BACKGROUND:There is still no consensus on the optimal internal fixation for the treatment of Pauwels Ⅲ femoral neck fracture,and most of the related finite element analyses have been performed using a single simplified loading condition,and the biomechanical properties of commonly used internal fixation devices need to be further investigated. OBJECTIVE:To analyze the biomechanical characteristics of Pauwels Ⅲ femoral neck fractures treated with cannulated compression screw,dynamic hip screw,and femoral neck system by finite element method under different loading conditions of single-leg standing loads and sideways fall loads. METHODS:The DICOM data of healthy adult femur were obtained by CT scanning,imported into Mimics 15.0 software to obtain the rough model of bone tissue.The data exported from Mimics were optimized by Geomagics software,and then three internal fixation models were built and assembled with the femur model according to the parameters of the clinical application of the cannulated compression screw,dynamic hip screw,and femoral neck system by using Pro/E software.Finally,the three internal fixation models were imported into Ansys software for loading and calculation to analyze the stress distribution and displacement of the femur and the internal fixation under different working conditions of single-leg standing loads and sideways fall loads,as well as the stress characteristics of the calcar femorale and Ward's triangle. RESULTS AND CONCLUSION:(1)Under the single-leg standing load and the sideways fall load,the proximal femoral stress of the three internal fixation models was mainly distributed above the fracture end of the femoral neck.The peak stress of the proximal femoral end,fracture end,Ward triangle,and calcar femorale of the three internal fixation models were the smallest in the femoral neck system model and the largest in the cannulated compression screw model.(2)Under the single-leg standing load and the sideways fall load,the peak displacement of the proximal femur of the three internal fixation models was all located at the top of the femoral head,and the peak displacement was the smallest in the femoral neck system model and the largest in the cannulated compression screw model.(3)The peak displacement of the three internal fixation models was all located at the top of the internal fixation device under the single-leg standing and sideways fall loading conditions,and the peak displacement values were the smallest in the femoral neck system internal fixation model and the largest in the cannulated compression screw internal fixation model.(4)The internal fixation stress of the three internal fixation models was mainly distributed in the area near the fracture end of the internal fixation device under the single-leg standing and sideways fall loads,and the peak value of internal fixation stress was the smallest in the femoral neck system model and the largest in the cannulated compression screw model.(5)These results suggest that the mechanical stability of the femoral neck system is the best,but there may be a risk of stress shielding of the fracture end and calcar femorale.The stress of the internal fixation device of the femoral neck system is more dispersed,and the risk of internal fixation break is lower.

Background/Aims: The World Health Organization set the goal of eliminating hepatitis C virus (HCV) by 2030, with 80% and 65% reductions in HCV incidence and mortality rates, respectively. We aimed to evaluate the health benefits, cost-effectiveness and return on investment (ROI) of HCV elimination. Methods: Using an HCV transmission compartmental model, we evaluated the benefits and costs of different strategies combining screening and treatment for Chinese populations. We identified strategies to achieve HCV elimination and calculated the incremental cost-effectiveness ratios (ICERs) per disability-adjusted life year (DALY) averted for 2022–2030 to identify the optimal elimination strategy. Furthermore, we estimated the ROI by 2050 by comparing the required investment with the economic productivity gains from reduced HCV incidence and deaths. Results: The strategy that results in the most significant health benefits involves conducting annual primary screening at a rate of 14%, re-screening people who inject drugs annually and the general population every five years, and treating 95% of those diagnosed (P14-R4-T95), preventing approximately 5.75 and 0.44 million HCV infections and deaths, respectively, during 2022–2030. At a willingness-to-pay threshold of $12,615, the P14-R4-T95 strategy is the most cost-effective, with an ICER of $5,449/DALY. By 2050, this strategy would have a net benefit of $120,997 million (ROI=0.868). Conclusions Achieving HCV elimination in China by 2030 will require significant investment in large-scale universal screening and treatment, but it will yield substantial health and economic benefits and is cost-effective.

