Association between placental DNA methylation and fetal congenital heart disease.

Congenital heart disease (CHD) is a worldwide problem with high morbidity and mortality. Early diagnosis of congenital heart disease is still a challenge in clinical work. In recent years, few studies indicated that placental methylation may be predictors of CHD. More studies are needed to confirm the association between placental methylation and CHD. The aim of this study was to investigate the association between prenatal placental DNA methylation and CHD. Placental tissues were obtained from four fetuses during the second trimester with isolated, non-syndromic congenital heart disease, including three cases with double outlet right ventricle (DORV) and one case with tetralogy of Fallot (TOF), and four unaffected fetuses as controls. The Illumina Infinium Human Methylation 850K BeadChip assay was employed to identify differential methylation sites (DMSs) and differential methylation regions (DMRs). Differential methylation was evaluated by comparing the ß-values for individual CpG loci in cases vs. controls. In addition, the function of genes was assessed through KEGG enrichment analysis, Gene Ontology (GO) analysis and KEGG pathway analysis. Compared with the control group, we identified 9625 differential methylation genes on 26,202 DMSs (p < 0.05), of which 6997 were hyper-methylation and 2628 were hypo-methylation. The top 30 terms of GO biological process and KEGG enrichment analysis of DMSs were connected with multiple important pathways of heart development and disease. Ten differentially methylated regions and the genes related to DMRs, such as TLL1, CRABP1, FDFT1, and PCK2, were identified. The deformity caused by the loss of function of these genes is remarkably consistent with the clinical phenotype of our cases. The DNA methylation level of placental tissue is closely associated with fetal congenital heart disease.

[Clinical and genetic characteristics of 12 cases of Loeys-Dietz syndrome].

OBJECTIVE: To summarize the clinical features and spectrum of genetic variants in 12 patients with Loeys-Dietz syndrome (LDS), and to explore the correlation between the type of genetic variants and clinical phenotypes. METHODS: Twelve patients suspected for LDS at Beijing Anzhen Hospital Affiliated to Capital Medical University from January 2015 to January 2022 were selected as the study subjects. Clinical data of the patients were collected. Genomic DNA was extracted from peripheral blood samples and subjected to genetic testing. Pathogenicity of candidate variants was analyzed. RESULTS: The clinical phenotypes of the 12 patients have mainly included cardiovascular, musculoskeletal, craniofacial, skin, ocular and other systemic signs. Four patients (patients 5-1, 5-2, 6, 7) have carried heterozygous missense variants of the TGFBR1 gene, 5 patients (patients 1-1, 1-2, 2, 3, 4) have carried heterozygous variants of the TGFBR2 gene, and 2 patients (patients 8-1, 8-2) had carried heterozygous frameshift variants of the TGFB3 gene. One patient (patient 9) had carried a heterozygous missense variant of the SMAD3 gene. Among these, TGFBR1 c.603T>G (p.1201M) and TGFB3 c.536delA (p.H179FS35) had not been reported previously. CONCLUSION: Variants of the TGFBR1, TGFBR2, SMAD3, TGFB2, TGFB3 and SMAD2 genes are mainly associated with LDS. The severity of the disease phenotype caused by the same variant may vary, whilst the clinical phenotype caused by different variant sites may be specific.

Analysis of ascending aortic diameter and long-term prognosis in patients with ascending aortic dissection.

OBJECTIVES: This study was designed to review the ascending aortic diameter of patients undergoing surgery for AAD in China and its influence on prognosis. METHODS: In the period between January 2018 and January 2020, 265 patients eligible for analysis of ascending aorta were included in this study. The maximum diameter of the ascending aorta was assessed using preoperative computed tomography (CT) scan for patients. RESULTS: The mean diameter of the ascending aorta of the reference population was 48.16 ± 9.37 mm, and the percentage of subjects with an aorta <55 mm was 80.38%. In this study, we found that BMI, hypertension, and bicuspid aortic valve are the main factors affecting the widening of the ascending aorta, and the diameter of the ascending aorta in patients with AAD is negatively correlated with the patient's long-term prognosis. However, there is no significant difference in survival rates among patients with different ascending aortic diameter. CONCLUSIONS: Ascending aortas with smaller diameter are also prone to dissection, most of which occur at a lower surgical threshold than recommended by current guidelines. Therefore, the diameter of ascending aorta cannot be used as an independent risk factor for high-risk patients with aortic dissection, but it can be used as an important indicator to evaluate the long-term prognosis of patients.

