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Wellbores drilled in igneous formation with weak interlayers face significant risk of instabilities. This study aims to investigate the underlying mechanisms of these instabilities by employing a combination of rock mechanics tests and numerical simulation techniques. The mechanical properties of igneous rocks are evaluated to determine core strength parameters and analyze the impact of drilling fluid immersion on core strength. The two-dimensional model of the igneous formation is refined, and theoretical derivations are made, including the linear elasticity principal equation and the extent of the plastic zone within the wellbore. A numerical simulation model is developed using ABAQUS to analyze the wellbore stability of the weak interlayer igneous formation, accounting for drilling fluid immersion and weak interlayer conditions. The numerical simulations focus on four key aspects of the weak interlayer formation: strength, permeability, horizontal in-situ stress anisotropy, and abnormal pore pressure. The study findings indicate that strengthening the weak interlayer effectively mitigates the risk of wellbore instability. Moreover, the permeability of the weak interlayer exhibits minimal impact on wellbore stability within the formation. However, an increase in horizontal in-situ stress anisotropy and the abnormal pore pressure both decrease wellbore stability along the direction of the maximum in-situ stress.

Background Cervical cancer (CC) is the fourth most frequent cancer in women worldwide, Patients with CC, those at an advanced stage or with recurrent disease, have a poor prognosis with limited treatment options. Cuproptosis, which is regulated by mitochondrial ferredoxin 1-mediated protein lipoylation, is a newly discovered form of cell death. This study aimed to explore the potential prognostic value of cuproptosis-related lncRNAs and their relationship to immune microenvironment in cervical cancer.Methods RNA-sequencing data and clinical data of female cervical cancer patients were obtained from The Cancer Genome Atlas (TCGA), and 19 cuproptosis-related genes were obtained from cuproptosis-related studies. 304 CC patients were randomly separated into training or validation cohorts in a 1:1 ratio. Pearson correlation analysis was used to screen out the lncrnas associated with copper-copper mineralization, and correlation analysis was conducted with 711 reported cuproptosis-related lncRNAs. Univariate, LASSO and multivariate Cox regression analyses were used to construct the characteristics of cuproptosis-related lncRNAs in the training cohort, and their prognostic value was further tested in the validation cohort. Patients were divided into high-and low-risk groups based on the median risk score. Independent prognostic analyses, ROC, C-index, and nomogram were carried out to assess the prognostic value of the signature. Subsequently, lncRNAs were analyzed for Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes Enrichment (KEGG), immune-related functions, and tumour mutation burden (TMB). Finally, we used tumor immune dysfunction and exclusion (TIDE) algorithms on immune escape and immunotherapy of cuproptosis-related lncRNAs for CC.Results A total of 10 cuproptosis-related lncRNAs were obtained, and patients were divided into high-and low-risk groups. We found that high-risk patients had worse overall survival (OS) and progression-free survival (PFS) and higher mortality. Independent prognostic analyses, ROC, C-index, and nomogram showed that the cuproptosis-related lncRNAs can accurately predict the prognosis of patients. The nomogram and heatmap showed a distinct distribution of the high- and low-risk cuproptosis-related lncRNAs. Enrichment analysis showed that the biological functions of lncRNAs are associated with tumor development. Tumor immune microenvironmental analyses the risk score was positively correlated with the number of M0 macrophages, and mast cell activated, negatively correlated with Dendritic cells resting, M1 macrophages, mast cell resting, T cell CD4 memory activated, T cell gamma delta and T cells CD8. we analyzed immune-related functions to evaluate the immune status of the low-risk and high-risk groups, and the results showed that HLA, cytolytic activity, inflammation-promoting, check point, T-cell co-inhibition, APC co-inhibition, APC co-stimulation, CCR, MHC-I, and type I IFN response were significantly more active in the low-risk group than in the high-risk group (p > 0.05). The results of the expression levels of immune checkpoint molecules in high-risk group and low-risk group showed that the expression levels of common immune checkpoint molecules such as PDCD1, CD274, HAVCR2, CTLA4, and TIGIT in low-risk group were all higher than those in high-risk group. In terms of TME scores, immune scores and ESTIMATE scores were higher in low-risk patients than in high-risk patients, with no difference in stromal scores between them, suggesting a higher infiltration of immune cells in the low-risk group. In addition, OS was poorer in patients with low TMB. We were surprised to find that there was a negative correlation between the TIDE and risk scores, further suggesting that high-risk patients might react more actively to immunotherapy.Conclusion We identified a novel cuproptosis-related lncRNA signature which could precisely predict the prognosis of cervical cancer patients. Cuproptosis -related lncRNAs may may provide new insights into clinical applications and immunotherapy.

At present, the Chinese government is vigorously promoting the use of PPP mode to attract social capital and financial capital into the field of forestry, including ecological construction, protection and utilization, which is of great significance for promoting the construction of ecological civilization and the development of both the economy and the society. Because the financing, organization, implementation and environmental factors of PPP forestry projects are relatively complicated, there are certain risks for both the government and social capital. In order to evaluate the risks of China's forestry projects for the government and social capital, 43 risk factors were identified and divided into 4 groups based on Delphi method and questionnaire survey. 23 key risk factors were selected according to the standardized values. Then, the probability of occurrence (PO), impact size (IS) and overall risk level (ORL) of each key factor were determined by fuzzy synthetic evaluation(FSE) method, and each KRF, KRG and overall risk level (ORL) were calculated. Based on the results, "Government Decision Risk" in KRF was the most critical risk factor, and KRG "Financial Risk" was the most critical risk factor group. Overall, fuzzy comprehensive results showed that the ORL of China's forestry PPP project is relatively high. According to the analysis results, countermeasures were put forward. The research results could provide reference for all participants in PPP forestry projects to make decisions, and formulate a comprehensive risk management plan to use limited resources. In addition, this study could expand professional knowledge and enrich relevant results.

