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Abstract Mouse models are crucial for understanding pulmonary hypertension (PH) mechanisms and developing therapies, but existing mouse models under hypoxia only exhibit mild PH. To address this, we established a double‐hit model combining unilateral pneumonectomy (LPx) or left pulmonary artery ligation (LPAL) with hypoxia exposure in C57BL/6 mice. Our detailed haemodynamic and histological evaluations post‐surgery demonstrated pronounced elevations in right ventricular systolic pressure (RVSP) (LPAL: 41.1 ± 4.63 mmHg, P = 0.005; LPx: 38.4 ± 2.95 mmHg, P = 0.002; Sham: 32.1 ± 2.21 mmHg) and pulmonary vascular wall thickness (LPAL: 56.9 ± 3.34%, P = 0.02; LPx: 54.3 ± 4.65%, P = 0.04; Sham: 44.8 ± 3.76%) compared to hypoxia‐exposed sham‐operated controls, reflecting a more severe PH phenotype. These novel models, which exhibit haemodynamic alterations akin to the established hypoxia with SU5416‐induced PH model as per published data, could offer a substantial contribution to future PH research and therapeutic development.

Abstract High-power inductors are fundamental components in high-power DC–DC converters, with their performance being a crucial metric of converter efficiency. This paper presents an in-depth analysis of a novel calculation method for the air gap length in such inductors. Taking into account the effects of air gap diffusion and the winding magnetic field, an expression for the air gap diffusion radius is derived, focusing on a distributed air gap structure. Furthermore, models for calculating the air gap and winding reluctance are developed, grounded in electromagnetic field theory. An equivalent magnetic circuit model, formulated based on Kirchhoff's second law, facilitates the proposed method for air gap length calculation. This study also involves the development of 3D models for both discrete and decoupled integrated inductors. The comparison between simulation outcomes and calculated air gap lengths indicates a maximum error of less than 8%, with the minimum error being as low as − 0.79%. Compared with traditional methods, the calculation method proposed in this paper has significant advantages. Additionally, the discrepancy between calculated values and experimental measurements is found to be 1.11%. These results validate the accuracy and applicability of the theoretical analysis and calculation method, underscoring their significance in the design and optimization of high-power DC–DC converters.

This investigation was conducted to examine the effect of the designed composite agent (DCA) on the shrinkage performance of the concrete high-volume natural pozzolans (PHVNC). Based on an economic-cost analysis, it was determined that natural pozzolans (NP) were a suitable replacement for fly ash (FA) in the production of sustainable concrete for high-speed railway concrete slab track design. The results confirmed that the inclusion of DCA effectively improved the early-age shrinkage performance of PHVNC with 30% or 50% NP content. As a result, the concrete containing high-volume NP and DCA (PHVNDC) exhibited a smaller crack density compared to PHVNC, and even outperformed concrete with a high volume of FA (PHVFC). In terms of the effect of DCA on the drying shrinkage performance of mixes containing NP, a similar trend was observed, where the mixes that included both NP and DCA exhibited lower levels of dry shrinkage and mass loss at 28 days compared to mixes with either NP or FA. The results from phase transformation and microstructure analysis further indicated that adding DCA can enhance the mechanical and shrinkage performance of the mixes containing high-volume NP. This enhancement is attributed to the optimization of the hydration reaction rate, increased production of hydration products, and an overall improvement in the microstructure performance of the mixes with NP. Hence, DCA can serve as a valuable support in preserving the characteristics of NP-based mixtures, making it a valuable discovery for implementing high-volume NP in practical engineering projects with abundant NP resources.

ObjectiveTo determine the cost-effectiveness of imported immune checkpoint inhibitors (ICIs) such as atezolizumab and durvalumab, and domestic ICIs like serplulimab and adebrelimab, in combination with chemotherapy for extensive-stage small cell lung cancer (ES-SCLC) in China.MethodsUsing a 21-day cycle length and a 20-year time horizon, a Markov model was established to compare the clinical and economic outcomes of five first-line ICIs plus chemotherapy versus chemotherapy alone, as well as against each other, from the perspective of the Chinese healthcare system. Transition probabilities were estimated by combining the results of the CAPSTONE-1 trial and a published network meta-analysis. Cost and health state utilities were collected from multiple sources. Both cost and effectiveness outcomes were discounted at a rate of 5% annually. The primary model output was incremental cost-effectiveness ratios (ICERs). A series of sensitivity analyses were preformed to assess the robustness of the model.ResultsIn the base-case analysis, the addition of first-line ICIs to chemotherapy resulted in the ICERs ranged from $80,425.31/QALY to $812,415.46/QALY, which exceeded the willing-to-pay threshold set for the model. When comparing these first-line immunochemotherapy strategies, serplulimab plus chemotherapy had the highest QALYs of 1.51286 and the second lowest costs of $60,519.52, making it is the most cost-effective strategy. Our subgroup-level analysis yielded results that are consistent with the base-case analysis. The sensitivity analysis results confirmed the validity and reliability of the model.ConclusionIn China, the combination of fist-line ICIs plus chemotherapy were not considered cost-effective when compared to chemotherapy alone. However, when these fist-line immunochemotherapy strategies were compared with each other, first-line serplulimab plus chemotherapy consistently demonstrated superiority in terms of cost-effectiveness. Reducing the cost of serplulimab per 4.5 mg/kg would be a realistic step towards making first-line serplulimab plus chemotherapy more accessible and cost-effective.

Background and aim: Triple-negative breast cancer (TNBC) is a highly invasive type of breast cancer with a poor prognosis. Currently, there are no effective management strategies for TNBC. Earlier, our lab reported the percolation of Spatholobus suberectus for the treatment of breast cancer. Lipid metabolic reprogramming is a hallmark of cancer. However, the anti-TNBC efficiency of S. suberectus extract and its causal mechanism for preventing lipogenesis have not been fully recognized. Hence, the present study aimed to investigate the inhibitory role of S. suberectus extract on lipogenesis and tumorigenesis in TNBC in vitro and in vivo by activating AMPK-ACC and K-Ras-ERK signaling pathways using lipidomic and metabolomic techniques. Experimental procedure: Dried stems of S. suberectus extract inhibited lipogenesis and tumorigenesis and promoted fatty acid oxidation as demonstrated by the identification of the metabolites and fatty acid markers using proteomic and metabolomic analysis, qPCR, and Western blot. Results and conclusion: The results indicated that S. suberectus extract promotes fatty acid oxidation and suppresses lipogenic metabolites and biomarkers, thereby preventing tumorigenesis via the AMPK-ACC and K-Ras-ERK signaling pathways. On the basis of this preclinical evidence, we suggest that this study represents a milestone and complements Chinese medicine. Further studies remain underway in our laboratory to elucidate the active principles of S. suberectus extract. This study suggests that S. suberectus extract could be a promising therapy for TNBC.

Abstract Background Right heart failure (RHF) is a complication of pulmonary hypertension (PH) and increases the mortality independently of the underlying disease. However, the process of RHF development and progression is not fully understood. We aimed to develop effective approaches for early diagnosis and precise evaluation of RHF. Methods Right ventricle (RV) pressure overload was performed via pulmonary artery banding (PAB) surgery in Sprague–Dawley (SD) rats to induce RHF. Echocardiography, right heart catheterization, histological staining, fibroblast activation protein (FAP) immunofluorescence and 18 F-labelled FAP inhibitor-42 ([18 F] -FAPI-42) positron emission tomography/computed tomography (PET/CT) were performed at day 3, week 1, 2, 4 and 8 after PAB. RNA sequencing was performed to explore molecular alterations between PAB and sham group at week 2 and week 4 after PAB respectively. Results RV hemodynamic disorders were aggravated, and RV function was declined based on right heart catheterization and echocardiography at week 2, 4 and 8 after PAB. Progressive cardiac hypertrophy, fibrosis and capillary rarefaction could be observed in RV from 2 to 8 weeks after PAB. RNA sequencing indicated 80 upregulated genes and 43 downregulated genes in the RV at both week 2 and week 4 after PAB; Gene Ontology (GO) analysis revealed that fibrosis as the most significant biological process in the RV under pressure overload. Immunofluorescence indicated that FAP was upregulated in the RV from week 2 to week 8 after PAB; and [18 F] -FAPI-42 PET/CT revealed FAPI uptake was significantly higher in RV at week 2 and further increased at week 4 and 8 after PAB. Conclusion RV function is progressively declined with fibrosis as the most prominent molecular change after pressure overload, and [18 F] -FAPI-42 PET/CT is as sensitive and accurate as histopathology in RV fibrosis evaluation.

Graphene oxide (GO) has been generally accepted can improve the microstructure of concrete because it can promote cement hydration, this nano-enhancement strategy is valuable for improving the weak interfacial transition zone in recycled aggregate concrete (RAC). This paper review aims to provide a comprehensive understanding and comparison of the impact of GO on the performance and microstructure of RAC through various modification methods. Initially, the characteristics of GO and its utilization in preparing RAC are introduced. Subsequently, the effects of admixing GO on the performance of RAC and its roles within the RAC system are analyzed and discussed. Furthermore, an economic, environmental evaluation, and research limitations of GO-modified RAC are analyzed. Finally, the conclusions and potential research prospects for future investigations are outlined. The findings of this review have the potential to expand the understanding of GO-modified RAC and can serve as a source of inspiration for future research endeavors.

