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Zheng Wang,1,2,* Yifan Wu,1,2,* Wanrong Yi,1,2 Yifeng Yu,1,2 Xue Fang,1,2 Zonghuan Li,1,2 Aixi Yu1,2 1Department of Orthopedic Trauma and Microsurgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, People’s Republic of China; 2Hubei Clinical Medical Research Center of Trauma and Microsurgery, Wuhan, Hubei, People’s Republic of China*These authors contributed equally to this workCorrespondence: Aixi Yu; Zonghuan Li, Email yuaixi@whu.edu.cn; lizonghuan@whu.edu.cnBackground: Traumatic heterotopic ossification (HO) is a devastating sequela of orthopedic surgeries and traumatic injuries; however, few studies have explored the effects of the estrogen-deficient state on HO formation. In the present study, we investigated the impact of estrogen deficiency on ectopic cartilage and bone formation in tendon after Achilles tenotomy in an ovariectomized mouse model.Methods: A total of 45 female C57BL/6 mice were randomly divided into three groups: sham-operated (control), estrogen depletion by ovariectomy (OVX) and OVX with 17β-estradiol supplementation (OVX + E2), with 15 animals in each group. Three weeks after OVX, all mice were subjected to an Achilles tenotomy using a posterior midpoint approach to induce HO. At 1, 3 and 9 weeks after tenotomy, the left hind limbs were harvested for histology, immunohistochemistry and immunofluorescence evaluations. The volume of ectopic bone was assessed by micro-CT.Results: Mice in the OVX group formed more ectopic cartilage 3 weeks after tenotomy, as well as ectopic bone 9 weeks after tenotomy, compared to the control group. Estrogen deficiency resulted in more severe inflammatory infiltration at the injury sites 1 week after tenotomy, involving the recruitment of more macrophages and mast cells, as well as increasing the expressions of pro-inflammatory mediators, including IL-1β, IL-6, and TNF-α. Moreover, the local TGF-β/SMAD signaling pathway was dysregulated after OVX, which manifested as upregulated expressions of TGF-β and pSMAD2/3. E2 supplementation protected against OVX-induced HO deterioration, inhibited inflammatory infiltration, and downregulated the TGF-β/SMAD signaling pathway.Conclusion: Estrogen deficiency exacerbated HO formation in the Achilles tenotomy model. These findings might be attributable to the disturbance of the inflammatory response and the activation of TGF-β/SMAD signaling at the injury sites during the early stages of HO development.Keywords: heterotopic ossification, estrogen deficiency, inflammation, TGF-β/SMAD signaling

Mengjie Yang, Kun Guo, Wenjing Liu, Xiuqing Fang, Ting Liu School of Nursing, Qingdao University, Qingdao, Shandong, People’s Republic of ChinaCorrespondence: Ting Liu, School of Nursing, Qingdao University, 1 Ningde Road, Qingdao, Shandong, 266073, People’s Republic of China, Tel +86 15066237573, Email liuting201516@163.comPurpose: The study aimed to explore the status of four common health problems (ie, smoking, internet addiction, physical inactivity, psychological disorder) among college students and analyze the relationship between psychological resilience, coping tendency and health problems.Participants and Methods: The convenience sampling method was used to recruit 500 college students from four universities. The General Information Questionnaire, Adolescent Psychological Resilience Scale, Simplified Coping Style Questionnaire and Health Risk Behavior Questionnaire were used for survey.Results: Among the students, there were 71 smokers (15.4%) and 61 internet addicts (13.2%). Over a third of the students reported physical inactivity (35.9%) and a minority had psychological disorder (6.3%). The psychological resilience score differed between students who smoked, had internet addiction, physical inactivity, psychological disorder and those without these health-risk behaviors. Logistic regression analysis showed that negative coping tendency was the common contributing factor of physical inactivity, internet addiction and psychological disorder. Coping tendency played a partial mediating effect in the relationship between psychological resilience and health problems, with a mediating effect of 37.93%.Conclusion: Psychological resilience can not only affect health problems directly but also influence health problems indirectly through coping tendency. Educators and administrators in universities can apply effective measures to improve psychological resilience and positive coping to prevent or reduce health problems among undergraduates.Keywords: undergraduates, psychological resilience, coping, health problems, mediating effect

Xuan Pan,1,* Ting Han,2,* Zixuan Zhao,3,4 Xiaoming Wang,1 Xiaosan Fang1 1Department of Hepato-Biliary-Pancreatic Surgery, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, 241000, People’s Republic of China; 2Department of Gastroenterology, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, 241000, People’s Republic of China; 3The Translational Research Institute for Neurological Disorders of Department of Neurosurgery, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, 241000, People’s Republic of China; 4The Institute of Brain Science, Wannan Medical College, Wuhu, 241000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiaosan Fang; Xiaoming Wang, Department of Hepato-Biliary-Pancreatic Surgery, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), 2 West Zheshan Road, Wuhu, 241002, People’s Republic of China, Tel +86-0553-5739219, Email 20142031@wnmc.edu.cn; wxm6901@126.comAbstract: The high malignant degree and poor prognosis of pancreatic cancer (PC) pose severe challenges to the basic research and clinical translation of next-generation therapies. The rise of immunotherapy has improved the treatment of a variety of solid tumors, while the application in PC is highly restricted by the challenge of immunosuppressive tumor microenvironment. The latest progress of nanotechnology as drug delivery platform and immune adjuvant has improved drug delivery in a variety of disease backgrounds and enhanced tumor therapy based on immunotherapy. Based on the immune loop of PC and the status quo of clinical immunotherapy of tumors, this article discussed and critically analyzed the key transformation difficulties of immunotherapy adaptation to the treatment of PC, and then proposed the rational design strategies of new nanocarriers for drug delivery and immune regulation, especially the design of combined immunotherapy. This review also put forward prospective views on future research directions, so as to provide information for the new means of clinical treatment of PC combined with the next generation of nanotechnology and immunotherapy. Keywords: pancreatic cancer, immunotherapy, nanomedicine, immunosuppressive tumor microenvironment regulation, combined drug delivery strategy

Yujie Wang,1 Tingting Deng,1 Xi Liu,2 Xueyang Fang,1 Yongpan Mo,3 Ni Xie,4 Guohui Nie,1 Bin Zhang,1 Xiaoqin Fan1,4 1Shenzhen Key Laboratory of Nanozymes and Translational Cancer Research, Department of Otolaryngology, Shenzhen Institute of Translational Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, Shenzhen, 518035, People’s Republic of China; 2Department of Nephrology, Shenzhen Longgang Central Hospital, Shenzhen, 518116, People’s Republic of China; 3Department of Breast Surgery, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, Shenzhen, 518035, People’s Republic of China; 4The Bio-Bank of Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, Shenzhen, Guangdong, 518035, People’s Republic of ChinaCorrespondence: Bin Zhang; Xiaoqin Fan, Email binzhang@email.szu.edu.cn; fanxiaoqin83@163.comAbstract: The tumor microenvironment (TME) is a complex and dynamic entity, comprising stromal cells, immune cells, blood vessels and extracellular matrix, which is intimately associated with the occurrence and development of cancers, as well as their therapy. Utilizing the shared characteristics of tumors, such as an acidic environment, enzymes and hypoxia, researchers have developed a promising cancer therapy strategy known as responsive release of nano-loaded drugs, specifically targeted at tumor tissues or cells. In this comprehensive review, we provide an in-depth overview of the current fundamentals and state-of-the-art intelligent strategies of TME-responsive nanoplatforms, which include acidic pH, high GSH levels, high-level adenosine triphosphate, overexpressed enzymes, hypoxia and reductive environment. Additionally, we showcase the latest advancements in TME-responsive nanoparticles. In conclusion, we thoroughly examine the immediate challenges and prospects of TME-responsive nanopharmaceuticals, with the expectation that the progress of these targeted nanoformulations will enable the exploitation, overcoming or modulation of the TME, ultimately leading to significantly more effective cancer therapy. Keywords: tumor microenvironment, stimulus-responsive, drug delivery, cancer therapy, intelligent biomedicine

