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Abstract Background TSPAN7 is an important factor in tumor progression. However, the precise function of TSPAN7 and its role in pan-cancer are not clear. Methods Based on Xinhua cohort incorporating 370 patients with kidney neoplasm, we conducted differential expression analysis by immunohistochemistry between tumor and normal tissues, and explored correlations of TSPAN7 with patients’ survival. Subsequently, we conducted a pan-cancer study, and successively employed differential expression analysis, competing endogenous RNA (ceRNA) analysis, protein-protein interaction (PPI) analysis, correlation analysis of TSPAN7 with clinical characteristics, tumor purity, tumor genomics, tumor immunity, and drug sensitivity. Last but not least, gene set enrichment analysis was applied to identify enriched pathways of TSPAN7. Results In Xinhua cohort, TSPAN7 expression was significantly up-regulated (P-value = 0.0019) in tumor tissues of kidney neoplasm patients. High TSPAN7 expression was associated with decreases in overall survival (OS) (P-value = 0.009) and progression-free survival (P-value = 0.009), and it was further revealed as an independent risk factor for OS (P-value = 0.0326, HR = 5.66, 95%CI = 1.155–27.8). In pan-cancer analysis, TSPAN7 expression was down-regulated in most tumors, and it was associated with patients’ survival, tumor purity, tumor genomics, tumor immunity, and drug sensitivity. The ceRNA network and PPI network of TSPAN7 were also constructed. Last but not least, the top five enriched pathways of TSPAN7 in various tumors were identified. Conclusion TSPAN7 served as a promising biomarker of various tumors, especially kidney neoplasms, and it was closely associated with tumor purity, tumor genomics, tumor immunology, and drug sensitivity in pan-cancer level.

Background: Annual influenza vaccination is crucially recommended for the elderly to maintain humoral immunity. Insufficient coverage requires us to understand the determinants of their influenza behaviors and how these patterns impact vaccination choices. Methods: Data from 540 Beijing residents aged over 65 were collected through interviews, capturing vaccination history and sociodemographic details. Individual influenza vaccination records from 2016 to 2020 were obtained from China’s Immunization Information Systems. A latent class model identified three vaccination patterns. Multinomial logistic regression assessed relative risk ratios (RRRs) for vaccination based on sociodemographic factors. Vaccination patterns were used to predict future vaccination likelihood. Results: The analysis revealed three groups: sporadically vaccinated (63.33%), occasionally vaccinated (18.71%), and frequently vaccinated (17.96%). Factors associated with frequent vaccination included age over 70 (RRR = 2.81), lower income (RRR = 0.39), higher vaccine hesitancy (RRR = 3.10), multiple chronic conditions (RRR = 2.72), and rural residence (RRR = 2.48). The frequently vaccinated group was more likely to sustain regular vaccination habits in subsequent years compared to the occasionally vaccinated group. Conclusions: Only 17.96% of Beijing’s older population exhibited a consistent influenza vaccination pattern. Older age, rural residency, and chronic diseases correlated with repeated influenza vaccination. Segmenting the population based on past vaccination behavior can aid in designing targeted interventions to improve vaccination rates.

A keloid is secondary to skin trauma or has spontaneously manifested as an overgrowth and occurs when the skin heals abnormally after an injury. The main pathological manifestations are abnormal proliferation of keloid fibroblasts (KEL-FIB). This study researched periostin (POSTN) on keloid fibroblasts (KEL-FIB) and the associated mechanism, aiming to provide a reference for the targeted therapy of keloid. We got tissues from Second People's Hospital of Guangxi Zhuang Autonomous Region between June 2022 and March 2023. POSTN expression was increased in keloid skin tissue and KEL-FIB than normal skin tissue and normal fibroblasts. We collected and inoculated KEL-FIB cells, transfection of si-NC (Silencing of POSTN negative control), si-POSTN (Silencing of POSTN), pcDNA-NC (Overexpression of POSTN negative control), and POSTN (Overexpression of POSTN) (Thermo Fisher Scientific) used Lipofectamine 2000 transfection reagent. Wound closure, cell proliferation viability, migrated cell numbers, and POSTN, p-JAK2, p-STAT3 protein levels were reduced in the si-POSTN group. Wound closure, cell proliferation viability, migrated cell numbers, and POSTN, p-JAK2, p-STAT3 protein levels were elevated in the POSTN group. POSTN protein levels did not changed and wound closure, cell proliferation viability, migrated cell numbers, were reduced in the POSTN + S-Ruxolitinib group. The study results indicated that POSTN promotes cell migration and proliferation by activating the JAK/STAT pathway, promoting KEL-FIB development.

Abstract Background Lung adenocarcinoma (LUAD) is a highly lethal form of lung cancer. Despite advancements in treatments, managing LUAD is still challenging due to its aggressive behavior. Recent studies indicate that various molecular pathways, including the dysregulation of ferredoxin 1 (FDX1), play roles in LUAD progression. FDX1, a crucial protein in cellular redox reactions and energy metabolism, has been linked to several cancers. However, its exact role in the development of LUAD is not yet fully understood. Methods We investigated the role of ferredoxin 1 (FDX1) in LUAD progression through analysis of its expression in LUAD tissues and its impact on patient survival. Functional assays were performed to assess the effects of FDX1 overexpression on LUAD cell proliferation, migration, and invasion. A xenograft model was employed to evaluate the tumorigenesis potential of LUAD cells with FDX1 overexpression. Mechanistic insights into FDX1 regulation were gained through depletion experiments targeting the G protein-regulated inducer of neurite outgrowth 2 (GPRIN2)/PI3K signaling pathway. Results FDX1 expression was down-regulated in LUAD tissues, correlating with shorter patient survival. Overexpression of FDX1 suppressed LUAD cell proliferation, migration, and invasion in vitro, and inhibited tumorigenesis in vivo. Mechanistically, the GPRIN2/PI3K signaling pathway was implicated in FDX1 regulation, as depletion of GPRIN2 reversed the effects of FDX1 overexpression on cellular functions. Conclusions Our findings highlight FDX1 as a potential tumor suppressor in LUAD, acting through modulation of the GPRIN2/PI3K signaling pathway. These results suggest FDX1 as a promising therapeutic target for LUAD treatment, warranting further investigation into its clinical relevance.

Abstract Background Pay-for-performance (P4P) schemes are commonly used to incentivize primary healthcare (PHC) providers to improve the quality of care they deliver. However, the effectiveness of P4P schemes can vary depending on their design. In this study, we aimed to investigate the preferences of PHC providers for participating in P4P programs in a city in Shandong province, China. Method We conducted a discrete choice experiment (DCE) with 882 PHC providers, using six attributes: type of incentive, whom to incentivize, frequency of incentive, size of incentive, the domain of performance measurement, and release of performance results. Mixed logit models and latent class models were used for the statistical analyses. Results Our results showed that PHC providers had a strong negative preference for fines compared to bonuses (− 1.91; 95%CI − 2.13 to − 1.69) and for annual incentive payments compared to monthly (− 1.37; 95%CI − 1.59 to − 1.14). Providers also showed negative preferences for incentive size of 60% of monthly income, group incentives, and non-release of performance results. On the other hand, an incentive size of 20% of monthly income and including quality of care in performance measures were preferred. We identified four distinct classes of providers with different preferences for P4P schemes. Class 2 and Class 3 valued most of the attributes differently, while Class 1 and Class 4 had a relatively small influence from most attributes. Conclusion P4P schemes that offer bonuses rather than fines, monthly rather than annual payments, incentive size of 20% of monthly income, paid to individuals, including quality of care in performance measures, and release of performance results are likely to be more effective in improving PHC performance. Our findings also highlight the importance of considering preference heterogeneity when designing P4P schemes.

BackgroundThe incidence of herpes zoster (HZ) is rapidly increasing, causing both clinical and economic burdens in China. Very little is known about Chinese residents’ HZ vaccine preferences and willingness to pay (WTP) for each vaccination attribute. ObjectiveThis study aims to elicit the preferences of Chinese urban adults (aged 25 years or older) regarding HZ vaccination programs and to calculate WTP for each vaccination attribute. MethodsIn this study, we interviewed 2864 residents in 9 cities in China. A discrete choice experiment was conducted to investigate the residents’ preferences for HZ vaccination and to predict the uptake rate for different vaccine scenarios. A mixed logit model was used to estimate the preferences and WTP for each attribute. Seven attributes with different levels were included in the experiment, and we divided the coefficients of other attributes by the coefficient of price to measure WTP. ResultsVaccine effectiveness, protection duration, risk of side effects, place of origin, and cost were proven to influence Chinese adults’ preferences for HZ vaccination. The effectiveness of the HZ vaccine was the attribute that had the most predominant impact on residents’ preferences, followed by protection duration. The residents were willing to pay CN ¥974 (US $145) to increase the vaccine effectiveness from 45% to 90%, and they would barely pay to exchange the vaccination schedule from 2 doses to 1 dose. It is suggested that the expected uptake could be promoted the most (by 20.84%) with an increase in the protection rate from 45% to 90%. ConclusionsChinese urban adults made trade-offs between vaccine effectiveness, protection duration, place of origin, side effects, and cost of HZ vaccination. Vaccine effectiveness was the most important characteristic. The residents have the highest WTP (CN ¥974; US $145) for enhancing the effectiveness of vaccines. To maximize HZ vaccine uptake, health authorities should promote vaccine effectiveness.

