Individualised surgical treatment strategy for subaortic stenosis.

OBJECTIVES: The clinical data of patients with subaortic stenosis who underwent surgical treatment in our centre in the past 12 years were reviewed. The short-term and long-term clinical outcomes were analyzed, and the long-term outcomes of different surgical methods for subaortic stenosis were compared to determine the optimal surgical treatment strategy for subaortic stenosis. METHODS: From December 2010 to December 2022, 90 patients undergoing surgical treatment for subaortic stenosis in our hospital were enrolled. There were 55 males and 35 females with a median age of 72 (46,132) months and an average surgical weight of (21.35 ± 15.84) kg. According to the operation method, 90 patients were divided into group A (50 patients with simple subaortic membrane resection) and group B (40 patients with subaortic membrane and muscle resection or modified Konno procedure). RESULTS: There were three early deaths (3.33%). One late death occurred in group B. There was no significant difference in long-term survival rate between the two groups (p = 0.904). The preoperative left ventricular outflow tract pressure gradient in group B was (91.56 ± 36.98) mm Hg, which was higher than that in group A(51.13 ± 36.04)mm Hg(p < 0.001). There was no significant difference in immediate postoperative left ventricular outflow tract pressure gradient between group B [(5.44 ± 8.43) mm Hg] and group A [(7.82 ± 13.44) mm Hg] (p = 0.343). In the long-term follow-up, left ventricular outflow tract pressure gradient in group B was (5.86 ± 9.53) mm Hg, which was not statistically significant compared with group A (8.83 ± 14.52) mm Hg (p = 0.294). Eleven patients with moderate or greater aortic regurgitation (group A/group B: 3/8) underwent simultaneous aortic valvuloplasty. In group B, moderate or greater aortic regurgitation was significantly improved immediately after operation (p = 0.013) and was not significantly aggravated in long-term follow-up (p = 0.083), and there was no significant improvement in group A after operation and long-term follow-up. CONCLUSIONS: According to the different anatomical lesions of left ventricular outflow tract, the individualised surgical treatment strategy for patients with subaortic stenosis can achieve good long-term outcomes. The long-term survival rate and freedom from reoperation due to late left ventricular outflow tract obstruction after simple subaortic membrane resection and extended left ventricular outflow tract resection are comparable. For patients with moderate or greater aortic regurgitation before extended left ventricular outflow tract resection, simultaneous aortic valvuloplasty is beneficial to improve postoperative aortic valve function.

Innovation in surgical treatment of hypertrophic obstructive cardiomyopathy in children.

Hypertrophic cardiomyopathy is the second most common cardiomyopathy affecting children and adolescents and is the main cause of sudden death of young athletes. The natural prognosis of children with severe hypertrophic obstructive cardiomyopathy is not optimistic, and it is not uncommon for children with hypertrophic obstructive cardiomyopathy who do not respond to medication. Surgical treatment is often the only solution. Conventional surgical methods in the past include classic or modified extended Morrow operation, classic or modified Konno operation, and Ross-Konno operation. In recent years, with the development of minimally invasive surgery, various minimally invasive surgical methods have emerged endlessly. Because the incision of minimally invasive cardiac surgery is significantly smaller than that of traditional surgery, it causes less trauma, recovers quickly after surgery, and has the advantage of no difference in surgical effect compared with traditional median sternotomy. Tally endoscopic transmitral myectomy, RTM, minimally right thoracotomy, and other surgical methods have achieved encouraging results in adults and some older children with hypertrophic obstructive cardiomyopathy. The appearance of transapical beating-heart septectomy has brought the treatment of hypertrophic obstructive cardiomyopathy from the era of cardiopulmonary bypass and cardiac arrest to a new era of minimally invasive beating-heart surgery. In the past, there were few articles about the treatment of children with hypertrophic obstructive cardiomyopathy. This article reviewed the new progress and prognosis of surgical treatment of children with hypertrophic obstructive cardiomyopathy at home and abroad.

Predictive Value of Myocardial Markers for Early Postoperative Mortality in Children with Congenital Heart Disease.

