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Xinyu Zhang,1,2 Mengcen Qian,1,3 Jiaqi Yan,1 Ruixin Wang,1 Dawei Lyu,1,4 Xiaohua Ying,1,3 Shenglan Tang2,5,6 1School of Public Health, Fudan University, Shanghai, People’s Republic of China; 2Global Health Research Center, Duke Kunshan University, Kunshan, Jiangsu, People’s Republic of China; 3Key Laboratory of Health Technology Assessment, National Health Commission (Fudan University), Shanghai, People’s Republic of China; 4Shanghai Healthcare Security Administration, Shanghai, People’s Republic of China; 5Duke Global Health Institute, Duke University, Durham, NC, USA; 6SingHealth Duke-NUS Global Health Institute, Duke-NUS, Singapore, SingaporeCorrespondence: Xiaohua Ying, School of Public Health, Fudan University, 130 Dong’an Road, Shanghai, 200030, People’s Republic of China, Email xhying@fudan.edu.cnPurpose: China has developed and widely piloted a new case-based payment, ie, the “Diagnosis-Intervention Packet” (DIP) payment, which has a granular classification system. We evaluated the impact of DIP payment on the quality of care in a large pilot city in China and explored potential mechanisms of quality change.Methods: The city started to implement DIP payment with a hospital-level cap on July 1, 2019. Using a 5% random sample of discharge records from July 2017 to June 2021, we employed a difference-in-differences approach to compare two mortality measures (in-hospital mortality, mortality of surgical patients), two readmission measures (all-cause readmission within 30 days, readmission with the same principal diagnosis within 30 days) and a patient safety measure (operation associated complications or adverse event) in 13 pilot hospitals and 27 non-pilot hospitals before and after DIP payment reform.Results: Of 122,637 discharge records included, 43,023 (35.1%) were from pilot hospitals. After DIP payment, the readmission rate within 30 days and readmission rate with the same principal diagnosis in pilot hospitals decreased significantly by 3.2 percentage points (P < 0.001) and 1.8 percentage points (P < 0.001), respectively. The in-hospital mortality rate, the mortality rate of surgical patients, and the rate of operation-associated complications or adverse events did not have significant changes. The decrease in quality measures was primarily driven by tertiary hospitals, was more obvious over time after the policy adoption, and was more pronounced in groups with higher intensity of care.Conclusion: This study indicated that DIP payment with a cap in the study city was associated with improved quality of care among patients in pilot hospitals. The provider’s behavior of increasing the intensity of care, especially for more severe patients, may partially contribute to the results.Keywords: prospective payment system, Diagnosis-Intervention Packet (DIP), quality of healthcare, policy evaluation, China

Yi Liang,1,2 Liping Feng,1 Yue Zheng,1 Yunzhen Gao,2 Rongying Shi,2 Zhirong Zhang,2 Xue Ying,1 Yingchun Zeng1 1School of Pharmacy, Chengdu Medical College, Chengdu, 610500, People’s Republic of China; 2Key Laboratory of Drug-Targeting and Drug Delivery System, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, 610041, People’s Republic of ChinaCorrespondence: Xue Ying; Yingchun Zeng, School of Pharmacy, Chengdu Medical College, No. 783, Xindu Avenue, Chengdu, 610500, People’s Republic of China, Tel +86-28-62739552 ; +86-28-62739516, Email Yingxueshzu@163.com; zych19900119@163.comIntroduction: Parkinson’s disease (PD) is a multifactor-induced neurodegenerative disease with high incidence in the elderly population. We found for the first time that the combination of dopamine (DA) and 3-n-butylphthalide (NBP) has great potential for the synergistic treatment of PD. To further improve the therapeutic performance of the drugs, a brain-targeting liposomal co-delivery system encapsulating NBP and DA ((NBP+DA)-Lips-RVG29) was designed using a rabies virus polypeptide with 29 amino acids (RVG29) as the targeting ligand.Methods: The synergistic neuroprotective effects of NBP and DA were assessed in 6-OHDA-induced PC12 cells. Then, (NBP+DA)-Lips-RVG29 loading with NBP and DA at an optimal ratio was prepared using the thin-film hydration and sonication method. The physicochemical and biological characterization of (NBP+DA)-Lips-RVG29 were systemically investigated, and the therapeutic efficiency and underlying mechanisms of (NBP+DA)-Lips-RVG29 were also explored in vitro and in vivo. Finally, the safety of (NBP+DA)-Lips-RVG29 was evaluated.Results: The synergistic effects of NBP and DA peaked at 1:1 (NBP/DA, mol/mol). The functionalized liposomes showed significantly higher uptake efficiency and blood-brain barrier (BBB) penetration efficiency in vitro. After systemic administration, (NBP+DA)-Lips-RVG29 prolonged the blood circulation of drugs, enhanced BBB penetration and increased drug accumulation in the striatum, substantia nigra and hippocampus. Moreover, (NBP+DA)-Lips-RVG29 showed excellent neuroprotective effects in a cellular PD model of PC12 cells and improved therapeutic efficacy in a PD mouse model. Furthermore, the safety evaluation of (NBP+DA)-Lips-RVG29 revealed no systemic toxicity.Conclusion: NBP and DA exhibited the synergistic anti-PD effects. The RVG29-modified liposomes encapsulating NBP and DA contributed to the accumulation of drugs in the brain lesions area of PD and further improved treatment efficacy. Therefore, (NBP+DA)-Lips-RVG29 represents a promising strategy for the treatment of PD and other neurodegenerative diseases. Keywords: Parkinson’s disease, brain targeting, liposomes, dopamine, 3-n-butylphthalide, synergistic effect

