Objective To explore the application status and development trend of machine learning in the field of pharmacovigilance worldwide,and to provide reference for the research on the application of machine learning in the field of pharmacovigilance.Methods Relevant literature was searched in the Web of Science with the key words of"machine learning"and"pharmacovigilance"from the inception to March 1,2023.R language and other software were used to quantitatively analyze the literature data in this field.The clustering,co-occurrence and emergence visual analysis were carried out on the characteristics of annual published papers,institutions,countries,keywords and other aspects.Results A total of 904 literature were included.The number of literature published showed a fluctuating upward trend since 1994.There was cross-regional,cross-regional and cross-agency cooperation among the cooperative network institutions.The top 5 countries in the number of publications were the United States,China,Japan,South Korea and India,China and the United States had relatively close cooperation in this field.Signal detection,social media and electronic health records were high-frequency keywords in this field.Clustering and association rule analysis showed that this field focused on three aspects signal recognition,unstructured text mining and analysis,and processing and analysis of electronic medical information.At present,machine learning has made significant progress in signal recognition,social media information mining,and unstructured text processing of electronic medical information,which broaden the data sources of pharmacovigilance,improve the real-time monitoring ability of adverse drug reactions,bringing innovation impetus to the field of pharmacovigilance.Conclusion The rapid development of big data and artificial intelligence technologies has led to an increasing integration of machine learning into the field of pharmacovigilance,which promotes technical exchanges and cooperation and cross-disciplinary integration.It is necessary to optimize each machine learning algorithm to improve its accuracy and stability in pharmacovigilance,strengthen the protection measures of data privacy and security to ensure the safety of patient information.Integrating expertise in the fields of science,medicine,and data statistics with a view to promoting technological progress in the field of pharmacovigilance.

Vitiligo is an immune memory skin disease. T-cell factor 1 (TCF1) is essential for maintaining the memory T-cell pool. There is an urgent need to investigate the characteristics of peripheral memory T-cell profile and TCF1⁺ T-cell frequencies in patients with vitiligo. In this study, 31 patients with active vitiligo (AV), 22 with stable vitiligo (SV), and 30 healthy controls (HCs) were included. We measured circulating memory and TCF1⁺ T-cell frequencies using flow cytometry. The Spearman's rank test was used to evaluate the correlation between cell frequencies and disease characteristics. Receiver operating characteristic curves (ROC) were constructed to investigate the discriminative power of the cell subpopulations. Circulating CD4⁺ and CD8⁺ terminally differentiated effector memory T-cell (T_EMRA) frequencies were significantly higher in the AV group than in HCs (P < 0.05). TCF1⁺ T-cell subpopulations were widespread increased in patients with vitiligo (P < 0.05). After adjusting for potential confounders, CD8⁺ and CD4⁺ central memory (T_CM) cells, and CD8⁺ T_EMRA were correlated with disease activity (P < 0.05). The combined diagnostic value of the four (naïve, effector memory, T_CM, and T_EMRA) CD8⁺TCF1⁺ T-cell subsets was relatively high (area under the ROC curve (AUC) = 0.804, sensitivity = 71.70%, specificity = 83.34%), and the CD8⁺ T-cell subsets combination performed well in discriminating disease activity (AUC = 0.849, sensitivity = 70.97%, specificity = 90.91%). We demonstrated an altered circulating memory T-cell profile and increased TCF1⁺ T-cell percentage in patients with vitiligo. T-cell subpopulations had a strong value for vitiligo diagnosis and activity evaluation. This evidence presents a potential new pharmacological target for inhibiting autoimmunity that leads to vitiligo.

