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Guanghui Zheng,1– 3 Yijun Shi,1– 3 Jialu Sun,1 Siqi Wang,1 Lingye Qian,4 Hong Lv,1– 3 Guojun Zhang,1– 3 Kelin Chen1– 3 1Clinical Laboratory of Beijing Tiantan Hospital, Capital Medical University, Beijing, People’s Republic of China; 2NMPA Key Laboratory for Quality Control of in vitro Diagnostics, Beijing, People’s Republic of China; 3Beijing Engineering Research Center of Immunological Reagents Clinical Research, Beijing, People’s Republic of China; 4Clinical Laboratory of Beijing Anzhen Hospital, Capital Medical University, Beijing, People’s Republic of ChinaCorrespondence: Guojun Zhang; Kelin Chen, Clinical Laboratory of Beijing Tiantan Hospital, Capital Medical University, NO. 119 Nansihuan West Road, Fengtai District, Beijing, People’s Republic of China, Tel +86 15811219411 ; +86 13810876107, Email zgjlunwen@163.com; chenkelin214316@163.comAim: To express the clinical characteristics of patients with post-neurosurgical meningitis (PNM) and launch a survival analysis to screen mortality predictors.Methods: A cohort analysis containing more than 70000 patients was evaluated, and all of them received neurosurgical procedure. Clinical and microbial epidemiology, therapy and mortality of PNM patients were reviewed. Multi-variable Cox proportional hazard models were applied to achieve survival analysis.Results: About 900 PNM patients from 3244 cases were selected for characteristics and survival analysis, the mean age of them was 41 (27– 54) years, 516 (57.3%) were men and 384 (42.7%) were women. The 28-day mortality was 12.4% (112 of 900) in patients with PNM. Hypertension, external ventricular drainage (EVD), and lumbar drainage (LD) are mortality predictors for PNM, with a hazard ratio (HR) of 2.641 (95% C.I. 1.563– 4.464, P< 0.001), 2.196 (95% C.I. 1.317– 3.662, P=0.003), and 1.818 (95% C.I. 1.126– 2.936, P=0.014). In treatment, the outcome of patients receiving three or more antibiotic combinations is better than that of patients receiving dual-drug combinations.Conclusion: The mortality of patients with PNM was relatively high, and the risk factors related to 28-days mortality were hypertension, EVD and LD and treatment with three or more antibiotics are much better.Keywords: Post-neurosurgical meningitis, survival analysis, mortality, characteristics, treatment

Lingling Ding,1,&ast; Guowan Zheng,1– 3,&ast; Aoni Zhou,4 Fahuan Song,1– 3 Lei Zhu,5 Yefeng Cai,6 Yehao Guo,1 Tebo Hua,7 Yunye Liu,1 Wenli Ma,1 Yiqun Hu,1– 3 Yawen Guo,1– 3 Chuanming Zheng1– 3 1Otolaryngology & Head and Neck Center, Cancer Center, Department of Head and Neck Surgery, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, 310000, People’s Republic of China; 2Zhejiang Provincial Clinical Research Center for Malignant Tumor, Hangzhou, Zhejiang, 310000, People’s Republic of China; 3Zhejiang Key Laboratory of Precision Medicine Research on Head & Neck Cancer, Hangzhou, Zhejiang, 310000, People’s Republic of China; 4Hangzhou Normal University, Hangzhou, Zhejiang, 311121, People’s Republic of China; 5Department of Thyroid Surgery, The Fifth Hospital Affiliated to Wenzhou Medical University, Lishui Central Hospital, Lishui, Zhejiang, 323000, People’s Republic of China; 6Department of Thyroid Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, People’s Republic of China; 7Department of Thyroid Surgery, Ningbo Medical Centre Lihuili Hospital, Ningbo, Zhejiang, 315000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yawen Guo; Chuanming Zheng, Department of Head and Neck Surgery, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, No. 158, Shangtang Road, Hangzhou, Zhejiang, People’s Republic of China, Email mingdoc@163.com; gyw20072644@126.comBackground: The incidence of papillary thyroid cancer (PTC) has been increasing annually; however, early diagnosis can improve patient outcomes. Pyroptosis is a programmed cell death modality that has received considerable attention recently. However, no studies have reported using pyroptosis-related genes in PTC diagnosis.Methods: Analyzed 33 pyroptosis-related genes in PTC transcriptome data from the Gene Expression Omnibus database. Subsequently, used the Least Absolute Shrinkage and Selection Operator (LASSO) model to construct a PTC molecular diagnostic model. Furthermore, confirmed differences in the expression of five genes between PTC and non-tumor tissues using immunohistochemistry. Collected 338 PTC and control samples to construct a five-gene PTC diagnostic model, which was then validated using a training set and underwent correlation analysis with immune cell infiltration. Additionally, validated the biological functions of the core gene NOD1 in vitro.Results: The five-gene PTC diagnostic model demonstrated good diagnostic value for PTC. Moreover, identified three reliable subtypes of pyroptosis and found that NOD1 is involved in tumor-suppressive microenvironment formation. Notably, patients with high NOD1 expression had lower Progression-Free Survival (PFS). Additionally, NOD1 expression was positively correlated with immune markers such as CD47, CD68, CD3, and CD8. Lastly, inhibiting NOD1 showed significant anti-PTC activity in vitro.Conclusion: Our results suggest that pyroptosis-related genes can be used for PTC diagnosis, and NOD1 could be a promising therapeutic target.Keywords: pyroptosis-related genes, papillary thyroid cancer, PTC, immune cell infiltration, bioinformatic, diagnosis model

Lifen Lu,1 Di Sheng,1 Xiaowei Xia,2 Guanghui Chen,3 Jiali Liang,4 Xiulan Shen,1 Gui Zheng1 1Department of Nursing, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People’s Republic of China; 2Ministry of Health, the Third Hospital of Ninghai County, Ningbo, Zhejiang, People’s Republic of China; 3Ministry of Health, the Liangzhu Street Community Health Service Center, Yuhang District, Hangzhou, Zhejiang, People’s Republic of China; 4Department of Nursing, the First People’s Hospital of Yuhang District, Hangzhou, Zhejiang, People’s Republic of ChinaCorrespondence: Xiulan Shen; Gui Zheng, Department of Nursing, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People’s Republic of China, Email shenxl@zju.edu.cn; zhenggui1119@zju.edu.cnAim: To investigate the emotional response of hospital staff to the Depression Anxiety Stress Scale-21 (DASS-21) over the COVID-19 pandemic and after the relaxation of prevention and control measures in Zhejiang Province, China, and identify influencing factors.Design: Multicenter online cross-sectional design.Methods: From January 10, 2023, to January 20, 2023, 1054 hospital employees in Zhejiang, China, were recruited using WeChat. Data was gathered via online, self-administered surveys. T-tests and one-way analyses of variance, Pearson’s correlation analysis, and multiple linear stepwise regression analyses were used to examine the data.Results: More than 90% of hospital employees were infected with COVID-19. Through regression analysis, the following variables were found to be independent predictors of emotional response to DASS-21: resilience (− 13.346, P < 0.0001), sleep (14.689, P < 0.0001), friend support (− 4.278, P < 0.0001), education level (2.699, P = 0.007), and marriage (− 2.214, P = 0.027). The emotional responses were not as severe as predicted, but they were still well above the Chinese norm. A longitudinal comparison of DASS-21 emotional responses with similar studies showed a parabolic downward trend over time.Conclusion: Our results identified education level, marriage, friend support, resilience, and sleep as independent predictors of emotional responses to the DASS-21 among hospital workers in this outbreak. Improving the mental resilience and sleep status of staff is a key target. Unmarried medical personnel with higher education should be given greater attention and support by management. In addition, there is still room for further improvement in the government and societal responses to similar outbreaks. The study also found a parabolic downward trend in DASS-21 emotional responses among hospital workers during the COVID-19 outbreak over time.Keywords: COVID-19, hospital staff, DASS-21 emotional response, influencing factors, trajectory of change

Yibin Lin,1,2 Lehua Liu,1 Siyang Lu,1 Linqi Fan,1 Huaqi Hu,1 Xuanyin Wang,1 Jichao Zhu,3 Xinhua Qiang,4 Jie He,5 Hongchang Zhou,1,2,6 Shengwen Shao,1,6 Gaoming Zheng7 1School of Medicine, Huzhou University, Huzhou, 313000, People’s Republic of China; 2Key Laboratory for Precise Prevention and Control of Major Chronic Diseases, Huzhou University, Huzhou, 31300, People’s Republic of China; 3Clinical Laboratory, Huzhou Central Hospital, Huzhou, 313000, People’s Republic of China; 4Clinical Laboratory, First People’s Hospital Affiliated to Huzhou University, Huzhou, 313000, People’s Republic of China; 5Infectious Diseases Department, First People’s Hospital Affiliated to Huzhou University, Huzhou, 313000, People’s Republic of China; 6Key Laboratory of Vector Biology and Pathogen Control of Zhejiang Province, Huzhou University, Huzhou, 313000, People’s Republic of China; 7Clinical Laboratory, Affiliated Hospital of Hangzhou Normal University, Hangzhou, 310015, People’s Republic of ChinaCorrespondence: Gaoming Zheng; Shengwen Shao, Email zheng151031@sina.com; shaoshw@zjhu.edu.cnBackground: Bacillus cereus is a common bacterium found in the environment. Some strains can cause food poisoning, and very few can cause clinically severe infections, leading to death. Here, we characterized the genome sequence of B. cereus LIN78 isolated from teeth with deep caries and compared it with those of 25 other related species.Methods: Third-generation sequencing technology, bacteriological analyses, biochemistry, and mass spectrometry were applied to characterize the drug-resistance genes and virulence factors of B. cereus LIN78.Results: The complete genome sequence of B. cereus Lin78 consists of 5647 genes distributed on a circular chromosome, a 393 kbp plasmid, and 928 pseudogenes (37.4% of whole-genome DNA). The LIN78 genome contains 14 sets of 16s, 23s, and 5s ribosomal RNA operons; 106 tRNA genes, one tmRNA, 12 genomic islands, six prophases, 64 repeats; 37 antibiotic-resistant genes; and 1119 putative virulence genes, including enterotoxins and cytolysins. The B. cereus LIN78 genome carries multiple copies of non-ribosomal polypeptide synthetase (NRPS) and post-translationally modified peptides (RiPPs). Phylogenetic analysis of the 26 B. cereus strains showed that B. cereus LIN78 is evolutionarily closely related to B. thuringiensis ATCC 10792 and B. cereus ATCC 14579.Conclusion: The newly isolated B. cereus carries many virulence genes, including enterotoxins and hemolysins, similar to B. anthracis, and multiple antibiotic resistance genes. These findings suggest that the strain has a potential risk of causing disease. Our studies are vital for further exploration of the evolution of B. cereus, its pathogenic mechanisms, and the control and treatment of bacterial infections.Keywords: bacillus cereus, whole-genome DNA sequencing, virulence factor, drug resistance gene, human teeth

