OBJECTIVE To evaluate the cost-effectiveness of ripretinib versus sunitinib as a second-line treatment option for patients with advanced gastrointestinal stromal tumors （GIST）. METHODS Based on the data of INTRIGUE study， a dynamic Markov model was constructed， with a cycle of 6 weeks； this model was used to simulate patients’ direct medical costs and quality- adjusted life years （QALYs） over 15 years. Using the incremental cost-effectiveness ratio （ICER） as the evaluation metric， a comparison was made between the ICER and the willingness-to-pay （WTP） threshold （3 times the per capita gross domestic product， which amounts to 268 200 yuan/QALY）. One-way sensitivity analyses and probabilistic sensitivity analyses were performed on the model outputs to examine the stability of the model. RESULTS The health benefits of ripretinib were lower than those of sunitinib （1.21 QALYs vs. 1.31 QALYs）. Still， the costs were higher （323 401.88 yuan vs. 227 532.40 yuan）， making it an inferior regimen. The results of the one-way sensitivity analysis suggested that the cost of ripretinib and sunitinib， and the health utility value in progression-free survival status had a greater impact on the ICER of the model. Probabilistic sensitivity analysis suggested that the results of the study were stable， and the probability of the cost-effectiveness advantage of ripretinib was always much lower than that of sunitinib with the increase of WTP threshold， and showed a decreasing trend. CONCLUSIONS In the current economic context of China， ripretinib does not have a cost-effectiveness advantage over sunitinib as a second-line treatment for advanced GIST.

Background Exposure to polycyclic aromatic hydrocarbons (PAHs) is associated with the development of metabolic syndrome (MS). However, the role of amino acids in PAH-induced MS remains unclear. Objective To explore the impact of PAHs exposure on the incidence of MS among coking workers, and to determine potential modifying effect of amino acid on this relationship. Methods Unmatched nested case-control design was adopted and the baseline surveys of coking workers were conducted in two plants in Taiyuan in 2017 and 2019, followed by a 4-year follow-up. The cohort comprised 667 coking workers. A total of 362 participants were included in the study, with 84 newly diagnosed cases of MS identified as the case group and 278 as the control group. Urinary levels of 11 PAH metabolites and plasma levels of 17 amino acids were measured by ultrasensitive performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Logistic regression was used to estimate the association between individual PAH metabolites and MS. Stratified by the median concentration of amino acids, Bayesian kernel machine regression (BKMR) model was employed to assess the mixed effects of PAHs on MS. Due to the skewed data distribution, all PAH metabolites and amino acids in the analysis were converted by natural logarithm ln (expressed as lnv). Results The median age of the 362 participants was 37 years, and 83.2% were male. Compared to the control group, the case group exhibited higher concentrations of urinary 2-hydroxyphenanthrene (2-OHPhe), 9-hydroxyphenanthrene (9-OHPhe), and hydroxyphenanthrene (OHPhe) (P=0.005, P=0.049, and P=0.004, respectively), as well as elevated levels of plasma branched chain amino acid (BCAA) and aromatic amino acid (AAA) (P<0.05). After being adjusted for confounding factors, for every unit increase in lnv_2-OHPhe in urine, the OR (95%CI) of MS was 1.57 (1.11, 2.26), and for every unit increase in lnv_OHPhe, the OR (95%CI) of MS was 1.82 (1.16, 2.90). Tyrosine, leucine, and AAA all presented a significant nonlinear correlation with MS. At low levels, tyrosine, leucine, and AAA did not significantly increase the risk of MS, but at high levels, they increased the risk of MS. In the low amino acid concentration group, as well as in the low BCAA and low AAA concentration groups, it was found that compared to the PAH metabolite levels at the 50th percentile (P₅₀), the log-odds of MS when the PAH metabolite levels was at the 75th percentile (P₇₅) were 0.158 (95%CI: 0.150, 0.166), 0.218 (95%CI: 0.209, 0.227), and 0.262 (95% CI: 0.241, 0.282), respectively, However, no correlation between PAHs and MS was found in the high amino acid concentration group. Conclusion Amino acids modify the effect of PAHs exposure on the incidence of MS. In individuals with low plasma amino acid levels, the risk of developing MS increases with higher concentrations of mixed PAH exposure. This effect is partly due to the low concentrations of BCAA and AAA.

