OBJECTIVE To evaluate the cost-effectiveness of anlotinib combined with penpulimab versus sorafenib as first- line treatment for unresectable hepatocellular carcinoma （uHCC） from the perspective of China’s healthcare system. METHODS Based on data from the APOLLO study， a partitioned survival model was established with a 21-day model cycle to simulate patient survival status over 10 years under anlotinib combined with penpulimab regimen or sorafenib monotherapy. Quality-adjusted life year （QALY） was used as the core evaluation parameter to assess the incremental cost-effectiveness ratio （ICER） of different treatment regimens. Using 3 times China’s per capita gross domestic product （GDP） in 2024 （287 247 yuan/QALY） as the willingness-to-pay （WTP） threshold， cost-utility analysis was performed to evaluate the cost-effectiveness of the treatment regimens. Sensitivity analysis was conducted to validate the robustness of the baseline analysis conclusion. Scenario analysis was performed to consider the impact of anlotinib and penpulimab assistance programs on the results； the price reduction of penpulimab to ensure the cost-effectiveness of the combination regimen was examined under varying WTP thresholds （specifically， 1， 2， and 3 times China’s per capita GDP in 2024）. RESULTS The baseline analysis revealed that the ICER of anlotinib combined with penpulimab regimen relative to the sorafenib regimen was 338 611.20 yuan/QALY， which exceeded the WTP threshold set in this study. Univariate sensitivity analysis indicated that the utility value of progression free survival and penpulimab price significantly influenced the baseline analysis results. Probabilistic sensitivity analysis validated the robustness of the baseline results. The results of scenario analysis indicated that when considering the assistance programs for anlotinib and penpulimab， the obtained ICER values were all below the WTP threshold set at 3 times China’s per capita GDP in 2024. When the price of penpulimab was reduced by 58%， 35%， and 13%， the ICER values were below the WTP threshold， which was 1， 2 and 3 times the per capita GDP of China in 2024， respectively. CONCLUSIONS From the perspective of China’s healthcare system， anlotinib combined with penpulimab regimen for first-line treatment of uHCC lacks cost-effectiveness compared to sorafenib regimen. However， this conclusion would be reversed if the anlotinib and penpulimab assistance programs are taken into account or if the price of penpulimab is reduced by more than 13% and above.

OBJECTIVE To evaluate the cost-effectiveness of amivantamab combined with lazertinib （hereinafter referred to as “AL”） regimen as first-line treatment for EGFR -mutated advanced non-small cell lung cancer （NSCLC） from the perspective of China’s healthcare system. METHODS A partitioned survival model was established based on updated data from the MARIPOSA study， with a 10-year time horizon and 28-day cycles. The primary outcome index was quality adjusted life year （QALY）， and the willingness-to-pay （WTP） threshold was set at three times China’s per capita GDP in 2024 （287 247 yuan/QALY）. Cost-utility analysis was used to calculate the incremental cost-effectiveness ratio （ICER） of AL regimen versus osimertinib monotherapy regimen as first-line treatment for EGFR -mutated advanced NSCLC. One-way and probabilistic sensitivity analyses were performed to test model robustness. Scena rio analyses were conducted to explore the impact of utility values for different health states on the outcomes and determine the required price reductions of amivantamab and lazertinib to achieve cost-effectiveness. RESULTS Compared with the osimertinib monotherapy regimen， the ICER for the AL regimen as first-line treatment for advanced EGFR -mutated NSCLC was 2 062 096.15 yuan/QALY， significantly exceeding the WTP threshold established in this study. One-way sensitivity analysis revealed that the utility value of progression-free survival state and the price of amivantamab were the primary factors influencing the ICER. Probabilistic sensitivity analysis revealed that the AL regimen only became cost-effective when the WTP threshold was set at 2 050 000 yuan/QALY. Scenario analysis indicated that altering the utility value still rendered the AL regimen non-cost-effective. When amivantamab （350 mg） prices decreased by 80%， 85%， and 90% respectively， lazertinib （80 mg） prices would need to decrease by 95.97%， 40.63%， 5.29%， respectively. This would enable the AL regimen’s ICER to consistently fall within the WTP threshold established in this study. CONCLUSIONS At the WTP threshold established in this study， the AL regimen does not demonstrate cost-effectiveness for first-line treatment of advanced EGFR -mutated NSCLC compared to the osimertinib monotherapy regimen. Significant price reductions for both drugs would be required to alleviate the financial burden on patients.

