Objective To study the safety of amlodipine post-marketing and to mine the potential adverse drug event(ADE)signals,and to construct an intelligent query platform for ADE signals that can be popularized and applied to a variety of drugs.Methods The data from the first quarter of 2004 to the fourth quarter of 2024 were retrieved from the U.S.Food and Drug Administration Adverse Event Reporting System(FAERS)database.A variety of disproportionality methods were used,including the reporting odds ratio(ROR)method,the United Kingdom Medicines and Healthcare products Regulatory Agency(MHRA)comprehensive standard method,Bayesian confidence propagation neural network(BCPNN)method,and the multi-item Gamma-Poisson shrinker(MGPS)method,to mine the signals of ADEs related to amlodipine.At the same time,a general query platform for mining ADE signals was developed based on the DeepSeek AI model to achieve the monitoring and analysis of the safety of various drugs.Results A total of 51,166 ADE reports were obtained,in which amlodipine was the primary suspected drug.Through the combined screening of the four algorithms,multiple potential ADE signals which had not been mentioned in the existing package inserts were found,including diseases of the ear and labyrinth(such as sensorineural hearing loss),diseases of the respiratory system,thorax and mediastinum(such as non-cardiogenic pulmonary edema),mental disorders(such as completed suicide),etc.The constructed digital intelligent platform had achieved the automated processing and monitoring of ADE data,providing a rapid access for clinicians and regulatory authorities to obtain drug safety information.Conclusion This study reveals potential safety risks associated with the use of amlodipine through real-world data mining.A risk assessment of patients' medication should be carried out before clinical use.In addition to paying attention to known ADEs,newly discovered potential risk signals should also be closely monitored.The construction of the digital intelligent platform provides an efficient tool for pharmacovigilance work.It can be popularized and applied to the safety monitoring of a variety of drugs,which is of great significance for improving the level of pharmacovigilance and the safety of medication.

Objective In response to the clinical needs for personalized wrist orthoses,a topological optimization design method was proposed to achieve an integrated macro-and micro-structural optimization of a personalized,lightweight,and comfortable wrist orthosis.Methods A composite biomechanical finite element model of the wrist orthosis and upper limb was established to quantify the effects of the orthosis geometry on its fixation performance and comfort.A multi-condition topological optimization and microstructure design approach was employed to optimize the non-load-bearing areas of the orthosis.The orthosis was manufactured using three-dimensional(3D)-printed polyether ether ketone(PEEK),and the feasibility of the design was validated.Results While maintaining mechanical strength,the weight of the 3D-printed PEEK orthosis was reduced by 28％compared to the traditional orthoses.Both the pressure at the skin contact interface and the results of a subjective questionnaire indicated that test subjects experienced a high level of comfort wearing the orthosis.Conclusions The orthosis design achieved personalization,lightweight structure,and high comfort while ensuring mechanical strength and fixation performance.

Objective In response to the clinical needs for personalized wrist orthoses,a topological optimization design method was proposed to achieve an integrated macro-and micro-structural optimization of a personalized,lightweight,and comfortable wrist orthosis.Methods A composite biomechanical finite element model of the wrist orthosis and upper limb was established to quantify the effects of the orthosis geometry on its fixation performance and comfort.A multi-condition topological optimization and microstructure design approach was employed to optimize the non-load-bearing areas of the orthosis.The orthosis was manufactured using three-dimensional(3D)-printed polyether ether ketone(PEEK),and the feasibility of the design was validated.Results While maintaining mechanical strength,the weight of the 3D-printed PEEK orthosis was reduced by 28％compared to the traditional orthoses.Both the pressure at the skin contact interface and the results of a subjective questionnaire indicated that test subjects experienced a high level of comfort wearing the orthosis.Conclusions The orthosis design achieved personalization,lightweight structure,and high comfort while ensuring mechanical strength and fixation performance.

