Objective:To investigate the gene detection results of 2 patients with familial hypercholesterolemia (FH) caused by complex heterozygous variation, and to clarify the relationship between clinical manifestations and gene variation.Methods:Two patients (patient 1 and 2) with FH who visited Beijing Anzhen Hospital Affiliated to Capital Medical University in 2018 were selected as research subjects. A retrospective study method was used to collect clinical and family history data of the two patients. And 2 mL of peripheral venous blood from each of the two patients was collected, and genomic DNA extraction was performed on the blood samples. Sanger sequencing was used to validate the variant sites of the two patients detected by whole-exome sequencing (WES). Pathogenicity of variants was classified based on the American College of Medical Genetics and Genomics (ACMG) Standards and Guidelines for the Classification of Genetic Variants (hereinafter referred to as the " ACMG Guidelines" ), and the impact of variant was analyzed using multiple bioinformatics tools including SIFT, PolyPhen-2, and SWISS-MODEL. This study has been approved by Beijing Anzhen Hospital Affiliated to Capital Medical University (Ethics No. 2024215X).Results:Patient 1 initially presented with early-onset coronary heart disease, with initial lipid levels of serum total cholesterol (TC) 9.86 mmol/L (normal reference value: 3.10~5.20 mmol/L) and serum low-density lipoprotein cholesterol (LDL-C) 8.37 mmol/L (normal reference value: 1.27~3.12 mmol/L) on admission. Patient 1 initially underwent treatment with rosuvastatin combined with ezetimibe for one month, but the lipid-lowering effect was not significant. The lipid-lowering therapy was then adjusted to atorvastatin combined with ezetimibe and probucol. After one year of treatment, the patient developed paroxysmal chest pain symptoms. A follow-up lipid profile showed a serum TC level of 4.50 mmol/L and a LDL-C level of 3.55 mmol/L. The lipid-lowering regimen was continued, and the serum LDL-C levels were maintained between 2.65 and 3.66 mmol/L. Patient 2 was found to have an abnormally high blood lipid level and carotid artery hardening during physical examination, with an initial blood lipid level of serum TC 11.82 mmol/L and serum LDL-C 9.63 mmol/L. After receiving rosuvastatain therapy, the lipid-lowering effect was significant. WES revealed that patient 1 carried the heterozygous variants c. 1871_1873del(p.Ile624del) and c. 1747C>T(p.His583Tyr) in the LDLR gene (NM_000527.4), while patient 2 carried the heterozygous variants c. 1747C>T(p.His583Tyr) in the LDLR gene and c. 6936_6937inv(p.Ile2313Val) in the APOB gene (NM_000384). According to the ACMG Guidelines, the LDLR gene c. 1747C>T(p.His583Tyr) was classified as a pathogenic variant (PS3+ PM1+ PM2_supporting+ PM5+ PP2+ PP3), and c. 1871_1873del(p.Ile624del) was classified as a pathogenic variant (PS3+ PS4+ PM2_supporting+ PM1+ PM4); the APOB gene c. 6936_6937inv(p.Ile2313Val) was classified as a variant of uncertain clinical significance (PM2_supporting BP4). Conclusions:Patients 1 and 2 in this study were patients with complex heterozygous variant FH, and their genotypic differences may be related to the differences in clinical serum LDL-C levels and the efficacy of hypolipidemic agents.