Liang Chen,1,&ast; Xiaomei Ying,2,&ast; Haohao Wang,1,&ast; Jiaheng Xie,3,&ast; Qikai Tang,4 Wen Liu1 1Department of Hepatobiliary and Pancreatic Surgery, Conversion Therapy Center for Hepatobiliary and Pancreatic Tumors, First Hospital of Jiaxing, Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, People’s Republic of China; 2Department of General Surgery, Suzhou Hospital of Anhui Medical University, Suzhou, Anhui, People’s Republic of China; 3Department of Plastic and Cosmetic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan Province, 410008, People’s Republic of China; 4Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wen Liu, Department of Hepatobiliary and Pancreatic Surgery, Conversion therapy center for Hepatobiliary and Pancreatic Tumors, First Hospital of Jiaxing, Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, People’s Republic of China, Email nickwen2006@163.comBackground: The role of cellular senescence in the tumor microenvironment of pancreatic cancer (PC) remains unclear, particularly regarding its impact on prognosis and immunotherapy outcomes.Methods: We utilized single-cell sequencing datasets (GSE155698 and GSE154778) for pancreatic cancer from the Gene Expression Omnibus (GEO) database and bulk RNA-seq data from the University of California, Santa Cruz (UCSC) and International Cancer Genome Consortium (ICGC) repositories, creating three patient cohorts: The Cancer Genome Atlas (TCGA) cohort, PAAD-AU cohort, and PAAD-CA cohort. Dimensionality reduction cluster analysis processed the single-cell data, while weighted gene co-expression network analysis (WGCNA) and differential expression gene analysis were applied to bulk RNA-seq data. Prognostic models were developed using Cox proportional hazards (COX) and least absolute shrinkage and selection operator (LASSO) regression, with validation through survival analysis, decision curve analysis, and principal component analysis (PCA). Tumor mutation data were analyzed using the “maftools” package, and the immune microenvironment was assessed with TIMER2 data.Results: We developed a senescence-related (SENR) six-gene prognostic signature for PC, which stratifies patients by risk, with high-risk groups showing poorer prognoses. This model also offers predictive insights into tumor mutations and immune microenvironment characteristics. Caveolin-1 (CAV1) emerged as a significant prognostic biomarker, with functional validation showing its role in promoting cancer cell proliferation and migration, highlighting its potential as a therapeutic target.Conclusion: This study provides a novel senescence-related prognostic tool for PC, enhancing patient stratification for prognosis and immunotherapy, and identifies CAV1 as a key gene with clinical significance for targeted interventions.Keywords: pancreatic cancer, cellular senescence, prognosis, biomarker, immunotherapy

