Time-dependent efficacy analysis of first-line immunotherapies for advanced non-small cell lung cancer.

BACKGROUND: Many randomized controlled trials (RCTs) and network meta-analyses have demonstrated that the progression-free survival (PFS) and overall survival (OS) of advanced non-small cell lung cancer (NSCLC) patients can be improved through combination immunotherapy or monotherapies. However, time-dependent analysis of the treatment effect is currently lacking. Thus, we aimed to evaluate the efficacy of first-line immunotherapy, and establish a hazard ratio function to reflect the time-varying progression or mortality risk of patients with NSCLC. METHODS: Seventeen clinical trials were selected based on search strategy. Baseline characteristics, including the age, sex, smoking status, geographical region, and Eastern Cooperative Oncology Group (ECOG) performance status of patients, were balanced, resulting in ten immunotherapies from nine appropriate clinical trials to conduct treatment effect comparison. RESULTS: We found that nivolumab plus ipilimumab (nivo + ipi) improved the PFS and OS over time. The hazard ratio of nivo + ipi, relative to that of pembrolizumab, decreased from 1.11 to 0.36 for PFS, and from 0.93 to 0.49 for OS over a 10-year period. In terms of the response to immunotherapy in patients with different PD-L1 expression levels, patients with PD-L1 > = 50% experienced lower rates of progression and a reduced mortality risk over time. The hazard ratio of patients with PD-L1 > = 50% relative to all of the patients decreased from 0.73 to 0.69 for PFS, and from 0.78 to 0.67 for OS. CONCLUSIONS: Based on the fact that time-dependent progression and mortality risk existed during the treatment duration, physicians should select a suitable treatment regimen for patients based on the hazard ratio.

Sporoderm-broken spores of Ganoderma lucidum modulate hepatoblastoma malignancy by regulating RACK1-mediated autophagy and tumour immunity.

Hepatoblastoma (HB), a primary liver tumour, is notorious for its high metastatic potential and poor prognosis. Ganoderma lucidum, an edible mushroom species utilized in traditional Chinese medicine for addressing various tumour types, presents an intriguing avenue for HB treatment. However, the effectiveness of G. lucidum in managing HB and its underlying molecular mechanism necessitates further exploration. Standard in vitro assays were conducted to evaluate the impact of sporoderm-broken spores of G. lucidum (SBSGL) on the malignant characteristics of HB cells. The mechanism of SBSGL in treating HB and its tumour immunomodulatory effects were explored and validated by various experiments, including immunoprecipitation, Western blotting, mRFP-GFP-LC3 adenovirus transfection and co-localization analysis, as well as verified with in vivo experiments in this regard. The results showed that SBSGL effectively inhibited the malignant traits of HB cells and suppressed the O-GlcNAcylation of RACK1, thereby reducing its expression. In addition, SBSGL inhibited immune checkpoints and regulated cytokines. In conclusion, SBSGL had immunomodulatory effects and regulated the malignancy and autophagy of HB by regulating the O-GlcNAcylation of RACK1. These findings suggest that SBSGL holds promise as a potential anticancer drug for HB treatment.

Cost-effectiveness of first-line immunotherapy for advanced non-small cell lung cancer with different PD-L1 expression levels: A comprehensive overview.

