing models that approximate the distribution of the normal states. Variational AutoEncoder (VAE) has been studied in anomaly detections despite being more suitable in generative tasks. This study aims to explore the usage of VAE in credit card anomaly detection and evaluate latent space sampling techniques. In this study, we evaluate the usage of the convolutional network-based VAE model on a credit card transaction dataset. We train two VAE models, one with a large number of normal data and one with a small number of anomalous data. We compare the performance of both VAE models and evaluate the latent space of both VAE models by rescaling them with reconstruction error vectors. We also compare the effectiveness of the VAE model with other anomaly detection models when they are trained on imbalanced dataset.

Abstract The diagnosis of neurodegenerative diseases (NDDs) remains challenging, and existing therapeutic approaches demonstrate little efficacy. NDD drug delivery can be achieved through the utilization of nanostructures, hence enabling multimodal NDD theranostics. Nevertheless, both biomembrane and non-biomembrane nanostructures possess intrinsic shortcomings that must be addressed by hybridization to create novel nanostructures with versatile applications in NDD theranostics. Hybrid nanostructures display improved biocompatibility, inherent targeting capabilities, intelligent responsiveness, and controlled drug release. This paper provides a concise overview of the latest developments in hybrid nanostructures for NDD theranostics and emphasizes various engineering methodologies for the integration of diverse nanostructures, including liposomes, exosomes, cell membranes, and non-biomembrane nanostructures such as polymers, metals, and hydrogels. The use of a combination technique can significantly augment the precision, intelligence, and efficacy of hybrid nanostructures, therefore functioning as a more robust theranostic approach for NDDs. This paper also addresses the issues that arise in the therapeutic translation of hybrid nanostructures and explores potential future prospects in this field.

Summary Due to the convenience of virtualization, the live migration of virtual machines is widely used to fulfill optimization objectives in cloud/edge computing. However, live migration may lead to side effects and performance degradation when migration is overused or an unreasonable migration process is carried out. One pressing challenge is how to capture the best opportunity for virtual machine migration. Leveraging rough sets and AI, this paper provides an innovative strategy based on Q-learning that is designed for migration decisions. The highlight of our strategy is the harmonious mechanism for applying rough sets and Q-learning. For the ABDS (adaptive boundary decision system) strategy in this paper, the exploration space of Q learning is confined by the boundary region of rough sets, while the thresholds of the boundary region can be dynamically adjusted by the reaction results from the computing cluster. The structure and mechanism of the ABDS strategy are described in this paper. The corresponding experiments show a firm advantage for the cooperation of rough sets and reinforcement learning algorithms. Considering both the energy consumption and application performance, the ABDS strategy in this paper outperforms the benchmark strategies in comprehensive performance.

The mining of shallow coal seams in Shendong Mining Area has resulted in well-developed surface fractures and complex three-dimensional air leakage. In order to study the distribution characteristics and dynamic evolution laws of surface fractures in Shendong Mining Area, take the shallow burial mining of Huojitu Well in Daliuta Coal Mine and Bulianta Coal Mine as the engineering background, a combination of on-site UAV fixed-point observation, infrared, geological radar and other technologies was used to study the distribution characteristics of macroscopic and hidden fractures on the surface, and to analyze the dynamic evolution laws of fractures. Research has shown that the goaf of the shallow coal seam mining face in Shendong Mining Area has a greater impact on surface strike fractures compared to inclined fractures. Among them, the effective influence range of 101 fissures in 12 lower 206 working face in Huojitu Well is 35 m, and 122 fissures in 22310 working face of Bulianta Coal Mine is 62 m. The maximum width of strike fissures is 80 cm, and dip fissures are generally less than 10 cm. The maximum width of strike fractures reaches 80 cm, and inclined fractures are generally below 10 cm; with the advance of the working surface, the width of the crack increases gradually until it is fully developed, and the spacing of the discontinuous section of the crack becomes larger and the drop increases. If the crack with a larger width (the crack width is greater than 10 cm) is close to the working face, the crack width will gradually shrink with the advance of the working face, and may even be closed.

Abstract In Si/SiGe heterostructures, the low-lying excited valley state seriously limits the operability and scalability of electron spin qubits. For characterizing and understanding the local variations in valley splitting, fast probing methods with high spatial and energy resolution are lacking. Leveraging the spatial control granted by conveyor-mode spin-coherent electron shuttling, we introduce a method for two-dimensional mapping of the local valley splitting by detecting magnetic field-dependent anticrossings of ground and excited valley states using entangled electron spin-pairs as a probe. The method has sub-μeV energy accuracy and a nanometer lateral resolution. The histogram of valley splittings spanning a large area of 210 nm by 18 nm matches well with statistics obtained by the established but time-consuming magnetospectroscopy method. For the specific heterostructure, we find a nearly Gaussian distribution of valley splittings and a correlation length similar to the quantum dot size. Our mapping method may become a valuable tool for engineering Si/SiGe heterostructures for scalable quantum computing.