OBJECTIVE: To investigate the gene detection results of 2 patients with familial hypercholesterolemia (FH) caused by complex heterozygous variation, and to clarify the relationship between clinical manifestations and gene variation. METHODS: Two patients (patient 1 and 2) with FH who visited Beijing Anzhen Hospital Affiliated to Capital Medical University in 2018 were selected as research subjects. A retrospective study method was used to collect clinical and family history data of the two patients. And 2 mL of peripheral venous blood from each of the two patients was collected, and genomic DNA extraction was performed on the blood samples. Sanger sequencing was used to validate the variant sites of the two patients detected by whole-exome sequencing (WES). Pathogenicity of variants was classified based on the American College of Medical Genetics and Genomics (ACMG) Standards and Guidelines for the Classification of Genetic Variants (hereinafter referred to as the "ACMG Guidelines"), and the impact of variant was analyzed using multiple bioinformatics tools including SIFT, PolyPhen-2, and SWISS-MODEL. This study has been approved by Beijing Anzhen Hospital Affiliated to Capital Medical University (Ethics No. 2024215X). RESULTS: Patient 1 initially presented with early-onset coronary heart disease, with initial lipid levels of serum total cholesterol (TC) 9.86 mmol/L (normal reference value: 3.10~5.20 mmol/L) and serum low-density lipoprotein cholesterol (LDL-C) 8.37 mmol/L (normal reference value: 1.27~3.12 mmol/L) on admission. Patient 1 initially underwent treatment with rosuvastatin combined with ezetimibe for one month, but the lipid-lowering effect was not significant. The lipid-lowering therapy was then adjusted to atorvastatin combined with ezetimibe and probucol. After one year of treatment, the patient developed paroxysmal chest pain symptoms. A follow-up lipid profile showed a serum TC level of 4.50 mmol/L and a LDL-C level of 3.55 mmol/L. The lipid-lowering regimen was continued, and the serum LDL-C levels were maintained between 2.65 and 3.66 mmol/L. Patient 2 was found to have an abnormally high blood lipid level and carotid artery hardening during physical examination, with an initial blood lipid level of serum TC 11.82 mmol/L and serum LDL-C 9.63 mmol/L. After receiving rosuvastatain therapy, the lipid-lowering effect was significant. WES revealed that patient 1 carried the heterozygous variants c.1871_1873del(p.Ile624del) and c.1747C>T (p.His583Tyr) in the LDLR gene (NM_000527.4), while patient 2 carried the heterozygous variants c.1747C>T (p.His583Tyr) in the LDLR gene and c.6936_6937inv (p.Ile2313Val) in the APOB gene (NM_000384). According to the ACMG Guidelines, the LDLR gene c.1747C>T (p.His583Tyr) was classified as a pathogenic variant (PS3+PM1+PM2_supporting+PM5+PP2+PP3), and c.1871_1873del (p.Ile624del) was classified as a pathogenic variant (PS3+PS4+PM2_supporting+PM1+PM4); the APOB gene c.6936_6937inv (p.Ile2313Val) was classified as a variant of uncertain clinical significance (PM2_supporting BP4). CONCLUSION Patients 1 and 2 in this study were patients with complex heterozygous variant FH, and their genotypic differences may be related to the differences in clinical serum LDL-C levels and the efficacy of hypolipidemic agents.
Humans ; Hyperlipoproteinemia Type II/drug therapy* ; Male ; Female ; Heterozygote ; Adult ; Middle Aged ; Receptors, LDL/genetics* ; Retrospective Studies ; Mutation ; Exome Sequencing

Objective:To fine-tune the mT5 (massively multilingual pre-trained text-to-text transformer) large language model, automatically generate report conclusions for teaching purposes from chest CT image descriptions, and assess the quality of automatically generated conclusions.Methods:The training set included 3 000 high-quality physical examination chest CT reports from one hospital, and the external validation set consisted of 600 physical examination chest CT reports from two other hospitals. Experienced radiology teaching physicians assessed the consistency between the generated conclusions and the original physician-written conclusions in the external validation set using a 5-point Likert scale across five linguistic indicators (correctness of examination information, correctness of lesion detection, standardization of terminology, applicability of the conclusions, and simplicity of conclusions). Using the original report conclusions as the reference, the accuracy of the conclusions generated based on the external validation set in describing four major thoracic conditions (pulmonary nodules, pneumonia, emphysema, pleural effusion) was evaluated. Perform chi square test using SPSS 25.0.Results:In the external validation set, the mean consistency score between the generated conclusions and the original conclusions given by the radiology teaching physicians was >4 points, indicating agreement with the original conclusions. In the generated conclusions, the description of the four major thoracic conditions demonstrated 0.95-1.00 (95% CI=0.91-1.00) accuracy, 0.76-1.00 (95% CI=0.59-1.00) sensitivity, and 0.97-1.00 (95% CI=0.91-1.00) specificity. Conclusions:The chest CT report conclusion generation system based on the mT5 large language model demonstrated high accuracy and is expected to provide immediate and efficient automated guidance for standardized residency training.

