Objective To investigate the association between 731 immunophenotypes and the risk of ischemic stroke based on the summary statistics from the largest publicly available genome-wide association studies. Methods The univariate Mendelian randomization （MR） analysis and multivariate Mendelian randomization （MVMR） analysis were used to investigate the association between 731 immunophenotypes and the risk of ischemic stroke. The types of immune cells significantly associated the risk of ischemic stroke were identified after false discovery rate （FDR） correction. The reverse MR analysis was used to validate the influence of immunophenotypes on ischemic stroke， and the sensitivity analysis was performed for all results to ensure stability. Results The univariate MR analysis identified four types of immune cells that were significantly associated with the risk of ischemic stroke，i.e.，CD39+ regulatory T cells （OR=1.017，95%CI 1.008-1.025，P<0.000 1），IgD-CD38+B cells with CD27+ phenotype （OR=1.073，95%CI 1.034-1.114，P<0.001），CD14+CD16-monocytes with CD40+phenotype （OR=0.973，95%CI 0.959-0.987，P<0.001），and CD14+CD16+ monocytes with CD40 phenotype （OR=0.979，95%CI 0.969-0.990，P<0.001）. The MVMR analysis showed that IgD-CD38+cells with CD27+phenotype had a significant independent effect in increasing the risk of ischemic stroke （OR=1.053，95%CI 1.006-1.100，P=0.028）. The reverse MR analysis did not yield statistically significant results after FDR correction， and the sensitivity analysis confirmed the stability of these findings. Conclusion This study shows that immunophenotype has a significant impact on the risk of ischemic stroke， and further experimental studies are needed to explore the underlying mechanisms of these associations.

Objective:To investigate the clinical and pathological significance of the DICER1 mutation in follicular thyroid carcinoma (FTC).Methods:Sixty-eight cases of primary FTC resected between 2009 and 2023 were retrieved from The Affiliated Hospital of Qingdao University, Qingdao, China. Sanger sequencing was performed to identify DICER1 and TERT promoter mutations in all cases. Cases with DICER1 or TERT promoter mutations were subject to additional examination of potential mutations in KRAS, HRAS, and NRAS. The clinical and pathological features of DICER1-mutant FTCs were then analyzed. The relationship between DICER1 mutations and TERT-promoter/RAS mutations was also assessed.Results:DICER1 mutations were detected in 16 of the 68 FTC cases (23.5%), with 11 near E1813 at exon 25, 6 near D1709 at exon 24, and 1 in the splice region of exon 25. Two cases harbored two (distinct) mutations. All patients with DICER1-mutant FTC were female. Compared with patients with DICER1-wild-type FTC, those with DICER1-mutant were much younger, and had a higher proportion of minimally invasive subtype. Nine FTCs with DICER1 mutations were subject to further sequencing on adjacent non-cancerous tissues or lymph node tissues, but no mutations were detected. TERT-promoter or RAS hotspot mutations were not identified in any of the DICER1-mutant cases. However, TERT-promoter mutation was found in 6 DICER1-wild-type cases (8.8%, 6/68), with 3 cases also having RAS hotspot mutations and exhibiting highly aggressive biological behaviors.Conclusion:DICER1 mutations may occur in FTCs and appear mutually exclusive with RAS and TERT-promoter mutations, warranting further study as RAS-like mutations.

Objective:To explore the genetic etiology for a child presenting with motor retardation, language delay, intellectual disability, and dysmorphic features.Methods:A child presented at Linyi People′s Hospital in June 2022 was selected as the study subject. Clinical data of the child was collected. Peripheral blood samples were obtained from the child and her parents. Following extraction of genomic DNA, whole-exome sequencing (WES) was carried out. Candidate variant was validated by Sanger sequencing. Amniotic fluid samples were obtained from the mother′s subsequent pregnancies for prenatal diagnosis. This study has been reviewed and approved by the Medical Ethics Committee of Linyi People′s Hospital (Ethics No.: 202402-H-034).Results:The proband was a 2-year-old girl showing developmental delays in motor, language, and intellectual domains, strabismus, hypertelorism, hearing impairment, obesity, and brachymesophalangy of the fifth finger. Magnetic resonance imaging revealed abnormalities of the white matter. Chromosomal microarray analysis (CMA) identified a 15q26.3 duplication (chr15: 101562020_102060896×3) inherited from her mother. WES has uncovered a heterozygous c. 1931A>G (p.Tyr644Cys) variant in the FBXO11 gene. Sanger sequencing confirmed the variant to be de novo in origin. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was classified as likely pathogenic. Prenatal diagnosis revealed that the fetuses from the mother′s second and third pregnancies did not harbor the same variant. Conclusion:The c. 1931A>G (p.Tyr644Cys) variant of the FBXO11 gene probably underlay the abnormal phenotype in the child. Based on its genotype and phenotype, the proband was diagnosed with Intellectual developmental disorder with dysmorphic facies and behavioral abnormalities.

