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Ye Ming,1– 3,* Xinyi He,1– 3,* Zhenxing Zhao,1– 3,* Xuehuan Meng,1– 3 Ye Zhu,1– 3 Hao Tan,1– 3 Guoyin Yang,1– 3 Yun Hu,1– 3 Leilei Zheng1– 3 1College of Stomatology, Chongqing Medical University, Chongqing, People’s Republic of China; 2Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing, People’s Republic of China; 3Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yun Hu; Leilei Zheng, Chongqing Key Laboratory for Oral Diseases and Biomedical Sciences, Chongqing, People’s Republic of China, Tel/Fax +86 23 88860151 ; +86 23 88860161, Email 500188@hospital.cqmu.edu.cn; zhengleileicqmu@hospital.cqmu.edu.cnPurpose: Oxidative stress and mitochondrial dysfunction are potential contributors to the compromised tissue regeneration capacity of alveolar bone in diabetic patients. Berberine, an active plant alkaloid, exhibits multiple pharmacological effects including antioxidation, blood glucose- and blood lipid-lowering properties. However, it remains uncertain whether berberine can improve impaired osteogenesis in type 2 diabetes mellitus (T2DM), and its poor solubility and oral bioavailability also constrain its applications in bone regeneration. Thus, our study aimed to probe the effects of berberine on bone marrow stem cells (BMSCs) in a diabetic microenvironment, with a greater emphasis on developing a suitable nano-delivery system for berberine and assessing its capability to repair diabetic alveolar bone defects.Methods: Firstly, BMSCs were exposed to berberine within a high glucose and palmitate (HG+PA) environment. Reactive oxygen species levels, mitochondrial membrane potential, ATP generation, cell apoptosis, and osteogenic potential were subsequently assessed. Next, we explored the regulatory mechanism of autophagy flux in the positive effects of berberine. Furthermore, a nanocarrier based on emulsion electrospinning for sustained local delivery of berberine (Ber@SF/PCL) was established. We assessed its capacity to enhance bone healing in the alveolar bone defect of T2DM rats through micro-computed tomography and histology analysis.Results: Berberine treatment could inhibit reactive oxygen species overproduction, mitochondrial dysfunction, apoptosis, and improve osteogenesis differentiation by restoring autophagy flux under HG+PA conditions. Notably, Ber@SF/PCL electrospun nanofibrous membrane with excellent physicochemical properties and good biological safety had the potential to promote alveolar bone remodeling in T2DM rats.Conclusion: Our study shed new lights into the protective role of berberine on BMSCs under T2DM microenvironment. Furthermore, berberine-loaded composite electrospun membrane may serve as a promising approach for regenerating alveolar bone in diabetic patients.Keywords: berberine, electrospun nanofibrous membrane, diabetes mellitus, alveolar bone remodeling, autophagy flux

Rui Bai,1,2 Yuhang Sui,1,2 Tianqi Lu,1,2 Hua Chen,1,2 Gang Wang,1,2 Rui Kong,1,2 Hongtao Tan,1,2 Yongwei Wang,1,2 Guanqun Li,1,2 Bei Sun1,2 1Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, People’s Republic of China; 2Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, People’s Republic of ChinaCorrespondence: Guanqun Li; Bei Sun, Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, No. 23 Youzheng Street, Nangang District, Harbin, 150001, People’s Republic of China, Email liguanqun@hrbmu.edu.cn; sunbei70@hrbmu.edu.cnPurpose: The effects of the step-jump approach on the survival and prognosis of infected pancreatic necrosis (IPN) patients have not yet been determined.Patients and Methods: Between November 2018 and June 2023, 188 patients were included in this study. There were 144 patients in the step-up group (the SU group) and 44 in the step-jump group (the SJ group). In the SU group, patients successfully treated with percutaneous catheter drainage (PCD) alone were classified into the SU-1 group (n=101), while those requiring additional surgery after PCD were categorized into the SU-2 group (n=43). In the SJ group, patients who underwent minimally invasive necrosectomy (MIN) without PCD were assigned to the SJ-1 group (n=34), whereas those who initially underwent PCD followed by immediate open surgery were placed in the SJ-2 group (n=10). Propensity score matching (PSM) was used to mitigate bias.Results: After PSM, a total of 34 pairs were successfully matched. A comparison of the SU group with the SJ-1 group (upfront MIN without PCD) revealed similar mortality rates (P=0.239); however, the incidences of multiple drug-resistant organisms (MDROs) (P=0.029) and surgical complications (P< 0.001) were significantly lower in the SJ-1 group. After comparing the SU-2 and SJ-2 groups (patients who underwent direct open necrosectomy without MIN after PCD failure), the incidences of surgical complications and MDRO in the SJ-2 group were significantly lower (P< 0.05).Conclusion: Compared with the step-up approach, the step-jump approach is safer and more effective and can significantly reduce the incidence of MDRO and surgical complications.Keywords: infected pancreatic necrosis, step-up approach, step-jump approach, propensity score match

Hongyan Tan, Bin Zhang, Xiawei Kang, Lvyao Wang, Xiao Qiu, Xiangyu Hu Department of Dermatology, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, 400011, People’s Republic of ChinaCorrespondence: Xiangyu Hu, Email 369930758@qq.comPurpose: At present, we have entered the era of using biological agents and small molecule targeted drugs to treat diseases. Although there have been many reports of biological agents treating pityriasis rubra pilaris recently, the clinical application of the JAK inhibitors in the treatment of pityriasis rubra pilaris has been rarely reported, and there is a lack of evidence on the safety and efficacy of these drugs. We explore the use of the JAK inhibitor tofacitinib in the treatment of pityriasis rubra pilaris with significant efficacy and no significant side effects, providing new ideas for the clinical treatment of pityriasis rubra pilaris.Methods: We cover a case of pityriasis rubra pilaris treated with the JAK inhibitor tofacitinib, which showed significant efficacy without any adverse effects.Results: This case report showed that the JAK inhibitor tofacitinib had significant clinical efficacy in the treatment of pityriasis rubra pilaris. We speculated that the treatment of pityriasis rubra pilaris with the JAK inhibitors may be related to blocking the activation of the JAK/STAT pathway, thereby blocking the high expression of cytokines IL-17, IL-12/IL-23, IL-23, TNF-α.Conclusion: The JAK inhibitor tofacitinib can become a new option for treating pityriasis rubra pilaris.Keywords: pityriasis rubra pilaris, JAK inhibitors, tofacitinib, secukinumab, ustekinumab

Haijie Tan,1,&ast; Yi Chen,2,&ast; Yan Jiang,1 Xiaojing Sun,1 Wei Ye,1 Xuefang Zhu,1 Xiangsheng Xiong1 1Department of Anesthesiology, The Fifth People’s Hospital of Huaian, Huaian, People’s Republic of China; 2Department of Anesthesiology and Perioperative Medicine, General Hospital of Ningxia Medical University, Yinchuan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiangsheng Xiong, Department of Anesthesiology, The Fifth People’s Hospital of Huaian, Huaian, People’s Republic of China, Email 158193942@qq.comBackground: Vasopressors remain an important strategy for managing spinal anesthesia-induced hypotension in women with preeclampsia. The aim of this study was to investigate the ED90s and efficacy ratio of phenylephrine and norepinephrine in managing spinal anesthesia-induced hypotension in women with preeclampsia during cesarean delivery.Methods: 60 women with preeclampsia, who underwent cesarean delivery, were randomly assigned to receive either a continuous intravenous infusion of phenylephrine or norepinephrine following spinal anesthesia. The initial dosage of phenylephrine or norepinephrine for the first women was 0.5 or 0.05 μg/kg/min, respectively, and subsequent infusion dosages were adjusted based on their efficacy in preventing spinal anesthesia-induced hypotension (defined as a systolic blood pressure less than 80% of the baseline level). The incremental or decremental doses of phenylephrine or norepinephrine were set at 0.1 or 0.01 μg/kg/min. The primary outcomes were the ED90s and efficacy ratio of phenylephrine and norepinephrine infusions for preventing spinal anesthesia-induced hypotension prior to delivery.Results: The results obtained from isotonic regression analysis revealed that the ED90 values of the phenylephrine and norepinephrine group for preventing spinal anesthesia-induced hypotension were 0.597 (95% CI: 0.582– 0.628) and 0.054 (95% CI: 0.053– 0.056) μg/kg/min, respectively, with an efficacy ratio of 11.1:1. The results of Probit regression analysis revealed that the ED90 values were determined to be 0.665 (95% CI: 0.576– 1.226) and 0.055 (95% CI: 0.047– 0.109) μg/kg/min, respectively, with an efficacy ratio of 12.1:1.Conclusion: The administration of 0.6 μg/kg/min phenylephrine and 0.05 μg/kg/min norepinephrine has been found to effectively manage a 90% incidence of spinal anesthesia-induced hypotension in women with preeclampsia.Keywords: ED90, phenylephrine, norepinephrine, spinal anesthesia-induced hypotension, preeclampsia, cesarean delivery

Jiaying Lao,1,2,&ast; Hang Tan,3,&ast; Yuyu Wu,2,&ast; Ting Ding,4 Xinqian Liu,1 Lanrong Sun,2 Xiyi Chen,2 Chongrong Zhu,2 Yiming Kang,5 Yu-Hsin Chen,2,6 Chonghui Tang,1 Fan Wang,7 Yanlong Liu2,6 1Department of Neurosurgery, Affiliated Cixi Hospital, Wenzhou Medical University, Ningbo, People’s Republic of China; 2School of Mental Health, Wenzhou Medical University, Wenzhou, People’s Republic of China; 3Department of neurosurgery, Hangzhou Mingzhou Brain Rehabilitation Hospital, Hangzhou, People’s Republic of China; 4Department of Infectious Diseases, The Affiliated Xiangshan Hospital of Wenzhou Medical University, Ningbo, People’s Republic of China; 5Psychosomatic Medicine Research Division, Inner Mongolia Medical University, Huhhot, People’s Republic of China; 6Zhejiang Provincial Clinical Research Center for Mental Disorders, The Affiliated Wenzhou Kangning Hospital, Wenzhou Medical University, Wenzhou, People’s Republic of China; 7Beijing Hui−Long−Guan Hospital, Peking University, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yanlong Liu, School of Mental Health, Medical University, Wenzhou, 325035, People’s Republic of China, Email benjaminlyl@wmu.edu.cn Chonghui Tang, Department of Neurosurgery, Affiliated Cixi Hospital, Wenzhou Medical University, Ningbo, 315300, People’s Republic of China, Email tangegg@163.comObjective: Cigarette smoking and low peripheral nitric oxide synthase (NOS) levels are strongly associated with sleep disorders. However, whether cerebrospinal fluid (CSF) NOS relates to sleep disorders and whether CSF NOS mediates the relationship between cigarette smoking and sleep disorders is unclear.Methods: We measured CSF levels of total NOS (tNOS) and its isoforms (inducible NOS [iNOS] and constitutive NOS [cNOS]) in 191 Chinese male subjects. We applied the Pittsburgh Sleep Quality Index (PSQI).Results: The PSQI scores of active smokers were significantly higher than those of non-smokers, while CSF tNOS, iNOS, and cNOS were significantly lower (all p < 0.001). CSF tNOS, iNOS, and cNOS were negatively associated with PSQI scores in the general population (all p < 0.001). Mediation analysis suggested that CSF tNOS, iNOS, and cNOS mediate the relationship between smoking and PSQI scores, and the indirect effect accounted for 78.93%, 66.29%, and 81.65% of the total effect, respectively.Conclusion: Cigarette smoking is associated with sleep disorders. Active smokers had significantly lower CSF levels of tNOS, iNOS, and cNOS. Furthermore, tNOS, iNOS, and cNOS mediate the relationship between cigarette smoking and sleep quality. This study provides insights into how cigarette smoke affects sleep disorders.Keywords: cerebrospinal fluid nitric oxide synthase, cigarette smoking, Pittsburgh Sleep Quality Index, sleep disorders, mediation

Xiaochen Chen,1,&ast; Jun Chen,2,&ast; Xue Zhao,2 Rongji Mu,1 Hongsheng Tan,1 Zhangsheng Yu1,3 1Clinical Research Institute & School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 2Clinical Research Center, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 3School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hongsheng Tan, Clinical Research Institute & School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People’s Republic of China, Email tanhs@shsmu.edu.cn Zhangsheng Yu, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 210240, People’s Republic of China, Email yuzhangsheng@sjtu.edu.cnAbstract: The coronavirus disease-2019 pandemic resulted in a major increase in depression and anxiety disorders worldwide, which increased the demand for mental health services. However, clinical interventions for treating mental disorders are currently insufficient to meet this growing demand. There is an urgent need to conduct scientific and standardized clinical research that are consistent with the features of mental disorders in order to deliver more effective and safer therapies in the clinic. Our study aimed to expose the challenges, complexities of study design, ethical issues, sample selection, and efficacy evaluation in clinical research for mental disorders. The reliance on subjective symptom presentation and rating scales for diagnosing mental diseases was discovered, emphasizing the lack of clear biological standards, which hampers the construction of rigorous research criteria. We underlined the possibility of psychotherapy in efficacy evaluation alongside medication treatment, proposing for a multidisciplinary approach comprising psychiatrists, neuroscientists, and statisticians. To comprehend mental disorders progression, we recommend the development of artificial intelligence integrated evaluation tools, the use of precise biomarkers, and the strengthening of longitudinal designs. In addition, we advocate for international collaboration to diversity samples and increase the dependability of findings, with the goal of improving clinical research quality in mental disorders through sample representativeness, accurate medical history gathering, and adherence to ethical principles.Keywords: clinical efficacy assessment, clinical trials, mental health, research design, statistical analysis

