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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

Yongkang Liu,1 Cuiping Yuan,1 Xiao Chen,1 Xiaokun Fang,1 Jingru Hao,1 Maodong Zhou,1 Xin Sun,1 Minghua Wu,2 Zhongqiu Wang1 1Department of Radiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, People’s Republic of China; 2Department of Encephalopathy Center, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, People’s Republic of ChinaCorrespondence: Zhongqiu Wang, Department of Radiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, People’s Republic of China, Tel/Fax +86 25-86618472, Email zhqwang2012@126.com Minghua Wu, Department of Encephalopathy Center, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, People’s Republic of China, Tel/Fax +86 25-86618472, Email yfy0069@njucm.edu.cnPurpose: White matter hyperintensities (WMH) are the common marker of cerebral small vessel disease (CSVD). Dyslipidemia plays a notable role in the pathogenesis of CSVD. However, the relationship between dyslipidemia and WMH is poorly elucidated. This study aims to investigate the association between serum lipid fractions and WMH in patients with acute ischemic stroke (AIS).Patients and Methods: A total of 901 patients with AIS were included in this study. The burden of WMH, including deep white matter hyperintensities (DWMH), periventricular white matter hyperintensities (PVWMH), and total WMH load, were evaluated on magnetic resonance imaging (MRI) by the Fazekas scale. All the WMH burden were set as dichotomous variables. Serum levels of triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c), and high-density lipoprotein cholesterol (HDL-c) were collected. The association of serum lipid fractions with WMH burden was analyzed using univariate and multivariate logistic regression models.Results: The average age of the participants was 67.6± 11.6 years, and 584 cases (64.8%) were male. About 33.5% (n = 302) patients were smoker, and 23.5% (n = 212) patients had a history of alcohol consumption. The proportion of previous diabetes, ischemic cardiomyopathy and hypertension was 39.0% (n = 351), 21.2% (n = 191) and 75.9% (n = 684), respectively. The average of serum HDL-c, TC, TG, LDL-c levels for all participants were 1.26 ± 0.28 mmol/l, 4.54 ± 1.06 mmol/l, 1.67 ± 1.09 mmol/l, 3.08 ± 0.94 mmol/l. There were no statistical associations between HDL-c, TG, TC, LDL-c and each type of WMH burden (P > 0.05) in multivariate logistic regression analysis. Similar findings were found in subgroup analysis based on gender classification.Conclusion: Serum lipid levels were not associated with the presence of any type of WMH in patients with AIS.Keywords: white matter hyperintensities, HDL-c, triglyceride, total cholesterol, LDL-c, acute ischemic stroke

Xue Wang,1,&ast; Chenghua Gao,2,&ast; Yuan Xia,1 Xiaoqian Xu,1 Lehui Li,1 Yan Liu,1 Xing Yao,3 Ning Cao,1 Zichao Li,1 Xin Fang1 1Public Health College, Inner Mongolia Medical University, Hohhot, People’s Republic of China; 2School of Public Health and Emergency Management, Southern University of Science and Technology, Shenzhen, 518055, People’s Republic of China; 3Infection Control Department, Inner Mongolia People’s Hospital, Hohhot, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xin Fang, Public Health College, Inner Mongolia Medical University, Hohhot, Inner Mongolia, People’s Republic of China, Tel +86 18686066179, Email 18686066179@163.comObjective: There is limited evidence that atmospheric pollutants are associated with the number of allergic rhinitis (AR) visits. This study aimed to investigate the relationship between atmospheric pollutants and meteorological factors and the number of daily visits for AR in Hohhot City, providing a theoretical basis for further research on the effects of atmospheric pollutants on AR.Methods: Microsoft Excel 2016 was used to collect and organize the AR outpatient consultation data, air pollution and meteorological data in Hohhot City during 2018– 2020, and the data were descriptively analyzed and Spearman correlation test was performed using SPSS22.0; A generalized additive model was built in R4.2.3 to analyze the effect of air pollution on the number of AR visits and its lagged and cumulative effects, while the robustness of the model was tested using a two-pollutant analysis. Finally, we analyzed the effects of the interaction of temperature, relative humidity and pollutants on the number of AR visits.Results: The daily average concentrations of PM2.5, PM10, SO2, NO2, CO, and O3 in Hohhot during 2018– 2020 were 38.1 μg/m3, 83.3 μg/m3, 36.1 μg/m3, 15.1 μg/m3, 14.2 mg/m3, and 99.95 μg/m3, respectively, with the concentrations of PM2.5 and PM10 exceeding the secondary limit of the national standard. The results of the generalized additive model analysis showed that the RR and 95% CI of the effect of each 10 μg/m3 increase in pollutant concentration (1 mg/m3 increase in CO) on the number of AR outpatient clinics were 1.008 (1.001– 1.016), 1.002 (1– 1.005), 1.072 (1.033– 1.113), 1.020 (1007– 1.034), 1.033 (1.014– 1.052), 0.987 (0.9804– 0.9936).Conclusion: Short-term exposure to PM2.5, PM10, SO2, NO2, and CO was significantly associated with an increase in AR clinic visits, and short-term exposure to O3 was significantly associated with a decrease in allergic rhinitis clinic visits.Keywords: allergic rhinitis, air pollutants, time series study, interaction effect