Autism spectrum disorder (ASD) is a highly heritable neurodevelopmental disorder with deficits in social communication and stereotypical behaviors. Whole-brain genome editing to correct single-base mutations and alleviate autistic-like behaviors in animal models has not been achieved. Here we developed an APOBEC-embedded cytosine base editor (AeCBE) system, for converting C·G to T·A base pairs. We demonstrate the effectiveness by targeting AeCBE to an ASD-associated mutation of the MEF2C gene (c.104T>C, p.L35P) in vivo. We constructed a Mef2c L35P heterozygous mouse, which exhibited autistic-like behavioral deficits. We programmed AeCBE to edit the mutated C·G base pairs of Mef2cin the mouse brain, via the intravenous injection of blood brain barrier (BBB)-crossing AAV. This treatment restored MEF2C protein levels and reversed impairments in social interactions and repetitive behaviors in Mef2c mutant mice. This work presents an in vivo base editing paradigm in which a single-base mutation in the brain could be successfully corrected. One-Sentence Summary Base editing in vivo in the mouse brain corrects autistic-like behaviors.

Backgrounds: To explore the value of umbilical artery cord blood glucose (UACBG) in predicting hypoglycemia in gestational diabetes mellitus (GDM) and other at-risk newborns, and to provide a cut-off UACBG value for predicting hypoglycemia occurrence. Methods: In this prospective study, we enrolled at-risk infants delivered vaginally, including neonates born to mothers with GDM, premature, macrosomia, and low birth weight. We separated the infants into GDM group and other at-risk group. All subjects underwent UACBG measurement during delivery. Neonatal peripheral blood glucose measurement was performed at 0.5 hand 2 h after birth. The predictive performance of UACBGfor neonatal hypoglycemia was assessed using receiver operating characteristic curve (ROC), area under curve (AUC), sensitivity and specificity. Results: 916 newborns were included, 538 in GDM group and 378 in other at-risk group. For hypoglycemia prediction within 2 h, the best cut-off of UACBG was 4.150 mmol/L, yielding an AUC of 0.688 (95% CI 0.625-0.751). UACBG had a better performance at 0.5 h (AUC 0.757; 95% CI 0.690-0.824). In detail, the AUC was 0.703 in GDM group (95% CI 0.594-0.811), with the optimal cut-off of 4.550 mmol/L. In other at-risk group, the AUC was 0.797（95% CI 0.716-0.877), and the best threshold was 4.350 mmol/L. No significant differences were observed between GDM group and other at-risk group in AUC at 0.5 h, 2 h and within 2 h. Conclusions: UACBG may be an efficient, non-invasive approach to predicting neonatal hypoglycemia within 2 h after birth.

Purpose To explore the value of umbilical artery cord blood glucose (UACBG) in predicting hypoglycemia in gestational diabetes mellitus (GDM) and other at-risk newborns, and to provide a cut-off UACBG value for predicting hypoglycemia occurrence. Methods In this prospective study, we enrolled at-risk infants delivered vaginally, including neonates born to mothers with GDM, premature, macrosomia, and low birth weight. We separated the infants into GDM group and other at-risk group. All subjects underwent UACBG measurement during delivery. Neonatal peripheral blood glucose measurement was performed at 0.5 h and 2 h after birth. The predictive performance of UACBG for neonatal hypoglycemia was assessed using receiver operating characteristic curve (ROC), area under curve (AUC), sensitivity and specificity. Results 916 newborns were included, 538 in GDM group and 378 in other at-risk group. For hypoglycemia prediction within 2 h, the best cut-off of UACBG was 4.150 mmol/L, yielding an AUC of 0.688 (95% CI 0.625–0.751). UACBG had a better performance at 0.5 h (AUC 0.757; 95% CI 0.690–0.824). In detail, the AUC was 0.703 in GDM group (95% CI 0.594–0.811), with the optimal cut-off of 4.550 mmol/L. In other at-risk group, the AUC was 0.797(95% CI 0.716–0.877), and the best threshold was 4.350 mmol/L. No significant differences were observed between GDM group and other at-risk group in AUC at 0.5 h, 2 h and within 2 h. Conclusions UACBG may be an efficient, non-invasive approach to predicting neonatal hypoglycemia within 2 h after birth.

An unprecedented 1,3-dipole cycloaddition between acyclic CF3-ketimines and N-benzyl azomethine ylide has been allowed by tungsten catalysis, furnishing a range of novel imidazolidines bearing a trifluoromethylated tetrasubstituted carbon center. This reaction appears as one of rare examples that challenging acyclic CF3-ketimines have been engaged in 1,3-cycloaddition reactions. The capability for gram-scale synthesis and variant derivatizations of cycloaddition adducts illustrates the synthetic potential of this approach. This protocol provides a facile access to a rapidly enlarging pool of motifs with a trifluoromethylated fully substituted carbon.

To realize a soft-switching inverter with the advantages of a simple structure, high efficiency, low-voltage stress, and easy to control, a novel parallel resonant dc-link inverter with the function of pulse current regeneration is proposed in this paper. All switches in the inverter main circuit can achieve zero-voltage switching (ZVS) turn- on and ZVS turn- off . In addition, all switches in the auxiliary commutation circuit (ACC) can achieve soft switching. The power in the ACC is small. Freewheeling diodes in the inverter turn off under zero current condition, which can reduce the reverse recovery loss of freewheeling diodes. In addition, the bulk capacitors are avoided in the circuit and there is no neutral point potential variation problem. At the same time, the zero-voltage duration is independent of the load current, and the time of transition can be selected freely. According to the equivalent circuits in different operation modes under the proposed modulation strategy, the operation principle, soft-switching implementation condition, and parameter design procedure of the proposed inverter are analyzed successively in this paper. Finally, a 10 kW, 10 kHz soft-switching inverter prototype with insulated gate bipolar transistor based switches is built. Experimental results are given to demonstrate the validity and features of the soft-switching inverter.

