BACKGROUND: The optimal antidepressant dosages remain controversial. This study aimed to analyze the efficacy of antidepressants and characterize their dose-response relationships in the treatments of major depressive disorders (MDD). METHODS: We searched multiple databases, including the Embase, Cochrane Central Register of Controlled Trials, PubMed, and Web of Science, for the studies that were conducted between January 8, 2016, and April 30, 2023. The studies are double-blinded, randomized controlled trials (RCTs) involving the adults (≥18 years) with MDD. The primary outcomes were efficacy of antidepressant and the dose-response relationships. A frequentist network meta-analysis was conducted, treating participants with various dosages of the same antidepressant as a single therapy. We also implemented the model-based meta-analysis (MBMA) using a Bayesian method to explore the dose-response relationships. RESULTS: The network meta-analysis comprised 135,180 participants from 602 studies. All the antidepressants were more effective than the placebo; toludesvenlafaxine had the highest odds ratio (OR) of 4.52 (95% confidence interval [CI]: 2.65-7.72), and reboxetine had the lowest OR of 1.34 (95%CI: 1.14-1.57). Moreover, amitriptyline, clomipramine, and reboxetine showed a linear increase in effect size from low to high doses. The effect size of toludesvenlafaxine increased significantly up to 80 mg/day and subsequently maintained the maximal dose up to 160 mg/day while the predictive curves of nefazodone were fairly flat in different dosages. CONCLUSIONS: Although most antidepressants were more efficacious than placebo in treating MDD, no consistent dose-response relationship between any antidepressants was observed. For most antidepressants, the maximum efficacy was achieved at lower or middle prescribed doses, rather than at the upper limit. REGISTRATION No. CRD42023427480; https://www.crd.york.ac.uk/prospero/display_record.php?
Humans ; Antidepressive Agents/therapeutic use* ; Depressive Disorder, Major/drug therapy* ; Dose-Response Relationship, Drug ; Randomized Controlled Trials as Topic

Objective:To explore the progress and trend in research of target trial emulation (TTE) and provide reference for research in this field.Methods:A literature retrival of research papers in this field published as of November 30, 2024 was conducted based on three databases (i.e. PubMed, Web of Science, and Scopus). The papers which were highly cited were analyzed by Bibliometrix package in R 4.3.2. The co-occurrence network of keywords were analyzed by using software VOSviewer. The keyword burst test was carried out with software CiteSpace.Results:A total of 685 papers from 314 journals were included. The annual number of the papers published showed a significant growth in recent three years. JAMA Network Open had the highest publication mumber related to TTE (34 papers), Annals of Internal Medicine had the highest H-index and American Journal of Epidemiology had the highest total citations. In the 2 997 authors, Hernán MA made a greatest contribution. In the 2 046 institutions, Harvard Medical School was at leading position. The analysis on highly cited papers and keyword co-occurrence showed that TTE was mainly used in the studies of COVID-19 vaccine, cancer and the treatment efficacy and safety of chronic diseases. The analysis on the co-occurence of keyword burst test showed that keywords frequently used until 2024 were COVID-19 vaccine, cardiovascular disease and breast cancer. Conclusions:TTE is mainly used in the studies of public health emergency (such as COVID-19), patients with cancer and chronic diseases. TTE will play a crucial role when randomized controlled trial is difficult to conduct or current evidence requirement can not be met.

