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Yun Zhu,1,&ast; Lingyan Li,2,&ast; Wenxiao Wang,3,&ast; Xiaodan Liu,1 Meng Xue Zhang,1 Xiumin Chen,4 Xiaofeng Hou,5 Weimei Wang,6 Tuo Min,7 Jinmei Liu,8 Lecui Liu,9 Chengjun Liu,10 Zhong Jiang,11 Yanping Wang,12 Dayun Chang,13 Hua Pan1 1Department of Pediatric Intensive Care Unit, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, People’s Republic of China; 2Department of Pediatrics, Zibo Maternal and Child Health Hospital, Zibo, Shandong, People’s Republic of China; 3Department of Pediatrics, Yantai Yuhuangding Hospital, Yantai, Shandong, People’s Republic of China; 4Department of Pediatrics, Qingzhou People’s Hospital, Weifang, Shandong, People’s Republic of China; 5Department of Pediatrics, Laizhou City People’s Hospital, Laizhou, Shandong, People’s Republic of China; 6Department of Pediatrics, Haiyang People’s Hospital, Haiyang, Shandong, People’s Republic of China; 7Department of Pediatrics, Jining First People’s Hospital, Jining, Shandong, People’s Republic of China; 8Department of Pediatrics, West Coast New District Hospital of Chinese Medicine, Huangdao, Shandong, People’s Republic of China; 9Department of Neonatology, People’s Hospital of Wulian, Wulian, Shandong, People’s Republic of China; 10Department of Pediatrics, Linyi Central Hospital, Linyi, Shandong, People’s Republic of China; 11Department of Pediatrics, Rehabilitation University Qingdao Central Hospital, Qingdao, Shandong, People’s Republic of China; 12Department of Pediatrics, Qingdao Traditional Chinese Medicine Hospital, Qingdao, Shandong, People’s Republic of China; 13Department of Pediatrics, Weihai Municipal Hospital, Weihai, Shangdong, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hua Pan, Department of Pediatric Intensive Care Unit, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, Shandong, 266003, People’s Republic of China, Tel +8618366205226, Email panhua1881@163.comIntroduction: The Omicron variant is the present predominant COVID-19 strain worldwide. Accurate mortality prediction can facilitate risk stratification and targeted therapies. The study aimed to evaluate the feasibility of the difference in hematocrit and albumin (HCT-ALB) levels, alone or combined with the pediatric Sequential Organ Failure Assessment (pSOFA) score and lactate level, to predict the in-hospital mortality of COVID-19 Omicron variant-infected pediatric patients.Methods: A multicenter retrospective cohort study was performed for children with COVID-19 Omicron variant infection between December 2021 and January 2022. The demographics, clinical characteristics, hospital admission laboratory test results, and treatments were recorded. The in-hospital mortality was documented. The associations between HCT-ALB levels and mortality, and between HCT-ALB+pSOFA+lactate and mortality were analyzed.Results: A total of 119 children were included. The median age was 1.6 (interquartile range: 0.5– 6.2) years old. There were 70 boys and 49 girls. The mortality rate was 14.3% (17/119). The univariate and multivariate Cox regression analysis revealed that HCT-ALB was associated to in-hospital mortality (hazard ratio: 1.500, 95% confidence interval: 1.235– 1.822, p< 0.001). The receiver operating characteristic curve analysis revealed that HCT-ALB can be used to accurately predict in-hospital mortality at a cut-off value of − 0.7 (area under the curve: 0.888, sensitivity: 0.882, specificity: 0.225, Youden index: 0.657, p< 0.001). These patients were assigned into three groups based on the HCT-ALB level, pSOFA score, and lactate level (low-, medium-, and high-risk groups). The Kaplan-Meier analysis revealed that the mortality increased in the high-risk group, when compared to the medium-risk group (p< 0.01). The latter group had a higher mortality, when compared to the low-risk group (p< 0.01).Conclusion: The HCT-ALB level can be applied to predict the in-hospital mortality of children infected with the COVID-19 Omicron variant. Its combination with other variables can improve prediction performance.Keywords: COVID-19, omicron variant, hematocrit, albumin, mortality

Lei Gao,1,2,&ast; Yidi Xu,1,2,&ast; Xixue Zhang,1,2 Zhaoshun Jiang,1,2 Jiajun Wu,1,2 Yanjun Dong,1,2 Ming Li,3 Liang Jin,3 Jianjian Qiu,4 Lijue You,5 Chunhui Qin,6 Weidong Gu1,2 1Department of Anaesthesiology, Huadong Hospital Affiliated to Fudan University, Shanghai, People’s Republic of China; 2Shanghai Key Laboratory of Clinical Geriatric Medicine, Huadong Hospital Affiliated to Fudan University, Shanghai, People’s Republic of China; 3Department of Radiology, Huadong Hospital affiliated to Fudan University, Shanghai, People’s Republic of China; 4Department of Radiation Oncology, Huadong Hospital affiliated to Fudan University, Shanghai, People’s Republic of China; 5Department of Computer Center, Huadong Hospital affiliated to Fudan University, Shanghai, People’s Republic of China; 6Department of Pain Management, Yueyang Integrated Traditional Chinese Medicine and Western Medicine Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Weidong Gu, Email hdmz0800@163.comBackground: Performing spinal anaesthesia in elderly patients with ligament calcification or hyperostosis is challenging for novice practitioners. This pilot study aimed to compare the effectiveness of mixed reality-assisted spinal puncture (MRasp) with that of landmark-guided spinal puncture (LGsp) by novice practitioners in elderly patients.Methods: In this pilot study, 36 patients (aged ≥ 65 years) scheduled for elective surgery under spinal anaesthesia by anaesthesiology residents were included. Patients were randomly assigned to the MRasp group (n = 18) or the LGsp group (n = 18). The outcomes included the number of needle insertion attempts, redirection attempts, passes, the rate of successful first-attempt needle insertion, the rate of successful first needle pass, the spinal puncture time, the total procedure time, and the incidence of perioperative complications.Results: The median number of needle insertion attempts was significantly fewer in the MRasp group than in the LGsp group (1.0 vs 2.0, P = 0.023). The proportion of patients with successful first-attempt needle insertion was 72.2% in the MRasp group and 44.4% in the LGsp group (P = 0.176). The incidence of perioperative complications did not significantly differ between the two groups.Conclusion: This pilot study found that novice practitioners made significantly fewer needle insertion attempts in the MRasp group compared to the LGsp group when performing spinal anaesthesia on elderly patients. A future randomized controlled trial (RCT) is warranted to validate its effectiveness.Trial Registration: This trial was registered at https://www.chictr.org.cn/showproj.html?proj=178960 (ChiCTR-IPR-2300068520). Public title: Mixed reality-assisted versus landmark-guided spinal puncture in elderly patients: a randomized controlled pilot study. Principal investigator: Lei Gao. The registration date was February 22, 2023. The date of the first participant enrolment was February 27, 2023.Plain Language Summary: We developed virtual spine-presenting technology and patented optimal trajectory design technology to assist in spinal puncture and reported that the median number of needle insertion attempts was significantly fewer in the mixed reality-assisted spinal puncture group than in the landmark-guided spinal puncture group.Keywords: augmented reality, computer simulation, mixed reality, spinal puncture

Ziwei Jiang,&ast; Lianglong Chen,&ast; Lei Huang, Shengxiang Yu, Jiabao Lin, Mengyao Li, Yanbin Gao, Lei Yang Department of Burns, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Lei Yang, Department of Burns, Nanfang Hospital, Southern Medical University, Jingxi Street, Baiyun District, Guangzhou, 510515, People’s Republic of China, Tel +86-20-6164-1841, Email yuanyang@smu.edu.cnAbstract: Endogenous stem cell homing refers to the transport of endogenous mesenchymal stem cells (MSCs) to damaged tissue. The paradigm of using well-designed biomaterials to induce resident stem cells to home in to the injured site while coordinating their behavior and function to promote tissue regeneration is known as endogenous regenerative medicine (ERM). ERM is a promising new avenue in regenerative therapy research, and it involves the mobilizing of endogenous stem cells for homing as the principal means through which to achieve it. Comprehending how mesenchymal stem cells home in and grasp the influencing factors of mesenchymal stem cell homing is essential for the understanding and design of tissue engineering. This review summarizes the process of MSC homing, the factors influencing the homing process, analyses endogenous stem cell homing studies of interest in the field of skin tissue repair, explores the integration of endogenous homing promotion strategies with cellular therapies and details tissue engineering strategies that can be used to modulate endogenous homing of stem cells. In addition to providing more systematic theories and ideas for improved materials for endogenous tissue repair, this review provides new perspectives to explore the complex process of tissue remodeling to enhance the rational design of biomaterial scaffolds and guide tissue regeneration strategies.Keywords: endogenous stem cell homing, in situ tissue regeneration, biomimetic design, wound healing, bioactive materials

Xiufeng Chen, Yong hong Jiang, Xiaoqin Fei, Mingjing Wang, Anqi Liu, Xuejun Li, Zhiyan Jiang Department of Pediatrics, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of ChinaCorrespondence: Zhiyan Jiang, Email jiangzhiyan@shutcm.edu.cnBackground: Asthma severely interferes with people’s lives through coughing, wheezing and inflammation of the lungs. Herbacetin is a class of natural compounds that inhibit the development of inflammation. However, whether Herbacetin inhibits asthma has not been definitively studied.Methods: Lipopolysaccharides (LPS)-induced lung epithelial (BASE-2B) cells injury model was established, and then the relief of damaged BASE-2B cells with different concentrations of Herbacetin was examined. The cell counting kit (CCK8) was used to detect the effect of Herbacetin on the proliferation ability in ovalbumin (OVA)-induced asthma mice model, and Western Blot and flow cytometry were used to detect the effect of Herbacetin on the apoptosis in OVA-induced asthma mice model. Additionally, pulmonary pathology was detected by HE and Masson staining, and serum inflammatory factors were detected by alveolar lavage fluid.Results: Herbacetin reduces BESA-2B cells induced by LPS level of inflammation, and reactive oxygen species (ROS) generation, inhibits cell apoptosis, promotes cell proliferation, OVA-induced mice lung histopathology test HE staining, serum inflammatory factors show the same results. Western Blot shows that Herbacetin regulates the expression of Caspase-3, Bax, and Bcl-2. SGK1 overexpression increased the rate of apoptosis, and Herbacetin reversed this phenomenon. By silencing the expression of SGK1, it was found that Herbacetin was an inhibitor of SGK1, which could inhibit the NF-κB/p-P65 pathway in asthmatic airway inflammation.Conclusion: Herbacetin reduces pro-inflammatory cytokine levels by inhibiting the SGK1/NF-κB pathway. Our data suggest that Herbacetin has a significant anti-inflammatory effect on asthma and can be used as a potential therapeutic agent.Keywords: asthma, herbacetin, SGK1, NF-κB, anti-inflammatory

Yixin Li,1– 6,&ast; Qi Sun,2,3,7,&ast; Lingjia Hao,1,8 Han Shan,2,3,7 Zixi Jiang,1– 6 Ying Wang,1– 6 Zeyu Chen,2,3,7 Wu Zhu,1– 6 Shuang Zhao1– 6 1Department of Dermatology, Xiangya Hospital, Central South University, Changsha, 410008, People’s Republic of China; 2Furong Laboratory (Precision Medicine), Changsha, 410008, People’s Republic of China; 3National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Xiangya Hospital, Central South University, Changsha, 410008, People’s Republic of China; 4Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, 410008, People’s Republic of China; 5Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, 410008, People’s Republic of China; 6National Clinical Research Center of Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, People’s Republic of China; 7School of Mechanical and Electrical Engineering, Central South University, Changsha, 410083, People’s Republic of China; 8Xiangya School of Medicine, Central South University, Changsha, 410083, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shuang Zhao; Wu Zhu, Department of Dermatology, Xiangya Hospital of Central South University, 87 Xiangya Road, Kaifu District, Changsha, Hunan Province, People’s Republic of China, Email shuangxy@csu.edu.cn; zhuwuxy@csu.edu.cnIntroduction: Pathological scars, such as hypertrophic scars and keloids, are characterized by the proliferation of fibroblasts and the deposition of collagen that often cause pruritus, pain, and disfigurement. Due to their high incidence and deformity, pathological scars have resulted in severe physical and psychological trauma for patients. Intralesional injection of 5-fluorouracil (5-Fu) is a recommended option for treating pathological scars. However, the efficacy of 5-Fu injection was limited and unstable due to limited drug penetration and short retention time.Methods: Liposomes are promising carriers that have advantages, such as high biocompatibility, controlled release property, and enhanced clinical efficacy. Here, we constructed a transdermal 5-Fu-loaded liposome (5-Fu-Lip) to provide a more effective and safer modality to scar treatment.Results: Compared to 5-Fu, 5-Fu-Lip showed superior ability in inhibiting primary keloid fibroblasts proliferation, migration, and collagen deposition, and also significantly inhibited human umbilical vein endothelial cells (HUVECs) proliferation and microvessel construction. In vivo experiments demonstrated that 5-Fu-Lip can significantly reduce the severity of hypertrophic scars in a rabbit ear wounding model.Discussion: 5-Fu-Lip provides a promising strategy to improve drug efficacy, which has great potential in the treatment of pathological scars.Keywords: liposome, pathological scar, 5-fluorouracil, fibroblast

Zhijie Jiang, Zhujun Fang, Dongsheng Hong, Xiaojuan Wang Department of Clinical Pharmacy, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310000, People’s Republic of ChinaCorrespondence: Xiaojuan Wang, Email xiaojuanwang1992@zju.edu.cnAbstract: Tumor vessels characterized by abnormal functions and structures hinder the infiltration and immune antigen presentation of immune cells by inducing the formation of an immunosuppressive microenvironment (“cold” environment). Vascular-targeted therapy has been proven to enhance immune stimulation and the effectiveness of immunotherapy by modulating the “cold” microenvironment, such as hypoxia and an acidic microenvironment. Notably, a therapeutic strategy based on “vascular-immune” crosstalk can achieve dual regulation of tumor vessels and the immune system by reprogramming the tumor microenvironment (TME), thus forming a positive feedback loop between tumor vessels and the immune microenvironment. From this perspective, we discuss the factors of tumor angiogenesis and “cold” TME formation. Building on this foundation, some vascular-targeted therapeutic drugs will be elaborated upon in detail to achieve dual regulation of tumor vessels and immunity. More importantly, we focus on cutting-edge nanotechnology in view of “vascular-immune” crosstalk and discuss the rational fabrication of tailor-made nanosystems for efficiently enhancing immunotherapy. Keywords: immunotherapy, nano-delivery systems, anti-angiogenic therapy, “vascular-immune” crosstalk, tumor vessels