During a woman's reproductive period, the endometrial tissue is shed and regenerated every month to prepare for pregnancy or for the next cycle. The aim of the present study was to isolate, culture and characterize human endometrial cells (ECs) derived from menstrual blood (MB) and the endometrium (E). MB-derived ECs (MB-ECs) were isolated from women's MB. E-derived ECs (E-ECs) were isolated from women's endometrial tissues. The present study investigated the epithelial cell marker cytokeratin 18 (CK18) in MB-ECs and E-ECs. Cell proliferation analyses indicated that E-ECs (population doubling time, 20.85 h) grew faster than MB-ECs (population doubling time, 22.05 h; P

The aim of this study was to evaluate the outcome of autotransplantation or replantation of extracted teeth combining with reconstruction of alveolar bone defects in use of artificial bone grafting clinically and radiographically. This article presents a more useful and convenient method for repairing tooth and reconstruction of bone defecting with some interesting cases. Eleven patients (seven men and four women) in whom teeth with complete root formation were extracted and autotransplanted, the bone of receiving area was Insufficient. All transplanted teeth were stabilized with orthodontic wire and resin or 4-0 silk sutures; at the same time, artificial bone powder was filled. In 11 cases, the missing teeth were restored by autogenous teeth and the alveolar bone defect was restored by artificial bone, the improvement in the radiographic and clinical parameters strongly suggest that it may be a useful therapy to solve the problem of the missing teeth and alveolar bone insufficiency simultaneously. However, the risk of replacement root resorption remains.

Objective: To evaluate Coagulation and fibrinolytic parameters after total joint arthroplasty (TJA) and provide evidence for optimization of timing of perioperative anticoagulation medicine. Methods: The prospective study was conducted at the Jishuitan Hospital of Peking University from January to April in 2016, and comprised patients who were scheduled consecutively to undergo primary total knee arthroplasty (TKA) or total hip arthroplasty (THA). Blood samples were obtained at day 1 preoperatively and day1, day 3 postoperatively. Antigenic levels of protein C (PC), endothelial protein C receptor (EPCR), tissue factor pathway inhibitor (TFPI), antithrombin III (AT-III), plasminogen activator inhibitor 1 (PAI-1) and tissue plasminogen activator (tPA) were measured with commercially available enzyme-linked immunosorbent assay kits. Results: Postoperative levels of coagulation parameters TFPI and AT-III were increased compared to preoperative values (118.7±34.6 vs 70.0±20.5 ?g/ml for AT-III, and 26.37±7.91vs 16.68±8.92 ?g/l for TFPI), while postoperative levels of coagulation parameters PC and EPCR were decreased (0.88±0.30 vs 2.03±0.66 ?g/ml for PC, and 100.8±31.0 vs 199.4±57.4 ?g/ml for EPCR). Postoperative levels of fibrinolytic parameter tPA was increased compared to preoperative values (2.87±0.83 vs 2.03±1.03 ?g/l), while its specific inhibitor PAI-1 was decreased (0.88±0.30 vs 2.03±0.66 ?g/l). Conclusion: These results demonstrated the perturbation of the coagulation and fibrinolytic system of patients undergoing TJA. Hypercoagulation and hyperfibrinolysis were observed in postoperative patients, which suggested anticoagulant therapy is effective and necessary. Keywords?Total joint arthroplasty, anticoagulation, fibrinolysis

Hybrid structures have the advantage of combining different types of materials at the same time. The trend of lightweight design in the transportation industry has promoted the development and application of composite materials with good crashworthiness performance. Low-density crushable foam-filled metal-composite hybrid structures have potential advantages as energy-absorbing components. This study investigated the mechanical characteristics of four different polyurethane foam-filled hybrid structures and their individual components under quasi-static axial compression. The experimental results showed foam-filled hybrid structures could change the deformation mode and improve stability during the compression process. Meanwhile, these hybrid structures could also improve energy absorption compared with their individual components. Among the different configurations, specimen C-PU-C (i.e., polyurethane foam filler between an outer CFRP tube and an inner CFRP tube) had the highest energy absorption capacity, at 5.4 kJ, and specific energy absorption, at 37.3 kJ/kg. Finally, a finite element (FE) model was established to analyze the mechanical characteristics of the hybrid structures by validating the simulation results against the experimental results.