Background: The sustainability and generalizability of China’s dynamic zero-COVID strategy on eliminating SARS-CoV-2 transmission has casted doubt globally, mainly because it has exacted high social and economic cost. This study aimed to estimate the disease burden during the first wave of Omicron in China and compared the cost-effectiveness of implementing a Real-world strategy (adjusted dynamic zero-COVID strategy) with two simulated strategies (routine and stricter dynamic zero-COVID strategy) to inform appropriate strategies for COVID-19 pandemic control. Methods: A dynamic state-transition simulation model was developed to compare the health and cost outcomes between different dynamic zero-COVID strategies. Omicron-related healthcare costs were estimated from the societal perspective. Epidemiological parameter values were derived from data of real-world or generated by model calibration; costs and effectiveness parameter values were informed either by local data or published literature. The primary outcomes were total social cost, disability adjusted life-years (DALYs) and net monetary benefit (NMB). Deterministic sensitivity analyses (DSA) and scenario analyses were performed to assess the model robustness. Results: The first wave of Omicron in Shanghai resulted in 47,646 DALYs lost and 415 billion RMB losses. At a willingness-to-pay threshold of 173,630 RMB (the GDP per capita of Shanghai in 2021) per DALY saved, the Real-world strategy was considered as the most cost-effective strategy due to its highest NMB (−407 billion). Results from DSA confirmed the robustness of our findings. Conclusion: Our finding supported the Real-world strategy taken by the Shanghai Municipal Government between March 1 and May 21, 2022 to control the first wave of Omicron outbreak. Moreover, our results indicated that whether the Stricter dynamic zero-COVID strategy is worth implementing at the beginning of the COVID-19 outbreak mainly depended on the infection rate of COVID-19 among primary contacts. Our analysis provides important evidence to inform policy makers to make appropriate decisions regarding COVID-19 pandemic management.

Christella dentata (Forssk.) Brownsey & Jermy (Thelypteridaceae) is endemic to the tropical and subtropical regions of Africa, Asia, and Asia Pacific. In this study, the complete chloroplast genome sequence of C. dentata was assembled using next-generation sequencing data. The complete chloroplast genome was 151,662 bp in length and had a typical quadripartite structure, which consisted of a small single-copy region (21,776 bp) and a large single-copy region (82,624 bp) that were separated by a pair of inverted repeats (23,631 bp each). A total of 131 genes were predicted, including 89 protein coding (CDS), 34 tRNA, and eight rRNA genes. The overall GC content of the chloroplast genome was 42.48%. Based on the concatenated shared unique CDS sequence dataset, phylogenetic analysis using both the maximum-likelihood and the Bayesian inference methods revealed that C. dentata is placed within Thelypteridaceae and is closely related to Christella appendiculata. Such genetic information would be useful for studies on the evolution pattern in ferns. The availability of chloroplast genome sequence for the species also paves the way to resolving the complicated relationship among members of Christella.

Abstract The drilling and blasting method is widely used in tunnel engineering. The accompanying airblast may damage structures and annoy nearby occupants. The prediction of airblast overpressure (p oa) outside the tunnel is necessary to improve the safety of blasting works. A study of propagation characteristics of airblasts induced by tunnel blasting was carried out through experimental and numerical studies. The results indicate that the distributions of the p oa outside the tunnel were anisotropic, which does not conform to the decay law of an explosion in free-field. The propagation of airblasts induced by tunnel blasting is related to the airblast shape. The phenomenon that the p oa along the axial direction of the tunnel was higher than along other directions can be explained by the numerical results of the process of airblasts. The airblasts outside the tunnel traveled as a spherical wave, but the pressure was not uniformly distributed. After an airblast plane wave with high speed and high pressure inside the tunnel was transmitted out of the tunnel, its inertia strengthened the pressure in the axial direction. The airblast outside the tunnel is related to the propagation distance R out, the angle from the measurement to the tunnel axis α, and the pressure intensity p 0 at the tunnel portal. Subsequently, an ellipsoidal contour curve of the p oa outside the tunnel was plotted, and therefore a new prediction equation was validated by numerical results and field data. Finally, the newly proposed methodology guided the blast design.

Background Oral multikinase inhibitors and immune checkpoint inhibitors (ICIs) are effective for treating advanced hepatocellular carcinoma (aHCC) but may increase cost. This study compared the cost-effectiveness of oral multikinase inhibitors and ICIs in the first-line treatment of patients with aHCC. Methods A three-state Markov model was established to study the cost-effectiveness of drug treatment from the perspective of Chinese payers. The key outcomes in this study were total cost, quality-adjusted life years (QALYs), and the incremental cost-effectiveness ratio (ICER). Results The total costs and QALYs of sorafenib, sunitinib, donafenib, lenvatinib, sorafenib plus erlotinib, linifanib, brivanib, sintilimab plus IBI305, and atezolizumab plus bevacizumab were $9070 and 0.25, $9362 and 0.78, $33,814 and 0.45, $49,120 and 0.83, $63,064 and 0.81, $74,814 and 0.82, $81,995 and 0.82, $74083 and 0.85, and $104,188 and 0.84, respectively. The drug regimen with the lowest ICER was sunitinib ($551 per QALY), followed by lenvatinib ($68,869 per QALY). For oral multikinase inhibitors, the ICER of lenvatinib, sorafenib plus erlotinib, linifanib and brivanib compared with sunitinib was $779576, $1534,347, $1768,971, and $1963,064, respectively. For ICIs, sintilimab plus IBI305 is more cost effective than atezolizumab plus bevacizumab. The model was most sensitive to the price of sorafenib, the utility of PD, and the price of second-line drugs. Conclusion For oral multikinase inhibitors, the order of possible treatment options is sunitinib > lenvatinib > sorafenib plus erlotinib > linifanib > brivanib > donafenib. For ICIs, the order of possible treatment options is sintilimab plus IBI305 > atezolizumab plus bevacizumab.

Yinlan lipid regulatory capsule (YL) is a composite traditional Chinese medicine (TCM) new drug to alleviate hyperlipidemia, while its therapeutic mechanism in vivo was not clarified with nontargeted metabolomics investigation. An animal model was established in rats fed a high-fat diet, and their body weights, body mass index (BMI) and blood cholesterol levels were measured. Serum, liver and kidney tissue samples were also extracted for PXR-CYP3A4-ABCB1-FXR signaling pathway research using PCR and UHPLC–MS. The obtained plasma samples were analyzed by UHPLC-Q-TOF-MS metabolomic investigation, which revealed PXR-CYP3A4-related metabolites and changes induced by YL. Finally, the key metabolites were chosen as index components, and their levels in the serum, liver, small intestine and bile were used for simultaneous UHPLC–MS-MS determination. The results indicated that YL was effective in rebalancing blood TG and TC levels (compared to controls). With respect to the PXR-CYP3A4-ABCB1 pathway, as a result of YL’s effect, gene expression or activity of the two targets decreased significantly in both the liver and kidney. The same trend was observed in the serum samples mentioned above. Metabolomics screening and data revealed that 44 metabolites can be regarded as biomarkers related to hyperlipidemia, fatty acids synthesis, and body energy consumption, as well as synthesis, transportation and exertion of cholesterol. YL’s treatment focused on 26 of them, primarily bile acids, indicating that the antihyperlipidemic effect of this drug lies in its inhibitory activity of cholesterol metabolism. Subsequent analysis of those in vivo components revealed that significant increases (compared to the model group) occurred in the blood, liver, small intestine and bile in groups that received medium and high doses of YL (while the low dose was relatively unchanged). Those target components exhibit a close relationship with PXR and/or CYP3A4. The use of YL repressed PXR expression and subsequently decreased CYP3A4 activity. As a result, synthesis of related bile acids increased, while cholesterol levels decreased, consequently leading to the attenuation of hyperlipidemia. This study comprehensively investigated the antihyperlipidemia mechanism of YL based on its repression of PXR-CYP3A4 activity and related metabolite yield, establishing an accurate method for evaluating the therapeutic effect of YL.

Objective The perioperative chemotherapy with fluorouracil, leucovorin, oxaliplatin plus docetaxel (FLOT) was recommended by the Chinese Society of Clinical Oncology Guidelines for gastric cancer (2018 edition) for patients with resectable gastric or gastro-oesophageal junction adenocarcinoma (class IIA). However, the economic impact of FLOT chemotherapy in China remains unclear. The analysis aimed to compare the cost-effectiveness of FLOT versus epirubicin, cisplatin plus fluorouracil or capecitabine (ECF/ECX) in patients with locally advanced resectable tumours.Design We developed a Markov model to compare the healthcare and economic outcomes of FLOT and ECF/ECX in patients with resectable gastric or gastro-oesophageal junction adenocarcinoma. Costs were estimated from the perspective of Chinese healthcare system. Clinical and utility inputs were derived from the FLOT4 phase II/III clinical trial and published literature. Sensitivity analyses were employed to assess the robustness of our result. The annual discount rate for costs and health outcomes was set at 5%.Outcome measures The primary outcome of incremental cost-effectiveness ratios (ICERs) was calculated as the cost per quality-adjusted life years (QALYs).Results The base-case analysis found that compared with ECF/ECX, the use of FLOT chemotherapy was associated with an additional 1.08 QALYs, resulting in an ICER of US$851/QALY. One-way sensitivity analysis results suggested that the HR of overall survival and progression-free survival had the greatest impact on the ICER. Probabilistic sensitivity analysis demonstrated that FLOT was more likely to be cost-effective compared with ECF/ECX at a willingness-to-pay threshold of US$31 513/QALY.Conclusions For patients with locally advanced resectable tumours, the FLOT chemotherapy is a cost-effective treatment option compared with ECF/ECX in China.Trial registration number NCT01216644.