Yuxi He,1,&ast; Shike Geng,1,&ast; Qing Mei,1,&ast; Lei Zhang,1,&ast; Tianjun Yang,1 Chunyan Zhu,1 Xiaoqin Fan,1 Yinzhong Wang,1 Fei Tong,1 Yu Gao,1 Xiaowei Fang,1 Renren Bao,2 Ximei Sheng,3 Aijun Pan1– 3 1Department of Intensive Care Unit, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, People’s Republic of China; 2Department of Intensive Care Unit, the Affiliated Provincial Hospital of Anhui Medical University, Hefei, Anhui, People’s Republic of China; 3Department of Intensive Care Unit, the Training Center of Anhui Provincial Hospital, Wannan Medical College, Wuhu, Anhui, 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 Sciences and Medicine, University of Science and Technology of China, No. 17, Lu Jiang Road, Hefei, Anhui Province, People’s Republic of China, Tel +86-0551-62286175, Email aijunpan868@ustc.edu.cn; meiqing@ustc.edu.cnObjective: To evaluate the diagnostic value and clinical application of metagenomic next-generation sequencing (mNGS) for infections in critically ill patients.Methods: Comparison of diagnostic performance of mNGS and conventional microbiological testing for pathogens was analyzed in 234 patients. The differences between immunocompetent and immunocompromised individuals in mNGS-guided anti-infective treatment adjustment were also analyzed.Results: The sensitivity and specificity of mNGS for bacterial and fungal detection were 96.6% (95% confidence interval [CI], 93.5%– 99.6%) and 83.1% (95% CI, 75.2%– 91.1%), and 85.7% (95% CI, 71.9%– 99.5%) and 93.2% (95% CI, 89.7%– 96.7%), respectively. Overall, 152 viruses were detected by mNGS, but in which 28 viruses were considered causative agents. The proportion of mNGS-guided beneficial anti-infective therapy adjustments in the immunocompromised group was greater than in the immunocompetent group (48.5% vs 30.1%; P=0.008). In addition, mNGS-guided anti-infective regimens with peripheral blood and BALF specimens had the highest proportion (39.0%; 40.0%), but the proportion of patients not helpful due to peripheral blood mNGS was also as high as 22.0%.Conclusion: mNGS might be a promising technology to provide precision medicine for critically ill patients with infection.Keywords: next-generation sequencing, critically ill patients, community-acquired infection, hospital-acquired infection, immunosuppression

Xiaoting Fang,1,&ast; Haijuan Liu,1,&ast; Mina Wang,1 Guohua Wang2 1Graduate School, Beijing University of Chinese Medicine, Beijing, China; 2Gynecology, Beijing University of Chinese Medicine Third Affiliated Hospital, Beijing, China&ast;These authors contributed equally to this workCorrespondence: Guohua Wang; Mina Wang, Email wgh1188@163.com; WMNmmm@126.comPurpose: This study aims to help researchers master the most active hotspots and trends quickly through bibliometric analysis in the field of dysmenorrhea.Methods: We retrieved literature on Web of Science from 2001 to 2021, and bibliometric analysis software CiteSpace was used in combination with VOSviewer.Results: We finally acquired 944 papers and an upward trend in articles continued in this field overall. Through the map, China contributed the most, followed by the USA and Turkey. For institutions, Beijing University of Chinese Medicine in China contributed the most, followed by National Yang-Ming University in Taiwan, China. Hsieh JC and Hellman KM were both the most prolific authors with 14 articles. Five major research groups, respectively, with Hsieh JC, Hellman KM, Zhu J, Liang F and Dun W were the key group. Dawood MY was the most dominant author and most frequently cited author. The Cochrane Database of Systematic Reviews Journal was the most productive, and the Fertility and Sterility Journal was the most cited. Advances in pathogenesis and management for primary dysmenorrhea written by Dawood MY was most cited and influential. Pathophysiology, the potential central mechanism, syndrome, evaluation index, diagnosis of adenomyosis-associated dysmenorrhea, treatment, etc., were the main trends and hotspots.Conclusion: Dysmenorrhea research has received a lot of attention from scholars. Strengthening international cooperation may promote the development of this field. The pathophysiology of dysmenorrhea, its impact on public health and its treatment are current research hotspots and are likely to be the focus of future study.Keywords: scientific knowledge graph, dysmenorrhea, bibliometric analysis, trends, hotspots