Objective:To optimize the image quality of PET/CT following 90Y-selective internal radiation therapy ( 90Y-SIRT) using block-sequential regularized expectation maximization (BSREM) reconstruction algorithm, and to evaluate its impact of different β values on image quality and quantitative analysis. Methods:A retrospective study was conducted on 8 male patients with hepatic tumors (age: 62(52, 71) years) treated at Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua Medicine Tsinghua University, between June 2024 and January 2025. All patients were treated with 90Y resin microspheres (2.6(0.9, 3.6)GBq) and underwent post-treatment 90Y PET/CT liver imaging. Imaging data were reconstructed using BSREM with different noise penalty weighting factors ( β values: 0, 300, 1000, 1500, 2500, 3500, 4000, 6000, 8000, 10000). Visual assessment was independently performed by two nuclear medicine physicians, using a 4-point scale (1=worst, 4=best). The mean score was considered as the final score. The consistency of the 2 reviewers was calculated and analyzed by Kappa test. Visual scores of different β value groups were compared by Friedman test. The β value demonstrating highest mean score and optimal consistency was selected as the optimal. Quantitative analysis was performed using MIM software to calculate the maximum absorbed dose ( Dmax) and the mean absorbed dose ( Dmean) for tumor, normal liver, and whole liver regions, and the CV was used to evaluate the impact of β values. Results:The visual assessment consistency of reviewers in 3 β value groups (0, 3500, 6000) were the highest (7/8) (all kappa=0.88, all P<0.05). Visual scores of the 10 β value groups were significantly different ( χ2=28.74, P<0.001), and the visual scores of 2 β value groups (3500, 4000) were the highest, both of which were 4.0(4.0, 4.0). Overall, visual assessment identified β=3500 as the optimal. Quantitative analysis revealed that, (1) Dmax in all regions (tumor, normal liver, whole liver) decreased with the increasing β values, stabilizing when β>1000 ( CV 56%-67%); (2) Dmean remained stable across different β values ( CV 0.04%-5.00%). Conclusions:In BSREM reconstruction, β=3500 is the optimal parameter for improving 90Y-PET image quality. β values significantly affect Dmax (stabilizing at β > 1000), but have no significant impact on Dmean, suggesting that reconstruction parameters primarily influence dose distribution morphology rather than average dose assessments.

Objective:To explore the progress and trend in research of target trial emulation (TTE) and provide reference for research in this field.Methods:A literature retrival of research papers in this field published as of November 30, 2024 was conducted based on three databases (i.e. PubMed, Web of Science, and Scopus). The papers which were highly cited were analyzed by Bibliometrix package in R 4.3.2. The co-occurrence network of keywords were analyzed by using software VOSviewer. The keyword burst test was carried out with software CiteSpace.Results:A total of 685 papers from 314 journals were included. The annual number of the papers published showed a significant growth in recent three years. JAMA Network Open had the highest publication mumber related to TTE (34 papers), Annals of Internal Medicine had the highest H-index and American Journal of Epidemiology had the highest total citations. In the 2 997 authors, Hernán MA made a greatest contribution. In the 2 046 institutions, Harvard Medical School was at leading position. The analysis on highly cited papers and keyword co-occurrence showed that TTE was mainly used in the studies of COVID-19 vaccine, cancer and the treatment efficacy and safety of chronic diseases. The analysis on the co-occurence of keyword burst test showed that keywords frequently used until 2024 were COVID-19 vaccine, cardiovascular disease and breast cancer. Conclusions:TTE is mainly used in the studies of public health emergency (such as COVID-19), patients with cancer and chronic diseases. TTE will play a crucial role when randomized controlled trial is difficult to conduct or current evidence requirement can not be met.

Objective:To optimize the image quality of PET/CT following 90Y-selective internal radiation therapy ( 90Y-SIRT) using block-sequential regularized expectation maximization (BSREM) reconstruction algorithm, and to evaluate its impact of different β values on image quality and quantitative analysis. Methods:A retrospective study was conducted on 8 male patients with hepatic tumors (age: 62(52, 71) years) treated at Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua Medicine Tsinghua University, between June 2024 and January 2025. All patients were treated with 90Y resin microspheres (2.6(0.9, 3.6)GBq) and underwent post-treatment 90Y PET/CT liver imaging. Imaging data were reconstructed using BSREM with different noise penalty weighting factors ( β values: 0, 300, 1000, 1500, 2500, 3500, 4000, 6000, 8000, 10000). Visual assessment was independently performed by two nuclear medicine physicians, using a 4-point scale (1=worst, 4=best). The mean score was considered as the final score. The consistency of the 2 reviewers was calculated and analyzed by Kappa test. Visual scores of different β value groups were compared by Friedman test. The β value demonstrating highest mean score and optimal consistency was selected as the optimal. Quantitative analysis was performed using MIM software to calculate the maximum absorbed dose ( Dmax) and the mean absorbed dose ( Dmean) for tumor, normal liver, and whole liver regions, and the CV was used to evaluate the impact of β values. Results:The visual assessment consistency of reviewers in 3 β value groups (0, 3500, 6000) were the highest (7/8) (all kappa=0.88, all P<0.05). Visual scores of the 10 β value groups were significantly different ( χ2=28.74, P<0.001), and the visual scores of 2 β value groups (3500, 4000) were the highest, both of which were 4.0(4.0, 4.0). Overall, visual assessment identified β=3500 as the optimal. Quantitative analysis revealed that, (1) Dmax in all regions (tumor, normal liver, whole liver) decreased with the increasing β values, stabilizing when β>1000 ( CV 56%-67%); (2) Dmean remained stable across different β values ( CV 0.04%-5.00%). Conclusions:In BSREM reconstruction, β=3500 is the optimal parameter for improving 90Y-PET image quality. β values significantly affect Dmax (stabilizing at β > 1000), but have no significant impact on Dmean, suggesting that reconstruction parameters primarily influence dose distribution morphology rather than average dose assessments.