OBJECTIVE To evaluate the cost-utility of benmelstobart combined with anlotinib and chemotherapy as first-line treatment for extensive-stage small cell lung cancer （ES-SCLC） from the perspective of China’s healthcare system. METHODS Based on the data from the ETER 701 study， a partitioned survival model was constructed with a cycle of 3 weeks to simulate the total cost， quality-adjusted life years （QALY）， and incremental cost-effectiveness ratio （ICER） over 10 years for patients with ES- SCLC treated with benmelstobart plus anlotinib and chemotherapy， or chemotherapy alone. One-way sensitivity analysis and probability sensitivity analysis were performed to verify the robustness of the simulation results. The willingness-to-pay （WTP） threshold was set at 3 times the per capita gross domestic product （GDP） of China in 2023， which amounted to 268 074 yuan/QALY. RESULTS Compared with chemotherapy alone， benmelstobart combined with anlotinib and chemotherapy gained 0.438 QALY more at the cost of 403 505.55 yuan more， with an ICER of 922 031.37 yuan/QALY， which was higher than the WTP threshold set in this study. One-way sensitivity analysis showed that benmelstobart’s cost and utility value of the progression-free survival state had a greater impact on the ICER value； probabilistic sensitivity analysis confirmed the robustness of the model； only when the price of benmelstobart was reduced by 75.4%， the combined regimen would be cost-effective. CONCLUSIONS The first-line treatment of ES-SCLC with benmelstobart combined with anlotinib and chemotherapy is not cost-effective from the perspective of China’s healthcare system at present.

OBJECTIVE To evaluate the efficacy， safety and economics of calcium channel modulators in the treatment of diabetic peripheral neuropathic pain （DPNP）， and provide evidence-based evidence for clinical drug selection and decision-making. METHODS PubMed， Embase， Cochrane Library， CNKI， Wanfang data， VIP net， CBM and official websites of foreign health technology assessment （HTA） institutions were systematically searched to collect HTA reports， systematic review/meta-analyses， and pharmacoeconomic studies of pregabalin， gabapentin， crisugabalin， and mirogabalin for the treatment of DPNP. The timeframe for all searches was from the inception to June 2024. After data extraction and quality assessment， the results of the included studies were analyzed descriptively. RESULTS A total of 16 articles were included， involving 1 HTA report， 7 systematic reviews/meta- analyses， and 8 pharmacoeconomic studies. No studies on crisugabalin were retrieved. Compared with placebo， both pregabalin and mirogabalin reduced end point pain scores and increased the proportion of patients with ≥30% and/or ≥50% reduction in pain scores. Pregabalin also improved patient global impression of change （PGIC）. Gabapentin was similar to placebo in reducing end point pain scores and increasing the proportion of patients with ≥30% and/or ≥50% reduction in pain scores， but gabapentin improved PGIC of patients. Compared with pregabalin， mirogabalin was more effective in the treatment of pain. The safety of pregabalin and mirogabalin was similar， and compared with placebo， both pregabalin and mirogabalin increased the risk of common adverse reactions such as dizziness and somnolence. The safety of gabapentin was similar to placebo and duloxetine. Compared with duloxetine， pregabalin and gabapentin were not cost-effective. Compared with gabapentin， pregabalin was cost-effective. Mirogabalin was cost-effective， as compared with placebo and pregabalin. CONCLUSIONS Pregabalin and mirogabalin are effective in the treatment of DPNP， the efficacy of mirogabalin is better than pregabalin， and the safety is similar between them. The economic conclusions vary from country to country， pending a pharmacoeconomic study based on our population.