Xiaoguang Xiao,1 Jianhai Sun,2 Dongsheng Zhang,3 Linjun Li,4 Haibo Zhou,5 Yongjun Li,6 Quan Li,7 Zhongshi He,8 Yang Fu,9 Qiwen Duan,10 Guping Zheng,11 Ze Tang,12 Qian Chu,1,&ast; Yuan Chen1,&ast; 1Department of Oncology, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China; 2Department of Oncology, Hubei Zhongshan Hospital, Wuhan, Hubei, People’s Republic of China; 3Department of Oncology, Suizhou Hospital, Hubei University of Medicine, Suizhou, Hubei, People’s Republic of China; 4Department of Oncology, Hubei Provincial Hospital of Integrated Chinese and Western Medicine, Wuhan, Hubei, People’s Republic of China; 5Department of Oncology, Yichang Central People’s Hospital, Yichang, Hubei, People’s Republic of China; 6Department of Oncology, Yichang Second People’s Hospital, Yichang, Hubei, People’s Republic of China; 7Department of Oncology, Xiangyang Central Hospital, Xiangyang, Hubei, People’s Republic of China; 8Department of Oncology, Xiangyang No 1 People’s Hospital Affiliated to Hubei University of Medicine, Xiangyang, Hubei, People’s Republic of China; 9Department of Oncology, Xiangyang Hospital of Traditional Chinese Medicine, Xiangyang, Hubei, People’s Republic of China; 10Department of Oncology, Taihe Hospital, Shiyan, Hubei, People’s Republic of China; 11Department of Oncology, Xiaogan Central Hospital, Xiaogan, Hubei, People’s Republic of China; 12Department of Oncology, Huangshi Central Hospital, Huangshi, Hubei, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qian Chu; Yuan Chen, Email qianchu@tjh.tjmu.edu.cn; chenyuantj2023@126.comBackground: Studies have shown that oral oxycontin tablets can be used for opioid titration. The European Society for Medical Oncology (ESMO) guidelines for adult cancer pain recommend opioid titration through the parenteral route, usually the intravenous or subcutaneous route. Patient-controlled subcutaneous analgesia (PCSA) with hydromorphone needs further evaluation for opioid titration. This prospective multicenter study was designed to compare the efficacy and safety of hydromorphone PCSA with oral oxycontin tablets for opioid titration of cancer pain.Patients and Methods: Eligible patients with cancer pain were randomly assigned in a 1:1 ratio to the PCSA group or the oxycontin group for dose titration. Different titration methods were given in both groups depending on whether the patient had an opioid tolerance. The primary endpoint of this study was time to successful titration (TST).Results: A total of 256 patients completed this study. The PCSA group had a significantly lower TST compared with the oxycontin group (median [95% confidence interval (CI)], 5.5[95% CI:2.5– 11.5] hours vs.16.0 [95% CI:11.5– 22.5] hours; p< 0.001). The frequency (median; interquartile) of breakthrough pain (Btp) over 24 hours was significantly lower in the PCSA group (2.5;2.0– 3.5) than in the oxycontin group.(3.0; 2.5– 4.5) (p=0.04). The pain was evaluated by numeric rating scale (NRS) score at 12 hours after the start of titration. The pain score (median; interquartile) was significantly lower in the PCSA versus the oxycontin group (2.5;1.5– 3.0) vs 4.5;3.0– 6.0) (p=0.02). The equivalent dose of oral morphine (EDOM) for a successful titration was similar in both groups (p=0.29), but there was a significant improvement in quality of life (QoL) in both groups (p=0.03). No between-group difference in the incidence of opioid-related adverse effects was observed (p=0.32).Conclusion: Compared with oral oxycontin tablet, the use of PCSA with hydromorphone achieved a shorter titration duration for patients with cancer pain (p< 0.001), without significantly increasing adverse events (p=0.32).Keywords: cancer pain, opioid titration, oxycontin tablets, hydromorphone, patient-controlled subcutaneous analgesia

Abstract Extracellular vesicles (EVs) have been implicated in metastasis and proposed as cancer biomarkers. However, heterogeneity and small size makes assessments of EVs challenging. Often, EVs are isolated from biofluids, losing spatial and temporal context and thus lacking the ability to access EVs in situ in their native microenvironment. This work examines the capabilities of label-free nonlinear optical microscopy to extract biochemical optical metrics of EVs in ex vivo tissue and EVs isolated from biofluids in cases of human breast cancer, comparing these metrics within and between EV sources. Before surgery, fresh urine and blood serum samples were obtained from human participants scheduled for breast tumor surgery (24 malignant, 6 benign) or healthy participants scheduled for breast reduction surgery (4 control). EVs were directly imaged both in intact ex vivo tissue that was removed during surgery and in samples isolated from biofluids by differential ultracentrifugation. Isolated EVs and freshly excised ex vivo breast tissue samples were imaged with custom nonlinear optical microscopes to extract single-EV optical metabolic signatures of NAD(P)H and FAD autofluorescence. Optical metrics were significantly altered in cases of malignant breast cancer in biofluid-derived EVs and intact tissue EVs compared to control samples. Specifically, urinary isolated EVs showed elevated NAD(P)H fluorescence lifetime in cases of malignant cancer, serum-derived isolated EVs showed decreased optical redox ratio in stage II cancer, but not earlier stages, and ex vivo breast tissue showed an elevated number of EVs in cases of malignant cancer. Results further indicated significant differences in the measured optical metabolic signature based on EV source (urine, serum and tissue) within individuals.

Fan Zhang,1,2 Yan Han,1,2 Guojun Zheng,3 Wenjian Li4 1Department of Endocrinology, Changzhou Third People’s Hospital, Changzhou Medical Center, Nanjing Medical University, Changzhou, Jiangsu, People’s Republic of China; 2Department of Clinical Nutrition, Changzhou Third People’s Hospital, Changzhou Medical Center, Nanjing Medical University, Changzhou, Jiangsu, People’s Republic of China; 3Clinical Laboratory, Changzhou Third People’s Hospital, Changzhou Medical Center, Nanjing Medical University, Changzhou, Jiangsu, People’s Republic of China; 4Department of Urology, Changzhou Third People’s Hospital, Changzhou Medical Center, Nanjing Medical University, Changzhou, Jiangsu, People’s Republic of ChinaCorrespondence: Wenjian Li, Department of Urology, Changzhou Third People’s Hospital, Changzhou Medical Center, Nanjing Medical University, 300 Lanling North Road, Changzhou, Jiangsu, 213001, People’s Republic of China, Tel +86-0519-82009011, Email bolite@163.comPurpose: This research aims to examine and scrutinize gender variations in the incidence of diabetic nephropathy (DN) and the trajectory of renal function in type 2 diabetes mellitus (T2DM) patients.Patients and Methods: We conducted a retrospective cohort study that enrolled 1549 patients diagnosed with T2DM from May 2015 to July 2023. We separately compared the clinical characteristics of male and female participants with and without DN. We utilized the Kaplan-Meier method to examine the cumulative incidence of DN among T2DM patients of varying genders. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated using univariable and multivariable Cox proportional hazards regression analysis to evaluate the correlation between various factors and the risk of DN incidence. Multiple linear regression was utilized to investigate the relationship between ΔeGFR% and each factor. Logistic regression with cubic spline function and smooth curve fitting was employed to analyze the nonlinear link between ΔeGFR% and the risk of DN among participants of different genders.Results: The prevalence of DN was higher in female participants (17.31%) than in male participants (12.62%), with a significant cumulative risk ratio (1.33 [1.02– 1.73], P = 0.034). Multiple linear regression analysis revealed that creatinine, female gender, blood urea nitrogen, alkaline phosphatase, and total cholesterol had a significant impact on ΔeGFR% in T2DM patients, with standardized β coefficients of − 0.325, − 0.219, − 0.164, − 0.084, and 0.071, respectively. The restricted cubic spline analysis demonstrated a strong negative association between ΔeGFR% and the risk of developing DN (P < 0.001).Conclusion: Both male and female patients with T2DM had a higher prevalence of DN over the 5-year follow-up period. However, women had a greater risk of developing DN and a faster decline in renal function compared to men.Keywords: gender differences, type 2 diabetes mellitus, nephropathy, renal function, glomerular filtration rate estimates

Jianjun Huang,1 Fangping Shao,2 Bin Chen,1 Guanrong Zheng,1 Jia Shen,1 Shenzhong Qiu1 1Department of Neurosurgery, The First People’s Hospital of Fuyang District of Hangzhou City, Hangzhou, People’s Republic of China; 2Emergency Department, The First People’s Hospital of Fuyang District of Hangzhou City, Hangzhou, People’s Republic of ChinaCorrespondence: Shenzhong Qiu, Department of Neurosurgery, The First People’s Hospital of Fuyang District of Hangzhou City, Hangzhou, People’s Republic of China, Email chengiftboy@163.comBackground: Secreted protein acidic and rich in cysteine-like 1 (SPARCL1) regulates synaptic stability and is up-regulated during axonal regeneration. Here, serum SPARCL1 was determined for estimating severity and prognosticating early neurological deterioration (END) and functional outcomes of acute intracerebral hemorrhage (ICH).Methods: In this prospective observational cohort study of 156 patients with supratentorial ICH, blood samples of 53 were acquired not only at admission but also ad days 1, 3, 5, 7 and 10. Another group of 53 healthy controls were recruited. The modified Rankin Scale (mRS) scores of 3– 6 at poststroke six months were regarded as poor prognosis.Results: As opposed to controls, serum SPARCL1 levels were markedly elevated during the early ten days after ICH, with the highest levels at days 1 and 3. Admission serum SPARCL1 levels were independently correlated with National Institutes of Health Stroke Scale scores and hematoma volume, were significantly increased in the order of six-month mRS scores from 0 to 6 and were independently correlated with six-month mRS scores. Serum SPARCL1 levels were linearly related to risks of poor six-month prognosis and END under restricted cubic spline, had significant efficiency under receiver operating characteristic (ROC) curve and were independently associated with END and poor prognosis. Subgroup analysis confirmed that no interactions existed for associations of serum SPARCL1 levels with other variables, such as age, gender and some specific vascular risk factors. END and poor prognosis prediction models integrating serum SPARCL1 were displayed using the two nomograms. The poor prognosis prediction model, but END prediction model not, performed well under calibration curve, decision curve and ROC curve.Conclusion: A substantial elevation of serum SPARCL1 levels during the early period after ICH is independently related to illness severity and poor neurological outcomes, thus signifying that serum SPARCL1 may appear as a prognostic biomarker of ICH.Keywords: Secreted protein acidic and rich in cysteine-like 1, intracerebral hemorrhage, early neurologic deterioration, prognosis, severity, biomarkers

Heng Wang,1,&ast; Tingting Gao,1,&ast; Ruijing Zhang,2,&ast; Jie Hu,1 Siqi Gao,1 Yuwen Wang,1 Xiaotong Qi,1 Yun Zhou,3 Guoping Zheng,1,4 Honglin Dong1 1Department of Vascular Surgery, The Second Hospital of Shanxi Medical University, Taiyuan, People’s Republic of China; 2Department of Nephrology, The Second Hospital of Shanxi Medical University, Taiyuan, People’s Republic of China; 3Shanxi Provincial Integrated TCM and WM Hospital, Taiyuan, People’s Republic of China; 4Centre for Transplant and Renal Research, Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW, Australia&ast;These authors contributed equally to this workCorrespondence: Honglin Dong, Department of Vascular Surgery, The Second Hospital of Shanxi Medical University, No. 382, Wuyi Road, Xinghualing District, Taiyuan City, Shanxi Province, 030001, People’s Republic of China, Email honglindong@sxmu.edu.cn Guoping Zheng, Centre for Transplant and Renal Research, Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW, Australia, Email guoping.zheng@sydney.edu.auBackground: Contrast-induced acute kidney injury (CI-AKI) is considered to be the third leading cause of hospital-acquired kidney injury. Current studies mostly suggest that contrast agents mainly harm renal tubular epithelial cells, but we hypothesized that the development of CI-AKI should be the result of the interaction of renal vascular and tubular injury.Methods: First we constructed a CI-AKI mouse model and verified the success of the model by pathological injury and serum creatinine level. Immunohistochemistry, protein quantification and qRT-PCR were used to detect the location and level of expression of neutrophil extracellular traps (NETs) in the kidney. Then, we blocked the in vivo accumulation of NETs using GSK484 and DNase I and detected the expression of NETs and the damage of glomerular and peritubular capillaries.Results: We first identified the presence of NETs in CI-AKI mice, and NETs were mainly accumulated in glomeruli and peritubular capillaries. The expression of NETs was positively correlated with the severity of CI-AKI kidney. After inhibition of NETs release or promotion of NETs degradation by drugs, renal vascular endothelial cell injury was reduced and renal pathological changes and creatinine levels were reversed in CI-AKI mice. In addition, inhibition of NETs reduced apoptosis and pyroptosis of renal cells and attenuated inflammation in vivo.Conclusion: These findings suggest that NETs are involved in the development of CI-AKI by damaging glomerular and peritubular capillary endothelial cells. This study will provide a new strategy for clinical prevention and treatment of CI-AKI.Keywords: contrast-induced acute kidney injury, neutrophils, neutrophil extracellular traps, glomeruli, peritubular capillaries