Hanfang Zhou,1 Qingyin Li,1 Zhijun Liu,2 Keman Li,1 Xiaomin Geng,3 Xiaoyi Fang1 1Institute of Developmental Psychology, Beijing Normal University, Beijing, People’s Republic of China; 2School of Education, Hunan University of Science and Technology, Xiangtan, People’s Republic of China; 3State Key Laboratory of Cognitive Neuroscience and Learning, Beijing Normal University, Beijing, People’s Republic of ChinaCorrespondence: Xiaoyi Fang, Institute of Developmental Psychology, Beijing Normal University, No. 19 Xin Jie Kou Wai Street, Hai Dian District, Beijing, 100875, People’s Republic of China, Email fangxy@bnu.edu.cnBackground: The significant influence of family emotional expressiveness (FEE) on adolescents’ face-to-face social interactions is well-established. However, there has been limited investigation into potential links between FEE and adolescents’ online social behaviors, especially cyberbullying bystander behaviors, which are pivotal in cyberbullying incidents. This study aimed to assess the relative importance of different aspects of FEE (positive FEE vs. negative FEE vs. the Positive-to-Negative ratio) in predicting adolescents’ cyberbullying bystander behaviors, and the mediating roles of affective and cognitive empathy in these relationships.Methods: A sample of 1,952 adolescents (Mage = 14.18, SD = 1.33) completed questionnaires, including the Family Emotional Expressiveness Questionnaire, Basic Empathy Scale, and Cyberbullying Bystander Behavior Scale. SPSS 26.0 and Mplus 8.3 were used for analysis.Results: (1) Positive FEE exhibited a positive association with protective behavior and a negative association with indifferent behavior. Conversely, negative FEE showed positive associations with reinforcing and indifferent behaviors. However, the Positive-to-Negative ratio did not exhibit significant associations with any of the three bystander behaviors. (2) Negative FEE emerged as relatively more significant than both positive FEE and the Positive-to-Negative ratio in predicting reinforcing and indifferent behaviors. (3) Affective empathy mediated the relationship between positive FEE and reinforcing behavior, while cognitive empathy mediated the relationship between positive FEE and protective and indifferent behaviors. Moreover, cognitive empathy exerted a more influential role than affective empathy in this mediation process.Conclusion: Various aspects of FEE demonstrated distinct relationships with three cyberbullying bystander behaviors, with affective and cognitive empathy playing an important mediating role in the association. This finding holds substantial implications for the development of cyberbullying prevention strategies. Such strategies could target the reduction of negative emotional expression within adolescent families and the cultivation of both cognitive and affective empathy.Keywords: family emotional expressiveness, positive-to-negative ratio, empathy, cyberbullying bystander behaviors, adolescent

Longmin Chen,1 Qing Zhou,2 Xun Fang,1 Qianqian Xu,2 Yuan Zou,2 Jing Zhang2 1Department of Rheumatology and Immunology, the Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 2Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Respiratory Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of ChinaCorrespondence: Jing Zhang, Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Respiratory Disease, Tongji Hospital Research Building, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Caidian, 430100, People’s Republic of China, Email jingzhang@tjh.tjmu.edu.cnBackground: Rheumatoid arthritis (RA) is a chronic and systemic autoimmune disease characterized by synovial inflammation and joint destruction. Despite progress in RA therapy, it remains difficult to achieve long-term remission in RA patients. Phosphodiesterase 3B (Pde3b) is a member of the phosphohydrolyase family that are involved in many signal transduction pathways. However, its role in RA is yet to be fully addressed.Methods: Studies were conducted in arthritic DBA/1 mice, a suitable mouse strain for collagen-induced rheumatoid arthritis (CIA), to dissect the role of Pde3b in RA pathogenesis. Next, RNAi-based therapy with Pde3b siRNA-loaded liposomes was assessed in a CIA model. To study the mechanism involved, we investigated the effect of Pde3b knockdown on macrophage polarization and related signaling pathway.Results: We demonstrated that mice with CIA exhibited upregulated Pde3b expression in macrophages. Notably, intravenous administration of liposomes loaded with Pde3b siRNA promoted the macrophage anti-inflammatory program and alleviated CIA in mice, as indicated by the reduced inflammatory response, synoviocyte infiltration, and bone and cartilage erosion. Mechanistic study revealed that depletion of Pde3b increased cAMP levels, by which it enhanced PKA-CREB-C/EBPβ pathway to transcribe the expression of anti-inflammatory program-related genes.Conclusion: Our results support that Pde3b is involved in the pathogenesis of RA, and Pde3b siRNA-loaded liposomes might serve as a promising therapeutic approach against RA.Keywords: rheumatoid arthritis, Pde3b, liposomes, macrophages

Min Zhou,1,&ast; Yuping Liu,2,&ast; Xue Fang,1 Zhezhen Jiang,1 Wang Zhang,1 Xin Wang1 1Department of Orthopaedics Trauma and Microsurgery, Zhongnan Hospital of Wuhan University, Wuhan City, People’s Republic of China; 2Sichuan University West China Second University Hospital, Department of Anesthesiology, Chengdu, Sichuan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xin Wang, Department of Orthopedics Trauma and Microsurgery, Zhongnan Hospital of Wuhan University, Wuhan Ctiy, Hubei Province, 430000, People’s Republic of China, Tel +86-027-67812557, Email wangxinznyy@whu.edu.cnPurpose: Polyhexanide is a safe and effective wound care antiseptic commonly used in clinics as wound rinsing solution and gel. However, the efficacy of Polyhexanide in treatment of wound infected with MRSA (methicillin-resistant Staphylococcus aureus) is unknown. The aim of this study is to assess the effectiveness of polyhexanide with povidone iodine in treating wound infected with MRSA.Patients and Methods: A prospective analysis of 62 patients with wound infections, who were admitted to our department from 2016 to 2020, was conducted in order to assess the efficacy of different treatment approaches. The patients were divided into two groups: the experimental group and the control group. In the experimental group, 30 patients underwent treatment with a combination of diluted povidone iodine and polyhexanide immersion. Conversely, in the control group, 32 patients received treatment with diluted povidone iodine along with systemic antibiotic therapy. The time required for dressing changes, bacterial clearance rates, and the Bates-Jasen wound assessment tool (BWAT) scores were utilized as indicators to evaluate the effectiveness of the treatments.Results: In our study, the findings indicated that the experimental group exhibited a lesser number of days for the bacteria culture to turn negative compared to the control group, with statistical significance (p< 0.05). Furthermore, the decline in the BWAT score was significantly greater in the experimental group than in the control group (p< 0.05). However, no significant differences were observed in terms of dressing times and wound coverage between the two groups (p> 0.05).Conclusion: Polyhexanide combined with povidone iodine can effectively remove MRSA infection in wounds and reduce antibiotic dosages.Keywords: methicillin-resistant staphylococcus aureus, wound, polyhexanide