Objective To study the safety of amlodipine post-marketing and to mine the potential adverse drug event(ADE)signals,and to construct an intelligent query platform for ADE signals that can be popularized and applied to a variety of drugs.Methods The data from the first quarter of 2004 to the fourth quarter of 2024 were retrieved from the U.S.Food and Drug Administration Adverse Event Reporting System(FAERS)database.A variety of disproportionality methods were used,including the reporting odds ratio(ROR)method,the United Kingdom Medicines and Healthcare products Regulatory Agency(MHRA)comprehensive standard method,Bayesian confidence propagation neural network(BCPNN)method,and the multi-item Gamma-Poisson shrinker(MGPS)method,to mine the signals of ADEs related to amlodipine.At the same time,a general query platform for mining ADE signals was developed based on the DeepSeek AI model to achieve the monitoring and analysis of the safety of various drugs.Results A total of 51,166 ADE reports were obtained,in which amlodipine was the primary suspected drug.Through the combined screening of the four algorithms,multiple potential ADE signals which had not been mentioned in the existing package inserts were found,including diseases of the ear and labyrinth(such as sensorineural hearing loss),diseases of the respiratory system,thorax and mediastinum(such as non-cardiogenic pulmonary edema),mental disorders(such as completed suicide),etc.The constructed digital intelligent platform had achieved the automated processing and monitoring of ADE data,providing a rapid access for clinicians and regulatory authorities to obtain drug safety information.Conclusion This study reveals potential safety risks associated with the use of amlodipine through real-world data mining.A risk assessment of patients' medication should be carried out before clinical use.In addition to paying attention to known ADEs,newly discovered potential risk signals should also be closely monitored.The construction of the digital intelligent platform provides an efficient tool for pharmacovigilance work.It can be popularized and applied to the safety monitoring of a variety of drugs,which is of great significance for improving the level of pharmacovigilance and the safety of medication.

Iodine accumulation represents a differentiation marker of thyroid cancer (TC) and a cornerstone of benefits from 131I therapy. However, dedifferentiation phenotypes occur in nearly 70% of recurrent or metastatic TCs driven by oncogenic mutations such as B-Raf proto-oncogene, serine/threonine kinase (BRAF), telomerase reverse transcriptase (TERT) promoters, and tumor proten p53 (TP53). Beyond genetic alterations, epigenetics, autophagy, tumor microenvironment and other pathways are also involved in the dedifferentiation of TC and the tolerance to 131I therapy. Targeting the above-mentioned pathways has potential to improve the malignant phenotype of TC and restore sensitivity to 131I therapy, which is of great clinical significance. Based on the relevant mechanisms of dedifferentiation, this paper elaborates on the progress of preclinical experiments and clinical studies related to differentiation therapies of TC.

Objective: To evaluate the dietary quality for preschool children by diet balance index(DBI_C), and to provide an empirical reference for scientific guidance for a reasonable diet and controlling and preventing iron deficiency anemia(IDA). Methods: During September to December of 2018, 306 left behind children and 598 non left behind children aged 3-6 years old of Anhui Province were selected. Four scoring methods (TS Total Score, LBS Low Bound Score, HBS High Bound Score, DQD Diet Quality Distance) were used to evaluate the dietary quality by DBI_C, and multivariate Logistic regression was used to assess the relationship between DBI_C and IDA. Results: The anemia prevalence (AP) was 13.3% among the 3-6 year old children in Anhui rural area, whereas the left behind children (LBC) was 16.7% and the non left behind children was 10.9%, and there was statistical significance of the differences ( χ 2=8.8, P <0.05). There were significant differences of TS[-18.3(25.2，-12.7)，-15.2(-19.8，-8.6)], LBS[25.4(18.3，32.5)，22.7(16.5，30.6)] and DQD[36.8(23.9，43.4)，34.1(27.5，41.0)] in DBI_C scores between anemia group and nonanemia group ( P <0.05). There were significant differences of milk and beans [-5.9(-10.7，-0.4)，-5.0(-8.7，0.2)], animal food [-2.4(-5.6，0.8)，-0.6(3.5，1.9)], food species [-7.5(-9.1，-4.8)，-6.3(-8.0，-2.9)] in food intake scores between anemia group and non anemia group ( P <0.05). Left behind children ( OR =1.27, 95% CI =1.15-1.49) had higher proportions of getting anemia. Meat consumption >3 times per week ( OR =0.81, 95% CI =0.68-0.94) and ≥two types of fresh vegetable consumption every day ( OR =0.84, 95% CI =0.73-0.95) were associated with lower rate of anemia( P <0.05). Conclusion The AP was relatively high in 3-6 year old children in Anhui rural area, especially in those LBC. Anemia should be reduced by improving the caregivers dietary literacy, increasing intakes of animal foods and fresh vegetables.