Abstract Background Managing the multimorbidity of diabetes and depression remains a clinical challenge for patients and healthcare professionals due to the fragmented healthcare delivery system. To effectively cope with multimorbidity, there is an urgent need for the health system to transform into people-centered integrated care (PCIC) system globally. Therefore, this paper describes the protocol of community-based integrated care for patients with diabetes and depression (CIC-PDD) project, an integrated and shared-care intervention project. Methods/design CIC-PDD project is conducted in two phases, namely “care model development” and “implementation and evaluation.” In the first phase, CIC-PDD model was designed and developed based on the four criteria of collaborative care model (CCM) and was subsequently adjusted to align with the context of China. The second phase entails a pragmatic, two-arm, cluster randomized controlled implementation trial, accompanied by parallel mixed-methods process evaluation and cost-effectiveness analysis. Discussion We anticipate CIC-PDD project will facilitate the development and innovation of PCIC model and related theories worldwide, particularly in low- and middle-income countries (LMICs). In addition, CIC-PDD project will contribute to the exploration of primary health care (PHC) in addressing the multimorbidity of physical and mental health issues. Trial registration ClinicalTrials.gov registration ChiCTR2200065608 (China Clinical Trials Registry https://www.chictr.org.cn ). Registered on November 9, 2022.

To solve the shortcomings of FDTD algorithm in electromagnetic wave propagation in communication applications.A FDTD algorithm under “unidirectional explicit” matrix was constructed and applied to cylindrical structure.Firstly, a new coefficient matrix was established by the ideology of WCS and WLP.Secondly, the perturbation terms were introduced to form the initial value and iterative equations.Finally, the fields on the z axis were treated in special way.Numerical examples prove that the proposed algorithm is superior to the WCS-FDTD and WLP-FDTD in electromagnetic wave propagation.The best improvement efficiency is 83%, accuracy is 88%, and memory consumption is reduced by 44%.Meanwhile, comparing with the conventional FDTD algorithm, it can improve the efficiency of 7 time steps size and reduce the memory consumption by 53% without losing accuracy.Moreover, under the boundary truncation of the PML, the proposed algorithm also shows good electromagnetic wave energy absorption performance, which can reach below -60 dB.

Abstract Objectives Vaccination is an important part of public health services. We aim to assess the efficiency of vaccination services in Beijing, the capital of China, and to further study the influencing factors of efficiency. Methods Using the immunization service data of Beijing, China in 2020, we firstly developed a data envelopment analysis (DEA) model to calculate the score of vaccination efficiency. Secondly, we used DEA model scenario simulations with different combinations of input–output factors to derive the magnitude of the effect of each input factor on the efficiency. Finally, combined with the data from the Beijing Regional Statistical Yearbook 2021, we developed the Tobit model to examine the effect of external social environmental factors on efficiency. Results The average scores of efficiency of POVs (Point of Vaccination) in different areas of Beijing vary greatly. Different input factors had different degrees of positive effects on the efficiency score. In addition, the number of populations served by POV was positively associated with efficiency, the GDP and financial allocation of the POVs’ district was also positively associated with efficiency score, while the total dependency ratio of the POVs’ district was negatively associated with efficiency score. Conclusion The efficiency of vaccination services varied considerably across POVs. Constrained by limited resources, efficiency scores can be increased by increasing input factors that have a larger impact on efficiency score and reducing those that have a smaller impact on efficiency. In addition, the social environment should be considered in allocating vaccination resources, and more resources should be invested in areas with low levels of economic development, low financial allocation, and high population.

Abstract Objective This study investigates the relationship between financial toxicity and medical cost‐coping behaviors (MCCB) in Chinese patients with lung cancer, with a particular focus on the moderating role of health insurance. Methods We surveyed 218 patients with lung cancer and assessed their Comprehensive Score for Financial Toxicity (COST) and self‐reported MCCB. Patients were categorized into Urban Employee's Basic Medical Insurance (UEBMI) group and Urban–Rural Resident Basic Medical Insurance Scheme (URRBMI) groups by their medical insurance, and matched for socioeconomic, demographic, and disease characteristics via propensity score. Results Significant different characteristics were noted between UEBMI patients and URRBMI patients. Patients with UEBMI had higher COST scores but lower levels of MCCB compared to URRBMI patients in the original dataset. After data matching, multivariate logit regression analysis showed that better financial toxicity was associated with lower levels of MCCB (OR = 0.95, 95% CI: 0.92–0.99). Health insurance type did not have a direct association with cost‐coping behaviors, but an interaction was observed between health insurance type and financial toxicity. Among patients with URRBMI, better financial toxicity was associated with lower levels of cost‐coping behaviors (OR = 0.89, 95% CI: 0.83–0.95). Patients with UEBMI had a lower probability of engaging in any cost‐coping behaviors in situations of worse financial toxicity compared to patients with URRBMI. Conclusion The findings suggest that financial toxicity is correlated with MCCB in Chinese patients with lung cancer. The type of health insurance, specifically UEBMI and URRBMI, plays a moderating role in this relationship. Understanding these dynamics is essential for developing targeted interventions and policies to mitigate financial toxicity and improve patients' management of medical costs.

Objective Previous studies have presented mixed evidence on retirement and inpatient healthcare utilisation. We aimed to examine the causal effect of retirement on inpatient healthcare utilisation in China and explore the heterogenous effects of sex, disease types and ways of hospital admission.Design This was a retrospective observational study from the electronic medical record at 376 tertiary hospitals in China between 2013 and 2018.Setting Nationwide data from China.Participants We included the male sample aged between 50 and 70, and the female sample aged between 40 and 60 and with basic medical insurance system or public medical insurance. Observations with total expenditures per visit at the top or bottom 1% were excluded.Primary and secondary outcome measures Inpatient expenditures per visit and inpatient days per visit.Methodology We examined the effects by a non-parametric fuzzy regression discontinuity design, exploiting the mandatory retirement age as a source of exogenous variation in retirement status.Results Retirement reduced drug expenditures (β=−467.46, p

Abstract Searching for reliable indicators for evaluating prognosis diagnosed with clear cell renal cell carcinoma (ccRCC) is crucial for improving clinical therapies. However, current researches have looked mainly at the prognostic value of a single intratumoral indicator, neglecting tumor‐infiltrating immune cells (TIICs) in the microenvironment. This study examined whether the integration of Ring finger protein 43 (RNF43) expression and CD163+ tumor‐associated macrophage (TAM) infiltration in combination with clinical indexes forecast ccRCC patient outcome with relatively high accuracy. Firstly, the expression of RNF43 and CD163 were detected with immunohistochemistry. Totally, 346 ccRCC patients were random separated evenly into training and validation datasets to make further analyses. We found that RNF43 expression was negatively correlated with infiltration level of CD163+ TAM in ccRCC, which was closely associated with the TNM stage and outcome of these patients. The multiple regression analysis demonstrated that RNF43, CD163, and TNM stage could function as independent risk factors in overall survival (OS) and progression‐free survival (PFS) prediction of ccRCC. Furthermore, a better postoperative prognosis index for ccRCC patients was obtained by combining RNF43 and CD163+ TAMs, which assessed with time‐dependent C‐index analyses and a nomogram. Consequently, combining RNF43 and CD163+ TAMs along with TNM stage acquired robust accuracy in forecasting outcome of patients with ccRCC. In conclusion, combining intratumoral RNF43 expression, CD163+ TAM infiltration, and TNM stage could significantly enhance the veracity in forecasting postoperative outcomes.

The success of viscoelastic-surfactant (VES) acid in heterogeneous carbonate reservoirs depends on the wormholes propagation and diverting performance of acid. However, with the continuous propagation of wormholes in the high-permeability zone, the highly viscous spent acid enters the low-permeability zone under the pressure difference, thus affecting the wormholes propagation and diverting performance of acid in the low-permeability zone, which has been neglected in recent studies. Therefore, in this paper, the rheological model of acid is modified by considering the velocity of VES acid viscosity increase, and a two-scale continuous model was established. Based on this model, the diverting process is described, and reservoir connectivity, permeability contrast, and velocity of acid viscosity increase are used to investigate the influence of spent acid on wormholes propagation and diverting performance of acid in the low-permeability zone. The results show that the formation of wormholes in the high-permeability zone makes a pressure difference between the high-permeability zone and the low-permeability zone. The high viscous spent acid flows from the high permeability layer to the low permeability layer under the pressure difference, thus inhibiting the wormholes propagation and diverting performance of acid in the low-permeability zone of heterogeneous carbonate reservoirs. The influence degree of spent acid is 30.6% when the permeability contrast is 3, and the influence degree decreases with the enhancement of heterogeneity. At permeability contrasts greater than 10, there is almost no effect. The velocity of acid viscosity increase affects the diverting performance of acid, and the faster the viscosity increase, the farther the highly viscous zone formed in a short time, the better its diverting performance. In the VES acid system commonly used in carbonate acidizing, the maximum difference of diverting performance is 4.25 times. The parallel coreflood experiments overestimate the diverting performance of VES acid by about 20%. When selecting the diverting technology for acidizing treatment, the diverting acid system with higher diverting performance in the laboratory experiments or diverting technology with stronger diverting performance can be appropriately selected. In addition, the velocity of spent VES acid viscosity increase is a significant parameter affecting the acid diverting performance. In the low calcite content reservoir or dolomite reservoir, the spent acid viscosity increases relatively slowly due to the slower reaction rate, which will reduce the diverting performance in the reservoir.