Objective:To fine-tune the mT5 (massively multilingual pre-trained text-to-text transformer) large language model, automatically generate report conclusions for teaching purposes from chest CT image descriptions, and assess the quality of automatically generated conclusions.Methods:The training set included 3 000 high-quality physical examination chest CT reports from one hospital, and the external validation set consisted of 600 physical examination chest CT reports from two other hospitals. Experienced radiology teaching physicians assessed the consistency between the generated conclusions and the original physician-written conclusions in the external validation set using a 5-point Likert scale across five linguistic indicators (correctness of examination information, correctness of lesion detection, standardization of terminology, applicability of the conclusions, and simplicity of conclusions). Using the original report conclusions as the reference, the accuracy of the conclusions generated based on the external validation set in describing four major thoracic conditions (pulmonary nodules, pneumonia, emphysema, pleural effusion) was evaluated. Perform chi square test using SPSS 25.0.Results:In the external validation set, the mean consistency score between the generated conclusions and the original conclusions given by the radiology teaching physicians was >4 points, indicating agreement with the original conclusions. In the generated conclusions, the description of the four major thoracic conditions demonstrated 0.95-1.00 (95% CI=0.91-1.00) accuracy, 0.76-1.00 (95% CI=0.59-1.00) sensitivity, and 0.97-1.00 (95% CI=0.91-1.00) specificity. Conclusions:The chest CT report conclusion generation system based on the mT5 large language model demonstrated high accuracy and is expected to provide immediate and efficient automated guidance for standardized residency training.

Objective:To investigate the gene detection results of 2 patients with familial hypercholesterolemia (FH) caused by complex heterozygous variation, and to clarify the relationship between clinical manifestations and gene variation.Methods:Two patients (patient 1 and 2) with FH who visited Beijing Anzhen Hospital Affiliated to Capital Medical University in 2018 were selected as research subjects. A retrospective study method was used to collect clinical and family history data of the two patients. And 2 mL of peripheral venous blood from each of the two patients was collected, and genomic DNA extraction was performed on the blood samples. Sanger sequencing was used to validate the variant sites of the two patients detected by whole-exome sequencing (WES). Pathogenicity of variants was classified based on the American College of Medical Genetics and Genomics (ACMG) Standards and Guidelines for the Classification of Genetic Variants (hereinafter referred to as the " ACMG Guidelines" ), and the impact of variant was analyzed using multiple bioinformatics tools including SIFT, PolyPhen-2, and SWISS-MODEL. This study has been approved by Beijing Anzhen Hospital Affiliated to Capital Medical University (Ethics No. 2024215X).Results:Patient 1 initially presented with early-onset coronary heart disease, with initial lipid levels of serum total cholesterol (TC) 9.86 mmol/L (normal reference value: 3.10~5.20 mmol/L) and serum low-density lipoprotein cholesterol (LDL-C) 8.37 mmol/L (normal reference value: 1.27~3.12 mmol/L) on admission. Patient 1 initially underwent treatment with rosuvastatin combined with ezetimibe for one month, but the lipid-lowering effect was not significant. The lipid-lowering therapy was then adjusted to atorvastatin combined with ezetimibe and probucol. After one year of treatment, the patient developed paroxysmal chest pain symptoms. A follow-up lipid profile showed a serum TC level of 4.50 mmol/L and a LDL-C level of 3.55 mmol/L. The lipid-lowering regimen was continued, and the serum LDL-C levels were maintained between 2.65 and 3.66 mmol/L. Patient 2 was found to have an abnormally high blood lipid level and carotid artery hardening during physical examination, with an initial blood lipid level of serum TC 11.82 mmol/L and serum LDL-C 9.63 mmol/L. After receiving rosuvastatain therapy, the lipid-lowering effect was significant. WES revealed that patient 1 carried the heterozygous variants c. 1871_1873del(p.Ile624del) and c. 1747C>T(p.His583Tyr) in the LDLR gene (NM_000527.4), while patient 2 carried the heterozygous variants c. 1747C>T(p.His583Tyr) in the LDLR gene and c. 6936_6937inv(p.Ile2313Val) in the APOB gene (NM_000384). According to the ACMG Guidelines, the LDLR gene c. 1747C>T(p.His583Tyr) was classified as a pathogenic variant (PS3+ PM1+ PM2_supporting+ PM5+ PP2+ PP3), and c. 1871_1873del(p.Ile624del) was classified as a pathogenic variant (PS3+ PS4+ PM2_supporting+ PM1+ PM4); the APOB gene c. 6936_6937inv(p.Ile2313Val) was classified as a variant of uncertain clinical significance (PM2_supporting BP4). Conclusions:Patients 1 and 2 in this study were patients with complex heterozygous variant FH, and their genotypic differences may be related to the differences in clinical serum LDL-C levels and the efficacy of hypolipidemic agents.