OBJECTIVE To evaluate the cost-effectiveness of capecitabine metronomic chemotherapy combined with aromatase inhibitor （AI） versus AI monotherapy as first-line treatment for hormone receptor-positive （HR+）/human epidermal growth factor receptor 2-negative （HER2－） metastatic breast cancer， thereby providing evidence-based support for clinical therapeutic decision- making and healthcare policy formulation. METHODS Based on the MECCA trial， a partitioned survival model was constructed using a 4-week cycle length to simulate outcomes over patients’ lifetime. The model outputs included total costs， quality-adjusted life year （QALY）， and incremental cost-effectiveness ratio （ICER）. Sensitivity analyses were performed to validate the robustness of base-case results， while scenario analyses examined the cost-effectiveness of both treatment strategies under 10-year， 20-year， and lifetime time horizons. RESULTS With the willingness-to-pay （WTP） threshold set at 1 times China’s 2024 per capita gross domestic product （GDP） （95 749 yuan/QALY）， patients receiving capecitabine metronomic chemotherapy combined with AI regimen gained incremental utility （0.66 QALYs） while incurring higher costs， with ICER of 27 684.85 yuan/QALY. Results of the one-way sensitivity analysis showed that factors with significant impacts on ICER included the cost discount rate， drug costs of the capecitabine metronomic chemotherapy combined with AI group， utility value in the progression-free survival state， follow-up costs， and treatment costs in the subsequent stablephase. Probabilistic sensitivity analysis indicated that when the WTP threshold ≥49 250 yuan/QALY， the capecitabine metronomic chemotherapy combined with AI regimen had a 100% probability of being cost-effective. Scenario analysis results demonstrated that capecitabine metronomic chemotherapy combined with AI regimen was more cost-effective than the AI alone regimen across 10-year， 20-year， and lifetime study horizons. CONCLUSIONS Under the premise that the WTP threshold is set at 1 times China’s per capita GDP in 2024， capecitabine metronomic chemotherapy combined with AI regimen is more cost-effective than the AI alone regimen as the first-line treatment for HR+/HER2－ metastatic breast cancer.

OBJECTIVE To evaluate the efficacy and safety of letermovir in preventing cytomegalovirus （CMV） infection after allogeneic hematopoietic stem cell transplantation （allo-HSCT）. METHODS A retrospective cohort study was conducted， enrolling patients who underwent allo-HSCT at the Department of Hematology， Shanghai General Hospital Affiliated to Shanghai Jiao Tong University School of Medicine， from August 30， 2022， to February 21， 2024. Patients who initiated letermovir prophylaxis within 28 days post-transplantation were assigned to the experimental group （99 cases）， while those who did not initiate letermovir within this period were assigned to the control group （18 cases）. The incidence and clinical characteristics of CMV infection （including the number of wangranran@xinhuamed.com.cn CMV infection cases， the number of cases progressing to CMV disease， recurrent CMV disease， onset time of CMV infection， and treatment duration）， immune function recovery within 120 days post-transplantation， and the occurrence of transplantation-related complications （including CD4+ and CD8+ T-cell recovery， Epstein-Barr virus infection， acute graft-versus-host disease， human herpesvirus 6 infection， and posttransplant lymphoproliferative disorders） and adverse events were recorded. Univariate and multivariate Cox regression analyses were performed to identify factors influencing CMV infection. RESULTS A total of 117 patients were included， among whom 15 developed CMV infection， 5 progressed to CMV disease， and 2 experienced recurrent CMV disease. The CMV infection rate in the experimental group was significantly lower than that in the control group （P＜0.001）， and the onset time of CMV infection was significantly delayed （P＝0.014）. The proportion of patients with CD4+ T-cell counts ≥200 cells/μL in the experimental group was significantly lower than that in the control group （P＝0.022）. During the follow-up period， elevated creatinine levels were observed in 1 patient， and nausea and vomiting were observed in 2 patients. Multivariate Cox regression analysis revealed that the use of high-dose corticosteroids was a risk factor for CMV infection （HR＝6.230， 95%CI of 1.255-30.926， P＝0.025）， while initiating letermovir within 28 days post-transplantation was a protective factor （HR＝0.125， 95%CI of 0.045-0.348， P＜0.001）. CONCLUSIONS Early initiation of letermovir after allo-HSCT significantly reduces the CMV infection rate and delays the onset of infection， with favorable short-term safety.