Caiyun Wang,1 Hongmei Xu,2 Gang Liu,3,4 Jing Liu,5 Hui Yu,6 Biquan Chen,7 Guo Zheng,8 Min Shu,9 Lijun Du,10 Zhiwei Xu,11 Lisu Huang,1,12 Haibo Li,13 Sainan Shu,14 Yinghu Chen,1 Corporate Authors of Chinese Pediatric Bacterial Meningitis Surveillance (CPBMS) Study Group:Dong Wang, Huiling Deng, Songting Bai, Qingwen Shan, Chunhui Zhu, Jianmei Tian, Jianhua Hao, Aiwei Lin, Daojiong Lin, Jinzhun Wu, Xinhua Zhang, Qing Cao, Zhongbin Tao, Yuan Chen, Guolong Zhu, Ping Xue, Zhengzhen Tang, Xuewen Su, Zhenghai Qu, Shiyong Zhao, Lin Pang On behalf of The CPBMS Study Group1Department of Infectious Disease, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, National Children’s Regional Medical Center, Hangzhou, Zhejiang, People’s Republic of China; 2Department of Infectious Disease, Children’s Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 3Department of Infectious Diseases, Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, People’s Republic of China; 4Research Unit of Critical Infection in Children, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China; 5Department of Infectious Disease, Hunan Children’s Hospital, Changsha, Hunan, People’s Republic of China; 6Department of Infectious Disease, The Children’s Hospital of Fudan University, Shanghai, People’s Republic of China; 7Department of Infection, Anhui Province Children’s Hospital, Hefei, Anhui, People’s Republic of China; 8Department of Neurology, Children’s Hospital of Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China; 9Department of Pediatrics, West China Second University Hospital, Sichuan University/ West China Women’s and Children’s Hospital, Chengdu, Sichuang, People’s Republic of China; 10Department of Neurology, Children’s Hospital of Shanxi, Taiyuan, Shanxi, People’s Republic of China; 11Pediatric Inpatient Ward, The 2nd Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China; 12Department of Infectious Disease, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 13Outpatient Department of Pediatrics, The First Hospital of Jilin University, Changchun, Jilin, People’s Republic of China; 14Department of Pediatric Infection and Gastroenterology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China; The CPBMS team: the Children’s Hospital of Zhejiang University School of Medicine; National Clinical Research Center for Child Health; National Children’s Regional Medical Center; Children’s Hospital of Chongqing Medical University; Beijing Children’s Hospital; Capital Medical University; National Center for Children’s Health; Research Unit of Critical Infection in Children; Chinese Academy of Medical Sciences, 2019RU016; Hunan Children’s Hospital; the Children’s Hospital of Fudan University; Anhui Province Children’s Hospital; Children’s Hospital of Nanjing Medical University; West China Second University Hospital; Sichuan University/ West China Women’s and Children’s Hospital; Shanxi Children’s Hospital; the 2nd Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University; Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine; the First Hospital of Jilin University; the Affiliated Children’s Hospital of Xi’an Jiaotong University; Xi’an Central Hospital; the First Affiliated Hospital of Zhengzhou University; the First Affiliated Hospital of Guangxi Medical University; Jiangxi Provincial Children’s Hospital; Children’s Hospital of Soochow University; Kaifeng Children’s Hospital; Children’s Hospital Affiliated to Shandong University; Hainan Women and Children’s medical center; Women and Children’s Hospital; School of Medicine; Xiamen University; Shanghai Children’s Medical Center; National Children’s Medical Center; Shanghai Jiaotong University School of Medicine; the First Hospital of Lanzhou University; the Second Hospital of Hebei Medical University; the Women’s and Children’s Hospital of Qinghai Province; Taiyuan Maternal and Child Health Care Hospital; the First People’s Hospital of Zunyi; Inner Mongolia People’s Hospital; the Affiliated Hospital of Qingdao University; Hangzhou Children’s Hospital; Beijing Ditan Hospital; Capital Medical University; Tongji Hospital; Tongji Medical College of Huazhong University of Science and TechnologyCorrespondence: Yinghu Chen, Department of Infectious Disease, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, National Children’s Regional Medical Center, 3333 Binsheng Road, Hangzhou, Zhejiang, 310052, People’s Republic of China, Tel +86 13857154891, Email cyh18@zju.edu.cnObjective: To explore the epidemiological and pathogenic characteristics of children with community-acquired bacterial meningitis.Methods: A multicenter, retrospective study was conducted among CABM patients under 15 years old from 33 hospitals in China from 2019 to 2020. The medical record, laboratory, and microbiological data were collected and analyzed.Results: A total of 1610 children with CABM were identified and presented at a median onset age of 45 days of whom 955 (59.3%) were males. CABM occurred mostly in infants < 1 year of age (84.0%, 1352/1610). In etiology-confirmed cases, the pathogens were isolated from CSF culture in 515 (32.0%), 400 (24.8%) in blood culture, and 186 (11.6%) both in CSF and blood culture. In total, 126 pathogens were identified through CSF mNGS in 330 CABM cases; 21 S. pneumoniae isolates were detected in 83 CABM cases by antigen detection method. Major pathogens were E. coli (195, 24.7%), GBS (170, 21.5%), and S. pneumoniae (157, 19.9%). GBS (29.3%, 22/75) was the first pathogen of CABM in neonates aged 0– 6 days old, while E. coli (44.7%, 76/170) in 7 to 28 days of age; S. pneumoniae (96.2%, 151/157) was the most common pathogen in > 3 months old cases. About 9.7% (19/195) strains of E. coli produced ultra‑broad‑spectrum β‑lactamases. The common intracranial imaging complications were subdural effusion and (or) empyema in 349 (21.7%), hydrocephalus in 233 (14.5%), and cerebral abscess in 178 (11.1%). A total of 389 (24.2%) cases were completely cured and 1088 (67.6%) cases improved. Among 166 patients (10.3%) with adverse outcomes, 32 cases (2.0%) died, and 37 cases (2.3%) relapsed.Conclusion: The onset age of CABM in children is usually within 1 year of age, especially < 3 months. The primary pathogens in infants less than 3 months old are E. coli and GBS, and the dominant pathogen in children older than 3 months old is S. pneumoniae. Subdural effusion and (or) empyema and hydrocephalus are common complications. CABM should not be excluded even if CSF leukocyte counts are within normal range. Due to the low detection rate of pathogens in children with CABM, standardized CSF bacteriological examination should be paid more attention to increase the pathogen detection rate. Non‑culture CSF detection methods may facilitate pathogenic diagnosis.Keywords: meningitis, bacterial, pathogen, childhood, diagnosis, outcome

Yong Ling,1,&ast; Xuejiao Hu,1,&ast; Guansheng Zheng,1 Weitao Ye,2 Kaixuan Yuan,1 Long Ye,1 Weiye Huang,3 Benshun Tian,1 Bing Gu1 1Department of Clinical Laboratory Medicine, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, 510000, People’s Republic of China; 2Department of Radiology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, 510000, People’s Republic of China; 3Department of Pathology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, 510000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Benshun Tian; Bing Gu, Department of Laboratory Medicine, Guangdong Provincial People’s Hospital, 106 Zhongshan 2nd Road, Yuexiu District, Guangzhou, Guangdong, 510000, People’s Republic of China, Email tbs20161017@163.com; gb20031129@163.comAbstract: Scrub typhus is a vector-borne infectious disease caused by Orientia tsutsugamushi. Accurate and timely diagnosis at the early infection stage could save the patients’ lives. Traditional technologies were limited to rapidly and successfully detecting Orientia tsutsugamushi due to poor specificity, especially in the condition of atypical symptoms. The technology of Metagenomic next-generation sequencing (mNGS) is amenable to finding the real pathogen because it holds potential as a diagnostic platform for unbiased pathogen identification and precision medicine. Herein, we reported two clinical case reports relative to the Orientia tsutsugamushi infection diagnosed by mNGS. We hope these two cases will improve clinical diagnosis.Keywords: scrub typhus, metagenomic next-generation sequencing, Orientia tsutsugamushi

Jialu Sun,1 Yijun Shi,1 Yaowei Ding,1 Siqi Wang,1 Lingye Qian,2 Xin Luan,1 Guoge Li,1 Yuxin Chen,1 Xiaotong Li,1 Hong Lv,1,3,4 Guanghui Zheng,1,3,4,&ast; Guojun Zhang1,3,4,&ast; 1Laboratory, Beijing Tiantan Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Laboratory, Beijing An Zhen Hospital, Capital Medical University, Beijing, People’s Republic of China; 3NMPA Key Laboratory for Quality Control of in vitro Diagnostics, Beijing Tiantan Hospital, Capital Medical University, Beijing, People’s Republic of China; 4Beijing Engineering Research Center of Immunological Reagents Clinical Research, Beijing Tiantan Hospital, Capital Medical University, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Guanghui Zheng; Guojun Zhang, Beijing Tiantan Hospital, NO. 119 Nansihuan West Road, Fengtai District, Beijing, People’s Republic of China, Tel +86 18600148997 ; +86 13811792425, Email zgh999@yeah.net; guojun.zhang@ccmu.edu.cnBackground: To investigate the factors associated with follow-up CSF cultures (FUCCs) in post-neurosurgical patients with gram-negative bacterial meningitis/encephalitis and the effect of FUCCs on treatment management and patient outcomes.Methods: This single-centered retrospective cohort study enrolled post-neurosurgical patients with gram-negative bacterial meningitis/encephalitis at a tertiary-care university hospital between 2012 and 2022. The risk factors for 28-day mortality were evaluated using multivariate Cox analysis. FUCC-related risk factors were also analyzed.Results: Among the 844 enrolled patients, 504 (59.7%) underwent FUCC, and FUCC was found to be associated with lower rates of both all-cause (hazard ratio (HR) 0.391; 95% confidence interval (CI), 0.235– 0.651; p< 0.001) and attributable mortality (HR 0.463; 95% CI, 0.239– 0.897; p=0.023) in Post-neurosurgical patients diagnosed with Gram-negative bacterial meningitis/encephalitis. Moreover, the results of the study underscored that patients with persistent gram-negative bacterial meningitis/encephalitis had a lower all-cause/attributable short-term survival rate according to 28-day mortality Kaplan–Meier analysis (P=0.001/0.006).Conclusion: Performing FUCC has been demonstrated to lower mortality rates in Post-neurosurgical patients suffering from Gram-negative bacterial meningitis/encephalitis. The higher mortality rate observed in patients with persistent gram-negative bacterial meningitis/encephalitis suggests that performing FUCC is a crucial component of proper patient care and management, and is therefore recommended for use by clinicians as a standard practice. This finding underscores the significance of consistent implementation of FUCC in the management and prognosis of patients with Post-neurosurgical infections.Keywords: gram-negative bacterial meningitis/encephalitis, follow-up cerebrospinal fluid cultures, all-cause 28-day mortality, persistent meningitis/encephalitis, risk factors

