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

BACKGROUND:Tendinopathy is a musculoskeletal disorder characterized by pain and decreased mobility,with pathological changes of disturbed collagen and hyperplasia of the vasculature.Tendinopathy tends to occur in athletes,physical workers,and the elderly.One of the mechanisms of tendinopathy is the"failed healing response",and part of what causes the failed healing response is the erroneous differentiation of tendon stem/progenitor cells. OBJECTIVE:By reviewing the relevant literature,we introduce the characteristics of tendon stem/progenitor cells,summarize the factors that affect the differentiation of tendon stem/progenitor cells to tendon cells and those that lead to mis-differentiation of tendon stem/progenitor cells(differentiation to adipocytes,osteocytes and chondrocytes),and also describe the limitations of tendon stem/progenitor cells in clinical applications. METHODS:PubMed and Web of Science databases were searched for the terms"tendon stem/progenitor cells,tendinopathy,tendon injury,differentiation".The relevant literature was screened by reading and 109 articles were included for the analysis of the results. RESULTS AND CONCLUSION:(1)Tendon stem/progenitor cells are a type of stem cells that can spontaneously differentiate into tendons and have the ability to self-renew,clone,and multi-differentiate.Various external conditions acting on tendon stem/progenitor cells can lead them to differentiate in diverse directions.The specific factors that regulate the fate of tendon stem/progenitor cells are not known with certainty.When stem cell renewal and differentiation in tendons becomes abnormal,it can lead to failure of tendon healing and consequently to tendinopathy.(2)Aging,changes in extracellular matrix composition,excessive mechanical stimulation,prostaglandin E2 and interleukin-6 as well as interleukin-10 and some systemic diseases may be important in regulating the mis-differentiation of tendon stem/progenitor cells.(3)Possible favorable factors that promote the differentiation of tendon stem/progenitor cells to tenocytes are:some growth factors and cytokines,moderate mechanical stimulation and topography of the extracellular matrix,low oxygen tension,drugs,and several transcriptional genes and proteins.(4)The most desirable therapeutic tools are the regulation of endogenous tendon stem/progenitor cells or the stimulation of endogenous tendon stem/progenitor cell proliferation and differentiation by exogenous tendon stem/progenitor cells.(5)Understanding the factors that regulate mis-differentiation of tendon stem/progenitor cells may provide insight into the pathogenesis of tendinopathy and identify therapeutic targets.Elaborating on the induction of tendon stem/progenitor cell differentiation into tendons could facilitate their use in tissue engineering.

OBJECTIVE Microgravity exerts several negative effects on the learning and memory of astro-nauts during space flight.Rg1 and Rb1,the key steroidal components of ginseng,have shown potent neuroprotec-tive effects with a high safety profile.The object of the current study is to investigate the influence of Rg1 and Rb1 on simulated microgravity-induced memory and learning dysfunction in the hindlimb suspension(HLS)rat model.METHODS The HLS rats were orally administered Rg1(30 and 60 μmol·kg-1)or Rb1(30 and 60 μmol·kg-1)for four weeks.The Morris water maze test(MWM)and reward operating conditioning reflex test(ROCR)were conducted to evaluate spatial and associative learning and memory.After the behavior tests,the serum and the prefrontal cortex(PFC)were dissected to measure the mechanism.RESULTS Rg1 and Rb1 treatment amelio-rated the cognitive deficits of HLS-exposure rats in MWM and ROCR,reduced reactive oxygen species generation and increased antioxidant enzyme activity.Rg1 and Rb1 also assisted in the recovery of mitochondrial complex Ⅰ(NADH dehydrogenase)activities and Mfn2,and decrea-sed Drp-1 expression.Furthermore,Rg1 and Rb1 reduced the ratio of Bax/Bcl-2 and the expression of cleaved-cas-pase 3,cytochrome c,increased the levels of SYN,PSD95 and activated BDNF-TrkB/PI3K-Akt pathway in the PFC.CONCLUSION Rg1 and Rb1 treatment attenuated cog-nitive deficits induced by HLS,mitigated mitochondrial dysfunction,attenuated oxidative stress,inhibited apopto-sis,and increased the synaptic plasticity,which was partly mediated by the modulation of the BDNF-TrkB/PI3K-Akt signaling.