Background The influencing factors of noise hazards in the automotive manufacturing industry are complex, diverse, and mutually correlated, resulting in significant health impacts on workers. Objective To explore the application of generalized estimating equations (GEE) to analyze the factors affecting high-frequency hearing loss among noise-exposed workers in an automotive manufacturing company, guiding enterprises to scientifically carry out employee hearing protection programs. Methods The data of occupational health field evaluation and occupational health surveillance of an automobile manufacturing company for five consecutive years from 2018 to 2022 were collected, and 806 noise-exposed workers with pure tone hearing test results for all five consecutive years were selected as study participants. The retrieved indicators were gender, physical examination year, noise intensity, blood pressure, white blood cell counts, red blood cell counts, platelet counts, concentrations of hemoglobin, alanine transaminase, aspartate aminotransferase, smoking, drinking, etc. Gender, noise intensity, blood pressure, white blood cell counts, red blood cell counts, concentrations of hemoglobin, platelet counts, glutamate aminotransferase, glutamate aminotransferase, smoking, and drinking were set as independent variables, and occurrence of high-frequency hearing loss was set as a dependent variable, and GEE were constructed by using the statistical software of SPSS 20.0 to analyze the influencing factors of high-frequency hearing loss. Results Of the 806 workers, 698 were male (86.6%) and 108 were female (13.4%). The detection rates of high-frequency hearing loss in each year from 2018 to 2022 were 66.4% (535/806), 69.8% (563/806), 70.0% (564/806), 68.9% (555/806), and 68.2% (550/806), respectively. The detection rate of high-frequency hearing loss in the company was varied significantly by gender, lowered white blood cell counts, lowered red blood cell counts, lowered platelet counts, smoking, and drinking (P<0.05). The results of GEE analysis showed that after adjusting for selected confounding factors and excluding interaction effects, the risk of high-frequency hearing loss was higher in men than in women (P=0.001; OR=1.907, 95%CI: 1.286, 2.829); it was higher in workplace with disqualified noise intensity than in those without (P=0.043; OR=1.289, 95%CI: 1.009, 1.648); it was also higher in smokers than in non-smokers (P=0.004; OR=1.507, 95%CI: 1.137, 1.999). Conclusion Gender, noise intensity, and smoking are the main influencing factors of high-frequency hearing loss in noise-exposed workers in this automobile manufacturing company. Controlling smoking and reducing noise exposure intensity may reduce the occurrence of high-frequency hearing loss in workers.

Antioxidant enzymes fused with cell-penetrating peptides could enter cells and protect cells from irradiation damage. However, the unselective transmembrane ability of cell-penetrating peptide may also bring antioxidant enzymes into tumor cells, thus protecting tumor cells and consequently reducing the efficacy of radiotherapy. There are active matrix metalloproteinase (MMP)-2 or MMP-9 in most tumor cellular microenvironments. Therefore, a fusion protein containing an MMP-2/9 cleavable substrate peptide X, a cell-penetrating peptide R9, a glutathione S-transferase (GST), and a human Cu, Zn superoxide dismutase (SOD1), was designed and named GST-SOD1-X-R9. In the tumor microenvironment, GST-SOD1-X-R9 would lose its cell-penetrating peptide and could not enter tumor cells due to the cleavage of substrate X by active MMP-2/9, thereby achieving selected entering normal cells. The complete nucleotide sequence of SOD1-X-R9 was synthesized and inserted into the prokaryotic expression vector pGEX-4T-1. The pGEX4T-1-SOD1-X-R9 recombinant plasmid was obtained, and soluble expression of the fusion protein was achieved. GST-SOD1-X-R9 was purified by ammonium sulfate precipitation and GST affinity chromatography. The molecular weight of the fusion protein was approximately 47 kDa, consistent with the theoretical value. The SOD and GST activities were 2 954 U/mg and 328 U/mg, respectively. Stability test suggested that almost no change in either SOD activity or GST activity of GST-SOD1-X-R9 was observed under physiological conditions. The fusion protein could be partially digested by collagenase Ⅳ in solution. Subsequently, the effect of MMP-2/9 activity on transmembrane ability of the fusion protein was tested using 2D and 3D cultured HepG2 cells. Little extracellular MMP-2 activity of HepG2 cells was observed under 2D culture condition. While under the 3D culture model, the size and the MMP-2 activity of the HepG2 tumor spheroid increased daily. GST-SOD1-R9 proteins showed the same transmembrane efficiency in 2D cultured HepG2 cells, but the transmembrane efficiency of GST-SOD1-X-R9 in 3D cultured HepG2 spheres was reduced remarkably. This study provided a basis for further investigating the selectively protective effect of GST-SOD1-X-R9 against oxidative damage in normal cells.
Ammonium Sulfate ; Antioxidants ; Cell-Penetrating Peptides/pharmacology* ; Endopeptidases ; Glutathione Transferase/metabolism* ; Humans ; Matrix Metalloproteinase 2/genetics* ; Matrix Metalloproteinase 9/genetics* ; Recombinant Fusion Proteins ; Recombinant Proteins ; Superoxide Dismutase/metabolism* ; Superoxide Dismutase-1