Xiucai Li,1,&ast; Xuee Fang,2,&ast; Ligang Zhou,1 Yanjun Mao3 1Department of Endocrinology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, People’s Republic of China; 2Department of Tuberculosis, Shanghai Pulmonary Hospital Affiliated to Tongji University, Shanghai, People’s Republic of China; 3Department of Nursing, Shanghai Pulmonary Hospital Affiliated to Tongji University, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ligang Zhou, Department of Endocrinology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, People’s Republic of China, Email zhouligang1n1@163.com Yanjun Mao, Department of Nursing, Shanghai Pulmonary Hospital Affiliated to Tongji University, Shanghai, People’s Republic of China, Email maoyanjun_fk@tongji.edu.cnBackground and Objectives: A high incidence of depression has been reported in patients with pulmonary tuberculosis and diabetes mellitus (DM-PTB). However, the association between depression and DM-PTB is poorly understood and requires further investigation. This study aimed to evaluate the prevalence of depression and the associated factors in patients with DM-PTB.Methods: A cross-sectional study was conducted among DM-PTB patients at the Tuberculosis Department of Shanghai Pulmonary Hospital Affiliated to Tongji University, China, enrolled between June 2021 and October 2021. The depression status, nutritional status, and the quality of life of the patients were evaluated using Patient Health Questionnaire– 9 (PHQ-9), Nutritional Risk Screening 2002 (NRS2002), and Quality of Life Instruments for Chronic Diseases-Pulmonary Tuberculosis (QLICD-PT), respectively.Results: A total number of 280 DM-PTB patients were screened, of whom 22 were excluded for missing data. Among the 258 DM-PTB patients subjected to analysis, 199 patients (77.13%) had PHQ-9 scores above 10. The patients with depression are more likely to have a lower monthly income, body mass index (BMI), and QLICD-PT than those without depression. The NRS2002 score and glutamic pyruvic transaminase (GPT) and glutamic oxaloacetic transaminase (GOT) levels in the depression group were more likely to be higher than those in the control group. Multivariate logistic regression analysis showed that physical function [OR = 0.798, 95% confidence interval (CI), 0.716– 0.889, P < 0.001] was a protective factor against depression, whereas NRS2002 ≥ 3 (OR = 2.299, 95% CI, 1.095– 4.825, P = 0.028), GPT (OR = 1.048, 95% CI, 1.018– 1.079, P = 0.002), and social function (OR = 1.103, 95% CI, 1.033– 1.179, P = 0.004) were risk factors of depression.Conclusion: Depression in DM-PTB patients may be associated with monthly income, BMI, QLICD-PT scores, NRS2002 scores, GPT, and GOT levels.Keywords: depression, pulmonary tuberculosis, diabetes mellitus, cross-sectional study

Huixian Li,1 Qinghua Tian,2 Xiujuan Shan,2 Zhenhua Wang,2 Xiangang Fang2 1Department of Sterilization Supply, Weifang People’s Hospital, Weifang, Shandong, People’s Republic of China; 2Department of Dermatology, Weifang People’s Hospital, Weifang, Shandong, People’s Republic of ChinaCorrespondence: Xiangang Fang, Department of Dermatology, Weifang People’s Hospital, 151 Guangwen Street, Weifang, Shandong, 261041, People’s Republic of China, Tel +86-0536-8192561, Email sdlntszqjlb@163.comAbstract: A 23-year-old man presented for evaluation of multiple dense asymptomatic papules on the entire glans. Histologically, the lesions resembled acral angiofibroma. A diagnosis of profound pearly penile papules was made. This is the third reported case and more serious and typical than described in previous reports.Keywords: pearly, penile papules, profound

Ruye Wang,1,&ast; Ying Zhao,2,&ast; Chenyun Miao,3 Yun Chen,1 Ning Ren,1 Liuqin Yang,1 Wei Cheng,4 Qin Zhang,1,5 Xiaohong Fang1 1Department of TCM Gynecology, Hangzhou TCM Hospital of Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China; 2School of Public Health, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China; 3School of Life Sciences, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China; 4Department of Orthopedics, Hangzhou TCM Hospital of Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China; 5Research Institute of Women’s Reproductive Health, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qin Zhang; Xiaohong Fang, Department of Medical TCM Gynecology, Hangzhou TCM Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310007, People’s Republic of China, Email zhaqin01@163.com; fxh13527806@163.comPurpose: The aim of this study is to examine, using network pharmacology analysis and experimental validation, the pharmacological processes by which Yulin Formula (YLF) reduces cyclophosphamide-induced diminished ovarian reserve (DOR).Methods: First, information about the active components, associated targets, and related genes of YLF and DOR was gathered from open-access databases. The primary targets and pathways of YLF to reduce DOR were predicted using studies of functional enrichment from the Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO), and Protein-Protein Interaction (PPI) networks. Second, we built a cyclophosphamide-induced diminished ovarian reserve (DOR) rat model to verify the primary target proteins implicated in the predicted signaling pathway to explore the mechanism of improve ovarian function of YLF.Results: 98 targets met the targets of the 82 active ingredients in YLF and DOR after searching the intersection of the active ingredient targets and DOR targets. Fourteen targets, including AKT and Caspase-3 among others, were hub targets, according to the PPI network study. The PI3K/AKT pathway was revealed to be enriched by numerous targets by the GO and KEGG enrichment studies, and it was used as a target for in vivo validation. Animal studies showed that YLF administration not only reduced the number of atretic follicles, the proportion of TUNEL-positive ovarian cells, the rate of apoptosis of granulosa cells (GCs) and the proportion of abnormal mitochondria in DOR rats, but also reversed the high expression of Caspase-3, Caspase-9, BAX, cytochrome C, PI3K and P-AKT, improving the ovarian reserve in cyclophosphamide (CTX)-induced DOR rats.Conclusion: Our research results predicted the active ingredients and potential targets of YLF-interfering DOR by an integrated network pharmacology approach, and experimentally validated some key target proteins participated in the predicted signaling pathway. A more comprehensive understanding of the pharmacological mechanism of YLF for DOR treatment was obtained.Keywords: diminished ovarian reserve, Yulin Formula, network pharmacology, pharmacological mechanisms, apoptosis, PI3K/AKT

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.