Objective:To analyze the clinicopathological characteristics of differentiated early cardia cancer and to evaluate the short-term and long-term efficacy of endoscopic submucosal dissection (ESD).Methods:A total of 329 patients (331 lesions) who underwent ESD at Nanjing Drum Tower Hospital from October 2014 to December 2019 and were pathologically confirmed as differentiated early cardia cancer were included in the study and followed up. The endoscopic and pathological data of patients were reviewed to analyze the clinicopathological characteristics of differentiated early cardia cancer. The short-term (including en bloc resection rate, curative resection rate and incidence of short-term complications) and long-term efficacy (including incidence of metachronous cancer, recurrence and distant metastasis, and overall survival rate) of ESD was evaluated.Results:The ratio of male to female in 329 patients with differentiated early cardia cancer was 4∶1, and their age was 65.69±8.02 years. Tumor diameter of ≤2.0 cm accounted for 65.9% (218/331). Most lesions were located on the posterior wall (50.5%, 167/331), followed by the minor curve (36.3%, 120/331). The endoscopic morphology of 0-Ⅱc type accounted for 49.5% (164/331). There were 69.8% (231/331) lesions confined to the mucosal layer. The en bloc resection rate was 100.0% (329/329), and the curative resection rate was 83.3% (274/329). Short-term complications occurred in 28 patients (8.5%). With a median follow-up time of 39 months, 11 patients (3.3%) developed metachronous cancer, 2 (0.6%) developed distant metastasis, and no recurrence occurred. Seven patients died, and the overall survival rate during the follow-up period was 97.9% (322/329). The survival rate of patients with curative resection and additional surgery was 100.0% (3/3), while that without additional surgery was 99.3% (269/271). The survival rate of patients with non-curative resection and additional surgery was 96.0% (24/25), and that without additional surgery was 86.7% (26/30).Conclusion:Most differentiated early cardia cancers are well-differentiated adenocarcinomas, with less than 2 cm in diameter at the time of diagnosis with a low rate of ulcer and vascular invasion. ESD is safe and effective for the treatment of differentiated early cardia cancer with a high rate of curative resection, fewer intraoperative and postoperative complications, low incidences of metachronous cancer, distant metastasis and recurrence, and a high overall survival rate. However, additional surgical treatment is recommended for patients with non-curative resection.

Objective:To investigate the efficacy and safety of targeted therapy with Crizotinib for children with ALK gene mutation positive inflammatory myofibroblastic tumor (IMT). Methods:A retrospective analysis was performed on 4 children with ALK gene mutation positive IMT admitted to Shanghai Children′s Hospital from January 2019 to June 2021.Among them, 3 cases were given the targeted drug Crizotinib[280 mg/(m 2· time), q12h] orally, and 1 case was observed after complete tumor resection to analyze the efficacy and adverse drug reactions. Results:All 4 cases were male, aged from 2 years and 3 months to 11 years and 3 months.The tumors originated from the abdominal cavity in 2 cases, the right orbit in 1 case, and the right lung in 1 case.Pathological immunohistochemistry and fluorescence in situ hybridization were both positive for ALK gene mutation, and complete remission was achieved after comprehensive treatment.Among them, 3 patients were treated with oral Crizotinib, and 2 patients were tried to stop taking the drug for 1 year, relapsed 1 month later, and still achieved complete remission after the second treatment.The 4 cases were followed up for 8-30 months, and all survived.All the cases showed no abnormalities in blood image, liver and kidney function, myocardial enzyme profile, cardiac function, hearing and vision, and 2 cases showed prolonged Q-T interval in the course of Crizotinib treatment, which could be recovered by temporary withdrawal of drug, and no abnormality in electrocardiogram was found in continued drug use. Conclusions:Crizotinib was used to treat ALK mutation positive IMT, shrink tumor and consolidate postoperative treatment, which is a good choice for IMT in children with difficult surgical resection and refractory recurrence.