Abstract Aqueous Zn‐ion batteries (AZIBs) are regarded as a promising alternative to the widely used lithium‐ion batteries in large‐scale energy storage systems. The researches on the development of novel aqueous electrolyte to improve battery performance have also attracted great interest since the electrolyte is a key component for Zn2+ migration between cathode and anode. Herein, we briefly summarized and illuminated the recent development tendency of aqueous electrolyte for AZIBs, then deeply analyzed its existing issues (water decomposition, cathode dissolution, corrosion and passivation, and dendrite growth) and discussed the corresponding optimization strategies (pH regulation, concentrated salt solution, electrolyte composition design, and functional additives). The internal mechanisms of these strategies were further revealed and the relationships between issues and solutions were clarified, which could guide the future development of aqueous electrolytes for AZIBs.

The high-speed maglev train will be subjected to extremely obvious aerodynamic load and instantaneous aerodynamic impact during passing another train, which brings significant challenges to the train’s suspension stability and safe operation. It’s necessary to consider the influence of aerodynamic load and shock waves in the design of suspension control algorithms. Traditional proportion integration differentiation (PID) control cannot follow the change of vehicle parameters or external disturbance, which is easy to cause suspension fluctuation and instability. To improve the suspension stability and vibration suppression of the high-speed maglev train under aerodynamic load and impact, we design a siding mode controller introducing the primary suspension’s deformation to replace the aerodynamic load on the electromagnet. Furthermore, we establish the train’s dynamic simulation model with three vehicles and compare the designed controller and the PID controller for their performance in controlling the model suspension stability in the presence of the train operating in open air. Simulation results show that the sliding mode control (SMC) method proposed in this paper can effectively restrain the electromagnet fluctuation of the train under aerodynamic loads.

Objective: To assess the cost effectiveness of radium-223 dichloride for patients with metastatic castration-resistant prostate cancer (mCRPC) in China.Materials and methods: A Markov model was developed to estimate the long-term health and economic outcomes of radium-223 plus best standard care (BSC) treatment and BSC only for bone mCRPC patients over a lifetime horizon. The patients and interventions were modeled according to the ALSYMPCA trial. Costs were collected from a Chinese health system perspective. Utility values were derived from the published literature. The base-case model results were quality-adjusted life year (QALY), total cost, and incremental cost-utility ratio (ICUR). Uncertainty analyses were performed to assess the robustness of our conclusions.Results: Compared with the BSC arm, radium-223 achieved an excess 0.344 QALYs with an incremental cost of $29,459, resulting in an ICUR of $85,647 per QALY. The probability of Ra-223 being cost effective for the patients with bone mCRPC was sharply low (

ObjectiveSix anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKIs), including one domestic (ensartinib) and five imported ALK-TKIs (crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib), have been recommended as first-line treatments for advanced ALK-positive NSCLC in China. This study sought to examine the cost-effectiveness of these six novel therapies in Chinese patients.Material and methodsWe constructed a Markov model to compare the cost-effectiveness of the six ALK-TKIs as a first-line treatment for patients with advanced ALK-positive NSCLC from the perspective of the Chinese healthcare system. Transition probabilities were estimated by synthesizing data from the PROFILE 1,029 trial and a network meta-analysis. Health state utilities and costs were sourced from published literature, publicly available national databases, and local general hospitals. The robustness of model was assessed via deterministic sensitivity analyses and probabilistic sensitivity analyses.ResultsCompared with crizotinib, ensartinib achieved additional 0.12 quality-adjusted life-year (QALY) with marginal costs of $3,249, resulting in an incremental cost-effectiveness ratio (ICER) of $27,553/ QALY. When compared with ceritinib and brigatinib, ensartinib achieved additional 0.06 and 0.03 QALYs with substantially reduced costs. When compared with lorlatinib and alectinib, ensartinib was associated with a lower QALY and decreased total costs; the ICERs for lorlatinib and alectinib were $934,101/ QALY and $164,888/ QALY, respectively.ConclusionFor Chinese patients with advanced ALK-positive NSCLC, ensartinib was a cost-effective option compared with crizotinib, and was a dominant alternative to ceritinib and brigatinib. Although lorlatinib and alectinib were associated with prolonged survival compared with ensartinib, they were less cost-effective than ensartinib due to the overwhelming total costs.

ObjectiveTo compare the cost-effectiveness of undertaking low-dose computed tomography (LDCT) screening for early detection of lung cancer (LC) with different frequencies within the healthcare system of China, and estimate the additional national healthcare expenditure and five-year LC mortality associated with different screening frequencies.Material and methodsA Markov model was established using national LC epidemiological data from the Chinese Center for Disease Control and Prevention, demographic data from the Chinese Statistical Yearbook, and cost and effectiveness data mainly from the Cancer Screening Program in China. The model included thirty sex-specific screening strategies, which were classified by initial screening age (30, 35, 40, 45, and 50), and screening intervals (intervals at single time point, 1, 2, 5, 10, and 20 years). The main model outputs were incremental cost-effectiveness ratios (ICERs), additional national healthcare expenditure and five-year LC mortality.ResultsThe ICERs for LDCT screening strategies vs. non-screening strategy ranged from $16,086 per quality-adjusted life-year (QALY) to $3,675,491 per QALY in the male cohort, and from $36,624 per QALY to $5,943,556 per QALY in the female cohort. The annual increment national healthcare expenditures related to LDCT screening were varied from $0.25 to $13.39 billion, with the lower cost in the cohort with older screening ages and lower screening frequencies. More frequent screening with LDCT was associated with a greater reduction in LC death: an annual LDCT screening was linked to an estimated reduction in five-year LC death by 27.27–29.07%, while a one-off screening was linked to a reduction by 5.56–5.83%.ConclusionUnder a willingness-to-pay (WTP) threshold of three times the Chinese gross domestic product (GDP) per capita (US $37,654), annual screening with an initiating age at 50 was most cost-effective in both male and female cohorts. By taking into account both the national healthcare expenditures and the effect of LDCT screening, our study results support undertaking LDCT screening annually from 50 years old in general populations.

Objective: Domestic PD-1inhibitor tislelizumab has emerged as a promising treatment for Chinese patients with driver-negative advanced or metastatic non-small cell lung cancer (NSCLC). The purpose of our study to evaluate whether tislelizumab is cost-effective as a second- or third-line treatment for this population compared with docetaxel (conventional chemotherapy) and nivolumab (imported PD-1inhibitor), from the perspective of the Chinese healthcare system.Material and Methods: A Markov model with a 3-week Markov cycle and a 30-year time horizon was built to compare the cost-effectiveness of second- or third-line tislelizumab versus docetaxel and nivolumab. Transition probabilities, including disease progression, survival, and adverse events (AEs)-related treatment discontinuation event, were estimated from the clinical trials. Costs and health utilities were collected from local hospitals, public database and published literature.Results: Compared with docetaxel, tislelizumab provided an additional 0.33 quality-adjusted life-years (QALYs) (1.37 vs. 1.04 QALYs) at an incremental cost of $9,286 ($23,646 vs. $14,360) for Chinese patients with driver-negative advanced or metastatic NSCLC, resulting in an incremental cost-effectiveness ratio (ICER) of $27,959/QALY under the WTP threshold of $35,663/QALY used in the model. Compared with nivolumab, tislelizumab was associated with a lower cost ($23,646 vs. $59,447) and higher QALYs (1.37 vs. 1.20 QALYs), resulting in its dominance of nivolumab.Conclusion: From the perspective of the Chinese healthcare system, domestic PD-1inhibitor tislelizumab immunotherapy represents a cost-effective treatment strategy compared with conventional docetaxel chemotherapy and imported PD-1inhibitor nivolumab immunotherapy in the treatment of driver-negative advanced or metastatic NSCLC beyond the first-line setting. In the era of “Universal Medical Insurance System”, the rational use of domestic anticancer drugs guided by cost-benefit evidence would be an effective means to balance the limited expenditure of medical insurance fund and the growing demand for cancer treatments.

ObjectiveCurrent guidelines recommend the gastric cancer risk score scale (GCRSS) for screening in gastric cancer (GC) high-risk populations in China. This study aimed to estimate the clinical benefits, harms, cost, and cost-effectiveness of the GCRSS screening strategy from a Chinese healthcare system perspective.Materials and methodsUsing a microsimulation model, we evaluated 7 screening scenarios of the GCRSS with varying starting ages. We simulated 100,000 individuals from the age of 20 for each screening scenario. The main outcomes included GC incidence reduction, number of cause-specific deaths, costs, quality-adjusted life year (QALY), incremental cost-effectiveness ratio (ICER), and benefit-to-harm ratio. Deterministic and probabilistic sensitivity analyses were done to explore the robustness of model findings.ResultsScreening with the GCRSS strategy at the age of 40 years (40-GCRSS) provided the greatest reduction of GC incidence by 70.6%, with 7,374 GC deaths averted per 100,000 individuals and the lowest benefit-to-harm ratio of 0.392. Compared with no screening or previous less costly strategy, at a willingness-to-pay (WTP) threshold of $37,655 per QALY, the 40-GCRSS strategy was cost-effective, with ICERs of $12,586 and $29,115 per QALY, respectively. Results were robust across univariate and probabilistic sensitivity analyses. The 40-GCRSS strategy showed a 0.856 probability of being cost-effective at a $37,655 per QALY WTP threshold.ConclusionsThe findings suggest that the GCRSS strategy is effective and cost-effective in reducing the GC disease burden in China from a Chinese healthcare system perspective. Screening from the age of 40 would be the optimal strategy.