OBJECTIVE To identify and analyze adverse drug event （ADE） signals associated with tirzepatide based on the FDA Adverse Event Reporting System （FAERS） database， providing a reference for clinical medication safety. METHODS ADE reports from January 1， 2022， to June 30， 2024， with tirzepatide as the primary suspected drug， were extracted from the FAERS database. Medical Dictionary for Regulatory Activities was used to systematically categorize the selected system organ class （SOC） and preferred term of ADE. Signal mining and analysis were performed using the reporting odds ratio method and the proportional reporting ratio method. RESULTS A total of 39 229 ADE reports related to tirzepatide were obtained， including 3 934 severe ADE reports （10.03%）. The majority of severe ADE reports were related to hospitalization or prolonged hospitalization （3.82%）， involving 131 positive ADE signals. Among the reports with documented patient gender and age， 26 195 were female （66.77%）， 7 869 were male （20.06%）， and the majority of patients were aged 18-64 years （54.26%）. The top three most frequently reported ADE were injection site pain， nausea， and injection site hemorrhage. Strong ADE signals not mentioned in the tirzepatide instruction included injection site coldness， starvation ketoacidosis， injection site hemorrhage， hunger， elevated adrenaline， injection site skin cracking， binge eating， skin laxity， intestinal sepsis， lack of satiety， and dysesthesia. Subgroup analysis for patient’s gender and age showed differences in the proportion of ADE reports across different SOC. Male patients or those aged≥65 years had a higher risk of gastrointestinal system disorders compared to female patients or those aged ＜65 years. CONCLUSIONS In clinical use of tirzepatide， in addition to monitoring ADE listed in the instruction， attention should also be paid to ADE not mentioned in the instruction， such as injection site coldness， starvation ketoacidosis， injection site hemorrhage， elevated adrenaline， and intestinal sepsis， to ensure patient safety.

The v-Raf murine sarcoma viral oncogene homolog B (BRAF) gene is one of the most critical proto-oncogenes and functions as a key regulator in the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling pathway. The incidence of BRAF mutations in non-small cell lung cancer (NSCLC) patients ranges from 1.5% to 5.5%, with BRAF V600 mutations accounting for approximately 30%-50% of all BRAF mutations, among which BRAF V600E represents the most prevalent mutation type. Currently, the combination of Dabrafenib and Trametinib has been recommended as first-line therapy for BRAF V600-mutant NSCLC by multiple domestic and international guidelines including National Comprehensive Cancer Network (NCCN), European Society of Medical Oncology (ESMO), and Chinese Society of Clinical Oncology (CSCO). However, there are no clear targeted treatment recommendations for BRAF non-V600 mutations. Although case reports suggest that Dabrafenib combined with Trametinib may be effective for patients with BRAF non-V600 mutations, the efficacy and safety require further validation due to limited sample size and lack of large-scale clinical trial data. This article reports a case of NSCLC with a rare BRAF insertion and deletion mutation that responded well to the treatment of Dabrafenib in combination with Trametinib, aiming to enhance clinicians' understanding of such NSCLC cases with extremely rare mutation and provide a reference for future treatment strategies.
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Humans ; Carcinoma, Non-Small-Cell Lung/pathology* ; Imidazoles/administration & dosage* ; Lung Neoplasms/pathology* ; Mutation ; Neoplasm Metastasis ; Oximes/administration & dosage* ; Proto-Oncogene Mas ; Proto-Oncogene Proteins B-raf/genetics* ; Pyridones/administration & dosage* ; Pyrimidinones/administration & dosage*