Jinrong Ning,1,&ast; Guodong Zheng,1,&ast; Yi Cai,1,&ast; Yunguang Hu,2,&ast; Yiqi Liu,1 Enping Lai,1 Baizhong Chen,3 Yujie Liu,1 Ziqi Liang,1 Jijun Fu,1 Minyan Wei1 1Key Laboratory of Molecular Target & Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, People’s Republic of China; 2Medical Department, Guangdong Yifang Pharmaceutical Co., Ltd, Foshan, Guangdong, 528200, People’s Republic of China; 3Guangdong Xinbaotang Biological Technology Co., Ltd, Jiangmen, Guangdong, 529000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Minyan Wei; Jijun Fu, Guangzhou Medical University, Guangzhou, 511436, People’s Republic of China, Tel +86-20-37103268, Email weiminyan@163.com; fujj@gzhmu.edu.cnPurpose: APAP-induced liver injury (AILI) is a common cause of acute liver failure (ALF). Nobiletin (NOB) is a potential hepatoprotective agent for the treatment of APAP-induced liver injury. However, the poor solubility and low bioavailability of NOB hinders its application. In this study, a novel self-assembly nano-drug delivery system of nobiletin (solid dispersion of NOB, termed as NOB/SD) was developed based on solid dispersion technology to improve the bioavailability and hepatoprotective ability of NOB for APAP-induced liver injury therapy.Methods: The optimized NOB/SD system was constructed using the amphiphilic copolymers of Soluplus and PVP/VA 64 via hot melt extrusion technology (HME). NOB/SD was characterized by solubility, physical interaction, drug release behavior, and stability. The bioavailability and hepatoprotective effects of NOB/SD were evaluated in vitro and in vivo.Results: NOB/SD maintained NOB in matrix carriers in a stable amorphous state, and self-assembled NOB-loaded nanomicelles in water. Nanostructures based on solid dispersion technology exhibited enhanced solubility, improved release behavior, and promoted cellular uptake and anti-apoptosis in vitro. NOB/SD displayed significantly improved bioavailability in healthy Sprague Dawley (SD) rats in vivo. Furthermore, NOB/SD alleviated the APAP-induced liver injury by improving anti-oxidative stress with reactive oxygen species (ROS) scavenging and nuclear factor erythroid 2-related factor 2 (Nrf2) activation.Conclusion: These results suggested that NOB/SD could be considered as a promising hepatoprotective nano-drug delivery system for attenuating APAP-induced acute liver injury with superior bioavailability and efficient hepatoprotection, which might provide an effective strategy for APAP-induced acute liver injury prevention and treatment.Graphical Abstract: Keywords: nobiletin, self-assembly micelles, solid dispersion technology, hot melt extrusion, acetaminophen-induced liver injury

Huang J, Shao F, Chen B, Zheng G, Shen J, Qiu S. Neuropsychiatr Dis Treat. 2023;19:2709–2728. The authors have advised that the funding statement on page 2727 is incorrect. The text “(No. 202107071918000249496)” should read “(No. 20201203B59)”. The authors apologize for this error.

Guo Pei,1,2,&ast; Qiong Ou,1,2,&ast; Miaochan Lao,1 Longlong Wang,1 Yanxia Xu,1 Jiaoying Tan,1 Gaihong Zheng1 1Department of Sleep Center, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, People’s Republic of China; 2School of Medicine, South China University of Technology, Guangzhou, 510006, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qiong Ou, Department of Sleep Center, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, People’s Republic of China, Tel +86-13609717251, Email ouqiong2776@hotmail.comPurpose: This study evaluated the treatment acceptance rate and cost-effectiveness of the telemedicine model in clinical practice for adult patients with obstructive sleep apnea (OSA).Patients and Methods: Patients admitted to the sleep center for snoring were randomly divided into telemedicine and control groups. Patients diagnosed with moderate-to-severe OSA using the Home Sleep Apnea Test (HSAT) were voluntarily treated with auto-adjusted positive airway pressure (APAP) therapy. The acceptance rate of the APAP treatment, cost of patient visits, time cost, and labor cost of doctors in the two groups were observed.Results: A total of 57 subjects were included, with an average age of 40.12± 11.73 years, including 47 males (82.5%); 26 patients were in the telemedicine group, and 31 were in the control group. Follow-up results showed that the acceptance rate of APAP treatment was 57.7% and 54.8% in the telemedicine and control groups, respectively, with no significant difference between the two groups (p=0.829). The cost-benefit analysis showed that the telemedicine group reduced the cost of patients’ medical treatment [− 457.84(− 551.19,1466.87)] but increased the extra intervention frequency and time outside the doctor’s office. Further analysis showed that male subjects of older age, higher education level, distant residence, no fatty liver, poor sleep quality, severe insomnia, and higher OSA severity were more likely to receive telemedicine diagnosis and treatment.Conclusion: The APAP treatment acceptance rate and compliance of OSA patients in the telemedicine group were similar to those in the control group, and the cost of patients’ medical treatment was reduced. However, telemedicine increases the frequency and duration of additional out-of-hospital interventions.Keywords: home sleep apnea, auto-adjusted positive airway pressure, cost-benefit analysis, telemedicine, clinical diagnosis, adults

Yushan Liu,1,2 Gezhi Zheng,1,3 Jing Li,1,3 Nan Yang,1– 4 Juan Li,1,2 Zhengwen Liu,1– 4 Qunying Han,1– 4 Yingren Zhao,1– 4 Fenjing Du,1,3 Yingli He,1,&ast; Taotao Yan1,&ast; 1Department of Infectious Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China; 2Institution of Hepatology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China; 3Clinical Research Center for Infectious Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China; 4Shaanxi Clinical Research Center for Infectious Diseases, Xi’an, Shaanxi, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yingli He; Taotao Yan, Department of Infectious Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, No. 277 Yanta Road(w), Xi’an, Shaanxi, People’s Republic of China, Tel +86 189-9123-2863 ; +86 186-9148-5175, Email heyingli2000@xjtu.edu.cn; yantaotao_sweet@163.comAbstract: Anthrax is caused by Bacillus anthracis. Humans are mainly infected through contact with the fur and meat of livestock. The cutaneous form is the most common form. The skin lesions of typical cutaneous anthrax are characterized by shallow ulcers with black crusts, surrounded by small blisters and nonpitting edema of nearby tissues. Metagenomic next-generation sequencing (mNGS) is a new pathogenic detection method which is rapid and unbiased. We reported the first case of cutaneous anthrax diagnosed by mNGS. Ultimately, the man received prompt antibiotic therapy and had a good prognosis. In conclusion, mNGS is proved to be a good method for etiological diagnosis, especially for rare infectious diseases.Keywords: cutaneous anthrax, metagenomic next-generation sequencing, mNGS, case report, etiology diagnosis

Guanghui Zheng,1– 3 Siqi Wang,4 Hong Lv,1– 3 Guojun Zhang1– 3 1Laboratory of Beijing Tiantan Hospital, Capital Medical University, Beijing, 100076, People’s Republic of China; 2NMPA Key Laboratory for Quality Control of in vitro Diagnostics, Beijing, 100076, People’s Republic of China; 3Beijing Engineering Research Center of Immunological Reagents Clinical Research, Beijing, 100076, People’s Republic of China; 4School of clinical laboratory diagnostics, Capital Medical University, Beijing, 100076, People’s Republic of ChinaCorrespondence: Guojun Zhang, Laboratory of Beijing Tiantan Hospital, Capital Medical University, NO. 119 Nansihuan West Road, Fengtai District, Beijing, People’s Republic of China, Tel +86 15811219411, Email zgjlunwen@163.comObjective: To explore the clinical characteristics of post-neurosurgical meningitis (PNM) patients infected with nonfermenting Gram-negative bacilli (NFGNB) and to evaluate the related mortality risk factors.Methods: A cohort analysis of PNM patients infected with NFGNB in Beijing Tiantan Hospital and Capital Medical University from 2012.1 to 2020.12. The microbial distribution, antimicrobial sensitivity and genotypes were tested, and potential mortality risk factors were evaluated using Mann–Whitney U or chi-squared tests. Independent risk factors for mortality were established by constructing a logistic model.Results: A total of 2940 PNM patients were enrolled in this study, of whom 207 (17.1%) were infected with NFGNB. Among these patients, 29 died of NFGNB meningitis, with an overall mortality rate of 14.0%. The top three NFGNBs were Acinetobacter baumannii (105 cases, 50.7%), Pseudomonas aeruginosa (29 cases, 14.0%) and Acinetobacter lwoffii (20 cases, 9.7%). Nomogram analysis revealed that hypertension (OR 4.551, 95% CI: 1.464– 14.154, P = 0.009), external ventricular drainage (EVD) (OR 3.944, 95% CI: 1.286– 12.095, P = 0.016), and assisted mechanical ventilator (AMV) (OR 6.192, 95% CI: 1.737– 22.081, P = 0.005) were independent risk factors for mortality. In addition, antibiotic prophylaxis was shown to play a vital role in NFGNB-induced PNM therapy.Conclusion: PNM patients infected with NFGNB have a high mortality rate. Hypertension, EVD and AMV were independent mortality risk factors, and clinical attention should be paid to their prevention and treatment.Keywords: clinical characteristics, nomogram analysis, meningitis, mortality, nonfermenting Gram-negative bacilli

Chao Li,1,&ast; ZhaoHui Deng,2,3,&ast; GuiXian Zheng,3,&ast; Ting Xie,3 XinYan Wei,3 ZengYu Huo,3 Jing Bai3 1Department of Respiratory Medicine, Hunan Provincial People’s Hospital, Changsha, Hunan, 410219, People’s Republic of China; 2Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Zhuzhou, Hunan, 412000, People’s Republic of China; 3Department of Respiratory Medicine, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jing Bai, Department of Respiratory Medicine, the First Affiliated Hospital of Guangxi Medical University, No. 6 Shuangyong Road, Nanning, Guangxi, Tel +86-771-5356702, Fax +86-771-5608132, Email bj1312002@aliyun.comObjective: The aim of this study was to investigate the effects of resveratrol (RSV) on cigarette smoke (CS)-induced skeletal muscle atrophy and senescence in mice with emphysema and to explore the underlying mechanisms.Methods: Gastrocnemius muscle weight and lung and muscular morphology were observed in CS-exposed mice with or without RSV treatment. The expression of atrophy-related markers (MURF1 and MAFbx), senescence-related markers (P53, P21 and SMP30) and NF-κB inflammatory pathways was detected by Western blotting and real-time PCR. The levels of IL-1β and TNF-α were also determined by ELISA, and the number of senescent cells was determined by SA-β gal staining. In addition, the expression of HDAC2 and the effect of HDAC2 on CSE-induced skeletal muscle atrophy and senescence by RSV treatment were investigated.Results: RSV prevented emphysema and skeletal muscle atrophy in long-term CS-exposed mice. RSV decreased the expression of MURF1, MAFbx, P53, and P21 and inhibited the NF-κB pathway both in vivo and in vitro. Moreover, RSV reversed CS-induced downregulation of HDAC2 expression both in gastrocnemius and in C2C12 cells. Moreover, knockdown of HDAC2 significantly abolished the inhibitory effect of RSV on the expression of MURF1, MAFbx, P53, P21 and inflammatory factors (IL-1β and TNF-α) in C2C12 cells.Conclusion: RSV prevents CS-induced skeletal muscle atrophy and senescence, and upregulation of HDAC2 expression and suppression of inflammation are involved.Keywords: resveratrol, skeletal muscle, histone deacetylase 2, cigarette smoke, inflammation