To investigate the influencing factors of postoperative creatine kinase-MB (CK-MB) elevation in children with congenital heart disease and its peak value in predicting early postoperative mortality. The clinical data of 521 children with congenital heart disease under the age of 14 who underwent elective surgery in Beijing Children's Hospital from December 2018 to December 2020 were retrospectively analyzed. Stepwise multiple linear regression was used to analyze independent risk factors for postoperative CK-MB elevation, receiver operating characteristic (ROC) curve was used to determine the predictive value of postoperative CK-MB peak, CK peak, and LDH peak on mortality, and linear correlation and regression analysis were used to analyze the interdependence among postoperative CK-MB peak, CK peak, and LDH peak, and multivariate Logistic regression was used to identify independent risk factors for early postoperative mortality. Preterm birth (P = 0.004), ventriculotomy (P = 0.009), the re-establish of bypass (P = 0.007), cardiopulmonary bypass time (P = 0.024), deep hypothermic circulatory arrest time (P = 0.000), assisted ventilation time (P = 0.049), CK peak (P = 0.000), and LDH peak (P = 0.000) were independently associated with increased postoperative CK-MB elevation. The ROC curve showed that CK-MB peak had the strongest predictive value for death (AUC = 0.924), followed by LDH peak (AUC = 0.864) and CK peak (AUC = 0.758). The cut-off value of the postoperative CK-MB peak was 144.5 IU/L, with a sensitivity of 87% and a specificity of 97%. CK-MB peak was moderately correlated with CK peak (Pearson Correlation coefficient r = 0.514, P = 0.000) and strongly correlated with LDH peak (Pearson Correlation coefficient r = 0.601, P = 0.000). Multivariate analysis showed that delayed chest closure (OR = 4.865, P = 0.004) and postoperative CK-MB peak (OR = 1.031, P = 0.000) were independent risk factors for postoperative mortality. The postoperative CK-MB peak has a certain predictive value for the early postoperative mortality of children with congenital heart disease. It is affected by many factors, and the risk of mortality is significantly increased in children with severely elevated postoperative CK-MB.

Case Report: Imaging features of a new type double inferior vena cava malformation and review.

Background: Double inferior vena cava (DIVC) is a rare vascular malformation. With advances in radiological techniques and diagnosis, more and more types of DIVC were identified and diagnosed. Recognition of the variety of DIVC seen on imaging is essential for subsequent venous interventions. Case presentation: A 77-year-old man presented with low back pain with left lower limb pain for 1 month. Scattered petechiae above the skin surface on the left lower leg, especially on the extensor surface, with flaking and mild tingling of the skin, were noted 3 weeks ago. Ultrasound revealed deep vein thrombosis (DVT) in the left lower limb. Computed tomography pulmonary angiography (CTPA) suggested no significant thrombus in the pulmonary artery. Computed tomography venography (CTV) of bilateral lower limbs showed that iliac vein compression syndrome with formation of deep and superficial venous traffic branches in bilateral lower limbs, predominantly on the left side. CTV of the inferior vena cava (IVC) suggested that the left common iliac vein crossed the common iliac artery bifurcation from dorsal to ventral and continued to travel cranially as a ventral vessel, and connected with the ventral IVC anterior to the right common iliac artery. The right common iliac vein extended cephalad as a dorsal vessel, which was narrowed at the level of 4th lumbar vertebra by compression of the hyperplastic bone and the osteophyte. The patient was discharged after right and left common iliac vein angiography and balloon dilation of bilateral common iliac vein. Conclusion: The formation of both ventrally and dorsally aligned DIVC is rarer. It should be clarified the effects of DIVC on DVT formation, and the importance of imaging for preoperative planning.

Clinical phenotype and genetic function analysis of a rare family with hereditary leiomyomatosis and renal cell carcinoma complicated with Birt-Hogg-Dubé syndrome.

To date, over 200 families with hereditary leiomyomatosis and renal cell carcinoma (HLRCC) and over 600 families with Birt-Hogg-Dubé (BHD) syndrome have been reported, with low incidence. Here, we describe a patient with suspected rare HLRCC complicated by BHD syndrome. The proband (II1) had characteristic cutaneous leiomyoma-like protrusions on the neck and back, a left renal mass and multiple right renal, liver and bilateral lung cysts. Three family members (I1, II2, II3) had a history of renal cancer and several of the aforementioned clinical features. Two family members (II1, II3) diagnosed with fumarate hydratase (FH)-deficient papillary RCC via pathological biopsy carried two heterozygous variants: FH (NM_000143.3) missense mutation c.1189G>A (p.Gly397Arg) and FLCN (NM_144997.5) frameshift mutation c.1579_1580insA (p.Arg527Glnfs*75). No family member carrying a single variant had renal tumours. In HEK293T cells transfected with mutant vectors, mRNA and protein expression after FLCN p.Arg527Glnfs*75 and FH p.Gly397Arg mutations were significantly lower than those in wild-type (WT) cells. Cell immunofluorescence showed altered protein localisation and reduced protein expression after FLCN p.Arg527Glnfs*75 mutation. The FH WT was uniformly distributed in the cytoplasm, whereas FH protein expression was reduced after the p.Gly397Arg mutation and scattered sporadically with altered cell localisation. Patients with two variants may have a significantly increased penetrance of RCC.