Xiaohong Fang,1 Kai Zhang,1 Jie Chen,1 Meitao Chen,1 Yanyan Wang,1 Jianping Zhong2 1School of Education, Huaibei Normal University, Huaibei, People’s Republic of China; 2School of Humanities and Education, Foshan University, Foshan, People’s Republic of ChinaCorrespondence: Kai Zhang, School of Education, Huaibei Normal University, Huaibei, Anhui, 235000, People’s Republic of China, Tel +86 15856116221, Email zhangkaitop@163.comPurpose: The prevalence of cyberbullying has increased along with the growth of social media, which has brought about many adverse effects on individual development. The current study aimed to explore the connection between covert narcissism and cyberbullying and to test the roles of hostile attribution bias and self-control in the relationship between covert narcissism and cyberbullying.Materials and Methods: A total of 672 Chinese college students filled up questionnaires measuring covert narcissism, cyberbullying, hostile attribution bias, and self-control.Results: The results indicated that covert narcissism positively and significantly predicted cyberbullying. Hostile attribution bias partially mediated the relationship between covert narcissism and cyberbullying. Additionally, self-control moderated the relationship between covert narcissism and cyberbullying. Specifically, the positive predictive effect of covert narcissism on cyberbullying gradually weakened as self-control improved.Conclusion: This study explored the underlying mechanism of cyberbullying and found that covert narcissism could affect cyberbullying through hostile attribution bias. Self-control moderated the relationship between covert narcissism and cyberbullying. The results have significant implications for the intervention and prevention of cyberbullying and additional evidence for the relationship between covert narcissism and cyberbullying.Keywords: covert narcissism, cyberbullying, hostile attribution bias, self-control, college students

Xiaoling Zhang, Xuting Jin, Jiajia Ren, Jueheng Liu, Haichang Ma, Xiaoming Fang, Huifan Zhang, Yujie Zhao, Yanli Hou, Yanni Luo, Lei Guo, Qi Ma, Ya Gao, Jingjing Zhang, Jiamei Li, Xiaochuang Wang, Gang Wang Department of Critical Care Medicine, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi Province, People’s Republic of ChinaCorrespondence: Xiaochuang Wang; Gang Wang, Department of Critical Care Medicine, the Second Affiliated Hospital of Xi’an Jiaotong University, 157 Xi 5 Lu, Xi’an, Shaanxi, 710004, People’s Republic of China, Tel +86-029-8767-9630 ; +86-029-8767-9633, Email dr_xc_wang@163.com; gang_wang@xjtu.edu.cnPurpose: In patients with carbapenem-resistant Gram-negative bacteria (CRGNB) infection, the impact of appropriate empirical antibiotic treatment (AEAT) initialized before culture results were available remains controversial. We aimed to investigate the effect of AEAT on the prognosis of critically ill patients with hospital-acquired pneumonia (HAP) caused by CRGNB.Patients and Methods: Patients with CRGNB-infected HAP and received empirical antibiotic treatment (EAT) for at least 3 days in the intensive care unit (ICU) of a tertiary teaching hospital in China from February 2017 to September 2021 were included in the retrospective cohort study. Patients were categorized into AEAT and inappropriate empirical antibiotic treatment (IEAT) groups based on whether they received EAT covering CRGNB. The associations of AEAT with ICU and 28-day mortality were assessed using multivariable logistic regression model.Results: A total of 94 patients were enrolled, including 29 patients in AEAT group and 65 patients in IEAT group. Patients in AEAT group had a higher Sequential Organ Failure Assessment (SOFA) score (P = 0.003), levels of procalcitonin (PCT) (P = 0.001), and lactic acid (LAC) (P = 0.026); while patients in the IEAT group had a higher platelet count (PLT) (P = 0.001). There was no significant difference in the length of ICU stay between the two groups (P = 0.051). Compared with IEAT, AEAT was associated with an increased risk of 28-day mortality in the univariable logistic regression model (OR: 2.618, 95% CI: 1.063– 6.448). However, after adjusted for SOFA score, PLT, PCT, and LAC level, the association between AEAT and 28-day mortality diminished (OR: 1.028, 95% CI: 0.353– 2.996). AEAT showed no significant association with ICU mortality in neither univariable (OR: 1.167, 95% CI: 0.433– 3.142) nor multivariable (OR: 0.357, 95% CI: 0.097– 1.320) models.Conclusion: AEAT showed no significant influence on ICU or 28-day mortality in critically ill patients with HAP caused by CRGNB infection.Keywords: appropriate empirical antibiotics, hospital-acquired pneumonia, carbapenem-resistant, gram-negative bacteria, ICU mortality