Guanxiong Liu,&ast; Duo Zhu,&ast; Quansheng He,&ast; Churen Zhou, Li He, Zhengran Li, Zaibo Jiang, Mingsheng Huang, Boyang Chang, Chun Wu Department of Interventional Radiology, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Boyang Chang; Chun Wu, Email changby3@mail.sysu.edu.cn; wuch26@mail.sysu.edu.cnPurpose: This study aimed to assess the effectiveness and safety of combining hepatic arterial infusion chemotherapy (HAIC) with lenvatinib (LEN) and PD-1 inhibitors in treating arterioportal shunt (APS) in hepatocellular carcinoma (HCC) patients with portal vein tumor thrombus (PVTT).Patients and Methods: Conducted retrospectively, the study enrolled 54 HCC patients with APS and PVTT treated with HAIC, LEN, and PD-1 inhibitors at our center between January 2021 and October 2023. APS improvement, APS recanalization, tumor response, PVTT response rate, overall survival (OS), intrahepatic progression-free survival (InPFS), and adverse events were evaluated.Results: APS improvement was observed in 42 patients (77.8%), with all improvement occurring within two treatment sessions. Complete APS occlusion was achieved in 40 patients (74.1%), and no recanalization occurred. The best objective response rate (ORR) and ORR after two HAIC sessions were 74.1% and 66.7%, respectively. The best PVTT response and PVTT response after two HAIC sessions were 98.1% and 94.4%, respectively. The median OS and InPFS were 10.0 months and 5.0 months, respectively. OS and InPFS were longer in patients with APS occlusion compared to those without (OS 12.1 vs 4.4 months, P< 0.001, InPFS 6.2 vs 2.3 months, P=0.049). ALBI grade, extrahepatic spread, APS disappearance were potential prognostic factors for OS, while APS grade and extrahepatic spread being independently associated with InPFS. No treatment-related mortality occurred.Conclusion: Combining HAIC with LEN and PD-1 inhibitors proves to be both effective and safe in managing APS in HCC with PVTT, potentially improving patient survival.Keywords: hepatocellular carcinoma, shunt, portal vein tumor thrombus, hepatic arterial infusion chemotherapy, combination therapy

Min Lei,1,2,&ast; Zheng Jiang,1,2,&ast; Peng Xu,1,2 Zhenglin Chang,1– 3 Yuyan Zhang,4 Shike Zhang,1,2 Lingyue An,1,2,5 Shujue Li,2,3 Tao Zeng,2,3 Hans-Göran Tiselius,6 Yuhao Zhou,1,2 Guohua Zeng,2,3 Wenqi Wu1,2 1Department of Urology, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, 510260, People’s Republic of China; 2Guangdong Key Laboratory of Urology, Guangzhou Medical University, Guangzhou, Guangdong, 510260, People’s Republic of China; 3Department of Urology, The First Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, 510260, People’s Republic of China; 4Guangzhou Institute of Dermatology, Guangzhou, Guangdong, 510095, People’s Republic of China; 5Department of Urology, Guizhou Provincial People’s Hospital, Guiyang, Guizhou, 550002, People’s Republic of China; 6Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institute, Stockholm, 14186, Sweden&ast;These authors contributed equally to this workCorrespondence: Wenqi Wu; Guohua Zeng, Email 2009681012@gzhmu.edu.cn; gzgyzgh@vip.sina.comBackground: The purpose of this study was to identify bacterial differences between urine cultures (UC) and stone cultures (SC) in patients with complex kidney stones and to determine any correlation with post-percutaneous nephrolithotomy Systemic Inflammatory Response Syndrome (SIRS).Methods: Perioperative data of 1055 patients with complex kidney stones treated with first-stage Percutaneous Nephrolithotomy (PCNL) from September 2016 until September 2021 were included. Preoperative mid-stream urine samples and surgically obtained stone material were subjected to bacterial culture and antibiotic sensitivity tests. Preoperatively, antibiotic usage was determined by the UC or local bacterial resistance patterns. After PCNL treatment, antibiotic selection was guided by stone bacterial culture result and clinical symptoms. The effect of different preoperative antibiotic regimens based on urine cultures and postoperative antibiotic treatment based on stone cultures were assessed.Results: Positive stone cultures (SC+) were significantly more common than positive urine cultures (UC+) (31.9% vs 20.9%, p < 0.05). Escherichia coli (E. coli) was the most common uropathogen in both urine (54.3%) and stones (43.9%). The difference was statistically significant (p < 0.05). Moreover, UC+SC-, UC-SC+, UC+SC+, and preoperative serum creatinine were independent risk factors of postoperative SIRS. The incidence of SIRS in the UC+SC+ patients with different bacteria in stones and urine (51.6%) was higher than that in other culture groups. The antibiotic resistance of E. coli inside the stone was increased when prolonged preoperative antibiotics were administered to UC+ patients.Conclusion: The bacterial spectrum and positive outcome of culture in urine and stones were significantly different. The incidence of postoperative SIRS was highest in patients with UC+SC+ but with different bacteria strains. Prolonged pre-surgical antibiotic treatment apparently induced higher drug resistance for bacteria inside the stone.Keywords: kidney stones, bacterial spectrum, antibiotic resistance, stone culture, urine culture

Yuwei Jiang,1,2,&ast; Wenjun Dang,3,&ast; Lirong Sui,1 Tianci Gao,1 Xiangying Kong,1 Jin Guo,1 Shuang Liu,1 Hong Nie,3 Zhimei Jiang1,2 1College of Rehabilitation Medicine, Jiamusi University, Jiamusi City, Hei longJiang Province, People’s Republic of China; 2Pediatric Cerebral Palsy Prevention and Treatment Center of Heilongjiang Province, Jiamusi City, Hei longJiang Province, People’s Republic of China; 3College of Jiamusi, HeiLongJiang University of Chinese Medicine, Jiamusi City, Hei longJiang Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhimei Jiang; Shuang Liu, Email 15704601990@163.com; 307692456@qq.comAbstract: We conducted an umbrella evaluation to quantitatively synthesize previous systematic reviews and meta-analyses, thereby collating evidence on the association between vitamin D and core symptoms in people with autism in anticipation of informing clinical vitamin D supplementation. Based on the pre-established protocol, we ended up with 9 studies. Based on rigorous analysis, we found that vitamin D deficiency early in life is a risk factor for the development of ASD and that vitamin D supplementation improves the core symptoms of ASD. Our study concludes that vitamin D supplementation is beneficial for individuals with autism, that vitamin D deficiency early in embryonic life increases the risk of ASD, and that our study supports the idea that prevention begins with vitamin D supplementation early in life. At the same time, we must recognize that our current conclusions support the benefits of vitamin D supplementation for children with ASD, but we are unable to determine the causal relationship, ie, how vitamin D works in ASD, and we need more basic research to explore the mechanisms involved.Keywords: autism spectrum disorders, vitamin D, core symptoms, 25(OH)D, umbrella review

Yan Xing,1,&ast; Rui Jing,2,&ast; Xiaoying Tang,2 Zhenqi Jiang2 1Department of Gynecology, The First Affiliated Hospital of Ningbo University, Ningbo, People’s Republic of China; 2School of Medical Technology, Beijing Institute of Technology, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhenqi Jiang; Xiaoying Tang, Email jiangzhenqi@bit.edu.cn; xiaoying@bit.edu.cnObjective: Ovarian cancer cells are prone to acquire tolerance to chemotherapeutic agents, which seriously affects clinical outcomes. The development of novel strategies to enhance the targeting of chemotherapeutic agents to overcome drug resistance and minimize side effects is significant for improving the clinical outcomes of ovarian cancer patients.Methods: We employed folic acid (FA)-modified ZIF-90 nanomaterials (FA-ZIF-90) to deliver the chemotherapeutic drug, cisplatin (DDP), via dual targeting to improve its targeting to circumvent cisplatin resistance in ovarian cancer cells, especially by targeting mitochondria. FA-ZIF-90/DDP could rapidly release DDP in response to dual stimulation of acidity and ATP in tumor cells.Results: FA-ZIF-90/DDP showed good blood compatibility. It was efficiently taken up by human ovarian cancer cisplatin-resistant cells A2780/DDP and aggregated in the mitochondrial region. FA-ZIF-90/DDP significantly inhibited the mitochondrial activity and metastatic ability of A2780/DDP cells. In addition, it effectively induced apoptosis in A2780/DDP cells and overcame cisplatin resistance. In vivo experiments showed that FA-ZIF-90/DDP increased the accumulation of DDP in tumor tissues and significantly inhibited tumor growth.Conclusion: FA-modified ZIF-90 nanocarriers can improve the tumor targeting and anti-tumor effects of chemotherapeutic drugs, reduce toxic side effects, and are expected to be a novel therapeutic strategy to reverse drug resistance in ovarian cancer.Keywords: ovarian cancer, drug resistance, targeted therapy, folic acid, ZIF-90, nanomedicine, mitochondria, cell apoptosis

Chenyu Zhang,1,2,&ast; Yalan Li,1,&ast; Wo Wang,1 Zhenghao Jiang,1 Chuan Liu,1 Yiting Kong,2 Daqi Li,1 Liuyi Ran,1 Li Kuang1,2 1Mental Health Center, University-Town Hospital of Chongqing Medical University, Chongqing, 401331, People’s Republic of China; 2Department of Psychiatry, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Liuyi Ran; Li Kuang, Mental Health Center, University-Town Hospital of Chongqing Medical University, Shapingba District, Chongqing, 401331, People’s Republic of China, Tel/Fax +86-023-65714061, Email ranliuyi@163.com; kuangli0308@163.comPurpose: The aim of our study was to explore the relation between serum levels of non-enzymatic antioxidants, thyroid function with the risk of non-suicidal self-injury (NSSI) in depressed adolescents.Patients and Methods: We retrospected the electronic records of 454 hospitalized patients aged 13– 17 years old with a diagnosis of major depressive disorder (239 patients with NSSI and 215 subjects without NSSI), and collected their demographic and clinical information, including serum levels of total bilirubin (Tbil), uric acid (UA), free triiodothyronine (FT3), free thyroxine (FT4) and thyroid stimulating hormone (TSH).Results: The incidence of NSSI was 52.6% among depressed adolescents aged 13– 17, 57.1% in female and 38.5% in male. After using the propensity scoring method to exclude the influence of age between the two groups, it was found that patients with NSSI showed lower levels of Tbil (P=0.046) and UA (P=0.015) compared with those without NSSI. Logistic regression results showed that serum UA was associated with NSSI behavior in female patients (OR=0.995, 95% CI: 0.991– 0.999, P=0.014), and TSH was associated with NSSI in male participants (OR=0.499, 95% CI: 0.267– 0.932, P=0.029).Conclusion: Female and male may have different pathological mechanisms of NSSI. NSSI is more likely to be related to antioxidant reaction in female adolescent patients, while more likely to be related to thyroid function in male depressed adolescent patients.Keywords: antioxidant system, depressed adolescents, incidence, non-suicidal self-injury, thyroid function

Zhimei Jiang,1– 3 Yuzhi Fu,1– 3 Hongxin Shen1– 3 1Department of Pharmacy, West China Second University Hospital of Sichuan University, Chengdu, People’s Republic of China; 2Evidence-Based Pharmacy Center, West China Second University Hospital of Sichuan University, Chengdu, People’s Republic of China; 3Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, People’s Republic of ChinaCorrespondence: Hongxin Shen, West China Second University Hospital, Sichuan University, No. 20, Third Section, Renmin South Road, Chengdu, Sichuan, 610041, People’s Republic of China, Email 1103747222@qq.comAbstract: Research for tumor treatment with significant therapy effects and minimal side-effects has been widely carried over the past few decades. Different drug forms have received a lot of attention. However, systemic biodistribution induces efficacy and safety issues. Intratumoral delivery of agents might overcome these problems because of its abundant tumor accumulation and retention, thereby reducing side effects. Delivering hydrogels, nanoparticles, microneedles, and microspheres drug carriers directly to tumors can realize not only targeted tumor therapy but also low side-effects. Furthermore, intratumoral administration has been integrated with treatment strategies such as chemotherapy, enhancing radiotherapy, immunotherapy, phototherapy, magnetic fluid hyperthermia, and multimodal therapy. Some of these strategies are ongoing clinical trials or applied clinically. However, many barriers hinder it from being an ideal and widely used option, such as decreased drug penetration impeded by collagen fibers of a tumor, drug squeezed out by high density and high pressure, mature intratumoral injection technique. In this review, we systematically discuss intratumoral delivery of different drug carriers and current development of intratumoral therapy strategies. Keywords: intratumoral drug delivery, drug carrier, treatment strategy, antitumor therapy