A novel intron mutation in FBN-1 gene identified in a pregnant woman with Marfan syndrome.

Marfan syndrome (MFS) is one of the most common hereditary connective tissue diseases, with great individual heterogeneity. We reported a Chinese pregnancy with Clinical diagnosis of MFS, performed whole-exome sequencing, and screened for the genetic abnormality. We also conducted an in vitro mini-gene splicing assay to demonstrate the predicted harmful effects of an intronic variant of FBN-1. Exome sequencing identified a novel intronic variant (c.6497-13 T>A) in intron 53 of the FBN-1 gene (NM_000138.4). It's predicted to insert 11 bp of intron 53 into the mature mRNA. The mini-gene splicing experiment demonstrated that c.6497-13 T>A could result in 11 bp retention in intron 53 to exon 54 (c.6496_6497ins gtttcttgcag) and the use of an alternative donor causing the frameshift p.Asp2166Glyfs*23. According to the results, the pregnant woman chose to continue the pregnancy and gave birth to a healthy baby. This study expands the genetic mutation spectrum of MFS patients and indicates the importance of intron sequencing.

The effect of technical details of percutaneous catheter drainage on the clinical outcomes of infected necrotizing pancreatitis patients

Background/aim: This study aimed to investigate the effect of technical details of percutaneous catheter drainage (PCD) on the clinical outcomes of patients with infected necrotizing pancreatitis (INP). Materials and methods: A total of 44 INP patients treated in our hospital from October 2013 to October 2015 were included. The correlations of the first PCD treatment data and the clinical outcomes were analyzed. Results: The number of catheters was positively correlated with hospital readmission (r = 0.335, P = 0.032). Receiver operating characteristic curve analysis showed that patients with ≥ 3 catheters were more likely to have hospital readmission. Patients with pleural effusion undergoing thoracentesis were more likely to have new intensive care unit admission (P = 0.025) and bleeding in need of intervention (P = 0.032). Patients with more effusion regions had higher incidences of mortality (P = 0.012) and new intensive care unit admissions (2.44 ± 1.03 vs. 1.88 ± 0.80; P = 0.059). Patients with PCD only were less likely to have new intensive care unit admissions (22.22% vs. 54.55%; P = 0.038) than those with PCD + small incision or/and videoscopic assisted retroperitoneal debridement. Conclusion: Number of catheters greater than three was associated with unfavorable outcomes of PCD treatment in INP patients. Patients that received PCD treatment only had better outcomes.

Bibliometric Analysis of Health Technology Research: 1990~2020.

This paper aims to summarize the publishing trends, current status, research topics, and frontier evolution trends of health technology between 1990 and 2020 through various bibliometric analysis methods. In total, 6663 articles retrieved from the Web of Science core database were analyzed by Vosviewer and CiteSpace software. This paper found that: (1) The number of publications in the field of health technology increased exponentially; (2) there is no stable core group of authors in this research field, and the influence of the publishing institutions and journals in China is insufficient compared with those in Europe and the United States; (3) there are 21 core research topics in the field of health technology research, and these research topics can be divided into four classes: hot spots, potential hot spots, margin topics, and mature topics. C21 (COVID-19 prevention) and C10 (digital health technology) are currently two emerging research topics. (4) The number of research frontiers has increased in the past five years (2016-2020), and the research directions have become more diverse; rehabilitation, pregnancy, e-health, m-health, machine learning, and patient engagement are the six latest research frontiers.

Placental DNA Methylation Abnormalities in Prenatal Conotruncal Heart Defects.