Hong Tan Department of Periodontal Mucosal Disease, The Affiliated Stomatology Hospital of Southwest Medical University, Oral & Maxillofacial Reconstruction and Regeneration of Luzhou Key Laboratory, Luzhou, Sichuan, 646000, People’s Republic of ChinaCorrespondence: Hong Tan, Email tanhongcloud@126.comObjective: To analyze the equity of bed allocation of the department of stomatology in Chinese hospitals and predict the development in the next 5 years, so as to provide a scientific basis for promoting the development of oral health.Methods: Data on the beds of the department of stomatology in Chinese hospitals from 2017 to 2021 were obtained from the China Health Statistical Yearbook. The Gini coefficient, Lorenz curve, Theil index and agglomeration degree were used to analyze the equity of the bed allocation, and the grey prediction model GM(1,1) was used to predict the development from 2022 to 2026.Results: From 2017 to 2020, the Gini coefficient of bed allocation of the department of stomatology in Chinese hospitals was below 0.2 by population. From 2017 to 2021, the Gini coefficient of beds was above 0.6 by geography and between 0.2 and 0.3 by economy. The Theil index of beds ranged from 0.022 to 0.056 by population, from 0.532 to 0.564 by geography, and from 0.042 to 0.047 by economy. The inequity in the allocation by population was mainly from between regions, and the inequity in the allocation by geography and economy was mainly from within regions. Health resource agglomeration degree (HRAD) was greater than 2 in the eastern and central regions and less than 1 in the western region. HRAD/ population agglomeration degree (PAD) was greater than 1 in the northeast, eastern, and central regions and less than 1 in the western region. According to the prediction, the number of beds of the department of stomatology in Chinese hospitals will continue to increase, reaching 47,862.485 in 2026.Conclusion: The equity of bed allocation was better by population and economy than by geography. The equity of beds in the western region is insufficient equity by population and geography, and the equity of beds in the eastern region is insufficient equity by economy.Keywords: department of stomatology, beds, equity, prediction, China

Wenjie Xie,1,2,&ast; Yixun Zhang,1,2,&ast; Qianfeng Xu,1,2,&ast; Guowei Zhong,1,2 Jundong Lin,2,3 Huichan He,3 Qiuling Du,2 Huijing Tan,1,2 Muqi Chen,1,2 Zhenjie Wu,1– 3 Yulin Deng,1,2 Zhaodong Han,1– 3 Jianming Lu,1,2,4 Jianheng Ye,1,2,4 Fen Zou,1,2 Yangjia Zhuo,1,2 Weide Zhong1– 4 1Department of Urology, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, 510180, People’s Republic of China; 2Guangdong Key Laboratory of Clinical Molecular Medicine and Diagnostics, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, 510180, People’s Republic of China; 3Urology Key Laboratory of Guangdong Province, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510230, People’s Republic of China; 4State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macau, 999078, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yangjia Zhuo; WeideZhong, Email eyyangjiazhuo@scut.edu.cn; zhongwd2009@live.cnPurpose: Current treatment approaches for Prostate cancer (PCa) often come with debilitating side effects and limited therapeutic outcomes. There is urgent need for an alternative effective and safe treatment for PCa.Methods: We developed a nanoplatform to target prostate cancer cells based on graphdiyne (GDY) and a copper-based metal-organic framework (GDY-CuMOF), that carries the chemotherapy drug doxorubicin (DOX) for cancer treatment. Moreover, to provide GDY-CuMOF@DOX with homotypic targeting capability, we coated the PCa cell membrane (DU145 cell membrane, DCM) onto the surface of GDY-CuMOF@DOX, thus obtaining a biomimetic nanoplatform (DCM@GDY-CuMOF@DOX). The nanoplatform was characterized by using transmission electron microscope, atomic force microscope, X-ray diffraction, etc. Drug release behavior, antitumor effects in vivo and in vitro, and biosafety of the nanoplatform were evaluated.Results: We found that GDY-CuMOF exhibited a remarkable capability to load DOX mainly through π-conjugation and pore adsorption, and it responsively released DOX and generated Cu+ in the presence of glutathione (GSH). In vivo experiments demonstrated that this nanoplatform exhibits remarkable cell-killing efficiency by generating lethal reactive oxygen species (ROS) and mediating cuproptosis. In addition, DCM@GDY-CuMOF@DOX effectively suppresses tumor growth in vivo without causing any apparent side effects.Conclusion: The constructed DCM@GDY-CuMOF@DOX nanoplatform integrates tumor targeting, drug-responsive release and combination with cuproptosis and chemodynamic therapy, offering insights for further biomedical research on efficient PCa treatment. Keywords: graphdiyne, biomimetic nanoplatform, cuproptosis, chemotherapy, prostate cancer

Xiaoxi Li, Ling Yu, Miao Fu, Jiaonan Yang, Hongyu Tan Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Anesthesiology, Peking University Cancer Hospital & Institute, Beijing, ChinaCorrespondence: Hongyu Tan, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Anesthesiology, Peking University Cancer Hospital & Institute, &num;52 Fucheng Street, Haidian District, Beijing, 100142, China, Tel/Fax +8610-88196107, Email maggitan@yeah.netBackground: Postoperative pulmonary complications (PPCs) are the most prevalent complication after esophagectomy and are associated with a worse prognosis. This study aimed to investigate the perioperative risk factors for PPCs after minimally invasive esophagectomy (MIE).Methods: Seven hundred and sixty-seven consecutive patients who underwent McKeown MIE via thoracoscopy and laparoscopy were retrospectively studied. Patient characteristics, perioperative data, and postoperative complications were analyzed.Results: The incidence of PPCs after MIE was 25.2% (193/767). Univariate analysis identified age (odds ratio [OR] 1.022, P = 0.044), male sex (OR 2.955, P < 0.001), pulmonary comorbidities (OR 1.746, P = 0.032), chronic obstructive pulmonary disease (COPD) (OR 2.821, P = 0.003), former smoking status (OR 1.880, P = 0.001), postoperative albumin concentration (OR 0.941, P = 0.007), postoperative creatinine concentration (OR 1.011, P = 0.019), and perioperative transfusion (OR 2.250, P = 0.001) as risk factors for PPCs. In multivariate analysis, the independent risk factors for PPCs were male sex (OR 3.135, P < 0.001), body mass index (BMI) (OR 1.088, P = 0.002), COPD (OR 2.480, P = 0.012), neoadjuvant chemoradiotherapy (OR 2.057, P = 0.035), postoperative albumin concentration (OR 0.929, P = 0.002), and perioperative transfusion (OR 1.939, P = 0.013). The area under the receiver operating characteristic curve for the predictive model generated by multivariate logistic regression analysis was 0.671 (95% confidence interval 0.628– 0.713).Conclusions: Male sex, BMI, COPD, neoadjuvant chemoradiotherapy, postoperative albumin concentration, and perioperative transfusion were independent predictors of PPCs after MIE.Keywords: esophageal cancer, minimally invasive esophagectomy, postoperative pulmonary complications, perioperative risk factors, predictive model

Xinni Pan,1 Yi Lu,2 Shanshan Fan,1 Hao Tang,2 Haisong Tan,3 Cheng Cao,2 Yingsheng Cheng,1 Yanlei Liu2 1Department of Radiology, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 2Department of Instrument Science and Engineering, Institute of Nano Biomedicine and Engineering, Shanghai Engineering Research Centre for Intelligent Diagnosis and Treatment Instrument, School of Electronic Information and Electrical Engineering, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 3Department of Urology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of ChinaCorrespondence: Yingsheng Cheng, Department of Radiology, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200235, People’s Republic of China, Tel +86-021-38297858, Email chengyingsheng@hotmail.com Yanlei Liu, Institute of Nano Biomedicine and Engineering, Shanghai Engineering Research Centre for Intelligent Diagnosis and Treatment Instrument, Department of Instrument Science and Engineering, School of Electronic Information and Electrical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, People’s Republic of China, Tel +86-18721788078, Email liuyanlei@sjtu.edu.cnBackground: Radiotherapy is one of the main clinical methods for the treatment of malignant tumors at present. However, its application is limited by the radiation resistance of some tumor cells and the irradiation damage to the surrounding normal tissues, and the limitation of radiotherapy dose also affects the therapeutic effect. Therefore, developing diagnostic and therapeutic agents with imaging and radiosensitizing functions is urgently needed to improve the accuracy and efficacy of radiotherapy.Materials and Strategy: Herein, we synthesized multifunctional nanotheranostic FRNPs nanoparticles based on gold nanocages (GNCs) and MnO2 for magnetic resonance (MR)/photoacoustic (PA) imaging and combined photothermal, radiosensitive and chemical therapy. A programmed therapy strategy based on FRNPs is proposed. First, photothermal therapy is applied to ablate large tumors and increase the sensitivity of the tumor tissue to radiotherapy, then X-ray radiation is performed to further reduce the tumor size, and finally chemotherapeutic agents are used to eliminate smaller residual tumors and distant metastases.Results: As revealed by fluorescence, MR and PA imaging, FRNPs achieved efficient aggregation and retention at tumor sites of mice after intravenous injection. In vivo studies have shown that the programmed treatment of FRNPs-injected nude mice which were exposed to X-ray after 808 laser irradiation achieved the greatest inhibition of tumor growth compared with other treatment groups. Moreover, no obvious systemic toxicity was observed in all groups of mice, indicating the good biocompatibility of FRNPs and the safety of the treatment scheme.Conclusion: To sum up, our work not only showed a new radiosensitizer, but also provided a promising theranostic strategy for cancer treatment.Keywords: gold nanoparticles, MnO2, radiosensitizing, multimodal imaging, cancer therapy

Yuying Zhao,1 Hanxu Tan,2 Juping Zhang,1,3 Bo Pan,1 Neng Wang,2 Tongkai Chen,4 Yafei Shi,1,2 Zhiyu Wang1,3,5 1State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; 2The Research Center for Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, People’s Republic of China; 3Guangdong-Hong Kong-Macau Joint Laboratory on Chinese Medicine and Immune Disease Research, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, People’s Republic of China; 4Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, People’s Republic of China; 5Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, Guangdong, People’s Republic of ChinaCorrespondence: Zhiyu Wang; Yafei Shi, Email wangzhiyu@gzucm.edu.cn; shiyafei@gzucm.edu.cnAbstract: Lipid-structured vesicles have been applied for drug delivery system for over 50 years. Based on their origin, lipid-structured vesicles are divided into two main categories, namely synthetic lipid vesicles (SLNVEs) and vesicles of mammalian origin (MDVEs). Although SLNVEs can stably transport anti-cancer drugs, their biocompatibility is poor and degradation of exogenous substances is a potential risk. Unlike SLNVEs, MDVEs have excellent biocompatibility but are limited by a lack of stability and a risk of contamination by dangerous pathogens from donor cells. Since the first discovery of plant-derived vesicles (PDVEs) in carrot cell supernatants in 1967, emerging evidence has shown that PDVEs integrate the advantages of both SLNVEs and MDVEs. Notably, 55 years of dedicated research has indicated that PDVEs are an ideal candidate vesicle for drug preparation, transport, and disease treatment. The current review systematically focuses on the role of PDVEs in cancer therapy and in particular compares the properties of PDVEs with those of conventional lipid vesicles, summarizes the preparation methods and quality control of PDVEs, and discusses the application of PDVEs in delivering anti-cancer drugs and their underlying molecular mechanisms for cancer therapy. Finally, the challenges and future perspectives of PDVEs for the development of novel therapeutic strategies against cancer are discussed. Keywords: plant-derived vesicles, cancer therapy, drug delivery, liposome nanoparticles, mammalian-derived exosomes