Bruton’s tyrosine kinase (BTK) is a member of the Tec family of non-receptor tyrosine kinases and plays critical roles in B-cell receptor (BCR) signaling. BTK is often overexpressed in B-cells of patients with hematological malignancies. BTK inhibition blocks BCR signals, prevents B-cell activation and malignant B-cell growth, and induces apoptosis. Early irreversible BTK inhibitors such as ibrutinib, which covalently binds to the cysteine residue (C481) of BTK, are effective against B-cell malignancies and have received approval for various B-cell lymphomas and leukemia including mantle cell lymphoma and chronic lymphocytic leukemia, but their effectiveness is often limited by toxicities from off-target inhibition of the Tec (e.g., ITK/TEC) and EGFR family (e.g., EGFR/HER2/HER4). Acquired resistance mutations in the C481 binding site are known to cause clinical resistance to irreversible BTK inhibitors, which accounts for over half of progression in patients received ibrutinib. There is thus unmet medical need for a novel BTK inhibitor with improved safety profile efficacious against C481 mutation. Here we introduce FCN-589, a novel and orally active next-generation BTK inhibitor. FCN-589 shows potent kinase activities against wild-type (WT) BTK and the most common resistant mutation BTK C481S with single-digit nanomolar IC50 and improved selectivity over clinically significant off-targets such as TRK and ITK compared with nemtabrutinib (MK-1026, ARQ 531), another BTK C481S inhibitor in development. FCN-589 exhibits remarkable anti-proliferating potency against a panel of human B-cell malignancies-derived cancer cell lines. FCN-589 is over 30x more potent against follicular lymphoma cells (DOHH2) and activated B-cell subset of diffuse large B-cell lymphoma (DLBCL) cells (OCI-LY10 and Ri-1), and about 4x more potent against germinal center B-cell like subset of DLBCL cells (SU-DHL-4) compared with ARQ 531. In HEK-293 cell line ectopically expressing WT or BTK C481S, FCN-589 markedly inhibits p-BTK expression with superior activity compared with ARQ 531. Consistently, FCN-589 shows significant and superior anti-tumor activities in mice xenograft models derived from human non-Hodgkin’s lymphomas compared with ARQ 531 and ibrutinib. In non-clinical studies, FCN-589 exhibits good pharmacokinetic (PK) and safety properties. In particular, FCN-589 has longer T1/2 in both rats and dogs, displays improved CYP450 inhibition profile, and is less plasma protein bound compared with ARQ 531. Overall, FCN-589 is a novel next-generation BTK inhibitor targeting WT and BTK C481S. FCN-589 possesses potent in vitro and in vivo anti-cancer activities with better selectivity against clinically significant off-targets and exhibits favorable PK and safety profiles compared with ARQ 531. FCN-589 has potential to be a more effective and safer option for patients with B-cell malignancies. Citation Format: Shu Lin, Haohan Tan, Qihong Liu, Yunling Wang, Bin Liu, Zhifu Li, Zhifang Chen, Xianlong Wang, Xingdong Zhao, Lihua Jiang, Xilei Wang, Tao Cheng, Jiashu Zhou, Weibo Wang. FCN-589, a novel, potent and selective BTK inhibitor, targets BTK C481S for the treatment of B-cell malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5438.

Fos-related antigen-1 (FRA-1) is a member of activator protein-1 (AP-1) transcription factor superfamily, and FRA-1 is highly expressed in colon cancer, breast cancer, gastric cancer, lung cancer, bladder cancer, and other tumors. The expression level of FRA-1 is closely related to the processes of tumor cell proliferation, apoptosis, transformation, migration, and invasion, which is a potential therapeutic target and prognostic factor for many tumors. Clarifying the detailed mechanism of action of FRA-1 could provide the theoretical basis for tumor diagnosis, treatment, and prognosis, and is of great significance for the study of tumor etiology and pathogenesis. In this paper, the expression levels and influencing factors of FRA-1 in various tumor tissues and cells are summarized, as well as the effect of FRA-1 expression level on the biological behavior of tumor cells and the signal transduction mechanism. At the same time, the signal transduction mechanism of FRA-1 in inflammation was expounded. In addition, the related metabolites, drugs and non-coding RNA that affect the expression and function of FRA-1 were summarized. Finally, it illustrates that FRA-1 may be taken as a key factor for tumor prognosis and a potential therapeutic target. This review provides a theoretical basis for the systematic understanding of the relationship between FRA-1 and tumors, its function, and possible mechanism.

This study aimed to explore the impact of social participation (SP) on physical functioning and depression among empty-nest elderly taking part in the fourth wave of the China Health and Retirement Longitudinal Survey (CHARLS, 2018). The instrumental variable (IV) method and propensity score matching (PSM) method were used to analyse the impact of SP. The two-stage regression results of the IV method showed that SP has a significant negative impact on the physical functioning scores of empty-nest elderly (&beta, = &minus, 3.539, p &lt, 0.001) and non-empty-nest elderly (&beta, 4.703, p &lt, 0.001), and SP has a significant negative impact on the depression scores of empty-nest elderly (&beta, 2.404, p &lt, 1.957, p &lt, 0.001). The results of the PSM method were basically consistent with the IV method. Compared with non-empty-nest elderly, SP had more positive effects on the depression of empty-nest elderly (Wald &chi, 2 = 6.62, p = 0.010). Providing a friendly and supportive environment for the SP of empty-nest elderly was an important measure to promote healthy ageing. Targeted SP may be one of the greatest opportunities to improve the mental health of empty-nest elderly.

The interaction between Tim-3 on T cell and its ligand, Galectin-9, negatively regulates cellular immune responses. However, the role of Tim-3/Galectin-9 pathway in the immune evasion of cervical cancer remains unknown. This study is to investigate the expression, function, and regulation of Tim-3/Galectin-9 signaling pathway in human papilloma virus (HPV) positive cervical cancer. Flow cytometry showed that Tim-3 expression on T cell and Galectin-9 expression on monocytes in HPV positive cervical cancer patients were significantly higher compared to cervical intraepithelial neoplasia and benign uterine fibroids Tim-3 + CD4+ Th1 cells and Tim-3 + CD8+ T cells in HPV positive cervical cancer patients were significantly reduced after surgery. Serum TGF-β and IL-10 levels were positively correlated with Tim-3 + Treg cells, while IFN-γ and IL-2 were negatively correlated with Tim-3 + Th1 cells. Additionally, Tim-3 + CD4+ T cells were positively correlated with Galectin-9 + monocytes. Survival curve analysis showed that Tim-3 + CD4+ T cells were negatively correlated with patient survival, and closely related to FIGO stage, degree of differentiation, and lymph node metastasis of HPV positive cervical cancer. In vitro experiments showed that by blocking the Tim-3/Galectin-9 pathway, the proliferation of T cells and their ability to express IFN-γ, IL-2, perforin, and granzyme B was significantly restored. In conclusion, high levels of Tim-3 and Galectin-9 in HPV positive cervical cancer patients play roles in the progression of disease by promoting Treg cells to inhibit the cytotoxic function of Th1 and CD8+ T cells. Tim-3/Galectin-9 may serve as a new immunotherapy target for patients with HPV positive cervical cancer.