Background/Aims: The World Health Organization set the goal of eliminating hepatitis C virus (HCV) by 2030, with 80% and 65% reductions in HCV incidence and mortality rates, respectively. We aimed to evaluate the health benefits, cost-effectiveness and return on investment (ROI) of HCV elimination. Methods: Using an HCV transmission compartmental model, we evaluated the benefits and costs of different strategies combining screening and treatment for Chinese populations. We identified strategies to achieve HCV elimination and calculated the incremental cost-effectiveness ratios (ICERs) per disability-adjusted life year (DALY) averted for 2022–2030 to identify the optimal elimination strategy. Furthermore, we estimated the ROI by 2050 by comparing the required investment with the economic productivity gains from reduced HCV incidence and deaths. Results: The strategy that results in the most significant health benefits involves conducting annual primary screening at a rate of 14%, re-screening people who inject drugs annually and the general population every five years, and treating 95% of those diagnosed (P14-R4-T95), preventing approximately 5.75 and 0.44 million HCV infections and deaths, respectively, during 2022–2030. At a willingness-to-pay threshold of $12,615, the P14-R4-T95 strategy is the most cost-effective, with an ICER of $5,449/DALY. By 2050, this strategy would have a net benefit of $120,997 million (ROI=0.868). Conclusions Achieving HCV elimination in China by 2030 will require significant investment in large-scale universal screening and treatment, but it will yield substantial health and economic benefits and is cost-effective.

Background/Aims: The World Health Organization set the goal of eliminating hepatitis C virus (HCV) by 2030, with 80% and 65% reductions in HCV incidence and mortality rates, respectively. We aimed to evaluate the health benefits, cost-effectiveness and return on investment (ROI) of HCV elimination. Methods: Using an HCV transmission compartmental model, we evaluated the benefits and costs of different strategies combining screening and treatment for Chinese populations. We identified strategies to achieve HCV elimination and calculated the incremental cost-effectiveness ratios (ICERs) per disability-adjusted life year (DALY) averted for 2022–2030 to identify the optimal elimination strategy. Furthermore, we estimated the ROI by 2050 by comparing the required investment with the economic productivity gains from reduced HCV incidence and deaths. Results: The strategy that results in the most significant health benefits involves conducting annual primary screening at a rate of 14%, re-screening people who inject drugs annually and the general population every five years, and treating 95% of those diagnosed (P14-R4-T95), preventing approximately 5.75 and 0.44 million HCV infections and deaths, respectively, during 2022–2030. At a willingness-to-pay threshold of $12,615, the P14-R4-T95 strategy is the most cost-effective, with an ICER of $5,449/DALY. By 2050, this strategy would have a net benefit of $120,997 million (ROI=0.868). Conclusions Achieving HCV elimination in China by 2030 will require significant investment in large-scale universal screening and treatment, but it will yield substantial health and economic benefits and is cost-effective.

BACKGROUND: P16 inactivation is frequently accompanied by telomerase reverse transcriptase ( TERT ) amplification in human cancer genomes. P16 inactivation by DNA methylation often occurs automatically during immortalization of normal cells by TERT . However, direct evidence remains to be obtained to support the causal effect of epigenetic changes, such as P16 methylation, on cancer development. This study aimed to provide experimental evidence that P16 methylation directly drives cancer development. METHODS: A zinc finger protein-based P16 -specific DNA methyltransferase (P16-Dnmt) vector containing a "Tet-On" switch was used to induce extensive methylation of P16 CpG islands in normal human fibroblast CCD-18Co cells. Battery assays were used to evaluate cell immortalization and transformation throughout their lifespan. Cell subcloning and DNA barcoding were used to track the diversity of cell evolution. RESULTS: Leaking P16-Dnmt expression (without doxycycline-induction) could specifically inactivate P16 expression by DNA methylation. P16 methylation only promoted proliferation and prolonged lifespan but did not induce immortalization of CCD-18Co cells. Notably, cell immortalization, loss of contact inhibition, and anchorage-independent growth were always prevalent in P16-Dnmt&TERT cells, indicating cell transformation. In contrast, almost all TERT cells died in the replicative crisis. Only a few TERT cells recovered from the crisis, in which spontaneous P16 inactivation by DNA methylation occurred. Furthermore, the subclone formation capacity of P16-Dnmt&TERT cells was two-fold that of TERT cells. DNA barcoding analysis showed that the diversity of the P16-Dnmt&TERT cell population was much greater than that of the TERT cell population. CONCLUSION P16 methylation drives TERT -mediated immortalization and transformation of normal human cells that may contribute to cancer development.
Humans ; Telomerase/genetics* ; DNA Methylation/physiology* ; Fibroblasts/cytology* ; Cyclin-Dependent Kinase Inhibitor p16/metabolism* ; Cell Line ; Cell Transformation, Neoplastic/genetics*