BACKGROUND: It is inaccurate to reflect the level of dust exposure through working years. Furthermore, identifying a predictive indicator for lung function decline is significant for coal miners. The study aimed to explored whether club cell secretory protein (CC16) levels can reflect early lung function changes. METHODS: The cumulative respiratory dust exposure (CDE) levels of 1,461 coal miners were retrospectively assessed by constructed a job-exposure matrix to replace working years. Important factors affecting lung function and CC16 were selected by establishing random forest models. Subsequently, the potential of CC16 to reflect lung injury was explored from multiple perspectives. First, restricted cubic spline (RCS) models were used to compare the trends of changes in lung function indicators and plasma CC16 levels after dust exposure. Then mediating analysis was performed to investigate the role of CC16 in the association between dust exposure and lung function decline. Finally, the association between baseline CC16 levels and follow-up lung function was explored. RESULTS: The median CDE were 35.13 mg/m³-years. RCS models revealed a rapid decline in forced vital capacity (FVC), forced expiratory volume in the first second (FEV₁), and their percentages of predicted values when CDE exceeded 25 mg/m³-years. The dust exposure level (<5 mg/m³-years) causing significant changes in CC16 was much lower than the level (25 mg/m³-years) that caused changes in lung function indicators. CC16 mediated 11.1% to 26.0% of dust-related lung function decline. Additionally, workers with low baseline CC16 levels experienced greater reductions in lung function in the future. CONCLUSIONS CC16 levels are more sensitive than lung indicators in reflecting early lung function injury and plays mediating role in lung function decline induced by dust exposure. Low baseline CC16 levels predict poor future lung function.
Uteroglobin/blood* ; Humans ; Dust/analysis* ; Occupational Exposure/analysis* ; Male ; Middle Aged ; Adult ; Retrospective Studies ; Lung Injury/chemically induced* ; Coal Mining ; Biomarkers/blood* ; China/epidemiology* ; Air Pollutants, Occupational ; Female

OBJECTIVE To comparatively analyze tumor staging versus clinical staging in reimbursement scope restrictions under medical insurance for antineoplastic agents in order to better implement the medicare drug payment policy. METHODS Antineoplastic agents included in the National Basic Medical Insurance， Workers’ Compensation Insurance and Maternity Insurance Drug Catalogue （2024） （hereinafter referred to as the “Medical Insurance Catalog”） were used as research subject to compile and analyze reimbursement scope restrictions regarding tumor staging. By consulting clinical diagnosis and treatment guidelines and relevant literature， the tumor staging in reimbursement scope restrictions of the Medical Insurance Catalog was mapped and compared with clinical staging. RESULTS & CONCLUSIONS A total of 89 antineoplastic agents’ medical insurance payments had tumor staging. Among these， there were 86 western drugs （including 17 ordinary western drugs， 68 negotiated drugs， and 1 competitive drug） and 3 Chinese patent medicines （including 1 ordinary Chinese patent medicine and 2 negotiated drugs）. Non-small cell lung cancer involved the most restricted payment drugs， with 36 drugs. The tumor staging in reimbursement scope restrictions was mostly “metastatic” and “locally advanced”， involving 67 and 48 drugs respectively. Tumor staging in most reimbursement scope restrictions could correspond to the clinical staging of the tumor. However， mid-advanced esophageal cancer， unresectable gastrointestinal stromal tumors， unresectable locally advanced neuroendocrine tumors， locally advanced basal cell carcinoma， and unresectable neurofibromatosis type Ⅰ did not have a corresponding clinical staging mentioned in authoritative guidelines or high-quality clinical studies and need to be determined by the clinic according to the actual situation of the patient. Therefore， it is recommended that the interpretation of tumor staging in reimbursement scope restrictions should be accurately defined and standardized， so as to improve the accuracy of the drug payment policy in the actual implementation process.

