Objective To explore the feasibility and corresponding implementation methods of constructing a sample resource bank based on individual-level data of completed clinical trials and using it to construct external controls for drug/device clinical trials.Methods Taking the pre-marketing clinical trial of transcatheter active valve replacement(TAVR)for the treatment of aortic valve stenosis as an example,the individual-level databases of multiple trials were standardized to form a sample bank.The original data of any trial in the sample bank were selected as the experimental group,and the remaining samples were selected as the control group.The potential confounding was handled by using the propensity score matching and stratification methods to clarify the process of constructing external controls based on the sample bank of individual-level data of clinical trials.Results This study included individual-level data of single-group trials of 4 TAVR devices,with a total of 569 subjects(59.2%male).The number of subjects in Trials 1 to 4 was 120,120,163,and 166,respectively.Propensity score matching enabled the matching of 113,117,125,and 147 subjects with comparable or similar characteristics from individual-level data from other trials,respectively,demonstrating a high matching success rate.The PS score distribution plot after stratification showed that the proportions of subjects in the experimental and control groups in strata 1 to 5 in scheme 1 were 4/103,11/103,22/92,32/87,and 51/64,respectively.For all constructed external controlled trials,a certain number of control samples with similar baseline characteristics to the experimental groups were distributed within each propensity score stratum.The results of the simulation test also reflected the potential differences between different devices in the 12-month all-cause mortality rate.Conclusions The sample bank constructed with individual-level data from clinical trials,as a high-quality data source,can serve as a source of external control for single-arm trials in the same field,and as a useful supplement to the external control scenario of real-world evidence to support drug and device development.At the same time,targeted research on research methods and bias control measures in related fields is also needed.

Objective To explore the feasibility and corresponding implementation methods of constructing a sample resource bank based on individual-level data of completed clinical trials and using it to construct external controls for drug/device clinical trials.Methods Taking the pre-marketing clinical trial of transcatheter active valve replacement(TAVR)for the treatment of aortic valve stenosis as an example,the individual-level databases of multiple trials were standardized to form a sample bank.The original data of any trial in the sample bank were selected as the experimental group,and the remaining samples were selected as the control group.The potential confounding was handled by using the propensity score matching and stratification methods to clarify the process of constructing external controls based on the sample bank of individual-level data of clinical trials.Results This study included individual-level data of single-group trials of 4 TAVR devices,with a total of 569 subjects(59.2%male).The number of subjects in Trials 1 to 4 was 120,120,163,and 166,respectively.Propensity score matching enabled the matching of 113,117,125,and 147 subjects with comparable or similar characteristics from individual-level data from other trials,respectively,demonstrating a high matching success rate.The PS score distribution plot after stratification showed that the proportions of subjects in the experimental and control groups in strata 1 to 5 in scheme 1 were 4/103,11/103,22/92,32/87,and 51/64,respectively.For all constructed external controlled trials,a certain number of control samples with similar baseline characteristics to the experimental groups were distributed within each propensity score stratum.The results of the simulation test also reflected the potential differences between different devices in the 12-month all-cause mortality rate.Conclusions The sample bank constructed with individual-level data from clinical trials,as a high-quality data source,can serve as a source of external control for single-arm trials in the same field,and as a useful supplement to the external control scenario of real-world evidence to support drug and device development.At the same time,targeted research on research methods and bias control measures in related fields is also needed.

Glioma is the most common malignancy of the central nervous system, originating mainly from glial cells. Because of its highly aggressive nature, glioma has one of the highest rates of death among all types of cancer. Therefore, it is very important to develop new therapeutic approaches and drugs for glioma treatment. Instead of activate the telomerase, approximately 30% of glioma use alternative lenthening of telomere (ALT) to maintain telomere length. The mechanism of ALT development is poorly understood, however, some genetic mutations have been reported to induce the development of ALT glioma, such as ATRX, IDH1, p53, etc. The lack of ALT glioma cell lines and preclinical ALT glioma models has limited the mechanistic studies of ALT glioma. Therefore, this review listed ALT glioma cell lines that derived from primary culture or gene editing in the last decade, as well as the xenografted animal models established by ALT glioma cell lines, and discussed the role and significance these cell and animal models play in preclinical studies.