Abstract Quantum processor architectures must enable scaling to large qubit numbers while providing two-dimensional qubit connectivity and exquisite operation fidelities. For microwave-controlled semiconductor spin qubits, dense arrays have made considerable progress, but are still limited in size by wiring fan-out and exhibit significant crosstalk between qubits. To overcome these limitations, we introduce the SpinBus architecture, which uses electron shuttling to connect qubits and features low operating frequencies and enhanced qubit coherence. Device simulations for all relevant operations in the Si/SiGe platform validate the feasibility with established semiconductor patterning technology and operation fidelities exceeding 99.9%. Control using room temperature instruments can plausibly support at least 144 qubits, but much larger numbers are conceivable with cryogenic control circuits. Building on the theoretical feasibility of high-fidelity spin-coherent electron shuttling as key enabling factor, the SpinBus architecture may be the basis for a spin-based quantum processor that meets the scalability requirements for practical quantum computing.

Abstract Background Mitochondrial diseases (MDs) can be caused by single nucleotide variants (SNVs) and structural variants (SVs) in the mitochondrial genome (mtDNA). Presently, identifying deletions in small to medium-sized fragments and accurately detecting low-percentage variants remains challenging due to the limitations of next-generation sequencing (NGS). Methods In this study, we integrated targeted long-range polymerase chain reaction (LR-PCR) and PacBio HiFi sequencing to analyze 34 participants, including 28 patients and 6 controls. Of these, 17 samples were subjected to both targeted LR-PCR and NGS to compare the mtDNA variant detection efficacy. Results Among the 28 patients tested by long-read sequencing (LRS), 2 patients were found positive for the m.3243 A > G hotspot variant, and 20 patients exhibited single or multiple deletion variants with a proportion exceeding 4%. Comparison between the results of LRS and NGS revealed that both methods exhibited similar efficacy in detecting SNVs exceeding 5%. However, LRS outperformed NGS in detecting SNVs with a ratio below 5%. As for SVs, LRS identified single or multiple deletions in 13 out of 17 cases, whereas NGS only detected single deletions in 8 cases. Furthermore, deletions identified by LRS were validated by Sanger sequencing and quantified in single muscle fibers using real-time PCR. Notably, LRS also effectively and accurately identified secondary mtDNA deletions in idiopathic inflammatory myopathies (IIMs). Conclusions LRS outperforms NGS in detecting various types of SNVs and SVs in mtDNA, including those with low frequencies. Our research is a significant advancement in medical comprehension and will provide profound insights into genetics.

Abstract Traditional village toponyms contain rich vernacular geographical information, profound cultural connotations, and social group memories. Studying the meanings and spatial distribution characteristics of traditional village toponyms and their formation mechanism is significant for the sustainable development and protection of the intangible culture of traditional villages. However, previous studies mainly focused on qualitative description combined with geospatial analysis techniques to explore their spatial distribution and influencing factors, but there has yet to be an in-depth study on why such a pattern is formed. Thus, this study employs statistics, a GIS kernel density estimation method, a geodetector, and historical data to examine the spatial distribution, influence factors, and formation mechanisms of various toponyms in traditional villages in western Hunan, China. The results show that (1) the toponyms in traditional villages in western Hunan can be categorized into natural and cultural landscape toponyms. Natural landscape toponyms predominate in the northwest, whereas cultural landscape toponyms are more concentrated in the southeast, with Huayuan, Longshan, and Dong Autonomous Counties as the primary focal points; (2)Natural toponyms are shaped by terrain, river proximity, and vegetation, whereas cultural toponyms cluster due to natural features and historic trail influence, mirroring the historical migration and settlement patterns in the development of western Hunan; (3)Multiple influencing factors, regulatory powers, and curing processes reveal the formation mechanism of the spatial patterns of toponyms. This study offers a novel lens for recognizing and understanding the characteristics of human settlement environments and culture in traditional villages. Moreover, the results of this study can provide scientific guidance for the cultural protection of traditional villages on a cross-regional scale.