BACKGROUND: Immunotherapies can substantially improve treatment efficacy, despite their high cost. A comprehensive overview of the cost-effectiveness analysis (CEA) of immune checkpoint inhibitors (ICIs) in patients with non-small cell lung cancer based on different tumor proportion scores (TPSs) was conducted. METHODS: PubMed, Embase, Cochrane Central Register of Controlled Trials, Health Technology Assessment Database, and NHS Economic Evaluation databases were searched from their inception until August 24, 2022. Data relevant to the CEA results were recorded, and quality assessments conducted based on the Quality of Health Economic Studies (QHES) process. FINDINGS: Fifty-one original studies from seven countries were included. The mean QHES score was 77.0 (range: 53-95). Twenty-seven studies were classified as high-quality, and the rest as fair quality. Pembrolizumab, nivolumab, ipilimumab, atezolizumab, camrelizumab, cemiplimab, sintilimab, tislelizumab, and durvalumab were identified using three TPS categories. While nivolumab plus ipilimumab and pembrolizumab plus chemotherapy were unlikely to be cost-effective in China, the results for the US were uncertain. Atezolizumab combinations were not cost-effective in China or the US, and tislelizumab and sintilimab were cost-effective in China. For TPSs ≥ 50%, the pembrolizumab monotherapy could be cost-effective in some developed countries. Cemiplimab was more cost-effective than chemotherapy, pembrolizumab, and atezolizumab in the US. For TPSs ≥ 1%, the cost-effectiveness of pembrolizumab was controversial due to the different willingness-to-pay thresholds. CONCLUSIONS: None of the atezolizumab combination regimens were found to be cost-effective in any perspective of evaluations. Camrelizumab, tislelizumab, and sintilimab have lower ICERs compared to atezolizumab, pembrolizumab, and nivolumab in China. Cemiplimab may be a more affordable alternative to pembrolizumab or atezolizumab. However, it remains unclear which ICIs are the best choices for each country. Future CEAs are required to select comprehensive regimens alongside randomized trials and real-world studies to help verify the economics of ICIs in specific decision-making settings.

Safety and Pharmacokinetic Assessment of the FIC CLDN18.2/4-1BB Bispecific Antibody in Rhesus Monkeys.

Gastric cancer is one of the most common cancers worldwide, particularly in China, with over half a million new cases and over 400 thousand deaths in 2022. Zolbetuximab, a first-in-class investigational monoclonal antibody (mAb) targeting tumor-associated antigen CLDN18.2 which is highly expressed on gastric cancer cells, was recently reported to meet the primary endpoint in Phase III trial as first-line treatment in CLDN18.2 positive and HER2-negative gastric cancers. In the present study, we developed a humanized bispecific antibody (bsAb) CLDN18.2/4-1BB named PM1032. PM1032 activates immune cells via CLDN18.2 mediated crosslinking of 4-1BB, a potent stimulator of T/NK cells. It induced strong immunological memory in multiple tumor-bearing animal models, indicating significant potential as an effective treatment for CLDN18.2 positive cancers such as gastric cancer. Since liver and gastrointestinal (GI) related toxicities were reported in 4-1BB and CLDN18.2 targeting programs during the clinical development, respectively, extensive pharmacokinetics (PK) and safety profile characterization of PM1032 was performed in rhesus monkeys. PM1032 had a half-life comparable to a conventional IgG1 mAb, and serum drug concentration increased in a dose-dependent pattern. Furthermore, PM1032 was generally well tolerated, with no significant abnormalities observed in toxicity studies, including the liver and stomach. In summary, PM1032 demonstrated good PK and an exceptional safety profile in rhesus monkeys supporting further investigation in clinical studies.

Cost-effectiveness of first-line immunotherapy combinations with or without chemotherapy for advanced non-small cell lung cancer: a modelling approach.

BACKGROUND: Many studies have explored the cost-effectiveness of immunotherapy versus chemotherapy alone. However, there is paucity of evidence on direct pharmacoeconomic studies related to immunotherapy combinations. Thus, we aimed at assessing the economic outcomes of first-line immunotherapy combinations in the treatment of advanced non-small cell lung cancer (NSCLC) from the Chinese health care perspective. METHODS: The mutual hazard ratios (HRs) of ten immunotherapy combinations and one chemotherapy regimen for the overall survival (OS) and progression-free survival (PFS) were obtained from a network meta-analysis. Based on proportional hazard (PH) assumption, adjusted OS and PFS curves were established to make the effects comparable. With the parameters of cost and utility, and of scale and shape from the fit of adjusted OS and PFS curves obtained from previous studies, a partitioned survival model was designed to estimate the cost-effectiveness of immunotherapy combinations versus chemotherapy alone. Parameter uncertainty in model inputs was assessed using one-way deterministic and probabilistic sensitivity analyses. RESULTS: The incremental cost of camrelizumab plus chemotherapy versus chemotherapy alone was $13,180.65, the lowest among all the other immunotherapy combinations. Furthermore, sintilimab plus chemotherapy (sint-chemo) provided the highest quality-adjusted life-year (QALY) benefit versus chemotherapy alone (incremental QALYs = 0.45). Sint-chemo yielded the best incremental cost-effectiveness ratio (ICER) versus chemotherapy alone (ICER = $34,912.09/QALY), at the current price. The cost-effectiveness probabilities were 32.01% and 93.91% for pembrolizumab plus chemotherapy, and atezolizumab plus bevacizumab plus chemotherapy, respectively (if the original price of the pembrolizumab, atezolizumab, and bevacizumab were decreased by 90%). CONCLUSIONS: Based on the fact that there is fierce competition in the PD-1/PD-L1 market, pharmaceutical enterprises should strive for greater efficacy, and optimal pricing strategy for therapies.

