Objective: To explore the efficacy and safety of clonidine adhesive patch in Tourette syndrome (TS) patients with comorbid attentiondeficit/hyperactivity disorder (ADHD). Methods: This study was conducted on a sample of children and adolescents with TS who had comorbid ADHD between May 2012 and March 2015. The patients were diagnosed according to Diagnostic and Statistical Manual of Mental Disorders Fourth Edition, and were randomly assigned to four different dose groups: 1.0 mg/week, 1.5 mg/week, 2.0 mg/week and placebo group, and the symptom was evaluated by Swanson, Nolan, and Pelham Rating Scale, Version IV (SNAP-IV) and Yale Global Tic Severity Scale scales every 2 weeks. The primary outcome was tic disorders (TD) effective rate at week 8. Results: One hundred and twenty-seven TS patients with comorbid ADHD in 2.0 mg/week (n=35), 1.5 mg/week (n=27), 1.0 mg/week (n=36) and placebo groups (n=29) were included in this subgroup analysis. The TD effective rate of the 2.0 mg, 1.5 mg, and 1.0 mg groups at week 8 were significantly better than that in placebo group (85.7%, 81.5%, and 86.1% vs. 20.7%, all p<0.0001). All groups demonstrated significant improvements in SNAP-IV total scale scores compared to baseline (p=0.0004), with treatment groups showing only a trend for better performance compared to placebo group at week 8, without statistical differences (22.1±15.41, 21.3±11.96, and 21.2±12.48 vs. 26.0±13.37, p=0.3385). A total of 9 adverse reactions occurred, all recovered spontaneously without additional medication. Conclusion Clonidine adhesive patch could safely and effectively reduce the tic symptoms of TS patients with comorbid ADHD, and might be potentially helpful in the ADHD symptoms control.

Objective To investigate the role of human umbilical cord mesenchymal stem cell-derived extracellular vesicle (hUC-MSC-EV) in the regeneration of fibrotic liver. Methods C57BL/6 mice were randomly divided into the 70% normal liver resection group (Oil+PHx group), 70% liver fibrosis resection group (CCl₄+PHx group) and 70% liver fibrosis resection+mesenchymal stem cell-derived extracellular vesicle (MSC-EV) treatment group (CCl₄+PHx+MSC-EV group), with 8 mice in each group. LX-2 cell lines were assigned into the phosphate buffer solution (PBS) group, transforming growth factor (TGF)-β group and TGF-β+MSC-EV group. The serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) in mice after partial liver resection were detected in each group. The expression levels of liver fibrosis and proliferation-related parameters were analyzed in each group. The messenger RNA (mRNA) expression levels of epidermal growth factor (EGF), fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) in LX-2 cells were detected in each group, and their effects on HGF expression in mouse liver were observed. Results Compared with the Oil+PHx group, the serum levels of AST, ALT and LDH were up-regulated, and the degree of fibrosis was more severe, the positive area of Sirius red and α-smooth muscle actin (α-SMA) staining was larger, and the expression level of α-SMA protein was up-regulated in the CCl₄+PHx group. Compared with the CCl₄+PHx group, the serum levels of AST, ALT and LDH were decreased, the degree of fibrosis was slighter, the positive area of Sirius red and α-SMA staining was decreased, and the expression level of α-SMA protein was down-regulated in the CCl₄+PHx+MSC-EV group, and the differences were statistically significant (all P < 0.05). Compared with the Oil+PHx group, the protein expression levels of Ki67 and proliferating cell nuclear antigen (PCNA) were lower in the CCl₄+PHx group. Compared with the CCl₄+PHx group, the protein expression levels of Ki67 and PCNA were increased in the CCl₄+PHx+MSC-EV group, and the differences were statistically significant (all P < 0.05). Compared with the PBS group, the expression level of CollagenⅠ mRNA in LX-2 cells was increased, the expression level of α-SMA protein was up-regulated and the expression level of HGF protein was decreased in the TGF-β group. Compared with the TGF-β group, the expression level of CollagenⅠ mRNA in LX-2 cells was decreased, the expression levels of HGF mRNA and protein were increased, and the expression level of α-SMA protein was decreased in the TGF-β+MSC-EV group, the differences were statistically significant (all P < 0.05). The expression level of HGF protein in the CCl₄+PHx group was lower than that in the Oil+PHx group, whereas the difference was not statistically significant (P > 0.05). The expression level of HGF protein in the CCl₄+PHx+MSC-EV group was higher than that in the CCl₄+PHx group, and the difference was statistically significant (P < 0.05). Conclusions The regenerative capacity of fibrotic liver is weaker than that of normal liver. hUC-MSC-EV may alleviate liver fibrosis and improve liver regeneration by promoting HGF secretion from actived hepatic stellate cells and effectively enhancing the regenerative capacity of fibrotic liver.