Kaixiong Liu,1– 3,&ast; Luling Wu,4,5,&ast; Gongping Chen,1– 3,&ast; Dunhuan Zeng,1– 3 Qiwei Zhong,6 Li Luo,1,2 Bin Song,7 Xiuhong Ying,1,2 Fayu Ni,8 Lifang Yu,8 Liyu Xu,9 Xin Lin,9 Xiaoyan Chen,10 Xin Zou,11 Jianhong Xiao,7 Yuekai Hu5,12,13 1Department of Respiratory and Critical Care medicine, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, People’s Republic of China; 2Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Fujian Medical University, Fuzhou, People’s Republic of China; 3Institute of Respiratory Disease, Fujian Medical University, Fuzhou, People’s Republic of China; 4Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China; 5Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China; 6Department of Respiratory and Critical Care Medicine, Minnan Hospital, the First Affiliated Hospital of Fujian Medical University, Quau zhou, People’s Republic of China; 7Department of Respiratory and Critical Care Medicine, Mindong Hospital Affiliated to Fujian Medical University, Ningde, People’s Republic of China; 8Department of Respiratory, Fuqing General Hospital Affiliated to Fujian Medical University, Fuzhou, People’s Republic of China; 9Department of Respiratory and Critical Care Medicine, Fuzhou First Hospital of Fujian Medical University, Fuzhou, People’s Republic of China; 10Department of Emergency Medicine, Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou, People’s Republic of China; 11Department of Respiratory and Critical Care Medicine, LongYan First Hospital Affiliated to Fujian Medical University, Longyan, People’s Republic of China; 12Department of Infectious Diseases, First Affiliated Hospital of Fujian Medical University, Fuzhou, People’s Republic of China; 13Department of Infectious Diseases, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yuekai Hu; Jianhong Xiao, Email huyuekai@fudan.edu.cn; xjh1030@sina.comObjective: This study aimed to describe and compare the epidemiological, demographic, clinical, laboratory and radiological characteristics as well as the complications, treatments, and outcomes of these patients.Methods: We retrospectively investigated clinical data of patients with C. psittaci infection (psittacosis) in eight Grade IIIA hospitals of Fujian. Metagenomic next-generation sequencing (mNGS) was used identify C. psittaci in clinical samples of all included patients.Results: A total of 74 patients (39 severe/35 non-severe) was diagnosed with psittacosis, 25 (33.8%) of whom had history of poultry exposure. Common symptoms included high fever (98% [37/74]), fatigue (52.7% [39/74]), and dyspnea (51.4% [38/74]). Common manifestations in imaging included consolidation (89.2%), pleural effusion (77.0%), and air bronchogram (66.2%). Common complications included acute respiratory distress syndrome (55.4% [41/74]), type I respiratory failure (52.7% [39/74]), acute liver injury (41.9% [31/74]), and secondary infection (27.0% [20/74]). The in-hospital mortality rate was 8.11% (6/74).Conclusion: C. psittaci infection is represents an underestimated cause of CAP. For SCAP patients with poultry and bird contact history, specimens were encouraged to be sended for mNGS test in time. C. psittaci infection can lead to severe, multiple system involvement, and several complications. mNGS facilitate timely diagnosis of C. psittaci infection.Keywords: Chlamydia psittaci, metagenomic next-generation sequencing, community-acquired pneumonia, bronchoalveolar lavage fluid

Hao Wu,1,2,&ast; Qianyu Chen,2,3,&ast; Yanxin Liu,4 Yingdan Tang,5 Yang Zhao,5 Xueying Zhang,6 Xun Chen,2 Xiaoyan Ying,1 Boqun Xu1 1Department of Obstetrics and Gynecology, the Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China; 2Department of Obstetrics and Gynecology, the Affiliated Sir Run Run Hospital of Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China; 3Department of Obstetrics and Gynecology, Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu, People’s Republic of China; 4Department of Obstetrics and Gynecology, Pukou Branch of Jiangsu People’s Hospital, Nanjing, Jiangsu, People’s Republic of China; 5Department of Statistics, Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China; 6Department of Obstetrics and Gynecology, the Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Boqun Xu, Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Nanjing Medical University, 121 Jiangjiayuan Road, Nanjing, Jiangsu, 210000, People’s Republic of China, Tel +86-13805164016, Email boqun_xu@njmu.edu.cnObjective: The purpose is to establish a model to predict endometrial carcinoma and assess its value in the preliminary diagnosis of endometrial carcinoma.Methods: The data of 381 patients undergoing hysteroscopy were incorporated into the model, including 282 cases in the training cohort and 99 cases in the validation cohort. Significant morphological indexes were selected using the chi-square test and subjected to the binary logistic regression analysis. Besides, the scoring interval was set, and the nomogram of the prediction model was established. Model calibration curves were drawn using the data from the validation cohort. The study was approved by the Ethics Committee of the Affiliated Sir Run Run Hospital of Nanjing Medical University, and written informed consent was obtained from the patients.Results: The sensitivity, specificity, positive predictive value, and negative predictive value of the model were 96.7%, 92.3%, 77.3%, and 99.0%, respectively. Analysis of the receiver operating characteristic curve in the training cohort showed an area under the curve of 0.984 (95% CI: 0.974– 0.995). The receiver operating characteristic curve in the validation cohort revealed an area under the curve of 0.976 (95% CI: 0.950– 1.000). The calibration curve indicated that the probability in the actual setting was consistent with that predicted by the nomogram in the training cohort.Conclusion: Our model has high sensitivity and specificity in predicting endometrial carcinoma, and helps clinicians to make accurate diagnosis.Keywords: hysteroscopy, endometrial carcinoma, morphology, prediction model