Tianzhuo Zhang,1,2,&ast; Nan Song,3,&ast; Shuo Li,2,&ast; Ling Yu,2 Yining Xie,2 Zhijie Yue,2 Rui Zhang,4 Lijie Wang,4 Hongyu Tan2 1Department of Gastroenterology, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, 100045, People’s Republic of China; 2Department of Anesthesiology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital & Institute, Beijing, 100142, People’s Republic of China; 3Department of Gynecology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital & Institute, Beijing, 100142, People’s Republic of China; 4Philips (China) Investment Co., Ltd., Beijing, 100600, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hongyu Tan, Department of Anesthesiology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital & Institute, Beijing, 100142, People’s Republic of China, Tel +86-10-88196409, Email maggitan@yeah.netPurpose: This study aims to evaluate the effect of S-ketamine on slow wave sleep (SWS) and the related changes in serum protein in gynecological patients after open abdomen surgery.Methods: This was a randomized controlled trial. One hundred gynecological patients undergoing open abdomen surgery were randomized into an S-ketamine group (group S) or placebo group (0.9% saline; group C). During operation, patients in group S received adjuvant S-ketamine infusion (0.2 mg·kg− 1·h− 1) while those in group C received 0.9% saline. All patients were connected to patient-controlled intravenous analgesia (PCIA) pump in the end of the surgery and the patients in group S with an additional S-ketamine in PCIA pump. Polysomnogram (PSG) was monitored during the next night after surgery with PCIA pump. Blood samples were collected for proteomic analysis at 6:00 AM after PSG monitoring. The primary outcome was the percentage of SWS (also known as stage 3 non-rapid eye movement sleep, stage N3) on the next night after surgery, and the secondary outcome was subjective sleep quality, pain scores, and the changes in serum proteomics.Results: Complete polysomnogram recordings were obtained from 64 study participants (31 in group C and 33 in group S). The administration of S-ketamine infusion resulted in a significant increase in the percentage of SWS/N3 compared to the control group (group C, median (IQR [range]), 8.9 (6.3, 12.5); group S, median (IQR [range]), 15.6 (12.4, 18.8), P< 0.001). However, subjective evaluations of sleep quality revealed no significant variances between the two groups. The protein affected by S-ketamine was primarily associated with posttranslational modification, protein turnover, carbohydrate transport, and metabolism.Conclusion: In patients undergoing open gynecological surgery, S-ketamine enhanced the percentage of objective sleep of SWS during the next night after surgery. Additionally, there were differences observed in serum protein levels between the two groups.Trial Registration: ChiCTR2200055180. Registered on 02/01/2022.Keywords: S-ketamine, slow wave sleep, serum proteomics, gynecologic surgery

Hua Tan, Ai-Fei Lou, Jian-Er Wu, Xin-Zhong Chen, Xiao-Wei Qian Department of Anesthesiology, Women’s Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of ChinaCorrespondence: Xiao-Wei Qian; Xin-Zhong Chen, Department of Anesthesiology, Women’s Hospital, Zhejiang University School of Medicine, Xueshi Road 1, Hangzhou, 310006, People’s Republic of China, Tel +86-571-87061501, Fax +86 571 87061878, Email qianxw@zju.edu.cn; chenxinz@zju.edu.cnPurpose: Remimazolam has demonstrated the potential as a valuable medication for procedural sedation. However, there were some shortcomings for higher doses of remimazolam during hysteroscopy in spite of less frequent adverse events. The aim of this study was to find the 50% and 95% effective dose (ED50 and ED95) of remimazolam when combined with propofol for intravenous sedation during day-surgery hysteroscopy.Patients and Methods: Patients were randomly assigned evenly (20 per group) to one of five different dosage of remimazolam: group A (0.05mg/kg), group B (0.075mg/kg), group C (0.1mg/kg), group D (0.125mg/kg) or group E (0.15mg/kg). Intravenous injection of sufentanil 0.1μg/kg was administered before sedative medication. Intravenous anesthesia was commenced with remimazolam. Subsequently, propofol was administered at 1mg/kg and maintained at 6mg/kg/h. Success was defined when the patient did not move during cervical dilation, had sufficient sedation as judged by SE < 60 and no requirement for rescue doses. The success rate, induce and average dosage of propofol, the induction time, total surgery time, recovery time, and adverse events were recorded. Estimate of ED50 and ED95 with 95% confidence interval (CI) was performed by probit regression.Results: The mean (95% CI) values for ED50 and ED95 of remimazolam in patients were 0.09 (0.08− 0.11) mg/kg and 0.21 (0.16– 0.35) mg/kg, respectively. There was no difference in the induction time, total surgery time, and recovery time among groups. No serious adverse events occurred in all patients.Conclusion: The dose–response effects of remimazolam were evaluated for intravenous sedation during hysteroscopy. A combination of remimazolam and propofol was recommended to produce stabler sedation, reduce the total dosage and have less effect on cardiovascular and respiratory depression.Keywords: effective dose, remimazolam, intravenous sedation, hysteroscopy

Guixiang Tao,1,&ast; Hua Tan,2,&ast; Qian Chen1 1Institute of Pediatrics, Children’s Hospital of Nanjing Medical University, Nanjing, People’s Republic of China; 2Department of Clinical Laboratory, Children’s Hospital of Nanjing Medical University, Nanjing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qian Chen, Institute of Pediatrics, Children’s Hospital of Nanjing Medical University, Nanjing, People’s Republic of China, Tel +8618951768213, Email js_chenqian@sina.comObjective: The aim of this study was to analyze the genetic characteristics of three Enterobacteriaceae strains (one strain of Escherichia coli and two strains of Klebsiella pneumoniae) that produce both the NDM-5 and OXA-181 carbapenemases in pediatric patients.Methods: Carbapenem-resistant Enterobacteriaceae (CRE) strains were collected from the Children’s Hospital Affiliated to Nanjing Medical University in 2022. Resistance genes were detected by PCR. CRE strains that produced both the blaNDM-5 and blaOXA-181 genes were further characterized by antimicrobial susceptibility testing, multilocus sequence typing (MLST), plasmid conjugation assay, S1 nuclease-PFGE, Southern blotting and whole-genome sequencing.Results: Three Enterobacteriaceae strains carrying both the blaNDM-5 and blaOXA-181 resistance genes were screened. MLST results showed that the strain of Escherichia coli carrying both blaNDM-5 and blaOXA-181 was ST410; the two strains of Klebsiella pneumoniae with both blaNDM-5 and blaOXA-181 were ST2601 and ST759. Conjugation assays showed that the plasmids harboring the blaNDM-5 and blaOXA-181 genes were self-transmissible. S1-PFGE and Southern blotting showed that the blaNDM-5 and blaOXA-181 genes were located on the plasmid with the size of about 60kb~. The genotyping results showed that the plasmid types were ColKP3 and IncX3.Conclusion: This is the first report of Enterobacteriaceae strains that produce both NDM-5 and OXA-181 isolated from pediatric patients in China. Active infection control measures are urgently needed to prevent the spread of bacteria in children.Keywords: Escherichia coli, Klebsiella pneumoniae, NDM-5, OXA-181, plasmid

Helen Hahn,1 Tzy-Chyi Yu,1 Chia-Chen Teng,2 Hiangkiat Tan2 1Mallinckrodt Pharmaceuticals, Hampton, NJ, USA; 2Healthcore, Inc., Wilmington, DE, USACorrespondence: Tzy-Chyi Yu, Mallinckrodt Pharmaceuticals, Shelbourne Building, 53 Frontage Road, Suite 300, Hampton, NJ, 08827, USA, Tel +1 908 238 6884, Email amanda.yu@mnk.comAim: This retrospective observational study provides a holistic view of the clinical and economic characteristics of inpatient treatment of patients with thermal burns undergoing autografting, by integrating real-world data (RWD) from medical records from healthcare providers (HCPs) and administrative claims.Methods: We identified eligible patients between July 1, 2010, and November 30, 2019, from the HealthCore Integrated Research Database® (HIRD®) and obtained their medical records from HCPs. We abstracted data from medical records to describe patient demographics and clinical characteristics and obtained costs of treatment from claims.Results: Two hundred patients were stratified into cohorts based on the percentage of total body surface area (%TBSA) burned: minor (< 10%), moderate (10%– 24%), and major (≥ 25%). Data obtained from medical records and administrative claims were comparable to previous findings from administrative claims data. This privately insured study cohort predominantly consisted of White men. Diabetes mellitus and hypertension were frequently reported in a relatively young population. Key clinical characteristics that could influence burn treatment decisions and long-term outcomes, such as body mass index, size of autograft donor site, and mesh ratio, were frequently underdocumented in patients’ medical records.Conclusion: Evidence generated from 2 orthogonal RWD sources confirmed that patients with larger %TBSA burned required more intensive care, thereby incurring higher costs. This study highlights considerable incompleteness in many critical fields in medical records, which limits the ability to generate broader insights. More comprehensive documentation of clinical characteristics and outcomes of autografts and donor sites in the operative and medical notes is critical to appropriately evaluate their impact on outcomes of burn treatments in future research using RWD.Keywords: burn injury, healthcare resource utilization, treatment patterns, real-world data

Yunxiao Zhang, Shuo Li, Zongchao Li, Jiheng Chen, Hongyu Tan Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Anesthesiology, Peking University Cancer Hospital & Institute, Beijing, People’s Republic of ChinaCorrespondence: Hongyu Tan, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Anesthesiology, Peking University Cancer Hospital & Institute, 52 Fucheng Street, Haidian District, Beijing, 100142, People’s Republic of China, Tel +86 10 88196553, Fax +86 10 88122437, Email maggitan@yeah.netPurpose: In patients undergoing surgical resection for gastric cancer, perioperative hemodynamic fluctuations may affect organ perfusion, increase the incidence of postoperative complications, and prolong hospital stay.Patients and Methods: We retrospectively identified patients who underwent resection for gastric cancer at our institution from April 1, 2015 to October 30, 2018. Demographic information, perioperative data, and information on postoperative recovery were recorded. The primary outcome was length of postoperative hospital stay; the secondary outcome was incidence of postoperative complications. Propensity score matching was performed. The associations between perioperative factors and postoperative hospital stay were analyzed using multivariable logistic regression models in the full and matched cohorts.Results: In total, 933 patients were included; of these, 676 had diastolic hypotension (defined as diastolic blood pressure < 60 mmHg for > 10 min). In both cohorts, patients with diastolic hypotension had statistically significantly longer postoperative hospital stay (full: mean 14.5 ± standard deviation 10.2 vs 11.6 ± 6.5 days, P < 0.001; matched: 13.7 ± 9.9 vs 11.7 ± 6.6 days, P = 0.009) and a higher incidence of postoperative complications (full: 170 [25.1%] vs 27 [10.5%] cases, P < 0.001; matched: 60 [24.4%] vs 33 [13.4%] cases, P = 0.003), compared with patients without diastolic hypotension. After correction for confounding factors, intraoperative diastolic hypotension was associated with longer postoperative hospital stay in both the full and the matched cohort (full: HR, 1.535 [95% CI, 1.115– 2.114], P = 0.009; matched: HR, 1.532 [95% CI, 1.032– 2.273], P = 0.034).Conclusion: For patients with gastric cancer, intraoperative diastolic hypotension may increase the incidence of postoperative complications and prolong postoperative hospital stay.Keywords: gastric cancer, diastolic hypotension, postoperative complications, hospital stay

Changquan Fang,1,&ast; Limin Xu,2,&ast; Jiarong Tan,1 Hongyi Tan,1 Junhong Lin,1 Ziwen Zhao3 1Department of Pulmonary and Critical Care Medicine, Huizhou Central People’s Hospital, Huizhou, Guangdong Province, Peoples’ Republic of China; 2Department of Geriatrics, Huizhou First People’s Hospital, Huizhou, Guangdong Province, Peoples’ Republic of China; 3Department of Pulmonary and Critical Care Medicine, Guangzhou First People’s Hospital Affiliated to South China University of Technology, Guangzhou, Guangdong Province, Peoples’ Republic of China&ast;These authors contributed equally to this workCorrespondence: Junhong Lin, Department of Pulmonary and Critical Care Medicine, Huizhou Central People’s Hospital, No. 41 Eling North Road, Huicheng District, Huizhou City, Guangdong Province, 516000, Peoples’ Republic of China, Tel +86 130-7528-2839, Email hz_ljh@163.com Ziwen Zhao, Department of Pulmonary and Critical Care Medicine, Guangzhou First People’s Hospital Affiliated to South China University of Technology, No. 1 Panfu Road, Yuexiu District, Guangzhou City, Guangdong Province, 510180, Peoples’ Republic of China, Tel +86 130-0687-2260, Email zhaozw@yeah.netAbstract: Psittacosis is a rare zoonotic disease caused by Chlamydia psittaci infection, and tetracyclines are the preferred treatment. Omadacycline is a novel tetracycline that has a strong in vitro antibacterial activity against atypical pathogens, including C. psittaci; however, clinical data for its usage are lacking. We report a patient with severe C. psittaci-induced pneumonia presenting with a high fever, muscle aches, severe hepatic and renal insufficiency, and acute respiratory failure requiring tracheal intubation and mechanical ventilation. The condition was diagnosed using metagenomic next-generation sequencing. The patient was discharged after treatment with omadacycline. The findings of this study suggest that metagenomic next-generation sequencing is valuable for the rapid and accurate diagnosis of psittacosis. With its good safety profile and no requirement for dose adjustment in special populations, omadacycline is a new option for the treatment of severe C. psittaci pneumonia. However, additional case reports are needed to support this conclusion.Keywords: Chlamydia psittaci, pneumonia, omadacycline, multiple organ failure, metagenomic next-generation sequencing