OBJECTIVE To evaluate the cost-effectiveness of sacituzumab tirumotecan （ST） versus chemotherapy treatment physician’s choice （TPC） as second-line and later-line treatment for metastatic triple-negative breast cancer （mTNBC） from the perspective of China’s healthcare system. METHODS A partitioned survival model was constructed based on the OptiTROP-Breast 01 trial， with a cycle length of 4 weeks and a time horizon of 10 years， applying a 5% discount rate. Quality adjusted life year （QALY） and costs were used as outcome measures， and the incremental cost-effectiveness ratio （ICER） of ST versus TPC for second-line and later-line treatment of mTNBC was calculated. Sensitivity analyses were conducted to validate the robustness of the base-case results. RESULTS At a willingness-to-pay threshold （WTP） of 3 times China’s 2024 per capita gross domestic product （GDP） （287 247 yuan/QALY）， patients receiving ST gained incremental utility （0.42 QALY） at a higher cost， yielding an ICER of 205 562.07 yuan/QALY， which was lower than WTP， indicating that ST was more cost-effective compared to TPC. One-way sensitivity analysis revealed that key factors influencing the ICER included the utility value of progression-free survival and the price of ST. Probabilistic sensitivity analysis and scenario analysis showed that the base-case results were robust. CONCLUSIONS From the perspective of China’s healthcare system， at a WTP of 3 times China’s per capita GDP， ST is more cost-effective than TPC as second-line and later-line treatment for mTNBC.

ObjectiveThe U6 promoter is an essential element for driving sgRNA expression in the clustered regularly interspaced short palindromic repeat sequences/CRISPR-associated protein 9（CRISPR/Cas9）gene editing system in dicotyledonous plants. Endogenous U6 promoters typically exhibit higher transcriptional activity， which can significantly improve gene editing efficiency. This study aims to identify endogenous U6 promoters in Artemisia annua to optimize its CRISPR/Cas9 gene editing system， which holds significant importance for its molecular breeding. MethodsOn the basis of the highly conserved U6 snRNA sequences in Arabidopsis thaliana， endogenous U6 promoters were screened in the A. annua genome. Expression vectors were constructed with candidate AaU6 promoter driving the firefly luciferase （LUC） reporter gene， and then transiently transformed into Nicotiana benthamiana. Transcriptional activities of the promoters were measured and compared by in vivo imaging and the Dual Luciferase Reporter assay. ResultsEight endogenous U6 promoters were successfully cloned from A. annua. Sequences alignment revealed that all these promoters contained the two conserved cis-acting elements， upstream sequence element （USE） and TATA-box， which affected their transcriptional activity. Dual-luciferase activity assays indicated that the transcriptional activities of AaU6-3， AaU6-1， and AaU6-5 were significantly higher than that of the Arabidopsis AtU6-26 promoter， with AaU6-3 exhibiting the highest activity. ConclusionThis study identified three endogenous AaU6 promoters with high transcriptional activity in A. annua， providing key functional elements for establishing an efficient gene editing system in A. annua. These findings will contribute to advancing precision molecular breeding and high-quality germplasm innovation in A. annua.