The transmembrane (TMEM) protein family is constituted by a large number of proteins that span the lipid bilayer. Dysregulation of TMEM protein genes widely occurs and is associated with clinical outcomes of patients with multiple tumors. Nonetheless, the significance of TMEM genes in the prognosis prediction of patients with osteosarcoma remains largely unclear. Here, we comprehensively analyzed TMEM protein family genes in osteosarcoma using public resources and bioinformatics methods. Prognosis-related TMEM protein family genes were identified by the univariate Cox regression analysis and were utilized to construct a signature based on six TMEM protein family genes (TMEM120B, TMEM147, TMEM9B, TMEM8A, TMEM59, and TMEM39B) in osteosarcoma. The prognostic signature stratified patients into high- and low-risk groups, and validation in the internal and external cohorts confirmed the risk stratification ability of the signature. Functional enrichment analyses of differentially expressed genes between high- and low-risk groups connected immunity with the prognostic signature. Moreover, we found that M2 and M0 macrophages were the most abundant infiltrated immune cell types in the immune microenvironment, and samples of the high-risk group showed a decreased proportion of M2 macrophages. Single-sample gene set enrichment analysis revealed that the scores of neutrophils and Treg were markedly lower in the high-risk group than these in the low-risk group in The Cancer Genome Atlas and GSE16091 cohorts. As for the related immune functions, APC co-inhibition and cytolytic activity exhibited fewer active levels in the high-risk group than that in the low-risk group in both cohorts. Of the six TMEM genes, the expression of TMEM9B was lower in the high-risk group than in the low-risk group and was positively associated with the overall survival of osteosarcoma patients. In conclusion, our TMEM protein family gene-based signature is a novel and clinically useful prognostic biomarker for osteosarcoma patients, and TMEM9B might be a potential therapeutic target in osteosarcoma.

Objective: To investigate the cost-effectiveness of adding Chinese-developed anti-PD-1 antibody tislelizumab to first-line pemetrexed-platinum chemotherapy in (1) a study population of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer (nsqNSCLC) and without known sensitizing EGFR mutations or ALK rearrangements and (2) its subgroups from the perspective of Chinese healthcare system.Material and Methods: Separate Markov models were constructed for the entire study population and its subgroups; 10,000 patients with locally advanced or metastatic nsqNSCLC and without driver gene mutations were simulated in the first-line tislelizumab plus pemetrexed-platinum (TPP) arm and first-line pemetrexed-platinum (PP) arm, respectively. Transition probabilities were extracted from the RATIONALE 304 trial. Public health state utilities and costs were obtained from published literature, public national databases, and local general hospitals. The main outputs were incremental cost-effectiveness ratios (ICERs). The ICERs were compared to a willingness-to-pay threshold of $35,663 per quality-adjusted life-years (QALYs) to determine the cost-effective treatment. Sensitivity analyses were employed to assess the uncertainty in the model.Results: For the entire patient population, first-line TPP versus PP use increased the effectiveness by 0.99 QALYs and healthcare costs by $28,749, resulting in an ICER of $28,749/QALY that was lower than the prespecified WTP threshold. For patient subgroups, first-line TPP conferred the greatest survival benefit in patients with PD-L1 expression ≥50%, followed by patients with liver metastasis and those who are current or former smokers. Overall, the ICERs for the first-line TPP versus PP ranged from $27,018/QALYs to $33,074/QALYs, which were consistently below the WTP threshold.Conclusion: For Chinese patients with locally advanced or metastatic nsqNSCLC who had no known sensitizing EGFR mutations or ALK rearrangements, adding the Chinese-developed anti-PD-1 antibody tislelizumab to the first-line pemetrexed-platinum chemotherapy was cost-effective regardless of their baseline characteristics.

The deterioration of environmental quality has attracted the attention of the Chinese government and the public. The Chinese government has delegated part of the power of environmental regulation to local governments. To fulfill the KPI, local governments tend to loosen environmental regulations to attract more settlement of enterprises, thus leading to an increasingly fierce local environmental regulation competition. The improvement of people’s living standards makes it possible for the public to participate in environmental regulation. This article seeks to carry out the empirical study to interpret the relationship between local environmental regulation competition, public participation, and enterprise location selection through a random effects (RE) spatial Durbin model with 29 provincial panel data in China from 2004 to 2017. The results show that the provincial spatial spillover effect of enterprise location selection is significant. More intensified local environmental regulation competition can attract more investment but may harm sustainable economic development. Active public participation can effectively avoid the excessive investment caused by local environmental regulation competition and sustain economic development. Therefore, we should establish and improve the local environmental prevention and regulation system and establish an information disclosure mechanism to ensure public participation. The local government’s environmental regulation and public participation mechanism should be effectively coordinated.

Objective: Pembrolizumab plus chemotherapy is recommended as the first-line treatment for advanced oesophageal cancer. The objective of this study is to evaluate the cost-effectiveness of pembrolizumab plus chemotherapy as first-line therapy for advanced oesophageal cancer from the healthcare system perspective in China.Methods: Based on the KEYNOTE-590 trial, a Markov model was constructed to estimate the cost and effectiveness of pembrolizumab plus chemotherapy and placebo plus chemotherapy, respectively. Total costs, life years (LYs), quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs) were calculated. One-way, probabilistic sensitivity analyses (PSA), and subgroup analyses were adapted to test the model robustness.Result: Compared with the placebo group, pembrolizumab group obtained an additional 1.05 QALY, but the cost was also increased by $121,478.76. The ICER was $115,391.84 per QALY gained, which was higher than the willingness-to-pay (WTP) of $31,304.31. The results of One-way sensitivity analyses showed that the ICER was sensitive to the hazard ratio of PFS and per cycle cost of pembrolizumab. At a WTP threshold of $31,304.31, the probability of pembrolizumab plus chemotherapy being cost-effective was 0%.Conclusion: From the perspective of China healthcare system, pembrolizumab plus chemotherapy as first-line treatment is not cost-effective for patients with advanced oesophageal cancer compared with placebo plus chemotherapy.

Objective: The objective of this study is to systematically review the economic evaluations of dapagliflozin in the treatment of patients with heart failure (HF) and describe their general and methodological features.Methods: This systematic review followed the PRISMA guidelines. MEDLINE/PubMed, Website Of Science, Embase, The Cochrane Library, ScienceDirect, CNKI, and Wanfang databases were searched to collect relevant studies, and the retrieval time ended on 31 October 2021. Articles on the economic evaluation of dapagliflozin in the treatment of heart failure were included. Secondary studies, incomplete economic indicators, and non-English-language and non-Chinese-language studies were excluded. Standard drug treatment was selected as the comparison. Basic characteristics, methods, and main results were extracted and analyzed systematically.Result: A total of eight studies were identified, and the overall quality was accepted, which were performed in nine developed countries (Austria, United States, Korea, Japan, Singapore, Spanish, Germany, and United Kingdom) and three developing countries (the Philippines, Thailand, and China). With the exception of the Philippines, the remaining countries considered that dapagliflozin was cost effective. In the analyses of all included studies, the incremental cost-effectiveness ratios were most sensitive to the cost of dapagliflozin, cardiovascular mortality, the duration of dapagliflozin effectiveness, and the probability of HF hospitalization.Conclusion: Dapagliflozin in the treatment of patients with heart failure with reduced ejection fraction was considered cost effective. Further studies are needed to evaluate the comprehensive value of dapagliflozin on HF.

Objective: To investigate whether LY01008, a locally developed bevacizumab biosimilar agent, is appropriate for widespread use among Chinese advanced or recurrent nonsquamous non-small cell lung cancer (NSCLC) patients, our current study was designed to evaluate the cost-effectiveness of first-line LY01008 combined with platinum-doublet chemotherapy versus chemotherapy alone from the perspective of the Chinese healthcare system.Material and Methods: This economic evaluation designed a Markov model to compare the healthcare cost and quality-adjusted life-year (QALY) of first-line LY01008 combined with chemotherapy versus first-line chemotherapy. Transition probabilities, including disease progression, survival, and adverse event (AE)-related discontinuation of first-line treatment, were estimated using data from the clinical trials. Costs and health utilities were derived from local databases, hospitals, and published literature. Our base case analysis and scenario analysis focused on the cost-effectiveness of chemotherapy combined with a clinical trial dosage (15 mg/kg every 3-week cycle) and a real-world dosage (7.5 mg/kg every 3-week cycle) of LY01008, respectively.Results: In the base case analysis, first-line LY01008 combined with chemotherapy was associated with an increase of 0.48 QALYs in effectiveness and an increase of CNY 189,988 (US$ 26,240) in healthcare costs compared with first-line chemotherapy, resulting an incremental cost-effectiveness ratio (ICER) of CNY 375,425 (US$ 54,430)/QALY. In the scenario analysis, first-line LY01008 combined with chemotherapy was associated with a mean healthcare cost of CNY 265,060 (US$ 38,429), resulting an ICER of CNY 221,579 (US$ 32,125/QALY) between first-line LY01008 combined with chemotherapy versus first-line chemotherapy. The parameters that determine the cost of LY01008 have the greatest impact on the cost-effectiveness results.Conclusion: From the perspective of the Chinese healthcare system, first-line LY01008 at a real-world dosage combined with chemotherapy is likely to represent a cost-effective strategy compared with first-line chemotherapy alone for Chinese advanced or recurrent nonsquamous NSCLC patients.