Chronic total occlusion (CTO) percutaneous coronary intervention (PCI) has substantially improved due to increasing operator experience and advancements in equipment, techniques, and management algorithms. However, the overall benefit of CTO PCI remains controversial, particularly since only a few randomized trials have been reported to date. Methods: We performed a meta-analysis to evaluate the efficacy of CTO PCI. The study outcomes were the occurrence of all-cause mortality, myocardial infarction, repeat revascularization, stroke, or freedom from angina at the longest documented follow-up period. Results: In five trials including 1790 patients, the mean age was 63 ± 10 years, 17% were female, with a median follow-up of 2.9 years. The procedural success rate ranged from 73% to 97% and the right coronary artery was the most involved artery (52%). There was no significant difference between CTO PCI and no intervention regarding all-cause mortality (odds ratio [OR]: 1.10, 95% confidence interval [CI]: 0.49–2.47, P = 0.82), myocardial infarction (OR: 1.20, 95% CI: 0.81–1.77, P = 0.36), repeat revascularization (OR: 0.67, 95% CI: 0.40–1.14, P = 0.14), or stroke (OR: 0.60, 95% CI: 0.26–1.36, P = 0.22). In two trials including 686 patients, significantly more patients were free of angina at 1 year, defined as the Canadian Cardiovascular Society grading of angina pectoris Grade 0, in the CTO PCI group compared to the no intervention group (OR: 0.52, 95% CI: 0.35–0.76, P < 0.001). Meta-regression analyses based on various trial-level covariates (gender, diabetes, previous myocardial infarction, PCI or coronary artery bypass graft, SYNTAX or J-CTO scores, and CTO-related artery percentages) did not suggest any statistically significant relationships. Conclusions: CTO PCI appears to have a similar efficacy profile compared to no intervention at long-term follow-up, but with a significant improvement of angina favoring PCI-treated patients. Further adequately powered and long-term trials are required to identify the best management strategy for patients with coronary CTO.

Summary: Hypofibrinolysis is a recently-recognized risk factor for recurrent cardiovascular events in patients with ST-segment elevation myocardial infarction (STEMI), but the mechanistic determinants of this are not well understood. In patients with STEMI, we show that the effectiveness of endogenous fibrinolysis in whole blood is determined in part by fibrinogen level, high sensitivity C-reactive protein, and shear-induced platelet reactivity, the latter directly related to the speed of thrombin generation. Our findings strengthen the evidence for the role of cellular components and bidirectional crosstalk between coagulatory and inflammatory pathways as determinants of hypofibrinolysis.

Since the energy crisis in the 1960s, crucial research and activities were spurred to improve energy efficiency and decrease environmental pollution. To deal with the various problems the construction industry are facing, the concept of green buildings (GBs) has been gradually shaped and put forward all over the world, and green building rating systems (GBRSs) have been developed. The concept of GBs covers a wide range of elements, and its definition is constantly updated as the construction industry develops. This paper compares the development of backgrounds and statuses of green building development in various countries. It also presents an overview of the green building development situation within these countries, summarizing two influences for GB development: one external and the other internal. External factors include GB development policy support, economic benefits, and certification schemes. Internal factors are the development and application of GB technology, the level of building management, and how users interact with the GB technology. Currently, 49 worldwide green building standards and application have been sorted out, including 18 standard expert appraisal systems. Moreover, it discusses the research results and lessons learned from green building projects in different countries and summarizes their achievements and challenges. To correctly understand and use green building technology, it is essential to improve the policy and incentive system, improve the professional quality and technical ability of employees and accredited consultants, constantly develop and update the evaluation system, strengthen technological innovation, and integrate design and management. This paper aims to draw a clear roadmap for national standard development, policy formulation, and construction design companies, provide solutions to remove the obstacles, and suggest research direction for future studies.

Background: Chronic lymphocytic leukaemia (CLL) is the most common form of leukaemia among adults, particularly in Western nations. The introduction of Bruton's tyrosine kinase (BTK) inhibitors as a treatment of CLL, namely, ibrutinib, which is a first-generation BTK inhibitor, has significantly improved the treatment landscape for CLL. However, ibrutinib has been associated with an increased risk of atrial fibrillation (AF) and hypertension. Real-world studies that compare the cardiovascular safety of ibrutinib with bendamustine plus anti-CD20 monoclonal antibody are not widely available. Methods: A retrospective cohort analysis using the TriNetX platform identified two patient groups: one treated with ibrutinib and the other with bendamustine and an anti-CD20 antibody. Propensity score matching balanced their demographic and clinical characteristics. The outcomes evaluated included the all-cause mortality and new-onset AF/flutter, hypertension, heart failure, ventricular arrhythmias, and bleeding. Results: No significant difference was observed in the all-cause mortality between the two cohorts. However, ibrutinib was associated with a higher risk of AF/flutter (HR 1.89, 95% CI 1.36–2.62; p < 0.05) and hypertension (HR 1.22, 95% CI 1.01–1.47; p = 0.04). Other outcomes, such as heart failure, ventricular arrhythmias, and bleeding, were not different between the cohorts. Conclusions: Ibrutinib remains a valuable option for the treatment of CLL, but is associated with significant cardiovascular risks, leading to it being superseded by the newer generation of BTKis, which offer less cardiovascular toxicities. These results highlight the TriNetX platform's reliability as a real-world data source for validating clinical trial findings and highlight the importance of incorporating cardio-oncology into treatment plans for CLL patients with significant comorbidities. [ABSTRACT FROM AUTHOR]