Wojciech G Lesniak,1 Srikanth Boinapally,1 Gabriela Lofland,1 Zirui Jiang,1 Catherine A Foss,1 Babak Behman Azad,1 Anna Jablonska,1,2 Mauro A Garcia,1 Maria Brzezinski,1 Martin G Pomper1,3 1Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, MD, 21287, USA; 2Institute for Cell Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA; 3Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USACorrespondence: Wojciech G Lesniak, Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, 600 N. Wolfe Street, Baltimore, MD, 21287, USA, Email wlesnia1@jhmi.eduIntroduction: Prostate cancer (PC) is the second most common cancer and the fifth most frequent cause of cancer death among men. Prostate-specific membrane antigen (PSMA) expression is associated with aggressive PC, with expression in over 90% of patients with metastatic disease. Those characteristics have led to its use for PC diagnosis and therapies with radiopharmaceuticals, antibody-drug conjugates, and nanoparticles. Despite these advancements, none of the current therapeutics are curative and show some degree of toxicity. Here we present the synthesis and preclinical evaluation of a multimodal, PSMA-targeted dendrimer-drug conjugate (PT-DDC), synthesized using poly(amidoamine) (PAMAM) dendrimers. PT-DDC was designed to enable imaging of drug delivery, providing valuable insights to understand and enhance therapeutic response.Methods: The PT-DDC was synthesized through consecutive conjugation of generation-4 PAMAM dendrimers with maytansinoid-1 (DM1) a highly potent antimitotic agent, Cy5 infrared dye for optical imaging, 2,2′,2”-(1,4,7-triazacyclononane-1,4,7-triyl)triacetic acid (NOTA) chelator for radiolabeling with copper-64 and positron emission tomography tomography/computed tomography (PET/CT), lysine-urea-glutamate (KEU) PSMA-targeting moiety and the remaining terminal primary amines were capped with butane-1,2-diol. Non-targeted control dendrimer-drug conjugate (Ctrl-DDC) was formulated without conjugation of KEU. PT-DDC and Ctrl-DDC were characterized using high-performance liquid chromatography, matrix assisted laser desorption ionization mass spectrometry and dynamic light scattering. In vitro and in vivo evaluation of PT-DDC and Ctrl-DDC were carried out in isogenic human prostate cancer PSMA+ PC3 PIP and PSMA− PC3 flu cell lines, and in mice bearing the corresponding xenografts.Results: PT-DDC was stable in 1×PBS and human blood plasma and required glutathione for DM1 release. Optical, PET/CT and biodistribution studies confirmed the in vivo PSMA-specificity of PT-DDC. PT-DDC demonstrated dose-dependent accumulation and cytotoxicity in PSMA+ PC3 PIP cells, and also showed growth inhibition of the corresponding tumors. PT-DDC did not accumulate in PSMA− PC3 flu tumors and did not inhibit their growth. Ctrl-DDC did not show PSMA specificity.Conclusion: In this study, we synthesized a multimodal theranostic agent capable of delivering DM1 and a radionuclide to PSMA+ tumors. This approach holds promise for enhancing image-guided treatment of aggressive, metastatic subtypes of prostate cancer. Keywords: prostate cancer, PSMA, PAMAM dendrimer, targeted cancer treatment, theranostics

Jie Liu,1,2,&ast; Yongkai Wang,3,&ast; Zhihui Jiang,4,&ast; Guangqi Duan,1 Xiaowen Mao,5 Danping Zeng2 1Department of Pediatric Surgery, Yijishan Hospital of Wannan Medical College, Wannan Medical College, Wuhu, People’s Republic of China; 2Department of General Surgery and Urology, Maternal and Child Health Hospital/Obstetrics and Gynecology Hospital of Guangxi Zhuang Autonomous Region, Nanning, People’s Republic of China; 3Department of Hepatobiliary Surgery, Yijishan Hospital of Wannan Medical College, Wannan Medical College, Wuhu, People’s Republic of China; 4Department of General Surgery, Qingdao Women and Children’s Hospital, Qingdao, People’s Republic of China; 5Department of Pediatric Surgery, Maternal and Child Health Hospital of Hubei, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Danping Zeng, Department of General surgery and urology, Maternal and Child Health Hospital/Obstetrics and Gynecology Hospital of Guangxi Zhuang Autonomous Region, No. 225, Xinyang Road, Nanning City, Guangxi Zhuang Autonomous Region, 530003, People’s Republic of China, Email zengdp000@icloud.com Xiaowen Mao, Department of Pediatric Surgery, Maternal and Child Health Hospital of Hubei, Tongji Medical College, Huazhong University of Science and Technology, 746 Wuluo Road, Hongshan District, Wuhan City, Hubei Province, 430070, People’s Republic of China, Email xiaowenmao0927@163.comPurpose: The objective of this study was to develop and validate a nomogram for predicting the need for surgical intervention in pediatric intussusception after pneumatic reduction.Patients and Methods: This retrospective study analyzed the clinical data of children with acute intussusception admitted to four hospitals in China from January 2019 to January 2022. Based on the results of pneumatic reduction, the patients were divided into two groups: the successful reduction group (control group) and the failed reduction group (operation group). The total sample was randomly divided into a training set and a validation set in a 7:3 ratio. Logistic regression analysis was performed to establish a predictive model for surgical risk.Results: A total of 1041 samples were included in this study, with 852 in the control group and 189 in the operation group. Among the total sample, 728 cases were used for training and 313 cases were used for validation. Logistic regression analysis of the training set identified age, time of abdominal pain, presence or absence of hematostoecia, C-reactive protein value from blood test on admission, and nested position indicated by B-ultrasound as independent predictors of intussusception intervention. Based on the five independent risk factors identified through multivariate logistic regression, a nomogram was successfully constructed to predict the failure of resetting by air enema under X-ray.Conclusion: A nomogram was developed to predict the need for surgical intervention after intussusception pneumatic reduction in children. The nomogram was based on clinical risk factors including age, time of abdominal pain, presence or absence of blood in stool, value of C-reactive protein in blood test on admission, and nested position indicated by B-ultrasound. Our internal validation demonstrated that this nomogram can serve as a useful tool for identifying risk factors associated with failure of air enema in children with intussusception.Keywords: pediatric, intussusception, pneumatic reduction, nomogram, surgical intervention

Peng Wu,1,&ast; Xiaoyong Wang,2,&ast; Min Yin,1,&ast; Wenjie Zhu,3,&ast; Zheng Chen,1 Yang Zhang,1 Ziyu Jiang,4 Longqing Shi,5 Qiang Zhu1 1Children’s Hospital of Nanjing Medical University, Nanjing, People’s Republic of China; 2The People’s Hospital of Rugao, Nantong, People’s Republic of China; 3Kangda College of Nanjing Medical University, Nanjing, People’s Republic of China; 4Department of Oncology, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, People’s Republic of China; 5Department of Hepatobiliary and Pancreatic Surgery, Third Affiliated Hospital of Soochow University, Jiangsu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Longqing Shi, Department of Hepatobiliary and Pancreatic Surgery, The Third Affiliated Hospital of Soochow University, Jiangsu, People’s Republic of China, Email 20204135017@stu.suda.edu.cn Qiang Zhu, Children’s Hospital of Nanjing Medical University, Nanjing, People’s Republic of China, Email zhu20081023@yeah.netBackground: Liver cancer remains to be one of the leading causes of cancer worldwide. The treatment options face several challenges and nanomaterials have proven to improve the bioavailability of several drug candidates and their applications in nanomedicine. Specifically, chitosan nanoparticles (CNPs) are extremely biodegradable, pose enhanced biocompatibility and are considered safe for use in medicine.Methods: CNPs were synthesized by ionic gelation, loaded with rutin (rCNPs) and characterized by ultraviolet–visible spectroscopy (UV-Vis), Fourier-transform infrared spectroscopy (FTIR), dynamic light scattering (DLS) and transmission electron microscopy (TEM). The rCNPs were tested for their cytotoxic effects on human hepatoma Hep3B cells, and experiments were conducted to determine the mechanism of such effects. Further, the biocompatibility of the rCNPs was tested on L929 fibroblasts, and their hemocompatibility was determined.Results: Initially, UV–vis and FTIR analyses indicated the possible loading of rutin on rCNPs. Further, the rutin load was quantitatively measured using Ultra-Performance Liquid Chromatography (UPLC) and the concentration was 88 μg/mL for 0.22 micron filtered rCNPs. The drug loading capacity (LC%) of the rCNPs was observed to be 13.29 ± 0.68%, and encapsulation efficiency (EE%) was 19.55 ± 1.01%. The drug release was pH-responsive as 88.58% of the drug was released after 24 hrs at the lysosomal pH 5.5, whereas 91.44% of the drug was released at physiological pH 7.4 after 102 hrs. The cytotoxic effects were prominent in 0.22 micron filtered samples of 5 mg/mL rutin precursor. The particle size for the rCNPs at this concentration was 144.1 nm and the polydispersity index (PDI) was 0.244, which is deemed to be ideal for tumor targeting. A zeta potential (ζ-potential) value of 16.4 mV indicated rCNPs with good stability. The IC50 value for the cytotoxic effects of rCNPs on human hepatoma Hep3B cells was 9.7 ± 0.19 μg/mL of rutin load. In addition, the increased production of reactive oxygen species (ROS) and changes in mitochondrial membrane potential (MMP) were observed. Gene expression studies indicated that the mechanism for cytotoxic effects of rCNPs on Hep3B cells was due to the activation of Unc-51-like autophagy-activating kinase (ULK1) mediated autophagy and nuclear factor kappa B (NF-κB) signaling besides inhibiting the epithelial–mesenchymal Transition (EMT). In addition, the rCNPs were less toxic on NCTC clone 929 (L929) fibroblasts in comparison to the Hep3B cells and possessed excellent hemocompatibility (less than 2% of hemolysis).Conclusion: The synthesized rCNPs were pH-responsive and possessed the physicochemical properties suitable for tumor targeting. The particles were effectively cytotoxic on Hep3B cells in comparison to normal cells and possessed excellent hemocompatibility. The very low hemolytic profile of rCNPs indicates that the drug could be administered intravenously for cancer therapy.Keywords: rCNPs, Hep3B, ROS, qPCR, mechanism

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

ZhongHao Jiang, Fan Yang, WanXiang Wang Inner Mongolia Medical University, Department of Hepatobiliary Surgery, Affiliated Hospital of Inner Mongolia Medical University, Inner Mongolia, 010050, People’s Republic of ChinaCorrespondence: WanXiang Wang, Inner Mongolia Medical University, Department of Hepatobiliary Surgery, Affiliated Hospital of Inner Mongolia Medical University, Hohhot North Street, Inner Mongolia, 010050, People’s Republic of China, Email WWX6188@163.comAbstract: Hepatocellular carcinoma (HCC) is the most common primary liver cancer, affecting millions of people worldwide. Due to the lack of systemic radiation therapy in hepatocellular carcinoma, researchers have been investigating the use of yttrium-90 (90Y) radioembolization for local-regional tumor control since the 1960s. With the development of glass and resin 90Y microspheres and the durable local control, good long-term efficacy, and equivalent tumor responsiveness and tolerability of 90Y-selective internal irradiation compared with alternative therapies such as transarterial chemoembolization (TACE) and sorafenib, 90Y radioembolization has gradually been applied in the treatment of hepatocellular carcinoma of all stages. In this article, we summarize the latest progress of 90Y in the treatment of hepatocellular carcinoma in terms of its principle, advantages, indications, contraindications, efficacy and adverse effects.Keywords: yttrium-90, hepatocellular carcinoma, internal radioembolisation

Lin Xu,&ast; Dongxu Zhao,&ast; Pengcheng Tian,&ast; Jiaan Ding,&ast; Zhengyu Jiang, Guanyin Ni, Zhongheng Hou, Caifang Ni Department of Interventional Radiology, The First Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Caifang Ni, Department of Interventional Radiology, The First Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China, Email szncf@suda.edu.cn Zhongheng Hou, Department of Interventional Radiology, Huzhou Central Hospital, Huzhou, People’s Republic of China, Email 1453713285@qq.comPurpose: We aimed to develop a prognostic nomogram utilizing preoperative serum prealbumin levels to predict the overall survival (OS) in patients undergoing transarterial chemoembolization (TACE) for unresectable hepatocellular carcinoma (HCC).Patients and Methods: A total of 768 individuals with unresectable HCC who underwent TACE at three medical facilities in Suzhou between January 2007 December 2018 were included. The patient cohort was assigned to a training set (n = 461) and a validation set (n = 307). Cox regression analysis identified independent prognostic factors, which were then used to construct a prognostic nomogram. Internal validation was performed in the testing group, and its effectiveness and capability were evaluated with reference to the concordance index (C-index), area under the curve (AUC), calibration curve, and decision curve analysis (DCA).Results: Independent risk factors identified through Cox regression analyses included the BCLC stage, cirrhosis, invasion, tumor number, preoperative serum PALB, performance status (PS), and tumor size. The nomogram demonstrated a C-index of 0.734 (95% confidence interval (CI): 0.710– 0.758) in the training set and 0.717 (95% CI: 0.678– 0.756) in the validation set, indicating strong discriminatory ability. The nomogram also demonstrated favorable discriminatory performance with AUC values of 0.873, 0.820, and 0.833 for 1-, 2-, and 3-year OS, respectively, in the training set, and 0.854, 0.765, and 0.724 in the validation set. The AUC value of the nomogram (0.843) was significantly higher than that of the four conventional staging systems. Moreover, calibration graphs confirmed a strong concordance between the predicted and observed results. Furthermore, DCA underscored the significant clinical utility of the nomogram. Additionally, the low-risk group exhibited considerably superior rates of survival compared to the high-risk group.Conclusion: The developed nomogram demonstrated excellent prognostic capability, which served as a valuable tool for personalized clinical decision-making for patients with HCC.Keywords: hepatocellular carcinoma, nomogram, prealbumin, overall survival, prognosis

Ying Zhou,1 Zhixian Luo,1 Mengying Yu,1 Chenyi Zhan,1 Haoli Xu,1 Ru Lin,1 Shuying Bian,1 Yunjun Yang,2,3 Zhenghao Jiang,4 Xinyi Tao,4 Zusen Ye,5 Meihao Wang,1 Dongqin Zhu2 1Department of Radiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of China; 2Department of Nuclear, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of China; 3Key Laboratory of Novel Nuclide Technologies on Precision Diagnosis and Treatment & Clinical Transformation of Wenzhou, Wenzhou, People’s Republic of China; 4The First School of Medicine, Wenzhou Medical University, Wenzhou, People’s Republic of China; 5Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of ChinaCorrespondence: Dongqin Zhu, Department of Nuclear, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, People’s Republic of China, Tel +86 0577 55579667, Email zhudongqin96@163.comObjective: Post-stroke hyperglycemia as a common phenomenon is associated with unfavorable outcomes. Focusing on admission hyperglycemia, other markers of dysglycemia were overlooked. This study aimed to explore the contribution of acute phase blood glucose levels in combination with other radiological signs to the prognostication of functional outcomes in patients with spontaneous intracerebral hemorrhage (sICH).Methods: Consecutive patients with sICH with at least five random plasma glucose measurements and complete radiological data during hospitalization were included. We calculated the average, maximum, minimum, standard deviation, and coefficient of variation of blood glucose levels for each patient. Radiological data, including island, black hole, blend, and satellite signs were collected. Functional outcomes were evaluated using the Barthel index. Unfavorable outcomes were defined as a Barthel index score ≤ 60. Univariate and multivariate analyses were performed to identify independent predictors of unfavorable outcomes.Results: Two hundred and thirty-eight patients (mean age 58.5, 163 men and 75 women) were included, and 71 had a history of diabetes. Unfavorable outcomes occurred in 107 patients (45.0%) at 3 months. Multivariate logistic regression analysis demonstrated that maximum blood glucose levels (odds ratio, 1.256; 95% confidence interval, 1.124‒1.404; p < 0.001) and island sign (odds ratio, 2.701; 95% confidence interval, 1.322‒5.521; p = 0.006) were independent predictors of unfavorable outcomes in the nondiabetic group. Meanwhile, patients without diabetes who experienced hematoma expansion had higher average (p = 0.036) and maximum blood glucose levels (p = 0.014).Interpretation: Maximum blood glucose levels and island sign were independently associated with unfavorable outcomes in patients without diabetes, whereas no glycemic variability indices were associated with unfavorable outcomes. Glucose levels influenced hematoma expansion and functional outcomes, particularly in patients without diabetes with sICH. Thus, clinical management of blood glucose levels should be strengthened for patients with sICH with or without a history of diabetes.Keywords: spontaneous intracerebral hemorrhage, glycemic variability, functional outcomes, island sign, diabetes