Identifying and comparing low-value care recommendations for coronary heart disease prevention, diagnosis, and treatment in the US and China.

BACKGROUND: Low-value care provides little or no benefit, causes harm and incurs unnecessary costs. Low-value care for coronary heart disease (CHD) is particularly prevalent in the US and China. Identifying low-value care services is the first step in reducing these services. There is currently limited data on identifying a comprehensive CHD low-value care list in the US and China. We aimed to identify and compare low-value care recommendations for CHD prevention, diagnosis, and treatment in the US and China. METHODS: Clinical practice guidelines (CPGs) related to CHD in the US and China were screened for do-not-do recommendations stating that specific services should be avoided. The similarities and discrepancies of low-value care recommendations for CHD between the two countries were then compared. RESULTS: We found a total of 38 low-value care recommendations in 6 Chinese CPGs and 98 recommendations in 11 US CPGs. In the US, the most common types of low-value care recommendations were therapeutic medications (44, 44.9%), followed by therapeutic procedures (27, 27.6%), diagnostic imaging (16, 16.3%), diagnostic testing (9, 9.2%) and primary prevention (2, 2.0%). In China, the most common types were therapeutic medications (18, 47.4%), followed by therapeutic procedures (13, 34.2%), diagnostic testing (4, 10.5%), and diagnostic imaging (3, 7.9%). CONCLUSION: In this study, a comprehensive list of low-value care for CHD in the US and China was established and potentially become the important targets for de-implementation for both countries. The findings may have important implications for other countries, especially low-and middle-income countries, to reduce low-value care for CHD.

Integrative proteomics and m6A microarray analyses of the signatures induced by METTL3 reveals prognostically significant in gastric cancer by affecting cellular metabolism.

METTL3-mediated RNA N6-methyladenosine (m6A) is the most prevalent modification that participates in tumor initiation and progression via governing the expression of their target genes in cancers. However, its role in tumor cell metabolism remains poorly characterized. In this study, m6A microarray and quantitative proteomics were employed to explore the potential effect and mechanism of METTL3 on the metabolism in GC cells. Our results showed that METTL3 induced significant alterations in the protein and m6A modification profile in GC cells. Gene Ontology (GO) enrichment indicated that down-regulated proteins were significantly enriched in intracellular mitochondrial oxidative phosphorylation (OXPHOS). Moreover, the protein-protein Interaction (PPI) network analysis found that these differentially expressed proteins were significantly associated with OXPHOS. A prognostic model was subsequently constructed based on the Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases, and the high-risk group exhibited a worse prognosis in GC patients. Meanwhile, Gene Set Enrichment Analysis (GSEA) demonstrated significant enrichment in the energy metabolism signaling pathway. Then, combined with the results of the m6A microarray analysis, the intersection molecules of DEPs and differential methylation genes (DMGs) were significantly correlated with the molecules of OXPHOS. Besides, there were significant differences in prognosis and GSEA enrichment between the two clusters of GC patients classified according to the consensus clustering algorithm. Finally, highly expressed and highly methylated molecules regulated by METTL3 were analyzed and three (AVEN, DAZAP2, DNAJB1) genes were identified to be significantly associated with poor prognosis in GC patients. These results signified that METTL3-regulated DEPs in GC cells were significantly associated with OXPHOS. After combined with m6A microarray analysis, the results suggested that these proteins might be implicated in cell energy metabolism through m6A modifications thus influencing the prognosis of GC patients. Overall, our study revealed that METTL3 is involved in cell metabolism through an m6A-dependent mechanism in GC cells, and indicated a potential biomarker for prognostic prediction in GC.

Models for Predicting Response to Immunotherapy and Prognosis in Patients with Gastric Cancer: DNA Damage Response Genes.