Youling Fang,1,2 Qiaoshi Zhong,1 Yanhui Chen,1 Yaping Hang,1 Xueyao Fang,1 Yanping Xiao,1 Xingwei Cao,1 Hongying Zhu,3 Hong Luo,1 Suqin Peng,1 Shumin Gu,1 Fuxing Li,1 Junqi Zhu,1 Jianqiu Xiong,4 Longhua Hu1 1Department of Jiangxi Provincial Key Laboratory of Medicine, Clinical Laboratory of the Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People’s Republic of China; 2School of Public Health, Nanchang University, Nanchang, Jiangxi, People’s Republic of China; 3Clinical Laboratory of Ganzhou People’s Hospital, Ganzhou, Jiangxi, People’s Republic of China; 4Department of Nursing, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People’s Republic of ChinaCorrespondence: Longhua Hu; Jianqiu Xiong, Email longhuahu@163.com; 1773014059@qq.comObjective: To analyze the clinical characteristics, outcomes, and risk factors of patients treated with ceftazidime/avibactam, polymyxin, or tigecycline (CPT) compared with those receiving a conventional therapy (CT) (ie, imipenem, levofloxacin, or gentamicin).Methods: A single-center retrospective cohort study included patients with carbapenem-resistant Klebsiella pneumoniae bloodstream infection (CRKP-BSI) treated at one Chinese tertiary hospital between March 2012 and November 2022 was performed. Clinical characteristics, outcomes, and risk factors of patients treated with CPT or CT were compared. Predictors of 30-day mortality of patients with CRKP-BSI were also analysed in our study.Results: Among 184 recruited patients with CRKP-BSI, 39.7% (73/184) were treated with CPT, while 60.3% (111/184) were treated with CT. Compared to patients treated with CT, patients treated with CPT had worse conditions, as evidenced by a higher rate of underlying diseases and invasive procedures; however, they also had a better prognosis and lower rates of 14-day treatment failure (p = 0.024). In addition, univariate analysis and multivariate analysis showed that SOFA score [odds ratio (OR) = 1.310, 95% confidence interval (CI) 1.157– 1.483; p < 0.001] and cold weather (OR = 3.658, 95% CI 1.474– 9.081; p = 0.005) were independent risk factors for 30-day mortality.Conclusion: Compared to CRKP-BSI patients treated with CT, patients treated with CPT had worse conditions but better prognoses. CRKP-BSI occurred more frequently in hot weather; however, higher 30-day mortality was associated with cold weather. A randomized trial is needed to confirm these observational results.Keywords: carbapenem-resistantKlebsiella pneumoniae, polymyxin, tigecycline, ceftazidime/avibactam, bloodstream infection, hot weather, cold weather

Shumin Gu,1,* Jianqiu Xiong,2,* Suqin Peng,1 Longhua Hu,1 Hongying Zhu,3 Yanping Xiao,1 Hong Luo,1 Yaping Hang,1 Yanhui Chen,1 Xueyao Fang,1 Xingwei Cao,1 Youling Fang,1 Fuxing Li,1 Junqi Zhu,1 Qiaoshi Zhong1 1Department of Jiangxi Provincial Key Laboratory of Medicine, Clinical Laboratory of the Second Affiliated Hospital of Nanchang University, Nanchang, People’s Republic of China; 2Departmentof Nursing, The Second Affiliated Hospital of Nanchang University, Nanchang, People’s Republic of China; 3Clinical Laboratory of Ganzhou People’s Hospital, Ganzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qiaoshi Zhong, Department of Jiangxi Provincial Key Laboratory of Medicine, Clinical Laboratory of the Second Affiliated Hospital of Nanchang University, Mingde Road No. 1, Nanchang, Jiangxi, 330006, People’s Republic of China, Tel +86151-8047-5673, Email zhong20000947@sina.comObjective: This study aimed to determine the clinical features, risk factors, and effective antimicrobial therapy for Carbapenem-resistant Acinetobacter baumannii (CRAB) bloodstream infection (BSI).Methods: This was a retrospective analysis of data from patients with CRAB bacteremia in a Chinese tertiary hospital between January 2012 and October 2021. Risk factors, predictors of 30-day mortality, and effective antimicrobial therapy for CRAB BSI were identified using logistic and cox regression analyses.Results: Data from 276 patients with Acinetobacter baumannii (AB) BSI were included, of whom 157 (56.9%) had CRAB BSI. The risk factors that were significantly associated with CRAB BSI included previous intensive care unit (ICU) stay (P < 0.001), immunocompromised status (P < 0.001), cephalosporin use (P = 0.014), and fluoroquinolone use (P = 0.007). The 30-day mortality of the CRAB BSI group was 49.7% (78/157). ICU stay after BSI (P = 0.047), sequential organ failure assessment (SOFA) score ≥ 10 (P < 0.001), and multiple organ failure (MOF) (P = 0.037) were independent predictors of 30-day mortality. Among antibiotic strategies for the treatment of patients with CRAB BSI, we found that definitive regimens containing cefoperazone/sulbactam were superior to those without cefoperazone/sulbactam in reducing the 30-day mortality rate (25.4% vs 53.4%, P = 0.005). After propensity score matching, we observed a significant increase in the 30-day mortality (77.8%vs 33.3%, P = 0.036) in patients receiving tigecycline monotherapy compared to those receiving cefoperazone/sulbactam monotherapy. The mortality rate of patients receiving tigecycline with cefoperazone/sulbactam was also higher than that of patients receiving cefoperazone-sulbactam monotherapy; however, the difference was not significant (28.6%vs 19.0%, P = 0.375).Conclusion: The severity of patient conditions was significantly associated with mortality in patients with CRAB BSI. Those Patients treated with cefoperazone/sulbactam had better clinical prognoses, and tigecycline should be used with caution.Keywords: carbapenem-resistant, Acinetobacter baumannii, bacteremia, tigecycline, cefoperazone/sulbactam