Yanrui Liang,1,&ast; Weihong Guo,1,&ast; Chuangji Li,1,&ast; Guodong Shen,1,&ast; Haoxian Tan,2 Peiwen Sun,2 Zhian Chen,1 Huilin Huang,1 Zhenhao Li,1 Zhenyuan Li,1 Yingxin Ren,1 Guoxin Li,1 Yanfeng Hu1 1Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China; 2The First School of Clinical Medicine, Southern Medical University, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Guoxin Li; Yanfeng Hu, Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, No. 1838 North Guangzhou Ave, Baiyun District, Guangzhou, 510515, People’s Republic of China, Tel +86-20-6164-1681 ; +86-20-6164-1682, Fax +86-20-6164-1681, Email yfenghu@qq.com; gzliguoxin@163.comPurpose: Lymphadenectomy with lymph node (LN) mapping is essential for surgical removal of solid tumors. Existing agents do not provide accurate multimodal mapping and antitumor therapy for metastatic LNs; therefore, we fabricated a polydopamine (PDA) nanoparticle (NP)-based tumor-targeted LN mapping agent capable of multimodal mapping and guided photothermal therapy (PTT) for metastatic LNs.Materials and Methods: PDA NPs modified with polyethylene glycol (PEG) were obtained by polymerization under alkaline conditions. The PEG-PDA NPs were loaded with the circular tripeptide Arg-Gly-Asp (cRGD) to achieve tumor-targeting capacity and with the fluorescent dye IR820 and magnetic resonance imaging (MRI) contrast Gd(NH2)2 for in situ detection. The resulting cRGD-PEG-PDA@IR820/Gd(NH2)2 (cRGD-PPIG) NPs were tested for their biosafety and metastatic LN mapping ability. They were drained specifically into LNs and selectively taken up by gastric MKN45 cells via αvβ 3 integrin-mediated endocytosis.Results: This phenomenon enabled MR/optical/near-infrared fluorescence multimodal metastatic LN mapping, guiding the creation of accurate and highly efficient PTT for gastric cancer metastatic LNs in mice.Conclusion: In summary, we fabricated tumor-targeted cRGD-PPIG NPs with MR/optical/near-infrared fluorescence multimodal metastatic LN mapping capacity for surgery and efficient PTT guidance post-surgery.Keywords: multimodal imaging, lymph node mapping, metastatic lymph node, photothermal therapy

Guixiang Tao,1 Hua Tan,2 Jingjing Ma,1 Qian Chen1 1Institute of Pediatrics, Children’s Hospital of Nanjing Medical University, Nanjing, People’s Republic of China; 2Department of Laboratory Medicine, Children’s Hospital of Nanjing Medical University, Nanjing, People’s Republic of ChinaCorrespondence: Qian Chen, Institute of Pediatrics, Children’s Hospital of Nanjing Medical University, Nanjing, People’s Republic of China, Tel +8618951768213, Email js_chenqian@sina.comObjective: The drug resistance phenotype and molecular epidemiological characteristics of carbapenem-resistant Klebsiella pneumoniae (CRKP) were identified among children in Jiangsu Province, China.Methods: CRKP strains were collected from the Children’s Hospital of Nanjing Medical University from December 2020 to March 2022. CRKP strains were characterized for further study: antimicrobial susceptibility testing, carbapenem resistance genes and homology analysis.Results: Among 86 strains of CRKP, 85 carried carbapenemase genes; the dominant gene was blaKPC-2 (88.2%, 75/85), followed by blaNDM-1 (4.7%, 4/85), blaNDM-5 (4.7%, 4/85), blaIMP-8 (2.3%, 2/85), and blaOXA-181 (1.2%, 1/85). Among the 86 strains of CRKP, one isolate contained both the blaNDM-5 and blaOXA-181 genes, which is the first time that Klebsiella pneumoniae has been shown to jointly carry these genes in China. Another CRKP strain did not carry any carbapenemase gene. MLST analysis identified a total of 10 different sequence types, among which sequence type (ST) 11 was the most common. PFGE analysis identified 75 blaKPC-2-producing CRKP ST11 strains, of which 68 were dominant clusters distributed among 11 different wards, mainly the neonatal medical centre (18 strains), neonatal surgery (17 strains) and cardiac care unit (CCU) (8 strains) wards.Conclusion: Clonal dissemination of KPC-2-producing CRKP ST11 was observed in multiple departments. Additionally, non-ST11 strains showed high polymorphism based on molecular typing, indicating increasing diversity in CRKP strains. To our knowledge, this is the first report of NDM-5 and OXA-181-coproducing Klebsiella pneumoniae causing infection in children in China, which poses a significant health risk for paediatric patients. Active surveillance and effective control measures are urgently needed to prevent further transmission of these strains among children.Keywords: Klebsiella pneumoniae, carbapenemase, KPC-2, ST11, clonal, dissemination, children

BackgroundThe European Association of Endoscopic Surgery (EAES) is a surgical society who promotes the development and expansion of minimally invasive surgery to surgeons and surgical trainees. It does so through its activities in education, training, and research. The EAES research committee aims to promote the highest quality clinical research in endoscopic and minimally invasive surgery. They have provided grant funding since 2009 in education, surgery, and basic science. Despite the success and longevity of the scheme, the academic and non-academic impact of the research funding scheme has not been evaluated.AimsThe primary aim of this project is to assess the short, long term academic and real world impact of the EAES funding scheme. The secondary aims are to identify barriers and facilitators for achieving good impact.MethodsThis will be a mixed qualitative and quantitative study. Semi-structured interviews will be performed with previous grant recipients. The questions for the interviews will be selected after a consensus is achieved amongst the members of the steering committee of this project. The responses will be transcribed and thematic analysis will be applied. The results of the thematic analysis will be used to populate a questionnaire which will be disseminated to grant recipients. This study is kindly funded by the EAES.DiscussionThe first question this project is expected to answer is whether the EAES research funding scheme had a significant positive impact on research output, career progression but also non-academic output such as change in clinical guidelines, healthcare quality and cost-effectiveness improvement. This project however is also expected to identify facilitators and barriers to successful completion of projects and to achieving high impact. This will inform EAES and the rest of the surgical and academic communities as to how clinicians would like to be supported when conducting research. There should also be a positive and decisive change towards removing factors that hinder the timely and successful completion of projects.

Nongzhang Xu,1,&ast; Jianwei Wan,1,&ast; Cuihong Wang,1 Jiatao Liu,2 Chenqai Qian,1 Hongyang Tan3 1Department of Pharmacy, Shanghai University of Medicine and Health Science Affiliated Zhoupu Hospital, Shanghai, People’s Republic of China; 2Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei, People’s Republic of China; 3Clinical Research Center for Mental Disorders, Chinese-German Institute of Mental Health Shanghai Pudong New Area Mental Health Center, School of Medicine, Tongji University, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hongyang Tan, Clinical Research Center for Mental Disorders, Chinese-German Institute of Mental Health, Shanghai Pudong New Area Mental Health Center, School of Medicine, Tongji University, Shanghai, People’s Republic of China, Tel +86-18321133996, Email tanhongyang2013@163.comPurpose: Trimethylamine N-oxide (TMAO) is a metabolite of phosphatidylcholine in red meat and other diets, which is associated with cardiovascular and other diseases. The aim of this study is to evaluate the associations of serum TMAO with mild cognitive impairment (MCI) in the Chinese type 2 diabetes mellitus (T2DM) population.Materials and Methods: A total of 253 hospitalized T2DM patients and 150 healthy controls were included in this cross-sectional study. Montreal Cognitive Assessment (MoCA) assessed the cognition function, and the 253 T2DM patients were divided into 74 subjects with MCI and 179 with non-MCI. Demographic data and biochemical test results were evaluated. Serum TMAO level was measured by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS).Results: A higher serum TMAO level was observed in T2DM patients compared with the healthy controls (P < 0.001). Among all T2DM patients, the MCI group (n = 74) showed higher serum TMAO levels than the non-MCI group. Spearman correlation test showed that TMAO levels were significantly positively correlated with age (r = 0.147, P = 0.019), body mass index (BMI) (r = 0.153, P = 0.015), diabetes duration (r = 0.160, P = 0.011), HbA1c (r = 0.138, P = 0.029), triglyceride (TG) (r = 0.138, P = 0.029), creatinine (r = 0.184, p = 0.003), hs-CRP (r = 0.243, P < 0.001), and were negatively correlated with HDL-C (r = − 0.144, P = 0.022), BDNF (r = − 0.165, p = 0.009), and MoCA (r = − 0.386, P < 0.001) score (all P < 0.05). Multivariable Logistic regression identified high serum TMAO level as a significant independent factor of MCI in the T2DM patients (OR = 1.404, 95% CI = 1.255– 1.571; P < 0.001).Conclusion: Our study showed that T2DM patients with MCI have elevated serum TMAO levels.Keywords: trimethylamine N-oxide, type 2 diabetes mellitus, mild cognitive impairment, Montreal Cognitive Assessment, healthy control

Chengxiao Fu,1,2,&ast; Qi Pei,3,&ast; Wu Liang,4 Bo Yang,2 Wei Li,5 Jun Liu,5 Hongyi Tan,1,4 Chengxian Guo,1,4 Hao Zhang,5 Guoping Yang1,4 1Center for Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 2The First Affiliated Hospital, Department of Pharmacy, Hengyang Medical School, University of South China, Hengyang, People’s Republic of China; 3Department of Pharmacy, The Third Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 4Research Center of Drug Clinical Evaluation of Central South University, Changsha, People’s Republic of China; 5Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Guoping Yang; Hao Zhang, Email ygp9880@126.com; zhanghaoliaoqing@163.comPurpose: Parathyroid hormone (PTH) can induce the downregulation of CYP3A in chronic kidney disease (CKD). Nevertheless, the effect of PTH on CYP3A-mediated clearance pathways from a clinical perspective remains unclear.Methods: This study employed population pharmacokinetic (PopPK) modeling to delineate potential changes in CYP3A activity in patients with CKD. Pharmacokinetic data for nifedipine, a typical CYP3A substrate, as well as covariate information, were prospectively collected from 157 patients with a total of 612 concentrations. PopPK data analysis was performed using a nonlinear mixed-effects model.Results: The pharmacokinetics of nifedipine were optimally described according to a one-compartment model with zero-order absorption and first-order elimination. The estimated population parameters (and interindividual variability) were apparent clearance (CL/F) 49.61 L/h (58.33%) and apparent volume of distribution (V/F) 2300.26 L (45.62%), and the PTH level negatively correlated with CL/F. In comparison with the reference level, it was observed that the dosage of nifedipine should be reduced with the maximum boundary value of PTH, after a Monte Carlo simulation.Conclusion: This study provides insight into the effects of PTH on CYP3A-mediated clearance pathways. Moreover, PTH could be used as a guide for the appropriate administration of CYP3A eliminated drugs in patients with CKD.Keywords: chronic kidney disease, parathyroid hormone, CYP3A, population pharmacokinetic, nifedipine

Jianing Li, Shuo Li, Ling Yu, Jin Wei, Shuang Li, Hongyu Tan Department of Anesthesiology, Peking University Cancer Hospital & Institute, Beijing, People’s Republic of ChinaCorrespondence: Hongyu Tan, Department of Anesthesiology, Peking University Cancer Hospital & Institute, Beijing, People’s Republic of China, Tel +86-10-88196107, Email maggitan@yeah.netPurpose: As an adipocyte-secreted hormone, resistin is linked to inflammation, insulin resistance and atherosclerosis. Currently, resistin is proposed as a novel biomarker for postoperative pain intensity. However, due to the various types of surgery and limited numbers of studies, previous conclusions should be validated. This study aimed to explore the effect of resistin polymorphism (rs3745367) on pain thresholds and sufentanil consumption in gastric cancer patients.Patients and Methods: A total of 148 gastric cancer patients enrolled in this study had their pain thresholds measured before surgery. After the exclusion of 16 patients, the characteristics of demography and clinic, numerical rating scale (NRS) and sufentanil consumption of 132 patients were recorded. Rs3745367 of resistin was identified by Sanger sequencing. Multivariate linear regression analysis was performed for sufentanil consumption and mechanical pain threshold.Results: The distributions of the GG, AG, and AA genotypes of rs3745367 among the participants were 54 (40.9%), 65 (49.2%), and 13 (9.9%), respectively. The mechanical pain threshold (P=0.04) and postoperative sufentanil consumption in the 1st 24 h (P=0.03) were significantly different among GG, AG, and AA genotype carriers. There was no significant difference among the three genotypes for the heat pain threshold and cold pain threshold. Regarding the NRS, no statistically significant difference among the three different genotypes was found 24 h postoperatively.Conclusion: Rs3745367 of resistin is associated with the mechanical pain threshold and postoperative sufentanil consumption in gastric cancer patients. Patients with the AA genotype of rs3745367 present an increased mechanical pain threshold and decreased postoperative sufentanil consumption.Keywords: gene polymorphism, pain threshold, postoperative pain, resistin, sufentanil consumption