Purpose: The purpose of this study was to evaluate a cost-effectiveness analysis of hepatic arterial infusion chemotherapy with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX-HAIC) as the first-line treatment for patients with large unresectable hepatocellular carcinoma (HCC) compared with transarterial chemoembolization (TACE).Methods: A Markov model was constructed to simulate the first-line treatment, disease recurrence, and survival of patients with large unresectable HCC. Transition probabilities were based on clinical trial data. The costs and health utilities were derived from the public literature. The outputs were total cost, quality-adjusted life year (QALY), and incremental cost-effectiveness ratios (ICER). One-way and probabilistic sensitivity analyses were performed to examine model uncertainty. We also performed subgroup analyses.Results: The results of the base case analysis found that FOLFOX-HAIC increased overall costs by $9,381 and improved effectiveness by 1.01 QALYs compared with TACE. The one-way sensitivity analysis showed that the hazard ratio of progression-free survival and overall survival for FOLFOX-HAIC relative to TACE had the greatest impact on the ICER. Probabilistic sensitivity analysis found that the probability of FOLFOX-HAIC treatment being cost-effective was 99.54% at the willingness-to-pay threshold of $30,552/QALY. Patients in most subgroups favored FOLFOX-HAIC treatment because it had a more than 50% probability of being cost-effective than TACE, except for patients with negative hepatitis B infection.Conclusion: In conclusion, our study found that the FOLFOX-HAIC was a cost-effective option compared to TACE for patients with large unresectable HCC in China.

Objective: The ORIENT-32 clinical trial revealed that sintilimab plus bevacizumab biosimilar significantly improved the median progression-free survival and median overall survival (OS) compared with sorafenib. This analysis evaluated the cost-effectiveness of sintilimab plus bevacizumab biosimilar as a first-line treatment for unresectable hepatocellular carcinoma from the Chinese perspective of healthcare system.Materials and methods: A Markov model with three mutual health states was constructed to evaluate the economic outcome of sintilimab plus bevacizumab biosimilar. The model cycle was 21 days, and the simulation time horizon was a lifetime. The output parameters of the model were the total cost, life-year (LY), quality-adjusted LY (QALY), and incremental cost-effectiveness ratio (ICER). Sensitivity analyses were conducted to assess the robustness of the results.Results: The base-case results found that sintilimab plus bevacizumab biosimilar provided an improvement of 1.27 QALYs and 1.84 LYs compared with sorafenib, and the ICER was $23,352/QALY. The hazard ratio for OS had the greatest influence on the ICER. The probability of sintilimab plus bevacizumab biosimilar was 85% at willingness-to-pay thresholds of $30,552/QALY.Conclusion: The findings of this analysis suggested that sintilimab plus bevacizumab biosimilar was a cost-effective first-line therapy for patients with unresectable hepatocellular carcinoma.

In a humid environment, the stray current generated by subway operation will corrode the underground pipe network and the internal steel structure of the track plate, which will seriously affect the service life of the subway track plate and increase the maintenance cost later. Groundwater in subway projects mainly enters the concrete interior through capillary action and affects the concrete resistivity, and there is a lack of research on the mechanism of groundwater effect on concrete resistance. In this study, the variation of cement mortar resistivity with capillary water absorption time for cement mortar with different amounts of mineral admixtures (fly ash, ground-granulated blast furnace slag, and silica fume) was measured by the four-electrode method, and the mechanism of the influence of the electrical properties of cementitious materials under the effect of capillary water absorption was analyzed based on the mercury-pressure method (MIP) and thermogravimetric method (TG-DTG). The results show that with the increase in capillary water absorption time, the change curve of cement mortar resistivity can be divided into two stages; in the first stage, capillary water absorption leads to gel pores and transition pores quickly connecting to capillary pores and other large pores to form a water-saturated conductive pathway, resulting in a rapid decrease in resistivity, when the gel pores and excessive pores have a greater impact on resistivity. The second stage is that of capillary water absorption, to a certain extent, after the specimen’s internal water upward development rate slows down; at this time, the formation speed of the conductive pathway decreases, resulting in the rate of change in resistivity decreasing and gradually stabilizing. The incorporation of silica fume can effectively improve the resistivity of cementitious materials under the action of capillary water absorption, in which the resistivity of specimens incorporated with 15% silica fume after 36 days of capillary water absorption is 10.39 times that of the reference group, which is mainly due to its lower porosity and a higher percentage of gel pores.

Objective To compare the cost-effectiveness of the combination of pembrolizumab and chemotherapy (Pembro+Chemo) versus pembrolizumab monotherapy (Pembro) as the first-line treatment for metastatic non-squamous and squamous non-small-cell lung cancer (NSCLC) with PD-L1expression ≥50%, respectively, from a US health care perspective.Material and Methods A comprehensive Makrov model were designed to compare the health costs and outcomes associated with first-line Pembro+Chemo and first-line Pembro over a 20-years time horizon. Health states consisted of three main states: progression-free survival (PFS), progressive disease (PD) and death, among which the PFS health state was divided into two substates: PFS while receiving first-line therapy and PFS with discontinued first-line therapy. Two scenario analyses were performed to explore satisfactory long-term survival modeling.Results In base case analysis, for non-squamous NSCLC patients, Pembro+Chemo was associated with a significantly longer life expectancy [3.24 vs 2.16 quality-adjusted life-years (QALYs)] and a substantially greater healthcare cost ($341,237 vs $159,055) compared with Pembro, resulting in an ICER of $169,335/QALY; for squamous NSCLC patients, Pembro+Chemo was associated with a slightly extended life expectancy of 0.22 QALYs and a marginal incremental cost of $3,449 compared with Pembro, resulting in an ICER of $15,613/QALY. Our results were particularly sensitive to parameters that determine QALYs. The first scenario analysis yielded lower ICERs than our base case results. The second scenario analysis founded Pembro+Chemo was dominated by Pembro.Conclusion For metastatic non-squamous NSCLC patients with PD-L1 expression ≥50%, first-line Pembro+Chemo was not cost-effective when compared with first-line Pembro. In contrast, for the squamous NSCLC patient population, our results supported the first-line Pembro+Chemo as a cost-effective treatment. Although there are multiple approaches that are used for extrapolating long-term survival, the optimal method has yet to be determined.

Objective: Three immune checkpoint inhibitors (ICIs), pembrolizumab, atezolizumab and cemiplimab, have been successively approved as first-line treatments for advanced non-small-cell lung cancer (NSCLC) patients with programmed cell death ligand 1(PD-L1) expression of at least 50%. This study was designed to compare the cost-effectiveness of these three novel therapies in this patient population.Material and Methods: Using Markov model and network meta-analysis, we conducted separate cost-effectiveness analyses for cemiplimab, pembrolizumab and atezolizumab among advanced NSCLC patients with PD-L1 of at least 50% from the United States health care sector perspective. Health states included progression-free survival, progressive disease, end-stage disease, and death. Clinical efficacy and safety data were derived from phase III clinical trials and health state utilities and costs data were collected from published resources. Two scenario analyses were conducted to assess the impact of varying subsequent anticancer therapies on the cost-effectiveness of these 3 ICIs and cost-effectiveness of pembrolizumab combined with chemotherapy versus these 3 first-line ICI monotherapies.Results: In base case analysis, cemiplimab compared with pembrolizumab was associated with a gain of 0.44 quality-adjusted life-years (QALYs) and an increased cost of $23,084, resulting in an incremental cost-effectiveness ratio (ICER) of $52,998/QALY; cemiplimab compared with atezolizumab was associated with a gain of 0.13 QALYs and a decreased cost of $104,642, resulting in its dominance of atezolizumab. The first scenario analysis yielded similar results as our base case analysis. The second scenario analysis founded the ICERs for pembrolizumab plus chemotherapy were $393,359/QALY, $190,994/QALY and $33,230/QALY, respectively, compared with cemiplimab, pembrolizumab and atezolizumab.Conclusion: For advanced NSCLC patients with PD-L1 of at least 50%, cemiplimab was a cost-effective option compared with pembrolizumab and a dominant alternative against atezolizumab. Our scenario analysis results supported the cemiplimab plus chemotherapy as a second-line therapy and suggested an extended QALY but overwhelming cost linking to pembrolizumab plus chemotherapy.