Dehua Kong,&ast; Wenyu Hong,&ast; Miao Yu, Yanxia Li, YaXin Zheng, Xue Ying Collaborative Innovation Center of Sichuan for Elderly Care and Health & Key Laboratory of Sichuan Province for Specific Structure of Small Molecule Drugs, School of Pharmaceutical Sciences, Chengdu Medical College, Chengdu, 610500, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xue Ying; YaXin Zheng, School of Pharmaceutical Sciences, Chengdu Medical College, Chengdu, 610500, People’s Republic of China, Tel +86 135-7945-5890 ; +86 173-8187-6167, Email yingxueshzu@163.com; zhengyaxinxyz@163.comIntroduction: The inability of many therapeutic molecules to cross the blood–brain barrier (BBB) combined with poor penetration into tumor tissue leads to difficult challenges for treatment of brain tumors. In order to settle these hurdles, we developed a novel multifunctional targeting carrier which enables drugs to transport across the BBB and targets brain tumor tissues.Methods: In the multifunctional targeting liposomes, the natural compound resveratrol (RES) was incorporated into the lipid bilayer membranes of liposomes, while p-aminophenyl-α-D-manno-pyranoside (MAN) and wheat germ agglutinin (WGA) were conjugated to the liposomal surface. Epirubicin (EPI) as an anticancer drug was then loaded into liposomes. Then, liposomes were characterized by evaluation on particle size, zeta potential and apparent morphology. The epirubicin plus resveratrol liposomes modified with WGA and MAN were applied to glioma cells and BBB model in vitro and C6 glioma-bearing rats in vivo.Results: The multifunctional targeting liposomes were round shaped with a smooth surface and uniform particle size. In consideration of the SRB results, the multifunctional targeting liposomes indicated a significant inhibitory effect, suggesting that MAN plus WGA generated robust drug delivery effects into the brain tumor cells. The glioma cells after administering epirubicin plus resveratrol liposomes modified with WGA and MAN displayed the most significant uptake and apoptosis conducted by flow cytometry. In the multifunctional targeting effects assay, the epirubicin plus resveratrol liposomes modified with WGA and MAN exhibited the strongest effects of crossing the BBB and then targeting brain tumor cells. In tumor-bearing rats after applying multifunctional targeting liposomes, the median survival time was evidently observed as being markedly longer than other controls.Conclusion: The epirubicin plus resveratrol liposomes modified with WGA and MAN exhibited strong ability to improve epirubicin and resveratrol transporting across the BBB and therapeutic effect on brain glioma, showing multifunctional targeting capability.Graphical Abstract: Keywords: multifunctional targeting liposomes, blood–brain barrier, apoptosis, resveratrol, brain gliomas

Xiao-Xiao Jin,1,2 Yan-Fei Xu,2 Xiang Ying,1 Ye-Qing Qian,2 Peng-Zhen Jin,2 Min-Yue Dong2 1Prenatal Diagnosis Center of Taizhou Hospital, Wenzhou Medical University, Taizhou, 317000, People’s Republic of China; 2Key Laboratory of Reproductive Genetics, Ministry of Education, Department of Reproductive Genetics, Women’s Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, People’s Republic of ChinaCorrespondence: Min-Yue DongDepartment of Reproductive Genetics, Women’s Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, People’s Republic of ChinaTel +86 18957100183Fax +86-571-87061878Email drdong_dmy1226@163.comObjective: This paper analyzes the clinical significance of noninvasive prenatal testing (NIPT) for fetal chromosome aneuploidy in the screening of in vitro fertilization–embryo transfer (IVF) pregnancies.Methods: The study subjects consisted of 3163 IVF-pregnant women who underwent NIPT at the Women’s Hospital, School of Medicine, Zhejiang University and Taizhou Hospital, Zhejiang Province from February 2015 to June 2019. Fetal or neonatal karyotype analysis was carried out in high-risk patients, with subsequent follow-up on pregnancy outcomes.Results: NIPT results of 3163 pregnant women suggested 20 cases of high-risk fetal chromosome aneuploidy, of which 2185 cases were a single pregnancy. Of the 13 cases of high-risk chromosome aneuploidy in single pregnancies, seven were true positive, and six were false positive according to fetal or newborn chromosomal karyotype diagnosis. Twin pregnancies accounted for 978 cases in which NIPT indicated seven cases of high-risk chromosome aneuploidy; six of these cases were true positive, and one case was false positive according to fetal or newborn chromosomal karyotype diagnosis. The specificity, positive predictive value, and false-positive rate of trisomy 21 syndrome in IVF single embryo NIPT were 99.86%, 62.5%, and 0.14%, respectively. The specificity, positive predictive value, and false-positive rate of trisomy 18 syndrome were 99.95%, 66.67%, and 0.05%, respectively. The specificity of trisomy 13 syndrome was 99.91%, and the false-positive rate was 0.09%. The specificity of trisomy 21 syndrome in IVF twin NIPT was 99.89%, the positive predictive value was 83.33%, and the false-positive rate was 0.11%. The specificity and positive predictive value of fetal trisomy 18 syndrome were 100.00%, and the false-positive rate of it were 0.00%. Sensitivity and false-negative rates were 100% in all cases.Conclusion: NIPT is an ideal prenatal test for IVF-pregnant women due to its high sensitivity and specificity in screening for fetal aneuploidy.Keywords: in vitro fertilization–embryo transfer, pregnancy, noninvasive prenatal testing, chromosome, aneuploidy, amniotic fluid