Objective: This study aims to characterize the abnormal changes in placental DNA methylation associated with conotruncal heart defects (CTDs) and the level of methylation as epigenetic biomarkers for CTDs detection. Methods: This was a prospective study involving 28 fetuses diagnosed with CTDs in the second trimester at Beijing Anzhen Hospital between September 2020 and June 2021. These cases were classified into four groups based on their subtypes. 12 normal fetuses were used as controls. Placental tissue was obtained after inducing labor in fetuses. To identify differential methylation sites (DMSs) and regions (DMRs) in cases vs. controls, an Infinium Human Methylation 850 k bead chip was used. Differential methylation was assessed by comparing the ß-values for individual CpG loci. Based on the p-value (<0.05), the most discriminating CpG sites were identified. The area under the receiver-operating-characteristics curve (AUC) was used to determine the predictive accuracy of CpG loci with significant methylation changes for CTDs. The function of genes was assessed through KEGG enrichment analysis, Gene Ontology (GO) analysis, and KEGG pathway analysis. Results: In comparison to the control group, the DNA methylation of the placental tissue is significantly different in fetuses with CTDs. We identified the most significantly different methylated loci and they demonstrated excellent individual predictive accuracy for CTDs detection with AUC >0.9 in cases compared with controls. HOXD9, CNN1, NOTCH1, and ECE1 were identified as CTDs-detection candidate genes. Conclusion Our study established the abnormal changes in placental methylation associated with CTDs and potential epigenetic biomarkers for CTDs detection.

Simultaneous Segmentation of Four Cardiac Chambers in Fetal Echocardiography.

Accurate segmentation of cardiac chambers is helpful for the diagnosis of Congenital Heart Disease (CHD) in fetal echocardiography. Previous studies mainly focused on single cardiac chamber segmentation, which cannot provide sufficient information for the cardiologists. In this paper, we present an instance segmentation approach capable of segmenting four cardiac chambers accurately and simultaneously. A novel object proposal recovery strategy is further deployed to retrieve possible missing objects. To alleviate the shortage of medical data and further improve the segmentation performance, we utilize a rotation and distortion method for data augmentation. Experiments on a fetal echocardiography dataset of 319 fetuses demonstrate that the proposed approach can achieve superior performance according to common-used evaluation metrics.Clinical relevance-This can be used to help the cardiologists to better analyze the structure and function of the fetal heart.

Detection of TSC1/TSC2 mosaic variants in patients with cardiac rhabdomyoma and tuberous sclerosis complex by hybrid-capture next-generation sequencing.

BACKGROUND: Fetal cardiac rhabdomyoma (CR) is strongly associated with tuberous sclerosis complex (TSC), which is caused by variants in TSC1 and TSC2. However, in 10%-15% of patients with clinically confirmed TSC, no TSC1/TSC2 variants are identified by panel sequencing or multiplex ligation-dependent probe amplification (MLPA). METHODS: We analyzed eight fetuses with CR and their families. No TSC1/TSC2 variants had previously been identified for six of these fetuses, and we suspected the other two families of gonadal mosaicism. We performed next-generation sequencing (NGS) using CR tissue, umbilical cord tissue, and parental blood. All positive results, involving two paternal semen, were verified by droplet digital polymerase chain reaction (ddPCR). RESULTS: Four fetuses carried low-level mosaic variants (0.05%-14.89%), and two only exhibited somatic mosaic variants in the CR tissue (15.76% and 37.69%). Two fathers had gonadal mosaicism (9.07% and 4.86%). We identified nine pathogenic variants in eight fetuses, including one fetus with a second-hit variant. CONCLUSION: The fetuses assessed in this study carried low-level and somatic mosaic variants, and CR tissue from one fetus exhibited a second-hit variant. Heterozygous gonadal variants can exist in patients with low-level mosaicism. Combining NGS with ddPCR improves the accuracy of prenatal TSC diagnosis.

Marfan syndrome: whole-exome sequencing reveals de novo mutations, second gene and genotype-phenotype correlations in the Chinese population.

Marfan syndrome (MFS) is a dominant monogenic disease caused by mutations in fibrillin 1 (FBN1). Cardiovascular complications are the leading causes of mortality among MFS. In the present study, a whole-exome sequencing of MFS in the Chinese population was conducted to investigate the correlation between FBNI gene mutation and MFS. Forty-four low-frequency harmful loci were identified for the FBN1 gene in HGMD database. In addition, 38 loci were identified in the same database that have not been related to MFS before. A strict filtering and screening protocol revealed two patients of the studied group have double mutations in the FBN1 gene. The two patients harboring the double mutations expressed a prominent, highly pathological phenotype in the affected family. In addition to the FBN1 gene, we also found that 27 patients had mutations in the PKD1 gene, however these patients did not have kidney disease, and 16 of the 27 patients expressed aortic related complications. Genotype-phenotype analysis showed that patients with aortic complications are older in the family, aged between 20 and 40 years.