Objective: DNA damage response (DDR) is a complex system that maintains genetic integrity and the stable replication and transmission of genetic material. m6A modifies DDR-related gene expression and affects the balance of DNA damage response in tumor cells. In this study, a risk model based on m6A-modified DDR-related gene was established to evaluate its role in patients with gastric cancer. Methods: We downloaded 639 DNA damage response genes from the Gene Set Enrichment Analysis (GSEA) database and constructed risk score models using typed differential genes. We used Kaplan-Meier curves and risk curves to verify the clinical relevance of the model, which was then validated with the univariate and multifactorial Cox analysis, ROC, C-index, and nomogram, and finally this model was used to evaluate the correlation of the risk score model with immune microenvironment, microsatellite instability (MSI), tumor mutational burden (TMB), and immune checkpoints. Results: In this study, 337 samples in The Cancer Genome Atlas (TCGA) database were used as training set to construct a DDR-related gene model, and GSE84437 was used as external data set for verification. We found that the prognosis and immunotherapy effect of gastric cancer patients in the low-risk group were significantly better than those in the high-risk group. Conclusion: We screened eight DDR-related genes (ZBTB7A, POLQ, CHEK1, NPDC1, RAMP1, AXIN2, SFRP2, and APOD) to establish a risk model, which can predict the prognosis of gastric cancer patients and guide the clinical implementation of immunotherapy.

Complementary protective effects of autophagy and oxidative response against graphene oxide toxicity in Caenorhabditis elegans.

Graphene oxide (GO) exposure may cause damage to C. elegans. However, the role of autophagy and its interactive effect with oxidative response in GO toxicity still remain largely unclear. In the present study, we investigated the protective role of autophagy against GO and its association with oxidative response using C. elegans as an in vivo system. Results indicated that GO exposure induced autophagy in a dose dependent manner in C. elegans. Autophagy inhibitor 3-methyladenine (3-MA) and silencing autophagy genes lgg-1, bec-1 and unc-51 exacerbated the toxicity of GO whereas autophagy activator rapamycin alleviated it. In addition, the antioxidant N-Acetyl-L-cysteine (NAC) effectively suppressed the toxicity of GO with increased resistance to oxidative stress. Worms with RNAi-induced antioxidative genes sod-1, sod-2, sod-3 and sod-4 knockdown were more sensitive to GO. 3-MA increased the expression of superoxide dismutase SOD-3 under GO exposure conditions and exacerbated the toxicity of GO under the anti-oxidation inaction condition by sod-3 RNAi. In contrast, NAC reduced autophagy levels in GO exposed nematodes and increased tolerance to GO in autophagy-defective worms. These results suggested that autophagy and antioxidative response provide complementary protection against GO in C. elegans.

Overexpression of TCERG1 as a prognostic marker in hepatocellular carcinoma: A TCGA data-based analysis.

Objective: Transcription elongation factor 1 (TCERG1) is a nuclear protein consisted of multiple protein structural domains that plays an important role in regulating the transcription, extension, and splicing regulation of RNA polymerase II. However, the prognostic and immunological role of TCERG1 in human cancer remains unknown. In this study, we analyzed the expression of TCERG1 gene in hepatocellular carcinoma (HCC) patients, its clinical significance, and its possible prognostic value by bioinformatics. Methods: RNA sequencing data and clinicopathological characteristics of patients with HCC were collected from TCGA and CCLE databases. The Wilcoxon rank-sum test was used to analyze the expression of TCERG1 in HCC tissues and normal tissues. The protein levels of TCERG1 between normal and liver cancer tissues were analyzed by the Human Protein Atlas Database (HPA) (www.proteinatlas.org). Validation was performed using the Gene Expression Omnibus (GEO) dataset of 167 samples. The expression of TCERG1 in HCC cells were verified by qRT-PCR, and CCK-8, scratch assay and Transwell assay were performed to detect cell proliferation, migration and invasion ability. According to the median value of TCERG1 expression, patients were divided into high and low subgroups. Logistic regression, GSEA enrichment, TME, and single-sample set gene enrichment analysis (ssGSEA) were performed to explore the effects of TCERG1 on liver cancer biological function and immune infiltrates. TCERG1 co-expression networks were studied through the CCLE database and the LinkedOmics database to analyze genes that interact with TCERG1. Results: The expression levels of TCERG1 in HCC patient tissues were significantly higher than in normal tissues. Survival analysis showed that high levels of TCERG1 expression were significantly associated with low survival rates in HCC patients. Multifactorial analysis showed that high TCERG1 expression was an independent risk factor affecting tumor prognosis. This result was also verified in the GEO database. Cellular experiments demonstrated that cell proliferation, migration and invasion were inhibited after silencing of TCERG1 gene expression. Co-expression analysis revealed that CPSF6 and MAML1 expression were positively correlated with TCERG1. GSEA showed that in samples with high TCERG1 expression, relevant signaling pathways associated with cell cycle, apoptosis, pathways in cancer and enriched in known tumors included Wnt signaling pathway, Vegf signaling pathway, Notch signaling pathway, MAPK signaling pathway and MTOR pathways. The expression of TCERG1 was positively correlated with tumor immune infiltrating cells (T helper two cells, T helper cells). Conclusion: TCERG1 gene is highly expressed in hepatocellular carcinoma tissues, which is associated with the poor prognosis of liver cancer, and may be one of the markers for the diagnosis and screening of liver cancer and the prediction of prognosis effect. At the same time, TCERG1 may also become a new target for tumor immunotherapy.