Abstract Wolfiporia cocos is a medicinal mushroom used in China. It biosynthesizes pachymic acid (PA), a main therapeutic triterpene associated with therapies. Nowadays, the unknown PA biosynthesis leads to difficulties in increasing its content in W. cocos. Herein, we report sequencing, assembling, and characterization of the genome and several transcriptomes of W. cocos. Sequence mining determined candidate genes that encode lanosterol synthase, sterol O-acyltransferase, and sterol C-24 methyltransferase likely involved in the steps from lanosterol to PA. Gene cluster analysis identified four CYP450 cDNAs likely involved in the biosynthesis of PA, namely WcCYP64-1, WcCYP64-2, WcCYP52, and WcCYP_FUM15, which were subjected to both overexpression and silencing in mycelia. The overexpression of each of WcCYP64-1, WcCYP52 and WcCYP_FUM15 increased the content of PA, 16α-hydroxytrametenolic acid, eburicoic acid, and tumulosic acid, while the silencing of each gene either significantly or slightly decreased the contents of these four compounds, indicating their involvement in the PA biosynthesis. In addition, different temperatures affected the expression of these genes and the formation of PA. By contrast, the overexpression and silencing of WcCYP64-2 did not alter the formation of these compounds. Taken together, these findings determine more potential steps in the biosynthetic pathway of PA for metabolic engineering.

Abstract The chromatin modifier GRAIN WEIGHT 6a (GW6a) enhances rice grain size and yield. However, little is known about its gene network determining grain size. Here, we report that MITOGEN-ACTIVED PROTEIN KINASE 6 (OsMAPK6) and E3 ligase CHANG LI GENG 1 (CLG1) interact with and target GW6a for phosphorylation and ubiquitylation, respectively. Unexpectedly, however, in vitro and in vivo assays reveal that both of the two post-translational modifications stabilize GW6a. Furthermore, we uncover two major GW6a phosphorylation sites (serine142 and threonine186) targeted by OsMAPK6 serving an important role in modulating grain size. In addition, our genetic and molecular results suggest that the OsMAPK6-GW6a and CLG1-GW6a axes are crucial and operate in a non-additive manner to control grain size. Overall, our findings identify a previously unknown mechanism by which phosphorylation and ubiquitylation non-additively stabilize GW6a to enhance grain size, and reveal correlations and interactions of these posttranslational modifications during rice grain development.

Purpose This study evaluated the elastic characteristics of the pulmonary trunk and distal branches in fetuses diagnosed with tetralogy of Fallot (TOF) using Doppler echocardiography. Methods Data on 42 fetuses diagnosed with TOF and 84 gestational age–matched normal fetuses were prospectively collected from the Second Xiangya Hospital of Central South University between August 2022 and January 2023. The severity of TOF was classified into three categories based on the z-score of the pulmonary annulus diameter: mild (z-score ≥-2), moderate (-40.05). Conclusion Fetuses diagnosed with TOF exhibited increased vascular stiffness in the MPA and reduced stiffness in the distal pulmonary artery (PA). Larger-scale follow-up studies are required to elucidate the relationships between these changes in vascular stiffness and PA development in patients with TOF.

Abstract Introduction Previous studies have reported controversial relationships between circulating vascular endothelial growth factors (VEGF) and ischemic stroke (IS). This study aims to demonstrate the causal effect between VEGF and IS using Mendelian randomization (MR). Methods Summary statistics data from two large-scale genome-wide association studies (GWAS) for 16,112 patients with measured VEGF levels and 40,585 patients with IS were downloaded from public databases and included in this study. A published calculator was adopted for MR power calculation. The primary outcome was any ischemic stroke, and the secondary outcomes were large-artery stroke, cardioembolic stroke, and small-vessel stroke. We used the inverse variance-weighted (IVW) method for primary analysis, supplemented by MR-Egger regression and the weighted median method. Results Nine SNPs were included to represent serum VEGF levels. The IVW method revealed no strong causal association between VEGF and any ischemic stroke (odds ratio [OR] 1.01, 95% CI 0.99–1.04, p = 0.39), cardioembolic stroke (OR 1.04, 95% CI 0.97–1.12, p = 0.28), large-artery stroke (OR 1.02, 95% CI 0.95–1.09, p = 0.62), and small-vessel stroke (OR 0.98, 95% CI 0.91–1.04, p = 0.46). These findings remained robust in sensitivity analyses. MR-Egger regression suggested no horizontal pleiotropy. Conclusions This Mendelian randomization study found no relationship between genetically predisposed serum VEGF levels and risks of IS or its subtypes.