Cervical cancer is one of the most common malignant tumors in women all over the world. However, the exact etiology of cervical cancer remains unclear. The receptor for activated protein kinase C (RACK1) is reported to be involved in tumorigenesis and tumor progression. Besides, the prognostic value of RACK1 in several kinds of tumors has been identified. However, there are limited studies on the functional role of RACK1 in cervical cancer. In this study, we tested the expression level of RACK1 by immunohistochemistry and western blot technologies and find that it is upregulated in cervical cancer. Colony formation and CCK8 assays indicate that RACK1 promotes cell proliferation in CaSki cervical cancer cells. While the silence of RACK1 decreases the cell proliferation in CCK8 analysis. β-galactosidase staining suggests that RACK1 decreases cell senescence in cervical cancer cells. Invasion and migration assay show that RACK1 promotes the invasion and migration of cervical cancer cells. Also, when RACK1 was silenced, it exerts the opposite result. Furthermore, the mRNA expression levels of MMP‑3, MMP‑9 and MMP‑10 were upregulated in RACK1‑overexpressed CaSki cells by qPCR analysis. RACK1 also induces S phase accumulation in cell cycle analysis and suppresses cell apoptosis in cervical cancer cells. Flow cytometry analysis of mitochondria functions suggests that RACK1 increases the mitochondrial membrane potential (Δψm) levels to prevent mitochondrial apoptosis in cervical cancer cells. To explore the possible mechanism of RACK1, we tested and found that RACK1 upregulates the expression of NF-κB, cyclin D1 and CDK4 and downregulates the expression of p53, p38, p21 and STAT1 in cervical cancer cells. These results suggest that RACK1 promotes cell growth and invasion and inhibits the senescence and apoptosis in cervical cancer cells probably by affecting the p53 pathway.

Background Inappropriate admissions cause excessive utilization of health services compared with outpatient services. However, it is still unclear whether inappropriate admissions cause excessive use of health services compared with appropriate admissions. This study aims to clarify the differences in the hospitalization performances between appropriately admitted inpatients and inappropriately admitted inpatients. Methods A total of 2575 medical records were obtained after cluster sampling in three counties. Admission appropriateness was assessed by appropriateness evaluation protocol (AEP). The propensity score matching (PSM) was computed to match patients in treatment and control group with similar characteristics, and to examine the differences in the utilization of hospitalization services between the two groups. The samples were matched in two major steps in this study. In the first step, total samples were matched to examine the differences in the utilization of hospital services between the two groups using 15 individual covariates. In the second step, PSM was computed to analyze the differences between the two groups in different disease systems using 14 individual covariates. Results For the whole sample, the inappropriate group has lower expenditure of hospitalization (EOH) (difference = − 0.12, p = 0.003) and shorter length of stay (LOS) (difference = − 0.73, p = 0.016) than the appropriate group. For number of clinical inspection (NCI), it has no statistically significant difference (difference = − 0.39, p = 0.082) between the two groups. Among different disease systems, no significant differences were observed between the two groups among EOH, LOS and NCI, except that the EOH was lower in the inappropriate group than that in the appropriate group for surgical disease (difference = − 0.169, p = 0.043). Conclusion Inappropriate admissions have generated excessive health service utilization compared with appropriate admissions, especially for internal diseases. The departments in charge of medical services and hospital managers should pay high attention to the health service utilization of the inappropriately admitted inpatients. Relevant medical policies should be designed or optimized to increase the appropriateness in health care service delivery and precision in clinical pathway management.

This study aimed to evaluate the effects of the differences between two typical payment methods for the new rural cooperative medical scheme (NRCMS) in China on the utilisation of inpatient services. Interrupted time-series analysis (ITSA) and propensity score matching (PSM) were used to measure the difference between two typical payment methods for the NRCMS with regard to the utilisation of inpatient services. After the reform was formally implemented, the level and slope difference after reform compared with pre-intervention (distribution of inpatients in county hospitals (DIC), distribution of inpatients in township hospitals (DIT) and the actual compensation ratio of inpatients (ARCI)) were not statistically significant. Kernel matching obtained better results in reducing the mean and median of the absolute standardised bias of covariates of appropriateness of admission (AA), appropriateness of disease (AD). The difference in AA and AD of the matched inpatients between two groups was &minus, 0.03 (p-value = 0.042, 95% CI: &minus, 0.08 to 0.02) and 0.21 (p-value &lt, 0.001, 95% CI: &minus, 0.17 to 0.25), respectively. The differences in the utilisation of inpatient services may arise owing to the system designs of different payment methods for NRCMS in China. The causes of these differences can be used to guide inpatients to better use medical services, through the transformation and integration of payment systems.

ObjectivesIn this study, we aim to evaluate the effect of urban and rural resident medical insurance scheme (URRMI) on the utilisation of medical services by urban and rural residents in the four pilot provinces.Setting and participantsThe sample used in this study is 13 305 individuals, including 2620 in the treatment group and 10 685 in the control group, from the 2011 and 2015 surveys of China Health and Retirement Longitudinal Study.Outcome measuresPropensity score matching and difference-in-differences regression approach (PSM-DID) is used in the study. First, we match the baseline data by using kernel matching. Then, the average treatment effect of the four outcome variables are analysed by using the DID model. Finally, the robustness of the PSM-DID estimation is tested by simple model and radius matching.ResultsKernel matching have improved the overall balance after matching. The URRMI policy has significantly reduced the need-but-not outpatient care and significantly increased outpatient care cost and inpatient care cost for rural residents, with DID value of −0.271, 0.090 and 0.256, respectively. After robustness test, the DID competing results of four outcome variables are consistent.ConclusionsURRMI has a limited effect on the utilisation of medical and health services by all residents, but the effect on rural residents is obvious. The government should establish a unified or income-matching payment standard to prevent, control the use of medical insurance funds and increase its efforts to implement URRMI integration in more regions to improve overall fundraising levels.