Zhuangzhuang Jiang, Dongjuan Xu, Hongfei Li, Xiaolan Wu Department of Neurology, Dongyang People’s Hospital, Affiliated to Wenzhou Medical University, Dongyang, Zhejiang, People’s Republic of ChinaCorrespondence: Dongjuan Xu, Tel +86 13588620108, Email xdj0108@126.comObjective: This study aimed to create and validate a novel nomogram to predict the risk of symptomatic intracranial hemorrhage (sICH) in patients with acute ischemic stroke (AIS) who underwent intravenous thrombolysis (IVT).Methods: In this retrospective study, 784 patients with AIS who received IVT were enrolled. The patients were randomly divided into two groups: a training set (n=550, 70%) and a testing set (n=234, 30%). Utilizing multivariable logistic regression analysis, relevant factors for the predictive nomogram were selected. The performance of the nomogram was evaluated using various metrics, including the area under the receiver operating characteristic curve (AUC-ROC), the Hosmer-Lemeshow goodness-of-fit test, calibration plots, and decision curve analysis (DCA).Results: Multivariable logistic regression analysis showed that specific factors, including National Institutes of Health Stroke Scale (NIHSS) scores, Early infarct signs (EIS), and serum sodium, were identified as independent predictors of sICH. Subsequently, a nomogram was constructed using these predictors. The AUC-ROC values of the nomogram were 0.864 (95% CI: 0.810– 0.919) and 0.831 (95% CI: 0.770– 0.891) in the training and the validation sets, respectively. Both the calibration plots and the Hosmer-Lemeshow goodness-of-fit test showed favorable agreement in both the training and the validation sets. Additionally, the DCA indicated the practical clinical utility of the nomogram.Conclusion: The novel nomogram, which included NIHSS, EIS and serum sodium as variables, had the potential for predicting the risk of sICH in patients with AIS after IVT.Keywords: ischemic stroke, symptomatic intracranial hemorrhage, thrombolysis, nomogram

Ziyu Jiang,1,2,&ast; Xiaoli Chen,2,3,&ast; Zhaoshen Sun,2,4 Xiaowei Shen,2,3 Yaju Huang,2,3 Jingbing Liu1,2 1Department of Oncology, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, People’s Republic of China; 2Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, 210028, People’s Republic of China; 3Department of Respiratory and Critical Care Medicine, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, People’s Republic of China; 4Department of Dermatology, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jingbing Liu; Yaju Huang, Department of Oncology, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, People’s Republic of China, Tel +86 025 85637121 ; +86 025 85639241, Email ljb0427@sina.com; huangyaju1113@163.comAbstract: Immune checkpoint inhibitors such as monoclonal antibodies have been used recently with greater effect for the management of non-small cell lung cancer (NSCLC). Sintilimab, a fully human IgG4 monoclonal antibody is specific for the immune checkpoint protein programmed cell death receptor-1 (PD-1). It is a common medication adopted for treating Hodgkin’s lymphoma and NSCLC. The adverse effects associated with the use of monoclonal antibodies should be closely monitored and in the current report, the use of sintilimab for treating NSCLC led to skin-associated adverse effects such as Stevens-Johnson syndrome and toxic epidermal necrolysis. Genetic testing showed that genes such as KRAS, CREBBP, NTRK1, RAF1, and TP53 were mutated. Initial visible symptom included the formation of a vesicular rash on the skin that had spread to the upper limbs, chest, and dorsum 1 week after the administration of sintilimab. The patient received anti-inflammatory agents to prevent worsening of the rashes and further infections. When the vesicles in back and limbs enlarged and the neck skin began to desquamate, the patient was diagnosed with Stevens-Johnson syndrome and sintilimab-induced toxic epidermal necrolysis. Toxic epidermal necrolysis was diagnosed via clinical symptoms and physical examination. The patient also reported the symptoms of oral mucositis. As soon as the dose of sintilimab was reduced to 20 mg/day, the skin-associated condition of the patient began to improve. Although the lump in the lungs decreased considerably 45 days after initial administration of sintilimab, the medication was stopped from use as soon as the skin-related symptoms improved after its withdrawal. This report suggests that close monitoring, personal care, and proper use of medications such as sintilimab should be implemented to avoid such rare skin-associated toxicities as an adverse effect.Keywords: sintilimab, checkpoint inhibitor, monoclonal antibody, NSCLC, adverse effects

Yanmei Luo,1,&ast; Jie Liu,2,&ast; Zhihui Jiang,3,&ast; Xinghai Yang,1 Song Lin,1 Xiaowen Mao1 1Department of Pediatric Surgery, Maternal and Child Health Hospital of Hubei, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 2Department of Pediatric Surgery, Yijishan Hospital of Wannan Medical College, Wannan Medical College, Wuhu, People’s Republic of China; 3Department of General Surgery, Qingdao Women and Children’s Hospital, Qingdao, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiaowen Mao; Song Lin, Department of Pediatric Surgery, Maternal and Child Health Hospital of Hubei, Tongji Medical College, Huazhong University of Science and Technology, No. 58 Guanggu Third Road, Donghu New Technology Development Zone, Wuhan City, 430070, Hubei Province, People’s Republic of China, Email xiaowenmao0927@163.com; yes888111@sina.cnPurpose: To compare and analyze the therapeutic effects of endoscopy-assisted laparoscopic surgery (EALS) and laparoscopic surgery (LS) in the treatment of gastric duplication cysts (GDCs).Patients and Methods: We reviewed the clinical data of children with GDCs who underwent surgical treatment at Hubei Maternal and Child Health Hospital, Yijishan Hospital of Wannan Medical College, and Qingdao Women and Children’s Medical Center from September 2014 to November 2022.Results: The study comprised 29 children with GDCs, including 14 in the EALS group and 15 in the LS group. There was no significant difference between the two groups in terms of age, sex, weight, and cyst size characteristics. There was a significant difference between the two groups in terms of average surgical time (P> 0.05), which was 1.100 ± 0.833 hours in the EALS group and 1.933 ± 0.159 hours in the LS group. There was a significant difference between the two groups (P< 0.05) in average intraoperative blood loss, which was 7.93 ± 3.81 milliliters in the EALS group and 11.80 ± 2.72 milliliters in the LS group. There was a significant difference between the two groups (P< 0.05) in average postoperative fasting time, which was 73.79 ± 8.36 hours in the EALS group and 114.1 ± 9.24 hours in the LS group. There was a significant difference between the two groups (P< 0.05) in average postoperative hospital stay, which was 10.21 ± 4.25 days in the EALS group and 14.47 ± 4.36 days in the LS group.Conclusion: EALS technology can not only shorten surgical time, accurately locate GDCs, reduce injuries, and decrease the probability of complications but also achieve treatment goals safely and reliably.Keywords: gastric duplication cyst, laparoscopic, endoscopic, surgery, children

Qiumei Lin,1,&ast; Zongwei Jiang,1,&ast; Dan Mo,2,&ast; Fengfei Liu,1 Yuling Qin,1 Yihua Liang,1 Yuchen Cheng,3 Hao Huang,1 Min Fang1,4 1Department of Clinical Laboratory, Guangxi Medical University Cancer Hospital, Nanning, People’s Republic of China; 2Department of Breast, Guangxi Zhuang Autonomous Region Maternal and Child Health Care Hospital, Nanning, 530025, People’s Republic of China; 3Department of Clinical Laboratory, Wuzhou Maternal and Child Health-Care Hospital, Wuzhou, People’s Republic of China; 4Engineering Research Center for Tissue & Organ Injury and Repair Medicine, Guangxi Medical University Cancer Hospital, Nanning, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hao Huang; Min Fang, Email 1057226867@qq.com; fangmin@sr.gxmu.edu.cnBackground: Accurate prognosis is crucial for improving hepatocellular carcinoma (HCC) patients, clinical management, and outcomes post-liver resection. However, the lack of reliable prognostic indicators poses a significant challenge. This study aimed to develop a user-friendly nomogram to predict HCC patients’ post-resection prognosis.Methods: We retrospectively analyzed the data from 1091 HCC patients, randomly split into training (n=767) and validation (n=324) cohorts. Receiver operating characteristic (ROC) curves determined the optimal cut-off value for alpha1-microglobulin (α 1MG) and Beta2-microglobulin (β 2MG). Kaplan–Meier analysis assessed microglobulin’s impact on survival, followed by Cox regression to identify prognostic factors and construct a nomogram. The predictive accuracy and discriminative ability of the nomogram were measured by the concordance index (C-index), calibration curves, area under the ROC curve (AUC), and decision curve analysis (DCA), and were compared with the BCLC staging system, Edmondson grade, or BCLC stage plus Edmondson grade.Results: Patients with high β 2MG (≥ 2.395mg/L) had worse overall survival (OS). The nomogram integrated β 2MG, BCLC stage, Edmondson grade, microvascular invasion (MVI), and serum carbohydrate antigen 199 (CA199) levels. C-index for training and validation cohorts (0.712 and 0.709) outperformed the BCLC stage (0.660 and 0.657), Edmondson grade (0.579 and 0.564), and the combination of BCLC stage with Edmondson grade (0.681 and 0.668), improving prognosis prediction. Calibration curves demonstrated good agreement between predicted and observed survival. AUC values exceeded 0.700 over time, highlighting the nomogram’s discriminative ability. DCA revealed superior overall net income compared to other systems, emphasizing its clinical utility.Conclusion: Our β 2MG-based nomogram accurately predicts HCC patients’ post-resection prognosis, aiding intervention and follow-up planning. Significantly, our nomogram surpasses existing prognostic indicators, including BCLC stage, Edmondson grade, and the combination of BCLC stage with Edmondson grade, by demonstrating superior predictive performance.Keywords: hepatocellular carcinoma, nomogram, microglobulin, prognosis

Xingrui Li,1,&ast; Yue Wang,1,&ast; Denghao Huang,1 Zhonghao Jiang,1 Zhiyu He,1 Maoxuan Luo,2 Jie Lei,1,2 Yao Xiao1– 3 1Oral & Maxillofacial Reconstruction and Regeneration of Luzhou Key Laboratory, the Affiliated Stomatological Hospital of Southwest Medical University, Institute of Stomatology, Southwest Medical University, Luzhou, People’s Republic of China; 2Department of Orthodontics, the Affiliated Stomatological Hospital of Southwest Medical University, Luzhou, People’s Republic of China; 3Department of Chengbei Outpatient, the Affiliated Stomatological Hospital of Southwest Medical University, Luzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yao Xiao; Jie Lei, Email orthoxiaoyao@outlook.com; 1067233579@qq.comAbstract: The critical challenges in repairing oral soft and hard tissue defects are infection control and the recovery of functions. Compared to conventional tissue regeneration methods, nano-bioactive materials have become the optimal materials with excellent physicochemical properties and biocompatibility. Dental-derived mesenchymal stem cells (DMSCs) are a particular type of mesenchymal stromal cells (MSCs) with great potential in tissue regeneration and differentiation. This paper presents a review of the application of various nano-bioactive materials for the induction of differentiation of DMSCs in oral and maxillofacial restorations in recent years, outlining the characteristics of DMSCs, detailing the biological regulatory effects of various nano-materials on stem cells and summarizing the material-induced differentiation of DMSCs into multiple types of tissue-induced regeneration strategies. Nanomaterials are different and complementary to each other. These studies are helpful for the development of new nanoscientific research technology and the clinical transformation of tissue reconstruction technology and provide a theoretical basis for the application of nanomaterial-modified dental implants. We extensively searched for papers related to tissue engineering bioactive constructs based on MSCs and nanomaterials in the databases of PubMed, Medline, and Google Scholar, using keywords such as “mesenchymal stem cells”, “nanotechnology”, “biomaterials”, “dentistry” and “tissue regeneration”. From 2013 to 2023, we selected approximately 150 articles that align with our philosophy.Keywords: nano-material, stem cell, tissue reconstruction, cell differentiation