Hong Luo,1 Yaping Hang,1 Hongying Zhu,2 Qiaoshi Zhong,1 Suqin Peng,1 Shumin Gu,1 Xueyao Fang,1 Longhua Hu1 1Jiangxi Provincial Key Laboratory of Medicine, Clinical Laboratory of the Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People’s Republic of China; 2Clinical Laboratory of Ganzhou People’s Hospital, Ganzhou, Jiangxi, People’s Republic of ChinaCorrespondence: Longhua Hu, Email longhuahu@163.comBackground: Carbapenemase-producing Klebsiella pneumoniae is an unprecedented threat to public health, and its detection remains challenging. Analysis of microbial volatile organic compounds (VOCs) may offer a rapid way to determine bacterial antibiotic susceptibility.Purpose: The aim of this study was to explore the VOCs released by carbapenemase-producing carbapenem-resistant Klebsiella pneumoniae (CRKP) using headspace solid-phase microextraction/gas chromatography-mass spectrometry (HS-SPME/GC-MS).Methods: Test bacteria were incubated in trypticase soy broth to the end of exponential growth phase, and imipenem was added in the middle time. Headspace VOCs were concentrated and analyzed using HS-SPME/GC-MS.Results: The compound 3-methyl-1-butanol was found to be a biomarker among the 26 bacterial isolates (10 KPC-positive, 10 NDM-positive, 2 IMP-positive, 2 carbapenemase-negative CRKP, and 2 carbapenem-susceptible K. pneumonoiae).Conclusion: This study explored a promising new strategy for the screening of carbapenemase-producing CRKP strains. Further research with larger sample sizes will potentially accelerate the application of biomarkers in routine microbiology.Keywords: carbapenem-resistantKlebsiella pneumoniae, volatile organic compounds, headspace solid-phase microextraction combined with gas chromatography-mass spectrometry

Huixian Li,1 Hui Li,2 Qinghua Tian,2 Xiangang Fang2 1Department of Sterilization Supply, Weifang People’s Hospital, Weifang, Shandong, People’s Republic of China; 2Department of Dermatology, Weifang People’s Hospital, Weifang, Shandong, People’s Republic of ChinaCorrespondence: Xiangang Fang, Department of Dermatology, Weifang People’s Hospital, 151 Guangwen Street, Weifang, Shandong, 261041, People’s Republic of China, Tel +86-536-8192561, Email sdlntszqjlb@163.comAbstract: Granular parakeratosis is a rare dermatosis characterized by erythematous scaly patches or papules, and plaques, often involving intertriginous areas. In this work, a 73-year-old Chinese male patient presented with a 6-month history of pruritic verrucous papules on the bilateral groin. A skin biopsy was performed and revealed the following: the horny layer showed highly compact hyperkeratosis and parakeratosis with basophilic granules; the epidermis showed obvious acanthosis with psoriasiform hyperplasia. The final diagnosis was verrucous granular parakeratosis. We also reviewed the progress in nomenclature, etiology, clinical manifestations, differential diagnosis and treatment. Different clinical manifestations may represent different clinical entities. Dermatologists should differentiate it from other diseases to make a correct diagnosis. Treatment options should be based on the variable etiologies and clinical manifestations.Keywords: granular parakeratosis, verrucous, papule, groin, glucocorticoid, tretinoin

Jia Zeng,1 Peng Sun,1 Xinning Fang,1 Yicheng Jiang,1 Zhenghong Wu,1 Xiaole Qi1,2 1Key Laboratory of Modern Chinese Medicines, China Pharmaceutical University, Nanjing, People’s Republic of China; 2Industrial Technology Innovation Platform, Zhejiang Center for Safety Study of Drug Substances, Hangzhou, People’s Republic of ChinaCorrespondence: Zhenghong Wu; Xiaole Qi, Key Laboratory of Modern Chinese Medicines, China Pharmaceutical University, No. 639 Longmian Road, Jiangning District, Nanjing City, Jiangsu Province, 210009, People’s Republic of China, Tel +86 15062208341 ; +86 25 83179703, Email zhenghongwu66@cpu.edu.cn; qixiaole523@cpu.edu.cnBackground: Synergistic chemotherapy has been proved as an effective antitumor means in clinical practice. However, most co-administration treatment often lacks simultaneous control over the release of different chemotherapeutic agents.Materials and Methods: β-cyclodextrin modified hyaluronic acid was the “shell”, and the oxidized ferrocene-stearyl alcohol micelles served as the “core”, where doxorubicin (DOX) and curcumin (CUR) were loaded in shell and core of the bilayer nanoparticles (BNs), respectively. The pH- and glutathione (GSH)-responsive synchronized release behavior was evaluated in different mediums, and the in vitro and in vivo synergistic antitumor effect and CD44-mediated tumor targeting efficiency were further investigated.Results: These BNs had a spherical structure with the particle size of 299 ± 15.17 nm, while the synchronized release behaviour of those two drugs was proved in the medium with the pH value of 5.5 and 20 mM GSH. The co-delivery of DOX and CUR reduced the IC50 value by 21% compared to DOX alone, with a further 54% reduction after these BNs delivery measurements. In tumor-bearing mouse models, these drug-loaded BNs showed significant tumor targeting, enhanced antitumor activity and reduced systemic toxicity.Conclusion: The designed bilayer nanoparticle could be considered as potential chemotherapeutic co-delivery platform for efficient synchronized microenvironment respond and drug release. Furthermore, the simultaneous and synergistic drug release guaranteed the enhanced antitumor effects during the co-administration treatment.Graphical Abstract: Keywords: tumor microenvironment, combination chemotherapy, pH- and GSH-responsive, tumor targeting