ObjectiveOur previous economic assessment found that nivolumab was not cost-effective for Chinese patients with advanced non-small cell lung cancer (NSCLC) and without EGFR mutations or ALK translocations, when compared with the standard second-line drug docetaxel. However, a greater survival benefit with nivolumab was observed for patients with 1% or greater tumor programmed death ligand 1 (PD-L1) expression. In view of this, we designed the present analysis to explore whether it is cost-effective to use the PD-L1 test to guide second-line nivolumab treatment in China.Material and MethodsA Markov model was established to project the lifetime costs and quality-adjusted life-years (QALYs) of three second-line treatment strategies: nivolumab and docetaxel (strategies without a PD-L1 test) and PD-L1 test-based strategy. Deterministic and probabilistic sensitivity analyses were performed to examine the robustness of our results. Additional price reduction and willingness-to-pay (WTP) threshold scenario analyses were performed to explore the impact of economic and health policies with Chinese characteristics on our results.ResultsThe PD-L1 test-based strategy costs approximately CNY 194,607 (USD 28,210) or more and yielded an additional 0.27 QALYs compared to the docetaxel strategy without a PD-L1 test, equating an incremental cost-effectiveness ratio (ICER) of CNY 731,089 (USD 105,978)/QALY. Deterministic sensitivity analyses showed that the price of nivolumab was the strongest source of variation in the ICERs. Probability sensitivity analysis showed that the probability for the PD-L1 test-based strategy being cost-effective increases with the increase of WTP thresholds.ConclusionFrom the perspective of the Chinese healthcare system, using a PD-L1 test to guide second-line nivolumab treatment was not cost-effective. The National Healthcare Security Administration negotiation on the price reduction of nivolumab was found to be the most effective action to improve its cost-effectiveness in China.

Objective: Camrelizumab is the first domestic PD-1inhibitor approved to be combined with chemotherapy as a first-line therapy for advanced nonsquamous non–small-cell lung cancer (NSCLC) in China. The purpose of this study was to determine whether using camrelizumab in the first-line setting is cost-effective in China when compared with traditional chemotherapy or the imported PD-1inhibitor pembrolizumab.Material and Methods: A Markov model was built to simulate 3-week patient transitions over a 30-year horizon from the perspective of the Chinese healthcare system. Health states included stable disease, first progression, second progression, and death. A direct comparison between first-line camrelizumab in combination with pemetrexed and carboplatin (CPC) and pemetrexed plus carboplatin (PC) was performed by calculating transition probabilities from the CameL trial. An indirect comparison between first-line CPC and pembrolizumab in combination with pemetrexed and platinum (PPP) was performed by calculating transition probabilities using a network meta-analysis. Costs in the Chinese setting were collected from the local public database and literatures. Sensitivity analyses explored the uncertainty around model parameters.Results: In the primary analysis, first-line CPC gained an additional 0.41 quality-adjusted life-years (QALYs) with an incremental cost of $3,486 compared with PC, resulting in an incremental cost-effectiveness ratio (ICER) of $8,378 per QALY gained. In the secondary analysis, first-line PPP yielded an additional 0.10 QALYs at an incremental cost of $6,710, resulting in an ICER of $65,563 per QALY gained.Conclusion: For Chinese patients with advanced nonsquamous NSCLC without targetable genetic aberrations, our primary analysis results supported first-line CPC as a cost-effective treatment compared with traditional PC chemotherapy. The findings of our secondary analysis suggested that first-line PPP would not be a cost-effective option compared with first-line CPC. This analysis provided strong evidence for promoting the widespread use of first-line CPC in China and, to some extent, stimulated the enthusiasm for the development of domestic cancer drugs.

ObjectiveThe use of ipilimumab plus anti-PD-1 has recently been shown to significantly improve the survival of patients with metastatic melanoma resistant to anti-PD-(L)1 monotherapy. The study assessed the cost-effectiveness of ipilimumab plus anti-PD-1 therapy in this population from the US payer perspective.Materials and MethodsA Markov model was created based on a retrospective analysis of patients with metastatic melanoma who were resistant to anti-PD-(L)1. Cost information was obtained from the Centers for Medicare and Medicaid Services and literature-based costs. The utility value was derived from the published literature. The results of the model was the total cost, quality-adjusted life-year (QALY), and incremental cost-effectiveness ratio (ICER). The uncertainty of the model was addressed through sensitivity analysis. In addition, we also conducted subgroup analysis.ResultsIpilimumab plus anti-PD-1 provided an improvement of 1.39 QALYs and 2.48 LYs, at a ICER of $73,163 per QALY. The HR of OS was the variable that had the greatest impact on ICER. Compared to ipilimumab, the probability of ipilimumab plus anti-PD-1 being cost-effective was 94% at the WTP of $150,000/QALY. The results of the subgroup analysis showed that the ICER in the majority of the subgroups was less than $150,000/QALY.ConclusionsIpilimumab plus anti-PD-1 was likely to be cost-effective compared to ipilimumab for patients with metastatic melanoma who are resistant to anti-PD-(L)1 at a WTP threshold of 150,000/QALY.

The blast vibration attenuation will change as the tunnel cut hole is blasted to create a new free surface. To guarantee safe tunnel construction and optimize blast design parameters, it is crucial to understand the impact of the free surface on blast vibration attenuation. Previous studies have often only qualitatively evaluated the effect of the free surface on blast vibration, failing to quantify these impacts on vibration attenuation. In this paper, by analyzing the decay law of the blast vibration velocity under different free surfaces, we quantitatively assessed the effect of the number of free faces and burden distance on the peak vibration velocity. Then, we introduced free-face parameters to enhance the current formula for predicting blast vibration velocity. The results show that the peak vibration velocity decreases with the increasing free surface number and increases with increasing burden distance; the free surface factor cannot be ignored in the decay of vibration velocity and contributes about 21% more to the total decay factor than the scale distance factor. The average tolerance rises from 24.79% in the Sadovsky formula to 13.32% in the correction formula, and the correction formula more precisely predicts the peak vibration velocity. The accuracy of the correction formula provides a good scientific basis for the design of tunnel blasting parameters. The research results were successfully applied to the Jiujiawan proximity tunnel on the Duyun-Anshun highway in Guizhou, effectively guaranteeing blasting safety with a minimum clear distance of 17.2 m.

Objective: This study evaluated the cost-effectiveness of nivolumab plus ipilimumab vs. chemotherapy in the first-line setting for patients with advanced non-small-cell lung cancer (NSCLC) from the US payer perspective.Materials and methods: A Markov model wasdeveloped to evaluate the cost and effectiveness of nivolumab plus ipilimumab vs. chemotherapy in the first-line treatment of advanced NSCLC. The survival benefits of nivolumab plus ipilimumab were based on the results of the CheckMate 227 trial. The main endpoints of the model were cost, life-years (LYs), quality-adjusted LYs (QALYs), and incremental cost-effectiveness ratio (ICER). Univariable and probabilistic sensitivity analyses were conducted to assess model uncertainty. Additonal subgroup analyses were also performed.Results: nivolumab plus ipilimumab produced a gain of 0.62 QALYs, at a cost of $104238 per QALY. The variables that had the greatest influence on the ICER were body weight and overall survival (OS) hazard ratio (HR). The probability of nivolumab plus ipilimumab being cost-effectiveness compared to chemotherapy is 50.7 and 66.2% when the willingness-to-pay (WTP) value is $ 100,000 and $ 150,000 per QALY. The results of subgroup analyses showed the ICER remained below $150,000/QALY regardless of the PD-L1 expression level.Conclusions: nivolumab plus ipilimumab was estimated to be cost-effective compared with chemotherapy for patients with advanced NSCLC at a WTP threshold from 100,000/QALY to 150,000/QALY.

Background: Yinlan capsule is a complex TCM formulation that is prescribed for the treatment and prevention of hyperlipidemia. Our previous study indicated that one of the key targets of Yinlan is the Pregnane X Receptor (PXR). Purpose: To verify that PXR is the main active target for Yinlan's anti-hyperlipidemia effect, and to discover the agonists and antagonists with both suitable content and pharmacokinetic profile accordingly. Methods: an UHPLC-TOF-MS method was first applied to screen components in Yinlan capsule, peaks found in the ion current chromatogram were identified by the database (AB Sciex Analyst Software 1.6), and those with obvious responses were set as candidates; cytobiological experiment was carried out in the subsequent step, using HepG2 cell incubated with midazolam and monomer of the candidate compounds, yield of 1’-hydroxy- midazolam was used as an index to evaluate the PXR-CYP3A4 regulation activity of each component; a UHPLC-MS method was used for determination of the candidates showed obvious changes in 1’-hydroxy- midazolam yield, and compounds had suitable content in Yinlan capsule were validated for their PXR regulatory activities by QT-PCR; then components with both good PXR/CYP3A4 regulatory activity and suitable content underwent pharmacokinetic research to evaluate their in-body movements, compounds with acceptable pharmacokinetic parameters were finally chosen as quality marker of Yinlan's anti-hyperlipidemia effect via regulation of PXR activity. Comparisons of results in each step of evaluation were carried out using SPSS software, and the compounds with obvious difference (p

The aim of this study was to develop a new efficient strategy that uses the Vector form Intrinsic Finite-element (VFIFE) method to conduct the static and dynamic analyses of marine pipes. Nonlinear problems, such as large displacement, small strain, and contact and collision, can be analyzed using a unified calculation process in the VFIFE method according to the fundamental theories of point value description, path element, and reverse motion. This method enables analysis without the need to integrate the stiffness matrix of the structure, because only motion equations of particles established according to Newton's second law are required. These characteristics of the VFIFE facilitate the modeling and computation efficiencies in analyzing the nonlinear dynamic problem of flexible pipe with large deflections. In this study, a three-dimensional (3-D) dynamical model based on 3-D beam element was established according to the VFIFE method. The deep-sea flexible pipe was described by a set of spatial mass particles linked by 3-D beam element. The motion and configuration of the pipe are determined by these spatial particles. Based on this model, a simulation procedure to predict the 3-D dynamical behavior of flexible pipe was developed and verified. It was found that the spatial configuration and static internal force of the mining pipe can be obtained by calculating the stationary state of pipe motion. Using this simulation procedure, an analysis was conducted on the static and dynamic behaviors of the flexible mining pipe based on a 1000-m sea trial system. The results of the analysis proved that the VFIFE method can be efficiently applied to the static and dynamic analyses of marine pipes.