Jiajun Wu,1,2,&ast; Lei Gao,1,2,&ast; Qiao Shi,3 Chunhui Qin,4 Kai Xu,1,2 Zhaoshun Jiang,1,2 Xixue Zhang,1,2 Ming Li,5 Jianjian Qiu,6,&ast; Weidong Gu1,2,&ast; 1Department of Anesthesiology, Huadong Hospital Affiliated to Fudan University, Shanghai, 200040, People’s Republic of China; 2Shanghai Key Laboratory of Clinical Geriatric Medicine, Shanghai, 200040, People’s Republic of China; 3Department of Anesthesiology, International Peace Maternity and Child Health Hospital of China, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200030, People’s Republic of China; 4Department of Pain Management, Yueyang Integrated Traditional Chinese Medicine and Western Medicine Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200437, People’s Republic of China; 5Department of Radiology, Huadong Hospital affiliated to Fudan University, Shanghai, 200040, People’s Republic of China; 6Department of Radiation Oncology, Huadong Hospital Affiliated to Fudan University, Shanghai, 200040, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Weidong Gu; Jianjian Qiu, Email hdmz0800@163.com; qiujianjian@fudan.edu.cnPurpose: To evaluate the accuracy of mixed reality (MR)-guided visualization technology for spinal puncture (MRsp).Methods: MRsp involved the following three steps: 1. Lumbar spine computed tomography (CT) data were obtained to reconstruct virtual 3D images, which were imported into a HoloLens (2nd gen). 2. The patented MR system quickly recognized the spatial orientation and superimposed the virtual image over the real spine in the HoloLens. 3. The operator performed the spinal puncture with structural information provided by the virtual image. A posture fixation cushion was used to keep the subjects’ lateral decubitus position consistent. 12 subjects were recruited to verify the setup error and the registration error. The setup error was calculated using the first two CT scans and measuring the displacement of two location markers. The projection points of the upper edge of the L3 spinous process (L3↑), the lower edge of the L3 spinous process (L3↓), and the lower edge of the L4 spinous process (L4↓) in the virtual image were positioned and marked on the skin as the registration markers. A third CT scan was performed to determine the registration error by measuring the displacement between the three registration markers and the corresponding real spinous process edges.Results: The setup errors in the position of the cranial location marker between CT scans along the left-right (LR), anterior-posterior (AP), and superior-inferior (SI) axes of the CT bed measured 0.09 ± 0.06 cm, 0.30 ± 0.28 cm, and 0.22 ± 0.12 cm, respectively, while those of the position of the caudal location marker measured 0.08 ± 0.06 cm, 0.29 ± 0.18 cm, and 0.18 ± 0.10 cm, respectively. The registration errors between the three registration markers and the subject’s real L3↑, L3↓, and L4↓ were 0.11 ± 0.09 cm, 0.15 ± 0.13 cm, and 0.13 ± 0.10 cm, respectively, in the SI direction.Conclusion: This MR-guided visualization technology for spinal puncture can accurately and quickly superimpose the reconstructed 3D CT images over a real human spine.Keywords: mixed reality, spinal puncture, immobilization, superimposition, setup error, registration error

Baozi Huang,1,2 Jianle Li,1 Pingping Li,1,2 Chunyong Chen,1,2 Suhan Cao,1 Zimu Jiang,1 Jinsheng Zeng1 1Department of Neurology and Stroke Center, Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases, The First Affiliated Hospital, Sun Yat-sen University, National Key Clinical Department and Key Discipline of Neurology, Guangzhou, People’s Republic of China; 2Department of Neurology of the First Affiliated Hospital of Guangxi Medical University, Nanning, People’s Republic of ChinaCorrespondence: Jinsheng Zeng, Department of Neurology and Stroke Center, Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases, The First Affiliated Hospital, Sun Yat-sen University, National Key Clinical Department and Key Discipline of Neurology, No. 58 Zhongshan Road 2, Guangzhou, 510080, People’s Republic of China, Tel +86-20-87755766-8253, Fax +86-20-87335935, Email zengjsh@mail.sysu.edu.cnObjective: We aimed to assess the prevalence and risk factors of new-onset paroxysmal atrial fibrillation (PAF) in patients hospitalized with ICH and determine whether the new-onset PAF had influenced functional outcomes.Methods: We analyzed a database of all consecutive patients with ICH from October 2013 to May 2022. Univariate and multivariable regression analyses were performed to identify risk factors for new-onset PAF in patients with ICH. Multivariate models were also constructed to assess whether the new-onset PAF was an independent predictor of poor functional outcome, as measured using the modified Rankin scale.Results: This study included 650 patients with ICH, among whom 24 patients had new-onset PAF. In the multivariable model, older age (OR per 10-y increase, 2.26 [95% CI, 1.52– 3.35]; P< 0.001), hematoma volume (OR per 10-mL increase, 1.80 [95% CI, 1.26– 2.57]; P=0.001), and heart failure (OR, 21.77 [95% CI, 5.52– 85.91]; P< 0.001) were independent risk factors for new-onset PAF. In a sensitivity analysis restricted to 428 patients with N-terminal pro-B-type natriuretic peptide (NT-proBNP), older age, larger hematoma volume, heart failure, and increased NT-proBNP were associated with new-onset PAF. After adjusting for baseline variables, new-onset PAF was an independent predictor of poor functional outcome (OR, 10.35 [95% CI, 1.08– 98.80]; P=0.042).Conclusion: Older age, larger hematoma volume, and heart failure were independent risk factors for new-onset PAF after ICH. Increased NT-proBNP is correlated with higher risks for new-onset PAF when their information is available at admission. Furthermore, new-onset PAF is a significant predictor of poor functional outcome.Keywords: intracerebral hemorrhage, paroxysmal atrial fibrillation, prognostic implication, risk factors

Zhihan Jiang,1,&ast; Xiaosen Wang,1,&ast; Lijiao Zhang,1,&ast; Drolma Yangzom,2,&ast; Yanping Ning,2 Baiyan Su,3,4 Meijiao Li,5 Meilang ChuTso,2 Yahong Chen,1,6 Ying Liang,1,2,6 Yongchang Sun1,6 1Department of Respiratory and Critical Care Medicine, Peking University Third Hospital, Beijing, 100191, People’s Republic of China; 2Department of Respiratory and Critical Care Medicine, Tibet Autonomous Region People’s Hospital, Lhasa, 850000, People’s Republic of China; 3Radiology Department, Peking Union Medical College Hospital, Beijing, 100730, People’s Republic of China; 4Radiology Department, Tibet Autonomous Region People’s Hospital, Lhasa, 850000, People’s Republic of China; 5Radiology Department, Peking University Third Hospital, Beijing, 100191, People’s Republic of China; 6Research Center for Chronic Airway Diseases, Peking University Health Science Center, Beijing, 100083, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ying Liang; Yongchang Sun, Department of Respiratory and Critical Care Medicine, Peking University Third Hospital, North Garden Road 49, Haidian District, Beijing, People’s Republic of China, Tel +86 138 1096 4766 ; +86 139 1097 9132, Email bysyliangying@126.com; suny@bjmu.edu.cnBackground: COPD patients living in Tibet are exposed to specific environments and different risk factors and probably have different characteristics of COPD from those living in flatlands. We aimed to describe the distinction between stable COPD patients permanently residing at the Tibet plateau and those in flatlands.Methods: We conducted an observational cross-sectional study that enrolled stable COPD patients from Tibet Autonomous Region People’s Hospital (Plateau Group) and Peking University Third Hospital (Flatland Group), respectively. Their demographic information, clinical features, spirometry test, blood routine and high-resolution chest CT were collected and evaluated.Results: A total of 182 stable COPD patients (82 from plateau and 100 from flatland) were consecutively enrolled. Compared to those in flatlands, patients in plateau had a higher proportion of females, more biomass fuel use and less tobacco exposure. CAT score and frequency of exacerbation in the past year were higher in plateau patients. The blood eosinophil count was lower in plateau patients, with fewer patients having an eosinophil count ≥ 300/μL. On CT examination, the proportions of previous pulmonary tuberculosis and bronchiectasis were higher in plateau patients, but emphysema was less common and milder. The ratio of diameters of pulmonary artery to aorta ≥ 1 was more often in plateau patients.Conclusion: Patients with COPD living at Tibet Plateau had a heavier respiratory burden, lower blood eosinophil count, less emphysema but more bronchiectasis and pulmonary hypertension. Biomass exposure and previous tuberculosis were more common in these patients.Keywords: chronic obstructive pulmonary disease, plateau, phenotype, computed tomography, emphysema

Annan Liu,1,2 Yiwen Lu,3 Chao Gong,1,2 Jiaxing Sun,1,2 Bobo Wang,1,2 Zhimei Jiang4 1College of Rehabilitation Medicine, Jiamusi University, Jiamusi, Heilongjiang Province, People’s Republic of China; 2Neurolab for Child Rehabilitation, Jiamusi University, Jiamusi, Heilongjiang Province, People’s Republic of China; 3The First Affiliated Hospital, Guangxi Medicine University, Nanning, Guangxi Province, People’s Republic of China; 4Jiamusi University, Jiamusi, Heilongjiang Province, People’s Republic of ChinaCorrespondence: Zhimei Jiang, Jiamusi University, Jiamusi, Heilongjiang Province, People’s Republic of China, Email mynard93@163.comBackground: In recent years, there has been a growing body of research suggesting that ASD and ADHD are two disorders that often co-exist. Despite the rapid development of research, little is known about their etiology, diagnostic markers, and interventions, which has led us to review and summarise the development of the field in the hope that this will provide an opportunity to look for future directions.Methods: A bibliometric approach was used to analyse papers in the field of ASD co-morbidities in ADHD on Web of Science from 1991– 2022, using CiteSpace and VOSview to map the country/institution, journal, author, co-citation, and keyword networks in the field and to visualise the results.Results: A total of 3284 papers were included, showing an increasing trend in terms of posting trends. Research on co-morbidities of ASD has proven to be mainly focused on universities. The USA (1662) published the most relevant literature in this area, followed by the UK (651) and Sweden (388). Lichtenstein P is the most published author (84), and research into the pathogenesis of ASD co-occurring ADHD and related clinical diagnostics is currently at the forefront of the field.Conclusion: This analysis identifies the most influential institutions and countries, cited journals, and authors in the field of ASD co-morbid ADHD research. The future direction of ASD co-occurring ADHD should be based on improving case identification, discovering the etiological and diagnostic markers of ASD and ADHD, and finding more effective clinical interventions.Keywords: autism, hyperactivity, bibliometrics, VOSviewer, CiteSpace, visualization analysis

Chengcheng Gai,1,&ast; Xiaohui Xing,1,2,&ast; Yan Song,1 Yijing Zhao,1 Zige Jiang,1 Yahong Cheng,1 Yilei Xiao,2,3 Zhen Wang1,4 1Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, People’s Republic of China; 2Department of Neurosurgery, Liaocheng People’s Hospital, Liaocheng, Shandong, 252000, People’s Republic of China; 3Liaocheng Neuroscience Laboratory, Liaocheng People’s Hospital, Liaocheng, Shandong, 252000, People’s Republic of China; 4Key Laboratory of Birth Regulation and Control Technology of National Health Commission of China, Maternal and Child Health Care Hospital of Shandong Province Affiliated to Qingdao University, Jinan, 250014, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yilei Xiao, Department of Neurosurgery, Liaocheng People’s Hospital, Liaocheng, Shandong, 252000, People’s Republic of China, Email yileixiao@163.com Zhen Wang, Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, 44 Wenhua Xi Road, Jinan, 250012, Shandong, People’s Republic of China, Email wangzhen@sdu.edu.cnIntroduction: Hypoxia-ischemia (HI) remains the leading cause of cerebral palsy and long-term neurological sequelae in infants. Despite intensive research and many therapeutic approaches, there are limited neuroprotective strategies against HI insults. Herein, we reported that HI insult significantly down-regulated microRNA-9-5p (miR-9-5p) level in the ipsilateral cortex of neonatal mice.Methods: The biological function and expression patterns of protein in the ischemic hemispheres were evaluated by qRT-PCR, Western Blotting analysis, Immunofluorescence and Immunohistochemistry. Open field test and Y-maze test were applied to detect locomotor activity and exploratory behavior and working memory.Results: Overexpression of miR-9-5p effectively alleviated brain injury and improved neurological behaviors following HI insult, accompanying with suppressed neuroinflammation and apoptosis. MiR-9-5p directly bound to the 3’ untranslated region of DNA damage-inducible transcript 4 (DDIT4) and negatively regulated its expression. Furthermore, miR-9-5p mimics treatment down-regulated light chain 3 II/light chain 3 I (LC3 II/LC3 I) ratio and Beclin-1 expression and decreased LC3B accumulation in the ipsilateral cortex. Further analysis showed that DDIT4 knockdown conspicuously inhibited the HI-up-regulated LC3 II/ LC3 I ratio and Beclin-1 expression, associating with attenuated brain damage.Conclusion: The study indicates that miR-9-5p-mediated HI injury is regulated by DDIT4-mediated autophagy pathway and up-regulation of miR-9-5p level may provide a potential therapeutic effect on HI brain damage.Keywords: hypoxia-ischemia, HI, miR-9-5p, DNA damage-inducible transcript 4, (DDIT4), autophagy

Wen Zhang,1,2,&ast; Yudong Lai,2,&ast; Tao Li,2 Xingpeng Wang,2 Weidong Mu,3,4 Zhensong Jiang2 1Department of Spine Surgery, Shandong University of Traditional Chinese Medicine, Jinan, People’s Republic of China; 2Department of spine surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, People’s Republic of China; 3Department of Traumatic Orthopaedics, Shandong University of Traditional Chinese Medicine, Jinan, People’s Republic of China; 4Department of Traumatic Orthopaedics, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhensong Jiang; Weidong Mu, Email jiangzhensongsph@163.com; Dr_muweidong@163.comAbstract: The incidence of a spinal epidural abscess (SEA), which can cause serious neurological complications, is low; however, the incidence of SEA caused by Streptococcus is even lower, most of which are reported in the thoracolumbar spine and lumbosacral segment. We reported a case of cervical SEA caused by Streptococcus constellatus infection, resulting in paralysis of the patient. The acute onset of SEA in a 44-year-old male led to decreased upper limb muscle strength, lower limb paralysis, and loss of bowel and bladder function, and imaging and blood tests suggested pyogenic spondylitis. Emergency decompression surgery and antibiotic therapy were given, the patient gradually recovered, and the muscle strength of the lower limbs gradually improved. This case report suggests the importance of early decompressive surgery and effective antibiotic therapy.Keywords: Streptococcus constellatus, epidural abscess, pyogenic spondylitis, vertebral destruction, diagnosis and treatment

Zhonghao Jiang, Chaoliu Dai Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, People’s Republic of ChinaCorrespondence: Chaoliu Dai, Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, People’s Republic of China, Email 18793198756@163.comAbstract: Liver cancer is highly malignant, has a low sensitivity to chemotherapy, and is associated with poor patient prognosis. The last 3 years have seen the emergence of promising targeted therapies for the treatment of hepatocellular carcinoma (HCC). For over 10 years, before the discovery of lenvatinib, sorafenib was only first-line therapeutic agent available for the treatment of advanced HCC. However, several clinical studies have shown that a considerable proportion liver cancer patients are insensitive to sorafenib. Very few patients actually substantially benefit from treatment with sorafenib, and the overall efficacy of the drug has not been satisfactory; therefore, sorafenib has attracted considerable research attention. This study, which is based on previous studies and reports, reviews the potential mechanisms underlying sorafenib resistance and summarizes combination therapies and potential drugs that can be used to sensitize HCC cells to sorafenib.Keywords: hepatocellular carcinoma, sorafenib, drug resistance, combination therapy, target therapy

Lead blast furnace slag (LBFS) generated during lead smelting is a hazardous solid waste containing potentially toxic elements (Pb, Zn, As, and Cd) with high mobility and solubility. In this study, a process for the utilization of LBFS by carbothermic reduction-magnetic separation method is proposed. Leaching toxicity and Tessier sequential extraction experiments were conducted on LBFS and magnetic separation tailings (TS), and the environmental risk was evaluated using the risk assessment coding index and potential ecological risk index. The obtained results showed that the potentially toxic elements in the TS were solidified in the spinel phase or silicate phase. In addition, the XRD, SEM-EDS, and FTIR results showed the formation of PbCa2Si3O9, ZnAl2O4, and Ca3(AsO4)2 phases. The leaching concentrations of Pb, Zn, As, and Cd in TS were much lower than the toxicity characteristic leaching procedure (TCLP) and China standard leaching test (CSLT) limits. The results of Tessier sequential extraction procedure confirmed that the proportions of the stable residual state of the potentially toxic elements in TS were significantly higher than in LBFS. Furthermore, the ecological environmental risk level for the TS decreased significantly compared to that of LBFS.