Guanlie Li,1,&ast; Haiqing He,1,&ast; Guodong Zheng,1,&ast; Wenjing Jiang,1 Shuwen Du,1 Hua Tao,1 Tao Xiao,1 Dazhi Zhou,2 Shangwei Ding,2 Xi-Yong Yu,1 Yu Zhang,1 Ao Shen1 1Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences, The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, People’s Republic of China; 2Department of Ultrasound, The First Affiliated Hospital, Guangzhou Medical University, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ao Shen; Yu Zhang Tel +86 20 3110 0902; +86 20 3710 3275Email shenao@gzhmu.edu.cn; qianedyzy@163.comBackground: Pulmonary fibrosis (PF) is a fatal lung disease and affects over 5 million patients worldwide. Precise and early detection of PF is of pivotal importance to slow the disease progression. However, there are currently no effective tools to detect PF directly.Purpose: This study aimed to develop an imaging modality to detect PF directly. Excessive collagen deposition is the hallmark of PF. Herein, we developed a novel PF diagnostic agent, namely PVD (platelets-derived nanovesicles labeled with dye), by utilizing near-infrared (NIR)-responsive biomimetic platelets that specifically recognize collagen.Methods: In brief, platelets membrane was extracted from purified platelets by freeze/thaw and formed to PVD nanovesicles via sonication and extrusion, when loaded with DiR dye. Red blood cells membrane loaded with DiR was prepared in the same way as PVD to form RVD as control. Collagen self-assembled on microplates was used as an in vitro collagen fibrils model and monocrotaline-induced rats were used as an in vivo PF model.Results: We demonstrated that PVD, but not RVD nor other controls, could bind collagen both in vitro and in vivo, and directly detect pulmonary fibrosis in vivo and ex vivo at the early PF stage.Conclusion: Collectively, PVD is a versatile NIR-responsive probe for the direct visualization of collagen, and can be particularly helpful in direct detecting PF. To the best of our knowledge, PVD is the first report of a NIR probe for the direct detection of pulmonary fibrosis.Keywords: pulmonary fibrosis, collagen, platelets, imaging diagnosis, near-infrared

Guoqiao Zheng,1– 3 Kristina Sundquist,3– 5 Jan Sundquist,3– 5 Tianhui Chen,6 Asta Försti,1,4,7,8 Akseli Hemminki,9,10 Vaclav Liska,11,12 Kari Hemminki1,2,4,12 1Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, D-69120, Germany; 2Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, D-69120, Germany; 3Center for Primary Health Care Research, Lund University, Malmö, 205 02, Sweden; 4Department of Family Medicine and Community Health, Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY, USA; 5Center for Community-based Healthcare Research and Education (CoHRE), Department of Functional Pathology, School of Medicine, Shimane University, Matsue, Japan; 6Department of Cancer Prevention, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer, Chinese Academy of Sciences, Hangzhou, 310022, People’s Republic of China; 7Hopp Children’s Cancer Center (KiTZ), Heidelberg, Germany; 8Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany; 9Cancer Gene Therapy Group, Translational Immunology Research Program, University of Helsinki, Helsinki, Finland; 10Comprehensive Cancer Center, Helsinki University Hospital, Helsinki, Finland; 11Department of Surgery, University Hospital, School of Medicine in Pilsen, Pilsen, Czech Republic; 12Biomedical Center, Faculty of Medicine and Biomedical Center in Pilsen, Charles University in Prague, Pilsen, 30605, Czech RepublicCorrespondence: Kari HemminkiBiomedical Center, Faculty of Medicine and Biomedical Center in Pilsen, Charles University, Pilsen, 30605, Czech RepublicTel +496221421800Fax +496221422203Email K.Hemminki@dkfz.deBackground: Second primary cancers (SPCs) are important clinically as they may negatively influence patient survival and they may tell about therapeutic side effects and general causes of cancer. Population-based literature concerning SPCs after hepatobiliary cancers is limited and here we assess risks of SPCs after hepatocellular cancer (HCC), and cancers of the gallbladder, bile ducts and ampulla of Vater. In reverse order, we consider the risk of hepatobiliary cancers as SPCs after any cancer.Methods: We used standardized incidence ratios (SIRs) to estimate bidirectional relative risks of subsequent cancers associated with hepatobiliary cancers. Cancer diagnoses were obtained from the Swedish Cancer Registry from years 1990 through 2015.Results: We identified 9997 primary HCCs, 1365 gallbladder cancers and 4721 bile duct cancers. After HCC, risks of four SPCs were increased: gallbladder (SIR = 4.38; 95% confidence interval 1.87– 8.67), thyroid (4.13; 1.30– 9.70), kidney (2.92; 1.66– 4.47) and squamous cell skin (1.55; 1.02– 2.26) cancers. In reverse order, HCC as SPC, in addition to the above cancers, associations included upper aerodigestive tract, esophageal, small intestinal and bladder cancers and non-Hodgkin lymphoma. For gallbladder and bile duct cancers, associations were found with small intestinal and pancreatic cancers.Conclusion: The results suggested that HCC is associated with two types of SPC, one related to shared environmental risk factors, such as alcohol, exemplified by upper aerodigestive tract and esophageal cancer, and the other related to immune dysfunction, exemplified by squamous cell skin cancer. SPCs associated with gallbladder and bile duct cancers suggest predisposition to mutations in the mismatch repair gene MLH1.Keywords: cancer incidence, relative risk, second primary cancer, cancer etiology, hepatobiliary cancer

Guoqiao Zheng,1– 3 Kristina Sundquist,3– 5 Jan Sundquist,3– 6 Tianhui Chen,7 Asta Försti,1,3,8,9 Akseli Hemminki,10,11 Kari Hemminki1– 3,12 1Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany; 2Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany; 3Center for Primary Health Care Research, Lund University, Malmö, Sweden; 4Department of Family Medicine and Community Health; 5Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY, USA; 6Center for Community-Based Healthcare Research and Education (CoHRE), Department of Functional Pathology, School of Medicine, Shimane University, Matsue, Shimane, Japan; 7Department of Cancer Prevention, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer, Chinese Academy of Sciences, Hangzhou, 310022, People’s Republic of China; 8Hopp Children’s Cancer Center (KiTZ), Heidelberg, Germany; 9Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany; 10Cancer Gene Therapy Group, Translational Immunology Research Program, University of Helsinki, Helsinki, Finland; 11Comprehensive Cancer Center, Helsinki University Hospital, Helsinki, Finland; 12Biomedical Center, Faculty of Medicine and Biomedical Center in Pilsen, Charles University in Prague, Pilsen, 30605, Czech RepublicCorrespondence: Kari HemminkiBiomedical Center, Charles University Medical Faculty in Pilsen, Pilsen, 30605, Czech RepublicEmail K.Hemminki@dkfz.deBackground: Second primary cancers (SPCs) are increasing, which may negatively influence patient survival. Gastric cancer (GC) has poor survival and when it is diagnosed as SPC it is often the cause of death. We wanted to analyze the risk of SPCs after GC and the risk of GC as SPC after any cancer. Such bidirectional analysis is important in relation to fatal cancers because SPCs may be under-reported in the short-term survival period.Methods: Cancers were obtained from the Swedish Cancer Registry from years 1990 through 2015. Standardized incidence ratios (SIRs) were used to estimate bidirectional relative.Results: We identified 23,137 GC patients who developed 1042 SPCs (4.5%); 2158 patients had GC as SPC. While the risk for three SPCs was increased after GC, seven first primary cancers were followed by an increased risk of GC as SPC, including esophageal, colorectal, bladder, squamous cell skin and breast cancers and non-Hodgkin lymphoma. Breast cancer, which was followed by a diagnosis of second GC, showed an excess of lobular histology.Conclusion: Multiple primary cancers in the same individuals may signal genetic predisposition. Accordingly, the association of GC with breast cancer may be related to mutations in the CDH1 gene, and clustering of colorectal, small intestinal and bladder cancers could be related to Lynch syndrome. The third line of findings supports a contribution of immune dysfunction on the increased risk of GC as SPC after skin cancer and non-Hodgkin lymphoma. Early detection of GC in the risk groups could save lives.Keywords: cancer incidence, relative risk, second primary cancer, cancer etiology, stomach cancer

Guanghui Zheng,1– 3,&ast; Chenxi Zhang,1– 3,&ast; Guojun Zhang,1– 3 Chunqing Shao1– 3 1Department of Clinical Diagnosis, Laboratory of Beijing Tiantan Hospital and Capital Medical University, Beijing, People’s Republic of China; 2NMPA Key Laboratory for Quality Control of in vitro Diagnostics, National Medical Products Administration, Beijing, People’s Republic of China; 3Beijing Engineering Research Center of Immunological Reagents Clinical Research, Beijing Municipal Science and Technology Commission, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Chunqing Shao; Guojun Zhang Tel +86 18600148997; +86 15811219411Email shaocq0210@163.com; zgjlunwen@163.comAim: To evaluate the diagnostic and prognostic value of CSF presepsin levels in patients with postneurosurgical ventriculitis/meningitis (PNVM).Methods: We conducted a case-control study to achieve our aims. First, we prospectively enrolled patients who had undergone neurosurgery in Beijing Tiantan Hospital from June to November 2020 and measured the CSF levels of 8 biomarkers, including presepsin and other meningitis biomarkers. The diagnostic and prognostic accuracies of presepsin levels were evaluated by determining the values for the area under the receiver operating characteristic curve (AUC).Results: Two hundred thirty-nine patients were enrolled in this study; 34 were diagnosed with confirmed ventriculitis/meningitis (cVM), 138 were classified as probable ventriculitis/meningitis (pVM), and the others were rejected ventriculitis/meningitis (rVM). Presepsin levels effectively diagnose cVM and predict the outcomes of patients with PNVM, with thresholds of 1257.4 pg/mL and 1276.2 pg/mL and AUCs of 0.746 and 0.825, respectively. Furthermore, a joint analysis with CSF lactate (C-Lac) levels shows that the AUCs of the two markers increased to 0.856 and 0.872, respectively.Conclusion: The rapid diagnosis and prediction of the clinical outcome is important in neurosurgery. CSF presepsin levels are an impressive diagnostic and prognostic biomarker for meningitis, and when combined with C-Lac, they indeed improve the diagnostic and predictive efficiency of PNVM.Keywords: presepsin, cerebrospinal fluid, postneurosurgical ventriculitis/meningitis