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 compare the optimal conditions, virus yield, viral titer and cell metabolism between culturing influenza virus H1N1 vaccine strain in MDCK and MDCK-G1 cells.Methods:The optimal culture conditions were investigated using chessboard method. The hemagglutination titer, half of the tissue infection dose (TCID 50) and the metabolism of glucose and lactic acid were monitored and compared between the two cell lines. Results:After MDCK-G1 cells were inoculated with H1N1 at the multiplicity of infection (MOI) of 0.001 with the presence of 1 μg/ml of trypsin, the hemagglutination titer reached the peak of 1∶512 at 72 h and the viral titer was 10 7.4TCID 50/ml. In the MDCK cell line group, the hemagglutination titer reached the peak of 1∶256 at 72 h and the viral titer was 10 6.6TCID 50/ml when using H1N1 at MOI=0.0001 and 1 μg/ml of trypsin. Conclusions:MDCK-G1 cells were more suitable than MDCK cells for the proliferation of influenza virus. This study provided reference data for further research on cell-derived influenza vaccine.

Objective: To reduce the residual proteins and DNA of host cells in the preparation of H5N1 influenza A virus. Methods: Core 700 was firstly used to remove residual host cell proteins, and then Capto Q was used to remove host cell DNA. Several batches of H5N1 influenza A virus cultured in Madin-Darby canine kidney (MDCK) cells were purified using this method. The efficiency of purification was evaluated using many methods including quantitative real-time PCR, hemagglutination (HA) test and single radial immunodiffusion assay. Moreover, Benzonase nuclease was used for comparison. Results: Without the use of Benzonase nuclease, the overall removal rates of host cell DNA and residual proteins were 99.62% and 98.1%, and the HA antigen recovery rate was 66.96%. Conclusions This study established a purification strategy with good effect for cell-based influenza vaccines. It can efficiently remove host cell DNA and proteins and achieve a high HA recovery rate. The purification result is no worse than that of adding Benzonase nuclease, suggesting the potential of its application in actual vaccine production.

Objective: To investigate the best amount of TPCK trypsin in Madin Darby canine kidney (MDCK) cell suspension for the culture of H7N9 avian influenza virus. Methods: Different concentrations of TPCK trypsin were added during the periods of cell growth and virus production. Their effects on cell growth, viability, glucose and lactate metabolism, and hemagglutination titer were monitored every 12 h. Inter-batch differences were analyzed. The amount of trypsin added in the cell growth phase was 0, 1 μg/ml, 2 μg/ml, 4 μg/ml, 6 μg/ml, 8 μg/ml, 10 μg/ml and 15 μg/ml. The amount of trypsin added during the virus production period was 0, 0.5 μg/ml, 1 μg/ml, 1.5 μg/ml, 2 μg/ml and 2.5 μg/ml. When the hemagglutination titers were same, the adding amount was further optimized at different multiplicity of infection (MOI) of 0.001, 0.005, 0.025 and 0.05. Results: No significant linear effects of TPCK trypsin concentration on cell number, viability, and glucose and lactate metabolism were observed. No toxicity to cell growth was observed when TPCK trypsin concentration reached 15 μg/ml. After the inoculation of H7N9 avian influenza virus, the hemagglutination titers in the 1 μg/ml, 1.5 μg/ml, 2 μg/ml and 2.5 μg/ml TPCK trypsin groups reached the peaks at 48 h, which were 1∶2^6.5. At 60 h, the hemagglutination titers of the latter two groups decreased faster than those of the former two groups. When the MOI was 0.005, the hemagglutination titer of the 1.5 μg/ml group at 48 h was 2^6.5 higher than 2⁶ in the 1 μg/ml group under the same condition. There were differences between different batches of TPCK trypsin. Conclusions Adding 1 μg/ml and 1.5 μg/ml of trypsin could better promote the proliferation of H7N9 avian influenza virus, and 1.5 μg/ml of trypsin had a wider range of MOI applicability.