Abstract Background China expanded health coverage to residents in informal economic sectors by the rural new cooperative medical scheme (NCMS) for rural population and urban resident basic medical insurance scheme (URBMI) for non-working urban residents. Fragmentation of resident social health insurance schemes exacerbated the health inequity and China started the integration of urban and rural resident medical insurance schemes since 2016. Beijing finished the insurance integration in 2017 and has been implementing a unified urban and rural resident basic medical insurance scheme (URRBMI) since the beginning of 2018. This study aims to examine changes in health care utilization and financial protection after integration of the rural and urban social health insurance schemes. Methods We used household survey data from Beijing Health Services Survey in 2013 and 2018. Respondents who were 15 or older and covered by URBMI, NCMS or URRBMI were included in this study. Our study finally included 8,554 individuals in 2013 and 6,973 individuals in 2018, about 70% of which were rural residents in each year. Descriptive analysis was used to compare the healthcare utilization, healthcare expenditure and incidence of catastrophic health expenditure between different groups. A series of two-part regression models were used to analyze the changes of healthcare utilization, healthcare expenditure and incidence of catastrophic health expenditure. Results From 2013 to 2018, urban–rural disparity in outpatient care utilization seemed widened because urban residents’ utilization of outpatient care increased 131% while rural residents’ utilization only increased 72%; both rural and urban residents’ spending on outpatient care increased about 50%. Utilization of inpatient care changed little and poor residents still used significantly less inpatient care compared with the rich residents. Poor residents still suffered heavily catastrophic health expenditures. Conclusion From 2013 to 2018, residents’ utilization of healthcare, especially outpatient care, increased in Beijing. Health insurance reforms increased residents’ utilization of healthcare but failed to reduce their healthcare financial burden, especially for poor people. Our study advocates more pro-poor insurance policies and more efforts on the efficiency of health system.

Background In this study, we examined the length of stay (LoS)-predictive comorbidities, hospital costs-predictive comorbidities, and mortality‐predictive comorbidities in immobile ischemic stroke (IS) patients; second, we used the Charlson Comorbidity Index (CCI) to assess the association between comorbidity and the LoS and hospitalization costs of stroke; third, we assessed the magnitude of excess IS mortality related to comorbidities. Methods Between November 2015 and July 2017, 5114 patients hospitalized for IS in 25 general hospitals from six provinces in eastern, western, and central China were evaluated. LoS was the period from the date of admission to the date of discharge or date of death. Costs were collected from the hospital information system (HIS) after the enrolled patients were discharged or died in hospital. The HIS belongs to the hospital’s financial system, which records all the expenses of the patient during the hospital stay. Cause of death was recorded in the HIS for 90 days after admission regardless of whether death occurred before or after discharge. Using the CCI, a comorbidity index was categorized as zero, one, two, and three or more CCI diseases. A generalized linear model with a gamma distribution and a log link was used to assess the association of LoS and hospital costs with the comorbidity index. Kaplan–Meier survival curves was used to examine overall survival rates.Results We found that 55.2% of IS patients had a comorbidity. Prevalence of peripheral vascular disease (21.7%) and diabetes without end-organ damage (18.8%) were the major comorbidities. A high CCI=3+ score was an effective predictor of a high risk of longer LoS and death compared with a low CCI score; and CCI=2 score and CCI=3+ score were efficient predictors of a high risk of elevated hospital costs. Specifically, the most notable LoS-specific comorbidities, and cost-specific comorbidities was dementia, while the most notable mortality-specific comorbidities was moderate or severe renal disease. Conclusion CCI has significant predictive value for clinical outcomes in IS. Due to population aging, the CCI should be used to identify, monitor and manage chronic comorbidities among immobile IS populations.

Background Integrated care is a global trend in international healthcare reform, particularly for piloting vertical integration involving hospitals and primary healthcare institutions (PHIs). However, evidence regarding the impact of vertical integration on primary healthcare has been mixed and limited. Our study aims to evaluate the empirical effects of vertical integration reform on PHIs in China, and examines variations across integration intensity (tight integration vs. loose collaboration). Methods This study used a longitudinal design. The time-varying difference-in-difference (DID) method with a fixedeffect model for panel data was adopted. A total of 370 PHIs in the eastern, central, and western areas of China from 2009 to 2018 were covered. Outcome measures included the indicators at three dimensions regarding inpatient and outpatient service volume, patient flow between PHIs and hospitals and quality of chronic disease care (hypertension and diabetes). Results Significant increases in absolute (the number) and relative (the ratio between PHIs and hospitals) volume of inpatient admissions have been found after reform under tight integration, peaking at 183% and 15.0% respectively, in the third reform year. The quality of hypertension and diabetes care (by indicators of control rate of blood pressure and blood glucose) showed significant improvements under both types of vertical integration after reform. It was much more distinct for the PHIs under tight integration, which had the most significant increase of 34.0% and 22.8% under tight integration for the control rate of hypertension and diabetes compared to the peak of 21.2% and 22.1% respectively under loose collaboration. Conclusion Our findings suggest that vertical integration (especially tight integration) in China significantly contributed to strengthening primary healthcare in terms of inpatient services and quality of hypertension and diabetes care, providing empirical evidence to other countries on integrating primary healthcare-based health systems.

Abstract Background The immune checkpoint inhibitors (ICIs) combined with other therapeutic strategies have shown exciting results in various malignancies, and ICIs have now become the gold standard for current cancer treatment. In several preclinical and clinical investigations, ablation coupled with immunotherapy has proved to be quite effective. Our previous studies have shown that ablation coupled with ICI is a potential anti-cancer regimen for colorectal cancer liver metastases (CRLM). Furthermore, we have reported that following microwave ablation (MWA), the expression of LAG3 is up-regulated in tumor microenvironment (TME), indicating that LAG3 is implicated in the regulation of immunosuppressive immune response, and combination therapy of MWA and LAG3 blockade can serve as a promising therapeutic strategy against cancer. Methods The expression of LAG3 was investigated in this study utilizing a preclinical mouse model treated with MWA. Moreover, we monitored the tumor development and survival in mice to assess the anti-cancer effects of MWA alone or in combination with LAG3 blockade. Flow cytometry was also used to phenotype the tumor-infiltrating lymphocytes (TILs) and CD8+ T cell effector molecules. We finally analyzed the single-cell RNA sequencing (scRNA-seq) data of infiltrating CD45+ immune cells in the tumors from the MWA alone and MWA combined with LAG3 blockade groups. Results After MWA, the expression of LAG3 was up-regulated on sub-populations of TILs, and introducing LAG3 blockade to MWA postponed tumor development and extended survival in the MC38 tumor model. Flow cytometry and scRNA-seq revealed that LAG3 blockade in combination with MWA markedly boosted the proliferation and the function of CD8+ TILs, leading to altered myeloid cells in the TME. Conclusion Combination therapy of LAG3 blockade and MWA was a unique therapeutic regimen for some solid tumors, and such combination therapy might reprogram the TME to an anti-tumor manner.

Anoikis and epithelial-mesenchymal transition (EMT) are significant phenomena occurring in distant metastasis of colon adenocarcinoma (COAD). A comprehensive understanding of their crosstalk and the identification of key genes are vital for treating the distant metastasis of COAD. The objective of this study was to design and validate accurate prognostic predictors for COAD patients based on the anoikis and EMT processes. We obtained gene signatures from various databases and performed univariate and multivariate Cox regression analyses, principal component analysis (PCA). The COAD patients were categorized into the worst prognosis group, the Anoikis Potential Index (API) Low + EMT Potential Index (EPI) High group and the others group. Then we utilized gene set enrichment analysis (GSEA) to identify differentially expressed genes and to establish a prognostic risk model. The model classified patients into high- or low-risk groups, with patients in the high-risk group displaying worse survival status. A nomogram was established to predict overall survival rates, demonstrating high specificity and sensitivity. Additionally, we connected the risk model to the tumor microenvironment (TME) using single-sample GSEA and the MCP counter tool, as well as evaluated the sensitivity to common chemotherapeutic drugs, such as Gefitinib and Gemcitabine. Lastly, cell and tissue experiments suggested a positive correlation among anoikis resistance, EMT, and liver/lung metastasis of COAD. This is the first study to comprehensively analyze the crosstalk between anoikis and EMT and offers new therapeutic targets for COAD metastasis patients.

Aiming to meet the growing demand for observation and analysis in power systems that based on Internet of Things (IoT), machine learning technology has been adopted to deal with the data-intensive power electronics applications in IoT. By feeding previous power electronic data into the learning model, accurate information is drawn, and the quality of IoT-based power services is improved. Generally, the data-intensive electronic applications with machine learning are split into numerous data/control constrained tasks by workflow technology. The efficient execution of this data-intensive Power Workflow (PW) needs massive computing resources, which are available in the cloud infrastructure. Nevertheless, the execution efficiency of PW decreases due to inappropriate sub-task and data placement. In addition, the power consumption explodes due to massive data acquisition. To address these challenges, a PW placement method named PWP is devised. Specifically, the Non-dominated Sorting Differential Evolution (NSDE) is used to generate placement strategies. The simulation experiments show that PWP achieves the best trade-off among data acquisition time, power consumption, load distribution and privacy preservation, confirming that PWP is effective for the placement problem.