Jiani Wang,1,&ast; Liudan Chen,2,&ast; Zhuangfei Wang,3 Xiaohong Fang,3 Yan Zhen2 1School of Nursing, Sun Yat-Sen University, Guangzhou City, Guangdong Province, People’s Republic of China; 2Department of Traditional Chinese Medicine, Sun Yat-Sen Memorial Hospital, Guangzhou City, Guangdong Province, People’s Republic of China; 3Department of Dermatology, Sun Yat-Sen Memorial Hospital, Guangzhou City, Guangdong Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yan Zhen, Department of Traditional Chinese Medicine, Sun Yat-sen Memorial Hospital, Guangzhou City, Guangdong Province, People’s Republic of China, Tel +86 020– 87334851, Fax +86 020– 87333043, Email Zhenyandyx@163.comIntroduction: Traditional Chinese medicine (TCM) holds great potential in promoting healing and relieving pain for herpes zoster (HZ) treatments. Evidence showed that both healthcare professionals’ (HCPs) belief and knowledge influence their attitudes, which result in their expression and direct behavior. However, little is known in this area regarding TCM treatments for HZ. This study aimed to understand the HCPs’ perceptions, attitudes, beliefs, and practices toward TCM and its services for HZ.Methods: During July 2021 and October 2022, a cross-sectional study of HCPs querying demographics, perceptions, attitudes, beliefs, and practices toward TCM and TCM services for HZ was conducted. The frequency and percentage or mean and standard deviation were used to present categorical data and continuous data, respectively. A Chi-square analysis compared nurses’ and doctors’ views on TCM treatments for HZ.Results: Out of 306 eligible respondents, 66.0% used TCM content in clinical practice less than 40% of the time. Respondents reported that there were three main advantages of TCM for HZ, including better crusting and healing, fewer side effects, and mitigating complications. A total of 41.3% (81/196) of the respondents who had cared for/treated HZ patients applied TCM treatments. The three factors most associated with referrals/providing TCM to patients were postherpetic neuralgia, early erythema or papules, and acute pain. Compared to nurses, doctors showed more endorsement of the efficacy and cost-effectiveness of TCM treatments for HZ patients.Conclusion: The study found that most healthcare professionals in HZ had a favorable view of TCM, but lacked practical experience administering it to patients. Programs should be developed to provide evidence-based TCM treatments and encourage combining TCM with Western medicine for better patient care.Keywords: Herpes Zoster, Traditional Chinese Medicine, Perception, Attitude, Healthcare Professionals

Suyang Guo,1 Wenqi Bai,1 Fengjie Cui,1 Xin Chen,1 Xiaojing Fang,1 Honghong Shen,2 Xianhua Gu1 1Department of Gynecology Oncology, First Affiliated Hospital of Bengbu Medical University, Bengbu, People’s Republic of China; 2Department of Medical Oncology, First Affiliated Hospital of Bengbu Medical University, Bengbu, People’s Republic of ChinaCorrespondence: Honghong Shen, Department of Medical Oncology, The First Affiliated Hospital of Bengbu Medical University, Anhui Province Key Laboratory of Translational Cancer Research, Bengbu Medical University, 287 Changhuai Road, Bengbu, Anhui, 233004, People’s Republic of China, Tel +8613385681156, Email shenhonghong1984@163.com Xianhua Gu, Department of Oncology Gynecology, The First Affiliated Hospital of Bengbu Medical University, Bengbu Medical University, 287 Changhuai Road, Bengbu, Anhui, 233004, People’s Republic of China, Tel +8613385680722, Email guxianhua1986@163.comIntroduction: GRHL1 belongs to the family of Grainyhead-like (GRHL). Previous studies have shown that dysregulation of growth and survival pathways is associated with the GRHL family of gene cancers. Immunotherapy with checkpoint inhibitors has changed the treatment paradigm for many tumors, including endometrial cancer (EC). However, the effect of GRHL1 on immunotherapy in EC and its relationship with immune cell infiltration are poorly understood.Methods: Differential expression of GRHL1 between EC and normal EC tissues was analyzed by searching the TCGA database, and the results were verified utilizing immunohistochemistry analyses. Next, the relationship between GRHL1, CD8+ T cells and tumor microenvironment (TME) was also investigated, and the effect of GRHL1 expression on immunotherapy in EC was evaluated.Results: According to the findings, EC tissues had elevated expression levels of GRHL1 relative to normal tissues. Patients with EC who expressed GRHL1 at high levels experienced worse overall survival (OS) and Progression-free survival (PFS) than those whose expression was lower. In addition, GRHL1 expression was negatively correlated with CD8+ T cells, and patients with high GRHL1 expression were less effective in receiving immunotherapy.Conclusion: The expression of GRHL1 was high in EC patients, and high expression of GRHL1 inhibits the proliferation of CD8+ T cells in the tumor microenvironment of EC and affect the efficacy of immunotherapy.Keywords: GRHL1, endometrial cancer, tumor microenvironment, CD8+ T cells, immunotherapy

Kun Li,1 Dongsheng Han,2 Ahmad Alhaskawi,3 Tingting Liu,1 Xiaojuan Wang,4 Wu Yang,1 Hui Lu,3 Xueling Fang1 1Department of Critical Care Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People’s Republic of China; 2Department of Laboratory Medicine, the First Affiliated Hospital, Zhejiang University school of Medicine, Hangzhou, Zhejiang, People’s Republic of China; 3Department of Orthopaedics, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People’s Republic of China; 4Department of Clinical Pharmacy, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of ChinaCorrespondence: Xueling Fang, Department of Critical Care Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, No. 79, Qingchun Road, Shangcheng District, Hangzhou, Zhejiang, People’s Republic of China, Fax +86 571-87236838, Email 1191012@zju.edu.cn Hui Lu, Department of Orthopaedics, The First Affiliated Hospital, Zhejiang University School of Medicine, No. 79, Qingchun Road, Shangcheng District, Hangzhou, Zhejiang, People’s Republic of China, Fax +86 571-87236121, Email HuiLu@zju.edu.cnBackground: Chromobacterium violaceum (C. violaceum) is a Gram-negative bacterium capable of causing severe infections in both humans and specific animals. Despite its infrequency, C. violaceum infections exhibit a notably high mortality rate. The timely and precise detection of this pathogen stands as a critical factor in achieving effective diagnosis and treatment. Traditional diagnostic approaches possess limitations, particularly in terms of their time-consuming nature and the range of pathogens they can identify. Metagenomic next-generation sequencing (mNGS) testing has emerged as a highly promising diagnostic tool for infectious diseases.Methods: Within this case report, we present a patient who developed a C. violaceum infection subsequent to a lower limb infection, leading to the progression of sepsis, a liver abscess, septic shock, multi-organ dysfunction, and altered mental status. Samples of the patient’s blood and tissue from the lower limb skin are collected, and the infection is swiftly diagnosed through mNGS, allowing for the immediate initiation of suitable treatment.Results: The mNGS results revealed the patient’s infection with C. violaceum. Subsequent conventional bacterial culture results were concordant with the mNGS findings. Following comprehensive management measures, including prompt and effective anti-infective treatment, the patient achieved cure and was successfully discharged.Conclusion: This case underscores the significance of employing advanced diagnostic methodologies like mNGS for the early detection of uncommon pathogens such as C. violaceum. The expedited diagnosis and timely intervention hold the potential to substantially enhance patient outcomes in cases of severe infections instigated by this bacterium.Keywords: chromobacterium violaceum, sepsis, infection, hepatapostema, liver, liver abscess, metagenomic next-generation sequencing

