OBJECTIVE To investigate the causal relationships between gut microbiota， blood metabolites and antidepressant treatment response from a genetic perspective， and to assess the potential mediating role of blood metabolites. METHODS This study utilized a two-sample Mendelian randomization （MR） design. Exposure data were derived from four large-scale gut microbiome genome-wide association study （GWAS） datasets and two blood metabolite GWAS datasets. The inverse variance weighted method was used as the primary method to evaluate the causal relationships between gut microbiota， blood metabolites and antidepressant effects. The robustness， heterogeneity and horizontal pleiotropy of the results were evaluated through various sensitivity analyses. Additionally， the false discovery rate （FDR） was applied to correct type Ⅰ errors caused by multiple hypothesis testing. Finally， MR mediation analysis was conducted to test the potential mediating effect of blood metabolites. RESULTS The s_ Bilophila was negatively associated with the effectiveness of antidepressant treatment （ P ＝8.030×10 －5 ， then P ＝0.033 after FDR correction）， and the f_Bacteroidales was positively associated with the effectiveness of antidepressant treatment （ P ＝3.275×10 －4 ， then P ＝0.034 after FDR correction）. Over a hundred blood metabolites were also screened out as being associated with antidepressant response， but after FDR correction， no significant causal relationship was observed. The P value of the mediation effect proportion of blood metabolites in the “gut microbiota-blood metabolites-antidepressant efficacy” pathway was greater than 0.05. CONCLUSIONS The s_ Bilophila may represent a risk factor for antidepressant effects， whereas the f_Bacteroidales may serve as a protective factor for antidepressant effects. The correlation between blood metabolites and antidepressant efficacy is not strong， and no genetic evidence is found to support that the investigated blood metabolites play a key mediating role between the gut microbiota and antidepressant response.

Objective:Based on value orientation,it aimed to scientifically define the concept and connotation of accessibility to novel anticancer drugs,in order to deeply understand the nature and current status of the accessibility issues of novel anticancer drugs,and to provide a reference for the formulation and optimization of policies related to novel anticancer drugs.Methods:Data was collected through literature review and expert interviews,and the concept of drug accessibility was defined using the atomic diagram method.Results:The core images include"affordability","availability","high quality"and"patients".The concept of accessibility to novel anticancer drugs is defined as"the process of ensuring the sustainable supply,equitable access,affordability,and rational use of high-quality anticancer drugs to safeguard the realization of patient benefit goals."The connotation of the value orientation in policies on the accessibility of novel anticancer drugs is profoundly reflected in the multi-dimensional value-driven approach to ensure the ultimate benefit of patients,which includes quality,sustainability,equity,affordability,and rational use.Conclusion:The proposal of the concept and connotation of accessibility provides a theoretical basis for a deep understanding of the accessibility of novel anticancer drugs and offers valuable references for subsequent policy-making and practical operations.

Serotonin-selective reuptake inhibitors （SSRIs）， as widely used antidepressants in clinical practice， exhibit significant individual differences in antidepressant efficacy. Gut microbiota plays an important role in the development and progression of depression， and the use of SSRIs exerts a significant impact on the gut microbiota of patients with depression. Based on this， this article reviews the research progress on the interactions between the antidepressant effects of SSRIs and gut microbiota. It has been found that SSRIs can influence the diversity， abundance， and function of the gut microbiota directly or indirectly. Conversely， the composition of the gut microbiota and differences in its functional metabolic pathways， and other factors， can in turn affect the antidepressant effects of SSRIs. Therefore， in clinical practice， gut microbiota diversity can be utilized as a predictive indicator for the antidepressant effects of SSRIs. Probiotics can be employed as an adjunct therapy alongside SSRIs， and dietary adjustments， as well as fecal microbiota transplantation， can be used to enhance the therapeutic efficacy of SSRIs. In the future， large-scale， multicenter clinical studies should be conducted， enrolling a broadly representative cohort of patients with depression， to uncover the true association between the antidepressant effects of SSRIs and gut microbiota， thereby opening up more effective avenues for the comprehensive treatment of depression.

