Objective:Time trade-off was employed to measure health state utilities associated with treatment attributes of hemophilia A patients to provide parameters for economic evaluations.Methods:Patients were recruited through patient organization and blood center of Shandong to measure health state utility values for 10 health states.Results:The utility values of preventive treatments for severe,moderate,and mild hemophilia A were 0.644,0.738,and 0.815,respectively.Compared with injections at 2-day intervals,the utility values were increased by 0.044 and 0.092 at 3-and 4-day intervals,respectively.Taking"severe hemophilia A patients injected every 2 days"as the base state,the disutility values for spontaneous bleeding and traumatic bleeding were 0.226 and 0.172.The disutility values for mild,moderate,and severe bleeding were 0.052,0.159,and 0.476,respectively,and the magnitude of the decrease gradually increased.Conclusion:Treatment attributes have an impact on patient preferences and more attention should be paid in pharmacoeconomic evaluations.

Objective To evaluate the cost-effectiveness of toripalimab plus axitinib compared to sunitinib in the first-line treatment of advanced renal cell carcinoma patients.Methods Based on the RENOTORCH trial,constructed a partitioned survival model to evaluate the long-term costs and health outcomes of toripalimab plus axitiniband sunitinib in the first-line treatment of advanced renal cell carcinoma(RCC)patients from the Chinese healthcare system perspective.The cycle length of the model was 3weeks,simulating the total cost,quality adjusted life years(QALYs),and incremental cost-effectiveness ratio(ICUR)for patients over 25 years.The costs were derived from the average bidding price of Yaozhi database in 2023 and published literature.The health state utility values were derived from clinical trials.The discount rate was 5%,and the willingness to pay(WTP)threshold was 3 times the per capita gross domestic product(GDP)in 2022.One-way and probability sensitivity analyses were used to test the robustness of the model.Results Based on the progression free survival(PFS)evaluated by the Independent Review Committee(IRC)and Investigator(IA),the ICUR values were 239 436.39 yuan/QALY and 175 440.39 yuan/QALY,respectively,both lower than the WTP threshold.One-way sensitivity analysis showed that the health state utility values of PFS status and the price of axitinib had a significant impact on the model.Probability sensitivity analysis showed that the probability of toripalimab plus axitinib being cost-effective was 63.64%and 98.03%according to the IRC and IA assessments,respectively.Conclusion Toripalimab plus axitinib was cost-effective in the first-line treatment of advanced RCC patients.

Objective To evaluate the cost-effectiveness of toripalimab plus axitinib compared to sunitinib in the first-line treatment of advanced renal cell carcinoma patients.Methods Based on the RENOTORCH trial,constructed a partitioned survival model to evaluate the long-term costs and health outcomes of toripalimab plus axitiniband sunitinib in the first-line treatment of advanced renal cell carcinoma(RCC)patients from the Chinese healthcare system perspective.The cycle length of the model was 3weeks,simulating the total cost,quality adjusted life years(QALYs),and incremental cost-effectiveness ratio(ICUR)for patients over 25 years.The costs were derived from the average bidding price of Yaozhi database in 2023 and published literature.The health state utility values were derived from clinical trials.The discount rate was 5%,and the willingness to pay(WTP)threshold was 3 times the per capita gross domestic product(GDP)in 2022.One-way and probability sensitivity analyses were used to test the robustness of the model.Results Based on the progression free survival(PFS)evaluated by the Independent Review Committee(IRC)and Investigator(IA),the ICUR values were 239 436.39 yuan/QALY and 175 440.39 yuan/QALY,respectively,both lower than the WTP threshold.One-way sensitivity analysis showed that the health state utility values of PFS status and the price of axitinib had a significant impact on the model.Probability sensitivity analysis showed that the probability of toripalimab plus axitinib being cost-effective was 63.64%and 98.03%according to the IRC and IA assessments,respectively.Conclusion Toripalimab plus axitinib was cost-effective in the first-line treatment of advanced RCC patients.