Abstract The occurrence of thrombotic complications, which can result in excess mortality and morbidity, represent an imbalance between the pro-thrombotic and fibrinolytic equilibrium. The mainstay treatment of these complications involves the use of antithrombotic agents but despite advances in pharmacotherapy, there remains a significant proportion of patients who continue to remain at risk. Endogenous fibrinolysis is a physiological counter-measure against lasting thrombosis and may be measured using several techniques to identify higher risk patients who may benefit from more aggressive pharmacotherapy. However, the assessment of the fibrinolytic system is not yet accepted into routine clinical practice. In this review, we will revisit the different methods of assessing endogenous fibrinolysis (factorial assays, turbidimetric lysis assays, viscoelastic and the global thrombosis tests), including the strengths, limitations, correlation to clinical outcomes of each method and how we might integrate the assessment of endogenous fibrinolysis into clinical practice in the future.

Zining Liu,* Yinkui Wang,* Fei Shan, Xiangji Ying, Yan Zhang, Shuangxi Li, Yongning Jia, Ziyu Li, Jiafu Ji Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Gastrointestinal Cancer Center, Peking University Cancer Hospital & Institute, Beijing 100142, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ziyu LiKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Gastrointestinal Cancer Center, Peking University Cancer Hospital & Institute, Beijing 100142, People’s Republic of ChinaEmail ziyu_li@hsc.pku.edu.cnBackground: The duration and the optimal time to adjuvant chemotherapy (TAC) in locally advanced gastric cancer (LAGC) have net not been sufficiently demonstrated. Sequential adjuvant chemotherapy (AC) after neoadjuvant chemotherapy plus gastrectomy is increasingly utilized, making the question more complicated.Patients and Methods: Data were collected from patients with LAGC who underwent 5-Fu-based doublet regimens as adjuvant treatment after gastrectomy in a single-center database. TAC and duration (cycles) were used to evaluate survival outcomes.Results: A total of 816 patients were included. Patients received over six cycles and TAC less than 42 days significantly correlated with better survival (log-rank Ptrend< 0.001). The analysis of TAC and number cycles were separately applied in perioperative chemotherapy (PEC) and postoperative chemotherapy (POC) group using Cox regression. The number of cycles revealed a statistical significance improving OS rate both in POC (HR=0.904, 95% CI=0.836– 0.977, P=0.011) and PEC (HR=0.887, 95% CI=0.798– 0.986, P=0.026), while only in POC did the TAC show an increasing trend of risk with borderline significance (OS: HR=1.008, 95% CI=0.999– 1.018, P=0.094; PFS: HR=1.009, 95% CI=1.000– 1.018, P=0.055). A spline model demonstrates the less improvement in survival after cycles of chemotherapy reaching six.Conclusion: Our findings suggest that TAC is more likely to downregulate the survival benefit in POC rather than PEC, while overall survival is susceptible to cumulative cycles of chemotherapy in both groups. Furthermore, six cycles of chemotherapy tended to reach the maximum survival benefits. Prospective confirmation is required.Keywords: gastric cancer, chemotherapy, time to initiation, duration, restricted cubic spline

Abstract Patients hospitalised with COVID-19 have a high mortality. Identification of patients at increased risk of adverse outcome would be important, to allow closer observation and earlier medical intervention for those at risk, and to objectively guide prognosis for friends and family of affected individuals. We conducted a single-centre retrospective cohort study in all-comers with COVID-19 admitted to a large general hospital in the United Kingdom. Clinical characteristics and features on admission, including observations, haematological and biochemical characteristics, were used to develop a score to predict 30-day mortality, using multivariable logistic regression. We identified 316 patients, of whom 46% died within 30-days. We developed a mortality score incorporating age, sex, platelet count, international normalised ratio, and observations on admission including the Glasgow Coma Scale, respiratory rate and blood pressure. The score was highly predictive of 30-day mortality with an area under the receiver operating curve of 0.7933 (95% CI 0.745–0.841). The optimal cut-point was a score ≥ 4, which had a sensitivity of 78.36% and a specificity of 67.59%. Patients with a score ≥ 4 had an odds ratio of 7.6 for 30-day mortality compared to those with a score