Abstract Background As an important N6-methyladenosine (m6A) regulator, abnormal expression of methyltransferase-like protein 3 (METTL3) has been reported in certain human cancers. Although some data have shown that METTL3 plays an essential role in the progression of clear-cell renal cell carcinoma RCC (ccRCC), the detailed mechanism still remains largely undetermined. Methods Immunohistochemistry (IHC) assay was used to examine the expression of METTL3 and its clinical implications in human ccRCC by using tissue-microarray (TMA). The cellular models based on ccRCC cell lines such as 786-O and ACHN, were established by operating METTL3 and HHLA2 via knockdown or overexpression, followed by in vitro cellular function studies and in vivo subcutaneous transplantation tumor model. Results We found that METTL3 expression in ccRCC tissues was significantly higher compared with adjacent normal tissues. We also found the overall survival (OS) of the patients with low METTL3 expression was significantly better compared with the patients with high METTL3 expression. Furthermore, HHLA2highMETTL3high could serve as a better prognostic predictor for ccRCC patients. Depletion of METTL3 could significantly inhibit the cell viability, migration, and invasion abilities in ccRCC cell lines. Cellular studies further revealed that METTL3 could regulate HHLA2 expression via m6A modification of HHLA2 mRNA. In vitro studies revealed that HHLA2 overexpression could reverse the inhibition of cellular functions mediated by METTL3 depletion. The subcutaneous transplantation tumor model confirmed that HHLA2 overexpression could reverse the inhibition of tumor growth mediated by METTL3 depletion. Conclusion Our study indicated that METTL3 served as an important prognostic predictor for ccRCC patients, and we demonstrated a novel regulatory mechanism of HHLA2 by mRNA epigenetic modification via METTL3. Moreover, we found that the METTL3/HHLA2 axis could promote tumorigenesis of ccRCC. Collectively, our current findings provided new insights into the therapeutic strategy against this malignancy targeting METTL3.

Although the natural hosts of avian influenza viruses (AIVs) are wild birds, multiple subtypes of AIVs have established epidemics in numerous mammals due to their cross-species spillover. Replication and evolution in intermedia mammalian hosts may facilitate AIV adaptation in humans. Because of their large population and intimacy with humans, dogs could act as such an intermedia host. To monitor the epidemiology of canine influenza viruses (CIVs) in Liaoning, China, we performed three surveillances in November 2018, March 2019, and April 2019. Five H3N2 and seven novel H3N6 CIVs had been isolated. Since the N6 neuraminidase (NA) genes were clustered with the H5N6 AIV, there is a high possibility that these H3N6 CIVs were generated from a H3N2 CIVs and H5N6 AIVs reassortment case. In addition, the H3N6 CIV showed increased mammalian adaptation ability compared to all the H3N2 strains in both in vitro and in vivo studies. Even though isolated 3 months later, the March 2019 isolated H3N2 viruses replicated more efficiently than the November 2018 isolated viruses. Our study indicated that H3 CIVs were undergoing an evolution process, through both genetic mutations and gene reassortment, at an incredible speed.

Abstract Background Hearing loss has been associated with serious health problems around the globe. Previous studies have found the positive effects of fitting hearing aids on health, but few studies were conducted in developing countries. The aim of this study is to examine the effects of hearing aids on multiple health outcomes among middle-aged and older adults with hearing loss in rural China. Methods In this randomized controlled trial (RCT), participants aged 45 and above were randomly assigned to the treatment group prescribing with hearing aids or to the control group with no intervention. Trial outcomes for 385 participants were collected during the 20-month follow-up study. Using the difference-in-difference approach, our primary outcomes were hearing-related quality of life (QoL) and generic QoL. Results The intervention led to improvements in hearing-related QoL, presenting as the reduction in Hearing Handicap Inventory for the Elderly Screening Version (HHIE-S) scores (interaction coefficient = − 2.86, p = 0.005), HHIE-S-Emotional scores (interaction coefficient = − 1.42, p = 0.029), and HHIE-S-Situational scores (interaction coefficient = − 1.43, p = 0.007). The intervention was also effective in alleviating the increase in depressive symptoms (interaction coefficient = − 0.14, p = 0.042). Subgroup analysis revealed that the effects were only shown among people with social activities or active social networks. Conclusions Our study is the first RCT in China to measure the health effects and heterogeneity of hearing aid interventions. Wearing hearing aids can help improve hearing-related QoL and alleviate the increase in depressive symptoms. The intervention is expected to be applicable to similar settings in other developing countries to combat hearing-related health problems. Trial registration Chinese Clinical Trial Registry, ChiCTR1900024739 . Registered on 26 July 2019.

BackgroundUnderstanding the treatment costs of stroke can guide health policies and interventions. However, few studies have analyzed the treatment costs of stroke in China. The aim of this study is to assess stroke-related medical service utilization, direct costs of stroke and associated stroke predictors, and, second, to understand the structure of medical resource use. MethodsThis study used a 5% random sample of claim data from China’s Urban Basic Medical Insurance between January 2013 to December 2016. The sampling design assigned a sample weight to each beneficiary. Weighted descriptive analyses, Poisson regression and generalized linear model were used to analyze the medical service utilization, costs and their associations with patient characteristics. ResultsIn urban China, the annual prevalence of stroke was 730.43 (95% CI = 730.10-730.76) cases per 100 000 people, and nearly 2% of total health expenditures of urban residents was spent on stroke-related medical costs. Weighted average annual total medical cost of stroke was RMB10 637 [95% CI = 10 435-10 840] (US$1682, 95% CI = 1650-1714), with annual out-of-pocket (OOP) cost of RMB3093 [95% CI = 3026-3161] (US$489, 95% CI = 478-500). The average yearly number of stroke-related outpatient visit was 1.67 [SD = 3.39] and inpatient admission was 0.79 [SD = 0.83], with an average cost of RMB440 [SD = 739] (US$70, SD = 117) for outpatients and RMB12 702 [SD = 21 424] (US$2008, SD = 3387) for inpatients. Inpatient costs accounted for 94% (RMB10 034 or US$ 1586) of medical costs, and tertiary hospitals were the main provider of stroke care. Stroke-related medical care utilization and direct costs were associated with gender, age, pathological stroke types and insurance status. Medication costs contributed to 50.6% (RMB5382 or US$ 851) of the average stroke-related medical costs. ConclusionChina’s health system bares a large economic burden from stroke. Specific policies are needed to strengthen the capacity of secondary hospitals, alter the structure of medical resource allocation, and target specific sections of the stroke population.

It is important to clarify the effects of starch fine structure and protein components on the eating quality of indica rice. In this study, seven indica rice varieties with similar apparent amylose content (AAC) and protein content (PC) but different sensory taste values were selected and compared systematically. It was found that except for AAC and PC, these varieties showed significant differences in starch molecular structure and protein components. Compared with rice varieties with a low sensory taste value, varieties with a higher sensory taste value showed significantly lower amylose and higher amylopectin short chains (degree of polymerization 6–12) content; the protein component showed that the varieties with good taste value had higher albumin and lower globulin and glutelin content (p < 0.05). Rice varieties with lower AC, globulin, and glutelin content, as well as a higher content of albumin and amylopectin short chains, resulted in a higher swelling factor, peak viscosity, breakdown value, and ratio of hardness to stickiness, in which condition cooked rice showed a higher sensory taste value. Moreover, this study indicated that rice varieties with a higher content of albumin and amylopectin short chains were conducive to the good appearance of cooked rice. This study lays the foundation for the taste evaluation of good-tasting indica rice.

Preventive health workers rather than general practitioners (GPs) are the principal providers of vaccines in China, which may be a determinant of the unmet demand for vaccination, especially for adults, in recent years. GPs’ preferences had a significant influence on alternative approaches to adult vaccination delivery. To better understand GP’s preferences for adult vaccination services, we employed a discrete choice experiment with seven attributes: income, setting, information system, workshop, workload, performance measurement, and managerial support. Mixed logit models and latent class models were used for statistical analyses. In general, support from primary healthcare managers was the strongest driver of choice, followed by a 10% increase in workload, separate adult vaccination clinic, 5% increase in workload, and independent information system. Monthly income was significantly associated with provision of adult vaccination services. Based on the influence of latent factors, GPs fell into three classes that were correlated with GPs’ years of practice, workload, income satisfaction, and knowledge-attitude-practicescore. Classes 1 and 2 valued the service setting and performance measurement differently, while Class 3 valued the service setting only (preferred separate adult vaccination clinics to provide service). This study generated actionable information to guide innovation in the adult vaccination delivery system in China.

ObjectiveTo develop and externally validate a frailty prediction model integrating physical factors, psychological variables and routine laboratory test parameters to predict the 30-day frailty risk in older adults with undernutrition.MethodsBased on an ongoing survey of geriatrics syndrome in elder adults across China (SGSE), this prognostic study identified the putative prognostic indicators for predicting the 30-day frailty risk of older adults with undernutrition. Using multivariable logistic regression analysis with backward elimination, the predictive model was subjected to internal (bootstrap) and external validation, and its calibration was evaluated by the calibration slope and its C statistic discriminative ability. The model derivation and model validation cohorts were collected between October 2018 and February 2019 from a prospective, large-scale cohort study of hospitalized older adults in tertiary hospitals in China. The modeling derivation cohort data (n = 2,194) were based on the SGSE data comprising southwest Sichuan Province, northern Beijing municipality, northwest Qinghai Province, northeast Heilongjiang Province, and eastern Zhejiang Province, with SGSE data from Hubei Province used to externally validate the model (validation cohort, n = 648).ResultsThe incidence of frailty in the older undernutrition derivation cohort was 13.54% and 13.43% in the validation cohort. The final model developed to estimate the individual predicted risk of 30-day frailty was presented as a regression formula: predicted risk of 30-day frailty = [1/(1+e−riskscore)], where riskscore = −0.106 + 0.034 × age + 0.796 × sex −0.361 × vision dysfunction + 0.373 × hearing dysfunction + 0.408 × urination dysfunction – 0.012 × ADL + 0.064 × depression – 0.139 × nutritional status – 0.007 × hemoglobin – 0.034 × serum albumin – 0.012 × (male: ADL). Area under the curve (AUC) of 0.71 in the derivation cohort, and discrimination of the model were similar in both cohorts, with a C statistic of nearly 0.7, with excellent calibration of observed and predicted risks.ConclusionA new prediction model that quantifies the absolute risk of frailty of older patients suffering from undernutrition was developed and externally validated. Based on physical, psychological, and biological variables, the model provides an important assessment tool to provide different healthcare needs at different times for undernutrition frailty patients.Clinical trial registrationChinese Clinical Trial Registry [ChiCTR1800017682].