Objective:To investigate the control status of out-of-hospital blood glucose and blood lipids in patients with acute myocardial infarction (AMI) complicated with diabetes mellitus and its correlation with prognosis.Methods:The clinical data of 406 patients with AMI complicated with diabetes mellitus from January 2017 to December 2022 in Xuanwu Hospital, Capital Medical University were retrospectively analyzed. The demographic and out-of-hospital clinical information of patients were recorded, and the control level of out-of-hospital risk factors and the occurrence of major adverse cardiovascular event (MACCE) were also recorded. The patients were grouped according to the levels of glycosylated hemoglobin (HbA 1c) and low-density lipoprotein cholesterol (LDL-C). HbA 1c<6.0% was the low HbA 1c group, HbA 1c 6.0% to 7.0% was the medium HbA 1c group, and HbA 1c>7.0% was the high HbA 1c group; LDL-C<1.4 mmol/L was low LDL-C group, LDL-C 1.4 to 1.8 mmol/L was medium LDL-C group, and LDL-C>1.8 mmol/L was high LDL-C group. Multivariate Cox regression analysis was used to analyze the independent risk factors for out-of-hospital MACCE in patients with AMI complicated with diabetes mellitus. Results:The HbA 1c data of 249 patients were recorded in detail, and only 51.0% (127/249) of patients with HbA 1c≤7%. There were statistical differences in the history of cerebral infarction, out-of-hospital fasting blood glucose, out-of-hospital total cholesterol (TC) and out-of-hospital LDL-C among the low HbA 1c group (24 cases), medium HbA 1c group (103 cases) and high HbA 1c group (122 cases) ( P<0.05). The incidences of out-of-hospital MACCE in low HbA 1c group, medium HbA 1c group and high HbA 1c group were 20.8%(5/24), 12.6%(13/103) and 32.0%(39/122), respectively. The incidence of out-of-hospital MACCE in high HbA 1c group was significantly higher than that in medium HbA 1c group, and there was statistical difference ( P<0.05); there was no statistical difference between low HbA 1c group and high HbA 1c group ( P>0.05). Among the 406 patients, 53.4%(217/406) had LDL-C≤1.8 mmol/L, and only 20.0%(81/406) had LDL-C<1.4 mmol/L. There were statistical differences in hyperlipidemia, out-of-hospital HbA 1c, out-of-hospital fasting blood glucose, out-of-hospital alanine aminotransferase (ALT), out-of-hospital TC and out-of-hospital triglyceride (TG) among low LDL-C group (81 cases), medium LDL-C group (136 cases) and high LDL-C group (189 cases) ( P<0.05). The incidences of MACCE in low LDL-C group, medium LDL-C group and high LDL-C group were 18.5% (15/81), 25.7% (35/136) and 36.5% (69/189), respectively. The incidence of MACCE in high LDL-C group was significantly higher than that in low LDL-C group, and there was statistical difference ( P<0.05); there was no statistical difference between low LDL-C group and medium LDL-C group ( P>0.05). In the different HbA 1c groups, multivariate Cox regression analysis result showed that HbA 1c>7% and high out-of-hospital fasting blood glucose were independent risk factors for out-of-hospital MACCE in patients with AMI complicated with diabetes mellitus ( OR = 2.575 and 1.064, 95% CI 1.345 to 4.927 and 1.005 to 1.128, P<0.01 and <0.05). In different LDL-C groups, multivariate Cox regression analysis result showed that high out-of-hospital HbA 1c was an independent risk factor for out-of-hospital MACCE in patients with AMI complicated with diabetes mellitus ( OR = 1.303, 95% CI 1.144 to 1.485, P<0.01). Conclusions:The control rates of out-of-hospital blood glucose and blood lipids are low in patients with AMI complicated with diabetes mellitus, and HbA 1c level can independently predict the risk of out-of-hospital MACCE in patients with AMI complicated with diabetes mellitus.