ObjectiveTo decipher the mechanism of Wenxiao powder in alleviating corticosterone-induced depression-like behaviors in mice. MethodMale ICR mice were randomized into normal， model， paroxetine （20 mg·kg^-1）， and low- and high-dose （3.27， 6.54 g·kg^-1， respectively） Wenxiao powder groups. The mice in normal and model groups received equal volume of saline. Other groups except the normal group were injected with corticosterone subcutaneously 0.5 h after gavage to induce depression. Mice were tested for depression-like behaviors after drug administration. Enzyme-linked immunosorbent assay （ELISA） was performed to measure the corticosterone content in the serum. Nissl staining was performed to observe the damage of hippocampal neurons. Immunofluorescence staining was employed to observe the expression of double cortin （DCX） in the dentate gyrus （DG） of the hippocampus. Western blot was employed to determine the expression of proteins in the brain-derived neurotrophic factor （BDNF）/tyrosine kinase receptor B （TrkB）/extracellular signal-regulated kinase （ERK）/cAMP-response element-binding protein （CREB） pathway in the hippocampus. ResultCompared with the normal group， the model group showed decreased sucrose preference rate， increased immobility time in the tail suspension test （P<0.01）， and reduced residence time in the central area of the open field and the total movement distance （P<0.05， P<0.01）. In addition， the modeling elevated the corticosterone level in the serum （P<0.01）， decreased the volume and intensified the nuclear staining of hippocampal neurons in the DG area， reduced the expression of DCX in the DG area， and down-regulated the protein levels of BDNF， phosphorylated （p）-TrkB， p-ERK， and p-CREB in the hippocampus （P<0.05， P<0.01）. Compared with the model group， low-dose Wenxiao powder improved the mouse behavivors in the sucrose preference， open field， and tail suspension tests （P<0.05， P<0.01）， and high-dose Wenxiao powder improved the behaviors in the sucrose preference and open field tests （P<0.05， P<0.01）. In addition， Wenxiao powder lowered the serum corticosterone level （P<0.01） and recovered the structure and morphology of neurons with obvious nuclei and presence of Nissl bodies in the DG area of the hippocampus. Moreover， Wenxiao powder at both doses promoted the expression of DCX in the DG area， and high-dose Wenxiao powder up-regulated the protein levels of BDNF， p-TrkB， p-ERK， and p-CREB in the hippocampus （P<0.05， P<0.01）. ConclusionWenxiao powder can alleviate corticosterone-induced depression-like behaviors and promote neurogenesis in mice possibly by activating the BDNF/TrkB/ERK/CREB signaling pathway.

Objective:To investigate the mechanism of benzyl isothiocyanate(BITC) in the treatment of anaplastic thyroid cancer(ATC).Methods:Using network pharmacological analysis, key targets of BITC and ATC were screened, followed by GO and KEGG enrichment analysis. In order to validate the findings, AutoDock software was used to dock BITC and ATC key targets. BITC was applied to two ATC cell lines(8505C and CAL-62). Flow cytometry was used to analyze cell apoptosis. Autophagy inhibitors hydroxychloroquine sulfate(HCQ) and 3-methyladenine(3MA) were used in combination with BITC. Real-time quantitative PCR was conducted to detect the gene level of LC3B, while Western blotting was utilized to examine the expression of NF-κB, LC3B Ⅱ, Beclin-1, and Bcl-2. In animal experiments, a mouse tumor model was constructed using CAL-62 cells, treated with intraperitoneal injections of BITC(100 mg/kg) and normal saline respectively, administered every other day for a total of 21 days. Immunoblotting of tumor tissue was performed to detect the expression of LC3B Ⅱ, Bcl-2, Beclin-1, and NF-κB.Results:A total of 10 key targets with binding energies≤-4.0 kcal/mol were identified. KEGG analysis showed that these genes are mainly involved in NF-κB signaling pathway and apoptosis. BITC inhibited ATC cells with IC50 values of 27.56 μmol/L for 8505C and 28.30 μmol/L for CAL-62. The expression levels of NF-κB, Beclin-1, and Bcl-2 decreased, while LC3B Ⅱ and LC3B gene expression increased. Combining 3MA with BITC enhanced cell inhibition LC3B Ⅱ expression. HCQ increased LC3B Ⅱ expression without enhancing cell and viability inhibition. In the mouse tumor model, compared to the control group, the treatment group had higher LC3B Ⅱ and lower Bcl-2, Beclin-1, and NF-κB levels.Conclusion:BITC could inhibit the growth of ATC cells in vitro and in vivo, disrupt the autophagy degradation, and inhibit the NF-κB pathway.