OBJECTIVE: Benzylisoquinoline alkaloids (BIAs) have pharmacological functions and clinical use. BIAs are mainly distributed in plant species across the order Ranunculales and the genus Phellodendron from Sapindales. The BIA biosynthesis has been intensively investigated in Ranunculales species. However, the accumulation mechanism of BIAs in Phellodendron is largely unknown. The aim of this study is to unravel the biosynthetic pathways of BIAs in Phellodendron amurens. METHODS: The transcriptome and metabolome data from 18 different tissues of P. amurense were meticulously sequenced and subsequently subjected to a thorough analysis. Weighted gene co-expression network analysis (WGCNA), a powerful systems biology approach that facilitates the construction and subsequent analysis of co-expression networks, was utilized to identify candidate genes involved in BIAs biosynthesis. Following this, recombinant plasmids containing candidate genes were expressed in Escherichia coli, a widely used prokaryotic expression system. The purpose of this genetic engineering endeavor was to express the candidate genes within the bacteria, thereby enabling the assessment of the resultant enzyme activity. RESULTS: The synonymous substitutions per synonymous site for paralogs indicated that at least one whole genome duplication event has occurred. The potential BIA biosynthetic pathway of P. amurense was proposed, and two PR10/Bet v1 members, 14 CYP450s, and 33 methyltransferases were selected as related to BIA biosynthesis. One PR10/Bet v1 was identified as norcoclaurine synthase, which could catalyze dopamine and 4-hydroxyphenylacetaldehyde into (S)-norcoclaurine. CONCLUSION Our studies provide important insights into the biosynthesis and evolution of BIAs in non-Ranunculales species.

Objective To explore the prescription rules of traditional Chinese medicine (TCM) in the treatment of diabetes periodontitis(DP) and the acting mechanisms of core drug combination. Methods Based on the relevant literature retrieved from the CNKI,Wanfang,VIP and Sinomed,a DP prescription database was established. Excel 2021,SPSS Modeler 18.0 and SPSS Statistics 26.0 were used to conduct the statistics of the frequency,efficacy classifications,properties,flavors,and meridian tropism of the included drugs. Association rule analysis and cluster analysis were performed to screen out the core drug combinations. The active components and action targets of core drug combinations were obtained through TCMSP and HERB. The DP related disease targets were predicted using GeneCards. The Venny platform was used to obtain the intersection of disease targets and drug targets. Key components were screened by Cytoscape to establish an "active component-target" network. Based on STRING platform data,PPI network was constructed by Cytoscape to screen core targets. GO functional annotation and KEGG signaling pathway enrichment analysis were carried out for the intersection targets by DAVID. AutoDockVina was applied for molecular docking between core targets and key components. Results A total of 36 articles were included,and 50 prescriptions involving 100 Chinese herbal medicines were extracted. Alismatis Rhizoma,Rehmanniae Radix Praeparata and Astragali Radix were the most common drugs. The most used drug category was deficiency-nourishing drugs. The properties of the herbs were mainly cold and warm,the major flavors were sweet and bitter,and the main meridian tropisms were kidney and liver. Six categories were classified by clustering analysis. Moutan Cortes-Corni Fructus-Rehmanniae Radix Praeparata was screened out as the core drug combination involving 18 active components,164 drug action targets and 104 intersection of DP targets and drug combination targets. Quercetin,stigmasterol,kaempferol,β-sitosterol,tetrahydroalstonine,and sitosterol were the key components,and AKT1,IL-6,TNF,IL-1B,PTGS2,JUN,TP53,ESR1,and MMP9 were the core targets. GO analysis revealed 3724 biological processes,228 cellular components and 404 molecular functions. KEGG analysis showed that DP was treated by the core drug combination through regulating 235 signaling pathways. Molecular docking results showed that there was a good affinity between the core target and the key component. Conclusion Tonifying deficiency is the main treatment methods of TCM for DP,accompanied by clearing heat and removing dampness,activating blood circulation and removing blood stasis,replenishing qi and nourishing yin. Core drug combination (Moutan Cortes-Corni Fructus-Rehmanniae Radix Praeparata) treats DP through multi-component,multi-target and multi-pathway,which provide a reference for clinical diagnosis and treatment.