Difference in oral microbiota composition between patients with stage 5 chronic kidney disease on hemodialysis and healthy controls.

Owing to the symbiotic relationship between the microbiota and the human body, the microbiome is considered a "second human genome". Microorganisms are inextricably associated with human diseases and can affect the host phenotype. In the present study, 25 female patients with stage 5 chronic kidney disease (CKD5) undergoing hemodialysis in our hospital and 25 healthy subjects were recruited. The structure of the oral microbiota of the study participants was analyzed using the MiSeq PE300 sequencing platform and high-throughput 16S rDNA sequencing. The microbiota was compared between the groups using QIIME and the stats package in R. In total, 1,336 operational taxonomic units (OTUs) were obtained, and the relative frequencies of 450 OTUs differed significantly between the two groups (P < 0.05), indicating that the samples were rich in OTUs. A comparison of ß-diversity indicated a significant difference in the microbial community structure between the two groups (P < 0.05). These results indicated that the biological diversity of the oral microbiota was highly correlated with CKD5. In this experiment, 189 genera, with significant differences in abundance between the groups (P < 0.05), were found. Furthermore, differences in the structure of the oral microbiota were observed between the groups at the phylum, class, order, family, and genus levels. Collectively, an imbalance in the oral microbiota may accelerate the progression of CKD and cause additional complications.

Stent Implantation and Balloon Angioplasty for Native and Recurrent Coarctation of the Aorta.

Evidence on the effectiveness and comparative effectiveness of stent implantation and balloon angioplasty for native coarctation of the aorta (CoA) and recurrent CoA separately is lacking. The present meta-analysis was performed to assess the efficacy and safety of stent implantation and balloon angioplasty in native (NaCo) and recurrent (ReCo) CoA.A systematic computerized literature search was conducted to retrieve all relevant studies of stent implantation and balloon angioplasty for CoA. Both single-arm and comparative studies were included. Data on NaCo and ReCo were pooled separately.A post-procedure gradient of ≤ 20 mmHg was achieved in 97% and 92% of patients undergoing stent implantation and balloon angioplasty for NaCo, and in 98% and 90% for ReCo, respectively. A post-procedure gradient of ≤ 10 mmHg was achieved in 97% and 83% of patients undergoing stent implantation and balloon angioplasty for NaCo, and in 86% and 78% for ReCo, respectively. Comparative results confirmed that stent implantation provided a significantly higher success rate compared with balloon angioplasty (odds ratio [OR] = 2.09; 95% confidence interval [CI] = 1.13-3.86; P = 0.019) in treating NaCo. Incidences of all-cause complications, mortality, reintervention, and aneurysm formation were similar between the groups. Patients undergoing stent implantation had a significantly lower incidence of dissection (OR = 0.15; 95% CI = 0.02-0.92; P = 0.040).Current evidence indicates that stent implantation might have superior efficacy compared with balloon angioplasty for the treatment of NaCo with higher success rates and similar complication rates. However, whether this superior effect is also present in ReCo patients needs further evaluation.

Han family with essential tremor caused by the P421L variant of the TENM4 gene in China.

BACKGROUND: Essential tremor (ET) is an autosomal dominant inheritance disorder. Mutations in fusion sarcoma (FUS), mitochondrial serine peptidase 2 (HTRA2), teneurin transmembrane protein 4 (TENM4), sortilin1 (SORT1), SCN11A, and notch2N-terminal-like (NOTCH2NLC) genes are associated with familial ET. METHODS: A proband with ET was tested using whole-exome sequencing and repeat-primed polymerase chain reaction. Subsequently, the family members were screened for the suspected mutation, and the results were verified using Sanger sequencing. The relationship between pedigree and phenotype was also analyzed, and structural and functional changes in the variants were predicted using bioinformatics analysis. RESULTS: In a family with ET, the proband (III4) and the proband's father (II1), grandfather (I1), uncle (II2), and cousin (III5) all presented with involuntary tremors of both upper limbs. The responsible mutation was identified as TENM4 c.1262C > T (p.P421L), which showed genetic co-segregation in the family survey. AlphaFold predicted a change in the spatial position of TENM4 after the P421L mutation, which may have affected its stability. AlphaFold also predicted P421L to be a deleterious variation, which would lead to lower degrees of freedom of the TENM4 protein, thereby affecting the protein's structure and stability. According to the bioinformatics analysis, TENM4 (p.P421L) may reduce the signal reaching the nucleus by affecting the expression of TENM4 messenger RNA (mRNA), thereby impairing the normal oligodendrocyte differentiation process and leading to impaired myelination. CONCLUSION: This study revealed that the TENM4 (p.P421L) pathogenic missense variation was responsible for ET in the proband.