Identification and Validation of METTL3-Related Molecules for Predicting Prognosis and Efficacy of Immunotherapy in Gastric Cancer Based on m6A Methylome and Transcriptome Sequencing Analysis.

Abnormal N6-methyladenosine (m6A) modification levels caused by METTL3 have been identified to be a critical regulator in human cancers, and its roles in the immune microenvironment and the relationship between targeted therapy and immunotherapy sensitivity in gastric cancer (GC) remain poorly understood. In this study, we assessed the transcriptome-wide m6A methylation profile after METTL3 overexpression by m6A sequencing and RNA sequencing in BGC-823 cells. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to analyze the function of core targets of METTL3. Eighteen methylation core molecules were identified in GC patients by combining transcriptome and methylome sequencing. GC patients can be separated into two subtypes based on the expression of 18 methylation core molecules. Furthermore, subgroup analysis showed that patients with different subtypes had a different OS, PFS, stage, grade, and TMB. Gene set enrichment analysis (GSEA) showed that immune-related pathways were enriched among subtype A. The ESTIMATE analysis suggested that the extent of infiltration of immune cells was different in two subtypes of GC patients. Tumor Immune Dysfunction and Exclusion (TIDE) and The Cancer Immunome Atlas (TCIA) database also showed that there were significant differences in the efficacy of immunotherapy among different types of GC patients. Altogether, our results reveal that METTL3-mediated m6A methylation modification is associated with the immune microenvironment and the effects of immunotherapy in GC patients. Our findings provide novel insights for clinicians in the diagnosis and optimal treatment of GC patients.

GPC1 promotes the growth and migration of colorectal cancer cells through regulating the TGF-ß1/SMAD2 signaling pathway.

In this study, we analyzed GPC family genes in colorectal cancer (CRC) and the possible mechanism of action of GPC1 in CRC. CRC patient data were extracted from The Cancer Genome Atlas, and the prognostic significance of GPC1 expression and its association with clinicopathological features were identified by Kolmogorov-Smirnov test. CRC patients with high GPC1 expression had poor overall survival compared with patients with low GPC1 expression. In vitro experiments demonstrated that knockdown of GPC1 significantly inhibited the proliferation and migration and promoted cell apoptosis in CRC cell lines. Gene Ontology analysis of differential genes indicated that GPC1 may influence the TGF-ß1 signaling pathway. Additional experiments revealed that silencing GPC1 suppressed the levels of TGF-ß1 and p-SMAD2 but increased the expression of SMAD2. Taken together, these findings suggest that GPC1 may function as a tumor promoter in CRC cells through promoting TGF-ß signaling pathway. Our results also indicate that GPC1 may serve as a critical effector in CRC progression and a new potential target for CRC therapy.

m7G-Related DNA Damage Repair Genes are Potential Biomarkers for Predicting Prognosis and Immunotherapy Effectiveness in Colon Cancer Patients.