Abstract Radial drilling‐fracturing is an innovative fracturing technology that achieves superior stimulation effects. This paper develops a model for radial drilling‐fracturing in shale reservoirs, which can predict fracture initiation pressure and failure mode of shale. Compared with published models, this model additionally considers shale hydration and inclinations of boreholes and reservoir. Then, the influences of 7 factors are studied and main conclusions are as follows. First, with the angle between radial borehole and formation strike increasing, matrix failure pressure declines only around 90° and 270°. Bedding tensile failure pressure ascends and then falls back. Bedding shear failure pressure rapidly descends, then reaches a plateau, and finally rebounds. A small or large angle is favorable for bedding tensile failure. Shale tends to crack with bedding shear failure under a moderate angle and with matrix failure only at 90° and 270°. Second, with the enlargement of azimuth difference between the radial borehole and main wellbore, matrix failure pressure periodically fluctuates, forming an inverted W‐shape curve. Bedding tensile failure pressure and bedding shear failure pressure both ascend, then slide downward, and finally rise again. Besides, a small azimuth difference inclines shale to bedding shear failure, and the other failure modes tend to occur when azimuth difference is around 90°. Third, pressures required for all failure modes descend as the dip of shale formation increases. However, the difference in descending rate leads to that the increase of dip angle can incline shale to bedding shear failure. Besides, pressures required for bedding tensile failure and matrix failure decline linearly with the increasing reservoir temperature. Temperature has no impact on bedding shear failure. Hence, matrix failure and bedding tensile failure are more prone to occur in the high‐temperature reservoir. The research provides a reference for field applications of radial drilling‐fracturing in the shale reservoir.

Objectives Depression is becoming a growing cause of disability, suicides and disease burden. It incurred substantial costs to societies all over the world. Estimating the medical costs of depression will provide implications for related policies and interventions. However, there is scarce of evidence on the economic costs of depression in China. The aim of this study is to assess depression-related medical service utilisation, the direct medical costs of depression and potential associated factors.Settings This study used data that comprised 5% random sample of claims data from China’s Urban Basic Medical Insurance between January 2013 and December 2016. Beneficiaries’ demographic information, diagnoses and cost of outpatient and inpatient services were recorded in the data set.Participants 26 123 patients with depression were identified as the study population in this study.Primary and secondary outcome measures The information on health service utilisation and cost was extracted based on the condition that depression was claimed as the index disease.Results From 2013 to 2016, weighted average annual total medical cost of depression in urban China was RMB2706.92, and the annual out-of-pocket cost was RMB786.4. The annual total medical cost of depression among urban residents in China was estimated to be 4.4 billion RMB (95% CI 4.15 to 4.67) (US$ 0.70, 95% CI 0.66 to 0.74). Nearly 65% of medical costs (RMB 1795.7 or US$ 285.0) were accounted by inpatient expenditure, and tertiary hospitals were the main provider of depression treatment. Depression-related medical care utilisation and direct costs were associated with gender, age, insurance status, severity of depression and diagnosis. Medication costs and medical service contributed to 41.7% and 56.6% of the average depression-related medical costs.Conclusion Depression poses a considerable burden on both the health system and the individual in urban China. Specific policies to strengthen the mental health resources in primary and secondary hospitals are in urgent need, and effective treatment strategies are important to prevent a progression and recurrence of depression, as well as an increase in medical cost.

Understanding the effects of genotype, environment and their interactions on rice quality is of great importance for rice breeding and cultivation. In this study, six rice varieties with two indica, two japonica and two indica–japonica types of rice were selected and planted at ten locations in Zhejiang Province to investigate the genotype (G) × environment (E) on physicochemical and sensory properties and the differences of volatile organic compounds (VOCs) among the three types of rice. Analysis of variances showed that apparent amylose content (AC), total protein content (PC), alkali spreading value (ASV), RVA profiles, and appearance (ACR), palatability (PCR), and sensory evaluation value (SEV) of cooked rice and texture of cooled cooked rice (TCCR) were mainly affected by genotypic variation, whereas the smell of cooked rice (SCR) was mainly affected by environment (p < 0.05). The G × E effect was significant for most parameters. The weather in the middle and late periods of filling had important effects on the formation of rice quality, especially on setback (SB) and pasting temperature (PT) (p < 0.01). They were negatively correlated with the texture of cooked rice (TCR) and SEV (p < 0.05). Peak viscosity (PV) and breakdown (BD) were positively related to the sensory evaluation parameters (p < 0.01) and could be used to predict cooked rice quality. A total of 59 VOCs were detected, and indica, japonica and indica–japonica had 9, 6 and 19 characteristic compounds, respectively. The principal component analysis showed that the physicochemical and sensory properties and VOCs of indica–japonica rice were more stable than those of indica and japonica rice at ten locations in Zhejiang Province. It is helpful for rice breeders to understand how the environment affects the physicochemical, sensory properties and VOCs of the three rice types, and it is also important for food enterprises to provide rice products with stable quality.

Abstract Background Goat milk is very similar to human milk in terms of its abundant nutrients and ease of digestion. To derive greater economic benefit, farmers require more female offspring (does); however, the buck-to-doe offspring sex ratio is approximately 50%. At present, artificial insemination after the separation of X/Y sperm using flow cytometry is the primary means of controlling the sex of livestock offspring. However, flow cytometry has not been successfully utilised for the separation of X/Y sperm aimed at sexing control in dairy goats. Results In this study, a novel, simple goat sperm sexing technology that activates the toll-like receptor 7/8 (TLR7/8), thereby inhibiting X-sperm motility, was investigated. Our results showed that the TLR7/8 coding goat X-chromosome was expressed in approximately 50% of round spermatids in the testis and sperm, as measured from cross-sections of the epididymis and ejaculate, respectively. Importantly, TLR7/8 was located at the tail of the X-sperm. Upon TLR7/8 activation, phosphorylated forms of glycogen synthase kinase α/β (GSK3 α/β) and nuclear factor kappa-B (NF-κB) were detected in the X-sperm, causing reduced mitochondrial activity, ATP levels, and sperm motility. High-motility Y-sperm segregated to the upper layer and the low-motility X-sperm, to the lower layer. Following in vitro fertilisation using the TLR7/8-activated sperm from the lower layer, 80.52 ± 6.75% of the embryos were XX females. The TLR7/8-activated sperm were subsequently used for in vivo embryo production via the superovulatory response; nine embryos were collected from the uterus of two does that conceived. Eight of these were XX embryos, and one was an XY embryo. Conclusions Our study reveals a novel TLR7/8 signalling mechanism that affects X-sperm motility via the GSK3 α/β-hexokinase pathway; this technique could be used to facilitate the efficient production of sexed dairy goat embryos.

Abstract Ovarian cancer is known as one of the most common malignancies of the gynecological system, whose treatment is still not satisfactory because of the unclear understanding of molecular mechanism. PSMC2 is an essential component of 19 S regulatory granules in 26 S proteasome and its relationship with ovarian cancer is still not clear. In this study, we found that PSMC2 was upregulated in ovarian cancer tissues, associated with tumor grade and could probably predict poor prognosis. Knocking down the endogenous PSMC2 expression in ovarian cancer cells could decrease colony formation ability, cell motility and cell proliferation rate, along with increasing cell apoptosis rate. Cells models or xenografts formed by cells with relatively lower expression of PSMC2 exhibited weaker oncogenicity and slower growth rate in vivo. Moreover, gene microarray was used to analyze the alteration of gene expression profiling of ovarian cancer induced by PSMC2 knockdown and identify CCND1 as a potential downstream of PSMC2. Further study revealed the mutual regulation between PSMC2 and CCND1, and demonstrated that knockdown of CCND1 could enhance the regulatory effects induced by PSMC2 knockdown and overexpression of CCND1 reverses it. In summary, PSMC2 may promote the development of ovarian cancer through CCND1, which may predict poor prognosis of ovarian cancer patients.

Background and Aim: The collaborative care (CC) is emerging as an effective method in treating patients with multimorbidity, but evidence whether this model is effective for people with comorbid depression and diabetes is unclear. This study aimed to investigate whether CC could improve depression outcomes and HbA1c in patients with depressive symptoms and diabetes, and assess its effects on Quality of Life (QoL). Method: The author searched Embase, Scopus, PubMed, Cochrane, PsycINFO and CINAHL to identify randomized controlled trials (RCTs) and cluster RCTs published up to October 21, 2020. Studies were required to assess CC in patients with depressive symptoms and diabetes. The primary outcomes were depression treatment response rate and HbA1c and secondary outcome was Quality of Life (QoL). Available individual patient data was collected from all eligible studies. Studies were independently screened by two reviewers and critically appraised using the Cochrane Risk of Bias tool. This study conducted a systematic review and meta-analysis, and the fixed effects and random effects model were used to pool Relative Risks (RRs) and Standard Mean Differences (SMDs). Results: Our research identified 7906 articles, and finally 12 RCTs were included. Study sample sizes ranged from 58 to 417. The total follow-up period ranged from 12 weeks to 24 months. At follow-up, depression treatment response rate had a significant increase (RR = 1·31, 95% CI 1·23 to 1·39, I2 = 0%) in CC patients compared to controls. There was no statistically significant difference in HbA1c between CC group and the control group (SMD = 0·15, 95% CI -0·35 to 0·65, I2 = 97·6%). Overall QoL at follow-up was greater (SMD = 0·12, 95% CI 0·03 to 0·21, I2 = 54·2%) in CC patients compared to controls but the difference was minor. Conclusion: This systematic review and meta-analysis supported the effectiveness of CC in reducing depression and improving QoL in people with comorbid depression and diabetes.