Zemin Hou,1,2,&ast; Wencheng Zhou,1,2,&ast; Xi Guo,2 Rui Zhong,3 Ao Wang,4 Jiehua Li,4 Ying Cen,1 Chao You,2 Hong Tan,4 Meng Tian2 1Department of Burn and Plastic Surgery, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 2Department of Neurosurgery and Neurosurgery Research Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 3Institute of Blood Transfusion, Chinese Academy of Medical Science & Peking Union Medical College, Chengdu, Sichuan, People’s Republic of China; 4College of Polymer Science and Engineering, State Key Laboratory of Polymer Materials Engineering, Sichuan University, Chengdu, Sichuan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Meng Tian, Department of Neurosurgery and Neurosurgery Research Laboratory, West China Hospital, Sichuan University, No. 37 Guoxue Alley, Wuhou District, Chengdu, Sichuan Province, 610041, People’s Republic of China, Tel +86 28 85164168, Email tianmeng@scu.edu.cnBackground: The main challenge of polymeric micelles as drug delivery systems is that the actual delivery efficiency is not as high as expected, which is closely related with the interactions with the complex biological environments such as blood components, phagocytosis, and biodistribution. Herein, we expect to understand these concerns for the clinically relevant micelles that composed of methoxypolyethylene glycol (MPEG) with identical chain length And poly(&epsiv;-caprolactone) (PCL) with tunable chain length (PCLn-MPEG) (n=20, 30, and 40) wherein doxorubicin was encapsulated as a model drug.Methods: The doxorubicin-loaded PCLn-MPEG micelles were prepared by a dialysis method and characterized by dynamic light scattering and transmission electron microscopy. The surface PEG density and chain conformation were investigated by dissipative particle dynamics simulation. The stability of the micelles was detected by nanoparticle tracking analysis. The effects of PCL chain length on the blood components, phagocytosis, and biodistribution were assayed in vitro and in vivo.Results: The micelles exhibited spherical morphology with a diameter about 30nm. The PEG chain conformation from “mushroom-like” to “brush-like” was evident. The micelles have no remarkable effect on the red blood cells, blood coagulation, and platelet activation. Interestingly, the protein adsorption was affected and dependent on the chain conformation, with lowest adsorption for PCL30-MPEG, which also has the loWest phagocytosis. The stability of the micelles was in the order of PCL40-MPEG>PCL30-MPEG>PCL20-MPEG which was dependent on the PCL chain length. The micelles mainly accumulated in liver, with the order consistent with their stability, indicating that, besides the phagocytosis, the stability of the micelle plays an important role in biodistribution as well. The related mechanisms were proposed and discussed.Conclusion: Manipulating the PEG/PCL ratio of the micelle is an effective approach to modulate the protein adsorption, phagocytosis, and biodistribution, which may be a prerequisite for clinical applications.Keywords: micelles, blood components, phagocytosis, biodistribution

Xiaonan Zhou,1,2,&ast; Kai Zhu,1,2,&ast; Yiqiu Zhang,3– 5,&ast; Yang Ming,1,2 Dai Shi,3– 5 Hui Tan,3– 5 Bitao Xiang,1,2 Shichao Zhu,1,2 Dengfeng Cheng,3– 5 Hao Lai,1,2 Chunsheng Wang,1,2 Guobing Liu3– 5 1Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, People’s Republic of China; 2Shanghai Institute of Cardiovascular Diseases, Shanghai, 200032, People’s Republic of China; 3Department of Nuclear Medicine, Zhongshan Hospital, Fudan University, Shanghai, 200032, People’s Republic of China; 4Institute of Nuclear Medicine, Fudan University, Shanghai, 200032, People’s Republic of China; 5Shanghai Institute of Medical Imaging, Shanghai, 200032, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Guobing Liu, Department of Nuclear Medicine, Zhongshan Hospital, Fudan University, No. 180 in Fenglin Road, Shanghai, 200032, People’s Republic of China, Tel +8618317086732, Fax +86-21-62489191, Email liu.guobing@zs-hospital.sh.cn Chunsheng Wang, Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, No. 180 in Fenglin Road, Shanghai, 200032, People’s Republic of China, Email wangchunsheng@fudan.edu.cnPurpose: To investigate the feasibility of a pre-targeted imaging strategy based on the cycloaddition between 1,2,4,5-terazine (Tz) and trans-cyclooctene (TCO) for evaluating CD11b expression in inflammatory aortic aneurysm (AA) using single photon emission computed tomography/computed tomography (SPECT/CT).Methods: C57BL/6J mice were fed β-aminopropionitrile (1 g/kg/day) for 4 weeks to establish AA models. Anti-CD11b-TCO was synthesized and 99mTc-HYNIC-PEG11-Tz was designed for pre-targeted SPECT/CT. The affinity and specificity of the probe for the inflammatory cell line Raw-264.7 were investigated. Then, anti-CD11b-TCO pre-targeted and 99mTc-HYNIC-PEG11-Tz based SPECT/CT were performed to detect in vivo inflammation in AA. Finally, ex vivo aortic breast-specific gamma imaging (BSGI), Western blot assays, and immunohistochemical CD11b staining were performed to confirm the in vivo findings of SPECT/CT.Results: In the AA models, 65.22% (15/23) had aortic lesions, including 43.48% (10/23) AA lesions. The anti-CD11b-TCO presented with a high TCO coupling ratio (7.43), and the 99mTc-HYNIC-PEG11-Tz showed high radio-purity (> 95%), good in vitro stability and a rapid clearance rate. Additionally, anti-CD11b-TCO and 99mTc-HYNIC-PEG11-Tz presented high click rate (∼ 89%). The in vitro clicked compound, 99mTc-HYNIC-PEG11-Tz/TCO-anti-CD11b, showed high affinity and specificity for Raw-264.7 cells. 99mTc-HYNIC-PEG11-Tz/TCO-anti-CD11b pre-targeting SPECT/CT successfully demonstrated inflammatory AA with a high AA-to-background ratio in AA mice, compared to AA mice that were injected with 99mTc-HYNIC-Tz/TCO-IgG (8.13 versus 3.71, P < 0.001) and control mice injected with 99mTc-HYNIC-Tz/TCO-anti-CD11b (8.13 versus 3.66, P < 0.001). This result was confirmed by ex vivo BSGI performed immediately after SPECT/CT and immunohistochemical CD11b staining.Conclusion: SPECT/CT imaging using the anti-CD11b-TCO/Tz-PEG11-HYNIC-99mTc based pre-targeting imaging strategy allows for the detection of inflammation in progressive AA.Keywords: aortic aneurysm, inflammation, SPECT/CT, CD11b, macrophage

Background: Acute kidney injury remains a common complication with a poor prognosis, and is a significant predictor of mortality in cirrhosis patients. We aimed to determine the percentage of acute kidney injury in decompensated cirrhosis patients and evaluate the treatment results of acute kidney injury as well as several factors related to the mortality of decompensated cirrhosis patients. Methods: A prospective study was conducted on decompensated cirrhosis patients in Can Tho City, Vietnam, from 2019 to 2020. Decompensated cirrhosis patients were found to have acute kidney injury on admission by a blood creatinine test. They were treated according to ICA 2015 standards, after which they were monitored and evaluated for treatment outcomes during hospitalization. Results: Of 250 decompensated cirrhosis patients, 64 (25.6%) had acute kidney injury and 37.5% died. Several factors were associated with mortality in decompensated cirrhosis patients, such as Child–Pugh C (p = 0.02; OR = 3, 95% CI 1.5–6.3), acute kidney injury (p < 0.0001; OR = 9.5, 95% CI 4.3–21.1), hyponatremia (p = 0.01; OR = 2.5, 95% CI 1.2–5.1), elevated total bilirubin > 51 µmol/L (p = 0.03; OR = 2.2, 95% CI 1.1–4.6), and prothrombin < 70% (p = 0.03; OR = 6.8, 95% CI 1–51.6). Hypoalbuminemia was unrelated to mortality in these patients (p = 0.8; OR = 1.2, 95% CI 0.5–2.7), but gastrointestinal bleeding significantly increased mortality in these patients up to 2.3 times (p = 0.03; OR = 2.3, 95% CI 1.1–4.9). Three independent factors regarding mortality in decompensated cirrhosis patients included acute kidney injury, hepatic encephalopathy, and gastrointestinal bleeding. The rate of acute kidney injury in patients with decompensated cirrhosis was 25.6%; the mortality rate was 37.5%. Conclusions: Acute kidney injury was a valuable predictor of mortality in Vietnamese patients with decompensated cirrhosis.

Kunlin Ni,1,&ast; Yishu Liu,2,&ast; Xiaoyu Zhu,1 Huiwen Tan,2 Yin Zeng,2 Qiyong Guo,1 Li Xiao,2,3 Bing Yu1 1Department of Radiology, Shengjing Hospital of China Medical University, Shenyang, 110004, People’s Republic of China; 2Department of Pulmonary and Critical Care Medicine, Shengjing Hospital of China Medical University, Shenyang, 110004, People’s Republic of China; 3Sleep Medicine Center, Shengjing Hospital of China Medical University, Shenyang, 110004, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Bing YuDepartment of Radiology, Shengjing Hospital of China Medical University, Shenyang, 110004, People’s Republic of China, Tel +86-24-96615-73266, Fax +86-24-23929902, Email yubingcmu@163.com; Li XiaoDepartment of Pulmonary and Critical Care Medicine, Shengjing Hospital of China Medical University, Shenyang, 110004, People’s Republic of China, Tel +86-24-96615-61713, Fax +86-24-22780097, Email xiaolicmu@163.comObjective: In the current study we investigated topological abnormalities of the cerebral white matter networks in narcolepsy type 1 (NT1) patients and its relationship with their cognitive abnormalities using diffusion tensor imaging (DTI) technology.Methods: DTI and the Beijing version of the Montreal Cognitive Assessment (MoCA-BJ) were applied to 30 NT1 patients and 30 age-matched healthy controls. DTI studies were also carried using the 3T MRI system. Next, DTI data was used to establish a cerebral white matter network for all subjects and graph theory was applied to analyze the topological characteristics of the white matter structural network. Topographical parameters (such as local efficiency (Eloc), global efficiency (Eglob) and small-world (σ)) between NT1 patients and controls were then compared. The correlation between MoCA-BJ scores and topological parameters was also analyzed.Results: MoCA-BJ scores in NT1 patients were lower than those in the healthy controls. Compared with healthy controls, the global efficiency of the white matter network and attributes of the small world network were significantly reduced in NT1 patients. Finally, the global efficiency of the white matter structural network was related to the MoCA-BJ score of NT1 patients.Conclusion: The abnormal topological characteristics of the white matter structural network in NT1 patients may be associated with their cognitive impairment.Keywords: cognitive dysfunction, graph theory analysis, narcolepsy type 1, diffusion tensor imaging, montreal cognitive assessment Beijing edition

Huijing Tan,1 Lijie Zuo,1,2 Shutao Ma,1 Dingyuan Wang,3 Rui Li,1,2 Yiqi Yang,1,2 Weili Liu,1,2 Yihebali Chi1 1Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People’s Republic of China; 2Beijing Chaoyang Sanhuan Cancer Hospital, Beijing, 100021, People’s Republic of China; 3Department of Breast Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People’s Republic of ChinaCorrespondence: Yihebali ChiDepartment of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 17 South Panjiayuan Lane, Chaoyang District, Beijing, 100021, People’s Republic of ChinaTel +8613911075626Email yihebalichi@hotmail.comBackground: Leiomyosarcoma (LMS) accounts for 24% of all soft tissue sarcomas (STSs) and this STS subtype has high metastatic potential. Previous studies indicated the best median progression-free survival (mPFS) time was 9.2 months and the best overall response rate (ORR) was 30.9%. We evaluated the efficacy and safety of epirubicin combined with temozolomide (EPI-TMZ) for treatment of advanced LMS.Methods: This was a retrospective review of the records of patients with advanced LMS at the National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College. All patients initiated EPI-TMZ treatment between January 2018 and December 2020.Results: We examined 15 patients who received EPI-TMZ for LMS. This was a first-line treatment in 6 patients, a second- or third-line treatment in 7 patients, and a fourth-line treatment in 2 patients. At the time of data cutoff (April 25, 2021), the median PFS was 10 months, 1 patient had clinical complete response (cCR), 7 had partial response (PR), and 7 had stable disease (SD). The overall response rate (ORR) was 53.3% (8/15) and the disease control rate (DCR) was 100.0% (15/15). The most common treatment-related adverse effects were leukopenia, neutropenia, thrombocytopenia, anemia, nausea, vomiting, fatigue, and oral mucositis. One patient had severe adverse effect (febrile neutropenia), but there were no treatment-related deaths.Conclusion: EPI-TMZ is potentially effective for treatment of advanced LMS, and the adverse effects appear tolerable. EPI-TMZ provided better outcomes than reported in previous studies of other treatments for advanced LMS.Keywords: epirubicin, temozolomide, advanced leiomyosarcoma, chemotherapy