Penghui Hu,1,2,* Qian Gao,1,2,* Huimin Zheng,1,2 Yujuan Tian,1,2 Guoying Zheng,1 Xiaoyu Yao,1 Junjiang Zhang,1 Xudong Wu,2 Lei Sui1 1Department of Prosthodontics, Tianjin Medical University School and Hospital of Stomatology, Tianjin, People’s Republic of China; 2Department of Cell Biology, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, Tianjin Medical University, Tianjin, People’s Republic of China*These authors contributed equally to this workCorrespondence: Lei SuiDepartment of Prosthodontics, Tianjin Medical University School and Hospital of Stomatology, Tianjin, People’s Republic of ChinaEmail suilei@tmu.edu.cnPurpose: To investigate the role and activation mechanism of TAZ in periodontal ligament stem cells (PDLSCs) perceiving hierarchical microgroove/nanopore topography.Materials and Methods: Titanium surface with hierarchical microgroove/nanopore topography fabricated by selective laser melting combined with alkali heat treatment (SLM-AHT) was used as experimental group, smooth titanium surface (Ti) and sandblasted, large-grit, acid-etched (SLA) titanium surface were employed as control groups. Alkaline phosphatase (ALP) activity assays, qRT-PCR, Western blotting, and immunofluorescence were carried out to evaluate the effect of SLM-AHT surface on PDLSC differentiation. Moreover, TAZ activation was investigated from the perspective of nuclear localization to transcriptional activity. TAZ knockdown PDLSCs were seeded on three titanium surfaces to detect osteogenesis- and adipogenesis-related gene expression levels. Immunofluorescence and Western blotting were employed to investigate the effect of the SLM-AHT surface on actin cytoskeletal polymerization and MAPK signaling pathway. Cytochalasin D and MAPK signaling pathway inhibitors were used to determine whether actin cytoskeletal polymerization and the MAPK signaling pathway were indispensable for TAZ activation.Results: Our results showed that SLM-AHT surface had a greater potential to promote PDLSC osteogenic differentiation while inhibiting adipogenic differentiation than the other two groups. The nuclear localization and transcriptional activity of TAZ were strongly enhanced on the SLM-AHT surface. Moreover, after TAZ knockdown, the enhanced osteogenesis and decreased adipogenesis in SLM-AHT group could not be observed. In addition, SLM-AHT surface could promote actin cytoskeletal polymerization and upregulate p-ERK and p-p38 protein levels. After treatment with cytochalasin D and MAPK signaling pathway inhibitors, differences in the TAZ subcellular localization and transcriptional activity were no longer observed among the different titanium surfaces.Conclusion: Our results demonstrated that actin cytoskeletal polymerization and MAPK signaling pathway activation triggered by SLM-AHT surface were essential for TAZ activation, which played a dominant role in SLM-AHT surface-induced stem cell fate decision.Keywords: TAZ, hierarchical micro/nanoscale topography, periodontal ligament stem cells, osteogenic differentiation, adipogenic differentiation

Weixian Hu,1,* Chengbin Zheng,1,* Renjie Li,2 Xingyu Feng,1 Guoliang Zheng,3 Zhichao Zheng,3 Wenjun Xiong,4 Guosheng Lin,5 Yongjian Zhou,5 Wei Wang,4 Yan Zhao,3 Yong Li1 1Department of General Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, People’s Republic of China; 2Department of Bariatric and Metabolic Surgery, Klinikum Ernst von Bergmann, Potsdam 14467, Germany; 3Department of Gastric Cancer, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, Liaoning 110042, People’s Republic of China; 4Department of Gastrointestinal Surgery, Guangdong Provincial Hospital of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510120, People’s Republic of China; 5Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, People’s Republic of China*These authors contributed equally to this work.Correspondence: Yong LiDepartment of General Surgery, Guangdong Provincial People’s Hospital; Guangdong Academy of Medical Sciences, 106 Zhongshan Road 2, Guangzhou, Guangdong 510080, People’s Republic of ChinaTel +86-13822177479Fax +86-83827812Email liyong@gdph.org.cnYan ZhaoDepartment of Gastric Cancer, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, Liaoning 110042, People’s Republic of ChinaTel +86-18900918909Email zhaoyan@CancerHosp-LN-CMU.comPurpose: Gastrointestinal stromal tumors (GISTs) are commonly known to be derived from the gastrointestinal (GI) tract, but recently there have been more and more literature describing lesions with similar pathological and immunohistochemical resembling GISTs but located outside the GI tract, and they have been termed as extra-GISTs (eGISTs). However, due to the rare incidence of eGISTs, its association with survival outcomes is poorly understood, especially in the Chinese population. Here, we aimed to identify the risk factors of eGISTs and to assess their association with overall survival (OS) and disease-free survival (DFS).Patients and Methods: Data of pathologically confirmed eGISTs cases, without radiological and perioperative evidence of other primary lesions, and with no microscopically identified adhesion between the tumor and the gastrointestinal serosa, which were surgically treated between January 2006 and September 2017 were retrieved from the database of four high-volume hospitals. Immunohistochemical and genetic testing were performed on the postoperative lesions and were staged using the National Institutes of Health (NIH) criteria.Results: A total of 55 cases were retrieved. eGISTs were identified from the retroperitoneum (36.4%), mesocolon (25.5%), small bowel mesentery (12.7%), abdominopelvic cavity (12.7%), lesser omental sac (5.5%), ovary (3.6%), pancreatic capsule (1.8%), or urinary bladder (1.8%). Based on the NIH risk classification, majority of the lesion were classified as high risk (85.5%). KIT 11 was the most common mutation site (76.5%) and 25.0% of the cases were wild-type eGISTs. Multivariate analyses showed that tumor location and size were independent factors affecting prognoses. Patients with tumors in the retroperitoneum had significantly poorer OS and DFS as compared to those in the non-retroperitoneum (HR [95% CI] for OS and DFS: 2.546 [1.023– 6.337] [P = 0.037] and 2.475 [0.975– 6.273] [P = 0.049], respectively). Similar findings were found for tumors of size > 15 cm, compared to ≤ 15 cm (HR [95% CI] for OS and DFS: 5.350 [2.022– 14.156] [P < 0.001] and 3.861 [1.493– 9.988] [P = 0.003], respectively).Conclusion: eGISTs were predominantly found from the retroperitoneum and mostly classified as high risk. Those located in the retroperitoneum and of size > 15 cm had the poorer OS and DFS as compared to those in the non-retroperitoneum and of size < 15 cm.Keywords: extra gastrointestinal stromal tumors, multicenter, immunohistopathology, gene mutation, National Institutes of Health criteria, risk factor, retroperitoneum, overall survival, disease-free survival, recurrence

Yinghao Guo,1,2,* Jinqiang Liu,1,3,* Wenming Zhang,1,4,* Shuao Xiao,1 Gaozan Zheng,1 Shushang Liu,1 Man Guo,1 Hongwei Zhang,1 Fan Feng1 1Department of Digestive Surgery, Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, Xi’an 710032, Shaanxi, People’s Republic of China; 2Health Company, 92667 Army of PLA, Qingdao 266100, Shandong, People’s Republic of China; 3Cadre’s Sanitarium, 62101 Army of PLA, Xinyang 464000, Henan, People’s Republic of China; 4Department of General Surgery, Linxia People’s Hospital, Linxia 731100, Gansu, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hongwei Zhang; Fan Feng Email zhanghwfmmu@126.com; surgeonfengfan@163.comPurpose: Data about the prognostic value of fibrinogen concentration and absolute lymphocyte count for the prognosis of gastrointestinal stromal tumors (GISTs) were limited. Thus, the aim of the present study was to investigate the predictive value of preoperative fibrinogen concentration and absolute lymphocyte count in GISTs.Patients and Methods: From March 2002 to December 2017, 143 intermediate and high risk GIST patients treated with R0 resection were enrolled in the present study. Clinicopathological characteristics were recorded. The optimal cut-off values of patients were calculated by X-tile software. Categorical variables were analyzed using Chi-square test or Fisher’s exact test. Disease-free survival was analyzed by the Kaplan–Meier method and compared by a Log rank test.Results: There were 71 males (49.65%) and 72 females. The median age was 56 years (range 19– 86). The optimal cut-off value was 4.5 g/L for fibrinogen concentration (P=0.000) and 1.0× 109/L for lymphocyte count (P=0.002). No significant association was found between lymphocyte level and clinicopathological features. However, elevated fibrinogen level was correlated with tumor location, tumor size and NIH risk category. Tumor size, fibrinogen concentration and lymphocyte count were independent risk factors for the prognosis of patients according to the multivariate analysis. The prognosis of patients with high fibrinogen concentration or low lymphocyte count was significantly worse than that with low fibrinogen concentration or high lymphocyte count. Further, combination of fibrinogen concentration and lymphocyte count could increase the prognostic value for GIST patients.Conclusion: Fibrinogen concentration and absolute lymphocyte count were independent prognostic factors for intermediate and high risk GIST patients. The combination of fibrinogen concentration and absolute lymphocyte count could further increase the predictive value for the prognosis of GIST patients.Keywords: gastrointestinal stromal tumors, GIST, mesenchymal tumor, fibrinogen, lymphocyte, prognosis

Guoqiao Zheng,1– 3 Kristina Sundquist,4– 6 Jan Sundquist,4– 6 Asta Försti,1,4,7,8 Akseli Hemminki,9,10 Kari Hemminki1,2,4,11 1Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg D-69120, Germany; 2Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg D-69120, Germany; 3Faculty of Medicine, University of Heidelberg, Heidelberg, Germany; 4Center for Primary Health Care Research, Lund University, Malmö 205 02, Sweden; 5Department of Family Medicine and Community Health, Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY, USA; 6Center for Community-Based Healthcare Research and Education (CoHRE), Department of Functional Pathology, School of Medicine, Shimane University, Izumo, Japan; 7Hopp Children’s Cancer Center (KiTZ), Heidelberg, Germany; 8Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany; 9Cancer Gene Therapy Group, Translational Immunology Research Program, University of Helsinki, Helsinki, Finland; 10Comprehensive Cancer Center, Helsinki University Hospital, Helsinki, Finland; 11Faculty of Medicine and Biomedical Center in Pilsen, Charles University in Prague, Pilsen 30605, Czech RepublicCorrespondence: Kari HemminkiDivision of Cancer Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, Heidelberg 69120, GermanyTel +49 6221421800Fax +49 6221421810Email kari.hemminki@dkfz.deBackground: Most literature on second primary cancers (SPCs) focuses on possible factors, which may increase the risk of these cancers, and little attention has been paid for the overall incidence differences between first primary cancers (FPCs) and same SPCs. We wanted to compare the incidence rates for all common cancers when these were diagnosed as FPCs and SPCs after invasive and in situ squamous cell carcinoma (SCC) of the skin, which are usually treated by surgery only.Methods: Cancers were identified from the Swedish Cancer Registry from the years 1990 through to 2015, and they included, in addition to skin cancers, 20 male cancers totaling 484,850 patients and 22 female cancers totaling 452,909 patients. Standardized incidence rates and relative risks (RRs) were calculated for sex-specific common cancers as FPC and as SPC after skin SCC. Spearman rank correlations were used in the analysis of incidence ranking of FPC and SPC.Results: Of total, 29,061 men and 23,533 women developed invasive SCC and 27,842 men and 36,383 women in situ SCC. The total number of 20 other male cancers was 484,850 and of 22 female cancers it was 452,909. Rank correlations ranged from 0.90 to 0.96 (P∼ 5× 10− 6), indicating that overall skin SCC did not interfere with SPC formation. The exceptions were increased SPC risks for melanoma, sharing risk factors with skin SCC, and non-Hodgkin and Hodgkin lymphoma, and cancers of the upper aerodigestive tract, connective tissue, and male and female genitals suggesting contribution by skin cancer initiated immune dysfunction.Conclusion: The incidence ranking of SPCs after skin cancers largely follows the incidence ranking of FPCs indicating that overall skin SCC does not greatly interfere with the intrinsic carcinogenic process. The main deviations in incidence between FPC and SPC appeared to be due to shared risk factors or immunological processes promoting immune responsive cancer types.Keywords: skin cancer, second cancer, first primary cancer, immune disturbance