OBJECTIVE To mine the risk sig nals o f iodine contrast media from spontaneous reporting system. METHODS Reporting odds ratio ，proportional reporting ratio ，Medicines and Healthcare Products Regulatory Agency and Bayesian confidence propagation neural network were used to mine risk signals of 5 iodine contrast media （iopamidol，iohexol，iopromide，ioversol， iodixanol）. RESULTS 1 164（2 446 case times ）adverse drug reaction of iodine contrast media were included ，a total of 14 risk signals involving systems/organs such as respiratory system （3，2，4，3，2 for the above 5 iodine contrast media ）and immune system and 32 specific adverse drug reaction signals including anaphylactic shock ，rash and flushing （11，7，7，3，4 for the above 5 iodine contrast media ）were found in 5 iodine contrast media. CONCLUSIONS The risk signals of 5 iodine contrast media verify that there is a certain correlation between these drugs and above adverse drug reactions. It is suggested that before using iodine contrast media in clinic ，it is necessary to pay attention to whether the patient has a history of tumor and combined medication ，evaluate the patient’s renal function ，and give preventive measures such as hydration in advance. When using iodine contrast media ，it is necessary to pay attention to the temperature ，dose and injection rate. And medical staff need to follow up the patient ’s situation in time after using iodine contrast media to avoiding the impact of delayed adverse reactions.

Objective To study the characteristics of noise hazards in automobile sand casting industry and understand the impact of noise on the health of automobile foundry workers, and to provide scientific data support for the control of noise hazards. Methods An automobile sand casting enterprise was selected as the research object. The post noise intensity test results from 2010 to 2019, the noise spectrum test results of each post in 2019, and the prevalence of occupational noise deafness in the 10 years from 2010 to 2019 were analyzed and sorted out. Using chi-square test and t-test the noise hazard characteristics and noise intensity changes were statistically analyzed. Results 1. The noise LEX.8h exceeding standard rate of foundry enterprises in the 10 years from 2010 to 2019 was not statistically significant（χ²=6.76, P=0.66), and the mean value of noise LEX.8h fluctuated horizontally in the 10 years, which was basically stable between 80 - 90 dB (A). 2. The mean value of noise intensity of sand falling, sand preparation, cleaning and shot blasting in the first five years was significantly different compared to that in the last five years. There was no statistically significant difference in other posts. 3. Among all posts in the foundry sand casting industry, the noise spectrum of core-making and cleaning posts was mainly medium and high frequency, while the noise spectrum of other posts was mainly medium and low frequency. 4, Cases of occupational noise deafness were mainly concentrated in cleaning and polishing workers, melting chemical workers, inspectors and other types of workers. Conclusions The noise hazards in the automobile foundry sand casting industry are mainly concentrated on the posts of molding, and sand falling, and the noise intensity and the over standard rate remain high in the past 10 years. The noise of each post is mainly medium and low frequency, and the noise of a few individual posts is mainly medium and high frequency. In recent years, due to the automatic renewal of equipment, the noise intensity of some posts such as sand dropping, sand mixing, cleaning and shot blasting has decreased, but the overall noise exceeding standard rate has basically not changed, and the noise hazard is still serious. The noise hazard of foundry sand casting enterprises is difficult to be controlled, and the risk of hearing loss of foundry workers is still high.

Objective:To explore the efficient construction of HSF1 gene knockout mouse model using CRISPR/Cas9 gene editing technology, and to establish the early basis for the mouse model of primary osteosarcoma.Methods:According to exon 9 of HSF1 gene structure, the corresponding GRNA (guideRNA) was selected and screened. Then the transcription template of sgRNA (small guide RNA) was amplified by PCR, and four up stream primers were obtained. Subsequently, sgRNA was transcribed in vitro and screened by Tube Screen platform to screen the sgRNA with effective cutting, and the sgRNA with the highest cutting efficiency was selected from the screening results for subsequent experiments. The transcription template of SPCas9mRNA was amplified by PCR, and then Cas9mRNA was transcribed in vitro. The sgRNA transcribed in vitro and Cas9mRNA were injected into the fertilized eggs of healthy C57BL/6 mice, and the tissue was extracted from the tail of the born mice and identified by PCR sequencing. Heterozygous female mice of F0 generation were selected to mate with wild-type male mice too btain F1 generation off spring. The mutation of gene bases of F1 generation mice was detected by AGAR gel electrophoresis and gene sequencing. The heterozygous male mice of the F1 generation and female mice of the F0 generation were back crossed to obtain the F2 generation daughter mice. The tail tissues were cut and sequenced to obtain the F2 generation homozygous knockout mice. PCR was used to observe the cutting efficiency of sgRNA and the sequencing of rat tail tissue, and SNAPGene software was used for gene sequence alignment to determine the deletion of base fragments.Results:The up stream primers sgRNA-1 Primer-f, sgRNA-2 Primer-f, sgRNA-3 Primer-f, sgRNA-4 Primer-f and down stream primers sgRNA-4 Primer -r were obtained by PCR amplification. After in vitro tran scription and screening of sgrRNA, sgrRNA-1, sgrRNA-2 and sgrRNA-4 had high cleavage efficiency and were selected for subsequent experiments. T7 promoter was added to the 5 'end of Cas9 mRNA, and Cas9 mRNA was obtained by PCR and in vitro transcription kit. Mixed Cas9-sgRNA solution was injected into the fertilized eggs of mice and cultured. The cultured two-cell fertilized eggs were injected into the ampulla of the pseudo pregnant female mice, and the F0 generation mice were obtained successfully. A total of 8 heterozygous mice of F0 generation were obtained by Agar gel electrophoresis. Three heterozygous knockout mice of F1 generation were obtained by breeding the female heterozygous mice of F0 generation with healthy wild-type male mice and PCR and sequencing. Three heterozygous male mice of F1 generation were back crossed with female mice of F0 generation 3 to obtain F2 generation mice. Through the observation of electrophoresis and sequencing results of F2 generation mice, it was confirmed that 7 mice were missing HSF1 base sequence, and the electrophoresis results showed mutant bands and no wild-type bands, which were identified as homozygous. The F2 generation homozygous mice were able to breed stably. As eries of results proved that the HSF1 gene knockout mouse model was successfully established in this experiment.Conclusion:CRISPR/Cas9 technology was successfully used to construct HSF1 gene knockout mouse model, with strong stability and high reproducibility, which laida foundation for further study of HSF1 gene expression products and establishment of mouse model of primary osteosarcoma.