OBJECTIVE: To explore the genetic etiology for a child presenting with motor retardation, language delay, intellectual disability, and dysmorphic features. METHODS: A child presented at Linyi People's Hospital in June 2022 was selected as the study subject. Clinical data of the child was collected. Peripheral blood samples were obtained from the child and her parents. Following extraction of genomic DNA, whole-exome sequencing (WES) was carried out. Candidate variant was validated by Sanger sequencing. Amniotic fluid samples were obtained from the mother's subsequent pregnancies for prenatal diagnosis. This study has been reviewed and approved by the Medical Ethics Committee of Linyi People's Hospital (Ethics No.: 2019-134). RESULTS: The proband was a 2-year-old girl showing developmental delays in motor, language, and intellectual domains, strabismus, hypertelorism, hearing impairment, obesity, and brachymesophalangy of the fifth finger. Magnetic resonance imaging revealed abnormalities of the white matter. Chromosomal microarray analysis (CMA) identified a 15q26.3 duplication (chr15:101562020_102060896 × 3) inherited from her mother. WES has uncovered a heterozygous c.1931A>G (p.Tyr644Cys) variant in the FBXO11 gene. Sanger sequencing confirmed the variant to be de novo in origin. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was classified as likely pathogenic. Prenatal diagnosis revealed that the fetuses from the mother's second and third pregnancies did not harbor the same variant. CONCLUSION The c.1931A>G (p.Tyr644Cys) variant of the FBXO11 gene probably underlay the abnormal phenotype in the child. Based on its genotype and phenotype, the proband was diagnosed with Intellectual developmental disorder with dysmorphic facies and behavioral abnormalities.
Humans ; Female ; Intellectual Disability/genetics* ; Child, Preschool ; F-Box Proteins/genetics* ; Protein-Arginine N-Methyltransferases/genetics* ; Exome Sequencing

Objective:To investigate the molecular markers involved in death related to acute myocardial infarction (AMI) and provide new targets for early intervention.Methods:Consecutive patients who hospitalized in department of cardiology, Xuanwu Hospital, Capital Medical University from January 2017 to December 2021 and diagnosed with AMI were enrolled. The clinical factors and markers associated with in-hospital death after AMI were analyzed. In addition, patients diagnosed with AMI hospitalized in department of cardiology, Xuanwu Hospital, Capital Medical University from September 2022 to April 2023 were enrolled. We prospectively analyzed the plasma protein of death related to AMI via Olink Precision Proteomics based on proximity extension assay (PEA) technology.Results:In the retrospective study, 2 325 patients with AMI were analyzed, including 75 patients in the in-hospital death group and 2 250 subjects in the survival group. The overall mortality rate during hospitalization was 3.23% (75/2325). The patients in the death group were older: 72 (64, 80) years vs. 63 (55, 71) years. And Interleukin-6 (IL-6), hypersensitive C-reactive protein (Hs-CRP), leukocyte counts and neutrophil counts were markedly higher in the death group than those in the survival group: 69.0 (26.7, 136.6) ng/L vs. 18.2 (9.4, 36.5) ng/L, 45.7 (28.7, 50.5) mg/L vs. 5.5 (2.0, 17.2) mg/L, 12.0 (9.8, 14.1) ×10 9/L vs. 8.9 (7.2, 11.2) × 10 9/L, 9.8 (7.8, 12.1) ×10 9/L vs. 6.5(4.7, 8.8) ×10 9/L ( P<0.01). In this prospective study, 86 patients with AMI were analyzed. 61 proteins including Insulin-like growth factor-binding protein 1, 2 (IGFBP-1, IGFBP-2), Chitotriosidase-1 (CHIT1), Complement component C1q receptor (CD93) were independently associated with in-hospital death related to AMI ( P<0.05). The differential proteins were mainly enriched in inflammatory response, cell adhesion, cytokine signaling pathway and apoptosis. Moreover, 22 proteins including Urokinase plasminogen activator surface receptor (U-PAR), Trefoil factor 3 (TFF3), Perlecan (PLC), Growth differentiation factor 15 (GDF-15), Junctional adhesion molecule A (JAM-A) were plotted according to a logistic regression model, and the area under the curve (AUC) was more than 0.9, showing the high accuracy in predicting in-hospital death after AMI. Conclusions:Molecular markers of the inflammatory response, cell adhesion, cell growth and apoptosis might be involved in death related to AMI, which provides new targets for early intervention.