Guanming Li,1 Airun Zhang,1 Silan Yang,2 Niyang Lin,2 Xiaoyi Fang1 1Department of Neonatology, Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, People’s Republic of China; 2Department of Neonatology, First Affiliated Hospital, Shantou University Medical College, Shantou, People’s Republic of ChinaCorrespondence: Xiaoyi Fang, Department of Neonatology, Seventh Affiliated Hospital, Sun Yat-sen University, No. 628, Zhenyuan Road, Guangming District, Shenzhen, Guangdong, 518107, People’s Republic of China, Tel +86-18923451061, Email fangxy29@mail.sysu.edu.cnAbstract: Aplasia cutis congenita (ACC) is a rare disease with an unclear pathogenic mechanism. ACC has been suggested to result from the disrupted development or degeneration of skin in the uterus. This study describes two cases that may have underlying pathogenic cause that have not been previously reported. Two neonates who were admitted to the neonatal intensive care unit due to “skin lesions on the limbs” without other deformities or complications were diagnosed with type VII ACC by dermatologist. The mothers showed positivity for hepatitis B virus (HBV) surface antigen and elevated level of HBV DNA copies, which may be related to ACC. But this association could be a coincidence. Both neonates were treated with antibacterial dressings and achieved satisfactory healing.Keywords: aplasia cutis congenita, case report, hepatitis B virus, newborn, skin defect

Xiangming Fang,1,&ast; Ting Zhang,2,&ast; Zhitao Chen1 1Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College, Hangzhou, People’s Republic of China; 2Department of Pathology, Hangzhou Tongchuang Medical Laboratory, Hangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiangming Fang, Obstetrics and Gynecology Department, Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College, 848&num; Dongxin Road, Hangzhou City, Zhejiang Province, 310000, People’s Republic of China, Tel +86-0571-87236570, Email fxm1213@126.comBackground: Uterine corpus endometrial carcinoma (UCEC) is a common type of gynecological cancers, second only to cervical cancer in incidence. Thus, it is necessary to develop effective therapies and identify biomarkers for its prognosis. Solute carrier family 7 member 11 (SLC7A11) is well known for its role in maintaining the intracellular glutathione level and preventing oxidative-stress-induced cell death. However, the association between SLC7A11 expression and prognosis as well as the correlation between tumor-infiltrating immune cells (TIICs) and immunotherapy of UCEC has rarely been reported. This study aims to evaluate the prognostic significance and immune cell infiltration level of SLC7A11 in UCEC.Methods: Bioinformatics analysis tools and databases, including R software, National Center for Biotechnology Information (NCBI), The Cancer Genome Atlas (TCGA), GEPIA2, Sangerbox, Kaplan–Meier (K-M) Plotter, TISIDB, and TIMER2, were utilized to measure the expression level and clarify the clinical significance of SLC7A11 in UCEC.Results: SLC7A11 expression was dramatically up-regulated in UCEC patients and associated with prognosis. DNA methylation levels in the SLC7A11-promoter region were significantly higher in normal participants than in patients with UCEC. We also showed that SLC7A11 overexpression was associated with TIICs, immune checkpoint blockers (ICBs), and immunotherapy response in UCEC. The half-maximal inhibitory concentration (IC50) results obtained with the cohort from TCGA showed that Z-VAD-FMK (Caspase inhibitor), S-Triphenylmethyl-L-cysteine (S-Trityl-L-cysteine), and TAE684 (ALK inhibitor) had higher IC50 values in low-expression patient (p < 0.05).Conclusion: SLC7A11 overexpression is associated with favorable prognosis of patients with UCEC and is associated with TIICs and the responses to immunotherapy.Keywords: solute carrier family 7 member 11, uterine corpus endometrial carcinoma, prognosis, tumor-infiltrating immune cells, bioinformatics analysis

Tingting Liu,&ast; Wu Yang,&ast; Kun Li, Siruo Guo, Manman Tian, Xueling Fang Department of Critical Care Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: 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, Tel +86-13588785095, Fax +86 571-87236838, Email 1191012@zju.edu.cnAbstract: Hemorrhagic fever with renal syndrome (HFRS), caused by hanta viruses (HTNV), can be complicated by severe complications. Seventeen percent of the HFRS patients with abdominal pain had acute pancreatitis (AP). The reported prevalence of AP among HFRS patients has a conspicuous high mortality rate. Of note, acute capillary cholangitis (ACC) among HFRS patients presenting with abdominal pain appears extremely rare, particularly independent of HFRS patients complicated with AP. The main pathophysiological mechanism of HFRS complicated with AP and ACC may be that it preferentially damages the microvascular and induces plasma leakage. To date, the management of severe HFRS cases is mainly based on supportive treatment, including extracorporeal blood purification and mechanical ventilation. Here, we describe an exceptionally rare case of a 34-year man who developed HFRS with AP and ACC while improving from HTNV infection via antiviral and supportive treatment.Keywords: hemorrhagic fever with renal syndrome, hantaviruses, abdominal pain, acute pancreatitis, acute acalculous cholangitis