Xin Fang,1 Yalong Yin,2 Haimei Lun,3 Yaoli Liu,1 Shangyong Zhu1 1Department of Medical Ultrasound, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People’s Republic of China; 2Department of Traditional Chinese Medicine, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People’s Republic of China; 3Department of Ultrasound, People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, People’s Republic of ChinaCorrespondence: Shangyong Zhu, Department of Medical Ultrasound, First Affiliated Hospital of Guangxi Medical University, No. 6 Shuangyong Road, Nanning, Guangxi, 530021, People’s Republic of China, Email zhushangyong2022@sina.cnPurpose: Few studies have assessed the effects of sphingosine kinase 1/sphingosine-1-phosphate (SPHK1/S1P) on microangiogenesis at rat myofascial trigger points (MTrPs) using contrast-enhanced ultrasonography (CEUS). This study aimed to address these deficiencies. Here, we investigated the effects of SPHK1/S1P on MTrP microangiogenesis and the value of CEUS in evaluating these effects.Methods: Forty Sprague‒Dawley rats were subdivided into two groups: control and MTrP groups. MTrPs were established by 8 weeks of the strike procedure combined with eccentric motion and 4 weeks of recovery. All rats were euthanized after having undergone CEUS with an overdose of pentobarbital sodium. MTrP and control tissue samples were removed for haematoxylin and eosin (H&E) staining and transmission electron microscopy (TEM) imaging. The tissue was dehydrated, cleared, and embedded before sectioning. The sections were then incubated overnight at 4°C, and immunohistochemistry was carried out with primary antibodies including rabbit anti-CD31, rabbit anti-SPHK1and rabbit anti-S1PR1.Results: MTrP rats exhibited spontaneous electrical activity (SEA) and a local twitch response (LTR) during electromyography (EMG) examination. The CEUS time-intensity curves (TICs) showed that the perfusion intensity in the MTrPs and surrounding tissue area was increased, with faster perfusion than in normal sites, while the TICs in the control group slowly increased and then slowly decreased. The correlation coefficient between the microvessel density (MVD) and sphingosine 1-phosphate receptor 1 (S1PR1) was 0.716 (p < 0.01). Spearman correlation analysis revealed that Spearman’s rho (ρ) values between the MVD and peak intensity (PI), between the MVD and area under the curve (AUC), and between the MVD and SPHK1 were > 0.5 (p < 0.05), > 0.7 (p < 0.01), and > 0.7 (p < 0.01), respectively.Conclusion: CEUS is valuable for detecting microangiogenesis within MTrPs, and SPHK1/S1P plays an important role in promoting MTrP tissue microangiogenesis.Keywords: ultrasound, myofascial pain syndrome, diagnosis, angiogenesis

Chenxi Li,1,2,&ast; Xueyang Fang,1,&ast; Han Zhang,1,3 Bin Zhang1 1Shenzhen Key Laboratory of Nanozymes and Translational Cancer Research, Institute of Translational Medicine Department of Otolaryngology Shenzhen Second People’s Hospital, the First Affiliated Hospital of Shenzhen University, Health Science Center, Shenzhen, 518035, People’s Republic of China; 2Graduate Collaborative Training Base of Shenzhen Second People’s Hospital, Heng Yang Medical School, University of South China, Hengyang, Hunan, 421001, People’s Republic of China; 3International Collaborative Laboratory of 2D, Materials for Optoelectronics Science and Technology of Ministry of Education, Institute of Microscale Optoelectronics, College of Physics and Optoelectronic Engineering, Shenzhen University, Shenzhen, 518060, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Bin Zhang; Xueyang Fang, Email binzhang@email.szu.edu.cn; FANGXueyang0210@163.comAbstract: In recent years, metal-containing two-dimensional (2D) nanomaterials, among various 2D nanomaterials have attracted widespread attention because of their unique physical and chemical properties, especially in the fields of biomedical applications. Firstly, the review provides a brief introduction to two types of metal-containing 2D nanomaterials, based on whether metal species take up the major skeleton of the 2D nanomaterials. After this, the synthetical approaches are summarized, focusing on two strategies similar to other 2D nanomaterials, top-down and bottom-up methods. Then, the performance and evaluation of these 2D nanomaterials when applied to cancer therapy are discussed in detail. The specificity of metal-containing 2D nanomaterials in physics and optics makes them capable of killing cancer cells in a variety of ways, such as photodynamic therapy, photothermal therapy, sonodynamic therapy, chemodynamic therapy and so on. Besides, the integrated platform of diagnosis and treatment and the clinical translatability through metal-containing 2D nanomaterials is also introduced in this review. In the summary and perspective section, advanced rational design, challenges and promising clinical contributions to cancer therapy of these emerging metal-containing 2D nanomaterials are discussed. Keywords: metal-containing two-dimensional nanomaterials, nanotechnology-based therapy, cancer precision treatment, theranostic platform

Luo H, Hang Y, Zhu H, et al. Infect Drug Resist. 2023;16:2601–2609 Following a review of the paper post-publication, the authors realized the Funding statement on page 2607 was incorrect. The correct Funding statement is as follows: Funding This work was supported by the National Natural Science Foundation of China (82060391), the Natural Science Foundation of Jiangxi Province (No. 20202BAB216021), the Health Commission of Jiangxi Province (No. 20201034). The authors apologize for any inconvenience caused to the readers.

Yu Wang,1,&ast; Hanning Zha,1,&ast; Xiang Fang,2 Tianjiao Shen,1 Kunyun Pan,1 Jianping Zhang,1 Keqiang He,1 Sheng Wang,1 Liguo Hu1 1Department of Anesthesiology, The First Affiliated Hospital of USTC (Anhui Provincial Hospital), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, People’s Republic of China; 2Department of Anesthesiology, Hefei BOE Hospital, Hefei, Anhui, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Sheng Wang; Liguo Hu, Email iamsheng2020@ustc.edu.cn; hulg@163.comObjective: The dose selection of ropivacaine for spinal anesthesia in clinical work mainly depends on the experience of the anesthesiologist. In this study, a prospective and modified up-down sequential allocation design was used to provide the optimal dose selection of ropivacaine for spinal anesthesia.Patients and methods: This study was divided into two stages, and a total of 164 elderly patients with elective hip fractures were included. In stage I, the dose of ropivacaine was selected using the up-down sequential method of height correction, and the 50% effective dose (ED50) and 95% effective dose (ED95) were obtained. A nomogram for predicting satisfactory anesthesia and a formula for predicting the optimal dose was also given in this stage. In stage II, the dose of ropivacaine was calculated by using the optimal dose prediction formula, so as to evaluate the efficacy and safety of the model.Results: The ED50 and ED95 of the stage I were 7.036 mg (95%CI 6.549– 7.585 mg) and 8.709 mg (95%CI 7.902– 14.275 mg), respectively. And provided a nomogram predicting satisfactory anesthesia with a C-index of 0.847 (95%CI 0.774– 0.92). The optimal dose prediction formula of ropivacaine was calculated, including variables for age, gender, height, and weight. This formula was found to be 90% efficient. It is worth mentioning that the incidence of direct transfer to the ward in the two stages was as high as 86.84% and 93.33%, respectively, and no patients were transferred to the ICU in stage II.Conclusion: The ED50 and ED95 of ropivacaine were 7.036 mg and 8.709 mg, respectively, and the nomograms are sufficiently accurate to predict satisfactory anesthesia. Beyond that, the dose prediction equation provided in this study has high efficacy and safety, and can guide the dose selection of spinal anesthesia in elderly patients with hip fracture in clinical practice.Clinical trials registration: ChiCTR2100046982Keywords: ropivacaine, dose selection, elder, spinal anesthesia, Hip fracture, sequential design