Surgical Outcomes for Children with Anomalous Origin of the Left Coronary Artery from the Pulmonary Artery.

Objective of this study is to summarize surgical outcomes of patients with anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA) in a single center. The clinical data of 89 children undergoing surgical treatment in Beijing Children's Hospital from January 2007 to January 2022 were retrospectively analyzed. seven patients underwent ECMO support for acute left heart failure after operation, and 2 patients were discharged after weaning successfully. Eight patients died in the early postoperative period, all of them were infants, of which 5 patients underwent ECMO support, 2 patients died of cerebral hemorrhage, 2 patients died of multiple organ dysfunction, and 4 patients died of left heart failure. Three patients died late, 3 patients were lost to follow-up, and 78 patients (96.3%) completed long-term follow-up. A logistic regression model multivariate analysis showed that postoperative moderate or severe mitral regurgitation (MR) (OR 26.948 P = 0.024) and prolonged aortic cross-clamp time (OR 1.038 P = 0.050) were independent risk factors of early mortality. Compared with the Non-MVP group (20/36), the MVP group (patients with moderate or severe MR who underwent MVP at the same time) (16/36) had more significant improvement in early postoperative LEVEF [(50.68 ± 13.85)% vs (40.50 ± 13.58)% P = 0.033] and had a lower proportion of moderate or severe MR after operation (2/16 vs 11/20 P = 0.014). Children with ALCAPA can obtain a good prognosis by reconstructing the blood supply of both coronary arteries. Mitral valvuloplasty (MVP) is more helpful in improving the prognosis of children with moderate or severe MR and mitral valve structural disease. Reasonable placement of ECMO can help reduce the mortality of critically ill children after operation, but be alert to complications in the central system.

When do patients with Tetralogy of Fallot need a transannular patch.

OBJECTIVES: The objective of this study was to evaluate the predictive value of main pulmonary artery (MPA) Z score, pulmonary valve annulus (PVA) prop, great aortic valve annulus (GA) ratio, PVA index (PAI), and PVA area index (PAAI) indicators in patients with Tetralogy of Fallot (TOF) and whether or not to undergo transannular patch (TAP). METHODS: A retrospective analysis was performed on the clinical data of 263 patients with TOF who underwent radical operations from 2010 to 2021 at Beijing Children's Hospital. Sixteen cases were excluded, and 247 cases (male/female = 155/92) were included in this study. Based on whether TAP was selected intraoperatively, the patients were divided into the TAP group (82/247) and the non-TAP group (165/247). The diameter of the PVA, the aortic valve annulus, and the MPA were measured by echocardiography, and the PVA Z score, MPA Z score, PVA prop, GA ratio, PAI, and PAAI indexes were calculated, and statistical analysis was carried out. RESULTS: The PVA Z score, MPA Z score, PVA prop, GA ratio, PAI, and PAAI of the TAP group were lower than those of the non-TAP group (p < .0001, p < .0001, p < .0001, p < .0001, p < .0001, and p < .0001). Receiver-operating curve analysis showed that the cut-off value of PVA Z score was -1.96 (area under the curve [AUC]: 0.822; 95% confidence interval [CI]: 0.769-0.874); the cut-off value of MPA Z score was -1.04 (AUC: 0.778; 95% CI: 0.711-0.845); the cut-off value of PVA prop was 0.37 (AUC: 0.812; 95% CI: 0.751-0.874); the cut-off value of GA ratio was 0.64 (AUC: 0.812; 95% CI: 0.750-0.874); the cut-off value of PAI is 0.78 (AUC: 0.812; 95% CI: 0.750-0.874); and the cut-off value of PAAI is 0.4 (AUC: 0.812; 95% CI: 0.750-0.874). Pulmonary valve bicuspid malformation is one reason why predictive models fail to predict the possible avoidance of TAP. Pearson's correlation and linear regression analysis showed that PAI had the strongest correlation with PVA Z score, followed by that between PVA prop and PVA Z score, and the weakest correlation between PAAI and PVA Z score. CONCLUSIONS: PVA prop, GA ratio, PAI, and PAAI can well predict TAP selection, and the measurement is simple and convenient. Compared with PVA Z score, they are not hindered by other confounding factors, and can well replace the application value of PVA Z score in TAP prediction. The predictive efficacy of PAI and PVA prop is numerically better than the GA ratio, and PAAI, PAI, and PVA prop combined with MPA Z score can improve the predictive value of PAI and PVA prop, respectively. Although various echocardiographic parameters can be used as indicators to predict surgical approach in patients with TOF, PV morphology and tissue characteristics should also be considered.