Abstract Objective This study aims to elucidate the dose‒response relationship between 24-h activity behaviors and body fat percentage (BFP) in Chinese preschool children using a compositional isotemporal substitution model (ISM). Methods In a cross-sectional design, 881 children aged 3–6 from urban and rural areas of Jiangxi Province were sampled. Activity behaviors, including sedentary behavior (SB), low-intensity physical activity (LPA), and moderate- to high-intensity physical activity (MVPA), were measured using accelerometers. Sleep patterns were assessed through questionnaires, and BFP was determined by bioelectrical impedance analysis (BIA). The study employed compositional data analysis (CoDA) and ISM to estimate the impact of reallocating durations of different activity behaviors on BFP. Results Higher BFP was found in urban vs. rural children, decreasing with age. Overweight and obesity rates were 10.6% and 7.6%, respectively, above national averages. MVPA and LPA were negatively correlated with BFP, while SB was positively correlated. A 30-min MVPA reduction significantly increased zBFR, particularly in overweight children. Gender-specific nuances revealed that boys' MVPA negatively influenced zBFP (β = -0.155), P

Facebook, the most popular social media platform in the United States, is used by 239 million US adults, which represents 71% of the population. Not only do most US adults use Facebook but they also spend an average of 40 minutes per day on the platform. Due to Facebook’s reach and ease of use, it is increasingly being used as a modality for delivering behavioral and health communication interventions. Typically, a Facebook-delivered intervention involves creating a private group to deliver intervention content for participants to engage with asynchronously. In many interventions, a counselor is present to facilitate discussions and provide feedback and support. Studies of Facebook-delivered interventions have been conducted on a variety of topics, and they vary widely in terms of the intervention content used in the group, use of human counselors, group size, engagement, and other characteristics. In addition, results vary widely and may depend on how well the intervention was executed and the degree to which it elicited engagement among participants. Best practices for designing and delivering behavioral intervention content for asynchronous delivery in Facebook groups are lacking, as are best practices for engaging participants via this modality. In this tutorial, we propose best practices for the use of private Facebook groups for delivery and testing the efficacy of behavioral or health communication interventions, including converting traditional intervention content into Facebook posts; creating protocols for onboarding, counseling, engagement, and data management; designing and branding intervention content; and using engagement data to optimize engagement and outcomes.

Objective The objective is to evaluate the diagnostic effectiveness of contrast-enhanced spectral mammography (CESM) in the diagnosis of breast cancer.Design Data sources PubMed, Embase and Cochrane libraries up to 18 June 2022.Eligibility criteria for selecting studies We included trials studies, compared the results of different researchers on CESM in the diagnosis of breast cancer, and calculated the diagnostic value of CESM for breast cancer.Data extraction and synthesis Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) evaluated the methodological quality of all the included studies. The study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses specification. In addition to sensitivity and specificity, other important parameters were explored in an analysis of CESM accuracy for breast cancer diagnosis. For overall accuracy estimation, summary receiver operating characteristic curves were calculated. STATA V.14.0 was used for all analyses.Results This meta-analysis included a total of 12 studies. According to the summary estimates for CESM in the diagnosis of breast cancer, the pooled sensitivity and specificity were 0.97 (95% CI 0.92 to 0.98) and 0.76 (95% CI 0.64 to 0.85), respectively. Positive likelihood ratio was 4.03 (95% CI 2.65 to 6.11), negative likelihood ratio was 0.05 (95% CI 0.02 to 0.09) and the diagnostic odds ratio was 89.49 (95% CI 45.78 to 174.92). Moreover, there was a 0.95 area under the curve.Conclusions The CESM has high sensitivity and good specificity when it comes to evaluating breast cancer, particularly in women with dense breasts. Thus, provide more information for clinical diagnosis and treatment.

Vectors incorporating the human H1 (hH1) promoter are being applied for RNA interference (RNAi) experiments and genome editing. Although extensive studies have been conducted on the hH1 promoter, our understanding of the mouse H1 promoter remains limited. In this study, we predicted the 163 bp mouse H1 (mH1) promoter and 84 bp mouse H1 core (mH1 core) promoter through global alignment and detected its RNA polymerase II (Pol II) and III activities through the expression of the EGFP and the abundance of artificial sequence, which were generally slightly weaker than those of the hH1 promoter. Furthermore, to boost its Pol III activity, we engineered various promoter mutants by introducing mutations or systematically swapping elements. Surprisingly, the Pol II activity of mH1 core mut5 with AT stretch was at least 2-fold greater than that of the wild type, making it a potential candidate for target protein expression purposes. Fortunately, the Pol III activities of mH1 mut1 and mH1 core mut5 were at least 1.5 times stronger than those of the parental promoters in human and mouse cell lines on account of AT stretch, as did the mH1 mut4 with AT stretch and proximal sequence element (PSE) and TATA box insertion mutations. We highly recommend these three promoters as valuable supplements to the type 3 Pol III promoter toolbox.