Xiaolei Liu, Zihuan Zhang, Jia Huang, Haidong Tan, Zhiying Yang Department of Hepatobiliary Surgery, China-Japan Friendship Hospital, Beijing, People’s Republic of ChinaCorrespondence: Zhiying YangDepartment of Hepatobiliary Surgery, China-Japan Friendship Hospital, 2 Yinghua Dongjie, Hepingli, Beijing, 100029, People’s Republic of ChinaTel +861084205054Email yangzhy@aliyun.comBackground: Hepatic epithelioid hemangioendothelioma (HEH) is a rare tumor type. No effective medicine or standard treatment for HEH has been established.Patients and Methods: From March 2014 to April 2021, 62 patients with pathologically diagnosed HEH were observed regularly, and interferon-alpha 2b (IFN-a 2b) was administered to patients with progressive disease or reoccurrence. Adverse events (AEs) were assessed and recorded, and a tumor assessment scan was performed every 3 months.Results: A total of 42 patients with HEH received IFN-a 2b treatment in this study. No severe (grade ≥ 3) AEs were reported in the group overall. The most common treatment-related AEs in patients receiving IFN-a 2b were fever (50.0%) and fatigue (21.4%). Partial response and complete response were achieved in 20 patients (47.6%) and 2 patients (4.8%), respectively, and the objective response rate was 52.4%. Stable disease was observed in 12 patients (28.6%), and the disease control rate was 81.0%. Progressive disease was observed in 8 patients (19.0%). The 1-, 3-, and 5-year progression-free survival rates were 81.0%, 69.2%, and 62.3%, respectively. Only 1 patient died as a result of disease progression during the study. The 1-, 3-, and 5-year overall survival rates were 100%, 97.2%, and 97.2%, respectively.Conclusion: IFN-a 2b is a safe and effective treatment for patients with HEH. The encouraging results with IFN-a 2b use make it a promising option for patients who have other types of epithelioid hemangioendothelioma; additional clinical trials are needed.Keywords: liver, epithelioid hemangioendothelioma, interferon, sarcoma, chemotherapy

Yanwu Jin,1 Shanshan Zhao,1 Jiahui Cai,2 Marcelle Blessing,3 Xin Zhao,1 Haizhu Tan,2 Jinlei Li3 1Department of Anesthesiology, Second Hospital of Shandong University, Shandong University, Jinan, Shandong, People’s Republic of China; 2Department of Preventive Medicine, Shantou University Medical College, Shantou, Guangdong, People’s Republic of China; 3Department of Anesthesiology, Yale University School of Medicine, New Haven, CT, USACorrespondence: Jinlei Li; Haizhu TanDepartment of Anesthesiology, Yale University School of Medicine, 333 Cedar Street, TMP 3, New Haven, CT, 06520-8051, USATel +1 203 785-2802Fax +1 203 785-6664Email jinlei.li@yale.edu; linnanqia@126.comBackground: Spine surgery causes severe pain and can be associated with significant opioid utilization; however, the evidence for opioid-sparing analgesic techniques such as erector spinae plane (ESP) block from controlled studies is limited. We aimed to investigate the analgesic effects of ESP block in lumbar laminoplasty.Methods: In this prospective, double-blind, controlled single-center trial, 62 consecutive elective lumbar laminoplasty patients were randomized into either a control group (Group G, N=32) or a treatment group (Group E, N=30). Group G received general anesthesia and multimodal analgesia, similar to group E, while Group E received additional bilateral ESP block after induction of general anesthesia. The primary outcome was postoperative pain scores for the first 48 h after surgery, and the secondary outcomes analyzed included intraoperative anesthetic usage, perioperative analgesic consumption, return of bowel function and satisfaction for acute pain management indicated by overall benefit of analgesia score (OBAS).Results: Significant differences in pain scores over time were found between the two groups (P=0.010), with Group E patients having significantly lower pain scores than Group G during the first six hours (P=0.000). The opioid consumption in Group G was significantly higher than in Group E both intraoperatively (P=0.000) and postoperatively (P=0.0005). Group E patients had lower intraoperative sevoflurane requirement, improved satisfaction with pain management, and earlier return of bowel function than Group G patients.Conclusion: ESP block is effective in reducing postoperative pain scores and lowering opioid utilization (both intraoperatively and postoperatively), resulting in improved patient satisfaction for pain management in lumbar laminoplasty.Keywords: erector spinae plane block, laminoplasty, spine, perioperative pain, opioid, short-term outcome

Huajing Yang, Hui Jing, Xue Han, Haoyan Tan, Wen Cheng Department of Ultrasound, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang Province, 150081, People’s Republic of ChinaCorrespondence: Wen ChengDepartment of Ultrasound, Harbin Medical University Cancer Hospital, No. 150, Haping Road, Nangang District, Harbin, Heilongjiang Province, 150081, People’s Republic of ChinaTel +86 13313677182Fax +86 451 85718392Email hrbchengwen@163.comPurpose: Sonodynamic therapy (SDT) is considered a promising therapeutic strategy for the effective elimination of cancer cells. However, developing novel sonosensitizers with potentially high SDT efficacy remains a considerable challenge. Herein, we utilized near-infrared dye IR820 nanobubbles (NBs) combined with a dual PI3K/mTOR inhibitor PI-103 for the SDT treatment of hepatocellular carcinoma (HCC) in vitro.Methods: The generated reactive oxygen species (ROS) were quantified using 2,7-dichlorodihydrofluorescein diacetate to determine the feasibility of using IR820 NBs as a potential sonosensitizer. The inhibition effects of the synergistic therapy was examined using the cell counting Kit 8 assay and apoptosis assay. JC-1 staining was performed to study mitochondrial membrane depolarization, and the transwell assay was used for cell migration analysis.Results: The particle size and zeta potential of IR820 NBs were 545.5± 93.1 nm and − 5.19± 1.73 mV, respectively. ROS accumulation was observed after HepG2 cells were treated with IR820 NBs under ultrasound irradiation. The SDT combined with PI-103 group inhibited cell viability and migration more strongly than the other groups (P < 0.01). The apoptosis assay also demonstrated a relatively high anti-HCC efficacy with the synergistic therapy, while JC-1 staining showed a decrease in the mitochondrial membrane potential after the combined treatment.Conclusion: The combination of SDT and PI-103 was very effective in suppressing HCC proliferation, which might help develop new minimally invasive cancer treatment strategies.Keywords: minimally invasive cancer treatment strategy, sonosensitizer, PI3K/mTOR inhibitor, IR820 nanobubbles

Yuying Zhao,1 Sha Xiong,1 Piaoxue Liu,1 Wei Liu,1 Qun Wang,1 Yao Liu,1 Hanxu Tan,2 Xiaojia Chen,3 Xuguang Shi,4 Qi Wang,1 Tongkai Chen1 1Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, People’s Republic of China; 2Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, People’s Republic of China; 3State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau 999078, People’s Republic of China; 4School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, People’s Republic of ChinaCorrespondence: Tongkai Chen; Qi WangScience and Technology Innovation Center, Guangzhou University of Chinese Medicine, 12 Jichang Road, Guangzhou 510405, People’s Republic of ChinaEmail chentongkai@gzucm.edu.cn; wangqi@gzucm.edu.cnPurpose: Ginkgolide B (GB) is a terpene lactone derivative of Ginkgo biloba that is believed to function in a neuroprotective manner ideal for treating Parkinson’s disease (PD). Despite its promising therapeutic properties, GB has poor bioavailability following oral administration and cannot readily achieve sufficient exposure in treated patients, limiting its clinical application for the treatment of PD. In an effort to improve its efficacy, we utilized poly(ethylene glycol)-co-poly(ϵ-caprolactone) (PEG-PCL) nanoparticles as a means of encapsulating GB (GB-NPs). These NPs facilitated the sustained release of GB into the blood, thereby improving its ability to accumulate in the brain and to treat PD.Methods and Results: Using Madin-Darby canine kidney (MDCK) cells, we were able to confirm that these NPs could be taken into cells via multiple nonspecific mechanisms including micropinocytosis, clathrin-dependent endocytosis, and lipid raft/caveolae-mediated endocytosis. Once internalized, these NPs tended to accumulate in the endoplasmic reticulum and lysosomes. In zebrafish, we determined that these NPs were readily able to undergo transport across the chorion, gastrointestinal, blood–brain, and blood-retinal barriers. In a 1-methyl-4-phenylpyridinium ion (MPP+)-induced neuronal damage model system, we confirmed the neuroprotective potential of these NPs. Following oral administration to rats, GB-NPs exhibited more desirable pharmacokinetics than did free GB, achieving higher GB concentrations in both the brain and the blood. Using a murine PD model, we demonstrated that these GB-NPs achieved superior therapeutic efficacy and reduced toxicity relative to free GB.Conclusion: In conclusion, these results indicate that NPs encapsulation of GB can significantly improve its oral bioavailability, cerebral accumulation, and bioactivity via mediating its sustained release in vivo.Keywords: drug delivery system, blood–brain barrier, endocytosis, zebrafish, PD treatment

Even though hematopoietic stem cells (HSC) are characterized by their ability to self-renew and differentiate, they primarily reside in quiescence. Despite the immense importance of this quiescent state, its maintenance and regulation is still incompletely understood. Schlafen2 (Slfn2) is a cytoplasmic protein known to be involved in cell proliferation, differentiation, quiescence, interferon response, and regulation of the immune system. Interestingly, Slfn2 is highly expressed in primitive hematopoietic cells. In order to investigate the role of Slfn2 in the regulation of HSC we have studied HSC function in the elektra mouse model, where the elektra allele of the Slfn2 gene contains a point mutation causing loss of function of the Slfn2 protein. We found that homozygosity for the elektra allele caused a decrease of primitive hematopoietic compartments in murine bone marrow. We further found that transplantation of elektra bone marrow and purified HSC resulted in a significantly reduced regenerative capacity of HSC in competitive transplantation settings. Importantly, we found that a significantly higher fraction of elektra HSC (as compared to wild-type HSC) were actively cycling, suggesting that the mutation in Slfn2 increases HSC proliferation. This additionally caused an increased amount of apoptotic stem and progenitor cells. Taken together, our findings demonstrate that dysregulation of Slfn2 results in a functional deficiency of primitive hematopoietic cells, which is particularly reflected by a drastically impaired ability to reconstitute the hematopoietic system following transplantation and an increase in HSC proliferation. This study thus identifies Slfn2 as a novel and critical regulator of adult HSC and HSC quiescence.

Gui-you Li,1 Hai-long Tan,1 Pei Chen,1 Hui-Yu Hu,1 Mian Liu,1 Deng-jie Ou-yang,1 Rooh-afza Khushbu,1 Deepak Pun,1 Jin-dong Li,1 Zhi-peng Zhang,2 Qiong Yang,1 Peng Huang,1 Shi Chang1 1Department of General Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China; 2Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of ChinaCorrespondence: Peng Huang; Shi ChangDepartment of General Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of ChinaTel +86 15273124136; +86 13973192319Email xiangyahp@csu.edu.cn; changshi@csu.edu.cnBackground: Therapeutic lateral neck dissection (LND) is recommended in papillary thyroid carcinoma (PTC) patients with clinically lateral lymph node metastasis (LLNM), whether underwent level V LND remains controversial for lacking of sensitive predicting system. BRAFV600E mutation is associated with aggressive tumor behavior, recurrence, and disease-specific mortality of PTC. However, the relationship between BRAFV600E mutation and level V LNM is unclear.Methods: Univariate and multivariate analyses were retrospectively conducted on the potential predictive factors of 252 PTC patients who underwent initial treatment of neck lymph node dissection from September 2015 to October 2018 in our institute. BRAFV600E mutation and the clinicopathological characteristics of the two groups were compared.Results: LLNM was presented in 208 (82.5%) patients and level II–V LNM was present in 42.8%, 71.2%, 85.1%, 17.8% patients, respectively. BRAFV600E mutation was observed in 188 (74.6%) patients and was significantly associated with patients’ age, lymphocytic thyroiditis, capsule invasion, bilateral central lymph node metastasis (CLNM) and level V LNM in PTC. Univariate analysis revealed that lymphocytic thyroiditis, tumor size, number of CLNM, Level II LNM, Level III LNM, simultaneous Level II+III, simultaneous Level III+IV and simultaneous Level II+III+IV were significantly correlated with Level V LNM. In addition, multivariate analysis revealed that tumor size ≥ 2.5 cm, number of CLNM≥ 3, level II metastases and BRAFV600E mutation were independent Level V LNM predictors (odds ratio 3.910, 3.660, 8.410, 0.439; 95% CI 1.737– 10.135, 1.054– 12.713, 1.233– 57.355, 0.280– 0.827, respectively).Conclusion: In summary, we presented several independent predictive factors for level V LNM in PTC patients. We constructed a risk prediction model consisting of tumor size ≥ 2.5 cm, number of CLNM≥ 3 and level II metastases and BRAFV600E mutation that may guide surgeons to evaluate the nodal status in PTC and perform tailored therapeutic LND.Keywords: papillary thyroid carcinoma, BRAFV600E mutation, level V lymph nodes metastasis, pathological features

