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 clinicopathological characteristics and prognosis of multiple-molecular classifier endometrioid adenocarcinomas with DNA polymerase epsilon catalytic subunit(POLE)mutations.Methods In this study,we involved 261 patients with endometrioid adenocarcinoma admitted to the Shengjing Hospital of China Medical University.We detected the expression of the POLE gene and that of p53 protein and mismatch repair(MMR)proteins using gene sequencing and immunohistochemistry,respectively.We analyzed the correlation between different molecular classifications and clinicopathological characteristics using x2 or Fisher test,and Kaplan-Meier survival curves to analyze patients' prognosis.Results We identified nine multiple-molecular classifier cases of endome-trioid adenocarcinoma with POLE mutations,including six POLE mutated+p53 abnormal(POLE mut+p53abn)and three POLE mutated+MMR-deficient(POLE mut+dMMR)cases.Patients with POLE mut+p53abn exhibited significant differences from those with p53abn in terms of the pathological characteristics of tumor-infiltrating lymphocytes and the presence of tumors with peritumoral lymphocyte infiltra-tion(P＜0.05),while no statistically significant difference was present compared to patients with POLE mut(P＞0.05).Kaplan-Meier sur-vival curve analysis revealed that the progression-free survival rates of patients with POLE mut+p53abn and POLE mut+dMMR(100.0％)were higher than those of patients with p53abn(50.0％)and dMMR(8.8％,P＜0.05).Conclusion The clinicopathological characteris-tics of patients with POLE mut+p53abn are similar to those with POLE mut.Both patients with POLE mut+p53abn and POLE mut+dMMR display a good prognosis.

Objective To explore the clinicopathological characteristics and prognosis of multiple-molecular classifier endometrioid adenocarcinomas with DNA polymerase epsilon catalytic subunit(POLE)mutations.Methods In this study,we involved 261 patients with endometrioid adenocarcinoma admitted to the Shengjing Hospital of China Medical University.We detected the expression of the POLE gene and that of p53 protein and mismatch repair(MMR)proteins using gene sequencing and immunohistochemistry,respectively.We analyzed the correlation between different molecular classifications and clinicopathological characteristics using x2 or Fisher test,and Kaplan-Meier survival curves to analyze patients' prognosis.Results We identified nine multiple-molecular classifier cases of endome-trioid adenocarcinoma with POLE mutations,including six POLE mutated+p53 abnormal(POLE mut+p53abn)and three POLE mutated+MMR-deficient(POLE mut+dMMR)cases.Patients with POLE mut+p53abn exhibited significant differences from those with p53abn in terms of the pathological characteristics of tumor-infiltrating lymphocytes and the presence of tumors with peritumoral lymphocyte infiltra-tion(P＜0.05),while no statistically significant difference was present compared to patients with POLE mut(P＞0.05).Kaplan-Meier sur-vival curve analysis revealed that the progression-free survival rates of patients with POLE mut+p53abn and POLE mut+dMMR(100.0％)were higher than those of patients with p53abn(50.0％)and dMMR(8.8％,P＜0.05).Conclusion The clinicopathological characteris-tics of patients with POLE mut+p53abn are similar to those with POLE mut.Both patients with POLE mut+p53abn and POLE mut+dMMR display a good prognosis.

Objective:To explore the application effect of nursing intervention based on Neil Noddings' caring theory in school-age children with asthma.Methods:From August 2018 to August 2019, a total of 112 school-age children with bronchial asthma were admitted to the Second Department of Pediatric Internal Medicine of Tangshan Maternal and Child Health Hospital. According to the random number table method, they were randomly divided into the control group and the observation group, with 56 cases in each group. The control group adopted routine nursing intervention, while the observation group adopted nursing intervention based on Neil Noddings' caring theory on the basis of routine intervention. The scores of The Screen for Child Anxiety Related Emotional Disorders (SCARED) , Self-Rating Scale for Depressive Disorder in Childhood (DSRSC) and self-management behavior of patients were compared between the two groups before the intervention and 1 month after the intervention.Results:After the intervention, the total scores and the scores of all dimensions of self-management behavior scale for children with asthma in the two groups were higher than those before the intervention ( P<0.05) , and score of the observation group was higher than that of the control group, and the differences were statistically significant ( P<0.05) . After the intervention, scores of SCARED and DSRSC of children in the two groups were lower than those before the intervention ( P<0.05) , and the score of the observation group was lower than that of the control group, and the differences were statistically significant ( P<0.05) . Conclusions:Nursing intervention based on Neil Noddings' caring theory can effectively reduce negative emotions of school-age children with asthma and improve their self-management behavior.