Objective: m7G is a post-transcriptional modification modality, however, limited research has been conducted on its role in colon cancer. DNA damage repair (DDR) is an important factor that contributes to colon cancer development, growth and chemoresistance. This study aimed to explore whether m7G-related DNA damage repair genes may be used as biomarkers to predict the prognosis of colon cancer patients. Methods: We use non-negative matrix factorization (NMF) to type CRC patients into. Risk models were constructed using different expression genes in two clusters. We assessed the reliability of risk models with DCA curves, and a Nomogram. Meanwhile, The receiver operating characteristic and C-index curves were used to compare the predictive significance of the constructed risk models with other studies. In additional, we examined the significance of risk models on patients' immunity microenvironment and response to immune therapy. Finally, we used a series of cellular experiments to validate the effect of model genes on the malignant progression of CRC cells. Results: Twenty-eight m7G genes were obtained from the GSEA database. Multivariate Cox and LASSO Cox regression analysis was performed and eleven m7G-related DDR genes were identified for constructing the risk model. Survival and stage of CRC patients were worser in the high-risk group than in the low-risk group for both the training and test sets. Additionally, the different immune microenvironment status of patients in the high- and low-risk groups, suggesting that patients in the low-risk group may be more sensitive to immunotherapy, particularly immune checkpoint inhibitors. Finally, we found that depletion of ATP2A1, one of the risk genes in our model, influence the biologic behaviour of CRC cells significantly. Conclusion: The m7G-related DDR genes can be used as important markers for predicting patient prognosis and immunotherapy response. Our data suggest that ATP2A1 may promote the proliferation of colon cancer cells. These findings may provide new therapeutic targets for the treatment of colon cancer.

Associations between academic burnout, resilience and life satisfaction among medical students: a three-wave longitudinal study.

BACKGROUND: Research shows that there are connections among academic burnout, resilience, and life satisfaction in medical students. However, no study has yet examined the temporal relationships between academic burnout, resilience, and life satisfaction among medical students. This longitudinal study aimed to examine the temporal associations between academic burnout, resilience, and life satisfaction and to explore the possible mediating role of resilience in the relationship between academic burnout and life satisfaction among medical students. METHODS: This is a three-wave longitudinal study covering the preclinical education period of 20 months. From October 2018 to June 2020, a total of 190 students majoring in clinical medicine filled out the Chinese College Student Academic Burnout Inventory (CCSABI), the Connor-Davidson Resilience Scale (CD-RISC) and the Satisfaction With Life Scale (SWLS) three times. Cross-lagged models were constructed to examine the temporal relationships between academic burnout, resilience, and life satisfaction and longitudinal mediation models were constructed to explore the possible mediating role of resilience in the association of academic burnout with life satisfaction. RESULTS: Among medical students, resilience uni-directionally and positively predicted life satisfaction, while academic burnout uni-directionally and negatively predicted life satisfaction. However, the temporal association between resilience and academic burnout was negative and somewhat bidirectional. Resilience had a significant mediating effect on the relationship between academic burnout and life satisfaction in medical students. CONCLUSIONS: Medical educators need to identify and take effective measures to combat academic burnout problems which can lead to reduced life satisfaction among medical students. Resilience-based interventions may be promising in buffering the negative impacts of academic burnout and improving life satisfaction. It is recommended that effective resilience-promotion interventions be developed and implemented in medical education to help enhance medical students' psychological well-being.

Associations of Chinese diagnosis-related group systems with inpatient expenditures for older people with hip fracture.

BACKGROUND: Hip fracture is frequent in older people and represents a major public health issue worldwide. The increasing incidence of hip fracture and the associated hospitalization costs place a significant economic burden on older patients and their families. On January 1, 2018, the Chinese diagnosis-related group (C-DRG) payment system, which aims to reduce financial barriers, was implemented in Sanming City, southern China. This study aimed to evaluate the associations of C-DRG system with inpatient expenditures for older people with hip fracture. METHODS: An uncontrolled before-and-after study employed data of all the patients with hip fracture aged 60 years or older from all the public hospitals enrolled in the Sanming Basic Health Insurance Scheme from January 1, 2016 to December 31, 2018. The 'pre C-DRG sample' included patients from January 1, 2016 to December 31, 2017. The 'post C-DRG sample' included patients from January 1, 2018 to December 31, 2018. A propensity score matching analysis was used to adjust the difference in baseline characteristic parameters between the pre and post samples. Data were analyzed using generalized linear models adjusted for the demographic, clinical, and institutional factors. Robust tests were performed by accounting for time trend, the fixed effects of the year and hospitals, and clustering effect within hospitals. RESULTS: After propensity score matching, we obtained two homogeneous groups of 1123 patients each, and the characteristic variables of the two matched groups were similar. We found that C-DRG reform was associated with a 19.51% decrease in out-of-pocket (OOP) payments (p < 0.001) and a 99.93% decrease in OOP payments as a share of total inpatient expenditure (p < 0.001); whereas total inpatient expenditure was not significantly associated with the C-DRG reform. All the sensitivity analyses did not change the results significantly. CONCLUSION: The implementation of C-DRG payment system reduced both the absolute amount of OOP payments and OOP payments as a share of total inpatient expenditure for older patients with hip fracture, without affecting total inpatient expenditure. These results may provide significant insights for policymakers in reducing the financial burden on older patients with hip fracture in other countries.