Environmental sanitation of maternal contact during pregnancy is extremely important for the development of different fetal tissues and organs. In particular, during early pregnancy, any adverse exposure may cause abnormal fetal growth or inhibit the development of embryogenic organs. The potential risks of phthalate exposure, which affects the development of humans and animals, are becoming a serious concern worldwide. However, the specific molecular mechanism of di-(2-ethylhexyl) phthalate (DEHP)-induced cardiotoxicity in fetal mice remains unclear. In this study, animal models of DEHP gavage at concentrations of 250, 500, and 1000 mg/kg/day within 8.5–18.5 days of pregnancy were established. The cell proliferation, survival, and apoptosis rates were evaluated using CCK8, EdU, TUNEL and flow cytometry. The molecular mechanism was assessed via transcriptome sequencing, immunohistochemistry, immunofluorescence, reverse transcription-quantitative polymerase chain reaction, and Western blot analysis. In vivo, DEHP increased apoptosis, decreased Ki67 and CD31 expression, reduced heart weight and area, slowed down myocardial sarcomere development, and caused cardiac septal defect in fetal mice heart. Transcriptome sequencing showed that DEHP decreased NRG1 expression and downregulated the ErbB2/ErbB4-PI3K/AKT signaling pathway-related target genes. In vitro, primary cardiomyocytes were cultured with DEHP at a concentration of 150 μg/mL combined with ErbB inhibitor (AG1478, 10 μmol/L) and/or NRG1 protein (100 ng/mL) for 72 h. After DEHP intervention, the expression of NRG1 and the phosphorylation level of ErbB2, ErbB4, PI3K, and AKT decreased, and the apoptosis-related protein levels increased. Moreover, the apoptosis rate increased. After adding exogenous NRG1, the phosphorylation level of the NRG1/ERbB2/ERbB4-PI3K/AKT pathway increased, and the apoptosis-related protein levels decreased. Further, the apoptosis rate reduced. Interestingly, after exposure to DEHP and AG1478 + NRG1, the anti-apoptotic effect of NRG1 and cardiomyocyte proliferation decreased by inhibiting the NRG1/ERbB2/ERbB4-PI3K/AKT pathway. Hence, the NRG1-dependent regulation of the ERbB2/ERbB4-PI3K/AKT signaling pathway may be a key mechanism of DEHP-induced myocardial cytotoxicity.

Spermatogenesis holds considerable promise for human-assisted reproduction and livestock breeding based on stem cells. It occurs in seminiferous tubules within the testis, which mainly comprise male germ cells and Sertoli cells. While the developmental progression of male germ cells and Sertoli cells has been widely reported in mice, much less is known in other large animal species, including dairy goats. In this study, we present the data of single cell RNA sequencing (scRNA-seq) for 25,373 cells from 45 (pre-puberty), 90 (puberty), and 180-day-old (post-puberty) dairy goat testes. We aimed to identify genes that are associated with key developmental events in male germ cells and Sertoli cells. We examined the development of spermatogenic cells and seminiferous tubules from 15, 30, 45, 60, 75, 90, 180, and 240-day-old buck goat testes. scRNA-seq clustering analysis of testicular cells from pre-puberty, puberty, and post-puberty goat testes revealed several cell types, including cell populations with characteristics of spermatogonia, early spermatocytes, spermatocytes, spermatids, Sertoli cells, Leydig cells, macrophages, and endothelial cells. We mapped the timeline for male germ cells development from spermatogonia to spermatids and identified gene signatures that define spermatogenic cell populations, such as AMH, SOHLH1, INHA, and ACTA2. Importantly, using immunofluorescence staining for different marker proteins (UCHL1, C-KIT, VASA, SOX9, AMH, and PCNA), we explored the proliferative activity and development of male germ cells and Sertoli cells. Moreover, we identified the expression patterns of potential key genes associated with the niche-related key pathways in male germ cells of dairy goats, including testosterone, retinoic acid, PDGF, FGF, and WNT pathways. In summary, our study systematically investigated the elaborate male germ cells and Sertoli cells developmental patterns in dairy goats that have so far remained largely unknown. This information represents a valuable resource for the establishment of goat male reproductive stem cells lines, induction of germ cell differentiation in vitro, and the exploration of sequential cell fate transition for spermatogenesis and testicular development at single-cell resolution.

Abstract Gallbladder cancer (GBC) is a common malignant tumor of the biliary tract, which accounts for 80–95% of biliary tumors worldwide, and is the leading cause of biliary malignant tumor-related death. This study identified PSMC2 as a potential regulator in the development of GBC. We showed that PSMC2 expression in GBC tissues is significantly higher than that in normal tissues, while high PSMC2 expression was correlated with more advanced tumor grade and poorer prognosis. The knockdown of PSMC2 in GBC cells induced significant inhibition of cell proliferation, colony formation and cell motility, while the promotion of cell apoptosis. The construction and observation of the mice xenograft model also confirmed the inhibitory effects of PSMC2 knockdown on GBC development. Moreover, our mechanistic study recognized GNG4 as a potential downstream target of PSMC2, knockdown of which could aggravate the tumor suppression induced by PSMC2 knockdown in vitro and in vivo. In conclusion, for the first time, PSMC2 was revealed as a tumor promotor in the development of GBC, which could regulate cell phenotypes of GBC cells through the interaction with GNG4, and maybe a promising therapeutic target in GBC treatment.

Abstract Background Comorbidity has been established as one of the important predictors of poor prognosis in lung cancer. In this study, we analyzed the prevalence of main comorbidities and its association with hospital readmission and fatality for lung cancer patients in China. Methods The analyses are based on China Urban Employees’ Basic Medical insurance (UEBMI) and Urban Residents’ Basic Medical Insurance (URBMI) claims database and Hospital Information System (HIS) Database in the Beijing University Cancer Hospital in 2013–2016. We use Elixhauser Comorbidity Index to identify main types of comorbidities. Results Among 10,175 lung cancer patients, 32.2% had at least one comorbid condition, and the proportion of patients with one, two, and three or more comorbidities was 21.7, 8.3 and 2.2%, respectively. The most prevalent comorbidities identified were other malignancy (7.5%), hypertension (5.4%), pulmonary disease (3.7%), diabetes mellitus (2.5%), cardiovascular disease (2.4%) and liver disease (2.3%). The predicted probability of having comorbidity and the predicted number of comorbidities was higher for middle elderly age groups, and then decreased among patients older than 85 years. Comorbidity was positively associated with increased risk of 31-days readmission and in-hospital death. Conclusion Our study is the first to provide an overview of comorbidity among lung cancer patients in China, underlines the necessity of incorporating comorbidity in the design of screening, treatment and management of lung cancer patients in China.

Abstract Background Evidence‐based policy making for delivering affordable lung cancer care relies on the breadth, depth and quality of knowledge of its treatment costs. This study estimates the annual prevalence, medical service utilization and direct treatment costs of lung cancer in urban China. Materials and Methods Using claim data from China's urban basic medical insurance between 2013 and 2016, we constructed a nationally representative sample of lung cancer patients in urban China. Weighted descriptive analyses, Poisson regressions and generalized linear modelling were used to analyse lung cancer medical service utilization and costs and their associations with patient characteristics. Results In urban China, the annual prevalence of lung cancer was 87.65/100000, with nearly 0.65% of total health expenditures of urban residents spent on lung cancer treatments. Weighted average annual total medical costs of lung cancer was RMB33.78 (US$5.36) thousand, with annual out‐of‐pocket costs of RMB10.26 (US$1.63) thousand. The average yearly number of lung cancer‐related outpatient visits was 2.42 and inpatient admissions was 2.07, with an average cost of RMB0.75 (US$0.12) thousand for outpatients and RMB 15.67 (US$2.49) thousand for inpatients. Inpatient expenses were the major component (95%) of lung cancer medical costs, with roughly 67% of inpatient services occurring in high‐level tertiary hospitals. Medical care utilization and direct medical costs were associated with sex, age and insurance status. Western medicine costs were the major contributor (39.4%) to average lung cancer‐related medical costs. Conclusion Lung cancer imposed a significant economic burden on China's health system and a financial cost on lung cancer sufferers and their families. Specific policies are required to efficiently allocate health resources, contain health expenditure and decrease the individual financial burden of lung cancer.