Gliomas are the most common primary intracranial neoplasms among all brain malignancies, and the microtubule affinity regulating kinases (MARKs) have become potential drug targets for glioma. Here, we report a novel dual small-molecule inhibitor of MARK3 and MARK4, designated as PCC0208017. PCC0208017 strongly inhibited kinase activity against MARK3 and MARK4, and strongly reduced proliferation in three glioma cell lines. This compound attenuated glioma cell migration, glioma cell invasion, and angiogenesis. Molecular mechanism studies revealed that PCC0208017 decreased the phosphorylation of Tau, disrupted microtubule dynamics, and induced a G2/M phase cell cycle arrest. In an glioma model, PCC0208017 showed robust anti-tumor activity, blood-brain barrier permeability, and a good oral pharmacokinetic profile. Molecular docking studies showed that PCC0208017 exhibited high binding affinity to MARK3 and MARK4. Taken together, our study describes for the first time that PCC0208017, a novel MARK3/MARK4 inhibitor, might be a promising lead compound for treatment of glioma.

Spinal surgery is a technically demanding and challenging procedure because of the complicated anatomical structures of the spine and its proximity to several important tissues. Surgical landmarks and fluoroscopy have been used for pedicle screw insertion but are found to produce inaccuracies in placement. Improving the safety and accuracy of spinal surgery has increasingly become a clinical concern. Computerassisted navigation is an extension and application of precision medicine in orthopaedic surgery and has significantly improved the accuracy of spinal surgery. However, no clinical guidelines have been published for this relatively new and fast-growing technique, thus potentially limiting its adoption. In accordance with the consensus of consultant specialists, literature reviews, and our local experience, these guidelines include the basic concepts of the navigation system, workflow of navigation-assisted spinal surgery, some common pitfalls, and recommended solutions. This work helps to standardize navigation-assisted spinal surgery, improve its clinical efficiency and precision, and shorten the clinical learning curve.

Tubulin has been shown to be an effective target for the development of cytotoxic agents against prostate cancer. Previously, we reported that Lx2-32c is an anti-tubulin agent with high binding affinity to tubulin. In this study, we investigated the potential of Lx2-32c to act as an effective cytotoxic agent in the treatment of prostate cancer. MTT assays showed that Lx2-32c was cytotoxic to all tested prostate cancer cell lines. The Lx2-32c-treated cells typically exhibited a rounded morphology associated with the onset of apoptosis, as evidenced by immunocytochemical staining. Human prostate cancer cell lines treated with Lx2-32c arrest in the G2/M phase of the cell cycle and the treatment is associated with an increased ratio of cells in the sub-G0/G1 phase as determined by flow cytometry. Furthermore, expression of the cleaved form of poly (ADP-ribose) polymerase in prostate cancer cell lines treated with Lx2-32c was shown by Western blotting assay. Xenograft implants of LNCaP and PC3-derived tumors in nude mice showed that Lx2-32c treatment significant inhibited tumor growth with effects equivalent to those of docetaxel. These findings demonstrate the potential of Lx2-32c as a candidate antitumor agent for the treatment of prostate cancer.