Objective:Differences between randomized controlled trial (RCT) results and real world study (RWS) results may not represent a true efficacy-effectiveness gap because efficacy-effectiveness gap estimates may be biased when RWS and RCT differ significantly in study design or when there is bias in RWS result estimation. Secondly, when there is an efficacy- effectiveness gap, it should not treat every patient the same way but assess the real-world factors influencing the intervention's effectiveness and identify the subgroup likely to achieve the desired effect.Methods:Six databases (PubMed, Embase, Web of Science, CNKI, Wanfang Data, and VIP) were searched up to 31 st December 2022 with detailed search strategies. A scoping review method was used to integrate and qualitatively describe the included literature inductively. Results:Ten articles were included to discuss how to use the RCT research protocol as a template to develop the corresponding RWS research protocol. Moreover, based on correctly estimating the efficacy-effectiveness gap, evaluate the intervention effect in the patient subgroup to confirm the subgroup that can achieve the expected benefit-risk ratio to bridge the efficacy-effectiveness gap.Conclusion:Using real-world data to simulate key features of randomized controlled clinical trial study design can improve the authenticity and effectiveness of study results and bridge the efficacy-effectiveness gap.

Objective:Randomized controlled trials (RCT) usually have strict implementation criteria. The included subjects' characteristics of the conditions for the intervention implementation are quite different from the actual clinical environment, resulting in discrepancies between the risk-benefit of interventions in actual clinical use and the risk-benefit shown in RCT. Therefore, some methods are needed to enhance the extrapolation of RCT results to evaluate the real effects of drugs in real people and clinical practice settings.Methods:Six databases (PubMed, Embase, Web of Science, CNKI, Wanfang Data, and VIP) were searched up to 31 st December 2022 with detailed search strategies. A scoping review method was used to integrate and qualitatively describe the included literature inductively. Results:A total of 12 articles were included. Three methods in the included literature focused on: ①improving the design of traditional RCT to increase population representation; ②combining RCT Data with real-world data (RWD) for analysis;③calibrating RCT results according to real-world patient characteristics.Conclusions:Improving the design of RCT to enhance the population representation can improve the extrapolation of the results of RCT. Combining RCT data with RWD can give full play to the advantages of data from different sources; the results of the RCT were calibrated against real-world population characteristics so that the effects of interventions in real-world patient populations can be predicted.

Objective:To assess the safety of sitagliptin added to metformin on cardiovascular adverse events in real world patients with type 2 diabetes mellitus(T2DM).Methods:Real world data from Yinzhou Regional Health Care Database were used to select T2DM patients with diagnosis and treatment records in the platform from January 1,2017 to December 31,2022.According to drug prescription records,the patients were divided into metformin plus sitagliptin group(combination group)and metformin monotherapy group(monotherapy group).A series of retrospective cohorts were constructed according to the index date.Finally,full retrospective cohorts were constructed according to propensity score model,including baseline covariates that might be related to outcomes,to match the subjects in the combination group and monotherapy group for the purpose of increasing the comparability of baseline characteristics.The participants were followed up from the index date until the first occurrence of the following events:Diagnosis of outcomes,death,or the end of the study period(December 31,2022).Cox proportional risk model was used to estimate the hazard ratio(HR)and 95％confidence interval(CI)of sitagliptin added to metformin on 3-point major adverse cardiovascular events(3P-MACE)combination outcome and secondary cardiovascular outcomes.Results:Before propensity score matching,the proportion of the pa-tients in combination group using insulin,α glucosidase inhibitors,sodium-glucose transporter 2 inhibi-tors(SGLT-2I)and glienides at baseline was higher than that in monotherapy group,and the baseline fasting blood glucose(FBG)and hemoglobin A1c(HbA1c)levels in combination group were higher than those in monotherapy group.After propensity score matching,5 416 subjects were included in the combination group and the monotherapy group,and baseline characteristics were effectively balanced be-tween the groups.The incidence densities of 3P-MACE were 6.41/100 person years and 6.35/100 per-son years,respectively.Sitagliptin added to metformin did not increase or decrease the risk of 3P-MACE compared with the metformin monotherapy(HR=1.00,95％CI:0.91-1.10).In secondary outcomes analysis,the incidence of cardiovascular death was lower in the combination group than in the monothera-py group(HR=0.59,95％CI:0.41-0.85),and no association was found between sitagliptin and the risk of myocardial infarction and stroke(HR=1.12,95％CI:0.89-1.41;HR=0.99,95％CI:0.91-1.12).Conclusion:In T2DM patients in Yinzhou district of Ningbo,compared with metformin alone,sitagliptin added to metformin may reduce the risk of cardiovascular death,and do not increase the inci-dence of overall cardiovascular events.The results of this study can provide real-world evidence for post-marketing cardiovascular safety evaluation of sitagliptin.