Abstract Background Hearing loss is quite prevalent and can be related to people’s quality of life. To our knowledge, there are limited studies assessing the efficacy of hearing interventions on quality of life in adults. Therefore, we aim to conduct a randomized controlled trial (RCT) to determine the impact and cost-effectiveness of community-based hearing rehabilitation on quality of life among Chinese adults with hearing loss. Methods/design In this two-arm feasibility study, participants aged 16 and above with some degree of hearing loss (n = 464) will be recruited from Linyi City, Shandong Province. They are randomly assigned to the treatment group or the control group. Those in the treatment group are prescribed with hearing aids, while those in the control group receive no intervention. Reinstruction in use of devices is provided for the treatment group during booster visits held 12 months post-randomization or unscheduled interim visits when necessary. Data are collected at baseline and the follow-up 20 months later. The primary outcome is changes in quality of life over a 20-month study period. Secondary outcomes include sub-dimensions in quality of life, physical functioning, chronic diseases, cognitive function, depression, social support, hospitalizations, falls, and healthcare costs. Finally, we will evaluate whether hearing aids intervention is cost-effective to apply in a large scale. Discussion The trial is designed to evaluate the impact and cost-effectiveness of a community-based rehabilitation intervention on quality of life among Chinese adults with hearing loss. We hope that it would help improve the well-being for Chinese adults and provide references in policy and practice for China and other countries. Trial registration Chinese Clinical Trial Registry ChiCTR1900024739 . Registered on 26 July 2019.

Abstract Background As a key part of the new round of health reform, the zero-markup drug policy (ZMDP) removed the profit margins of drug sales at public health care facilities, and had some effects to the operation of these institutions. This study aims to assess whether the ZMDP has different impacts between county general and traditional Chinese medicine (TCM) hospitals. Methods We obtained longitudinal data from all county general and TCM hospitals of Shandong province in 2007–2017. We used difference-in-difference (DID) method to identify the overall and dynamic effects of the ZMDP. Results On average, after the implementation of the ZMDP, the share of revenue from medicine sales reduced by 16.47 and 10.42%, the revenue from medicine sales reduced by 24.04 and 11.58%, in county general and TCM hospitals, respectively. The gross revenue reduced by 5.07% in county general hospitals. The number of annual outpatient visits reduced by 11.22% in county TCM hospitals. Government subsidies increased by 199.22 and 89.3% in county general and TCM hospitals, respectively. The ZMDP reform was not significantly associated with the revenue and expenditure surplus, the number of annual outpatient visits and the number of annual inpatient visits in county general hospitals, the gross revenue, the revenue and expenditure surplus and the number of annual inpatient visits in county TCM hospitals. In terms of dynamic effects, the share of revenue from medicine sales, revenue from medicine sales, and gross revenue decreased by 20.20, 32.58 and 6.08% respectively, and up to 28.53, 63.89 and 17.94% after adoption, while government subsidies increased by around 170 to 200% in county general hospitals. The number of annual outpatient visits decreased by 9.70% and up to 18.84% in county TCM hospitals. Conclusion The ZMDP achieved its some initial goals of removing the profits from western medicines in county hospitals’ revenue without disrupting the normal operation, and had different impacts between county general and TCM hospitals. Meanwhile, some unintended consequences were also recognized through the analysis, such as the decline of the utilization of the TCM.

Background: This study compared the epidemiology of carbapenem-resistant (CRKP) and carbapenem-sensitive (CSKP) K. pneumoniae bloodstream infections (BSIs), and assessed risk factors for 28-day mortality of patients with K. pneumoniae BSIs. Methods: A retrospective cohort study was conducted in a 2000-bed tertiary teaching hospital of Beijing between Jan 1st 2013 to Dec 31st, 2019. All patients with K. pneumoniae BSI were identified through the Hospital Information System. The endpoints included incidence rate, mortality and risk factors for mortality of patients with K. pneumoniae BSIs. Results: 496 patients with K. pneumoniae BSIs were included in the analysis, with 108 CRKP BSIs. The incidence rate of K. pneumoniae BSI was 10.6 (CI: 9.7, 11.6) per 100 000 patient-days, with the rate for CRKP BSI was 2.3 (95% CI: 1.9, 2.8). The 28-day mortality was 38.0% for CRKP BSI and 8.8% for CSKP BSI, respectively. Logistic analysis showed, higher Charlson Comorbidity Index score (OR = 1.26, 95%CI 1.12–1.43, p < 0.001), respiratory failure (OR = 2.73, 95%CI1.28−5.84, p = 0.010), renal failure (OR = 4.13, 95%CI1.93−8.83, p < 0.001), septic shock (OR = 8.77, 95%CI3.60−21.32, p < 0.001), mechanical ventilation (OR = 4.41, 95%CI1.59−12.25, p = 0.004) and CRKP infection (OR = 3.04, 95%CI1.28−7.22, p = 0.012) were independently associated with 28-day mortality. Conclusions: Considerable incidence rate and remarkable mortality of patients with K. pneumoniae (especially CRKP) BSI was declared in the study. Patient conditions before (higher CCI) and after presentation (respiratory failure, renal failure, septic shock), and healthcare factors (mechanical ventilation and CRKP infection) were independently associated with 28-day mortality. Understanding these risks helps better establishment of infection control strategies.

Abstract Background Hearing impairment is a common chronic condition which can be closely related to people’s health. However, current studies on this topic are quite limited in developing countries, and few with standardized audiometric measurement and multiple health outcomes. Therefore, we aimed to explore the association between hearing impairment and its severity with physical and mental health among Chinese middle-aged and older adults. Methods We obtained data from two sources: (1) China Health and Retirement Longitudinal Study (CHARLS) 2011, 2013, and 2015, in which hearing impairment was measured by asking whether participants aged 45 years old had hearing problems; and (2) Hearing Survey 2019, the baseline survey of a randomized controlled trial conducted in Shandong Province of China, including 376 middle-aged and older participants. The severity of hearing impairment was identified by pure tone average of hearing thresholds at 0.5, 1, 2, and 4 kHz. Results In CHARLS, 1248 (8.36%) participants suffered from hearing impairment at baseline, and hearing-impaired individuals were more likely to have chronic diseases, impaired activities of daily living (ADLs), impaired instrumental activities of daily living (IADLs) and depressive symptoms. For the 376 hearing-impaired participants in Hearing Survey 2019, 30.32, 38.30 and 31.38% of them had moderate, severe and profound hearing impairment, respectively. As the severity of hearing impairment increased, individuals were likely to have impaired ADLs, impaired IADLs and depressive symptoms. Conclusions Hearing impairment and its severity were closely related to multiple physical and mental health outcomes among Chinese middle-aged and older adults. Actions should be taken to prevent and treat hearing impairment, so as to improve people’s health and well-being.

Using current Embedded Discrete Fracture Models (EDFM) to predict the productivity of fractured wells has some drawbacks, such as not supporting corner grid, low precision in the near wellbore zone, and disregarding the heterogeneity of conductivity brought by non-uniform sand concentration. An EDFM is developed based on the corner grid, which enables high efficient calculation of the transmissibility between the embedded fractures and matrix grids, and calculation of the permeability of each polygon in the embedded fractures by the lattice data of the artificial fracture aperture. On this basis, a coupling method of local grid refinement (LGR) and embedded discrete fracture model is designed, which is verified by comparing the calculation results with the Discrete Fracture Network (DFN) method and fitting the actual production data of the first hydraulically fractured well in Iraq. By using this method and orthogonal experimental design, the optimization of the parameters of the first multi-stage fractured horizontal well in the same block is completed. The results show the proposed method has theoretical and practical significance for improving the adaptability of EDFM and the accuracy of productivity prediction of fractured wells, and enables the coupling of fracture modeling and numerical productivity simulation at reservoir scale. Key words: hydraulic fracturing, grid refinement, embedded discrete fracture method, reservoir numerical simulation, productivity prediction, parameters optimization

Abstract Background It is evident that comorbidity exacerbate the complexity of the management of lung cancer, however, limited research has been conducted to investigate the impact of comorbidity on health service utilization and cost, as well as the treatment choice among lung cancer patients. We examined the association of comorbidity with medical service utilization, cost and treatment choice among lung cancer patients in China. Methods We used claims data from China Urban Employees’ Basic Medical Insurance (UEBMI) and Urban Residents’ Basic Medical Insurance (URBMI) between 2013 to 2016 and data from Hospital Information System (HIS) Database in Beijing Cancer Hospital (BCH). Elixhauser Comorbidity Index was used to assess comorbidity. Negative binomial regression, generalized linear model (GLM) with a gamma distribution and a log link, and logistic regression was applied to assess the associations between comorbidity and medical service utilization, cost and treatment choice, respectively. Results Among 8655 patients with lung cancer, 31.3% of had at least one comorbid conditions. Having comorbidity was associated with increased number of annual outpatient visits (1.6, 95%CI: 1.3, 1.9) and inpatients admissions (0.8, 95%CI, 0.70, 0.90), increased outpatient (USD635.5, 95%CI: 490.3, 780.8) and inpatient expenditure (USD2 470.3, 95CI%: 1998.6, 2941.9), as well as increased possibility of choosing radio therapy (OR: 1.208, 95%CI:1.012–1.441) and chemotherapy (1.363, 1.196–1.554), and decreased possibility of choosing surgery (0.850, 0.730–0.989). The medical utilization and expenditure, the possibility of choosing radiotherapy increases, and the possibility of choosing surgery decreases with the increasing number of chronic conditions. There are variations in the association with medical service utilization and expenditure, and treatment choice among individuals with different types of comorbid conditions. Conclusion Comorbidity among lung cancer patients restricts the potential treatment choices and poses an extra substantial health care burden. Our findings provide implications for both the clinical management and health service planning and financing for lung cancer patients.