Objective: To analyze the disease burden and trend of attention deficit hyperactivity disorder (ADHD) in China from 1990 to 2019, so as to provide the basic theoretical basis for the health administrative departments to formulate policies. Methods: Using the 2019 Global Burden of Disease Database, the incidence, prevalence and disability adjusted life year (DALY) rates of ADHD were analyzed for both sex and different age groups, and the trends of ADHD were predicted. Results: In 2019, the incidence, prevalence and DALY rate of ADHD in China were 70.41/100 000, 1 546.15/100 000 and 18.87/100 000 respectively. Compared with 1990, the rates decreased by 27.30%, 25.35% and 55.80% respectively, and these rates of females were lower than those of males. In 2019, the incidence rate of ADHD was the highest in the age group 5-9 years old (837.76/100 000), while the highest prevalence and DALY rates were found in ages groups of 10-14 years old (5 740.47/100 000 and 70.49/100 000). The results of the Joinpoint regression model showed that the incidence, prevalence and DALY rate had a downward trend from 1990 to 2019. The AAPC was -1.35%, -1.16% and -1.16%, respectively, with a statistically significant difference ( P <0.05). The prediction results of grey prediction model GM (1,1) indicated that the incidence and prevalence rate of ADHD in China would decline from 2020 to 2030. Conclusion The burden of ADHD in China showed a decreasing trend from 1990 to 2019, indicating that the prevention and treatment effect of ADHD in children and adolescents of China was effective. China should take active preventive measures to reduce the burden of ADHD in children and adolescents.

Objective:To explore the application value of computed tomography (CT) plain scan and dynamic enhanced scan in the diagnosis of solitary pulmonary nodules.Methods:The clinical data of 120 patients with solitary pulmonary nodules detected by physical examination in Baoding First Central Hospital from January 2018 to December 2020 were retrospectively reviewed. All patients were confirmed by surgery and pathology, including 77 benign lesions and 43 malignant lesions; All patients underwent CT plain scan and dynamic enhanced scan before operation. The accuracy of the two examination methods in the diagnosis of benign and malignant lesions of solitary pulmonary nodules was analyzed and compared. The detection rate of CT dynamic enhanced scan imaging characteristics (vacuole sign, ground glass sign, spinous sign, lobulation sign, hair prick sign, blood vessel cluster, pleural depression) of benign and malignant lesions of solitary pulmonary nodules was compared, and the diagnostic value of CT plain scan and dynamic enhanced scan in the differential diagnosis of benign and malignant solitary pulmonary nodules was evaluated based on the results of surgical pathological diagnosis. The manifestations and characteristic curves of CT dynamic enhanced scan of solitary pulmonary nodules was analyzed.Results:The diagnostic accuracy of CT dynamic enhanced scan for solitary pulmonary nodules was 80.00% (96/120), which was higher than that of CT plain scan (63.33%) (76/120) ( P<0.05). The sensitivity, specificity, and negative predictive value of CT dynamic enhanced scan for the diagnosis of benign and malignant lesions of solitary pulmonary nodules were higher than those of CT plain scan (all P<0.05). Among the imaging characteristics of CT dynamic enhanced scans of malignant lesions, the ground glass sign, spinous process sign, lobulation sign, spiculation sign, vascular clustering and pleural indentation were detected more frequently than those of benign lesions (all P<0.05). Benign lesions usually showed homogeneous enhancement, and a few showed heterogeneous enhancement; Malignant nodules often showed uneven enhancement, and a few had even enhancement. The time density curves of dynamic enhanced CT values in the regions of interest of benign and malignant solitary pulmonary nodules were different. Conclusions:The value of dynamic enhanced CT scan in the differential diagnosis of benign and malignant lesions of solitary pulmonary nodules is higher than that of CT plain scan, and the imaging features are obvious, with higher sensitivity and specificity, which is worthy of application.