Xiaoqiong Wu,1,&ast; Pu Li,1,&ast; Maimaitiaili Yimiti,1 Zhiqiu Ye,2 Xuqian Fang,2 Peizhan Chen,3 Zhidong Gu1,4 1Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 2Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 3Clinical Research Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 4Department of Laboratory Medicine, Ruijin-Hainan Hospital, Shanghai Jiao Tong University School of Medicine (Hainan Boao Research Hospital), Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhidong Gu, Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201821, People’s Republic of China, Tel +86 13801653534, Email guzhidongruijin@163.com Peizhan Chen, Clinical Research Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201821, People’s Republic of China, Tel +86 13918550745, Email pzchen@me.comBackground: Chromosome is the basic framework for eukaryotic cells to store genetic information, but certain genes exist in circulation, such as extrachromosomal circular DNA (eccDNA). The unique genetic characteristics and structure of eccDNA provide a new vision on the early diagnosis of cancer; however, whether eccDNA contributes to the early diagnosis and progression of lung cancer remains unclear.Methods: We performed next-generation sequencing (NGS) analysis of eccDNA from the plasma of 6 lung adenocarcinoma (LUAD) patients. The data of plasma eccDNA of healthy people were obtained from public available database. We compared size distribution, chromosome origin, formation and expression patterns of eccDNA between LUAD patients and those of 6 healthy people and 4 healthy gravidas.Results: A total number of 716,059 eccDNA ranging from 22 bp to 3,297,519 bp were detected with an average size less than 800bp and distinctive bimodality in size around 191 bp and 320 bp. After comparison of eccDNA abundance in each sequencing sample, nine eccDNA were ranked on top with higher frequency in lung adenocarcinoma patients than healthy people. Among them, four eccDNA (DOCK1, PPIC, TBC1D16, and RP11-370A5.1) were uniquely expressed in lung adenocarcinoma patients, which may serve as potential biomarkers for early diagnosis LUAD.Conclusion: Cancer-specific eccDNA was presented in LUAD compared to normal people, which might serve as a promising biomarker in LUAD.Keywords: eccDNA, lung adenocarcinoma, plasma, early diagnosis

Tianjun Yang,1,2,&ast; Qing Mei,1,2,&ast; Xiaowei Fang,1,2 Shoujun Zhu,1,2 Yinzhong Wang,1,2 Wanli Li,1,2 Aijun Pan1,2 1Department of Intensive Care Unit, The First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, Anhui Province, 230001, People’s Republic of China; 2Department of Intensive Care Unit, The Affiliated Provincial Hospital of Anhui Medical University, Hefei, Anhui Province, 230001, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Aijun Pan; Qing Mei, Department of Intensive Care Unit, The First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, No. 17, Lu Jiang Road, Hefei, Anhui Province, 230001, People’s Republic of China, Fax +86-551-62283114, Email aijunpan@fsyy.ustc.edu.cn; qingmei@fsyy.ustc.edu.cnBackground: Metagenomics next-generation sequencing (mNGS) is more efficient in identifying pathogens responsible for pneumonia. However, whether these patients ultimately benefit from this improvement remains unknown.Methods: In this retrospective, nested, case–control study, patients with severe hospital-acquired pneumonia (HAP) who had undergone mNGS of bronchoalveolar lavage fluid while in our intensive care unit from March 2017 to December 2020 (n = 33) were matched in a ratio of 1 to 2 (n = 66) by sex, age, comorbidities, immune status, Acute Physiology and Chronic Health Evaluation II score, severity of pulmonary infection, and use of extracorporeal life support with patients who had undergone conventional microbiological testing only. The primary outcome was 90-day mortality; secondary outcomes being length of intensive care unit stay, duration of mechanical ventilation support, 7-day and 28-day mortality, and efficacy of treatment of pulmonary infection.Results: In the CMT group, 17 patients (25.8%) had negative results, whereas only one (3.0%) had negative results in the mNGS group (P < 0.001). After receipt of microbiology results, antibiotics were altered in 23/33 patients (70.0%) in the mNGS group, but in only 29/66 (43.9%) in the CMT group (P = 0.016). Pulmonary infection-related findings improved in 20/33 patients (60.6%) in the mNGS group in the subsequent 7 days, but in only 25/66 (37.9%) in the CMT group (P = 0.032). However, the 28-day (33.3% vs 31.2%, P = 1.0) and 90-day (48.5% vs 45.5%, P = 0.78) mortality rates did not differ significantly between the two groups. These findings were supported by Cox-regression and Kaplan–Meier survival curve analyses.Conclusion: mNGS is helpful in the treatment of severe HAP but does not improve medium or long-term survival rates, especially in patients with severe comorbidities.Keywords: next generation sequencing, severe hospital-acquired pneumonia, bronchoalveolar lavage fluid, mortality, pathogenic microbes

Dingli Xu,1,2,&ast; Kaifeng Gan,3,&ast; Yang Wang,1 Zeting Wu,1 Yulong Wang,1 Song Zhang,1 Yujie Peng,2 Xuguang Fang,4 Hua Wei,5 Yansheng Zhang,5 Weihu Ma,2 Jing Chen5 1The Affiliated Hospital of Ningbo University Medical School, Ningbo, 315000, People’s Republic of China; 2Ningbo No.6 Hospital, Ningbo, 315000, People’s Republic of China; 3The Affiliated Lihuili Hospital of Ningbo University, Ningbo, 31500, People’s Republic of China; 4The First Affiliated Hospital of Xi ‘an Medical University, Xi’an, 710082, People’s Republic of China; 5Zhejiang International Scientific and Technological Cooperative Base of Biomedical Materials and Technology, Zhejiang Engineering Research Center for Biomedical Materials, Cixi Institute of Biomedical Engineering, Ningbo Institute of Materials Technology and Engineering, Chinese Academy of Sciences, Ningbo, 315300, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Weihu Ma; Jing Chen, Email 944973034@qq.com; jing.chen@nimte.ac.cnIntroduction: Bone delay union is mostly caused by lack of blood supply. Although autografts, allografts and artificial bone have been widely used to treat bone delay union, the bone regeneration fails in the ischemic site accompanied by the bone donor site complications and disease transmission. Recently, there is a growing recognition of the importance of hydrogel scaffolds which are regarded as an eligible engineer tissue for bone repair. However, hydrogel is still limited in improving neovascularization.Methods: In this work, black phosphorus nanosheet and deferoxamine (BPN-DFO) were loaded in the gelatin hydrogel to overcome the high risk of bone delay union and systemically investigated the regeneration capability of BPN-DFO hydrogel in vitro and vivo.Results: The resulting BPN-DFO hydrogel scaffold showed superior swollen, degradation and release rate, as well as satisfied biocompatibility. BPN-DFO hydrogel shown the significant up-expression of mRNA related to bone regeneration and cell proliferation. In vivo, the proposed BPN-DFO hydrogel significantly improved osteogenesis and neovascularization in the ischemic tibial bone site of SD rats with acute femoral artery occlusion. Both macroscopic and histological evaluation of new regenerated bone showed newly formed blood vessel and collagen using BPN-DFO hydrogel. The immunohistochemistry and RT-PCR revealed that the bone regeneration could be improved via BMP/Runx2 pathway.Conclusion: The BPN-DFO hydrogel possesses potential tissue engineer material for ischemic bone defect treatment. However, furthermore studies are needed to testify the safety and efficacy of BPN-DFO hydrogel.Keywords: ischemic bone defect regeneration, hydrogel scaffolds, black phosphorus nanosheets, deferoxamine