Background Polycyclic aromatic hydrocarbons represented by benzo[a]pyrene are among the most significant occupational and environmental pollutants. Exposure to benzo[a]pyrene during pregnancy can cause delayed intellectual development in offspring, and the mechanism may be related to the expression of protocadherin (Pcdh), a key molecule for learning and memory. Objective To explore the possible role of Pcdh in impaired learning and memory function of pups caused by benzo[a]pyrene exposure during pregnancy by establishing an animal model of cognitive impairment in pups caused by benzo[a]pyrene exposure during pregnancy, and detecting the expression of Pcdh and its transcription-related factors in the hippocampal tissues of pups at different developmental stages. Methods Sixty female and male SPF-grade rats were caged in a 1:1 ratio overnight, and the successfully mated female mice were randomly divided into blank control, 0 mg·kg⁻¹, 10 mg·kg⁻¹, 20 mg·kg⁻¹, and 40 mg·kg⁻¹ groups, with 6 mice in each group. They were intraperitoneally injected with benzo[a]pyrene from the 17th to the 19th day of pregnancy to establish an exposure model. Learning and memory functions of the offspring were tested through Morris water maze on the 45th day after the birth (PND) of the pups. On the PND45 and PND75 of the pups, hippocampal tissues of 6 pups (per group) were collected respectively. The expression levels of PcdhαC1 and wings apart-like homolog (WAPL) genes and proteins were detected by fluorescence quantitative polymerase chain reaction (PCR) and Western blotting. Results The results of Morris water maze showed that there was no interaction between the escape latency time of the pups and the dose groups of 0 mg·kg⁻¹, 10 mg·kg⁻¹, 20 mg·kg⁻¹, and 40 mg·kg⁻¹ (F _{time × group}=0.515, P>0.05). The escape latency of pups decreased with increase of training time (F _time=24.678, P<0.001, F _group=12.803, P<0.001). The PCR results showed that at PND45, compared with the blank group, the relative expression levels of PcdhαC1 mRNA in the 10 mg·kg⁻¹, 20 mg·kg⁻¹, and 40 mg·kg⁻¹ groups decreased (P<0.05), and the relative expression levels of WAPL mRNA increased (P<0.05). At PND75, compared with the blank group, the relative expression levels of PcdhαC1 mRNA in the 20 mg·kg⁻¹ and 40 mg·kg⁻¹ groups decreased (P<0.05), and the relative expression levels of WAPL mRNA increased (P<0.05). The Western blotting results showed that at PND45, compared with the blank group, the expression levels of PcdhαC1 protein in the 10 mg·kg⁻¹, 20 mg·kg⁻¹, and 40 mg·kg⁻¹ groups decreased (P<0.05), and the expression levels of WAPL protein increased (P<0.05). At PND75, compared with the blank group, the expression levels of PcdhαC1 protein in the 10 mg·kg⁻¹, 20 mg·kg⁻¹, and 40 mg·kg⁻¹ groups decreased (P<0.05), and the expression levels of WAPL protein increased (P<0.05). Conclusion Exposure to benzo[a]pyrene during pregnancy can cause impairment in the learning and memory abilities of PND45 offspring and may alter the expression of PcdhαC1 and WAPL genes and proteins.

BACKGROUND: Durvalumab after chemoradiotherapy (CRT) failed to bring survival benefits to patients with epidermal growth factor receptor ( EGFR ) mutations in PACIFIC study (evaluating durvalumab in patients with stage III, unresectable NSCLC who did not have disease progression after concurrent chemoradiotherapy). We aimed to explore whether locally advanced inoperable patients with EGFR mutations benefit from tyrosine kinase inhibitors (TKIs) and the optimal treatment regimen. METHODS: We searched the PubMed, Embase, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov databases from inception to December 31, 2022 and performed a meta-analysis based on a Bayesian framework, with progression-free survival (PFS) and overall survival (OS) as the primary endpoints. RESULTS: A total of 1156 patients were identified in 16 studies that included 6 treatment measures, including CRT, CRT followed by durvalumab (CRT-Durva), TKI monotherapy, radiotherapy combined with TKI (RT-TKI), CRT combined with TKI (CRT-TKI), and TKI combined with durvalumab (TKI-Durva). The PFS of patients treated with TKI-containing regimens was significantly longer than that of patients treated with TKI-free regimens (hazard ratio [HR] = 0.37, 95% confidence interval [CI], 0.20-0.66). The PFS of TKI monotherapy was significantly longer than that of CRT (HR = 0.66, 95% CI, 0.50-0.87) but shorter than RT-TKI (HR = 1.78, 95% CI, 1.17-2.67). Furthermore, the PFS of RT-TKI or CRT-TKI were both significantly longer than that of CRT or CRT-Durva. RT-TKI ranked first in the Bayesian ranking, with the longest OS (60.8 months, 95% CI = 37.2-84.3 months) and the longest PFS (21.5 months, 95% CI, 15.4-27.5 months) in integrated analysis. CONCLUSIONS: For unresectable stage III EGFR mutant NSCLC, RT and TKI are both essential. Based on the current evidence, RT-TKI brings a superior survival advantage, while CRT-TKI needs further estimation. Large randomized clinical trials are urgently needed to explore the appropriate application sequences of TKI, radiotherapy, and chemotherapy. REGISTRATION PROSPERO; https://www.crd.york.ac.uk/PROSPERO/ ; No. CRD42022298490.
Humans ; Carcinoma, Non-Small-Cell Lung/therapy* ; ErbB Receptors/genetics* ; Lung Neoplasms/drug therapy* ; Mutation/genetics* ; Protein Kinase Inhibitors/therapeutic use* ; Chemoradiotherapy ; Antibodies, Monoclonal/therapeutic use*