Clustering of receptors associated with immunoreceptor tyrosine-based activation motifs (ITAMs) initiates the macrophage antimicrobial response. ITAM receptors engage Src-family tyrosine kinases (SFKs) to initiate phagocytosis and macrophage activation. Macrophages also encounter nonpathogenic molecules that cluster receptors weakly and must tune their sensitivity to avoid inappropriate responses. To investigate this response threshold, we compared signaling in the presence and absence of receptor clustering using a small-molecule inhibitor of Csk, which increased SFK activation and produced robust membrane-proximal signaling. Surprisingly, receptor-independent SFK activation led to a downstream signaling blockade associated with rapid degradation of the SFK LynA. Inflammatory priming of macrophages upregulated LynA and promoted receptor-independent signaling. In contrast, clustering the hemi-ITAM receptor Dectin-1 induced signaling that did not require LynA or inflammatory priming. Together, the basal-state signaling checkpoint regulated by LynA expression and degradation and the signaling reorganization initiated by receptor clustering allow cells to discriminate optimally between pathogens and nonpathogens.

A recent finding reports that co-stimulation of the high-affinity immunoglobulin E (IgE) receptor (FcεRI) and the chemokine receptor 1 (CCR1) triggered formation of membrane nanotubes among bone-marrow-derived mast cells. The co-stimulation was attained using corresponding ligands: IgE binding antigen and macrophage inflammatory protein 1α (MIP1 α), respectively. However, this approach failed to trigger formation of nanotubes among rat basophilic leukemia (RBL) cells due to the lack of CCR1 on the cell surface (Int. Immunol. 2010, 22 (2), 113-128). RBL cells are frequently used as a model for mast cells and are best known for antibody-mediated activation via FcεRI. This work reports the successful formation of membrane nanotubes among RBLs using only one stimulus, a hapten of 2,4-dinitrophenyl (DNP) molecules, which are presented as nanostructures with our designed spatial arrangements. This observation underlines the significance of the local presentation of ligands in the context of impacting the cellular signaling cascades. In the case of RBL, certain DNP nanostructures suppress antigen-induced degranulation and facilitate the rearrangement of the cytoskeleton to form nanotubes. These results demonstrate an important scientific concept; engineered nanostructures enable cellular signaling cascades, where current technologies encounter great difficulties. More importantly, nanotechnology offers a new platform to selectively activate and/or inhibit desired cellular signaling cascades.

Mei-ling Wu, Yi-ping Lin, Yan-li Wei, Hong-jian Du, Xiao-qian Ying, Wen-zhuang Tan, Bi-e Tang Faculty of Medicine, Jinhua Polytechnic, Zhejiang, People’s Republic of ChinaCorrespondence: Bi-e TangFaculty of Medicine, Jinhua Polytechnic, No. 1188 Wuzhou Street, Jinhua City, Zhejiang Provinc, People’s Republic of ChinaEmail tangbiejh@163.comBackground: Calycosin (CAL), a type of O-methylated isoflavone extracted from the herb Astralagusmembranaceus (AM), is a bioactive chemical with antioxidative, antiphlogistic and antineoplastic activities commonly used in traditional alternative Chinese medicine. AM has been shown to confer health benefits as an adjuvant in the treatment of a variety of diseases.Aim: The main objective of this study was to determine whether CAL influences the cytochrome P450 (CYP450) system involved in drug metabolism.Methods: Midazolam, tolbutamide, omeprazole, metoprolol and phenacetin were selected as probe drugs. Rats were randomly divided into three groups, specifically, 5% Carboxymethyl cellulose (CMC) for 8 days (Control), 5% CMC for 7 days + CAL for 1 day (single CAL) and CAL for 8 days (conc CAL), and metabolism of the five probe drugs evaluated using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS).Results: No significant differences were observed for omeprazole and midazolam, compared to the control group. Tmax and t1/2 values of only one probe drug, phenacetin, in the conc CAL group were significantly different from those of the control group (Tmax h: 0.50± 0.00 vs 0.23± 0.15; control vs conc CAL). Cmax of tolbutamide was decreased about two-fold in the conc CAL treatment group (conc vs control: 219.48 vs 429.56, P< 0.001).Conclusion: Calycosin inhibits the catalytic activities of CYP1A2, CYP2D6 and CYP2C9. Accordingly, we recommend caution, particularly when combining CAL as a modality therapy with drugs metabolized by CYP1A2, CYP2D6 and CYP2C9, to reduce the potential risks of drug accumulation or ineffective treatment.Keywords: calycosin, herb-drug interactions, UPLC-MS/MS, cocktail, CYP450