Objective To evaluate the dosimetric effects of air cavity on primary tumor and organs at risk (OARs) during intensity-modulated radiation therapy (IMRT) for nasopharyngeal carcinoma patients.Methods Nine patients with nasopharyngeal carcinoma had CT simulation before treatment and on the 25 fraction of radiotherapy.Radiotherapy plan1 was first created by delineating the target volumes and OARs on the first CT image, which was then copied and merged with the second CT image.Air cavity that was formed following tumor volume regression was delineated on the first CT image, and the density of air cavity was set to zero.A new gross target volume (GTV) was formed by subtracting the air cavity from the original GTV, and the new CT image was named CTAir.Plan2 was then created by calculating the dose distribution on CTAir using the same portals and parameters as Plan1.Assuming that Plan1 and Plan2 were both used throughout the course of radiotherapy, the dosimetric parameters of nasopharyngeal tumor and OARs in the absence and presence of air cavity were then compared using the paired t-test.Results Dmean, D95, D90, D10, and D5 of tumor were significantly higher in plan2 than in plan1(P=0.000, 0.001, 0.001, 0.001, and 0.005, respectively), with a<0.5 Gy increase in dose.A dose build-up effect was observed within the tumor region posterior to the air cavity, where the highest dose was 1.4 cm posterior to the air cavity, resulting in a dose difference of 0.36 Gy.In addition, D2cc and D1cc of the brain stem were significantly higher in plan2 than in plan1(P=0.036 and 0.044, respectively).Dmax of the optical chiasm, left optical nerve, and right optical nerve were also increased in the presence of air cavity (P=0.438, 0.434, and 0.477, respectively), but the change in dose was<0.12 Gy.Conclusions Air cavity induces a small but negligible increase in the tumor and OARs dose in patients with nasopharyngeal carcinoma during IMRT.However, closer monitoring should be conducted for patients with OARs that is close to or has surpassed tolerance prior to radiotherapy.

Objective To investigate the effect of tiaozhi granules on the autophagy of HU-VECs in the cell,protein and molecular levels.Methods HUVECs were induced by tiaozhi granule medicated serum,6-amino-3-methyl purine (3-MA) and rapamycin.MTT was used to detect the cell viability after 48 hours with tiaozhi granule medicated serum.Western blot was used to detect the expressive level of LC3-Ⅱ.Immunofluorescence was used to detect change in the numbers of autophagosomes.Results After HUVECs was processed by tiaozhi granule medicated serum,the cell viability had not change,the relative expression of autophagy related protein LC3-Ⅱ increased,and the number of autophagosomes increased (P ＜ 0.05).After HUVECs was processed by tiaozhi granule medicated serum and rapamycin,cell viability had no change,while the relative expression of autophagy related protein LC3-Ⅱ and the number of autophagosomes decreased significantly when compared with the results of intervention with rapamycin only (P ＜ 0.05 or P ＜ 0.01).Conclusion Tiaozhi granules can inhibit excessive autophagy of endothelial cells and promote moderate autophagy in endothelial cells.

Objective To investigate the effect of tiaozhi granules on the autophagy of HU-VECs in the cell,protein and molecular levels.Methods HUVECs were induced by tiaozhi granule medicated serum,6-amino-3-methyl purine (3-MA) and rapamycin.MTT was used to detect the cell viability after 48 hours with tiaozhi granule medicated serum.Western blot was used to detect the expressive level of LC3-Ⅱ.Immunofluorescence was used to detect change in the numbers of autophagosomes.Results After HUVECs was processed by tiaozhi granule medicated serum,the cell viability had not change,the relative expression of autophagy related protein LC3-Ⅱ increased,and the number of autophagosomes increased (P ＜ 0.05).After HUVECs was processed by tiaozhi granule medicated serum and rapamycin,cell viability had no change,while the relative expression of autophagy related protein LC3-Ⅱ and the number of autophagosomes decreased significantly when compared with the results of intervention with rapamycin only (P ＜ 0.05 or P ＜ 0.01).Conclusion Tiaozhi granules can inhibit excessive autophagy of endothelial cells and promote moderate autophagy in endothelial cells.