BackgroundHome-based intervention occupies a prominent place in the treatment of autism spectrum disorder （ASD） in children， whereas previous studies on the effect of home-based early intensive behavioral intervention on verbal ability of children with ASD are somewhat inadequate. ObjectiveTo study the effects of intensive family behavioral of intervention based on Verbal Behavior Milestones Assessment and Placement Program （VB-MAPP） on the language ability of children with ASD， so as to provide references for the development of family intervention strategies for children with ASD. MethodsChildren aged 2 to 3 years old who attended the Children's Rehabilitation Department of the Second Affiliated Hospital of Shantou University Medical College from September 2020 to December 2021 and met the Diagnostic and Statistical Manual of Mental Disorders， fifth edition （DSM-5） diagnostic criteria for ASD were selected as the study objects. A non-randomized concurrent control trial was conducted to compare a study group （n=24） receiving home-based early intensive behavioral intervention using VB-MAPP with a control group （n=14） receiving training from other special institutions or early childhood education institutions. The intervention lasted for 6 months in both groups. Before and after the intervention， the VB-MAPP milestone assessment was performed in the two groups， and the VB-MAPP milestone score， mand， trac and listener responds were selected as the study indicators. Then the intervention effect was compared between two groups， and the multiple linear regression was performed to screen the related influencing factors. ResultsAfter intervention， the total milestone assessment score， mand， tact and listener responds scores of study group were higher than those of control group， with statistical difference （Z=-4.339~-2.195， P<0.05 or 0.01）. Multiple linear regression analysis denoted that the average weekly hours of home-based intervention in the first three months had certain effect on listener responds （β=1.029， P<0.05）. ConclusionApplication of home-based early intensive behavior intervention using VB-MAPP may contribute to the improvement of verbal abilities such as mand， tact and listener responds in children with ASD. ［Funded by 2020 Guangdong Provincial Science and Technology Innovation Strategy Special Fund （number， 20200601）］

OBJECTIVE: To analyze the preservation effect and related influencing factors of human peripheral blood mononuclear cells under serum-free condition at 4 ℃. METHODS: Human peripheral blood mononuclear cells were isolated by density gradient centrifugation, and stored at 4 ℃ under different cell concentrations, supplemented with human serum albumin, and glucose. The cell viability, total cell number, viable cell number and cell phenotype were detected during preservation of 72 h. RESULTS: With the prolongation of storage time, the number of human peripheral blood mononuclear cells gradually decreased(r=0.982). Compared with the cell concentration of (5-6)×10⁶ cells/ml, the cell number decreased more slowly when the cell storage concentration was (1-2)×10⁶ cells/ml; Adding human serum albumin and glucose can effectively improve the survival rate of human peripheral blood mononuclear cells, among which 2% human serum albumin has a better preservation effect; Compared with the blank control group, the analysis results of cell subsets showed that the downward trends of NK cells and T cells were significantly slowed after adding albumin and glucose. CONCLUSION The cell density of (1-2)×10⁶/ml and 2% human serum albumin are more suitable for the preservation of PBMC, and 5% glucose can improve the preservation effect of human peripheral blood mononuclear cells at 4 ℃.
Humans ; Leukocytes, Mononuclear

OBJECTIVES: To establish a carbofuran intragastric administration death model in rabbits, and to observe the postmortem distribution and postmortem redistribution of carbofuran-7-phenyl glucuronic acid (Glu-7PH) in rabbits. METHODS: The postmortem distribution: Rabbits were given an administration of 1/2LD50, LD50, 2LD50 carbofuran. Dead rabbits were dissected immediately. Rabbits that had remained alive 2 hours were sacrificed by carbon dioxide (CO₂) inhalation and dissected immediately. The myocardium, cardiac blood, liver, spleen, lung, kidney, brain and right hindlimb muscle were collected. The postmortem redistribution: After giving an administration of 4LD50 carbofuran, the myocardium, cardiac blood, liver, spleen, lung, kidney, brain, and right hindlimb muscle were collected at 0, 12, 24, 48, and 72 h postmortem in supine position at 15 ℃ room temperature. The quantity of Glu-7PH was determined by LC-MS/MS. RESULTS: The postmortem distribution: Among the three dose groups, there were significant differences in the quantities of Glu-7PH in different tissues. The postmortem redistribution: There was no significant difference in the Glu-7PH quantities in cardiac blood, mycardium, spleen, kidney, brain and right hindlimb muscle, but there was a significant difference in the Glu-7PH quantities in the liver and lung. CONCLUSIONS The mycardium, cardiac blood, liver, lung, kidney, brain and hindlimb muscle of rabbits can be used as appropriate samples for Glu-7PH detection. However, it should be noted that Glu-7PH was redistributed postmortem in rabbit liver and lung.
Animals ; Rabbits ; Carbofuran ; Chromatography, Liquid ; Postmortem Changes ; Tandem Mass Spectrometry ; Autopsy