Objective To explore the effect of Taishan Panshi powder combined with dydrogesterone on unexplained recurrent abortion(URSA)and its mechanism.Methods A total of 180 URSA patients at early pregnancy who were admitted to Guangdong Maternal and Child Health Hospital from January 2021 to June 2022 were enrolled and randomly assigned(1∶1)to combined group or control group.The control group was treated with dydrogesterone,and the combined group was treated with Taishan Panshi powder on the basis of dydrogesterone.The clinical efficacy,delivery outcome,TCM syndrome score,coagulation function(fibrinogen[FIB],platelet count[PLT],and D-dimer[D-D]),helper T lymphocyte 17(Th17)/regulatory T lymphocyte(Treg)level,the mRNA expression of retinoid-associated orphan nuclear receptor γt(RORγt)and spiral transcription factor(Foxp3),and the incidence of adverse reactions were compared between the 2 groups.Results The total effective rate of the combined group was significantly higher than that of the control group(P<0.05).After treatment,the TCM syndrome score and the levels of FIB,PLT,and D-D of the combined group were significantly lower than those of the control group(P<0.05).The combined group had higher success rate of delivery than the control group(P<0.05).Th17/CD4+ and Th17/Treg in the combined group were lower than those in the control group,while Treg/CD4+ was significantly higher than that in the control group(P<0.05).The combined group had lower RORγt mRNA level and higher Foxp3 mRNA level than the control group after treatment(P<0.05).There was no significant difference in the incidences of adverse reactions between the 2 groups(P>0.05).Conclusion Taishan Panshi powder combined with dydrogesterone has a significant effect in the treatment of URSA.It can improve hypercoagulable state,maintain Th17/Treg immunologic balance by regulating the expression of RORγt and Foxp3,improve symptoms,and increase success rate of delivery with high safety.

Objective:To examine the association between parental characteristics and risk of autism spectrum disorder (ASD) in children.Methods:In this case-control study, the cases were defined as children who were diagnosed with ASD and were recruited from June 2018 to February 2019 in Shanghai Mental Center ( n=104). The controls were defined as children who did not have ASD and were recruited in the two community health centers in Jing-an District of Shanghai during the same period ( n=149). All children recruited in this study were 2-6 years old. A multivariate logistic regression model was used to examine the association between parental characteristics and the risk of ASD in offspring, and further to estimate the interaction coefficient. Results:According to multivariate regression analysis, the association between maternal age, previous pregnancy complication and the risk of ASD in children appeared to be not statistically significant. After adjusted, advanced paternal age (≥35 years old)( OR=3.65, 95% CI=1.19-11.15, P=0.023), parental disease before or during pregnancy ( OR=3.34, 95% CI=1.41-7.94, P=0.006) and gender of child (male) ( OR=5.84, 95% CI=2.98-11.44, P<0.001) were associated with increased risk of ASD. The results also showed that the boys whose father was 35 years old or more had a higher risk of ASD than the boys whose fahter was less 35 years old and the girls whose father was 35 years old or more ( P=0.005, P=0.006). Conclusion:Advanced paternal age was associated with increased risk of ASD in offspring and this effect may be more pronounced in boys.

Objective:To examine the association between parental characteristics and risk of autism spectrum disorder (ASD) in children.Methods:In this case-control study, the cases were defined as children who were diagnosed with ASD and were recruited from June 2018 to February 2019 in Shanghai Mental Center ( n=104). The controls were defined as children who did not have ASD and were recruited in the two community health centers in Jing-an District of Shanghai during the same period ( n=149). All children recruited in this study were 2-6 years old. A multivariate logistic regression model was used to examine the association between parental characteristics and the risk of ASD in offspring, and further to estimate the interaction coefficient. Results:According to multivariate regression analysis, the association between maternal age, previous pregnancy complication and the risk of ASD in children appeared to be not statistically significant. After adjusted, advanced paternal age (≥35 years old)( OR=3.65, 95% CI=1.19-11.15, P=0.023), parental disease before or during pregnancy ( OR=3.34, 95% CI=1.41-7.94, P=0.006) and gender of child (male) ( OR=5.84, 95% CI=2.98-11.44, P<0.001) were associated with increased risk of ASD. The results also showed that the boys whose father was 35 years old or more had a higher risk of ASD than the boys whose fahter was less 35 years old and the girls whose father was 35 years old or more ( P=0.005, P=0.006). Conclusion:Advanced paternal age was associated with increased risk of ASD in offspring and this effect may be more pronounced in boys.