Humans ; Incretins/therapeutic use* ; Diabetes Mellitus, Type 2/drug therapy* ; Hypoglycemic Agents/therapeutic use* ; Risk Assessment

Objective:To investigate the application value of renal depth correction by the integrated CT in glomerular filtration rate (GFR) determination by 99Tc m-diethylene triamine pentoacetic acid (DTPA) renal dynamic imaging for patients with hydronephrosis. Methods:A total of 338 patients (191 males, 147 females, age (49.6±14.5) years) in Beijing Tsinghua Changgung Hospital from April 2016 to June 2019 with different degrees of hydronephrosis were respectively analyzed. Patients were divided into groups of normal-mild, normal-moderate, normal-heavy, mild-mild, mild-moderate, mild-heavy, moderate-moderate, moderate-heavy and heavy-heavy according to the degree of bilateral hydronephrosis. The renal depth was measured by the integrated CT method and the routine method, and the absolute value of bilateral renal depth difference in normal-mild, normal-moderate and normal-heavy groups was calculated by the 2 methods. Based on the renal depth measured by the 2 methods, the single renal GFR was measured by 99Tc m-DTPA dynamic renal imaging Gates method and compared between the 2 methods. Total GFR measured by the 2 methods were compared with estimated GFR (eGFR). One-way analysis of variance analysis, paired t test, and Pearson correlation analysis were used. Results:For the integrated CT measurements, the absolute value of bilateral renal depth difference in normal-mild, normal-moderate and normal-heavy groups were significantly different ((0.39±0.24), (1.16±0.65) and (1.00±0.90) cm; F=15.241, P<0.05). The renal depth and the single renal GFR measured by the integrated CT method were higher than those measured by the routine method ( t values: 16.06-19.78, 14.27-17.23, all P<0.05) in the kidneys with normal, mild, moderate and heavy hydronephrosis. There were significant differences between the total GFR measured by the routine method and eGFR in all groups ( t values: from -8.178 to 5.879, all P<0.05); however, in the integrated CT method, except that the total GFRs in moderate-heavy group and heavy-heavy group were overestimated ( t values: 3.035 and 11.247, both P<0.05), there were no significant differences between the total GFR ((111.57±17.37), (103.71±15.22), (79.79±12.62), (100.33±18.49), (100.28±15.43), (84.09±20.72) and (74.14±14.57) ml·min -1·1.73 m -2) and eGFR ((109.16±12.81), (103.20±13.26), (78.60±14.12), (100.98±15.20), (99.89±14.05), (84.61±20.24) and (73.44±14.57) ml·min -1·1.73 m -2) in normal-mild, normal-moderate, normal-heavy, mild-mild, mild-moderate, mild-heavy and moderate-moderate groups ( t values: from -0.301 to 1.948, all P>0.05). The total GFR measured by the 2 methods were significantly correlated with eGFR in 338 patients with hydronephrosis ( r values: 0.888 and 0.928, both P<0.01). Conclusion:Compared with the routine method, except for the moderate-heavy group and heavy-heavy group, renal depth correction by the integrated CT may have greater clinical significance in GFR measurement by renal dynamic imaging for patients with hydronephrosis.