This study aimed to assess the effect of the county-level medical centre policy on the health outcomes of trauma patients transported by emergency medical service (EMS) system in rural China. The methodology involved the use of electronic health records (EHRs, after 2016) of patients with trauma conditions such as head injury (n = 1931), chest (back) injury (n = 466), abdominal (waist) injury (n = 536), and limb injury (n = 857) who were transported by EMS to the county-level trauma centres of Huining County and Huan County in Gansu, China. Each patient was matched with a counterpart to a county-level trauma centre hospital by propensity score matching. Cox proportional hazard models were used to estimate the hazard ratios (HRs) of such patients in different hospitals. The HRs of all patients with the abovementioned traumatic conditions transported by EMS to county-level trauma centre hospitals were consistently higher than those transported by EMS to traditional hospitals after adjusting for numerous potential confounders. Higher HRs were associated with all patients with trauma (HR = 1.249, p &lt, 0.001), head injury (HR = 1.416, p &lt, 0.001), chest (back) injury (HR = 1.112, p = 0.560), abdominal (waist) injury (HR = 1.273, p = 0.016), and limb injury (HR = 1.078, p = 0.561) transported by EMS to the county-level trauma centre hospitals. Our study suggests that the construction of county-level medical centre provides an effective strategy to improve the health outcomes of EMS-transported trauma patients in Gansu, China. Policy makers can learn from the experience and improve the health outcomes of such patients through a personalised trauma treatment system and by categorizing the regional trauma centre.

This study is to investigate the role of regulatory B (Breg) cells in cervical cancer. In total, 70 cases of cervical cancer, 52 cases of cervical intraepithelial neoplasia (CIN), and 40 normal controls were enrolled. The percentage of Breg cells was detected by flow cytometry. Serum levels of IL-10 were measured by ELISA. The correlation between Breg cells and the clinical characterizations of cervical cancer was analyzed. The inhibition effect of Breg cells on CD8+ T cells was tested by blocking IL-10 in vitro. The percentage of CD19+CD5+CD1d+ Breg cells and the level of IL-10 of patients with cervical cancer or CIN were significantly higher than those in the control group (P<0.05). And the postoperative levels of Breg cells and IL-10 were significantly lower than the preoperative levels (P<0.05). Breg cells and the IL-10 level were positively correlated in cervical cancer patients (r=0.516). In addition, the Breg cell percentage was closely related to the FIGO stages, lymph node metastasis, tumor differentiation, HPV infection, and the tumor metastasis of cervical cancer (P<0.05). The Breg cell percentage was negatively correlated with CD8+ T cells of cervical cancer patients (r=‐0.669). The level of IL-10 in the culture supernatant of Bregs treated with CpG was significantly higher than that of non-Bregs (P<0.05). After coculture with Bregs, the quantity of CD8+ T cells to secrete perforin and Granzyme B was significantly decreased, and this effect was reversed after blocking IL-10 by a specific antibody. Breg cells are elevated in cervical cancer and associated with disease progression and metastasis. Moreover, they can inhibit the cytotoxicity of CD8+ T cells.

Nowadays, the application of all levels of industry in society has the participation of computer information system. At this stage, the participation of computers and network technology in all aspects of our lives has become more and more obvious. In the process of reforming some ideological and political education systems in today’s schools, people do not realize how to construct some effective ways of students’ ideological and political thinking. Of course, in order to adequately respond to the reform measures of the school’s ideological and political service system, many schools have begun to propose integrating computer information technology into the establishment of an ideological and political system. As far as the current form is concerned, the so-called informatization platform itself does not have a very dazzling halo. However, it can bring a huge development and forward momentum to the school’s ideological and political education service system[1].

The present study is to measure the expression of programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1), as well as its clinical significance in cervical cancer patients. Our results showed that different T cell subsets in patients with cervical cancer had high expression of PD-1, and DCs had high expression of PD-L1. High expression of PD-1 on Treg cells in cervical cancer patients facilitated the production of TGF-βand IL-10 but inhibited the production of IFN-γ. Cervical cancer elevated the expression of PD-1 and PD-L1 in mRNA level. PD-1 expression in peripheral blood of cervical cancer patients was related with tumor differentiation, lymph node metastasis, and invasiveness. PD-1/PD-L1 pathway inhibited lymphocyte proliferation but enhanced the secretion of IL-10 and TGF-βin vitro. In summary, our findings demonstrate that elevated levels of PD-1/PD-L1, TGF-β, and IL-10 in peripheral blood of cervical cancer patients may negatively regulate immune response against cervical cancer cells and contribute to the progression of cervical cancer. Therefore, PD-1/PD-L1 pathway may become an immunotherapy target in the future.

Teaching content is the core of classroom teaching. Physical education teachers generally choose appropriate teaching methods and teaching organization forms based on the features of teaching content. The current physical education materials of the new curriculum did not give the relative teachers the specific teaching content of each class, and provided a broad stage for the most relative teachers. How to choose and match teaching content reasonably and effectively is the fundamental guarantee for ameliorating the classroom teaching results. This article probes into the implementation path of college political thought education based on multimedia tech.