Objective:To investigate the control status of out-of-hospital blood glucose and blood lipids in patients with acute myocardial infarction (AMI) complicated with diabetes mellitus and its correlation with prognosis.Methods:The clinical data of 406 patients with AMI complicated with diabetes mellitus from January 2017 to December 2022 in Xuanwu Hospital, Capital Medical University were retrospectively analyzed. The demographic and out-of-hospital clinical information of patients were recorded, and the control level of out-of-hospital risk factors and the occurrence of major adverse cardiovascular event (MACCE) were also recorded. The patients were grouped according to the levels of glycosylated hemoglobin (HbA 1c) and low-density lipoprotein cholesterol (LDL-C). HbA 1c<6.0% was the low HbA 1c group, HbA 1c 6.0% to 7.0% was the medium HbA 1c group, and HbA 1c>7.0% was the high HbA 1c group; LDL-C<1.4 mmol/L was low LDL-C group, LDL-C 1.4 to 1.8 mmol/L was medium LDL-C group, and LDL-C>1.8 mmol/L was high LDL-C group. Multivariate Cox regression analysis was used to analyze the independent risk factors for out-of-hospital MACCE in patients with AMI complicated with diabetes mellitus. Results:The HbA 1c data of 249 patients were recorded in detail, and only 51.0% (127/249) of patients with HbA 1c≤7%. There were statistical differences in the history of cerebral infarction, out-of-hospital fasting blood glucose, out-of-hospital total cholesterol (TC) and out-of-hospital LDL-C among the low HbA 1c group (24 cases), medium HbA 1c group (103 cases) and high HbA 1c group (122 cases) ( P<0.05). The incidences of out-of-hospital MACCE in low HbA 1c group, medium HbA 1c group and high HbA 1c group were 20.8%(5/24), 12.6%(13/103) and 32.0%(39/122), respectively. The incidence of out-of-hospital MACCE in high HbA 1c group was significantly higher than that in medium HbA 1c group, and there was statistical difference ( P<0.05); there was no statistical difference between low HbA 1c group and high HbA 1c group ( P>0.05). Among the 406 patients, 53.4%(217/406) had LDL-C≤1.8 mmol/L, and only 20.0%(81/406) had LDL-C<1.4 mmol/L. There were statistical differences in hyperlipidemia, out-of-hospital HbA 1c, out-of-hospital fasting blood glucose, out-of-hospital alanine aminotransferase (ALT), out-of-hospital TC and out-of-hospital triglyceride (TG) among low LDL-C group (81 cases), medium LDL-C group (136 cases) and high LDL-C group (189 cases) ( P<0.05). The incidences of MACCE in low LDL-C group, medium LDL-C group and high LDL-C group were 18.5% (15/81), 25.7% (35/136) and 36.5% (69/189), respectively. The incidence of MACCE in high LDL-C group was significantly higher than that in low LDL-C group, and there was statistical difference ( P<0.05); there was no statistical difference between low LDL-C group and medium LDL-C group ( P>0.05). In the different HbA 1c groups, multivariate Cox regression analysis result showed that HbA 1c>7% and high out-of-hospital fasting blood glucose were independent risk factors for out-of-hospital MACCE in patients with AMI complicated with diabetes mellitus ( OR = 2.575 and 1.064, 95% CI 1.345 to 4.927 and 1.005 to 1.128, P<0.01 and <0.05). In different LDL-C groups, multivariate Cox regression analysis result showed that high out-of-hospital HbA 1c was an independent risk factor for out-of-hospital MACCE in patients with AMI complicated with diabetes mellitus ( OR = 1.303, 95% CI 1.144 to 1.485, P<0.01). Conclusions:The control rates of out-of-hospital blood glucose and blood lipids are low in patients with AMI complicated with diabetes mellitus, and HbA 1c level can independently predict the risk of out-of-hospital MACCE in patients with AMI complicated with diabetes mellitus.