Objective To analyze the policy texts related to pediatric medications in China over the past decade,to explore the deficiencies in existing policy formulation from the perspective of stakeholders,and to propose reasonable optimization suggestions based on the current situation.Methods Collecting national-level policies related to pediatric drugs in China from 2013 to 2023,a two-dimensional policy analysis framework of"Policy tools-Stakeholder"were established.And the content analysis method was used to code,categorize,and statistically analyze the policy texts.Results A total of 54 pediatric drug policies were included in the analysis.In terms of policy tools,a total of 197 policy codes were formed,with environmental tools being the most prevalent with 92 codes(46.70％),primarily consisting of regulatory management tools(28 codes,30.43％).This was followed by supply-oriented tools with 53 codes(26.90％),mainly focused on the issuance of technical guidelines(21 codes,39.62％).Demand-oriented tools accounted for the least with 52 codes(26.40％),with inter-departmental collaboration tools having the highest proportion(17 codes,32.69％).In the dimension of stakeholders,a total of 223 policy codes were formed,with the government having the highest number of codes at 133(59.64％),followed by medical institutions with 56 codes(25.11％).The proportions for medical personnel,pharmaceutical companies,and patients were similar,with 14 codes(6.28％),11 codes(4.93％),and 9 codes(4.04％),respectively.Conclusions Pediatric drugs face challenges with policy tools where supply-oriented tools,particularly those providing financial support,suffer from insufficient policy depth and customization.The demand-oriented tools have a low proportion,leading to structural imbalance and underutilized effectiveness;the environment-oriented tools focus more on regulation than incentives,restricting the accessibility of pediatric drugs;the potential of multiple stakeholders is not fully activated,and there is a lack of policies centered around pediatric patients.To address these issues,supply-oriented policy tools need to establish a diversified financial support model and clearly define the scope of coverage.Demand-oriented policy tools require further adjustments to the catalog,procurement upgrades,and international collaborative research to reshape the pediatric drug security system.Environmental policy tools should enhance economic support,strengthen intellectual property rights,and implement targeted education to build a development ecosystem for pediatric drugs.Regarding stakeholders,it is essential to strengthen multi-stakeholder collaboration and optimize pediatric drug policy tools with a patient-centered approach.

Objective To analyze the policy texts related to pediatric medications in China over the past decade,to explore the deficiencies in existing policy formulation from the perspective of stakeholders,and to propose reasonable optimization suggestions based on the current situation.Methods Collecting national-level policies related to pediatric drugs in China from 2013 to 2023,a two-dimensional policy analysis framework of"Policy tools-Stakeholder"were established.And the content analysis method was used to code,categorize,and statistically analyze the policy texts.Results A total of 54 pediatric drug policies were included in the analysis.In terms of policy tools,a total of 197 policy codes were formed,with environmental tools being the most prevalent with 92 codes(46.70％),primarily consisting of regulatory management tools(28 codes,30.43％).This was followed by supply-oriented tools with 53 codes(26.90％),mainly focused on the issuance of technical guidelines(21 codes,39.62％).Demand-oriented tools accounted for the least with 52 codes(26.40％),with inter-departmental collaboration tools having the highest proportion(17 codes,32.69％).In the dimension of stakeholders,a total of 223 policy codes were formed,with the government having the highest number of codes at 133(59.64％),followed by medical institutions with 56 codes(25.11％).The proportions for medical personnel,pharmaceutical companies,and patients were similar,with 14 codes(6.28％),11 codes(4.93％),and 9 codes(4.04％),respectively.Conclusions Pediatric drugs face challenges with policy tools where supply-oriented tools,particularly those providing financial support,suffer from insufficient policy depth and customization.The demand-oriented tools have a low proportion,leading to structural imbalance and underutilized effectiveness;the environment-oriented tools focus more on regulation than incentives,restricting the accessibility of pediatric drugs;the potential of multiple stakeholders is not fully activated,and there is a lack of policies centered around pediatric patients.To address these issues,supply-oriented policy tools need to establish a diversified financial support model and clearly define the scope of coverage.Demand-oriented policy tools require further adjustments to the catalog,procurement upgrades,and international collaborative research to reshape the pediatric drug security system.Environmental policy tools should enhance economic support,strengthen intellectual property rights,and implement targeted education to build a development ecosystem for pediatric drugs.Regarding stakeholders,it is essential to strengthen multi-stakeholder collaboration and optimize pediatric drug policy tools with a patient-centered approach.