Xinxin Zhu,1,* Shiyun Huang,1,* Yuxuan Tang,1,* Zhonglan Wu,2,* Yue Sun,1 Huiyan Ren,1 Hongmei Lu,1 Tingting Yin,1 Qing Zuo,1,* Zhiping Ge,1,* Ziyan Jiang1,* 1Department of Obstetrics and Gynecology, First Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China; 2Department of Obstetrics and Gynecology, Women’s Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital), Nanjing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ziyan Jiang, Department of Obstetrics, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, People’s Republic of China, Tel +86-13512534017, Email zyjiangchm@163.comBackground: Grade III meconium stained amniotic fluid (MSAF) is a common obstetric disease, and has the greatest impact on poor maternal and neonatal outcomes.Question or Hypothesis or Aim: There is no consensus on treatment, especially on the timing of delivery.Methods: We collected the medical records of 345 women who gave birth with grade III MSAF and analyzed the difference in baseline characteristics and maternal and neonatal outcomes relative to different labor stage, observation times in the first stage of labor, and the presence or absence of abnormal fetal heart rate (FHR) or thick amniotic fluid.Findings: Higher rate of cesarean section was observed when grade III MSAF was found in active labor. Intervention occurred at an observation time of 90– 120 min, but there were no significant differences in maternal or neonatal outcomes shown when the observation time was greater than 3 or 4 hours. However, a higher rate of admission to the neonatal intensive care unit was demonstrated in cases with grade III MSAF with abnormal FHR either in the first or second stage of labor or in cases with thick MSAF in the second stage of labor.Discussion: Higher rate of composite adverse neonatal outcomes was found when secondary MSAF (a transition from clear AF to MSAF) was diagnosed > 3 h before delivery.Conclusion: In the first stage of labor, an observation time of greater than 4 hours might be possible after grade III MSAF is found if the labor has progressed and is without abnormal FHR.Keywords: MSAF, grade III MSAF, observation time, abnormal FHR, thick AF

Zhaosheng Jiang,1,&ast; Jiahao Wang,2,&ast; Wei Meng,1,&ast; Youlang Zhou,3 Limin Ma,1 Yangbo Guan1 1Department of Urology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, People’s Republic of China; 2Department of Urology, Wuxi Hospital Affiliated to the Nanjing University of Chinese Medicine, Wuxi, People’s Republic of China; 3Research Central of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yangbo Guan; Limin Ma, Tel +86 18912888908 ; Tel +86 13404292020, Email guanyangbo123@ntu.edu.cn; ntmalimin@163.comIntroduction: Ureteral stricture caused by iatrogenic ureteral injury induced ureteral injury is more common and challenging to recover quickly. The effective prevention of ureteral stricture due to iatrogenic ureteral injury-induced ureteral damage is a current challenge for urologists. The purpose of this study was to evaluate the effectiveness of nanoparticle/pirfenidone complex-coated ureteral stents with slow-release pirfenidone for the prevention of ureteral stricture in rabbits. In this study, we developed a nanoparticle/pirfenidone complex-coated ureteral stent to deliver pirfenidone into the injured ureter to inhibit ureteral stricture.Methods: Twelve New Zealand rabbits were divided into four groups: Sham, US, US+ Unmodified ureteral stent, and US+NP/PFD ureteral stent; we constructed an irreversible electroporation model of ureteral injury in rabbits and placed unmodified ureteral stents and nanoparticle/pirfenidone complex-coated ureteral stents into the ureter. Two weeks later, we euthanized the rabbits and removed their bilateral kidneys and ureters. We evaluated the effect of ureteral stent prophylaxis by gross specimen observation, section staining, and Western Blot.Results: We found that the nanoparticle/pirfenidone complexes could adhere uniformly to the surface of the ureteral stent. After placement into the ureter, the nanoparticle/pirfenidone complexes were able to remain on the surface of the ureteral stent. We found nanoparticle/pirfenidone complexes could diffuse in the ureteral epithelial tissue two weeks after the order. The study showed that nanoparticle/pirfenidone complex-coated ureteral stents placed into the ureter showed significantly less stenosis due to fibrosis than in US control rabbits and rabbits treated with unmodified ureteral stents.Conclusion: We used a novel platform based on nanoparticle/pirfenidone complex-coated ureteral stents for local and sustained delivery of pirfenidone, which can effectively deliver pirfenidone to the tissue and can slowly control the release of pirfenidone. Therefore, combining ureteral stents with nanoparticle/pirfenidone complexes was an effective measure to prevent ureteral stricture.Keywords: nanoparticles, ureteral stricture, fibrosis, ureteral stents, pirfenidone

Shifei Li,1 Qijun Wu,1 Zhuyan Jiang,1 Yaguang Wu,1 Yuhong Li,2 Bing Ni,3 Jun Xiao,4 Zhifang Zhai1 1Department of Dermatology, Southwest Hospital of Third Military Medical University, Chongqing, People’s Republic of China; 2Department of Cell Biology, Third Military Medical University, Chongqing, People’s Republic of China; 3Department of Pathophysiology, Third Military Medical University, Chongqing, People’s Republic of China; 4Department of Cardiovascular Medicine, Chongqing University Central Hospital, Chongqing, People’s Republic of ChinaCorrespondence: Jun Xiao, Department of Cardiovascular Medicine, Chongqing University Central Hospital, Chongqing, People’s Republic of China, Email xj73wy@163.com Zhifang Zhai, Department of Dermatology, Southwest Hospital of Third Military Medical University, Chongqing, People’s Republic of China, Email zhaizf1004@163.comBackground: Plasmacytoid dendritic cells (pDCs) are the main producers of type I interferon (IFN-I), and the excessive production of IFN-I is a hallmark of systemic lupus erythematosus (SLE). Both SLC15A4 and miR-31-5p are SLE susceptibility-related genes, and SLC15A4 has been implicated an important role in endolysosomal toll-like receptor (TLR) activation in pDCs. However, whether miR-31-5p exerts a regulating effect on SLC15A4 expression in pDCs is unclear.Methods: The expression of SLC15A4 and miR-31-5p in peripheral blood mononuclear cells (PBMCs) of SLE patients was measured by RT-qPCR analyses. The quantitative analysis of IFN-α secretion in the patients’ serum was performed by ELISA assay. Luciferase-reporter assay was applied to confirm the interaction between miR-31-5p and SLC15A4. The expression of miR-31-5p, SLC15A4 and IFN-stimulated genes (ISGs, such as MX1, OAS1 and IFIT3) was detected by Western blot and RT-qPCR assays and further IRF5 phosphorylation was evaluated by immunofluorescence after transfected with miR-31-5p mimics or inhibitor in THP-1 and CAL-1 cells.Results: The expression of miR-31-5p was downregulated and negatively correlated with the overexpression of SLC15A4 in PBMCs of SLE patients. In addition to this, the secretion of IFN-α was overexpressed in sera of SLE and positively correlated with SLC15A4 level. We found that miR-31-5p directly targeted SLC15A4 and negatively regulated the expression of SLC15A4 in THP-1 and CAL-1 cells. In vitro inhibition of miR-31-5p increased the phosphorylation of IRF5 and the induction of ISGs stimulated by R848, overexpression of miR-31-5p get the reverse results.Conclusion: miR-31-5p might involve in SLE pathogenesis through regulating IFN-I expression by negatively regulating SLC15A4 to increase the levels of IFN-α and ISGs in pDCs.Keywords: systemic lupus erythematosus, miR-31-5p, SLC15A4, type I interferon, plasmacytoid dendritic cell, inflammation

Zengxin Jiang,1,&ast; Zeng Zhang,1,&ast; Shuo Li,2,&ast; Sen Lin,3 Hengfeng Yuan1 1Department of Orthopaedics, Shanghai Jiaotong University Affiliated Sixth People’s Hospital, Shanghai, People’s Republic of China; 2Department of Joint Bone Disease Surgery, Changhai Hospital, Second Military Medical University, Shanghai, People’s Republic of China; 3National Engineering Research Center, East China University of Science and Technology, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Sen Lin; Hengfeng Yuan, Email linsen@ecust.edu.cn; yuanhf@shsmu.edu.cnBackground: Degenerative joint disease or osteoarthritis (OA) is a leading cause of disability worldwide. Intra-articular injection is the mainstay nonsurgical treatment for OA. However, dense cartilage and a lack of vasculature often limit the ability of drugs to reach cell or tissue targets at the concentrations necessary to elicit the desired biological response. Kartogenin (KGN), a small molecular compound, possesses a strong capacity to promote chondrogenic differentiation of mesenchymal stem cells (MSCs). However, the rapid clearance of KGN from the intra-articular cavity limits its feasibility.Materials and Methods: We constructed a magnetically guided biodegradable nanocarrier system (MNP) which enabled intracartilaginous delivery of KGN to promote chondrogenic differentiation by MSCs embedded within the articular matrix. Moreover, in preclinical models of OA, KGN-loaded MNPs exhibited increased tissue penetration and retention within the joint matrix under external magnetic guidance.Results: Histological examination showed that compared with KGN alone, KGN-loaded MNPs enhanced chondrogenic differentiation and improved the structural integrity of both articular cartilage and subchondral bone.Conclusion: This study demonstrates a practical method for intracartilaginous delivery using engineered nanocarriers, thus providing a new strategy to improve the efficacy of molecular therapeutic agents in the treatment of OA.Graphical Abstract: Keywords: osteoarthritis, kartogenin, magnetic nanoparticles, intracartilaginous

Zhengting Jiang,1,&ast; Wenjie Zhang,1,&ast; Jie Zhang,1 Tian Liu,1 Juan Xing,1 Huan Zhang,1 Dong Tang2 1Clinical Medical College, Yangzhou University, Yangzhou, 225000, People’s Republic of China; 2Department of General Surgery, Institute of General Surgery, Northern Jiangsu Province Hospital, Clinical Medical College, Yangzhou University, Yangzhou, 225000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Dong Tang, Department of General Surgery, Institute of General Surgery, Northern Jiangsu Province Hospital, Clinical Medical College, Yangzhou University, Yangzhou, 225000, People’s Republic of China, Email 83392785@qq.comAbstract: Cancer immunotherapy, a major breakthrough in cancer treatment, has been successfully applied to treat a number of tumors. However, given the presence of factors in the tumor microenvironment (TME) that impede immunotherapy, only a small proportion of patients achieve a good clinical response. With the ability to increase permeability and cross biological barriers, nanomaterials have been successfully applied to deliver immunotherapeutic agents, thus realizing the anti-cancer therapeutic potential of therapeutic agents. This has driven a wave of research into systems for the delivery of immunotherapeutic agents, which has resulted in widespread interest in nanomaterial-based drug delivery systems. Nanomaterial-based drug delivery systems are able to overcome the challenges from TME and thus achieve good results in cancer immunotherapy. If it can make a breakthrough in improving biocompatibility and reducing cytotoxicity, it will be more widely used in clinical practice. Different types of nanomaterials may also have some subtle differences in enhancing cancer immunotherapy. Moreover, delivery systems made of nanomaterials loaded with drugs, such as cytotoxic drugs, cytokines, and adjuvants, could be used for cancer immunotherapy because they avoid the toxicity and side effects associated with these drugs, thereby enabling their reuse. Therefore, further insights into nanomaterial-based drug delivery systems will provide more effective treatment options for cancer patients.Keywords: drug repurposing, delivery system, immunotherapy, tumor microenvironment, nanomaterial

Weijie Cao,&ast; Jieyong Zhang,&ast; Zhilei Bian, Li Li, Suping Zhang, Yang Qin, Dingming Wan, Zhongxing Jiang, Ran Zhang Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ran Zhang; Zhongxing Jiang, Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450002, People’s Republic of China, Tel +86 137 8359 0246 ; +86 185 3805 3607, Fax +86 370 66295122, Email zhangran19880310@126.com; jiangzx@zzu.edu.cnPurpose: To investigate the prevalence, risk factors of intestinal carbapenem-resistant Enterobacteriaceae (CRE) colonization and bloodstream infection (BSI) caused by CRE in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients.Methods: We analyzed the clinical data of 185 patients with hematological malignancies who underwent allo-HSCT from May 2019 to December 2021. All patients received regular CRE monitoring by rectal swab during allo-HSCT, and some CRE strains were further identified for carbapenemase phenotypes. The rates, distribution and risk factors of CRE colonization, CRE-induced BSI were analyzed.Results: CRE was detected in 44 of 185 recipients, with colonization rate of 23.8%. A total of 46 strains of CRE were isolated, including 22 Escherichia coli, 17 Klebsiella pneumoniae, three Klebsiella oxytoca, two Enterobacter hormaechei, and two other Enterobacteriaceae. Among the 19 strains identified with carbapenemase phenotypes, eight strains of E. coli produced metal β-lactamase, five K. pneumoniae produced serine carbapenemase, two K. pneumoniae produced metal β-lactamase, two K. oxytoca produced metal β-lactamase, a Citrobacter malonic acid-free produced metal β-lactamase and a Citrobacter freundii produced metal β-lactamase. In 10 patients developed with CRE-related BSI, the types and combined drug sensitivity of strains detected by rectal swab were highly consistent with blood culture. Multivariate analysis revealed that pulmonary infection, perianal infection and carbapenem application in the 3 months pre-transplant were independent risk factors for rectal CRE colonization, while rectal colonization with carbapenem-resistant K. pneumoniae (CR-KP) was an independent risk factor for CRE-induced BSI. The mortality rate within 30 days of CRE-related BSI was 50.0%, and patients receiving multi-drug therapy within 24 hours showed slightly lower mortality than that in the single-drug treatment group.Conclusion: Allo-HSCT patients with CRE-induced BSI have poor prognosis, and CR-KP rectal colonization is an independent risk factor for CRE-related BSI. Rectal swab screening during allo-HSCT could provide early warning for later CRE-induced BSI.Keywords: allogeneic hematopoietic stem cell transplantation, carbapenem-resistant enterobacteriaceae, bloodstream infection, intestinal colonization