Objective To investigate the expressions of glycolysis-related factors and changes in Notch1 signaling in endometrial tissues of adenomyosis(AM)and Ishikawa cells to explore the pathogenesis of AM.Methods Eutopic endometrial tissues were collected from 8 patients with AM and 8 patients with uterine fibroids matched for clinical characteristics(control group).The expressions of Notch1 signaling proteins and glycolysis-related factors in the collected tissues were detected using qRT-PCR and Western blotting,and the levels of glucose and lactic acid were determined.An Ishikawa cell model with lentivirus-mediated stable Notch1 overexpression was established for assessing cell survival rate with CCK-8 assay,cell migration and invasion abilities with Transwell migration and invasion assays,and glycolytic capacity by determining the extracellular acidification rate.Results Compared with those in the control group,the endometrial tissues in AM group showed significantly increased expression level of carbohydrate antigen 125(CA125),increased mRNA expression levels of Notch1,HK2 and PDHA and protein expressions of Notch1,GLUT1,HK2,PKM and PDHA,lowered glucose level and increased lactate level.The Ishikawa cell models with stable Notch1 overexpression exhibited significantly increased cell survival rate with attenuated cell migration and invasion abilities and decreased glycolysis capacity and reserve.Conclusion The Notch1 signaling pathway participates in the pathogenesis of AM possibly by regulating the proliferation,migration,invasion and glycolysis of endometrial cells.

Objective To investigate the expressions of glycolysis-related factors and changes in Notch1 signaling in endometrial tissues of adenomyosis(AM)and Ishikawa cells to explore the pathogenesis of AM.Methods Eutopic endometrial tissues were collected from 8 patients with AM and 8 patients with uterine fibroids matched for clinical characteristics(control group).The expressions of Notch1 signaling proteins and glycolysis-related factors in the collected tissues were detected using qRT-PCR and Western blotting,and the levels of glucose and lactic acid were determined.An Ishikawa cell model with lentivirus-mediated stable Notch1 overexpression was established for assessing cell survival rate with CCK-8 assay,cell migration and invasion abilities with Transwell migration and invasion assays,and glycolytic capacity by determining the extracellular acidification rate.Results Compared with those in the control group,the endometrial tissues in AM group showed significantly increased expression level of carbohydrate antigen 125(CA125),increased mRNA expression levels of Notch1,HK2 and PDHA and protein expressions of Notch1,GLUT1,HK2,PKM and PDHA,lowered glucose level and increased lactate level.The Ishikawa cell models with stable Notch1 overexpression exhibited significantly increased cell survival rate with attenuated cell migration and invasion abilities and decreased glycolysis capacity and reserve.Conclusion The Notch1 signaling pathway participates in the pathogenesis of AM possibly by regulating the proliferation,migration,invasion and glycolysis of endometrial cells.