Yi-jun Shi,1,2,* Guang-hui Zheng,1,2,* Ling-ye Qian,1,2 Rasha Alsamani Qsman,1,2 Guo-ge Li,1,2 Guo-jun Zhang1,2 1Department of Clinical Diagnosis, Laboratory of Beijing Tiantan Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Beijing Engineering Research Center of Immunological Reagents Clinical Research, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Guo-jun Zhang Fax +86 10-59976881Email zgjlunwen@163.comPurpose: Our study is a retrospective observational study conducted in one of the largest clinical centers of neurosurgery in China. We aimed to investigate the antimicrobial susceptibility patterns of the Enterobacteriaceae isolates responsible for nosocomial meningitis/encephalitis in post-neurosurgical patients. Meanwhile, we tried to evaluate the risk factors for mortality following Enterobacteriaceae meningitis/encephalitis.Patients and Methods: Medical data on clinical characteristics, antibiotic susceptibilities, and mortality were reviewed until patients’ discharge or death in the hospital. Data for a total of 164 cerebrospinal fluid (CSF) infection cases due to Enterobacteriaceae after neurosurgery were collected between January 2014 and November 2019 in order to identify risk factors affecting the outcome. Kaplan–Meier survival analysis and multivariable Cox proportional hazard models were applied.Results: In this study, a total of 2416 neurosurgical meningitis/encephalitis cases were reported between 2014 and 2019. Enterobacteriaceae accounted for 7.3% (176/2416) of all the bacterial infections. Of them, 164 Enterobacteriaceae isolates were available to divide into two groups according to the final outcome of whether the patient died or survived. In total, 38 patients died (23.2%) and 126 patients survived (76.8%). The most frequent infecting species was Klebsiella pneumoniae (47.0%, 77/164). Fourteen-day and 30-day mortality rates were 7.9% (13/164) and 15.2% (25/164). Kaplan–Meier survival analysis revealed that the risk factors of Enterobacteriaceae meningitis/encephalitis that resulted in poor outcomes included comorbidities, Glasgow Coma Scale (GCS) score, sepsis, intensive care unit (ICU) admission, extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae, and ventilation. A GCS score of less than or equal to 8 (P=0.04, HR 2.562) was identified to be a significant risk factor for mortality according to the multivariable Cox proportional hazards model.Conclusion: In-hospital mortality caused by Enterobacteriaceae meningitis/encephalitis in neurosurgery was high. A GCS score of ≤ 8 was an independent risk factor for mortality following Enterobacteriaceae meningitis/encephalitis in post-neurosurgical patients.Keywords: Enterobacteriaceae, post-neurosurgical meningitis/encephalitis, antibiotic susceptibility, antibiotic resistance, in-hospital mortality

Fang Liu,1 Aifang Xu,1 Huaqing Zhao,2 Zongxing Yang,3 Chen Chen,4 Brona Ranieri,4 Jianfeng Bao,5 Guoxiang Zheng,3 Miaochan Wang,1 Ying Wang,1 Yunhao Xun5 1Medical Laboratory, Xixi Hospital of Hangzhou, Hangzhou, People’s Republic of China; 2Temple University School of Medicine, Department of Clinical Sciences, Philadelphia, PA, USA; 3Department of Infectious Diseases, Xixi Hospital of Hangzhou, Hangzhou, People’s Republic of China; 4Department of Neuroscience, Temple University, Philadelphia, PA, USA; 5Department of Integrated Chinese and Western Medicine, Xixi Hospital of Hangzhou, Hangzhou, People’s Republic of ChinaCorrespondence: Yunhao XunDepartment of Integrated Chinese and Western Medicine, Xixi Hospital of Hangzhou, Zhejiang Chinese Medical University Affiliated Sixth Hospital, 2 Hengbu Road, Hangzhou 310023, People’s Republic of ChinaTel +86-571-86481581Fax +86-571-86481822Email hzxxgb@outlook.comPurpose: Estimated glomerular filtration rate (eGFR) decline in HIV-1-infected patients exposure to tenofovir disoproxil fumarate (TDF) has been widely assessed using linear models, but nonlinear assumption is not well validated. We constructed a retrospective cohort study to assess whether eGFR decline follows nonlinearity during antiviral therapy.Patients and Methods: We examined 823 (299 of TDF users and 524 of non-TDF users) treatment-naïve HIV-1-infected participants (age ≥ 17 years, initial eGFR ≥ 90 mL/min/1.73m2). Estimated GFR trajectories were compared by one-linear and piecewise-linear mixed effects models, before and after propensity score matching, respectively. Whether the incidence of renal dysfunction (reduced renal function [RRF], eGFR < 90 mL/min/1.73 m2 and rapid kidney function decline [RKFD], eGFR > − 3 mL/min/1.73 m2/year) follows nonlinearity was assessed by logistic regression.Results: The median follow-up time of this study was 10 (interquartile range, 2– 20) months, during which 178 (21.6%) experienced RRF, and 451 (54.8%) experienced RKFD. The slopes (mL/min/1.73 m2/year) of eGFR were − 5.31 (95% CI: − 6.57, − 4.06) before 1.40 years, 4.83 (95% CI: 1.38, 8.28) from years 1.40 to 2.30 and − 3.71 (95% CI: − 5.97, − 1.45) after 2.30 years among TDF users. Within years 1.40– 2.30, each year of TDF exposure was associated with a 78% decreased risk of RKFD (95% CI: − 91%, − 49%). In comparison, eGFR increased slightly at the initiation of antiviral therapy, declined after 2.15 years (− 4.96; 95% CI: − 5.76, − 4.17) among non-TDF users. Such a progression nonlinear trajectory was missed on the assumption of one-linearity, whether in TDF or non-TDF users.Conclusion: Over the piecewise mixed-effects analyses with the advantage of revealing the true nature of the exposure outcome relationships, an interesting reverse S-shaped relationship was observed. A routine screen based on nonlinearity could be more helpful for patient management.Keywords: nonlinear trajectory, renal function, human immunodeficiency virus-1

Guoqiao Zheng, 1, 2 Subhayan Chattopadhyay, 1, 2 Kristina Sundquist, 3– 6 Jan Sundquist, 3– 6 Asta Försti, 1, 3 Akseli Hemminki, 7, 8 Kari Hemminki 1, 3, 9 1Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg D-69120, Germany; 2Faculty of Medicine, University of Heidelberg, Heidelberg, Germany; 3Center for Primary Health Care Research, Lund University, Malmö 205 02, Sweden; 4Department of Family Medicine and Community Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA; 5Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY, USA; 6Center for Community-based Healthcare Research and Education (CoHRE), Department of Functional Pathology, School of Medicine, Shimane University, Matsue, Shimane, Japan; 7Cancer Gene Therapy Group, Translational Immunology Research Program, University of Helsinki, Helsinki, Finland; 8Comprehensive Cancer Center, Helsinki University Hospital, Helsinki, Finland; 9Faculty of Medicine and Biomedical Center in Pilsen, Charles University in Prague, Pilsen 30605, Czech RepublicCorrespondence: Guoqiao ZhengDivision of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, Heidelberg 69120, GermanyTel +49-6221-421805Fax +49-6221-421810Email g.zheng@dkfz.deBackground: Survival in malignant cutaneous melanoma has improved but increasing survival will result in an increased likelihood of the occurrence of second primary cancers (SPCs). SPCs may adversely interfere with survival. We quantified survival in patients with different types of SPCs, in comparison to known poor prognostic indicators of metastatic disease.Methods: Data for melanoma and any SPCs were obtained from the Swedish Cancer Registry for years 2003 through 2015, including clinical TNM classification. SPCs were grouped into three ‘prognostic groups’ based on 5-year relative survival of these cancers as first primary cancer. Kaplan-Meier survival curves were generated and hazard ratios were estimated using Cox regression, adjusted for a number of variables and treating diagnosis of SPC as a time-dependent variable.Results: The total number of first melanoma patients was 28,716 followed by 3,202 (11.1%) SPCs, 1/3 of which had a second melanoma while 2/3 had other SPCs. Among men diagnosed at age over 70 years, who survived at least 10 years, 31.4% had SPC. HRs (95% CI) for survival increased systematically from the reference rate of 1.00 (no SPC) to 1.59 (1.35– 1.87) with SPC of good prognosis (78.6% of SPCs) to 3.49 (2.58– 4.72) of moderate prognosis (12.0%) and to 7.93 (5.50– 11.44) of poor prognosis (9.4%). In patients without SPC, the HRs increased to 2.62 (2.02– 3.39) with any nodal metastases and to 5.88 (4.57– 7.57) with any distant metastases compared to patients without local or distant metastases.Conclusion: The data showed that SPCs are an increasingly common negative prognostic factor for melanoma. Future attempts to improve melanoma survival need to target SPCs.Keywords: melanoma, second cancer, metastasis, prognosis, survival

Ailin Qu,1 Wenfei Wang,2,3 Yongmei Yang,4 Xin Zhang,4 Yuhuan Dong,4 Guixi Zheng,4 Qiuyan Wu,4 Mingjin Zou,4 Lutao Du,1 Yunshan Wang,1 Chuanxin Wang11Department of Clinical Laboratory, The Second Hospital of Shandong University, Jinan, Shandong 250033, People’s Republic of China; 2Humanistic Medicine Research Center, Qilu Hospital, Shandong University, Jinan, Shandong 250012, People’s Republic of China; 3Humanistic Medicine Research Center, Shandong University, Jinan, Shandong 250012, People’s Republic of China; 4Department of Clinical Laboratory, Qilu Hospital, Shandong University, Jinan, Shandong 250012, People’s Republic of ChinaPurpose: Piwi-interacting RNAs (piRNAs) are a novel class of small non-coding RNAs, which are not easily degraded but detectable in human body fluids. Recent studies have shown that aberrant piRNA expression is a signature feature across multiple tumor types. However, the expressions of piRNAs in serum of tumor patients and their potential clinical values remain largely unclear.Patients and methods: High-throughput sequencing was performed to investigate the serum piRNA profiles, followed by evaluations in serum samples of 220 colorectal cancer (CRC) patients and 220 healthy controls using reverse transcription quantitative real-time PCR (RT-qPCR). Biomarker panels including piRNA-based Panel I and carcinoembryonic antigen (CEA)-based Panel II, were developed by logistic regression model, and their diagnostic potentials were compared. Fagan’s nomogram was plotted to promote clinical application.Results: We identified five differentially expressed serum piRNAs (piR-001311, piR-004153, piR-017723, piR-017724 and piR-020365), which, when combined in the piRNA-based Panel I, outperformed the CEA-based Panel II (P