Genetic composition plays critical roles in the pathogenesis of autism spectrum disorder (ASD). Especially, inherited and de novo intronic variants are often seen in patients with ASD. However, the biological significance of intronic variants is difficult to address. Here, among a Chinese ASD cohort, we identified a recurrent inherited intronic variant in the CHD7 gene, which is specifically enriched in East Asian populations. CHD7 has been implicated in numerous developmental disorders including CHARGE syndrome and ASD. To investigate whether the ASD-associated CHD7 intronic variant affects neural development, we established human embryonic stem cells carrying this variant using CRISPR/Cas9 methods and found that the level of CHD7 mRNA significantly decreased compared to control. Upon differentiation towards the forebrain neuronal lineage, we found that neural cells carrying the CHD7 intronic variant exhibited developmental delay and maturity defects. Importantly, we found that TBR1, a gene also implicated in ASD, was significantly increased in neurons carrying the CHD7 intronic variant, suggesting the intrinsic relevance among ASD genes. Furthermore, the morphological defects found in neurons carrying CHD7 intronic mutations were rescued by knocking down TBR1, indicating that TBR1 may be responsible for the defects in CHD7-related disorders. Finally, the CHD7 intronic variant generated three abnormal forms of transcripts through alternative splicing, which all exhibited loss-of-function in functional assays. Our study provides crucial evidence supporting the notion that the intronic variant of CHD7 is potentially an autism susceptibility site, shedding new light on identifying the functions of intronic variants in genetic studies of autism.

Objective:To analyze key aspects in cultural integration for cross-region specialists alliances of closed cooperation, for promoting such integration and identifying efficient operation of the practice.Methods:Quantitative and qualitative methods were used. 192 employees of primary hospitals participated in a questionnaire survey about their personal information and hospital culture self-evaluation on 18th February, 2019. Data so collected were subject to descriptive analysis. On February 21, 2019, the deans of the hospitals were invited for in-depth interviews, and focus group discussions were arranged for 7 doctors from the center hospital who had provided medical support for the primary hospital for more than half and a year, and for 5 doctors and 2 head nurses from the obstetric and neonatal department of the primary hospital respectively. The purpose is to understand the direction, key aspects, achievements and challenges of cultural integration between the two hospitals. Content analysis method was used to study recordings and interview documentation.Results:Employees of the primary hospital had a high satisfaction with indicators of organizational citizenship behavior, and the quality of medical care and team orientation, with the self-rated original scoring for the elements of hospital culture being 3.755, 3.754 and 3.698 respectively. On the other hand, they found insufficiencies in the innovation, poor orientation and incentive mechanism, with the self-rated original scoring for the elements of hospital culture being 3.469, 3.391 and 3.297 respectively. The self-rated total scoring was lower among medical technicians and those with bachelor′s degree or above, which were 3.029 and 3.202 respectively. Hospital culture integration is designed to strengthen technical guidance and care for doctors and patients, and to strengthen cooperation and support in HR training, scientific research innovation and spiritual culture construction. The key to integration is acceptance. The current roadblocks for efficient operation of this model come from medical insurance policy, material resources policy, logistics support, informationization management, personnel training and support and performance management.Conclusions:The cultural integration of cross-region specialists alliances of closed cooperation should be realized through the interactions of values, systems, behaviors and material resources dimensions. Government should play a leading and coordinating role and improve supporting measures.

Objective To investigate the effects and mechanisms of glutamine (Gln) supplementation on oxidative stress,autophagy response and neurobehavioral outcome after traumatic brain injury (TBI) in rats.Methods TBI animal models were established using Feeney's method.Eighty SD rats were randomly divided into 4 groups:sham operation group (group Sham),Sham + glutamine supplementation group (group Sham+ GLN),traumatic brain injury group (group TBI),and TBI + glutamine supplementation group (group TBI+ GLN).We measured rat behavioral outcomes by modified neurologic severity score (mNSS) tests at day 1,3,7 and 14 after TBI.The apoptosis neurons in TBI cerebral cortex were determined by TUNEL staining.The expression of reactive oxygen species (ROS) was tested by ROS kits.Oxidative stress and autophagy related cytokines (HO-1,NQO1,Nrf2,LC3-Ⅱ and Beclin-1) were tested with Western blotting.Results Compared with the TBI group,the neurological function was improved [(9.79±0.43) vs.(8.43±0.30),F =6.775,P =0.010] and the apoptosis rate decreased (19.88％ ± 1.60％ vs.15.35％ ± 1.28％,P =0.013) in the TBI+ GLN group after 7-day treatment.Compared with the Sham group,the protein expression of ROS increased (P=0.000),and the expression of anti-oxidative stress factors (HO-1,NQO1) and Nrf2 pathway significantly decreased in the TBI group.After glutamine supplementation was given,the expression of ROS decreased and the expressions of HO-1 and NQO1 increased.The Nrf2 pathway and autophagy response also were activated with the expressions of Nrf2,LC3-Ⅱ and Beclin-1 increasing.Conclusion Glutamine supplementation can markedly reduce neuron apoptosis and improve neurological outcomes after TBI,thus has the protective effect on nerves by inhibiting TBI-induced oxidative stress response,activating Nrf2 pathway and autophagy response.