Objective:To explore the role of fibroblast growth factor 21 (FGF21) in rats with severe acute pancreatitis-associated acute lung injury (SAP-ALI) and its related molecular mechanisms.Methods:Twenty-four healthy male SD rats were randomly divided into 4 groups (random number, n=6 per group): Control group, SAP group, FGF21 intervention group (SAP+FGF21 group), and autophagy inhibitor group (SAP+FGF21+3-MA group). The SAP model was established by retrograde injection of 3.5% sodium taurocholate into the pancreatic duct. In SAP+FGF21 group, FGF21 10 mg/kg was intraperitoneally injected at 1 hour before modeling. In SAP+FGF21+3-MA group, FGF21 10 mg/kg and 3-MA 20 mg/kg were intraperitoneally injected at 1 h before modeling. Serum amylase activity was detected by biochemical kit. Plasma levels of tumor necrosis factor alpha (TNF-α) and FGF21 were detected by ELISA. HE staining was used to observe the pathological changes of pancreas and lung tissues. Immunofluorescence was used to detect the protein level of FGF21 in lung tissue. Western blot was used to detect the expression levels of autophagy-related proteins in lung tissue. Autophagosomes in lung tissue were observed by electron microscopy. Results:Compared with the Control group, the plasma and lung tissue FGF21 levels in SAP group were significantly decreased (both P<0.001) , severe pancreatic and lung tissue damage, and elevated plasma TNF-α levels ( P<0.001). Western Blot and transmission electron microscopy showed that: The expression of LC3Ⅱ/Ⅰ in lung tissue of SAP group was down-regulated [(0.912±0.052) vs. (0.700±0.135), P<0.001], and P62 protein level was up-regulated [(0.475±0.068) vs. (0.687±0.070), P<0.001] , and reduced autophagosome counts in the SAP group. In contrast, the SAP+FGF21 group showed elevated FGF21 levels (both P<0.01), attenuated pancreatic and lung injury ( P<0.001), decreased TNF-α levels [(280.10±49.36) pg/mL vs. (86.32±66.00) pg/mL, P<0.001]. Lung tissue of LC3 Ⅱ/Ⅰ levels increase [(0.700±0.135) vs. (0.853±0.073), P<0.01], P62 protein levels cut [(0.687±0.070) vs. (0.538±0.030), P<0.01] ], and increased autophagosomes and autolysosomes under electron microscopy. Compared with SAP+FGF21 group, the expression levels of FGF21 in plasma and lung tissue in SAP+FGF21+3-MA group were not significantly changed, and the level of autophagy was decreased. Pancreas and lung tissue injury was severe ( P<0.001), Plasma TNF-α level obviously higher [(86.32±66.00) pg/mL vs. (212.90±11.56) pg/mL, P<0.05]. Conclusion:FGF21 may play a protective role in SAP-ALI by up-regulating the level of autophagy.

Objective:Time trade-off was employed to measure health state utilities associated with treatment attributes of hemophilia A patients to provide parameters for economic evaluations.Methods:Patients were recruited through patient organization and blood center of Shandong to measure health state utility values for 10 health states.Results:The utility values of preventive treatments for severe,moderate,and mild hemophilia A were 0.644,0.738,and 0.815,respectively.Compared with injections at 2-day intervals,the utility values were increased by 0.044 and 0.092 at 3-and 4-day intervals,respectively.Taking"severe hemophilia A patients injected every 2 days"as the base state,the disutility values for spontaneous bleeding and traumatic bleeding were 0.226 and 0.172.The disutility values for mild,moderate,and severe bleeding were 0.052,0.159,and 0.476,respectively,and the magnitude of the decrease gradually increased.Conclusion:Treatment attributes have an impact on patient preferences and more attention should be paid in pharmacoeconomic evaluations.

Purpose: Chronic low-grade inflammation is linked to the biology of aging; however, evidence supporting a causal relationship between periodontitis—a dysbiotic biofilminitiated inflammatory disease—and accelerated aging remains limited. This study investigated the causality between periodontitis and biological aging and identified potentially shared genomic loci, genes, and pathways. Methods: We conducted a 2-sample Mendelian randomization (MR) analysis to explore the causality of periodontitis on age acceleration measures (DNAm PhenoAge acceleration, GrimAge acceleration, Hannum age acceleration, and intrinsic epigenetic age acceleration) using a dataset from genome-wide association studies of European ancestry populations.Independent genetic variants associated with each trait were used as instrumental variables.The inverse variance-weighted (IVW) method served as the primary MR approach, supplemented by sensitivity testing. We also performed additional statistical genetic analyses to identify pleiotropic loci, shared functional genes, and potential biological pathways, integrating large-scale expression quantitative trait loci data from blood samples. Results: The MR analysis indicated a causal relationship between periodontitis and DNAm PhenoAge acceleration (IVW β=0.308; 95% confidence interval, 0.056–0.561; P=0.017), a finding corroborated by sensitivity analyses. There was a significant genetic overlap between periodontitis and age acceleration. Pleiotropic analysis revealed 24 shared SNPs associated with 242 genes, predominantly involved in immune functions and pathways related to cellular processes. Further integration analysis showed that 91 of these pleiotropic genes were causally linked to both conditions, with C6orf183 identified as a potential mediator. Conclusions This study presents compelling genetic evidence supporting a causal relationship between periodontitis and accelerated aging. Further research is required to validate these findings and investigate the underlying mechanisms.