Qiong Yang,1 Pei Chen,1 Hui-Yu Hu,1 Hai-long Tan,1 Gui-you Li,1 Mian Liu,1 Deng-jie Ou-yang,1 Rooh-afza Khushbu,1 Deepak Pun,1 Zhi-peng Zhang,2 Peng Huang,1 Shi Chang1 1Department of General Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China; 2Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of ChinaCorrespondence: Peng Huang; Shi ChangDepartment of General Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of ChinaTel +86 15273124136Email xiangyahp@csu.edu.cn; changshi@csu.edu.cnBackground: Cervical lymph node metastasis (LNM) is an independent risk factor for poor prognosis of papillary thyroid carcinoma (PTC), but the scope of PTC lateral neck dissection (LND) is controversial. Solitary lateral lymph node metastasis (SLNM) is a special type of PTC with lateral LNM. Currently, study on the preoperative clinical characteristics of SLNM has been seldomly reported. This study evaluated the preoperative characteristics for predicting the SLNM of PTC.Methods: We included 391 patients diagnosed with PTC between May 2011 and July 2017. Among those patients, 44 had SLNM and 347 had multiple lateral neck node metastasis (MLNM). The clinicopathologic characteristics and other central lymph node metastasis risk factors were retrospectively analyzed.Results: Univariate analysis revealed that age and tumor size (≤ 1 cm) were significantly correlated with SLNM. In ROC curve analysis, the optimal cutoff age of preoperative predictors for the prediction of SLNM was 46.5 years (AUC=0.623, 0.536– 0.710). Besides, the frequency and mean number of CLNM was significantly less in the SLNM than MLNM group. The oval and round tumor shape and well-defined margin of the tumor were more common in the SLNM group (p =0.001; p=0.024, respectively). In addition, multivariate analysis revealed that age ≥ 47, capsular invasion, no extrathyroidal extension, with central lymph node metastases and irregular shape were independent SLNM predictors of PTCs (odds ratio 2.386, 0.173, 0.284, 0.239, 0.188; 95% CI 1.07– 5.140, 0.058– 0.840, 0.066– 0.926, 0.091– 0.437, 0.167– 0.864, respectively).Conclusion: This study supported that SLNM is more likely to happen in PTC patients with age ≥ 47 years, capsular invasion, no extrathyroidal extension, with central lymph node metastases and irregular shape. That denotes, selective single level neck dissection can be considered as an alternative to systemic lateral neck dissection in those patients.Keywords: solitary lateral lymph node metastasis, papillary thyroid carcinoma, central lymph node dissection

Introduction: Little is known whether the duration of opioid use influences the concentrations of pro- and anti-inflammatory cytokines. Objectives: This study examined the plasma concentration of pro-inflammatory cytokine, interleukin 6 (IL-6), and anti-inflammatory cytokine, interleukin 10 (IL-10), in short-, and long-term opioid users with noncancer pain. Materials and Methods: Adult patients with opioid therapy for noncancer pain were recruited from pain clinics at two tertiary hospital settings in Malaysia between February 2016 and March 2017. They were stratified into short- or long-term users based on opioid prescriptions ≥ 90 days per year. A 10 mL blood sample was taken for the analysis of plasma concentrations of IL-6 and IL-10 and were quantified using a highly sensitive multiplex assay. Results: Of 38 patients recruited, 24% (n = 9/38) and 76% (n = 29/38) were respectively short- and long-term opioid users. Short-term use of opioid was associated with higher levels of IL-6 (mean ± SD, 173.9 ± 13.7 pg/mL) and IL-10 (50 ± 5.8 pg/mL), whereas long-term use of opioids was associated with lower levels (no significant difference) of both cytokines IL6 (125 ± 16.1 pg/mL) and IL10 (41.3 ± 6.7 pg/mL). There was strong correlation between IL-6 and IL-10 within the same group (r² = 0.72, P < 0.05) and (r² = 0.76, P < 0.05) for short- and long-term users, respectively. Conclusion: The duration of opioid use may modulate the level of pro-inflammatory cytokines in which it was higher in short-term use and lower in long-term use, but the effect of pain relief was similar as both cytokines were well correlated.

Yuhang Tian,* Zhao Liu,* Haoyan Tan, Jiahui Hou, Xin Wen, Fan Yang, Wen Cheng Department of Ultrasound, Harbin Medical University Cancer Hospital, Harbin 150080, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wen ChengDepartment of Ultrasound, Harbin Medical University Cancer Hospital, 150 Haping Road, Nangang District, Harbin 150080, People’s Republic of ChinaTel +86 13313677182Email chengwen69@yahoo.comAbstract: Ultrasound-mediated targeted delivery (UMTD), a novel delivery modality of therapeutic materials based on ultrasound, shows great potential in biomedical applications. By coupling ultrasound contrast agents with therapeutic materials, UMTD combines the advantages of ultrasound imaging and carrier, which benefit deep tissue penetration and high concentration aggregation. In this paper we introduced recent advances in ultrasound contrast agents and applications in tumor therapy. Ultrasound contrast agents were categorized by their functions, mainly including thermosensitive, pH-sensitive and photosensitive ultrasound contrast agents. The various applications of UMTD in tumor treatment were summarized as follows: drug therapy, transfection of anti-oncogene, RNA interference, vaccine immunotherapy, monoclonal antibody immunotherapy, adoptive cellular immunotherapy, cytokine immunotherapy, and so on. In the end, we elaborated on the current challenges and provided perspectives of UMTD for clinical applications.Keywords: ultrasound, targeted delivery, immunotherapy, gene therapy

Lipoprotein(a) (Lp[a]) blood levels >50 mg/dL is a major cardiovascular disease risk factor in humans. Lp(a) associates with increased cardiovascular calcification, a critical pathology with no clinically available drug therapies. The mechanisms through which Lp(a) increases cardiovascular calcification risk remain undefined. We hypothesized that Lp(a) promotes the release of calcifying extracellular vesicles (EVs) that contribute to formation of microcalcification in cardiovascular tissues. Here, we show Lp(a) increased calcification in both primary human smooth muscle cells (SMCs) and valvular interstitial cells (VICs), potentially through inflammation-related mechanisms that were suppressed with E06 antibody that neutralizes pro-inflammatory oxidized phospholipids. Incubating human SMCs and VICs with Lp(a) altered the composition of EVs, increasing CD29+/tetraspanin− microvesicle release, demonstrated with a tailored single-EV microarray assay that can distinguish multivesicular body-derived exosomes and plasma membrane budded microvesicles at a single-vesicle level. Lp(a) stimulation led to release of SMC and VIC EVs that readily calcified in acellular 3D-collagen hydrogels mimicking formation of ectopic microcalcification occurring in extracellular matrix of human atherosclerotic arteries and stenotic aortic valves. Our study mechanistically demonstrates that Lp(a) partially mediates cardiovascular calcification formation via inducing the release of calcifying EVs. Additionally, we provide a customized method to assess calcifying EVs at a single-vesicle level that can be more broadly applied to assist in quantitatively differentiating exosome and microvesicle EV subpopulations.

Hongying Ma,1,2 Jian Qu,3 Jian Luo,1,2 Tingting Qi,3 Huanmiao Tan,4 Zhaohui Jiang,1 Haiwen Zhang,1 Qiang Qu1,2 1Department of Pharmacy, Xiangya Hospital, Central South University, Changsha 410008, Hunan, People’s Republic of China; 2Institute for Rational and Safe Medication Practices, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, Hunan, People’s Republic of China; 3Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha 410078, Hunan, People’s Republic of China; 4College of Bioscience and Biotechnology, Hunan Agricultural University, Changsha 410128, Hunan, People’s Republic of ChinaCorrespondence: Qiang QuDepartment of Pharmacy, Xiangya Hospital, Central South University, Changsha 410008, Hunan, People’s Republic of ChinaTel/Fax +86 731 84327460Email quqiang@csu.edu.cnPurpose: Super-enhancer (SE)-associated oncogenes extensively potentiate the uncontrolled proliferation capacity of cancer cells. In this study, we aimed to identify the SE-associated hub genes associated with the clinical characteristics of chronic myeloid leukemia (CML).Methods: Eigengenes from CML clinical modules were determined using weighted gene co-expression network analysis (WGCNA). Overlapping genes between eigengenes and SE-associated genes were used to construct protein–protein interaction (PPI) networks and annotate for pathway enrichment analysis. Expression patterns of the top-ranked SE-associated hub genes were further determined in CML patients and healthy controls via real-time PCR. After treatment of K562 cells with the BRD4 inhibitor, JQ1, for 24 hrs, mRNA and protein levels of SE-associated hub genes were evaluated using real-time PCR and Western blotting, respectively. H3K27ac, H3K4me1 and BRD4 ChIP-seq signal peaks were used to predict and identify SEs visualized by the Integrative Genomics Viewer.Results: The yellow module was significantly related to the status and pathological phase of CML. SE-associated hub candidate genes were mainly enriched in the cell cycle pathway. Based on the PPI networks of hub genes and the top rank of degree, five SE-associated genes were identified: specifically, BUB1, CENPO, KIF2C, ORC1, and RRM2. Elevated expression of these five genes was not only related to CML status and phase but also positively regulated by SE and suppressed by the BRD4 inhibitor, JQ1, in K562 cells. Strong signal peaks of H3K27ac, H3K4me1 and BRD4 ChIP-seq of the five genes were additionally observed close to the predicted SE regions.Conclusion: This is the first study to characterize SE-associated genes linked to clinical characteristics of CML via weighted gene co-expression network analysis. Our results support a novel mechanism involving aberrant expression of hub SE-associated genes in CML patients and K562 cells, and these genes will be potential new therapeutic targets for human leukemia.Keywords: chronic myeloid leukemia, WGCNA, super-enhancer, hub gene, eigengene

Yi Zhong,1,* Tao Su,1,* Qiuxiao Shi,1 Yanru Feng,1 Ze Tao,1 Qiuxia Huang,1 Lan Li,1 Liqiang Hu,1 Shengfu Li,1 Hong Tan,2 Shan Liu,3 Hao Yang1 1Key Lab of Transplant Engineering and Immunology, MOH, West China-Washington Mitochondria and Metabolism Research Center, West China Hospital, Sichuan University, Chengdu 610041, People’s Republic of China; 2Department of General Surgery, Chengdu Integrated TCM & Western Medicine Hospital (Chengdu First People’s Hospital), Chengdu 610041, People’s Republic of China; 3Department of Laboratory Medicine, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu 610072, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shan LiuDepartment of Laboratory Medicine, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, No. 32, West Second Section First Ring Road, Chengdu, Sichuan 610072, People’s Republic of ChinaTel +86 28 6138 2518Email shanliusyy@163.comHao YangKey Lab of Transplant Engineering and Immunology, MOH, West China Hospital, No. 1, Keyuan 4th Road, Hi-tech Zone, Chengdu 610041, People’s Republic of ChinaTel +86 28 85164031Email yanghao@scu.edu.cnBackground: Nanoparticles exhibit great promise for improving the solubility and tissue-specific distribution of chemotherapeutic agents; however, the passive and highly variable enhanced permeability and retention (EPR) effects observed in tumors frequently leads to insufficient delivery of nanodrugs into tumors. The tumor-penetrating peptide iRGD can actively enhance tumor-selective delivery of nanoparticles into tumors by binding to integrin and interacting with tissue-penetrating receptor neuropilin-1.Materials and methods: To improve colorectal cancer treatment, in this study, we prepared a paclitaxel (PTX)-loaded PLGA nanoparticle (PLGA-PTX) and evaluated its tumor-targeting and antitumor activity by co-administration with iRGD.Results: Compared to free PTX, encapsulated PTX retained preferential cytotoxicity toward various colorectal cancer cells while effectively sparing healthy cells. PLGA-PTX treatment resulted in cell cycle arrest at the G2/M phase and apoptosis, leading to inhibition of cancer cell migration and invasion. PLGA-PTX combined with iRGD displayed little enhancement of cytotoxicity in vitro. Despite this, iRGD receptors integrin and neuropilin-1 were found to be primarily overexpressed on abundant tumor vessels in mice bearing colorectal tumors. Consequently, co-administration of nanoparticles with iRGD promoted the selective delivery of nanoparticles into tumor tissues in vivo. Additionally, the combined regimen enhanced the antitumor effects compared to those of each individual reagent.Conclusion: Our findings suggest that PLGA nanoparticles combined with the iRGD peptide provide a promising drug delivery strategy for facilitating active drug accumulation into tumors, given that iRGD receptors are overexpressed on tumor vessels. This co-administration system lacking covalent conjugation provides a more convenient means to combine various therapeutic agents with iRGD to achieve personalized nanotherapy.Keywords: tumor penetrating peptide, nanoparticle, iRGD, paclitaxel, tumor vasculature, colorectal cancer