Unbalanced Treatment Costs of Breast Cancer in China: Implications From the Direct Costs of Inpatient and Outpatient Care in Liaoning Province.

BACKGROUND: The increasing incidence of breast cancer and its financial burden highlights the need for controlling treatment costs. This study aimed to assess the direct costs of inpatient and outpatient care for breast cancer patients in Liaoning Province to provide a policy reference for cost containment. METHODS: Based on the System of Health Accounts 2011 (SHA 2011), systematic data collection was conducted via multistage stratified cluster random sampling. A total of 1160 health institutions, including 83 hospitals, 16 public health institutions, 120 primary health institutions, and 941 outpatient institutions were enrolled in 2017. A database was established containing 20 035 patient-level medical records from the information system of these institutions. Curative care expenditure (CCE)was calculated, and generalized linear modeling was performed to determine cost-related factors. RESULTS: In 2017, the CCE for breast cancer was approximately CNY 830.19 million (US$122.96 million) in Liaoning province (0.7% of the total health expenditure and 9.9% of cancer-related healthcare costs). Inpatient care costs were estimated to be CNY 617.27 million (US$91.42 million), accounting for 74.4% of the CCE for breast cancer, almost three times as large as outpatient costs (25.6%). The average inpatient and outpatient costs for breast cancer were estimated to be CNY 12 108 (US$1793) and CNY 829 (US$123) per visit. Medication cost was the main cost driver, which comprised 84.0% of the average outpatient cost and 37.2% of the mean inpatient cost. CONCLUSION: Breast cancer imposes a large economic burden on patients and the social health insurance system. Results show an irrational cost pattern of inpatient and outpatient services, with patients relying excessively on inpatient services for treatment. Promoting outpatient care whenever relevant is conducive to cost containment and rational utilization of resources.

LINC02381 aggravates breast cancer through the miR-1271-5p/FN1 axis to activate PI3K/AKT pathway.

Emerging investigations have demonstrated that lncRNAs are key crucial modulators in cancer. In this study, we investigated the role of LINC02381 in breast cancer (BC). Reverse transcriptase quantitative polymerase chain reaction measured the LINC02381 level in BC tissues and cells. Colony formation, EdU staining, wound healing and Transwell experiments examined the impact of LINC02381 depletion on BC cell phenotypes. Relationship among miR-1271-5p, LINC02381, and FN1 was tested through applying RIP, luciferase reporter, and RNA pull-down assays. We found that LINC02381 expression was elevated in BC. Functionally, LINC02381 knockdown hampered BC cell proliferation, migration, and invasion. LINC02381 overexpression accelerated tumor formation in vivo. Mechanistically, LINC02381 acted as a ceRNA to increase FN1 via decoying miR-1271-5p. Additionally, LINC02381 activated PI3K/AKT pathway by upregulating FN1. Rescue assays indicated that FN1 upregulation or PI3K/AKT activation rescued the LINC02381 knockdown-mediated inhibition on malignant phenotypes of BC cells. Overall, LINC02381 exerts carcinogenic effects in BC by the miR-1271-5p/FN1 axis to activate PI3K/AKT pathway.

Sublethal toxicity of graphene oxide in Caenorhabditis elegans under multi-generational exposure.