Objective To investigate the effect of diammonium glycyrrhizinate(DG)on pulmonary injury of rats with pulmonary tuberculosis.Methods The rat models of pulmonary tuberculosis were constructed and then the an-imals were randomly divided into model group,diammonium glycyrrhizinate treatment groups(low-dose,medium-dose and high-dose)groups,high dose of diammonium glycyrrhizinate plus peroxisome proliferator-activated receptor γ(PPARγ)inhibitor group(H-DG+GW9662 group),and another 18 rats were selected as control group.The colony count of Mycobacterium tuberculosis(Mtb)in lung tissue was detected.HE staining microscopy was ap-plied to detect lung histopathology.TUNEL was applied to detect apoptosis of lung tissue cells.ELISA was applied to detect serum level of inflammatory factors.Western blot was applied to measure PPARγ,phosphorylated p38 mi-togen-activated protein kinase(p-p38MAPK)and p38 mitogen-activated protein kinase(p38MAPK)in lung tissue.Results Compared with the control group,the lung tissue structure in model group was severely damaged with a large number of proliferative tuberculosis nodules,changes of alveolar morphology,inflammatory cell infiltration and even caseous necrosis were found,and the number of tuberculosis colonies,apoptosis rate,TNF-α,IL-6,IFN-γ,COX-2 levels,and p-p38MAPK/p38MAPK expression were all increased,while PPARγ expression was decreased(P＜0.05).In L-DG,M-DG,H-DG groups improvement of lung tissue structure,alveolar morphology,inflammatory cell infiltration,and caseous necrosis were found as compared to the model group,while the counting number of tuberculosis colonies decreased and rate of cell apoptosis decreased.The level of TNF-α,IL-6,IFN-γ,COX-2 and expression of p-p38MAPK/p38MAPK reduced,the expression of PPARγ all increased.The H-DG group showed the most significant changes(P＜0.05).GW9662 treatment significantly reversed the improvement of DG on pulmonary injury in rats with pulmonary tuberculosis.Conclusions DG improves lung injury in rats with pul-monary tuberculosis and its mechanism is potentially related to the activation of PPARγ pathway and inhibition of p38MAPK pathway.

Background::Acute-on-chronic liver failure (ACLF) is a severe liver disease with complex pathogenesis. Clinical hypoglycemia is common in patients with ACLF and often predicts a worse prognosis. Accumulating evidence suggests that glucose metabolic disturbance, especially gluconeogenesis dysfunction, plays a critical role in the disease progression of ACLF. Lon protease-1 (LONP1) is a novel mediator of energy and glucose metabolism. However, whether gluconeogenesis is a potential mechanism through which LONP1 modulates ACLF remains unknown.Methods::In this study, we collected liver tissues from ACLF patients, established an ACLF mouse model with carbon tetrachloride (CCl 4), lipopolysaccharide (LPS), and D-galactose (D-gal), and constructed an in vitro hypoxia and hyperammonemia-triggered hepatocyte injury model. LONP1 overexpression and knockdown adenovirus were used to assess the protective effect of LONP1 on liver injury and gluconeogenesis regulation. Liver histopathology, biochemical index, mitochondrial morphology, cell viability and apoptosis, and the expression and activity of key gluconeogenic enzymes were detected to explore the underlying protective mechanisms of LONP1 in ACLF. Results::We found that LONP1 and the expressions of gluconeogenic enzymes were downregulated in clinical ACLF liver tissues. Furthermore, LONP1 overexpression remarkably attenuated liver injury, which was characterized by improved liver histopathological lesions and decreased serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in ACLF mice. Moreover, mitochondrial morphology was improved upon overexpression of LONP1. Meanwhile, the expression and activity of the key gluconeogenic enzymes were restored by LONP1 overexpression. Similarly, the hepatoprotective effect was also observed in the hepatocyte injury model, as evidenced by improved cell viability, reduced cell apoptosis, and improved gluconeogenesis level and activity, while LONP1 knockdown worsened liver injury and gluconeogenesis disorders.Conclusion::We demonstrated that gluconeogenesis dysfunction exists in ACLF, and LONP1 could ameliorate liver injury and improve gluconeogenic dysfunction, which would provide a promising therapeutic target for patients with ACLF.