Objective:Based on value orientation,it aimed to scientifically define the concept and connotation of accessibility to novel anticancer drugs,in order to deeply understand the nature and current status of the accessibility issues of novel anticancer drugs,and to provide a reference for the formulation and optimization of policies related to novel anticancer drugs.Methods:Data was collected through literature review and expert interviews,and the concept of drug accessibility was defined using the atomic diagram method.Results:The core images include"affordability","availability","high quality"and"patients".The concept of accessibility to novel anticancer drugs is defined as"the process of ensuring the sustainable supply,equitable access,affordability,and rational use of high-quality anticancer drugs to safeguard the realization of patient benefit goals."The connotation of the value orientation in policies on the accessibility of novel anticancer drugs is profoundly reflected in the multi-dimensional value-driven approach to ensure the ultimate benefit of patients,which includes quality,sustainability,equity,affordability,and rational use.Conclusion:The proposal of the concept and connotation of accessibility provides a theoretical basis for a deep understanding of the accessibility of novel anticancer drugs and offers valuable references for subsequent policy-making and practical operations.

Objective To observe the changes in the subfoveal choroidal thickness(SFCT)of children and adoles-cents with different refractive states using optical coherence tomography angiography.Methods A total of 171 children and adolescents were followed.They were divided into the lower primary school group(6-8 years old),upper primary school group(9-11 years old),and junior high school group(12-14 years old)according to their age at the time of en-rollment.Dioptric examinations(including best corrected visual acuity,diopter,intraocular pressure,corneal curvature,axial length and SFCT)were performed,data collection was conducted twice in half a year(initial examination and review after half a year),and the eyeball parameters and changes in eyeball parameters after half a year among all groups were compared.Results The axial length and SFCT of subjects had significant differences among all groups(both P＜0.05).In children and adolescents,the axial length gradually lengthened and SFCT gradually thickened with age,while intraocular pressure and corneal curvature were not associated with age(both P＞0.05).In the initial examination and review after half a year,there was no significant difference in intraocular pressure,corneal curvature and SFCT of subjects with differ-ent refractive states in all groups(all P＞0.05),while the axial length of myopic subjects was greater than that of non-my-opic subjects in all groups(all P＜0.05).In the review after half a year,the SFCT of non-myopic subjects in the lower pri-mary school group and upper primary school group was significantly thickened(P＜0.001,P=0.003),while there was no significant difference in SFCT of myopic subjects in all groups compared with the value half a year ago(all P＞0.05).The axial length of all subjects showed a positive correlation with the SFCT in the initial examination and review after half a year(r=0.354,0.228,P＜0.05).Conclusion Myopia affects the increase in SFCT in children and adolescents.