Tropomyosin receptor kinases (TRK or NTRK) are the transmembrane tyrosine kinases activated by soluble growth factors named neurotrophins (NT). TRK family includes three different members, namely TRKA, TRKB and TRKC. Extracellular recognition of NT to TRK proteins induces receptor dimerization, phosphorylation, and activation of the downstream signal transduction pathways via PI3K, RAS/MAPK/ERK, and PLC-gamma. TRKs are expressed primarily in neuronal tissues and regulate differentiation and survival of neuronal cells. Alteration of TRK pathway caused by gene fusion of TRK is frequently associated with the poor prognosis of a wide range of solid malignancies, such as neuroblastoma, breast cancer, pancreatic cancer, melanoma, thyroid cancer, glioblastoma, colorectal cancer, sarcomas, cholangiocarcinoma, and non-small cell lung cancer. The efficacy of TRK inhibition in TRK fusion-positive cancers has been demonstrated by the high response rate and lasting effect of the first-generation TRK inhibitors larotrectinib and entrectinib. However, acquired resistance mutations of TRK, such as solvent front mutations, gatekeeper mutations and DFG motif mutations, often emerge and abrogate the inhibitory effect of first-generation inhibitors. Thus, developing novel TRK inhibitors that can effectively overcome resistance mutations can provide great clinical benefits to patients. Here we introduce FCN-098, a potent second-generation TRK inhibitor. FCN-098 demonstrated marked kinase inhibition activity against wild-type (WT) and mutant TRK with IC50 at sub-nano or single nanomolar range. FCN-098 significantly and dose-dependently inhibited phosphorylation of TRK and its downstream effector ERK in TRK fusion-positive KM12 human colon cancer cells and BaF3 cells ectopically overexpressing WT or mutant TRK fusions. FCN-098 potently inhibited proliferation of KM12 cells and BaF3 cells overexpressing WT or various mutant TRK fusions while sparing TRK-negative cell lines. Consistent with in vitro results, FCN-098 showed remarkable anti-tumor activity in xenograft models driven by WT or mutant TRK fusions in a dose-dependent manner. In particular, the anti-tumor activity of FCN-098 was superior to another second-generation TRK inhibitor LOXO-195 at the same dose in xenografts driven by TPM3-TRKA G595R or ETV6-TRKC G623R mutation, and exhibited comparable potency to LOXO-195 in LMNA-TRKA G667C-driven xenografts. In non-clinical studies, FCN-098 exhibited excellent pharmacokinetic (PK) and safety properties, demonstrating longer T1/2 in both dogs and rats along with higher Cmax and larger dose-normalized AUC in dogs compared to LOXO-195. Overall, FCN-098 overcomes TRK resistance mutations in vitro and in vivo and exhibits favorable PK and safety profiles. FCN-098 has the potential to become an effective and safe therapeutic choice for a wide range of solid tumors harboring WT or mutant TRK fusions. Citation Format: Shu Lin, Tongshuang Li, Xianlong Wang, Lijun Yang, Zhifang Chen, Yue Rong, Xingdong Zhao, Yanxin Liu, Zongyao Zou, Min Lin, Yuwei Gao, Jiashu Zhou, Weibo Wang. FCN-098, a novel second-generation TRK inhibitor, overcomes TRK resistance mutations in vitro and in vivo [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3087.

The incidence and mortality of cervical cancer, which mainly results from the infection of human papillomavirus (HPV) is significantly increasing in Xinjiang. According to the previous research, the incidence of HPV-68 in cervical cancer patients in Xinjiang is significantly higher than in other parts of China. HPV E6 and E7 oncoproteins play a crucial role in cervical cancer, and can be used as ideal targets for therapeutic vaccines. Therefore, we analyzed and identified the possible T-cell and B-cell dominant epitopes and various aspects of HPV-68 E6 and E7 oncoproteins, including the physicochemical properties, secondary and tertiary structures using a bioinformatic approach, which provided a basis for designing an effective HPV infection therapeutic vaccine. The results showed that E6 oncoproteins was an unstable and hydrophilic protein, while E7 oncoproteins was unstable and hydrophilic protein. The secondary structure of the E6 oncoproteins consisted of 45.57% alpha helixes, 14.56% extended strands, 4.43% beta turns and 35.44% random coils. The secondary structure of E7 oncoproteins consisted of 35.45% alpha helixes, 17.27% extended strands, 0.91% beta turns and 46.36% random coils. Moreover, our results identified 5 dominant T-cell epitopes and 6 dominant B-cell epitopes in the E6 oncoproteins structure and 5 dominant T-cell epitopes and 3 dominant B-cell epitopes in E7 oncoproteins. In conclusion, this study provides comprehensive biological information about the HPV-68 E6 and E7 oncoproteins, which will lay a theoretical foundation for multi-epitope vaccines against HPV infection.

BACKGROUND This study analyzed the epidemiology and the risk factors of menopause syndrome (MPS) among Uyghur, Han, and Kazak women in Xinjiang. MATERIAL AND METHODS This was a cross-sectional study. The stratified-cluster random-sampling method was used. A total of 3382 women aged 40 to 60 years of age were included from Urumqi City, Kashgar City, Altay City, Ili Kazakh Autonomous Prefecture, Kunes County, Mongolkure County, Tekes County,Talede town, Alemale Township, and Ulugchat County (Kashgar Prefecture) in Xinjiang Province. A questionnaire was used to survey the clinical characteristics of MPS. Logistic regression analysis was used to analyze the MPS risk factors among Uyghur, Han, and Kazak women. RESULTS Oral contraceptives, negative life events, and menopause stages can influence MPS in Han women. In addition, occupation, body weight, mental illness, drug or alcohol abuse, and income level also affect the MPS of Uyghur women. In contrast to Han and Uyghur participants, education, menopausal pattern (natural or artificial), reproductive factors, and smoking are risk factors of MPS in Kazakh women. CONCLUSIONS The menopausal stages and the risk factors for MPS are different among Uyghur, Han, and Kazak women.