Objective:To study the safety and efficacy of endoscopic submucosal dissection (ESD) for early gastric cardia cancer (EGCC) in elderly patients.Methods:A retrospective analysis was performed on data of 499 EGCC patients who underwent ESD from January 2011 to June 2018 in Nanjing Drum Tower Hospital. The patients were divided into two groups by age, the young/middle-aged group (<65 years old) and the elderly group (≥65 years old). The baseline data, lesion features, postoperative complications, short-term efficacy and long-term efficacy of the two groups were compared.Results:The elderly group included 272 patients (283 lesions) and the young/middle-aged group included 227 patients (229 lesions). Except that there were significant differences in the age ( P<0.001) and body mass index ( P=0.002) between the elderly group and the young/middle-aged group, there were no significant differences in the baseline data or pathological features between the two groups. The rate of curative resection in the elderly group was 77.0%, lower than that in the young/middle-aged group (84.3%, P=0.045). No significant differences were found in en bloc resection rate (100.0% VS 99.6%, P=1.000), complete resection rate (94.7% VS 93.9%, P=0.705), postoperative complications incidence (6.4% VS 5.7%, P=0.747), operation time (64.02±39.24 min VS 66.16±44.62 min, P=0.566) or hospitalization time (6.76±2.06 d VS 6.47±1.74 d, P=0.092]. After the median follow-up of 47.9 months, 13.4% patients in the elderly group received additional surgery, which was slightly lower than that in the young/middle-aged group ( P=0.891). There were no significant differences in postoperative recurrence, lymph node metastasis, distant metastasis, overall mortality and disease-related mortality between the two groups. The survival analysis showed that five-year overall survival rates were 94.41% and 96.34% in the elderly group and the young/middle-aged group respectively ( P=0.156), and five-year disease-specific survival rate were 99.18% and 99.03% in the two groups respectively ( P=0.858). Conclusion:ESD is safe and effective for EGCC in elderly patients with satisfactory short-term and long-term efficacy.

Objective: To investigate the positive rate for 2019-nCoV tests and co-infections in Wuhan district. Methods: A total of 8 274 cases in Wuhan were enrolled in this cross-sectional study during January 20 to February 9, 2020, and were tested for 2019-nCoV using fluorescence quantitative PCR. Both respiratory tract samples (nasopharynx, oropharynx, sputum and alveolar lavage fluid) and non-respiratory tract samples (urine, feces, anal swabs, blood and conjunctival sac swabs) were collected. If both orf1ab and N genes are positive, they are classified as nucleic acid test positive group; if both orf1ab and N genes are negative, they are classified as negative group; if single gene target is positive, they are classified as suspicious group. Individuals were divided into male group and female group according to sex. At the same time, 316 patients were tested for 13 respiratory pathogens by multiplex PCR. Results: Among the 8 274 subjects, 2 745 (33.2%) were 2019-nCoV infected; 5 277 (63.8%) subjects showed negative results in the 2019-nCoV nucleic acid test; and 252 cases (3.05%) was not definitive (inconclusive result). The age of cases with COVID-19 patients and inconclusive cases was significantly higher than that of cases without 2019-nCoV infection (40 vs 56, t=27.569, P<0.001; 52 vs 56, t=6.774, P<0.001). The positive rate of 13 respiratory pathogens multiple tests was significantly lower in 104 subjects who were positive for 2019-nCoV compared with those in subjects who were negative for 2019-nCoV test (5.77% vs 18.39%, χ²=24.105, P=0.003). Four types of respiratory tract samples and five types of non-respiratory tract samples were found to be positive for 2019-nCoV nucleic acid test. Conclusion The 2019-nCoV nucleic acid positive rate in male is higher than in female. Co-infections should be pay close attention in COVID-19 patients. 2019-nCoV nucleic acid can be detected in non-respiratory tract samples.

Objective:To investigate the clinicopathological characteristics and cost-effectiveness of endoscopic resection and surgical resection for gastric schwannomas arising from the muscularis propria layer.Methods:Thirty-eight consecutive cases of gastric schwannomas diagnosed by histopathology between October 2011 and July 2016 were divided into the endoscopy group(including endoscopic submucosal excavation and endoscopic full-thickness resection) and the surgery group. Complications, complete resection rate and cost-effectiveness were analyzed.Results:The age was 52±10 years (range, 41-63 years) with 11(28.9%) males and 27(71.1%) females. The most common site of gastric schwannomas was the body (71.1%) and the antrum (21.1%). All 38(100%) lesions were protruded. The maximum diameter of the lesions was 2.5±1.2 cm (range 0.6-4.5 cm). Under endoscopic ultrasonography (EUS), 60.5% lesions were heterogeneous hypoechoic, and 15 (39.5%) hypoechoic. The complete resection rate of endoscopy group was 100.0% (17/17). The median operation time of the endoscopy group was 54 minutes. Perforations occurred in 11 patients (64.7%, 11/17), and metal clips or the nylon rope combined with metallic clips were used to close the defect in the endoscopy group. Compared with the surgery group, the length of hospital stay was significantly shorter (4.6±0.6 d VS 9.6±4.4 d, P<0.001); the time to the first fluid diet was significantly shorter (1.2±0.4 d VS 2.7±0.7 d, P<0.001), and the costs were significantly lower (21 965.0±9 342.4 yuan VS 34 253.3±10 520.9 yuan, P<0.001) in the endoscopy group. S100 immunoreactivity was present in all tumors. Local recurrence and distant metastasis did not occur during the median 34 months of follow-up. Conclusions:Endoscopic resection appears to be safe and effective for diagnosis and treatment of gastric schwannomas from the muscularis propria layer. The cost-effectiveness of endoscopic resection is significantly higher than surgical resection.