Abstract Background We recently showed that intravenous sodium nitroprusside treatment (SNP) could relieve the pulmonary vasospasm of pulmonary embolism (PE) and non-pulmonary embolism (non-PE) regions in a rabbit massive pulmonary embolism (MPE) model associated with shock. The present study explored the potential role of cardiopulmonary sympathetic activity on the pathogenesis and the impact of vasodilators on cardiopulmonary sympathetic activity in this model. Methods Rabbits were randomly divided into sham operation group (S group, n = 8), model group (M, equal volume of saline intravenously, n = 11), SNP group (3.5 μg/kg/min intravenously, n = 10) and diltiazem group (DLZ, 6.0 μg/kg/min intravenously, n = 10). Results MPE resulted in reduced mean arterial pressure and increased mean pulmonary arterial pressure as well as reduced PaO2 in the M, SNP and DLZ groups. Tyrosine hydroxylase (TH), neuropeptide Y (NPY) and endothelin-1 (ET-1) expression levels were significantly increased, while nitric oxide (NO) levels were reduced in both PE and non-PE regions in the M group. Both SNP and DLZ decreased mean pulmonary arterial pressure, reversed shock status, downregulated the expression of TH, NPY and ET-1, and increased NO levels in PE and non-PE regions. Conclusion Present results indicate that upregulation of the sympathetic medium transmitters TH and NPY in whole lung tissues serves one of the pathological features of MPE. The vasodilators SNP and DLZ could relieve pulmonary vasospasm in both embolization and non-embolization regions and reverse circulatory shock, thereby indirectly downregulating the sympathetic activation of the whole lung tissues and breaking a vicious cycle related to sympathetic activation in this model.

ObjectiveThis study aimed to assess the cost-effectiveness of two recently approved first-line chemo-immunotherapies [atezolizumab combined with etoposide and platinum (AEP) and durvalumab combined with etoposide and platinum (DEP)] for patients with extensive-stage small-cell lung cancer (ES-SCLC) in the United States.Material and MethodsA Markov model was built to compare the cost and effectiveness of AEP, DEP, and etoposide plus platinum (EP) over a 10-year time horizon. Clinical efficacy and safety data were extracted from the IMpower 133 and CASPIAN trials. Health state utilities were obtained from published literature. Costs were collected from an US payer perspective. Deterministic and probabilistic sensitivity analyses were used to explore the uncertainty bound to model parameters.ResultsFor the model cohort of adult patients with treatment-naive ES-SCLC, AEP was associated with marginal improved quality adjusted life years (QALYs) by 0.016 and reduced costs by $5,737 compared with DEP. When comparing the two chemo-immunotherapies with EP chemotherapy, AEP and DEP increased the QALYs by 0.162 QALYs and 0.146, respectively. However, both chemo-immunotherapies were associated with substantially health costs than EP, resulting in ICERs of $382,469 per QALY and $464,593 per QALY, respectively.ConclusionIn this cost-effectiveness study, first-line AEP represented a dominant treatment strategy compared with DEP. Despite neither first-line AEP nor first-line DEP was cost-effective compared with EP chemotherapy, AEP was able to provide a more efficient balance between incremental cost and QALY than DEP. When new combination therapies with remarkable effect become pivotal in the first-line treatment, the price reduction of these drugs may be essential to achieving cost-effectiveness.

Background: Propolis and its preparations are components of TCM and functional food sources for antihyperlipidemia therapy. However, due to the metabolic properties of propolis, its individual components remain ambiguous, especially those that are therapeutically active. Purpose: The study presented here identified the primary target (PXR/CYP3A4) of propolis activity against hyperlipidemia and evaluated individual compounds of propolis to select a quality control marker based on this activity. Methods: Mice fed a high-fat diet were used to study the efficacy of propolis, followed by identification of substantially influenced glycolipid regulatory target(s) by propolis. Since propolis had the strongest effect on PXR expression, we took advantage of its downstream target CYP3A4, the drug metabolism activity of such enzyme is affected by alterations in PXR expression. Thus, we used the production of 1’-hydroxy-midazolam as an indicator. Compounds found by UHPLC-TOF-MS were added to a HepG2 cell solution (transfected by PXR mRNA and the CYP3A4 plasmid to simulate drug metabolism in the body) in the form of a monomer, followed by the addition of midazolam. Changes in the amount of “indicator” were used to investigate each compound's qualitative (promote or suppress) and quantitative activity. Compounds with obvious effects were quantified in propolis extract, as confirmed via Western Blot analysis regarding their PXR regulatory activity, and subjected to pharmacokinetic analysis to biter understand their metabolism in the body. Finally, components passing these screens could be regarded as quality control markers capable of indicating the efficacy of antihyperlipidemic activity via PXR/CYP3A4 regulation. Results: The use of propolis was effective in lowering TG and TC levels in mice, as well as in repairing their injured livers; its activity was comparable to the chemical and TCM positive controls. Propolis mainly suppressed PXR expression compared with other regulatory targets that were tested. Most of the individual compounds from propolis (13 out of 15) showed obvious regulatory activity of PXR/CYP3A4; however, content quantification and pharmacokinetic analyses narrowed the selection to 2 compounds, kaempferol and chrysin, as the main active components responsible for the antihyperlipidemic effect of propolis. In other words, this study suggested that propolis mainly acts on the PXR/CYP3A4 pathway to regulate glycolipid metabolism, and the 2 compounds mentioned above can be used as quality control markers (QM) to evaluate the efficacy of this activity. Conclusion: Propolis's antihyperlipidemic effect relies on its regulation of PXR/CYP3A4 expression. Kaempferol and chrysin can be regarded as QMs. In addition, the metabolite-based method for evaluating regulatory activity is much faster, more effective, and more reliable than the conventional screening method, paving the way for its future applications.

BackgroundThe phase III KEYNOTE-604 study confirmed the benefit of pembrolizumab combined with chemotherapy in the first-line treatment of extensive-stage small-cell lung cancer (ES-SCLC). Taken into account the clinical benefits of pembrolizumab and its high cost, this study aimed to assess the cost-effectiveness of adding pembrolizumab to standard first-line etoposide-platinum (EP) for patients with ES-SCLC from the US payer perspective.MethodsA Markov model was developed to compare the cost and quality-adjusted life-year (QALY) of pembrolizumab plus EP and placebo plus EP over a 10-year time horizon. Clinical efficacy and safety data were pooled from the KEYNOTE-604 trial. Utilities were obtained from published resources. Costs were mainly collected from Medicare in 2020. Sensitivity analyses were performed to examine the robustness of our model.ResultsAdding pembrolizumab to standard first-line EP resulted in the better effectiveness than EP chemotherapy alone for ES-SCLC by 0.22 QALYs. Pembrolizumab plus EP was dominated economically by placebo plus EP, leading to an incremental cost-effectiveness ratio (ICER) of $334,373/ QALY. Deterministic sensitivity analyses indicated that the uncertainty in model parameters exerted no substantial effect on our results. Probability sensitivity analysis indicated that probabilities for pembrolizumab plus EP being cost-effective within a wide range of willingness to pay were modest.ConclusionFrom the US payer perspective, the first-line treatment for ES-SCLC with pembrolizumab plus EP was not cost-effective compared with placebo plus EP. Although pembrolizumab combination chemotherapy was beneficial to the survival of ES-SCLC, price reduction may be the necessary to improve its cost-effectiveness.