B-cell lymphoma-2 (Bcl-2) family proteins are key regulators of apoptosis, which is vital for proper tissue development and cellular homeostasis. Apoptosis occurs via activation of two different pathways: the extrinsic pathway, triggered by a death ligand binding to a death receptor, such as TNF-α to TNFR1; and the intrinsic pathway, regulated by Bcl-2 family proteins and their complex protein-protein interactions. Bcl-2 family proteins are functionally classified as either anti-apoptotic, such as Bcl-2, Bcl-xL and Mcl-1, or pro-apoptotic, including Bid, Bim, Bad, Bak and Bax. Anti-apoptotic Bcl-2 family members are often found to be up-regulated in many types of human cancers, such as different subtypes of B-cell lymphoma and diverse solid tumors, and are frequently been correlated with decreased susceptibility to chemotherapeutics and to increased radio-resistance. Overexpression of Bcl-2 proteins is an independent indicator of poor prognosis in tumors including chronic lymphocytic leukemia (CLL), prostate cancer, and small cell lung cancer (SCLC). Therefore, targeting Bcl-2 and its pro-survival relatives that form the core anti-apoptotic machinery, has emerged as a promising therapeutic approach in cancer. To that end, we have developed a novel and selective Bcl-2 inhibitor, FCN-338, with nanomolar affinity to Bcl-2 and physicochemical properties suitable for oral administration. FCN-338 exhibits much greater affinity to Bcl-2 than Bcl-xL, suggesting its good potential to avoid thrombocytopenia caused by the inhibition of Bcl-xL. FCN-338 has shown remarkable anti-proliferation potency against a panel of Bcl-2-addicted human B-cell lymphoma cell lines, including DOHH2 follicular lymphoma (FL) cell line (IC50 2 nM), Mino diffuse large B-cell lymphoma (DLBCL) cell line (IC50 23 nM), and RS4;11 acute lymphoblastic leukemia (ALL) cell line (IC50 35 nM), but not in Bcl-xL-dependent H146 SCLC cell line (IC50 >4,500 nM). Correspondingly, in vivo efficacy of FCN-338 was demonstrated in a variety of xenograft models derived from FL, DLBCL and ALL tumors. FCN-338 dramatically caused tumor regression in a dose-dependent manner. In the non-clinical studies, FCN-338 exhibits much improved pharmacokinetic properties with higher T1/2, dose-normalized AUC and bioavailability in dogs compared with the FDA-approved Bcl-2 inhibitor ABT-199. Preferable safety profiles of FCN-338 were shown with no potential hERG inhibitory effect and less drug-drug interaction potential, as evidenced by no inhibitory effect (IC50 >50 μM) on CYP2C9 enzyme compared with ABT-199 (IC50 1.05 μM). Together, our findings highlight the therapeutic potential of FCN-338 to be used as effective therapy across a broad range of Bcl-2-addicted B-cell malignancies. Citation Format: Shu Lin, Xingdong Zhao, Hongbin Liu, Huajie Zhang, Zhifang Chen, Lihua Jiang, Yanxin Liu, Min Lin, Yue Rong, Rui Tan, Zuwen Zhou, Zongyao Zou, Yuwei Gao, Weibo Wang. FCN-338, a novel and selective Bcl-2 inhibitor, exhibits potent anti-tumor activity in B-cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2497.

Rural China is piloting an integrated payment system, which prepays a budget to a medical alliance rather than a single hospital. This study aims to evaluate the effect of this reform on the direct economic burden and readmission rates of cerebral infarction inpatients. The settlement records of 78,494 cerebral infarction inpatients were obtained from the New Rural Cooperative Medical Scheme (NRCMS) database in Dingyuan and Funan Counties in the Anhui Province. The direct economic burden was estimated by total costs, out-of-pocket expenditures, the out-of-pocket ratio, and the compensation ratio of the NRCMS. Generalized additive models and multivariable linear/logistic regression were applied to measure the changes of the dependent variables along with the year. Within the county, the total costs positively correlated to the year (&beta, = 313.10 in 2015, 163.06 in 2016). The out-of-pocket expenditures, out-of-pocket ratios, and the length-of-stay positively correlated to the year in 2015 (&beta, = 105.10, 0.01, and 0.18 respectively), and negatively correlated to the year in 2016 (&beta, = &minus, 58.40, &minus, 0.03, and &minus, 0.30, respectively). The odds ratios of the readmission rates were less than one within the county (0.70 in 2015, 0.53 in 2016). The integrated payment system in the Anhui Province has considerably reduced the direct economic burden for the rural cerebral infarction inpatients, and the readmission rate has decreased within the county. Inpatients&rsquo, health outcomes should be given further attention, and the long-term effect of this reform model awaits further evaluation.

In this study the principal component analysis (PCA) and geographically weighted regression (GWR) are combined to estimate the spatial distribution of water requirement of the winter wheat in North China while the effect of the macro- and micro-topographic as well as the meteorological factors on the crop water requirement is taking into account. The spatial distribution characteristic of the water requirement of the winter wheat in North China and its formation are analyzed based on the spatial variation of the main affecting factors and the regression coefficients. The findings reveal that the collinearity can be effectively removed when PCA is applied to process all of the affecting factors. The regression coefficients of GWR displayed a strong variability in space, which can better explain the spatial differences of the effect of the affecting factors on the crop water requirement. The evaluation index of the proposed method in this study is more efficient than the widely used Kriging method. Besides, it could clearly show the effect of those affecting factors in different spatial locations on the crop water requirement and provide more detailed information on the region where those factors suddenly change. To sum up, it is of great reference significance for the estimation of the regional crop water requirement.

The aim of this study was to investigate human papillomavirus (HPV) infection and HPV genotype distributions in Urumqi, Xinjiang, China. The related risk factors for high-risk HPV infection was also analyzed. A stratified cluster sampling method was used for the population-based cervical cancer screening of women aged 18–69 years in the Urumqi Saybagh district. Exfoliated cervical cell samples were collected for liquid-based cytology detection and HPV genotyping DNA microarrays. Education level, number of sexual partners, condom use and occupation were used in the multivariate analysis model. The HPV infection rate of women working in service industries was significantly higher compared with those of white-collar workers, community residents and migrant workers. The 35–44-year-old migrant worker group had the highest HPV infection rates among all of the groups in the three different age ranges. The number of marriages, education level, smoking history, number of abortions, use of condoms, number of sexual partners, number of sexual partners in the past five years and occupation were all associated with female HPV infection rate (P