Oligoasthenozoospermia is the main cause of male infertility， with complex and diverse causes. Currently， there are still some unclear causes of oligoasthenozoospermia in clinical practice， known as idiopathic oligoasthenozoospermia. With the development of high-throughput sequencing technology， it has been found that intestinal microbiota disorder may be an important promoting factor for the onset of oligoasthenozoospermia. Traditional Chinese medicine believes that "deficiency of kidney essence" is the core pathogenesis of oligoasthenozoospermia. In clinical practice， the method of tonifying the kidney and strengthening the essence has a significant therapeutic effect on oligoasthenozoospermia， but its mechanism of action has not been fully elucidated. Based on the basic theories of traditional Chinese medicine and molecular biology research， it has been found that there is a similarity between "kidney essence" and intestinal microbiota. During the onset of oligoasthenozoospermia， the disorder of intestinal microbiota has similarities with the pathogenesis of "deficiency of kidney essence" in traditional Chinese medicine. Moreover， traditional Chinese medicine for tonifying the kidney and strengthening the essence can regulate the disorder of intestinal microbiota， which may be one of the effective mechanisms for the treatment of oligoasthenozoospermia with the Bushen Yijing method. Based on this， this article explored the mechanism of Bushen Yijing method of traditional Chinese medicine in treating oligoasthenozoospermia from the perspective of intestinal microbiota， so as to provide new ideas for the treatment of oligoasthenozoospermia with traditional Chinese medicine.

Chronic prostatitis is a common and frequently occurring disease in male clinics. Due to the diverse symptoms， complex etiology， unclear mechanisms， and recurrent episodes of chronic prostatitis， Western medicine often faces the challenge of limited treatment options and unsatisfactory outcomes. In order to fully leverage the unique advantages of traditional Chinese medicine （TCM） in the treatment of chronic prostatitis， the China Association of Chinese Medicine organized a discussion among experts from the fields of TCM urology， Western urology， and related pharmacy. The experts focused on the advancements in the understanding of chronic prostatitis in modern medicine， various theories on the etiology， pathogenesis， and treatment of chronic prostatitis in TCM， entry points from interdisciplinary fields， the role and advantages of TCM in the comprehensive management of chronic prostatitis， and research into mechanisms related to chronic prostatitis. After discussions， the experts concluded that chronic prostatitis is one of the diseases where TCM has a distinct advantage. TCM can effectively improve the clinical syndromes of chronic prostatitis， including urinary issues， social psychology， organ specificity， infection， nervous system problems， pain and discomfort， sexual dysfunction， etc.， and can enhance the quality of life. For patients with chronic prostatitis who cannot tolerate or may not accept the adverse effects of Western medicine， as well as for those with non-inflammatory chronic prostatitis/chronic pelvic pain syndrome （CP/CPPS）， those with pain as the primary symptom， those with urinary tract symptoms， those with coexisting anxiety and depression， and those with abnormal semen liquefaction， TCM-based treatment can be the main approach. Currently， the optimal diagnosis and treatment strategy for chronic prostatitis has not yet been established， and further research from perspectives such as clinical epidemiology， evidence-based medicine， and molecular biology is needed. Both TCM and Western medicine should integrate their respective strengths， clarify the role and advantages of TCM interventions based on mutual reference， and improve the diagnosis and treatment standards for chronic prostatitis in China.