Current in vitro methods to assess nanomaterial cytotoxicity involve various assays to monitor specific cellular dysfunction, such as metabolic imbalance or inflammation. Although high throughput, fast, and animal-free, these in vitro methods suffer from unreliability and lack of relevance to in vivo situations. New approaches, especially with the potential to reliably relate to in vivo studies directly, are in critical need. This work introduces a new approach, single cell mechanics, derived from atomic force microscopy-based single cell compression. The single cell based approach is intrinsically advantageous in terms of being able to directly correlate to in vivo investigations. Its reliability and potential to measure cytotoxicity is evaluated using known systems: zinc oxide (ZnO) and silicon dioxide (SiO2) nanoparticles (NP) on human aortic endothelial cells (HAECs). This investigation clearly indicates the reliability of single cell compression. For example, ZnO NPs cause significant changes in force vs relative deformation profiles, whereas SiO2 NPs do not. New insights into NPs-cell interactions pertaining to cytotoxicity are also revealed from this single cell mechanics approach, in addition to a qualitative cytotoxicity conclusion. The advantages and disadvantages of this approach are also compared with conventional cytotoxicity assays.

Minmin Yu,1,2,* Baozhen Xu3,*, Hui Yang4,*, Songlin Xue,2 Rong Zhang,2 Hongmei Zhang,5 Xiaoyan Ying,1 Zhiqin Dai61Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing 210011, People’s Republic of China; 2Department of Obstetrics and Gynecology, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing 210003, People’s Republic of China; 3Department of Obstetrics and Gynecology, Nanjing Lishui People’s Hospital, Nanjing 211200, People’s Republic of China; 4Department of Obstetrics and Gynecology, Huaian Maternal and Child Health Care Hospital, Huaian 223002, People’s Republic of China; 5Department of Clinical Research Center, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing 210003, People’s Republic of China; 6Department of Gynecologic Oncology, Jiangsu Cancer Hospital, Nanjing 210009, People’s Republic of China*These authors contributed equally to this workBackground: Cervical cancer is one of the most lethal malignancies among women in the world. Every year about 311,365 women die because of cervical cancer. Chemo-resistance is the main reason of the lethal malignancies, and the mechanism of chemo-resistance in cervical cancer still remains largely elusive.Purpose: Previous studies reported that microRNAs played important biological roles in the chemo-resistance in many types of cancers, in the present study we tried to investigate the biological roles of microRNA-218 in chemo-resistance in cervical cancer cells.Results: Real-time PCR results indicated microRNA-218 was downregulated in cisplatin-resistant HeLa/DDP and SiHa/DDP cells compared with the mock HeLa and SiHa cells. CCK-8 assay results showed upregulation of microRNA-218 enhanced the cisplatin sensitivity of cervical cancer cells; while downregulation of microRNA-218 decreased the cisplatin sensitivity of cervical cancer cells. Dual-luciferase assay indicated survivin was a direct target of microRNA-218. Western blotting and PCR results indicated the expression of survivin in HeLa/DDP and SiHa/DDP cells was significantly increased compared with HeLa and SiHa cells. Further study indicated induction of microRNA-218 decreased the expression of survivin while inhibition of microRNA-218 increased the expression of survivin in cervical cancer cells. Cell apoptosis results indicated induction of microRNA-218 induced the cell apoptosis in cervical cancer cells.Conclusion: Our data revealed microRNA-218 enhanced the cisplatin sensitivity in cervical cancer cells through regulation of cell growth and cell apoptosis, which could potentially benefit to the cervical cancer treatment in the future.Keywords: miR-218, cervical cancer, cisplatin resistant, apoptosis, survivin

Ying Gue and Gregory Lip discuss the accompanying study by Ana-Catarina Pinho-Gomes and co-workers on blood pressure lowering treatment in patients with atrial fibrillation.

MI with non-obstructive coronary artery (MINOCA) is a condition previously thought to be benign that has recently been shown to have comparable mortality to that of acute coronary syndrome with obstructive coronary disease. The heterogeneity of the underlying aetiology makes the assessment, investigation and treatment of patients with MINOCA challenging. The majority of patients with MINOCA presenting with ST-segment elevation MI generally have an underlying coronary or myocardial cause, predominantly plaque disruption or myocarditis. In order to make the correct diagnosis, in addition to the cause of the presentation, a meticulous and methodical approach is required, with targeted investigations. Stratification of patients to guide investigations that are more likely to provide the diagnosis will allow the correct treatment to be initiated promptly. In this article, the authors review the contemporary incidence, aetiology, recommended assessment and treatment of patients with MINOCA presenting with ST-segment elevation MI.