Nanomaterials have received increasing attentions owing to their potential hazards to the environment and human health; however, the multi-generational toxicity of graphene oxide under consecutive multi-generational exposure scenario still remains unclear. In the present study, Caenorhabditis elegans as an in vivo model organism was employed to explore the multi-generational toxicity effects of graphene oxide and the underlying mechanisms. Endpoints including development and lifespan, locomotion behaviors, defecation cycle, brood sizes, and oxidative response were evaluated in the parental generation and subsequent five filial generations. After continuous exposure for several generations, worms grew smaller and lived shorter. The locomotion behaviors were reduced across the filial generations and these reduced trends were following the impairments of locomotion-related neurons. In addition, the extended defecation cycles from the third filial generation were in consistency with the relative size reduction of the defecation related neuron. Simultaneously, the fertility function of the nematode was impaired under consecutive exposure as reduced brood sizes and oocytes numbers, increased apoptosis of germline, and aberrant expression of reproductive related genes ced-3, ced-4, ced-9, egl-1 and ced-13 were detected in exposed worms. Furthermore, the antioxidant enzyme, SOD-3 was significantly increased in the parent and filial generations. Thus, continuous multi-generational exposure to graphene oxide caused damage to the neuron development and the reproductive system in nematodes. These toxic effects could be reflected by indicators such as growth inhibition, shortened lifespan, and locomotion behavior impairment and induced oxidative response.

Diversified demand for health tourism matters: From a perspective of the intra-industry trade.

Previous studies on health tourism were limited to a small range of topics related to medical tourism. At present, the concept of health tourism has become profound because medical care has been altered from "disease-centered" to "health-centered". The main purpose of this study is to identify the key factors influencing the development of health tourism in China. To this end, in the first stage, an intra-industry trade theory was introduced and quantitative methods were applied to discover the important factors. In the second stage, multiple sources, including empirical studies, official data, research reports, and notably field investigations and case studies were incorporated to take in-depth discussions. The results indicated the foremost factors affecting the health tourism trade were total health expenditure per capita and the number of domestic health consumers. Notably, health tourism was substantially determined by the "willingness to spend on health" of domestic health consumers. In addition, Chinese health tourists were more likely to positively accept health tourism services in China. An important conclusion is that China should diversify health tourism offerings for different consumer groups. Once diversified products for health tourism are provided, the number of health tourism consumers will soar accordingly, which thus contributes to forming economies of scale, lowering the average costs of health treatment, increasing health tourism profit, and stimulating economic development.

Cost-Effectiveness Analysis of Pembrolizumab Plus Pemetrexed and Platinum Versus Chemotherapy Alone as First-Line Treatment in Metastatic Non-Squamous Non-Small Cell Lung Cancer: A Reconstruction of Partitioned Survival Model Based on Time Dependent Pricing Mechanism of Patient Assistance Program.

OBJECTIVES: A new patient assistance program (PAP) for pembrolizumab was started in China in 2021. The researchers aimed to evaluate the economic outcomes of pembrolizumab plus pemetrexed and platinum versus chemotherapy alone in the first-line treatment of patients with metastatic non-squamous non-small cell lung cancer, based on the pricing mechanism of PAP. MATERIAL AND METHODS: Survival analysis and partitioned survival model were performed to evaluate the incremental cost-effectiveness ratio (ICER) in the pembrolizumab group compared with the chemotherapy group. Survival probabilities were extracted from the data of the KEYNOTE-189 trial. Cost and utility data were gathered from published literature. The pricing mechanism of PAP was set in each cycle in the partitioned survival model, according to the progression-free survival (PFS) data of the KEYNOTE-189 trial, which included PFS-1 and PFS-2. Deterministic sensitivity analysis and probabilistic sensitivity analysis were conducted. RESULTS: The ICER of the pembrolizumab group versus chemotherapy group was $65,272/quality-adjusted life year (QALY), which still exceeded the willingness-to-pay threshold of three times per capita gross domestic product (GDP) of China ($33,581.22), although PAP was calculated. Sensitivity analysis implied that the price of chemotherapeutic drugs combined with pembrolizumab was one of the main influencing factors of ICER. CONCLUSIONS: Due to various prices set by PAP and the payment for combined chemotherapy, the economic advantage of pembrolizumab plus chemotherapy in the first-line treatment of non-small cell lung cancer (NSCLC) is still not achieved in China.