Xiaojuan Dai,1,&ast; Xuan Fang,1,&ast; Yuan Xia,1 Manyun Li,1 Xiaomei Li,1 Yiping Wang,2 Jinhui Tao,1 Xiangpei Li1 1Department of Rheumatology and Immunology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, People’s Republic of China; 2Centre for Transplantation and Renal Research, Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW, Australia&ast;These authors contributed equally to this workCorrespondence: Xiangpei Li; Jinhui Tao, Email lixiangpei55@126.com; taojinhui@ustc.edu.cnObjective: To investigate the effect of P2X7R on MSU crystal-induced acute gouty arthritis in rats and its mechanism on inflammatory responses.Methods: In vivo activation or inhibition of P2X7R was examined in the ATP group or the BBG group of rats, and the control group were injected with PBS. All three groups of rats were injected with MSU in the right joint cavity. The development of acute gouty arthritis was observed and evaluated at 6h, 12h, 24h, 48h and 72h. The clinical manifestations of acute arthritis, the expression level of P2X7R in spleen macrophages, the ability of macrophages to take up YO-PRO-1, and the level of Tregs, Th17 cells and inflammatory cytokines were assessed. Besides, mRNA expression levels of P2X7R, NLRP3 and IL-1β were also detected.Results: After 12h and 24h administration, P2X7R agonist ATP significantly accelerated the development of acute gouty arthritis, while the P2X7R inhibitor BBG had the opposite effect on this process. Activation of P2X7R significantly aggravated the ankle joint arthritis of the rat and promoted the infiltration of neutrophils and macrophages in the synovial tissue. In addition, the expression of P2X7R in macrophages of ATP group, the uptake of YO-PRO-1 and the expression of NLRP3 mRNA were significantly higher than that in other two groups. At 12h or 24h, activation or inhibition P2X7R had a significant effect on the IL-1β, IL-6, IL-17, IL-10 and TGF-β 1. The ratios of Treg/Th17 gradually decreased in the First three time points, it was the lowest at 24h.Conclusion: Activation of P2X7R by ATP aggravated the development of acute gouty arthritis through P2X7R/NLRP3 pathway, promoted the secretion of related inflammatory cytokines, which affected radio of Tregs/Th17 cells. The whole pathogenesis process appeared a pattern from acute attack to remission in time-dependent trend.Keywords: purinergic receptor P2X ligand-gated ion channel 7, adenosine triphosphate, acute gouty arthritis, rat

Turbulent flows are investigated upstream of a bar rack system that is recommended as optimum in recent literature from tests with several fish species of different morphology, swimming ability, and behavior. Both two‐dimensional two‐component and two‐dimensional three‐component state‐of‐the‐art particle image velocimetry were used to quantify and analyze hydrodynamic metrics important for downstream migrating species. The inclination angles of the bar and rack were 45° and 30°, respectively, and the thickness of the bottom overlay was 13% of the water depth. The two Reynolds numbers investigated, based on incoming velocity and bar thickness, were 4,000 and 6,000. The statistical and structural characteristics of turbulent flows in the streamwise‐spanwise plane at 5% water depth, and the streamwise‐vertical plane at channel mid‐span are discussed. Upstream of the bottom overlay, the mean flow is deflected and accelerated toward the bypass, leading to an increase in the Reynolds stresses, while the turbulence eddies become smaller. For effective fish guidance, it is recommended that sweeping velocity (Vp) be larger than normal velocity (Vn), with Vp parallel and Vn perpendicular to the bar rack and bottom overlay. In the downstream half of the bar rack, Vn may increase sufficiently to surpass Vp near the bypass, possibly reducing effective guidance for some species and sizes. Upstream of the bars, the levels of streamwise mean velocity vary abruptly, which may deter fish from contacting the bars. Although inferences on passage effectiveness are made based on previous studies, tests with different species and sizes are needed to confirm fish responses. Key Points: Turbulent flows upstream of a bar rack system with bottom overlay are characterized using particle image velocimetryUpstream, levels of the mean velocity and flow acceleration are significant and vary abruptly, which may deter fish from contacting the barsFlow conditions upstream of the bottom overlay may disorient fish and may affect guidance toward the bypass for safer downstream passage [ABSTRACT FROM AUTHOR]

Jinlong Yuan,1,&ast; Chenlei Huang,2,&ast; Zhenbao Li,1 Xiaochun Jiang,1 Xintong Zhao,1 Niansheng Lai,1 Dayong Xia,1 Degang Wu,1 Bingbing Zhang,1 Xuanzhi Wang,3 Xinggen Fang1 1Department of Neurosurgery, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, People’s Republic of China; 2Department of Clinical Laboratory, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, People’s Republic of China; 3Department of Neurosurgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xinggen FangDepartment of Neurosurgery, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Zheshan West Road 2, Wuhu, 241001, People’s Republic of ChinaEmail 18805536056@163.comObjective: Hemodynamic parameters are associated with the recurrence of intracranial aneurysms (IAs). Studies showed that high velocity and wall shear stress (WSS) were associated with IAs recurrence after endovascular treatment; nevertheless, factors such as small sample size, locations of IAs, and types of IAs (ie, sidewall or bifurcation) were neglected. The purpose of this study was to identify the hemodynamic characteristics associated with recurrence of middle cerebral artery bifurcation aneurysms (MCABAs) after total embolization by the method of computer fluid dynamics (CFD).Methods: Following inclusion criteria, we included 92 MCABAs treated with coils only after total embolization from January 2014 to January 2019. We segmented into recurrent and non-recurrent groups according to follow-up digital subtraction angiography (DSA). The MCABA models, including pre-operatively and immediate post-operatively, were reconstructed using 3D-DSAs. The hemodynamic parameters pre-operatively and immediately post-operatively between the groups were calculated and analyzed.Results: There were no significant differences between the recurrent and non-recurrent groups for spatially averaged wall shear stress (SAWSS), maximum wall shear stress (MWSS), velocity, or oscillatory shear index (OSI) at the neck pre-operatively. In the recurrent group, the WSS (22.02± 5.11 vs 37.43± 8.27 pa, p < 0.001), MWSS (42.59± 17.02 vs 66.98± 18.61 pa, p=0.014), velocity (0.86± 0.19 vs 1.44± 0.61 m/s, p=0.01) preoperatively were significantly higher than postoperative values. By contrast, in the non-recurrent group, the WSS (26.53± 8.18 vs 22.29± 8.64pa, p=0.002), MWSS (42.71± 14.01 vs 37.15± 15.56 pa, p=0.013), velocity (1.08± 0.43 vs 0.23 (0.52, 0.57) m/s, p < 0.001) postoperatively were significantly lower than preoperative values. The OSI, whether in the recurrent group or the non-recurrent group, did not differ significantly between groups (p=0.79 and p=0.19).Conclusion: Higher WSS (SAWSS, MWSS) and flow velocity at the aneurysm neck after embolization might be related to recurrence of bifurcation IAs. These might be applied to clinical post-embolization management for the evaluation of bifurcation IAs recanalization.Keywords: computational fluid dynamic, hemodynamics, middle cerebral artery bifurcation aneurysms, recurrence