Yike Huang,1 Lu Hu,2 Shan Huang,1 Wanjun Xu,1 Jingyuan Wan,2 Dandan Wang,1 Guocan Zheng,3 Zhining Xia1 1Department of Pharmaceutical Analysis, School of Pharmaceutical Sciences and Innovative Drug Research Centre, Chongqing University, Chongqing, China; 2Department of Pharmacology, Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, School of Pharmacy, Chongqing Medical University, Chongqing, China; 3Analytical and Testing Center, Chongqing University, Chongqing, China Background: The main objective of this study was to develop novel BSA nanoparticles (BSA NPs) for improving the bioavailability of curcumin as an anticancer drug, and those BSA NPs were galactosylated for forming the curcumin-loaded galactosylated BSA nanoparticles (Gal-BSA-Cur NPs), thus enhancing their ability to target asialoglycoprotein receptor (ASGPR) overexpressed on hepatocellular carcinoma (HCC) cells. Materials and methods: Gal-BSA-Cur NPs were prepared by the desolvation method and showed a spherical shape and well distribution with the average particle size of 116.24 nm. Results: In vitro drug release assay exhibited that Gal-BSA-Cur NPs had higher release rates and improved the curcumin solubility. Cell uptake studies confirmed that Gal-BSA-Cur NPs could selectively recognize receptors on the surface of HCC (HepG2) cells and improve internalization ability of drug compared with BSA NPs-loaded curcumin (BSA-Cur NPs), which might be due to high affinity to galactose. Further, the effects of Gal-BSA-Cur NPs were evaluated by cytotoxicity assay, crystal violet assay, cell apoptosis assay, and wound healing assay, respectively, which revealed that Gal-BSA-Cur NPs could inhibit HepG2 cells proliferation, induce cell apoptosis, and inhibit cell migration. Conclusion: Immunofluorescence staining has proved that the effects of Gal-BSA-Cur NPs related to the suppression of the nuclear factor κB-p65 (NF-κB-p65) expression in HepG2 cell nucleus. Therefore, these results indicate that novel Gal-BSA-Cur NPs are potential candidates for targeted curcumin delivery to HCC cells. Keywords: albumin, curcumin, nanoparticles, galactosylated, hepatocellular carcinoma

Guoqiao Zheng,1,2 Subhayan Chattopadhyay,1,2 Asta Försti,1,3 Kristina Sundquist,3–6 Kari Hemminki1,3 1Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Baden-Württemberg, Germany; 2Faculty of Medicine, University of Heidelberg, Heidelberg, Baden-Württemberg, Germany; 3Center for Primary Health Care Research, Lund University, 205 02 Malmö, Skåne County, Sweden; 4Department of Family Medicine and Community Health, 5Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY, USA; 6Center for Community-Based Healthcare Research and Education (CoHRE), Department of Functional Pathology, School of Medicine, Shimane University, Izumo, Japan Background: With improving survival in ovarian cancer, second primary cancers (SPCs) and their etiological foundations are becoming an issue. The ways in which family history may influence the occurrence of SPCs and the related mortality are not well known. Methods: Based on the Swedish Family-Cancer Database, we identified 11,300 ovarian cancer patients and followed them for diagnoses of SPCs until the end of 2015. Relative risks (RRs) of SPC in patients who had parents or siblings diagnosed with the same cancer (positive family history) were compared to those in patients without a family history (negative family history). Causes of death were compared between patients with and without SPC. Results: A total of 1,111 (9.8%) ovarian cancer patients developed SPC with a median follow-up of 8 years. The impact of a family history of cancer on the risk of the same cancer as SPC was significant for colon (RRpositive family history [95% CI] vs RRnegative family history [95% CI]: 4.95 [3.03–8.09] vs 2.00 [1.63–2.47]), lung (3.32 [1.88–5.84] vs 1.45 [1.16–1.83]), and breast (2.08 [1.58–2.73] vs 1.01 [0.88–1.15]) cancers. With a family history of any cancer, the RR for non-ovarian SPCs was 1.66 (1.54–1.74), in contrast to 1.38 (1.24–1.54) for SPCs without any family history (P-trend

Guoyin Zheng,1,* Fengfeng Mo,2,* Chen Ling,3,* Hao Peng,1 Wei Gu,1 Min Li,2 Zhe Chen1 1Department of Traditional Chinese Medicine, Changhai Hospital, 2Department of Military Hygiene, Second Military Medical University, 3Department of Biology, School of Life Science, Fudan University, Shanghai, People’s Republic of China *These authors contributed equally to this work Abstract: Purslane is a widespread succulent herb that exhibits various pharmacological effects. The purpose of this study was to evaluate the protective effect of Portulaca oleracea L. (purslane) on streptozotocin-induced diabetes in mice. Oral glucose-tolerance tests were carried out to assess blood glucose levels and body weight and food intake were recorded. The biochemical parameters anti-aspartate aminotransferase, alanine aminotransferase, insulin, triglycerides, total cholesterol, IL-6, IL-1β, and TNFα were also measured. The pathological condition of liver tissues were examined by hematoxylin–eosin staining. Rho, ROCK1, ROCK2, NFκBp65, p-NFκBp65, IκBα, and p-IκBα expression in liver tissue were analyzed by Western blot. Purslane increased body weight and decreased food intake. Purslane also significantly reduced concentrations of glucose, anti-aspartate aminotransferase, alanine ­aminotransferase, triglycerides, total cholesterol, IL-6, IL-1β, and TNFα in serum. Serum insulin was elevated with purslane treatment. In addition, pathologic liver changes in diabetic mice were also alleviated by purslane. Obtained data revealed that purslane restored the levels of Rho–NFκB signaling-related proteins in comparison with those of diabetic mice. Above all, it can be assumed that purslane might play a positive role in regulating streptozotocin-induced liver injury through suppressing the Rho–NFκB pathway. Keywords: Portulaca oleracea L., diabetes, liver injury, Rho–NFκB

Jian-min Han,1,2 Guang Hong,3 Hong Lin,1 Yoshinaka Shimizu,4 Yuhan Wu,2 Gang Zheng,1 Hongyu Zhang,5 Keiichi Sasaki2 1Department of Dental Materials, National Engineering Laboratory for Digital and Material Technology of Stomatology, Peking University School and Hospital of Stomatology, Beijing, People’s Republic of China; 2Division of Advanced Prosthetic Dentistry, 3Liaison Center for Innovative Dentistry, 4Department of Oral Pathology, Graduate School of Dentistry, Tohoku University, Sendai, Japan; 5State Key Laboratory of Tribology, Department of Mechanical Engineering, Tsinghua University, Beijing, People’s Republic of China Abstract: The purpose of this study was to evaluate the biomechanical and histological behavior of a ceria-stabilized zirconia–alumina nanocomposite (NanoZr) in comparison with that of yttria-stabilized tetragonal zirconia polycrystalline (3Y-TZP) in Sprague Dawley rats. Cylindrical NanoZr and 3Y-TZP implants (diameter 1 mm, length 2 mm) were used. Implant-surface morphology and surface roughness were determined by scanning white-light interferometry and scanning electron microscopy, respectively. The cylindrical zirconia implants were placed at the distal edge of the femur of Sprague Dawley rats. At weeks 2, 4, and 8, the interfacial shear strength between implant and bone was measured by push-in test. Histological analysis was performed using hard-tissue sections. Bone–implant contact (BIC), the thickness of new bone around the implant within the bone marrow area, and osteoclast numbers were evaluated. The average surface roughness of 3Y-TZP (Sa 0.788 µm) was significantly higher than that of NanoZr (Sa 0.559 µm). The shear strengths of 3Y-TZP and NanoZr were similar at 2 weeks, but at 4 and 8 weeks the shear strength of NanoZr was higher than that of 3Y-TZP. The average BIC values within the bone marrow area for 3Y-TZP and NanoZr were 25.26% and 31.51% at 2 weeks, 46.78% and 38% at 4 weeks, and 47.88% and 56.81% at 8 weeks, respectively. The average BIC values within the cortical area were 38.86% and 58.42% at 2 weeks, 66.82% and 57.74% at 4 weeks, and 79.91% and 78.97% at 8 weeks, respectively. The mean BIC value did not differ significantly between the two zirconia materials at any time point. The NanoZr implants were biocompatible, capable of establishing close BIC, and may be preferred for metal-free dental implants. Keywords: zirconia, dental implant, zirconia–alumina nanocomposite, push-in test, histomorphometry

Haiying Lu,1,* Mei Jiang,2,* Lei Lu,3 Guo Zheng,1 Qiang Dong3 1Department of Neurology, Nanjing Children’s Hospital, Nanjing Medical University, Nanjing, 2Department of Neurology, Shanghai Pudong New Area Gongli Hospital, Shanghai, 3Department of Neurology, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China *These authors contributed equally to this work Aim: The purpose of the study was to observe the ultrastructural changes of neuronal mitochondria in perihematomal brain tissue and assess the therapeutic potential of Huperzine A (HA, a mitochondrial protector) following intracerebral hemorrhage (ICH). Methods: Brain hemorrhage was induced in adult Sprague Dawley rats by injecting autologous blood into the striatum and then removing the brains 3, 6, 12, 24, or 48 hours later to analyze mitochondrial ultrastructure in a blinded manner. Parallel groups of ICH rats were treated with HA or saline immediately after ICH. Perihematomal apoptosis was determined by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), caspase-3 activation and cytochrome C translocation were tracked by immunoblots, and neurobehavioral test results were compared between the groups. Results: Mitochondria in perihematomal neurons demonstrated dramatic changes including mitochondrial swelling, intracristal dilation, and decreased matrix density. HA treatment decreased mitochondrial injury and apoptosis, inhibited caspase-3 activation and cytochrome C translocation, and improved behavioral recovery. Conclusion: These data show that ICH induces dramatic mitochondrial damage, and HA exhibits protective effects possibly through ameliorating mitochondrial injury and apoptosis. Collectively, these findings suggest a new direction for novel therapeutics. Keywords: apoptosis, intracerebral hemorrhage, mitochondria, huperzine A, neuroprotection

Granular materials in rotating drums are of wide interest not only because of their extensive use in the industrial contexts, but also as model systems in the study of natural disasters, such as avalanches or landslides. Most of available experimental methods are restricted to surface layer flows and dilute systems whilst the remainder can only resolve the granular dynamics to a fine scale with relatively poor temporal resolution or vice versa. In contrast, speckle visibility spectroscopy (SVS) is able to resolve the average of the three components of motion of grains in dense systems in small volume of granular media several layer deep with spatio-temporal resolutions that allow the probing of the granular micro-dynamics. We have used this technique to study granular dynamics of surface avalanche flow in the slumping regime using both spherical glass and irregular sand particles. Although results are very similar, we determined that visually observed compaction at the beginning of avalanche process for irregular sand particles influence time evolution of the particle fluctuation velocity during avalanches.

Quinoidal-aromatic conjugated polymers hold great application potential in organic field-effect transistors (OFETs). However, the development of high mobility quinoidal-aromatic conjugated polymers still lags behind the more popular donor-acceptor (D-A) conjugated polymers, mainly owing to the lack of a rational design strategy and efficient building block. Herein, a novel quinoid-donor-acceptor (Q-D-A) strategy is demonstrated to modulate the energy-level and boost the charge carrier transport mobility of conjugated polymers as opposed to the D-A system. On the basis of this strategy, a quinoidal-aromatic conjugated polymer, namely PAQM-BT, is designed and synthesized. With the combined use of quinoid, donor and acceptor units in the backbone, the resulting Q-D-A polymer PAQM-BT displays the narrowest bandgap with the deepest-lying lowest unoccupied molecular orbital (LUMO) energy level, highest backbone coplanarity, enhanced thin-film crystallinity and smallest effective hole mass in comparison with the corresponding D-A polymer PT3B1 and quinoid-donor (Q-D) polymer PAQM-3T. Benefitting from the more effective intra- and inter-chain charge transport, as corroborated by experiment and theoretical calculations, OFET devices based on PAQM-BT exhibit a highly boosted hole mobility of up to 5.10 cm2 V-1 s-1, which is one and four orders of magnitude higher than that of PAQM-3T and PT3B1, respectively, and is among the highest for quinoidal-aromatic conjugated polymers. The potent Q-D-A strategy not only allows the energy level to be modulated but also leads to effective charge carrier transport, opening up possibilities to the development of high mobility quinoidal-aromatic conjugated polymers based on a variety of quinoids, donors, and acceptors. This journal is