OBJECTIVE To review the current research progress on pharmacoeconomics evaluation related to spinal muscular atrophy （SMA）， in order to provide valuable insights for clinical treatment， screening and medical insurance payment decision- making. METHODS A computerized search was conducted across multiple databases including PubMed， Web of Science， Embase， Scopus， Cochrane Library， EBSCOhost， CNKI， VIP， CBM and Wanfang database as well as other important health technology assessment （HTA） websites， such as National Institute for Health and Care Research，International Society of Technology Assessment in Health Care， Agency for Healthcare Research and Quality， etc. The pharmacoeconomics evaluation studies related to SMA were collected from the inception to December 31st， 2023. The literature/reports were rigorously screened based on predefined inclusion and exclusion criteria by two researchers， and the essential information from the included literature/ reports was extracted using Excel 2019. The quality of the included literature/reports was evaluated by Consolidated Health Economic Evaluation Reporting Standards 2022. RESULTS Finally， 9 articles and 15 HTA reports were included， with overall good quality of literature， but poor quality of HTA reports. There were a total of 24 studies on the pharmacoeconomics evaluation of SMA， including treatment options such as nusinersen sodium， sovaprevir， risperidone， and best supportive therapy.The review results showed that nusinersen sodium was not cost-effective in the treatment of SMA； there was no consensus on the economic viability of treatment options such as risperidone and sovaprevir； newborn/prenatal screening combined withmedication therapy was cost-effective. CONCLUSIONS newborn/prenatal screening combined with SMA medication therapy demonstrates economic advantages. It is suggested to further investigate the cost-effectiveness of new SMA drugs and SMA screening in China， taking localization parameters and medical insurance prices into account， and gradually incorporate SMA screening into the scope of neonatal genetic disease detection， in order to alleviate the financial burden of patients’ families and healthcare systems.

The STAR tool was used to evaluate and analyze the science, transparency, and applicability of Chinese pathology guidelines and consensus published in medical journals in 2022. There were a total of 18 pathology guidelines and consensuses published in 2022, including 1 guideline and 17 consensuses. The results showed that the guideline score was 21.83 points, lower than the overall guideline average (43.4 points). Consensus ratings scored an average of 27.87 points, on par with the overall consensus level (28.3 points). Areas that scored above the overall level were "conflict of interest" and "working groups", while areas that scored below the overall level were "proposals", "funding", "evidence", "consensus approaches" and "accessibility". To sum up, the formulation of pathology guidelines and consensuses in 2022 is not standardized, and the evidence retrieval process, evidence evaluation methods and grading criteria for recommendations on clinical issues are not provided in the formulation process; the process and method for reaching consensus are not provided, the plan is lacking, and registration is not carried out. It is therefore suggested that guidelines/consensus makers in the field of pathology should attach importance to evidence-based medical evidence, strictly follow guideline formulation methods and processes, further improve the scientific, applicable and transparent guidelines/consensuses in the field, and better provide support for clinicians and patients.

OBJECTIVE: To investigate the effects of Jin's three-needles therapy combined with low-frequency repetitive transcranial magnetic stimulation (rTMS) on sleep disorders and EEG activity in children with spastic cerebral palsy (CP). METHODS: By using stratified randomization method, 100 children of spastic CP with sleep disorders were randomly assigned to a control group and an observation group, with 50 cases in each group. The patients in the control group were treated with medication, comprehensive rehabilitation training, and low-frequency rTMS, while the patients in the observation group were treated with Jin's three-needles therapy in addition to the interventions given to the control group. Acupoints selected included temporal three needles, brain three needles, intelligence three needles, four spirits needles, and bilateral Ganshu (BL 18), Shenshu (BL 23), Shenmai (BL 62), and Zhaohai (KI 6). Treatment was given once daily, five times a week, for 12 weeks. The Pittsburgh sleep quality index (PSQI) and children's sleep habits questionnaire (CSHQ) scores, modified Ashworth grade, Peabody developmental motor scales-2 (PDMS-2) score, and relative power values of δ, θ, β1, and β2 frequency bands in EEG were observed before and after treatment in both groups. Treatment safety was also evaluated. RESULTS: Compared before treatment, PSQI and CSHQ scores were decreased in both groups after treatment (P<0.05), with lower scores in the observation group than the control group (P<0.05). The modified Ashworth grade showed improvement (P<0.05), with better results in the observation group (P<0.05). PDMS-2 scores were increased in all dimensions (P<0.05), with higher scores in the observation group (P<0.05). Relative power values of δ and θ frequency bands in EEG were decreased (P<0.05), with lower values in the observation group (P<0.05), while relative power values of β1 and β2 frequency bands were increased (P<0.05), with higher values in the observation group (P<0.05). Children in both groups did not occurred obvious adverse reactions. CONCLUSION Jin's three-needles therapy combined with low-frequency rTMS can effectively improve sleep disorders, spasticity and motor function, regulate EEG activity in children with spastic CP and sleep disorder, and have good safety.
Humans ; Male ; Cerebral Palsy/physiopathology* ; Female ; Child ; Electroencephalography ; Transcranial Magnetic Stimulation ; Acupuncture Points ; Child, Preschool ; Acupuncture Therapy ; Sleep Wake Disorders/physiopathology* ; Combined Modality Therapy ; Treatment Outcome