Objective:To evaluate the feasibility of using two-dimensional shear wave elastography (2D-SWE) based liver and spleen elastic hardness (L/S-SWE) in patients with liver cirrhosis, and to determine the exclusion and diagnostic thresholds for early identification of liver cirrhosis.Methods:A total of 574 patients with chronic hepatitis B (hepatitis B for short) were included in this study. The clinical characteristics, L-SWE and S-SWE of the patients were collected, and the differences between cirrhosis group ( n=311) and non cirrhosis group ( n=263) were analyzed. The success rate and stability of liver and spleen elastic surgery were evaluated in two groups. The receiver operating characteristic (ROC) curve was used to analyze the efficacy of L-SWE, S-SWE, aspartate aminotransferase to platelet ratio index (APRI) alone and in combination in diagnosing liver cirrhosis. By analyzing the ROC curve, the double threshold for excluding and diagnosing liver cirrhosis was determined. Results:There was a statistically significant difference in platelet count and APRI between the cirrhosis group and the non cirrhosis group (all P<0.05). In the feasibility assessment of 2D-SWE technology, the success rate and stability of liver and spleen elastic operation were relatively high (success rate: 97.2% vs 81.3%; stability: 0.92 vs 0.84), and the success rate and stability of L-SWE operation were slightly better than S-SWE. The success rate of S-SWE operation in the cirrhosis group was higher than that in the non cirrhosis group ( P<0.05). The correlation analysis results showed that L-SWE, S-SWE, APRI were positively correlated with liver tissue pathological grading ( r=0.677, 0.528, 0.149, all P<0.05). The areas under the ROC curve for identifying liver cirrhosis using L-SWE, S-SWE, and APRI were 0.959, 0.896, and 0.706, respectively. When L-SWE and S-SWE were combined, the area under the ROC curve was 0.987, the sensitivity was 92.6%, and the specificity was 96.0%. The Delong test showed that the combined diagnosis of L-SWE and S-SWE had the same diagnostic efficacy as using L-SWE alone for liver cirrhosis ( P>0.05). Further analysis of the ROC curve showed that the likelihood of liver cirrhosis was low when L-SWE was less than 9.4 kPa, and high when L-SWE was greater than 12.0 kPa. Patients between 9.4 and 12.0 kPa can undergo further S-SWE testing; If the S-SWE was between 17.5 and 29.3 kPa, it was classified as 2D-SWE, which was difficult to determine whether there was liver cirrhosis, and further liver puncture and other examinations were needed. Conclusions:2D-SWE technology has high operational feasibility in the diagnosis of liver cirrhosis, and combined with S-SWE, it helps to improve the diagnostic efficiency of early non-invasive identification of liver cirrhosis, enabling more patients to avoid unnecessary liver puncture examinations.

Along with the develoipment of high-throughput sequencing technologies, both sample size and SNP number are increasing rapidly in genome-wide association studies (GWAS), and the associated computation is more challenging than ever. Here, we present a memory-efficient, visualization-enhanced, and parallel-accelerated R package called"rMVP"to address the need for improved GWAS computation. rMVP can 1) effectively process large GWAS data, 2) rapidly evaluate population structure, 3) efficiently estimate variance components by Efficient Mixed-Model Association eX-pedited (EMMAX), Factored Spectrally Transformed Linear Mixed Models (FaST-LMM), and Haseman-Elston (HE) regression algorithms, 4) implement parallel-accelerated association tests of markers using general linear model (GLM), mixed linear model (MLM), and fixed and random model circulating probability unification (FarmCPU) methods, 5) compute fast with a globally efficient design in the GWAS processes, and 6) generate various visualizations of GWAS-related information. Accelerated by block matrix multiplication strategy and multiple threads, the association test methods embedded in rMVP are significantly faster than PLINK, GEMMA, and FarmCPU_pkg. rMVP is freely available at https://github.com/xiaolei-lab/rMVP.