Yuan Wei Liau,1 Celine Cheow,1 Kenneth Tin Yau Leung,2 Hejing Tan,3 Suat Fern Low,4 Hua Heng McVin Cheen,5 Woan Chyi Lim,6 Li Ling Tan,6 Joyce Zhen Yin Tan,7 Eng Sing Lee,8 Sandra Jialun Xu,9 Corrinne Yong Koon Tan,10 Jie Wen Phang,11 Jie Kie Phang,12 Miao Hui Lam,2 Dan V Blalock,13,14 Corrine I Voils,15,16 Kai Zhen Yap,1 Yu Heng Kwan2,171Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore, Singapore; 2Department of Pharmacy, Khoo Teck Puat Hospital, Singapore, Singapore; 3Department of Pharmacy, Woodlands Health Campus, Singapore, Singapore; 4Department of Pharmacy, Yishun Community Hospital, Singapore, Singapore; 5Department of Pharmacy, Singapore General Hospital, Singapore, Singapore; 6Department of Pharmacy, Tan Tock Seng Hospital, Singapore, Singapore; 7Department of Pharmacy, Admiralty Medical Centre, Singapore, Singapore; 8Clinical Research Unit, Family Medicine Development Division, National Healthcare Group Polyclinics, Singapore, Singapore; 9Department of Pharmacy, National Healthcare Group Polyclinics (Hougang), Singapore, Singapore; 10Pharmacy Transformation Office, National Healthcare Group Pharmacy, Singapore, Singapore; 11Department of Pharmacy, Ng Teng Fong General Hospital, Singapore, Singapore; 12Department of Rheumatology and Immunology, Singapore General Hospital, Singapore, Singapore; 13Center of Innovation to Accelerate Discovery and Practice Transformation (ADAPT), Durham Veterans Affairs Health Care System, Durham, NC, USA; 14Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, NC, USA; 15Department of Surgery, University of Wisconsin School of Medicine and Public Health, Wisconsin, WI, USA; 16William S Middleton Memorial Veterans Hospital, Wisconsin, WI, USA; 17Program in Health Services and Systems Research, Duke-NUS Medical School, Singapore, SingaporeBackground: This self-report measure is a new instrument to measure the extent of and reasons for medication adherence separately. However, few studies have assessed its psychometric properties in diabetic patients and also in Asian populations.Objectives: To validate this self-report measure in diabetic patients in Singapore.Methods: We collected data prospectively using a questionnaire among 393 diabetic patients from hospitals in Singapore from July 2018 to January 2019. Using the COnsensus-based Standards for the selection of health Measurement INstruments framework, we assessed face validity, internal consistency, test–retest reliability, structural validity, and measurement error. We tested four a priori hypotheses on correlation of extent score with patient-reported outcome measures to assess construct validity. We examined cross-cultural validity via measurement invariance across gender, age groups, and languages.Results: We performed cognitive interviews with 30 consenting English-literate, Chinese-literate, and Malay-literate (10 patients per language) diabetic patients (age range 48–76 years, 53% male, disease duration range 1–30 years) and face validity was supported. Among 393 patients (mean age: 59.4±12.2 years, 50.9% female, 52.4% Chinese), we showed moderate internal consistency (Cronbach’s alpha =0.67) and test–retest reliability (intra-class coefficient=0.56 [95% CI 0.37–0.70]). We calculated smallest detectable change as 0.80. We established construct validity by meeting all four hypotheses. We showed structural validity as confirmatory factor analysis confirmed a one-factor model, with excellent fit statistics (Comparative Fit Index=1.0; Tucker-Lewis Index=1.0; Root Mean Square Error of Approximation

Liang Xing,1,2,* Feng Sun,1,2,* Zhendong Wang,1,2 Yan Li,1,2 Zhifang Yang,1,2 Fengshan Wang,1,3 Guangxi Zhai,3 Haining Tan1,2 1National Glycoengineering Research Center, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, Shandong, People’s Republic of China; 2Shandong Provincial Key Laboratory of Carbohydrate Chemistry and Glycobiology, Shandong University, Jinan 250012, Shandong, People’s Republic of China; 3School of Pharmaceutical Sciences, Shandong University, Jinan 250012, Shandong, People’s Republic of China *These authors contributed equally to this work Background: In the past few years, significant progress has been made in inhibiting neovascularization at the tumor site, cutting off the nutrient supply of the tumor, and inhibiting tumor growth and metastasis. However, many proteins/peptides have the disadvantage of poor stability, short half-life, and uncertain targeting ability. Chemical modification can be used to overcome these disadvantages; many polyethylene glycol-modified proteins/peptides have been approved by US FDA. The purpose of this study was to obtain a novel anti-angiogenic chondroitin sulfate (CS)-peptide nanoparticle conjugate with efficient anti-neovascularization and tumor targeting ability and an acceptable half-life. Materials and methods: The CS-ES2-AF nanoparticle conjugate was synthesized and characterized using 1H-nuclear magnetic resonance spectroscopy, transmission electron microscopy, and particle size and zeta potential analyzer. The anti-angiogenic ability was studied using MTT, migration, tube formation, and chick chorioallantoic membrane assays. The targeting ability of CS-ES2-AF was studied by ELISA, surface plasmon resonance, and bioimaging. The pharmacokinetics was also studied.Results: The CS-ES2-AF could self-assemble into stable nanoparticles in aqueous solution, which significantly enhances its anti-neovascularization activity, tumor targeting more explicit, and prolongs its half-life.Conclusion: CS is an effective protein/peptide modifier, and CS-ES2-AF displayed good potential in tumor targeting therapy. Keywords: chondroitin sulfate, ES2-AF, nanoparticles, anti-angiogenesis, targeting

Objective Barrett’s oesophagus (BE) screening outside the endoscopy suite can identify patients for surveillance and reduce mortality. Tethered capsule optical coherence tomography (OCT) can volumetrically image oesophageal mucosa in unsedated patients and detect features of BE. We investigated ultrahigh-speed tethered capsule swept-source OCT (SS-OCT), improved device design, developed procedural techniques and measured capsule contact, longitudinal pullback non-uniformity and patient toleration.Design OCT was performed in 16 patients prior to endoscopic surveillance/treatment. Unsedated patients swallowed the capsule with sips of water and the tether was pulled back to image the oesophagus. SS-OCT at 1 000 000 A-scans/s enabled imaging 10 cm oesophageal lengths in 10 s with 30 µm transverse and 8 µm axial resolution. Capsule contact, longitudinal image coverage and patient toleration were assessed.Results Nine patients had non-dysplastic BE, three had ablative treatment-naïve neoplasia and four had prior ablation for dysplasia. Dry swallows facilitated capsule transit through the lower oesophageal sphincter (LES), and waiting 10 s before pullback reduced swallow induced LES relaxation. Slow nasal inhalation facilitated capsule retrieval and minimised gag reflex. The procedure was well tolerated. Ultrahigh-speed SS-OCT generated cross-sectional and subsurface en face images showing BE features, while subsurface en face images were required to assess the gastro-oesophageal junction. Candidate features of dysplasia were also identified which could inform follow-up endoscopy/biopsy. BE features were seen in all patients with histologically confirmed BE. Mean capsule contact over BE was 75%±27% for all patients and better in short segment BE. Mean longitudinal image coverage over BE was 59%±34% and better for long segment BE.Conclusions Ultrahigh-speed tethered capsule SS-OCT can image en face and cross-sectional mucosal features over wide areas. Device and procedure optimisation improved performance. BE features could be identified in all patients, but limited capsule contact and longitudinal coverage could cause sampling errors for focal pathologies.

Xiaoshun Shi,1,2,* Haoming Tan,3 Xiaobing Le,4,5,* Haibing Xian,6,* Xiaoxiang Li,1 Kailing Huang,4,5 Viola Yingjun Luo,4,5 Yanhui Liu,4,5 Zhuolin Wu,7 Haiyun Mo,8 Allen M Chen,4,5,* Ying Liang,9 Jiexia Zhang1 1National Clinical Research Center for Respiratory Disease, State Key Laboratory of Respiratory Disease, Department of Medicine, Guangzhou Institute of Respiratory Disease, Guangzhou Institute of Respiratory Health, Guangzhou 510120, China; 2Department of Thoracic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; 3Department of Thoracic Surgery, Shunde Lecong Affiliated Hospital of Guangzhou Medical University, Guangdong 528315, China; 4Mendel Genes Inc, Guangzhou 510515, China; 5Mendel Genes Inc, Manhattan Beach, CA 90266, USA; 6Department of Head and Neck/Thoracic Medical Oncology, The First People’s Hospital of Foshan, Guangdong 528000, China; 7Department of Biomedical Engineering, University of Minnesota, Twin Cities, MN, USA; 8Department of Public Health, Guangzhou Medical University, Guangzhou 510000, China; 9Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China *These authors contributed equally to this work Background: The current TNM staging system plays a central role in lung adenocarcinoma (LUAD) prognosis. However, it may not adequately stratify the risk of tumor recurrence. With the aid of gene expression profiling, we identified 31 lncRNAs whose expressions in tumor tissues could be used as a risk indicator for the guidance of lung cancer therapy. This exploratory analysis may shed new light on identification of potential prognostic factors. Materials and methods: A survival prediction scoring model was developed from the data that are publicly available in The Cancer Genome Atlas (TCGA) LUAD RNA Sequencing dataset. Multivariate Cox regression analysis and Kaplan–Meier analysis were performed on a cohort of 254 stage I lung carcinoma patients with survival records. Results: Our model indicates that the panels comprising 31 lncRNAs are highly associated with overall survival (OS): 18.9% (95% CI: 10.4%–34.5%) and 89.5% (95% CI: 80.7%–99.2%) for the high- and low-risk group, respectively. The specificity and sensitivity of the model are verified, which show that the area under receiver operating characteristic curve yields 0.881, meaning our model has good accuracy and it is feasible for further applications. Conclusion: The 31-lncRNA model might be able to predict OS in patients with LUAD with high accuracy. Its further applications in biomolecular experiments using clinical samples with independent cohorts of patients are needed to verify the results. Keywords: lung adenocarcinoma, lncRNA, signature, survival analysis, prognosis, RNA-seq

Wentao Deng,1,* Juhui Qiu,1,* Shaoting Wang,1 Zhi Yuan,1 Yuefeng Jia,2 Hailin Tan,2 Jiru Lu,1 Ruqiang Zheng1 1Department of Urinary Surgery, Dongying People’s Hospital, Dongying, 2Department of Urinary Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China *These authors contributed equally to this work Abstract: In this study, we performed the characterization and synthesis of biocompatible and targeted albumin and graphene oxide (GO) dual-carrier paclitaxel (PTX) nanoparticles for photothermal-triggered tumor therapy. PTX absorbed on GO nanosheets as cores were coated with human serum albumin (HSA), following surface conjugation with monoclonal antibodies (mAb) against vascular endothelial growth factor (VEGF; denoted as mAbVEGF) via polyethylene glycol linker to form targeted nanoparticles (PTX-GHP-VEGF). The spherical nanoparticles were 191±5 nm in size with good stability and biocompatibility. GO functioned as the first carrier and a near infrared absorber that can generate photothermal effects under 5-minute 808-nm laser irradiation to thermal trigger the release of PTX from the second carrier HSA nanoparticles. The mechanism of thermal-triggered drug release was also investigated preliminarily, in which the heat generated by GO induced swelling of PTX-GHP-VEGF nanoparticles which released the drugs. In vitro studies found that PTX-GHP-VEGF can efficiently target human SW-13 adrenocortical carcinoma cells as evaluated by confocal fluorescence microscopy as well as transmission electron microscopy, and showed an obvious thermal-triggered antitumor effect, mediated by apoptosis. Moreover, PTX-GHP-VEGF combined with near infrared irradiation showed specific tumor suppression effects with high survival rate after 100 days of treatment. PTX-GHP-VEGF also demonstrated high biosafety with no adverse effects on normal tissues and organs. These results highlight the remarkable potential of PTX-GHP-VEGF in photothermal controllable tumor treatment. Keywords: paclitaxel, graphene oxide, human serum albumin, tumor targeting, photothermal-triggered tumor therapy

Judith J Stephenson,1 Mayura U Shinde,1 Winghan Jacqueline Kwong,2 An-Chen Fu,1 Hiangkiat Tan,1 William S Weintraub3 1HealthCore, Inc., Wilmington, DE, 2Daiichi Sankyo, Inc., Basking Ridge, NJ, 3Christiana Care Health System, Newark, DE, USA Objective: To compare oral anticoagulant (OAC) adherence among patients with nonvalvular atrial fibrillation (NVAF) using patient-reported and claims-based measures, and to evaluate the effect of OAC adherence on health care costs and patient satisfaction with OAC therapy.Methods: This was a hybrid US observational study consisting of a longitudinal cohort survey followed by linkage and analysis of respondents’ administrative claims data. Patients with NVAF receiving warfarin, dabigatran, rivaroxaban, or apixaban completed an initial survey and follow-up surveys at 4, 8, and 12 months. Patient-reported adherence was measured at each survey by Morisky Medication Adherence Scale (MMAS-8) and pharmacy claims-determined adherence by the proportion of days covered (PDC) for the 12-month period following the initial survey date; adherence was defined as MMAS-8 score =8 and PDC ≥80%. Patient satisfaction with OAC therapy was assessed by the Duke Anticoagulation Satisfaction Scale (DASS).Results: Overall, 675 patients completed at least the initial survey (warfarin, n=271; dabigatran, n=266; rivaroxaban, n=128; apixaban, n=10). Fewer than half (47.9%) were PDC adherent, 37.2% were MMAS-8 adherent, and 19.4% were adherent by both measures. Total medical costs of PDC-adherent patients were significantly lower vs PDC-nonadherent patients (US$640 vs $993 per-patient per-month, respectively, p