Timing, distribution, and microbiology of infectious complications after necrotizing pancreatitis.

BACKGROUND: Acute pancreatitis (AP) is a common acute abdominal disease worldwide, and its incidence rate has increased annually. Approximately 20% of AP patients develop into necrotizing pancreatitis (NP), and 40% to 70% of NP patients have infectious complications, which usually indicate a worse prognosis. Infection is an important sign of complications in NP patients. AIM: To investigate the difference in infection time, infection site, and infectious strain in NP patients with infectious complications. METHODS: The clinical data of AP patients visiting the Department of General Surgery of Xuanwu Hospital of Capital Medical University from January 1, 2014 to December 31, 2018 were collected retrospectively. Enhanced computerized tomography or magnetic resonance imaging findings in patients with NP were included in the study. Statistical analysis of infectious bacteria, infection site, and infection time in NP patients with infectious complications was performed, because knowledge about pathogens and their antibiotic susceptibility patterns is essential for selecting an appropriate antibiotic. In addition, the factors that might influence the prognosis of patients were analyzed. RESULTS: In this study, 539 strains of pathogenic bacteria were isolated from 162 patients with NP infection, including 212 strains from pancreatic infections and 327 strains from extrapancreatic infections. Gram-negative bacteria were the main infectious species, the most common of which were Escherichia coli and Pseudomonas aeruginosa. The extrapancreatic infection time (9.1 ± 8.8 d) was earlier than the pancreatic infection time (13.9 ± 12.3 d). Among NP patients with early extrapancreatic infection (< 14 d), bacteremia (25.12%) and respiratory tract infection (21.26%) were predominant. Among NP patients with late extrapancreatic infection (> 14 d), bacteremia (15.94%), respiratory tract infection (7.74%), and urinary tract infection (7.71%) were predominant. Drug sensitivity analysis showed that P. aeruginosa was sensitive to enzymatic penicillins, third- and fourth-generation cephalosporins, and carbapenems. Acinetobacter baumannii and Klebsiella pneumoniae were sensitive only to tigecycline; Staphylococcus epidermidis and Enterococcus faecium were highly sensitive to linezolid, tigecycline, and vancomycin. CONCLUSION: In this study, we identified the timing, the common species, and site of infection in patients with NP.

A meta-analysis and systematic review of percutaneous catheter drainage in treating infected pancreatitis necrosis.

BACKGROUND: In the current meta-analysis, we focus on the exploration of percutaneous catheter drainage (PCD) in terms of its overall safety as well as efficacy in the treatment of infected pancreatitis necrosis based on qualified studies. METHODS: The following electronic databases were searched to identify eligible studies through the use of index words updated to May 2018: PubMed, Cochrane, and Embase. Relative risk (RR) or mean difference (MD) along with 95% confidence interval (95% CI) were utilized for the main outcomes. RESULTS: A total of 622 patients in the PCD group and 650 patients in the control group from 13 studies were included in the present meta-analysis. The aggregated results indicated that the incidence of bleeding was decreased significantly (RR: 0.42, 95% CI: 0.25-0.70) in the PCD group as compared with the control group. In addition, PCD decreased the mortality (RR: 0.76, 95% CI: 0.41-1.42), hospital duration (SMD: -0.22, 95% CI: -0.77 to -0.33), duration in intensive care unit (ICU) (SMD: -0.13, 95% CI: -0.30 to -0.04), pancreatic fistula (RR: 0.73, 95% CI: 0.46-1.17), and organ failure (RR: 0.91, 95% CI: 0.45-1.82) in comparison with the control group, but without statistical significance. CONCLUSION: Our findings provide evidence for the treatment effect of PCD in the decrease of bleeding, mortality, duration in hospital and ICU, pancreatic fistula, organ failure as compared with the surgical treatment. In conclusion, further studies based on high-quality RCTs with larger sample size and long-term follow-ups are warranted for the confirmation of PCD efficacy in treating infected pancreatitis necrosis.