Objective To investigate the effects of glutamine (Gln) supplementation on neurologica severity score,brain edema,neuron apoptosis,and endoplasmic reticulum stress (ERS) response after traumatic brain injury (TBI) in rats.Methods TBI rat models were established using modified Feeney's method.Eighty Sprague-Dawley rats were divided into 4 groups with a random number table:sham operation group (Sham group),TBI group,Gln supplementation group (TBI + Gln group) and ERS inducer 2-deoxy-D-glucose group (TBI +Gln + 2-DG group).We measured the rats' neurobehavioral outcomes by modified neurologic severity score (mNSS) on day 1,3,7 and 14 after TBI.Neuron apoptosis was detected using TUNEL staining.Brain water content was measured with wet-dry weight method.The apoptosis-related protein (caspase-12,caspase3,and Bcl-2) and ERS-related cytokines [inositol-requiring enzyme 1 (IRE-1),C/EBP homologous protein (CHOP)] expressions in TBI cerebral cortex were determined by immunohistochemistry staining and Western blot.Results Compared with the Sham group,the levels of brain edema,mNSS,apoptosis-related protein (caspase-12,caspase-3,Bcl-2) and ERS-related proteins (IRE-1,CHOP) were significantly increased in the other three groups (all P =0.00).Compared with the TB1 group,the TBI +Gln group showed significant lower brain water content [3 d:(81.39±0.59)％ vs.(83.54±0.52)％,P=0.04;7 d:(74.86±0.38)％ vs.(77.32±0.66)％,P=0.03],improved mNSS (8.63 ±0.22 vs.10.37±0.29,P=0.03),suppressed expressions of apoptosis-and ERS-related proteins (caspase-12,caspase-3,IRE-1,and CHOP)(P =0.01,P ＜ 0.01),and increased expression of anti-apoptotic protein Bcl-2 (P =0.02).Compared withthe TBI + Gln group,the expression of ERS-related factors (IRE-1 and CHOP),brain edema level,and neurological severity were increased in the TBI + Glu + 2-DG group.Conclusion Glutamine supplementation may have neuroprotection function,demonstrated as reducing brain edema and neuron apoptosis,and improving neurobehaviroal outcomes after TBI,possibly mediated by inhibiting TBI-induced ERS response.

Objective To compare the rates of regimen modification between patients with different initial antiretroviral therapy, and to investigate risk factors associated with drug toxicity-related regimen modification.Methods A two-years retrospective cohort study was conducted in 14 060 patients who initiated antiretroviral treatment with Zidovudine (AZT)/Tenofovir disoproxil (TDF)+Lamivudine (3TC)+Efavirenz (EFV) since 2012.There were 5 126 patients initiated TDF+3TC+EFV therapy (TDF group) and 8 934 patients initiated AZT+3TC+EFV therapy (AZT group).Chi-square test was used to compare the rate of first-line regimen modification and the rate of toxicity-related regimen modification between two groups.Cox proportional hazard model was used to investigate the risk factors associated with regimen modification.Results A total of 14 060 acquired immunodeficiency syndrome patients were observed for a median period of 1.85 person-years.There were 2 795 patients who changed their initial antiretroviral regimen and the rate of initial regimen modification was 19.9%.Two hundred patients who changed their initial regimen due to pregnancy were excluded.There were 2 070 patients in AZT group who changed their initial regimen with a rate of 23.5%.Among them, 1 652 patients changed their regimen due to drug toxicity and the rate was 18.8%.There were 525 patients in TDF group who changed their initial regimen with a rate of 10.4% and the rate of toxicity-related regimen modification was 6.2%.The differences between two groups were statistical significance (χ2=366.68 and 416.89, respectively, both P<0.01).The risk of regimen modification in AZT group were significantly higher than that in TDF group (aHR=2.89, 95%CI: 2.57-3.24).The risk of toxicity-related regimen modification in AZT group was also significantly higher than that in TDF group (aHR=3.85, 95%CI: 3.34-4.45).Conclusions Patients initiated antiretroviral treatment with AZT+3TC+EFV are more likely to change their initial regimen than those who initiated treatment with TDF+3TC+EFV.Female, age >45 years old, BMI<18.5 kg/cm2 and baseline CD4+ T cell count<200/mL were risk factors associated with regimen modification.