Tetanus consists of neonatal tetanus and non-neonatal tetanus. Non-neonatal tetanus remains a serious public health problem, although neonatal tetanus has been eliminated in China since 2012. Non-neonatal tetanus is a potential fatal disease. In the absence of medical intervention, the mortality rate of severe cases is almost 100%. Even with vigorous treatment, the mortality rate remains 30%-50% globally. These specifications aim to regulate non-neonatal tetanus diagnosis and treatment in China, in order to improve medical quality and safety. These specifications introduce the etiology, epidemiology, pathogenesis, clinical manifestations and laboratory tests, diagnosis, differential diagnosis, grading and treatment of non-neonatal tetanus.

Objective:To investigate the expression and cellular provenance of interleukin 17A (IL-17A) in non-eosinophilic chronic rhinosinusitis with nasal polyps (nECRSwNP), and to analyze the possible reasons for its different expression.Methods:Samples were collected from 14 patients with eosinophilic chronic rhinosinusitis with nasal polyps (ECRSwNP) and 28 patients with nECRSwNP, who underwent functional endoscopic sinus surgery in the Third Affiliated Hospital of Sun Yat-sen University from January 2017 to May 2018, including 33 males and 9 females, with the age ranging from 18 to 65 years old. Enzyme linked immune sorbent assay (ELISA) and flow cytometry were used to investigate the expression and cellular origins of IL-17A in the nasal tissue of ECRSwNP and nECRSwNP groups. Then the difference of quantity and differentiation ability of the major cells producing IL-17A between ECRSwNP and nECRSwNP groups were analyzed by flow cytometry. Finally, the expressions of IL-6, transforming growth factor-β(TGF-β), and IL-23, which were considered as the important factors in promoting Th17/Tc17 differentiation in CRSwNP and their correlation with IL-17A, were analyzed by ELISA. Statistical analysis was performed using IBM SPSS 20.Results:The IL-17A protein levels and IL-17A +lymphocyte percentages were higher in nECRSwNP group compared with that of the ECRSwNP group (158.56 (167.76) pg/ml ( M( QR)) vs. 9.42 (11.33) pg/ml, 10.21%±1.54% ( ± s) vs. 3.93%±0.80%, Z=2.95, t=3.62, all P<0.01). Tc17 cells (CD8 +T cells producing IL-17A) and Th17 cells (CD4 +T cells producing IL-17A) were major IL-17A producers in both ECRSwNP and nECRSwNP group. Further analysis revealed that there was no significant difference in quantity of CD8 +and CD4 +T cells between ECRSwNP and nECRSwNP group, but the differentiation ability about CD8 +and CD4 +T cells differentiating into Tc17 and Th17 in nECRSwNP group was stronger than that in ECRSwNP. The high expressions of IL-6 and TGF-β, which were considered as the important factors in promoting Th17/Tc17 differentiation were also found in nECRSwNP group compared with ECRSwNP (56.07 (234.25) pg/ml vs. 8.27 (12.51) pg/ml, (5.44±0.34) pg/ml vs. (4.17±0.22) pg/ml, Z=2.426, t=2.29, all P<0.05). But the difference in expression of IL-23 was not significant difference between the two groups. Moreover, the expression of IL-17A showed significantly positive correlation with IL-6 ( r=0.615, P=0.009). No positive correlation between IL-17A and TGF-β or IL-23 was observed. Conclusions:The expression of IL-17A in nasal mucosa of nECRSwNP patients is significantly higher than that of ECRSwNP, which is due to the increase of expression and differentiation of Tc17/Th17 cells. IL-17A shows positive correlation with IL-6 in CRSwNP, which is the important factor in promoting Th17/Tc17 differentiation.