Shi-Ji Li,&ast; Zhi-Wen Cai,&ast; Hong-Fu Yang,&ast; Xu-Dong Tang, Xiao Fang, Le Qiu, Fei Wang, Xu-Lin Chen Department of Burns, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xu-Lin ChenDepartment of Burns, The First Affiliated Hospital of Anhui Medical University, 120 Wanshui Road, Hefei, Anhui, 230088, People’s Republic of ChinaTel/Fax +86-551-65908495Email okcxl@126.comBackground: Plasma exosome-derived microRNA (miRNA) profiles following thermal injury and their relationship with gene expression derangements in burned skin remain unexplored. This study focused on the identification of key miRNA-mRNA axes in potential blood-to-tissue interactions at early burn stage.Methods: Plasma exosomes were obtained from 6 severe burn patients 4– 7 days post injury and 6 healthy volunteers. Next-generation sequencing (NGS) of exosomal small RNAs presented the differentially expressed miRNAs (DEMs). Target genes of the DEMs were predicted in the mirDIP database. Dataset GSE8056 was enrolled to acquire differentially expressed genes (DEGs) in burned skin compared to normal skin. Overlap between the DEGs and target genes of the DEMs were focus genes. The protein–protein interaction (PPI) network and enrichment analyses of the focus genes demonstrated hub genes and suggested underlying mechanisms and pathways. The hub genes and upstream DEMs were selected to construct key miRNA-mRNA axes.Results: The NGS of plasma exosome-derived small RNAs identified 85 DEMs (14 downregulated miRNAs and 71 upregulated miRNAs) with 12,901 predicted target genes. Dataset GSE8056 exhibited 1861 DEGs in partial-thickness burned skins 4– 7 days postburn. The overlap between DEGs and target genes of DEMs displayed 1058 focus genes. The top 9 hub genes (CDK1, CCNB1, CCNA2, BUB1B, PLK1, KIF11, AURKA, NUSAP1 and CDCA8) in the PPI network of the focus genes pointed to 16 upstream miRNAs in DEMs, including 4 downregulated miRNAs (hsa-miR-6848-3p, has-miR-4684-3p, has-miR-4786-5p and has-miR-365a-5p) and 12 upregulated miRNAs (hsa-miR-6751-3p, hsa-miR-718, hsa-miR-4754, hsa-miR-6754-3p, hsa-miR-4739, hsa-miR-6739-5p, hsa-miR-6884-3p, hsa-miR-1224-3p, hsa-miR-6878-3p, hsa-miR-6795-3p, hsa-miR-550a-3p, and hsa-miR-550b-3p). A key miRNA-mRNA network in potential blood-to-tissue interactions at early burn stage was therefore constructed.Conclusion: An NGS and bioinformatic analysis in the study identified key miRNA-mRNA axes in potential blood-to-tissue interactions at early burn stage, suggesting plasma exosome-derived miRNAs may impact on the alteration patterns of gene expressions in a burn wound.Keywords: burn, exosome, miRNA, next-generation sequencing, bioinformatics

Xinhui Wu,1,2,&ast; Kangxian Zhao,1,2,&ast; Xiaoxin Fang,3,4 Feng Lu,3,4 Weikang Zhang,1,2 Xiaoting Song,1,2 Lihua Chen,5 Jiacheng Sun,1,2 Haixiao Chen1,2,4 1Wenzhou Medical University, Wenzhou, People’s Republic of China; 2Department of Orthopedics, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, People’s Republic of China; 3Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 4Taizhou Hospital of Zhejiang Province, Zhejiang University, Linhai, People’s Republic of China; 5Enze Medical Research Center, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Haixiao ChenDepartment of Orthopedics, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, 317000, People’s Republic of ChinaEmail drchx@126.comBackground: Osteolytic diseases such as osteoporosis are featured with accelerated osteoclast differentiation and strong bone resorption. Considering the complications and other limitations of current drug treatments, it is necessary to develop a safer and more reliable drug to deal with osteoclast-related diseases. Saikosaponin D (SSD) is the active extract of Bupleurum, which has anti-inflammation, anti-tumor and liver protection functions. However, the role of SSD in regulating the differentiation and function of osteoclasts is not clear.Purpose: To explore whether SSD could prevent osteoclast differentiation and bone resorption induced by M-CSF and RANKL, and further evaluate the potential therapeutic properties of SSD in LPS-induced inflammatory bone loss mouse models.Methods: BMMs were cultured in complete medium stimulated by RANKL with different concentrations of SSD. TRAP staining, bone resorption determination, qRT-PCR, immunofluorescence and Western blotting were performed. A mouse model of LPS-induced calvarial bone loss was established and treated with different doses of SSD. The excised calvaria bones were used for TRAP staining, micro-CT scan and histological analysis.Results: SSD inhibited the formation and bone resorption of osteoclasts induced by RANKL in vitro. SSD suppressed LPS-induced inflammatory bone loss in vivo.Conclusion: SSD inhibited osteoclastogenesis and LPS-induced osteolysis in mice both which served as a new potential agent for the treatment of osteoclast-related conditions.Keywords: saikosaponin D, osteoclastogenesis, NF-κB, MAPKs, PI3K-AKT, therapy

Yang Yao,1,2,* Xinggen Fang,1,* Jinlong Yuan,1 Feiyun Qin,1 Tao Yu,1 Dayong Xia,1,3 Zhenbao Li,1 Niansheng Lai1,3 1Department of Neurosurgery, First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, 241001, Anhui Province, People’s Republic of China; 2Department of Nursing, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, 241001, Anhui Province, People’s Republic of China; 3Key Laboratory of Non-Coding RNA Transformation Research of Anhui Higher Education Institution (Wannan Medical College), Wuhu, 241001, Anhui Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Niansheng Lai; Zhenbao LiDepartment of Neurosurgery, First Affiliated Hospital of Wannan Medical College (Yijishan Hospital), 2 West Zheshan Road, Wuhu, 241001, Anhui Province, People’s Republic of ChinaTel +86-15155308793Fax +86-05535739594Email mlns@wnmc.edu.cn; zhenbaoli123@126.comObjective: Aneurysmal subarachnoid hemorrhage (aSAH) is a severe form of stroke characterized by high rates of mortality and disability. Identifying circulating biomarkers is helpful to improve outcomes. In this study, for the first time, we identify interleukin-6 (IL-6) in cerebrospinal fluid (CSF) small extracellular vesicles (sEVs) as potential biomarkers for prognosis of aSAH.Methods: We extracted small extracellular vesicles from the CSF of 103 aSAH patients and 40 healthy controls in a prospective observational study. Subsequently, we measured IL-6sEVs levels using an enzyme-linked immunosorbent assay. Results were statistically analyzed to determine the function of IL-6sEVs for disease monitoring of aSAH.Results: CSF IL-6 sEVs showed distinct pattern differences between healthy controls and aSAH patients. The concentration of IL-6sEVs in CSF is significantly correlated with the severity of aSAH patients. The areas under the receiver operating characteristic curves of IL-6sEVs for identifying severe aSAH patient from aSAH patients were 0.900. After multivariate logistic regression analysis, IL-6sEVs were associated with neurological outcome at 1 year. IL-6sEVs levels were greater and positively associated with disease processes and outcome.Conclusion: There is a neuroinflammatory cascade in aSAH patients. IL-6sEVs in CSF may be a biomarker for the progression of aSAH.Keywords: subarachnoid hemorrhage, cerebrospinal fluid, small extracellular vesicles, interleukin-6, biomarker