OBJECTIVE: To investigate the effects of fecal microbiota transplantation (FMT) on intestinal microbiome and organism in patients with severe pneumonia during the convalescence period. METHODS: A prospective non-randomized controlled study was conducted. From December 2021 to May 2022, patients with severe pneumonia during the convalescence period who received FMT (FMT group) and patients with severe pneumonia during the convalescence period who did not receive FMT (non-FMT group) admitted to the First Affiliated Hospital of Guangzhou Medical University were enrolled. The differences of clinical indicators, gastrointestinal function and fecal traits between the two groups were compared 1 day before and 10 days after enrollment. The 16S rDNA gene sequencing technology was used to analyze the changes of intestinal flora diversity and different species in patients with FMT before and after enrollment, and metabolic pathways were analyzed and predicted by Kyoto Encyclopedia of Genes and Genomes database (KEGG). Pearson correlation method was used to analyze the correlation between intestinal flora and clinical indicators in FMT group. RESULTS: The level of triacylglycerol (TG) in FMT group was significantly decreased at 10 days after enrollment compared with before enrollment [mmol/L: 0.94 (0.71, 1.40) vs. 1.47 (0.78, 1.86), P < 0.05]. The level of high-density lipoprotein cholesterol (HDL-C) in non-FMT group was significantly decreased at 10 days after enrollment compared with before enrollment (mmol/L: 0.68±0.27 vs. 0.80±0.31, P < 0.05). There were no significant differences in other clinical indexes, gastrointestinal function or fecal character scores between the two groups. Diversity analysis showed that the α diversity indexes of intestinal flora in FMT group at 10 days after enrollment were significantly higher than those in non-FMT group, and β diversity was also significantly different from that in non-FMT group. Differential species analysis showed that the relative abundance of Proteobacteria at the level of intestinal flora in FMT group at 10 days after enrollment was significantly lower than that in non-FMT group [8.554% (5.977%, 12.159%) vs. 19.285% (8.054%, 33.207%), P < 0.05], while the relative abundance of Fusobacteria was significantly higher than that in non-FMT group [6.801% (1.373%, 20.586%) vs. 0.003% (0%, 9.324%), P < 0.05], and the relative abundance of Butyricimonas, Fusobacterium and Bifidobacterium at the genus level of the intestinal flora was significantly higher than that in non-FMT group [Butyricimonas: 1.634% (0.813%, 2.387%) vs. 0% (0%, 0.061%), Fusobacterium: 6.801% (1.373%, 20.586%) vs. 0.002% (0%, 9.324%), Bifidobacterium: 0.037% (0%, 0.153%) vs. 0% (0%, 0%), all P < 0.05]. KEGG metabolic pathway analysis showed that the intestinal flora of FMT group was changed in bisphenol degradation, mineral absorption, phosphonate and phosphinate metabolism, cardiac muscle contraction, Parkinson disease and other metabolic pathways and diseases. Correlation analysis showed that Actinobacteria and prealbumin (PA) in intestinal flora of FMT group were significantly positively correlated (r = 0.53, P = 0.043), Bacteroidetes was positively correlated with blood urea nitrogen (BUN; r = 0.56, P = 0.029) and complement C3 (r = 0.57, P = 0.027), Firmicutes was positively correlated with BUN (r = 0.56, P = 0.029) and complement C3 (r = 0.57, P = 0.027), Fusobacteria was significantly positively correlated with immunoglobulin M (IgM; r = 0.71, P = 0.003), Proteobacteria was significantly positively correlated with procalcitonin (PCT; r = 0.63, P = 0.012) and complement C4 (r = 0.56, P = 0.030). CONCLUSIONS FMT can reduce TG level, reconstruct intestinal microecological structure, change body metabolism and function, and alleviate inflammatory response by reducing the relative abundance of harmful bacteria in patients with severe pneumonia during the convalescence period.
Humans ; Fecal Microbiota Transplantation ; Complement C3 ; Convalescence ; Prospective Studies ; Feces