Objective To investigate the relationship between different brain developmental stages and changes of cognitive function in rats. Methods 1-month, 2-month and 8-month-old rats were selected to imitate the juvenile, adolescent and adulthood, respectively, and their behavioral functions were compared. The reward operant conditioning and Morris water maze task were used to investigate the differences in exploration interest, executive and recognition ability, spatial learning and memory of the rats at different ages. Results In the reward operant conditioning and Morris water maze task, there was no significant difference in the cognitive function between 1-month and 2-month-old rats. In the reward conditioning phase, the nose pokes numbers of 8-month-old rats were significantly decreased compared with the 1-month-old rats (P＜ 0. 01). There was no significant difference in nose pokes accuracy. During the operant conditioning phase, the lever press numbers and accuracy of 8-month-old rats were significantly decreased ( P ＜ 0. 05 or P ＜ 0. 01) and the press latency was longer (P ＜ 0. 05). At the phase of visual identification, the press and reward numbers, and the visual identification index were significantly decreased ( P ＜ 0. 05 or P ＜ 0. 01). In the Morris water maze test, compared with the 1-month-old rats, the total swimming distance and escape latency of the 8-month-old rats were significantly increased (P＜ 0. 05), as well as average swimming speed ( P ＜ 0. 05 or P ＜ 0. 01) in spatial learning phage. In spatial memory phage, the swimming distance and time spent in the target quadrant were obviously decreased (P＜ 0. 01). Conclusions The cognitive functions of rats at different brain developmental stages are different. The juvenile and adolescent rats have similar cognitive functions, but 8-month-old adult rats appear decline in the exploration interest, executive and recognition ability, and spatial learning and memory function.

Objective To study the effects of different color light stimulus, duration of stimulus and day/night training on the incentive conditioned reflex of rats,and to provide a data basis for the methodology of incentive conditional reflection experiments. Methods Three experiments were included in this study. During the experiment 1, a total of 30 male 8-week-old Wistar rats were divided into three groups:red light stimulation group,yellow light stimulation group and blue light stimulation group. During the experiment 2, a total of 32 male 8-week-old Wistar rats were divided into three groups:the group I(with a light stimulation duration of 10 s), the group II(with a light stimulation duration of 30 s), and the group III(with a light stimulation duration of 60 s). During the experiment 3,a total of 16 male 8-week-old Wistar rats were randomly divided into two groups,of which the first group was trained at 9:00 a.m. every day, and the second group was trained at 21:00 every day. All the laboratory animals were given reward conditioned reflex training, and indicators such as the number of correct nose pokes,the number of incorrect nose pokes,the ratio of correct nose pokes and so on were counted and calculated. Results During the experiment 1,there was no significant difference in the numbers of correct nose pokes and incorrect nose pokes,movement distances and average speeds of the rats among the three groups. During the experiment 2,compared with the group with a light duration of 10 s,the rats in the groups with a light duration of 30 s or 60 s had a higher number of correct nose pokes(P< 0.05). Moreover,on the 13th and 14th days,the ratio of correct nose pokes of the group with a light duration of 30 s was significantly higher than that of the group with a light duration of 10 s(P< 0.001). During the experiment 3,there were no significant differences in the number of correct nose pokes and the nose poke accuracy of the rats between the two groups. Conclusions In the reward conditioned reflex test, red,yellow and blue light stimuli have similar reward prediction effect. When stimulated with the same light, the time of stimulation has an impact on the learning ability of the rats,and an appropriate extension of stimulation is beneficial to the formation of conditioned reflex in them. The day/night training has no effect on the learning and memory ability of the rats.