Objective To investigate the cost-effectiveness of ramucirumab plus erlotinib compared with placebo plus erlotinib in the first-line setting for patients with EGFR-mutated metastatic non-small cell lung cancer (mNSCLC) from the Chinese healthcare system perspective.Design A Markov model consisting of three health states using clinical survival data from the RELAY phase III randomised clinical trial, a lifetime horizon for costs and quality-adjusted life-years (QALYs) was constructed to analyse the cost-effectiveness of ramucirumab plus erlotinib. One-way and probabilistic sensitivity analyses were performed to evaluate the robustness of the model. Additional price reduction scenario analyses were performed.Setting The Chinese healthcare system perspective.Participants A hypothetical Chinese cohort of patients with confirmed previously documented ex19del or Leu858Arg mutation stage IV NSCLC, and without known epidermal growth factor receptor (EGFR) Thr790Met mutation and central nervous system metastases.Interventions Ramucirumab plus erlotinib versus placebo plus erlotinib.Primary outcome measure Costs, QALYs, incremental cost-effectiveness ratio (ICER).Results In base-case analysis, ramucirumab plus erlotinib yield an additional 4.21 QALYs at a cost of $540 590, resulting in an ICER of $128 302/QALY. In price reduction scenario analysis, the ICER ($65 227/QALY) was decreased significantly when the National Reimbursement Drug List (NRDL) negotiation was available for ramucirumab, and the ICER ($131 554/QALY) was increased slightly when the NRDL negotiation was unavailable for erlotinib. Sensitivity analyses demonstrated our results to be most sensitive to the unit cost of ramucirumab (10 mg/kg), and more than 52.1% reduction in the price of ramucirumab resulted in the ICER under the willingness-to-pay threshold set for affluent regions ($70 353/QALY).Conclusions Ramucirumab plus erlotinib is unlikely to be cost-effective for patients with untreated EGFR-mutated mNSCLC in China. Reducing the price of ramucirumab through the National Healthcare Security Administration negotiation was found to be the most realistic action to improve cost-effectiveness.

It is unclear if allergen immunotherapy (AIT) can reduce allergy effector cell activation. We evaluated the basophil response during Dermatophagoides pteronyssinus (Der p) subcutaneous immunotherapy (SCIT) and its relationship to allergen-specific immunoglobulin G4 (sIgG4) in allergic rhinitis and/or asthma patients. The study included 55 subjects, of which 35 cases received Der p SCIT and 20 controls received standard medications. Symptom and medication scores (SMSs), sIgG4 levels, specific immunoglobulin E (sIgE) levels, allergen-induced basophil activation tests (BATs) in whole blood, and BAT inhibition assays in serum were determined at weeks 0, 4, 12, 16, 52, and 104 of SCIT. Levels of Der p sIgG4 in SCIT patients significantly increased after 12 weeks of treatment compared to week 0. Serum obtained from SCIT patients significantly inhibited basophil activation after 12 weeks of treatment. Removal of immunoglobulin G4 (IgG4) antibodies at week 104 reduced the ability of serum to block basophil activation. An increase of Der p sIgG4 rather than reduction of Der p sIgE correlated with the reduction of basophil activation during SCIT. The sIgG4 antibodies may compete with sIgE binding to allergens to form an immunoglobulin E (IgE)–allergen complex. SCIT reduced the sensitivity of allergen-triggered basophil activation in Der p allergic rhinitis and/or asthma patients through induction of sIgG4.

Background: The FIRE-3 phase III clinical trial demonstrated the marked advantage of prolonging the median overall survival of patients with final RAS wild-type (WT) left-sided metastatic colorectal cancer (mCRC) by 38.3 months after treatment with irinotecan, fluorouracil, and leucovorin (FOLFIRI) plus cetuximab and by 28.0 months after treatment with FOLFIRI plus bevacizumab. However, the substantial cost increase and economic impact of using cetuximab imposes a considerable burden on patients and society. Methods: A Markov model based on the data collected in the FIRE-3 trial was developed to investigate the cost-effectiveness of treating patients with FOLFIRI plus either cetuximab or bevacizumab from the perspective of the Chinese health-care system. Costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs) were calculated over a lifetime horizon. One-way and probabilistic sensitivity analyses were performed by varying potentially modifiable parameters. Results: In our analysis, the total treatment costs in the bevacizumab and cetuximab groups were $92 549.31 and $94 987.31, respectively, and the QALYs gained were 1.58 and 2.05. In the base-case analysis, compared with bevacizumab, left-sided RAS WT patients receiving cetuximab gained 0.47 more QALYs at an ICER of $5187.23/QALY ($3166.23/LY). The 1-way sensitivity analysis showed that the most influential parameter was the cost of cetuximab. Probabilistic sensitivity analysis indicated that the cost-effective probability of cetuximab group was 92.8% under the willingness-to-pay threshold of $24 081. Conclusions: Treatment with FOLFIRI plus cetuximab in Chinese patients with left-sided RAS WT mCRC may improve health outcomes and use financial resources more efficiently than FOLFIRI plus bevacizumab.

In order to further improve the power-generating capacity of the wave energy converter (WEC) of oscillating buoy type, this paper puts forward a novel type where the WEC can move and extract power in five degrees of freedom. We make a detailed hydrodynamic analysis of such WECs. Each buoy is modeled as a floating truncated cylinder with five degrees of freedom: surge, sway, heave, roll, and pitch, and there are relative motions among buoys in the array. Linear power take-off (PTO) characteristics are considered for simplicity. Under the linear wave theory, a semi-analytical method based on the eigenfunction expansion and Graf’s addition theorem for Bessel functions is proposed to analyze the hydrodynamic interactions among the WEC array under the action of incident waves, and the amplitude response and power extraction of the WEC array are then solved. After verifying the accuracy of hydrodynamic analysis and calculation, we make preliminary case studies, successively investigating the power-generating capacity of a single WEC, an array of two WECs, and an array of five WEC; then, we compare their results with the conventional heaving WECs. The results show that the WEC with five degrees of freedom can significantly improve the power extraction performance.

AimThat clinical trial (RAINBOW) showed that a 7.4 months overall survival benefit with the combination therapy with ramucirumab (RAM) and paclitaxel (PAC) as second-line therapy for patients with recurrent or metastatic gastric or gastro-oesophageal junction adenocarcinoma, compared with placebo (PLA) plus paclitaxel. We performed an analysis to assess the cost-effectiveness of RAM from a Chinese perspective and recognized the range of drug costs.MethodsBy building a Markov model to estimate quality-adjusted life-years (QALYs), life-years (LYs) and lifetime costs. Transition probabilities, costs and utilities were estimated for the published literature, Chinese health care system and local price setting. We performed threshold analyses and probabilistic sensitivity analyses to evaluate the uncertainty of the model.ResultsCompared with PLA strategy, RAM strategy provided an incremental survival benefit of 1.22 LYs and 0.64 QALYs. The probabilistic sensitivity analysis showed that when RAM costs less than $151 or $753 per 4 weeks, the incremental cost-effectiveness ratio (ICER) approximated the willingness-to-pay threshold (WTP), suggesting that there was 50% likelihood that the ICER for RAM + PAC would be less than $44528.4 per QALY or $48121 per QALY, respectively.ConclusionsFor patients with advanced gastric or gastro-oesophageal junction adenocarcinoma who fail first-line chemotherapy, our results are conducive to the multilateral drug price guidance negotiations of RAM in China.

Objectives Evaluating the cost-effectiveness of pembrolizumab plus standard chemotherapy in the first-line setting for patients with metastatic non-small cell lung cancer (NSCLC) from the US payer perspective.Design A Markov model was constructed to analyse the cost-effectiveness of pembrolizumab plus chemotherapy in the first-line treatment of metastatic NSCLC. Health outcomes were estimated in quality-adjusted life-years (QALYs). The cost information was from Medicare in 2018. One-way and probabilistic sensitivity analyses examined the impact of uncertainty and assumptions on the results.Setting The US payer perspective.Participants A hypothetical US cohort of patients with previously untreated metastatic nonsquamous NSCLC without EGFR or ALK mutations.Interventions Pembrolizumab plus chemotherapy versus chemotherapy.Primary outcome measures Costs, QALYs, incremental cost-effectiveness ratio (ICER) of pembrolizumab plus chemotherapy expressed as cost per QALY gained compared with chemotherapyResults The base case analysis demonstrated that pembrolizumab plus chemotherapy provided an additional 0.78 QALYs at incremental cost of $151 409, resulting in an ICER of $194 372/QALY. ICER for pembrolizumab plus chemotherapy was >$149 680/QALY in all of our univariable and probabilistic sensitivity analyses.Conclusions Pembrolizumab in addition to chemotherapy provides modest incremental benefit at high incremental cost per QALY for the treatment of previously untreated metastatic NSCLC.

BACKGROUND:There is no single standard chemotherapy regimen for elderly patients with advanced gastric cancer (AGC). A phase III trial has confirmed that both capecitabine monotherapy and capecitabine plus oxaliplatin are well tolerated for elderly patients with AGC, but their economic influence in China is unknown. OBJECTIVE:The purpose of this cost-effectiveness analysis was to estimate the effects of capecitabine monotherapy and capecitabine plus oxaliplatin in elderly patients with AGC on health and economic outcomes in China. METHODS:We created a Markov model based on data from a Korean clinical phase III trial to analyze the cost-effectiveness of the treatment of elderly patients in the capecitabine monotherapy (X) group and capecitabine plus oxaliplatin (XELOX) group. The costs were obtained from published reports and the local health system. The utilities were assumed on the basis of the published literature. Costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICER) were estimated. One-way and probabilistic sensitivity analyses (Monte Carlo simulations) were performed. RESULTS:In the cost-effectiveness analysis, X had a lower total cost ($45,731.68) and cost-effectiveness ratio ($65,918.93/QALY). The one-way sensitivity analysis suggested that the most influential parameter was the risk of requiring second-line chemotherapy in XELOX group. The probabilistic sensitivity analysis predicted that the X regimen was cost-effective 100% of the time, given a willingness-to-pay threshold of $26,598. CONCLUSIONS:Our findings show that the XELOX regimen is less cost-effective compared to the X regimen for elderly patients with AGC in China from a Chinese healthcare perspective.