Objective:To explore the dose-response relationship between cumulative noise exposure and high-frequency hearing loss, and further to provide a basis for the control of occupational hazards of noise.Methods:A Meta-analysis of dose-response relationships was performed on the data of eligible literatures published in China from January 2000.1 to December 2019.12.Results:The initial combined Odds Ratio ( OR) and its 95%CI in the Meta-analysis were 1.10 (1.08-1.12) . As the Begg's funnel plot and Egger's test indicated publication bias ( t=5.97, P<0.01) , the Trim-and-Fill Method was used for OR value adjustment. The adjusted-OR was 1.09 (1.07-1.12) ; sensitivity analysis showed that the results of this Meta-analysis have high stability; subgroup analysis indicated that the ORs of the steady-state noise group and the non-steady-state noise group were 1.10 (1.08-1.12) and 1.14 (1.07-1.21) , the ORs of the old standard group and the new standard group were 1.10 (1.08-1.12) and 1.11 (1.00-1.24) , respectively. The nonlinear dose-response relationship curve demonstrated that the risk of high-frequency hearing loss increases rapidly after CNE reaches 95 dB (A) ·years. Conclusion:There is a definite dose-response relationship between CNE and high-frequency hearing loss, which can be used to predict the risk of high-frequency hearing loss in noisy workers.

The adjacent anatomy of the pelvis is complicated, with digestive, urinary, reproductive and other organs as well as important blood vessels and nerves. Therefore, accurate resection of pelvic tumors and precise reconstruction of defects after resection are extremely difficult. The development of medical 3D printing technology provides new ideas for precise resection and personalized reconstruction of pelvic tumors. The “triune” application of 3D printing personalized lesion model, osteotomy guide plate and reconstruction prosthesis in pelvic tumor limb salvage reconstruction treatment has achieved good clinical results. However, the current lack of normative guidance standards such as preparation and application of 3D printing personalized lesion model, osteotomy guide plate and reconstruction prosthesis restricts its promotion and application. The formulation of this consensus provides normative guidance for 3D printing personalized pelvic tumor limb salvage reconstruction treatment.

Objective:To explore the dose-response relationship between cumulative noise exposure and high-frequency hearing loss, and further to provide a basis for the control of occupational hazards of noise.Methods:A Meta-analysis of dose-response relationships was performed on the data of eligible literatures published in China from January 2000.1 to December 2019.12.Results:The initial combined Odds Ratio ( OR) and its 95%CI in the Meta-analysis were 1.10 (1.08-1.12) . As the Begg's funnel plot and Egger's test indicated publication bias ( t=5.97, P<0.01) , the Trim-and-Fill Method was used for OR value adjustment. The adjusted-OR was 1.09 (1.07-1.12) ; sensitivity analysis showed that the results of this Meta-analysis have high stability; subgroup analysis indicated that the ORs of the steady-state noise group and the non-steady-state noise group were 1.10 (1.08-1.12) and 1.14 (1.07-1.21) , the ORs of the old standard group and the new standard group were 1.10 (1.08-1.12) and 1.11 (1.00-1.24) , respectively. The nonlinear dose-response relationship curve demonstrated that the risk of high-frequency hearing loss increases rapidly after CNE reaches 95 dB (A) ·years. Conclusion:There is a definite dose-response relationship between CNE and high-frequency hearing loss, which can be used to predict the risk of high-frequency hearing loss in noisy workers.