PM _2.5 components may promote the development of breast cancer and increase the risk of mortality. This study aims to investigate the associations between long-term exposure to PM _2.5 components and multiple causes of mortality among women with breast cancer living in Inner Mongolia, China. We constructed an Inner Mongolia cohort of 33 952 breast cancer patients from 2012 to 2021 using data from the Inner Mongolia Regional Health Information Platform. We assessed each patient’s exposure to PM _2.5 components using the Tracking Air Pollution in China database. Cox regression models were used to estimate adjusted hazard ratios and 95% confidence intervals (95% CIs). A total of 3295 deaths were identified. For each interquartile increase in concentration in the 5 years before diagnosis, the all-cause mortality increased significantly by 5% (HR: 1.05, 95%CI: 1.00–1.10) for black carbon and by 4% (HR: 1.04, 95%CI: 1.00–1.09) for sulfate (SO _4 ^2− ), and decreased by 7% (HR: 0.93, 95%CI: 0.88–0.98) for nitrate (NO _3 ^− ). An association between organic matter and an increased all-cause mortality was also observed. Similar results were found for associations with risk of death from breast cancer-specific causes, cardio-cerebrovascular disease (CCVD) causes, and respiratory causes. Stronger associations were observed in older age groups and in Han Chinese patients. Our results showed that long-term exposure to black carbon, organic matter, and SO _4 ^2− were more responsible for the increased risk of death from all causes, breast cancer-specific causes, CCVD causes, and respiratory causes. This suggests that more effective measures to control coal combustion emissions in Inner Mongolia are urgently needed. The elderly and Han Chinese populations may be at high risk.

Objectives: To test the hypothesis that higher salary levels of the medical staff are associated with lower medical service utilization and expenditure.Methods: Using longitudinal data from 31 Chinese provinces for the period 2007-2016, we constructed fixed effects models to analyze the association between the salary of medical staff and medical service utilization, medical expenditure, medication expenditure, and medication proportion.Results: A 10,000 CNY increase in medical staff's salaries was associated with a 0.89% decrease in the average number of annual inpatient admissions per person; 1.88 and 1.59% decreases in average expenditures per outpatient visit and inpatient admission, respectively; 3.05 and 2.66% decreases in drug expenditures per outpatient visit and inpatient admission, respectively; 0.58 percent point and 0.39 percent point decreases in the share of drug expenditure in outpatient and inpatient, respectively. When medical staff's salaries increased by 450,000 CNY, the turning point was reached when the maximum medical expenditure savings offset the medical staff salary increases, yielding a 634 billion CNY surplus from medical expenditure.Conclusions: Our results supported the hypothesis that higher salary levels of the medical staff are associated with lower medical service utilization and expenditure. Further studies are requested to test whether higher medical staff's salaries will attenuate over-treatment and that savings from reduced prescriptions and service charges will offset the increased salaries of medical staff.

Purpose: Evidence of the impact of nutritional risk on health outcomes and hospital costs among Chinese older inpatients is limited. Relatively few studies have investigated the association between clinical and cost outcomes and nutritional risk in immobile older inpatients, particularly those with neoplasms, injury, digestive, cardiac, and respiratory conditions.Methods: This China-wide prospective observational cohort study comprised 5,386 immobile older inpatients hospitalized at 25 hospitals. All patients were screened for nutritional risk using the Nutrition Risk Screening (NRS 2002). A descriptive analysis of baseline variables was followed by multivariate analysis (Cox proportional hazards models and generalized linear model) to compare the health and economic outcomes, namely, mortality, length of hospital stay (LoS), and hospital costs associated with a positive NRS 2002 result.Results: The prevalence of a positive NRS 2002 result was 65.3% (n = 3,517). The prevalence of “at-risk” patients (NRS 2002 scores of 3+) was highest in patients with cardiac conditions (31.5%) and lowest in patients with diseases of the respiratory system (6.9%). Controlling for sex, age, education, type of insurance, smoking status, the main diagnosed disease, and Charlson comorbidity index (CCI), the multivariate analysis showed that the NRS 2002 score = 3 [hazard ratio (HR): 1.376, 95% CI: 1.031–1.836] were associated with approximately a 1.5-fold higher likelihood of death. NRS 2002 scores = 4 (HR: 1.982, 95% CI: 1.491–2.633) and NRS scores ≥ 5 (HR: 1.982, 95% CI: 1.498–2.622) were associated with a 2-fold higher likelihood of death, compared with NRS 2002 scores

AbstractRadial drilling-fracturing, the combination of radial drilling and hydraulic fracturing, can guide fractures toward the target area and effectively enhance the recovery of the low permeable reservoir. In this paper, based on the stress superposition principle, we establish an analytical model to predict fracture initiation pressure (FIP) and the shale failure mode for radial drilling-fracturing applied in shale formations. In contrast with the former studies, this model can additionally consider the failure from shale beddings and is more applicable in the shale reservoir. The model classifies the shale failure into three modes and, respectively, gives the criterion for each failure mode. Then, a series of sensitivity analyses is conducted by examining effects of various parameters. By analyzing the variation characteristic of the initiation pressures required for three failure modes, the main conclusions are as follows. Firstly, matrix failure and shear failure along bedding tend to take place when the azimuth of radial borehole is moderate. Small and large azimuths are favorable for the occurrence of tensile failure along bedding. Secondly, a high ratio of horizontal in situ stress predisposes shale to generate matrix failure, and bedding tensile failure and bedding shear failure are apt to occur when the ratio of horizontal in situ stress is low. Thirdly, with the increasing intersection angle of the radial borehole wall and bedding plane, the failure mode apt to occur changes from bedding tensile failure to bedding shear failure and then to matrix failure. Fourthly, shale prefers to yield bedding shear failure under a small Biot coefficient and generate the other two failure modes when Biot coefficient is large. Fifthly, permeability coefficient virtually has no influence on the failure mode of shale. The research clarifies the fracture initiation characteristics of radial drilling-fracturing in shale formations and provides a reference for the field application of radial drilling-fracturing.

Abstract The oil reservoir of Mishrif Formation is of strong heterogeneity vertically and laterally, and its single‐well production rate after conventional acidizing is low and declines fast. Therefore, we intend to carry out the pilot test on diverting acid fracturing so as to improve the stimulation effect of acid fracturing by enlarging the lateral and vertical stimulation range. In this paper, a series of experimental studies (eg, rock mechanics, acid rheology, acid‐rock reaction kinetics, and full‐diameter core etching diversion) were carried out to deal with the reservoir characteristics and stimulation demand of Mishrif Formation, the principal oil reservoir in Halfaya Oilfield in Iraq, the Middle East. It is shown that calcite content of Mishrif Formation reservoir is higher than 95%, indicating the strong acid dissolution. As for rock mechanics, the characteristics of “low Young's modulus and high Poisson's ratio” are presented, and the stress‐strain curves show certain elastic‐plastic characteristics. Additionally, a large number of wormholes appear on the surface of the full‐diameter cores after acid etching, so it is necessary to consider the serious filtration of acidizing fluid near the wellbore. The mechanical strength of rock plates decreases after acid etching, so it is recommended to adopt and optimize the closed acidizing technology so as to avoid excessive etching. Furthermore, the self‐support flow conductivity of etched fractures is weak, so it is recommended to adopt the sand fracturing or the combined stimulation technology of acid fracturing + sand fracturing to improve the reservoir stimulation effects.

Abstract Background It is well known that human clear cell renal cell carcinoma (ccRCC) is a highly immunogenic and chemo-resistant tumor. Recently, emerging data suggest that the immune checkpoint blockade therapy is an important breakthrough in the treatment against ccRCC. HHLA2, a recently reported member of B7 family, is uniquely expressed in humans but not in mice, and it plays an important role in the functional inhibition of CD4 and CD8 T cells. Herein, we aimed to study the clinical implications of HHLA2 expression in human ccRCC and its potential regulatory role in the biological functions of the cancer cells. Methods In the present study, we examined HHLA2 expression in human ccRCC tissues and analyzed the clinical implications as well as prognostic value. The intervention of HHLA2 in human ccRCC cell lines ACHN and 786-O was performed and its effect on the cellular function of the cells was also analyzed. We also identified the differentially expressed genes upon HHLA2 knockdown in ccRCC cell lines by using gene microarray analysis. Results We found that higher HHLA2 mRNA expression level in human ccRCC tissues compared with that in adjacent normal tissues based on TCGA data, and the HHLA2 expression at mRNA level was positively and significantly correlated with PD-L1, PD-L2, B7-H6, but negatively and significantly correlated with B7-H3. Moreover, our immunohistochemistry study showed that the staining intensity of HHLA2 in human ccRCC tissues was significantly higher than that in the adjacent normal tissues, and the overall survival rate of ccRCC patients with higher HHLA2 expression was significantly poorer than that of the patients with lower HHLA2 expression. Higher expression of HHLA2 in ccRCC tissues was positively and significantly associated with larger tumor size and advanced TNM stage. The COX model revealed that the parameters including patient’s age, TNM stage and HHLA2 expression level could be used as the independent risk factors respectively for the prognostic prediction of the patients. Our cellular study showed that upon knockdown of HHLA2 expression in human ccRCC cell lines, the cell viability, the migration and the invasion ability were significantly inhibited, while the cell cycle arrest at G1 phase was induced and the expressions of Cyclin D1, c-Myc and Cyclin E1 were decreased. In addition, according to the microarray data, the expressions of epithelia-to-mesenchymal transition markers, such as E-cadherin, N-cadherin and Vimentin, were significantly changed after knockdown of HHLA2 expression. Conclusions Our findings indicated that HHLA2 was involved in the progression of human ccRCC and could be used as an important prognostic predictor for this malignancy.