Dong Xu,1 Xu Zhu,2 Junyu Huo,2 Xupin Xie,1 Changpin Huang,1 Xin Fang,1 Ting Yin3 1Department of Vascular Surgery, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People’s Republic of China; 2Department of Cardiology, Jiangsu Province Hospital and Nanjing Medical University, First Affiliated Hospital, Nanjing, Jiangsu, People’s Republic of China; 3Intensive Care Unit, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People’s Republic of ChinaCorrespondence: Ting Yin, Intensive Care Unit, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310000, People’s Republic of China, Tel +86 13777879077, Fax +86 56005600, Email ameliyt@163.com Xin Fang, Department of Vascular, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310000, People’s Republic of China, Tel +86 13867478324, Fax +86 56005600, Email fangxin324@hotmail.comPurpose: Peripheral arterial disease (PAD) presenting with underlying hypertension (HTN) poses a higher risk of bilateral lower limb amputation than PAD patients without HTN. While the role of HTN management of PAD patients has received limited attention. We analyzed the clinical characteristics of PAD in adults with HTN and explored risk factors for PAD to construct a nomogram for evaluating critical limb ischemia (CLI) and lesion severity.Methods Patients and Methods: Between January 2014 and December 2019, we retrospectively evaluated 1886 patients with peripheral artery disease with coexisting HTN. Patients were randomly divided into training (n = 1320, 70%) and validation cohorts (n = 566, 30%), and according to the subjective experience of PAD [Fontaine classification (I–II vs III–IV)], patients were further classified into intermittent claudication (IC) and CLI groups. LASSO regression and multivariate Cox proportional hazard analyses were used to construct a nomogram using variables defined in the training cohort, which was validated in the validation cohort. The evaluation of the predictive discriminative, accuracy and clinical application are further analyzed.Results: In the training cohort, optimal independent factors included age, male sex, body mass index, diabetes mellitus, heart rate, triglyceride, and uric acid (AM-BDHTU), which were included in the nomogram predicting the CLI risk (all P < 0.05). The C-index values for CLI risk in PAD with HTN patients were 0.729 (95% CI: 0.704– 0.807) and 0.728 (95% CI: 0.652– 0.744) in the training and validation sets, respectively. Calibration curves indicated good consistency between predicted and actual outcomes. DCA confirmed the clinical utility of the diagnostic model.Conclusion: The AM-BDHTU nomogram, constructed and validated using simple to obtain clinical variables, when combined with the Fontaine classification, effectively predicts the risk of CLI among PAD patients with HTN.Keywords: peripheral arterial disease, hypertension, vascular-related complications, LASSO regression, nomogram, predictive diagnosis

Xuejie Fang,1,&ast; Zhengtong Qiao,2,&ast; Xinjuan Yu,3,4,&ast; Rujin Tian,5 Kai Liu,5 Wei Han3 1School of Clinical Medicine, Weifang Medical University, Weifang, People’s Republic of China; 2School of Rehabilitation Medicine, Binzhou Medical University, Yantai, People’s Republic of China; 3Department of Respiratory and Critical Medicine, Respiratory Disease Key Laboratory of Qingdao, University of Health and Rehabilitation Sciences Qingdao Hospital (Qingdao Municipal Hospital), Qingdao, People’s Republic of China; 4Clinical Research Center, University of Health and Rehabilitation Sciences Qingdao Hospital (Qingdao Municipal Hospital), Qingdao, People’s Republic of China; 5Department of Rehabilitation Medicine, University of Health and Rehabilitation Sciences Qingdao Hospital (Qingdao Municipal Hospital), Qingdao, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wei Han, Department of Respiratory and Critical Medicine, Respiratory Disease Key Laboratory of Qingdao, University of Health and Rehabilitation Sciences Qingdao Hospital (Qingdao Municipal Hospital), No. 5 Donghaizhong Road, Qingdao, 266071, People’s Republic of China, Tel +86 532 85937579, Email hanw@qdu.edu.cn Kai Liu, Department of Rehabilitation Medicine, University of Health and Rehabilitation Sciences Qingdao Hospital (Qingdao Municipal Hospital), No. 5 Donghaizhong Road, Qingdao, 266071, People’s Republic of China, Tel +86 532 85937671, Email liukaidpt@126.comBackground: Chronic obstructive pulmonary disease (COPD) is a chronic lung disease which feature is progressive airflow obstruction. Singing is a popular and convenient activity that requires people to manage their lung volumes and airflow actively. Despite the well-known benefits of singing to healthy people, the specific effect still remains unclear.Objective: To investigate the mental and psychological benefits of singing in patients with stable COPD.Search Methods: We used Preferred Reporting Items for Systematic Reviews and Meta-Analyses Guidelines (PRISMA) on randomized controlled trials (RCTs) including singing exercise as the main intervention in stable COPD. We searched 8 electronic databases, including Web of Science, PubMed, Embase, Cochrane Library, Clinical Trials.gov, and the Physical Therapy Evidence Database (PEDro), CNKI, and Wanfang Database from inception until May 2022. The searching languages was English or Chinese. Data extraction using standardized templates was performed by two independent reviewers. The quality of the studies was assessed using the PEDro scale. Data synthesis was performed with Revman 5.4. The pooled effect sizes are reported by MD and 95% CI.Results: Five RCTs involving 333 patients with stable COPD were included in this meta-analysis. Singing was regarded as the main intervention in the experimental group. Meta-analysis revealed that singing improves quality of life on Short Form 36 physical component summary (SF-36 PCS) (MD = 12.63, 95% CI: 5.52 to 19.73, P < 0.01) and respiratory muscle in maximal expiratory pressure (PEmax) (MD = 14.30, 95% CI: 0.87 to 27.73, P = 0.04) in patients with COPD. However, it has limited effects on Short Form 36 mental component summary (SF-36 MCS), lung function, exercise capability, and adverse mental state.Conclusion: Based on results of the meta-analysis, singing could be used to improve quality of life (SF-36 PCS) and respiratory muscles (PEmax) in patients with COPD.Keywords: COPD, singing, pulmonary function, pulmonary rehabilitation

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