ZhiHong Jiang, YiFan Ren, ChuanXin Zhang, Yu Yin, ChaoHui Li Department of Paediatrics, ShaoXing KeQiao Women And Children’s Hospital, ShaoXing, Zhejiang Province, People’s Republic of ChinaCorrespondence: ZhiHong Jiang, Email JZH710470401@163.comBackground: Stenotrophomonas maltophilia (S. maltophilia) is a pathogen causing opportunistic and nosocomial infections that are invasive and fatal, especially in hospitalized and immunocompromised patients. However, community-acquired S. maltophilia is rarely reported in children with normal immunity. S. maltophilia is a multi-drug-resistant bacterium, and the preferred drug is trimethoprim/sulfamethoxazole (TMP/SMX), which has greater side effects in children.Case Presentation: Herein, we reported the case of a child with clinical manifestations of fever, high C-reactive protein (CRP) and white blood cells, and severe pneumonia. The blood culture yielded S. maltophilia. The initial treatment regimen was meropenem IV, which was subsequently changed to ceftazidime IV, and finally to oral cefixime, which has less side effects in children. The child recovered completely. At the 1-month follow-up, anteroposterior chest X-ray was normal, and the child was in good general health.Conclusion: Although community-acquired S. maltophilia infection in children is rare, it can occur. The doctor encountered such a child in clinical work. This child has a normal immune system, his disease comes from a community infection and has lobar pneumonia located in the lower lung area. At the same time, the child’s white blood cells and CRP values are high, the doctor should be concerned that the child may have S. maltophilia infection. When treating patients, doctors can try to use drugs empirically, such as ceftazidime, instead of using ciprofloxacin, SMZ and other drugs that have relatively large side effects in children. It is worth mentioning that doctors also need to adjust the medication in a timely manner according to the efficacy evaluation and drug sensitivity of the children after the medication, so as to minimize the drug resistance of community-acquired infections. This will prevent the misuse of Meropenem, which has been given in a community patient and that too in a child. Its important to prevent this malpractise.Keywords: Stenotrophomonas maltophilia, community-acquired, children, treatment

Ziqi Jiang,&ast; Shanglin Jin,&ast; Xiaoyao Fan, Ke Cao, Ye Liu, Xuan Wang, Ying Ma, Leihong Xiang Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, 200040, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Leihong Xiang; Ying Ma, Department of Dermatology, Huashan Hospital, Fudan University, No. 12 Wulumuqizhong Road, Shanghai, 200040, People’s Republic of China, Tel: +86 21 52889999, Fax: +86 21 62489191, Email flora_xiang@vip.163.com; alle_ma@163.comBackground: Acne is a common inflammatory skin disease, while cannabidiol (CBD) is a representative non-psychoactive phytocannabinoid which has been proved to exert universal anti-inflammatory properties. This study aimed to explore the effect of CBD on acne inflammation induced by Cutibacterium acnes-derived extracellular vesicles (CEVs) in keratinocytes and reveal the underlying mechanisms.Methods: Normal human epidermal keratinocytes (NHEKs) were stimulated by CEVs in the presence of CBD or vehicle. Interleukin (IL)-6, IL-8, and tumor necrosis factor (TNF)-α levels were examined by RT-PCR and ELISA. The expression of cannabinoid type-2 (CB2) receptor and transient receptor potential vanilloid type-1 (TRPV1) was detected by Western blotting. TNF-α levels in the presence of CB2 receptor antagonist (AM630) or TRPV1 antagonist (Capsazepine) were detected by RT-PCR. The activation of MAPK and NF-κB signaling pathways and the nuclear translocation of NF-κB p65 upon CBD treatment were analyzed by Western blotting and immunofluorescence assay, respectively.Results: The expression of inflammatory cytokines (IL-6, IL-8 and TNF-α) in CEVs-stimulated NHEKs was suppressed by CBD. CB2 receptor expression was upregulated by CBD, whereas CEVs-promoted TRPV1 expression was downregulated by CBD. AM630 reversed TNF-α levels inhibited by CBD. Capsazepine exerted an inhibitory effect on CEVs-induced inflammation and had synergistic effect with CBD. The phosphorylation of ERK1/2 and NF-κB p65 and nuclear translocation of NF-κB p65 were induced by CEVs but reduced by CBD.Conclusion: The results indicated that CBD could inhibit inflammation induced by CEVs in NHEKs, which was mediated by activation of CB2 receptor and enhanced by the TRPV1 antagonist, through inactivation of the MAPK and NF-κB signaling pathways. CBD might be a potential novel strategy for acne treatment in the future.Keywords: cannabidiol, acne, inflammation, Cutibacterium acnes, keratinocytes

Xiaolei Han,1,2,&ast; Yongxiang Wang,2,3,&ast; Ziying Jiang,1 Yuanjing Li,4 Yi Dong,1 Lin Cong,1– 3 Tingting Hou,1– 3 Yajun Liang,4,5 Erika J Laukka,4 Yifeng Du,1– 3 Chengxuan Qiu1,4 1Department of Neurology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, People’s Republic of China; 2Department of Neurology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, People’s Republic of China; 3Shandong Provincial Clinical Research Center for Neurological Diseases, Jinan, Shandong Province, People’s Republic of China; 4Aging Research Center and Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet-Stockholm University, Stockholm, Sweden; 5Department of Global Public Health, Karolinska Institutet, Stockholm, Sweden&ast;These authors contributed equally to this workCorrespondence: Yifeng Du, Department of Neurology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, No. 324 Jingwuweiqi Road, Jinan, Shandong, 250021, People’s Republic of China, Tel +86-531-68776354, Fax +86-531-68773274, Email du-yifeng@hotmail.comPurpose: We explore the associations of individual and composite cardiovascular health metrics with all-cause dementia, Alzheimer’s disease, and vascular dementia among rural-dwelling older adults and the potential age variations in their associations.Patients and Methods: This community-based cross-sectional study included 4980 older adults (age ≥ 65 years; 57.23% women) from the baseline examination of MIND-China. In March–September 2018, data were collected via face-to-face interviews, clinical examinations, and laboratory test. We defined six cardiovascular health metrics according to the modified American Heart Association’s recommendations. We diagnosed dementia and its subtypes following the international criteria. Data were analyzed using logistic regression models.Results: Of all the participants, 250 were diagnosed with dementia, including 165 with Alzheimer’s disease and 75 with vascular dementia. Ideal composite global cardiovascular health metrics (vs poor composite metrics) were associated with a multi-adjusted odds ratio (95% confidence interval) of 0.62 (0.42– 0.93) for dementia, 0.88 (0.52– 1.48) for Alzheimer’s disease, and 0.31 (0.16– 0.60) for vascular dementia. Moreover, ideal biological cardiovascular health metrics were associated with multi-adjusted odds ratio of 0.52 (0.28– 0.95) for dementia and 0.21 (0.06– 0.77) for vascular dementia in young–old adults (65– 74 years), whereas ideal behavioral cardiovascular health metrics were associated with multi-adjusted odds ratio of 0.48 (0.26– 0.89) for dementia and 0.16 (0.06– 0.43) for vascular dementia in old–old adults (≥ 75 years).Conclusion: Our results suggest that ideal cardiovascular health metrics are cross-sectionally associated with a low likelihood of dementia and vascular dementia among rural-dwelling older Chinese adults. The associations vary with age, components of cardiovascular health metrics, and dementia subtypes.Keywords: cardiovascular health, dementia, Alzheimer’s disease, vascular dementia, population-based study

Min Jiang,&ast; Xiaoyao Fan,&ast; Ziqi Jiang, Huyan Chen, Ye Liu, Tianze Yu, Qiong Huang, Ying Ma Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, 200040, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qiong Huang; Ying Ma, Department of Dermatology, Huashan Hospital, Fudan University, No. 12 Wulumuqizhong Road, Shanghai, 200040, People’s Republic of China, Email blueqiong1972@163.com; alle_ma@163.comPurpose: Cutibacterium acnes (C. acnes) is closely associated with the pathogenesis of acne, and antibiotics targeting C. acnes have been widely used for decades. However, antibiotic resistance has been increasing rapidly. Membrane vesicles (MVs) have been found to play important roles in antibiotic resistance in some bacteria. We aimed to explore the mechanism of antibiotic resistance and the virulence components within C. acnes-derived MVs.Materials and Methods: We isolated clinical C. acnes strains from the lesions of acne patients who were sensitive or resistant to the antibiotics erythromycin and clindamycin. We analyzed the proteome of MVs from four sensitive C. acnes isolates and three resistant isolates by LC-MS/MS.Results: We identified 543 proteins within the MVs of clinical C. acnes strains. Several lipases, NlpC/P60, CAMP factor, and Hta domain protein were detected as virulence factors in the C. acnes-derived MVs. The levels of two lipases and FtsZ were significantly higher in resistant C. acnes-derived MVs compared with sensitive strains (p < 0.05).Conclusion: According to the implications of this study, improper antibiotic use might not only increase antibiotic resistance in C. acnes but could also further alter the cutaneous lipid composition and aggravate host inflammation, thus resulting in worse clinical manifestations in acne patients. This study re-emphasizes that the improper use of antibiotics should be treated more seriously in clinical practice. Furthermore, to combat multidrug resistance in C. acnes, this study suggests that FtsZ inhibitors could be useful.Keywords: Cutibacterium acnes, antibiotics, FtsZ inhibitor, membrane vesicles

Wei Zhang,1 Yue Qian,1 Xue Jin,2 Yixian Wang,1 Lili Mu,1 Zhixia Jiang2 1Department of Pathogen Biology, Guizhou Nursing Vocational College, Guiyang, People’s Republic of China; 2Guizhou Nursing Vocational College, Guiyang, People’s Republic of ChinaCorrespondence: Wei Zhang, Department of Pathogen Biology, Guizhou Nursing Vocational College, Guiyang, 550000, Guizhou, People’s Republic of China, Email lawrence2013@163.comBackground: SIRT7 has been shown to be expressed in many cancer types, including clear cell renal cell carcinoma (KIRC), but its functional role in this oncogenic context remains to be firmly defined. This study was designed to explore correlations between SIRT7 and KIRC characteristics using the TCGA database.Methods: Relationships between SIRT7 expression and KIRC patient clinicopathological characteristics were assessed through Kruskal–Wallis tests, Wilcoxon signed-rank tests, and logistic regression analyses. Area under the ROC curve (AUC) values were used to assess the prognostic value of SIRT7 as a means of classifying clear cell renal cell carcinoma patients. The functional role of SIRT7 in this cancer type was assessed through GO/KEGG enrichment analyses and immune cell infiltration analyses.Results: In KIRC patients, higher levels of SIRT7 expression were associated with Race, M stage, T stage (all P < 0.05). SIRT7 offered significant diagnostic value in ROC curve analyses (AUC = 0.912), and elevated SIRT7 levels were linked to worse patient overall survival (OS; P < 0.001). The expression of SIRT7 was independently related with KIRC patient OS (HR: 1.827; 95% CI: 1.346– 2.481; P< 0.001). In GO/KEGG analyses, SIRT7 was found to be associated with ubiquitin-mediated proteolysis and nucleotide excision repair. Higher SIRT7 expression was related to the enhanced infiltration of certain immune cells.Conclusion: Increased SIRT7 expression was associated with a worse KIRC patient prognosis, and immune infiltrates, suggesting it may offer value as a prognostic biomarker for this cancer type.Keywords: SIRT7, biomarker, KIRC, prognosis, tumor-immune infiltration

Jiangbo Ren,1,2,&ast; Anli Ren,1,2,&ast; Xizhi Deng,2 Zhengrong Huang,1 Ziyu Jiang,1 Zhi Li,2 Yan Gong1,3 1Department of Biological Repositories, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, People’s Republic of China; 2Department of Ophthalmology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, People’s Republic of China; 3Human Genetics Resource Preservation Center of Wuhan University, Wuhan University, Wuhan, Hubei, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yan Gong; Zhi Li, Tel +86 27 6781 1461; +86 27 6781 2622, Fax +86 27 6781 1471; +86 27 6781 3133, Email yan.gong@whu.edu.cn; 1103945483@qq.comAbstract: Age-related macular degeneration (AMD) is a blinding eye disease, whose incidence strongly increases with ages. The etiology of AMD is complex, including aging, abnormal lipid metabolism, chronic inflammation and oxidative stress. Long-chain polyunsaturated fatty acids (LCPUFA) are essential for ocular structures and functions. This review summarizes the regulatory effects of LCPUFA on inflammation in AMD. LCPUFA are related to aging, autophagy and chronic inflammation. They are metabolized to pro- and anti-inflammatory metabolites by various enzymes. These metabolites stimulate inflammation in response to oxidative stress, causing innate and acquired immune responses. This review also discusses the possible clinical applications, which provided novel targets for the prevention and treatment of AMD and other age-related diseases.Keywords: inflammation, long-chain polyunsaturated fatty acids, age-related macular degeneration