Objective:To investigate the molecular markers involved in death related to acute myocardial infarction (AMI) and provide new targets for early intervention.Methods:Consecutive patients who hospitalized in department of cardiology, Xuanwu Hospital, Capital Medical University from January 2017 to December 2021 and diagnosed with AMI were enrolled. The clinical factors and markers associated with in-hospital death after AMI were analyzed. In addition, patients diagnosed with AMI hospitalized in department of cardiology, Xuanwu Hospital, Capital Medical University from September 2022 to April 2023 were enrolled. We prospectively analyzed the plasma protein of death related to AMI via Olink Precision Proteomics based on proximity extension assay (PEA) technology.Results:In the retrospective study, 2 325 patients with AMI were analyzed, including 75 patients in the in-hospital death group and 2 250 subjects in the survival group. The overall mortality rate during hospitalization was 3.23% (75/2325). The patients in the death group were older: 72 (64, 80) years vs. 63 (55, 71) years. And Interleukin-6 (IL-6), hypersensitive C-reactive protein (Hs-CRP), leukocyte counts and neutrophil counts were markedly higher in the death group than those in the survival group: 69.0 (26.7, 136.6) ng/L vs. 18.2 (9.4, 36.5) ng/L, 45.7 (28.7, 50.5) mg/L vs. 5.5 (2.0, 17.2) mg/L, 12.0 (9.8, 14.1) ×10 9/L vs. 8.9 (7.2, 11.2) × 10 9/L, 9.8 (7.8, 12.1) ×10 9/L vs. 6.5(4.7, 8.8) ×10 9/L ( P<0.01). In this prospective study, 86 patients with AMI were analyzed. 61 proteins including Insulin-like growth factor-binding protein 1, 2 (IGFBP-1, IGFBP-2), Chitotriosidase-1 (CHIT1), Complement component C1q receptor (CD93) were independently associated with in-hospital death related to AMI ( P<0.05). The differential proteins were mainly enriched in inflammatory response, cell adhesion, cytokine signaling pathway and apoptosis. Moreover, 22 proteins including Urokinase plasminogen activator surface receptor (U-PAR), Trefoil factor 3 (TFF3), Perlecan (PLC), Growth differentiation factor 15 (GDF-15), Junctional adhesion molecule A (JAM-A) were plotted according to a logistic regression model, and the area under the curve (AUC) was more than 0.9, showing the high accuracy in predicting in-hospital death after AMI. Conclusions:Molecular markers of the inflammatory response, cell adhesion, cell growth and apoptosis might be involved in death related to AMI, which provides new targets for early intervention.

Objective:To investigate the clinical and pathological significance of the DICER1 mutation in follicular thyroid carcinoma (FTC).Methods:Sixty-eight cases of primary FTC resected between 2009 and 2023 were retrieved from The Affiliated Hospital of Qingdao University, Qingdao, China. Sanger sequencing was performed to identify DICER1 and TERT promoter mutations in all cases. Cases with DICER1 or TERT promoter mutations were subject to additional examination of potential mutations in KRAS, HRAS, and NRAS. The clinical and pathological features of DICER1-mutant FTCs were then analyzed. The relationship between DICER1 mutations and TERT-promoter/RAS mutations was also assessed.Results:DICER1 mutations were detected in 16 of the 68 FTC cases (23.5%), with 11 near E1813 at exon 25, 6 near D1709 at exon 24, and 1 in the splice region of exon 25. Two cases harbored two (distinct) mutations. All patients with DICER1-mutant FTC were female. Compared with patients with DICER1-wild-type FTC, those with DICER1-mutant were much younger, and had a higher proportion of minimally invasive subtype. Nine FTCs with DICER1 mutations were subject to further sequencing on adjacent non-cancerous tissues or lymph node tissues, but no mutations were detected. TERT-promoter or RAS hotspot mutations were not identified in any of the DICER1-mutant cases. However, TERT-promoter mutation was found in 6 DICER1-wild-type cases (8.8%, 6/68), with 3 cases also having RAS hotspot mutations and exhibiting highly aggressive biological behaviors.Conclusion:DICER1 mutations may occur in FTCs and appear mutually exclusive with RAS and TERT-promoter mutations, warranting further study as RAS-like mutations.

Objective:To explore the genetic etiology for a child presenting with motor retardation, language delay, intellectual disability, and dysmorphic features.Methods:A child presented at Linyi People′s Hospital in June 2022 was selected as the study subject. Clinical data of the child was collected. Peripheral blood samples were obtained from the child and her parents. Following extraction of genomic DNA, whole-exome sequencing (WES) was carried out. Candidate variant was validated by Sanger sequencing. Amniotic fluid samples were obtained from the mother′s subsequent pregnancies for prenatal diagnosis. This study has been reviewed and approved by the Medical Ethics Committee of Linyi People′s Hospital (Ethics No.: 202402-H-034).Results:The proband was a 2-year-old girl showing developmental delays in motor, language, and intellectual domains, strabismus, hypertelorism, hearing impairment, obesity, and brachymesophalangy of the fifth finger. Magnetic resonance imaging revealed abnormalities of the white matter. Chromosomal microarray analysis (CMA) identified a 15q26.3 duplication (chr15: 101562020_102060896×3) inherited from her mother. WES has uncovered a heterozygous c. 1931A>G (p.Tyr644Cys) variant in the FBXO11 gene. Sanger sequencing confirmed the variant to be de novo in origin. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was classified as likely pathogenic. Prenatal diagnosis revealed that the fetuses from the mother′s second and third pregnancies did not harbor the same variant. Conclusion:The c. 1931A>G (p.Tyr644Cys) variant of the FBXO11 gene probably underlay the abnormal phenotype in the child. Based on its genotype and phenotype, the proband was diagnosed with Intellectual developmental disorder with dysmorphic facies and behavioral abnormalities.