Lianglan Shen,* Hongli Yang,* Xingxing Fang, Huaxing Huang, Wubin Yao, Dongmei Chen, Yan Shen Department of Nephrology, The Second Affiliated Hospital of Nantong University, Nantong, Jiangsu, 226001, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yan Shen Tel/Fax +86-0513-85061346Email ntmcsy@126.comPurpose: To investigate the association of Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors and acute kidney injury in comparison to other classes of drugs.Patients and Methods: A total of 4966 diabetes mellitus patients were investigated for developing Acute Kidney Injury (AKI) who were under prescription with the following class of drugs viz. SGLT2 Inhibitors, Dipeptidyl peptidase-4 (DDP4) inhibitors, Nonsteroidal anti-inflammatory drugs (NSAIDs), first-line drugs and anti-biotics. The primary outcome was based on the hospital encounter and Kidney Disease Improving Global Outcome (KDIGO) threshold values were used to assess the serum creatinine concentration. The secondary outcome was assessed based on the concentration level of serum creatinine after 90 days of hospital admission and evaluation of the KDIGO threshold values.Results: The study observed that the risk of causing AKI for SGLT2 inhibitors was 5.59% which was comparatively low compared to other class of the investigated drugs (DPP4 inhibitors = 6.47%, antibiotics = 6.30%, first-line drugs = 6.82% and NSAIDs = 10.65%). The multivariate analysis observed that ibuprofen, celecoxib, indomethacin, insulin, cephalexin, and alogliptin were mostly associated with an increased rate of AKI. SGLT2 inhibitors have the lowest risk for developing AKI compared to other drugs and control.Conclusion: AKI incidence is relatively low after initiation of SLGT2 inhibitors and concludes that regulatory warnings from certain health agencies about its risk for AKI on prescription are unwarranted.Keywords: SGLT2 inhibitor, DPP4, acute kidney injury, NSAID, type-2 diabetes

Zhongmin Li, Yilun Liu, Xuedong Fang, Zhenbo Shu Department of Gastrointestinal Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun, 130033, People’s Republic of ChinaCorrespondence: Zhenbo Shu Email shuzb@jlu.edu.cnAbstract: Molecular targeted therapy, a tumor therapy strategy that inhibits specific oncogenic targets, has been shown to modulate the immune response. In addition to directly inhibiting the proliferation and metastasis of tumor cells, molecular targeted drugs can activate the immune system through a variety of mechanisms, including by promoting tumor antigen processing and presentation, increasing intratumoral T cell infiltration, enhancing T cell activation and function, and attenuating the immunosuppressive effect of the tumor microenvironment. However, poor water solubility, insufficient accumulation at the tumor site, and nonspecific targeting of immune cells limit their application. To this end, a variety of nanomaterials have been developed to overcome these obstacles and amplify the immunomodulatory effects of molecular targeted drugs. In this review, we summarize the impact of molecular targeted drugs on the antitumor immune response according to their mechanisms, highlight the advantages of nanomaterials in enhancing the immunomodulatory effect of molecular targeted therapy, and discuss the current challenges and future prospects.Keywords: nanomaterial, molecular targeted therapy, immunomodulation, immunotherapy, cancer therapy

Le Qiu,* Xu Jin,* Jun-Jie Wang,* Xu-Dong Tang,* Xiao Fang, Shi-Ji Li, Fei Wang, Xu-Lin Chen Department of Burns, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xu-Lin ChenDepartment of Burns, The First Affiliated Hospital of Anhui Medical University, 120 Wanshui Road, Hefei, Anhui, 230088, People’s Republic of ChinaTel +86-551-65908495 Email okcxl@126.comIntroduction: Neutrophil-to-lymphocyte ratio (NLR) is a marker of inflammation. This study aimed to evaluate the potential role of NLR to predict 90-day mortality.Methods: Data of 577 patients with burns over 30% of total body surface area were collected and retrospectively analyzed. The risk factors for 90-day mortality were evaluated using logistic regression analyses. Receiver operating characteristic (ROC) curve analysis of the 3rd day NLR was performed and the optimal cut-off value was calculated. The 90-day mortality rates were compared between high and low NLR groups using Kaplan-Meier analysis.Results: Age, mechanical ventilation, burn index, 3rd day NLR, and 7th day red blood cell and platelet (PLT) counts were found to be independent predictive values for 90-day mortality. In contrast, percentage of total body surface area burned, inhalation injury, 1st day white blood cell and neutrophil counts, the 3rd day lymphocytes and PLT counts, and 7th day hemoglobin level were not independently associated with 90-day mortality. The area under the ROC curve of the 3rd day NLR for severe burn–delayed death prediction was 0.665 (95% confidence interval, 0.591– 0.739), and the optimal cut-off value of the 3rd day NLR was 10.50. The 90-day mortality rates differed significantly between the NLR > 10.5 group and the NLR ≤ 10.5 group (17.03% vs 5.92%, respectively; P < 0.01).Conclusion: These results suggested that the 3rd day NLR was associated with an increased risk of death in severely burned patients; thus, it can provide useful information to predict 90-day mortality.Keywords: burns, neutrophil-to-lymphocyte ratio, 90-day mortality

Objective: Birth weight is a good predictor of fetal intrauterine growth and long‐term health, and several studies have evaluated the relationship between metabolites and birth weight. The aim of this study was to investigate the association of cord blood metabolomics and lipidomics with birth weight, using a two‐stage discovery and validation approach. Methods: Firstly, a pseudotargeted metabolomics approach was applied to detect metabolites in 504 cord blood samples in the discovery set enrolled from the Wuhan Healthy Baby Cohort, China. Metabolome‐wide association scan analysis and pathway enrichment were applied to identify metabolites and metabolic pathways that were significantly associated with birth weight adjusted for gestational age Z‐score (BW Z‐score). Logistic regression models were used to analyze the association of metabolites in the most significantly associated pathways with small‐for‐gestational age (SGA) at delivery and low birth weight (LBW). Subsequently, 350 cord blood samples in a validation cohort were subjected to targeted analysis to validate the metabolites identified by screening in the discovery cohort. Results: In the discovery set, of 2566 metabolites detected, 2418 metabolites were retained for subsequent analysis after data preprocessing. Of these, 513 metabolites were significantly associated with BW Z‐score (P‐value adjusted for false discovery rate (PFDR) < 0.05), of which 298 Kyoto Encyclopedia of Genes and Genomes (KEGG)‐annotated metabolites were included in the pathway analysis. The primary bile acid biosynthesis pathway was the most relevant metabolic pathway associated with BW Z‐score. Elevated cord plasma primary bile acids were associated with lower BW Z‐score and higher risk of SGA or LBW in the discovery and validation cohorts. In the validation set, a 2‐fold increase in taurochenodeoxycholic acid (TCDCA) and in taurocholic acid (TCA) was associated with a decrease in BW Z‐score (estimated β coefficient, −0.10 (95% CI, −0.20 to 0.00) and −0.18 (95% CI, −0.31 to −0.04), respectively), after adjusting for covariates. In addition, a 2‐fold increase in cord plasma TCDCA and of cord plasma TCA was associated with an increased risk of SGA (adjusted odds ratio (OR), 1.52 (95% CI, 1.00–2.30) and 1.77 (95% CI, 1.05–2.98), respectively). The adjusted OR for LBW, for a 2‐fold increase in TCDCA and TCA concentration, were 2.39 (95% CI, 1.00–5.71) and 3.21 (95% CI, 0.96–10.74), respectively. Conclusions: These results indicate a significant association of elevated primary bile acids, particularly TCDCA and TCA, in cord blood with lower BW Z‐score, as well as increased risk of SGA and LBW. Abnormalities of primary bile acid metabolism may play an important role in restricted fetal development. © 2024 International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]