Xiao-kun Liu,1 Shan-lin Chen,1 Dan-ling Huang,1 Zi-shang Jiang,1 Yu-ting Jiang,1 Li-juan Liang,1 Lu-lu Qin2 1The First Affiliated Hospital of Hainan Medical University, Haikou, People’s Republic of China; 2Department of Social Medicine and Health Management, School of Medicine, Hunan Normal University, Changsha, People’s Republic of ChinaCorrespondence: Xiao-kun LiuThe First Affiliated Hospital of Hainan Medical University, 3 Xueyuan Road, Haikou, 571199, Hainan, People’s Republic of ChinaEmail lacyfairy@qq.comPurpose: Road safety research is important due to the large number of road traffic fatalities globally. This study investigated the influences of age, driving experience and other covariates on aggressive driving behavior.Methods: A cross-sectional survey was conducted in Yixing City, Wuxi City, Jiangsu Province, China. Regression analysis was applied to explore the influences of age and driving experience and their interactions with other covariates on aggressive driving behavior. Two analyses methodologies were used to assess the simple effect of the interactions. Firstly, the Jamovi automatic analysis classification program was used to calculate the simple slope test. Second, the SPSS macro program was also used to calculate the simple slope test also.Results: A total of 570 drivers (247 males, 282 females) participated in the survey. A negative correlation was found between age and aggressive driving behaviors, and a positive correlation was found between neuroticism and aggressive driving behaviors in the multiple regression analysis. Significant associations were also found between age, driving experience, and depression, as well as age, driving experience, and neuroticism. Simple slope tests showed that depressive symptoms could increase aggressive behaviors in the elderly and experienced drivers. When experiencing neuroticism, individuals with higher driving experience were more aggressive in driving than shorter experienced drivers.Conclusion: Age and neuroticism influenced aggressive driving behaviors. Veteran drivers could be aggressive drivers when experiencing depressive symptoms or neuroticism. Mobile intervention could be sent to the potentially risky drivers, which would be safe and broadly feasible to prevent aggressive driving behavior in the background of COVID-19.Keywords: aggressive driving behavior, age, driving experience, depressive symptoms, neuroticism

Yanhong Deng,1,&ast; Lishuo Shi,2,&ast; Jianxia Li,1,&ast; Zhipeng Jiang,3,&ast; Chaojun Xie,4 Shuangling Luo,3 Li Ling,5 Hualiang Lin,6 Zongqiu Chen,4 Yunlong Zhao,7 Liang Kang,3 Jun Yuan,4 Weiping Wen8 1Department of Medical Oncology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, Guangzhou, 510655, People’s Republic of China; 2Clinical Research Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, Guangzhou, 510655, People’s Republic of China; 3Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, Guangzhou, 510655, People’s Republic of China; 4Guangzhou Center for Disease Control and Prevention, Guangzhou, Guangdong Province, 510440, People’s Republic of China; 5Department of Medical Statistics, School of Public Health, Sun Yat-sen University, Guangzhou, 510080, People’s Republic of China; 6Department of Epidemiology, School of Public Health, Sun Yat-sen University, Guangzhou, 510080, People’s Republic of China; 7Medical Department, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, Guangzhou, 510655, People’s Republic of China; 8Department of Otolaryngology, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, Guangzhou, 510655, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Weiping WenDepartment of Otolaryngology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, No. 26 Yuan Cun Er Heng Road, Guangzhou, 510655, People’s Republic of ChinaTel +86-20-87333733Email wenwp@mail.sysu.edu.cnJun YuanGuangzhou Center for Disease Control and Prevention, No. 1, Qide Road of Baiyun District, Guangzhou, Guangdong Province, 510440, People’s Republic of ChinaTel +86-20-36052333-1816Email yuanjuncom@163.comBackground: The quarantine in dedicated hotels has become an inevitable safety measure due to the frequent cross-border travel since the outbreak of COVID-19. The aim of the present study was to explore the trends in the psychological status of individuals entering from high-risk areas of COVID-19 coronavirus while quarantining in dedicated hotels.Methods: A total of 591 individuals who isolated in dedicated hotels were recruited between March and June 2020. Participants self-reported mental symptoms [Self-rating Anxiety Scale (SAS) and Self-rating Depression Scale (SDS)] every three days during the quarantine. A mixed-effects linear regression model was used to assess the trends.Results: Participants reporting anxiety and depression symptoms at least one time during quarantine accounted for 4.5% and 18.4%, respectively. Their psychological status was alleviated during some first 9 days, and then it slightly deteriorated, which was suggested by SAS and SDS scores that were negatively correlated with the days of quarantine (T) (adjusted coefficient [β] − 0.81, 95% CI − 1.00 to − 0.62; and β − 0.75, 95% CI − 0.97 to − 0.53, respectively), and were positively correlated with the square of T (β 0.04, 95% CI 0.02 to 0.06; and β 0.04, 95% CI 0.02 to 0.06, respectively). The unemployed and 18∼ 30-year-old participants were prone to greater levels of psychological distress. No significant difference in the trend of mental health was found among different subgroups.Conclusion: The mental health of the people entering Guangzhou from high-risk areas of COVID-19 coronavirus resulted positive during the early period of quarantine in dedicated hotels, after which it deteriorated. The psychological status of individuals should be closely monitored at the beginning and after more than 9 days of quarantine, especially for individuals who are unemployed and 18∼ 30-year-old ones.Keywords: quarantine, dedicated hotels, psychological distress, COVID-19

Xiaoying Chao,1,&ast; Weiran Dai,1,&ast; Shuo Li,1 Chenyang Jiang,1 Zhiyuan Jiang,2 Guoqiang Zhong1 1Department of Cardiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People’s Republic of China; 2Hypertension Division, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Guoqiang ZhongDepartment of Cardiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, People’s Republic of ChinaTel +86 13978635329Email drguoqiang@sina.comZhiyuan JiangHypertension Division, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, People’s Republic of ChinaTel +86 13597006702Email drjzy123@sina.comBackground: Circular RNA (circRNA) has been receiving increased attention in the research of atrial fibrillation (AF). Our study aims to find potential circRNAs and identify the circRNA-miRNA-mRNA regulatory network in AF based on bioinformatics analysis.Methods: GSE129409 was retrieved from the Gene Expression Omnibus (GEO) database, and we used R software to analyze the differentially expressed circRNAs (DECs). Subsequently, we used several bioinformatics methods to obtain the target miRNAs and the target genes. Next, we performed Gene Ontology (GO) classification and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of the target genes. Then, we used Cytoscape 3.8.2 software to visualize and construct the circRNA-miRNA-mRNA regulatory network, the protein–protein interaction (PPI) network, and the autophagy-related genes network.Results: We identified a total of 21 DECs, including 6 upregulated DECs and 15 downregulated DECs. After further analysis, we obtained a circRNA-miRNA-mRNA regulatory network consisting of 11 DECs, 9 target miRNAs and 410 target genes, and a PPI network. Finally, the potential novel genes of autophagy in AF were revealed by bioinformatics analysis.Conclusion: This study could explore the potential role of circRNA, autophagy-related genes and construct the circRNA-miRNA-mRNA regulation network in AF.Keywords: circular RNA, bioinformatics analysis, ceRNA, autophagy, atrial fibrillation

Lemeng Zhang, Yongzhong Luo, Tianli Cheng, Jianhua Chen, Hua Yang, Xiaoping Wen, Zhou Jiang, Haitao Li, Changqie Pan Thoracic Medicine Department 1, Hunan Cancer Hospital, Changsha, Hunan Province, 410013, People’s Republic of ChinaCorrespondence: Yongzhong Luo Tel/Fax +86-731-89762220Email luoyongzhong@hnca.org.cnPurpose: The prognostic value of an N6-methyladenosine (m6A) methylation-related immune gene signature for lung adenocarcinoma (LUAD) was investigated.Patients and Methods: Gene expression and clinical phenotype data of LUAD patients were downloaded from The Cancer Genome Atlas database. A list of immune-related genes was retrieved from the InnateDB database. Correlation analysis, survival analysis, and univariate and multivariate Cox regression analyses were performed. After allocating patients into a high-risk or a low-risk group, the corresponding survival rates, immune microenvironment, expression of immune checkpoint genes, and modulation of Kyoto Encyclopedia of Genes and Genomes pathways were examined. Finally, the expression levels of prognostic biomarkers were assessed in the GSE126044 dataset.Results: Seven m6A-related immune prognostic genes were identified. High expression of PSMD10P1, DIDO1, ABCA5, and CIITA was associated with high survival rates, while that of PRC1, ZWILCH, and ANLN was associated with low survival rates. The high- and low-risk groups showed significant differences in terms of the abundance of six tumor-infiltrating immune cell types and expression of 12 immune checkpoint genes. The risk group acted as an independent prognostic factor (hazard ratio = 0.398, 95% confidence interval = 0.217– 0.729, P = 0.003). Finally, the developed nomogram could predict most efficiently the 1-, 2-, and 3-year survival probability of LUAD patients with a C-index of 0.833.Conclusion: A seven-gene risk signature, associated with the immune microenvironment in LUAD, showed independent prognostic value.Keywords: lung adenocarcinoma, N6-methyladenosine methylation, immune-related genes, immune microenvironment, prognostic signature

Huan Wu,1,2,* Hanchu Wang,3,* Zhenyou Jiang,4 Yue Chen1 1Department of Medical Laboratory, The Second Clinical Medical College, Jinan University (Shenzhen People’s Hospital), Shenzhen, People’s Republic of China; 2Integrated Chinese and Western Medicine Postdoctoral Research Station, Jinan University, Guangzhou, People’s Republic of China; 3The Second Clinical Medical College, Jinan University, Guangzhou, People’s Republic of China; 4Department of Microbiology and Immunology, College of Basic Medicine and Public Hygiene, Jinan University, Guangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yue ChenDepartment of Medical Laboratory, The Second Clinical Medical College, Jinan University (Shenzhen People’s Hospital), Shenzhen, People’s Republic of ChinaTel/Fax +86-13662278187Email chenyue_dr@163.comZhenyou JiangDepartment of Microbiology and Immunology, College of Basic Medicine and Public Hygiene, Jinan University, Guangzhou, People’s Republic of ChinaTel/Fax +86-20-85226677Email tjzhy@jnu.edu.cnBackground: Secretome genes, encoding proteins secreted from the cell, are involved in the tumor immune response and correlated with levels of tumor mutation burden (TMB) in multiple tumors. This study aimed to identify core secretome genes and their potential association with immunomodulators and immune infiltration in high TMB groups across 14 major solid tumors through bioinformatics analysis.Methods: Multi-omics data for 14 major solid tumors were downloaded from The Cancer Genome Atlas (TCGA) database. Patients were divided into high TMB (TMB-high) and low TMB (TMB-low) groups using the median TMB values for each of the solid tumors. The CIBERSORT algorithm was conducted to estimate the proportion of 22 tumor-infiltrating immune cells (TIICs). Kaplan–Meier analysis and the log-rank test were utilized to screened prognosis-related genes. The correlations between core secretome genes and TIICs were analyzed using Spearman correlation coefficients.Results: In TMB-high groups, multi-omics data analysis revealed that secretome genes were strongly associated with clinical characteristics, and 65 prognosis-related secretome genes were screened. Among the prognosis-related genes, 21 core secretome genes were identified, and strongly associated with five types of TIICs, namely activated NK cells, follicular helper T cells, CD8 T cells, and macrophages M0 and M2. Notably, three secretome genes (ADAMTS12, COL12A1, and COL5A2) were significantly related to immunomodulators and TIICs in multiple solid tumors. In addition, 12 core secretome genes were significantly differentially expressed between responding and non-responding patients receiving immunotherapy. Furthermore, core secretome genes may be involved in the PI3K/AKT signaling pathway.Conclusion: We examined the prognostic significance of secretome genes and their potential association with immunomodulators and immune infiltration across 14 major solid tumors. In summary, three secretome genes (ADAMTS12, COL12A1, and COL5A2) may be pivotal mediators of immune infiltration in TMB-high patients, which may help to identify patients who could benefit from immunotherapy.Keywords: secretome genes, tumor mutation burden, immune infiltration, prognosis, solid tumors

Zhiying Pang,&ast; Zengxin Jiang,&ast; Runwen Zhu, Chunfeng Song, Han Tang, Lu Cao, Changan Guo Department of Orthopedic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Changan Guo; Lu CaoDepartment of Orthopedic Surgery, Zhongshan Hospital, Fudan University, NO. 180 Feng Lin Road, Xuhui District, Shanghai, 200032, People’s Republic of ChinaTel +86 13681975321; +86 13482794964Email changanguo@hotmail.com; caolu922@126.comPurpose: Oxidative stress-induced chondrocyte apoptosis and extracellular matrix (ECM) degradation plays an important role in the progression of osteoarthritis (OA). Bardoxolone methyl (BM), a semisynthetic triterpenoid, exerts strong effect against oxidative stress. The purpose of the present study was to determine the effectiveness of bardoxolone-methyl (BM) in preventing oxidative stress-induced chondrocyte apoptosis and extracellular ECM degradation in vitro and the role of alleviating OA progression in vivo.Methods: Oxidative damage was induced by 25 mM tert-butyl hydroperoxide (TBHP) for 24 h in rat chondrocytes. 0.025 and 0.05 μM bardoxolone-methyl (BM) were used in vitro treatment. Ex-vivo cartilage explant model was established to evaluate the effect of BM on oxidative stress-induced ECM degradation. The mouse OA model was induced by surgical destabilization of the medial meniscus.Results: In vitro, 0.025 and 0.05 μM BM reduced TBHP-induced excessive ROS generation, improved cell viability, increased malondialdehyde level and decreased superoxide dismutase level. 0.025 and 0.05 μM BM prevented TBHP-induced mitochondrial damage and apoptosis in chondrocytes BM activated heme oxygenase-1 (HO-1)/NADPH quinone oxidoreductase 1 (NOQ1) signaling pathway through targeting nuclear factor erythroid derived-2-related factor 2 (Nrf2). Additionally, BM treatment enhanced the expression levels of aggrecan and collagen II and inhibited the expression levels of matrix metalloproteinase 9 (MMP 9), MMP 13, Bax and cleaved-caspase-3. BM increased proteoglycan staining area and IOD value in ex vivo cultured experiment cartilage explants and improved the OARSI score, stands, max contact mean intensity, print area and duty cycle in mouse OA model.Conclusion: BM prevented oxidative stress-induced chondrocyte apoptosis and ECM degradation in vitro and alleviated OA in vivo, suggesting that BM serves as an effective drug for treatment with OA.Keywords: osteoarthritis, chondrocyte apoptosis, extracellular matrix degradation, oxidative stress, bardoxolone-methyl