Tetanus consists of neonatal tetanus and non-neonatal tetanus.Non-neonatal tetanus remains a serious public health problem,although neonatal tetanus has been eliminated in China since 2012.Non-neonatal tetanus is a potential fatal disease.In the absence of medical intervention,the mortality rate of severe cases is almost 100％.Even with vigorous treatment,the mortality rate is still 30％-50％ globally.These specifications aim to regulate non-neonatal tetanus diagnosis and treatment in China,in order to improve medical quality and safety.These specifications introduce the etiology,epidemiology,pathogenesis,clinical manifestations and laboratory tests,diagnosis,differential diagnosis,grading and treatment of non-neonatal tetanus.

Tetanus consists of neonatal tetanus and non-neonatal tetanus. Although neonatal tetanus in China has been eliminated since 2012, non-neonatal tetanus remains a serious public health problem. Non-neonatal tetanus is a potential fatal disease, and the mortality rate of severe cases is almost 100% in the absence of medical intervention. Even with vigorous treatment, the mortality rate is still 30~50% globally. In order to standardize the diagnosis and treatment of non-neonatal tetanus in China, this specification is hereby formulated. This standard includes etiology, epidemiology, pathogenesis, clinical manifestations, laboratory tests, diagnosis, differential diagnosis, classification, grading and treatment of non-neonatal tetanus.

Objective To explore the effect of luteolin on the proliferation of osteosarcoma stem cells.Methods CD133 +osteosarcoma stem cells were separated from MG63 cells by flow cytometer.MTT was used to investigate the effects of luteolin(0,0.01,0.02,0.04 mg/mL)on the proliferation of osteosarcoma stem cells.Western blot was used to detect the levels of Ki67 protein and components of JAK2/STAT3 signal pathway in osteosarcoma stem cells induced.Results After sorting,the content of the CD133 +fraction was enriched up to(87.60 ±5.06)%.MTT assay showed that,compared with the control group,luteolin(0.01,0.02,0.04 mg/mL)inhibited proliferation of CD133 + osteosarcoma stem cells(P <0.05).Western blot also showed that luteolin significantly decreased the level of Ki67 compared with the control group(P<0.05).In addition,the luteolin inhibited the expression of p-JAK2 and p-STAT3 in JAK2/STAT3 signal pathway of CD133 + osteosarcoma stem cells compared with the control group ( P <0.05 ) . Conclusion Luteolin might be a suppressor of osteosarcoma stem cells.