Objective:To investigate the effects of berberine on Sprague Dawley (SD) rat retinal Müller cells cultured by high concentration glucose.Methods:The cultured SD rat retinal Müller cells were divided into normal-glucose group, high-glucose group, high-glucose+ 10 μmol/L berberine group and high-glucose+ 25 μmol/L berberine group, and the cells were cultured in 5 mmol/L glucose, 25 mmol/L glucose, 25 mmol/L glucose+ 10 μmol/L berberine, and 25 mmol/L glucose+ 25 μmol/L berberine, respectively.After 72 hours cultured, cell apoptosis rate was detected by flow cytometry; the expressions levels of tumor necrosis factor-α (TNF-α), interleukin-8 (IL-8) and cyclooxygenase-2 (COX-2) in the culture supernatant were detected by enzyme linked immunosorbent assay (ELISA); the L-glutamate-L-aspartate transporter (GLAST) and the related protein expression levels were detected by real-time fluorescence quantitative PCR; the expressions levels of GLAST, protein phosphatase magnesium-dependent 1A (PPM1A), nuclear factor-κB (NF-κB) and cleaved caspase-3 in the cytoplasm, and the expression level of NF-κB protein in the nucleus were detected by Western blot.Results:The cell apoptosis rate was (1.37±0.21)%, (17.67±1.17)%, (10.60±0.17)% and (5.57±0.35)% in the normal-glucose group, high-glucose group, high-glucose+ 10 μmol/L berberine group and high-glucose+ 25 μmol/L berberine group, respectively, and the overall comparative difference was statistically significant ( F=375.97, P<0.01). The cell apoptosis rates in the high-glucose group was increased in comparison with those in the normal-glucose group ( P<0.01). The cell apoptosis rates in the high-glucose+ 10 μmol/L berberine group and high-glucose+ 25 μmol/L berberine group were significantly reduced in comparison with that in the high-glucose group (both at P<0.01). And the cell apoptosis rate in the high-glucose+ 25 μmol/L berberine group was lower than that in the high-glucose+ 10 μmol/L berberine group ( P<0.01). ELISA results revealed that the overall comparative differences of the concentrations of TNF-α, IL-8 and COX-2 among the four groups were statistically significant ( F=28.36, 35.88, 41.59; all at P<0.01). The concentrations of TNF-α, IL-8 and COX-2 in the high-glucose group were significantly higher than those in the normal-glucose group ( P<0.01). Compared with the high-glucose group, the concentrations of TNF-α and COX-2 were significantly decreased in the high-glucose+ 10 μmol/L berberine group and high-glucose+ 25 μmol/L berberine group (both at P<0.05). The concentrations of TNF-α and IL-8 in the high-glucose+ 25 μmol/L berberine group were lower than those in the high-glucose+ 10 μmol/L berberine group (both at P<0.05). Real-time fluorescence quantitative PCR showed that the relative expression levels of GLAST mRNA in Müller cells among the four groups were statistically significant ( F=268.60, P<0.01). Compared with the normal-glucose group, the relative expression level of GLAST mRNA was significantly decreased in the high-glucose group ( P<0.01). In the high-glucose+ 10 μmol/L berberine group and high-glucose+ 25 μmol/L berberine group, the relative expression level of GLAST mRNA was significantly elevated compared with the high-glucose group (both at P<0.05). Western blot analysis results showed that the overall comparative differences of the GLAST, PPM1A, cleaved caspase-3, NF-κB in cytoplasm and NF-κB in nucleus among the four groups were statistically significant ( F=135.20, 156.98, 80.96, 128.07, 47.36; all at P<0.01). The relative expression levels of GLAST, PPM1A and NF-κB protein in cytoplasm in the high-glucose group were significantly lower than those in the normal-glucose group, high-glucose+ 10 μmol/L berberine group and high-glucose+ 25 μmol/L berberine group (all at P<0.05). The relative expression levels of cleaved caspase-3 and NF-κB protein in nucleus in the high-glucose group were significantly higher than those in the normal-glucose group, high-glucose+ 10 μmol/L berberine group and high-glucose+ 25 μmol/L berberine group (all at P<0.05). Conclusions:High-concentration glucose can induce cell apoptosis and inflammatory response of SD rats retinal Müller cells in vitro.However, berberine can inhibit cell apoptosis and inflammatory response induced by high-concentration glucose via suppressing NF-κB translocation and transcription activity, and thereby inhibiting the expression of inflammatory cytokines.