Comprehensive analysis of immune ferroptosis gene in renal clear cell carcinoma: prognosis and influence of tumor microenvironment.

OBJECTIVE: We conducted an in-depth study of the immune system and ferroptosis to identify prognostic biomarkers and therapeutic targets for renal clear cell carcinoma. METHODS: Immune ferroptosis-related differentially expressed genes (IFR-DEGs) were selected from The Cancer Genome Atlas (TCGA). A lasso-Cox risk scoring model was established; its prognostic value was determined using prognostic analysis and single multivariate Cox analysis. Model genes were subjected to subcellular fluorescence localization, mRNA and protein expression analyses, and single-cell RNA sequencing localization analysis. Risk score was analyzed using the immune score, immune infiltrating cell correlation, immune checkpoint, TIDE, and drug sensitivity. RESULTS: A total of 103 IFR-DEGs were identified; a risk model comprising ACADSB, CHAC1, LURAP1L, and PLA2G6 was established. The survival curve, single multivariate Cox regression, and receiver operating characteristic (ROC) curve analysis showed that the model had good predictive ability (p < 0.05). It was also validated using the validation set and total cohort. Subcellular fluorescence localization revealed that ACADSB, CHAC1, and PLA2G6 were distributed in the cytoplasm and LURAP1L in the nucleus. The mRNA and protein expression trends were consistent. Single-cell RNA sequencing mapping revealed that ACADSB was enriched in distal tubule cell clusters. In the Kidney renal clear cell carcinoma (KIRC) mutation correlation analysis, 1.56% of the patients were found to have genetic alterations; The Spearman correlation analysis of model gene mutations showed that ACADSB was positively correlated with LURAP1L, which may have a synergistic effect; it was negatively correlated with CHAC1 and PLA2G6, and CHAC1 was negatively correlated with LURAP1L, which may have an antagonistic effect. Model and immune correlation analyses found that high-risk patients had significantly higher levels of CD8+ T cells, regulatory T cells (Tregs), immune checkpoints, immune scores, and immune escape than those in low-risk patients. High-risk patients had a higher susceptibility to small-molecule drugs. CONCLUSION: A novel prognostic model of immune ferroptosis-related genes (ACADSB, CHAC1, LURAP1L, and PLA2G6), which plays an important role in immune infiltration, microenvironment, and immune escape, was constructed. It effectively predicts the survival of patients with KIRC.

Application of sutureless technique in total anomalous pulmonary venous connection repair.

The sutureless technique was initially used for the treatment of postoperative pulmonary vein obstruction (PVO) in patients with total anomalous pulmonary venous connection (TAPVC). However, as the effectiveness of the sutureless technique has been confirmed and widely developed, the sutureless technique has been used for the primary treatment of high-risk children with TAPVC who are at high risk of PVO. Compared with traditional surgery, the sutureless technique significantly reduces the incidence of postoperative PVO, re-intervention rate due to PVO, and postoperative mortality, but there are potential complications such as pericardial and confluent venous anastomosis, phrenic nerve damage, air embolism. In addition, the sutureless technique is not effective in dealing with the progressive stenosis of the pulmonary veins after sutureless surgery and diffuse stenosis of extrapulmonary proximal veins and intrapulmonary veins. These make the efficacy and safety of this procedure controversial. This paper reviews the research status of the sutureless technique in TAPVC repair at home and abroad over the years.

Incidence and risk factors for late complications after the arterial switch operation.

OBJECTIVE: The purpose of this study was to evaluate our institution's 16-year arterial switch operation (ASO) experience and to determine early and late mortality and late morbidity, as well as the need for reoperation and catheter intervention, and finally, to explore risk factors for late complications and reintervention. METHODS: The clinical data of 185 transposition of the great arteries (TGA) patients who received ASO treatment in our center from January 2006 to January 2022 were continuously included for retrospective study. RESULTS: There were 13 early deaths (7.03%), 5 late deaths (3.01%), and 6 lost to follow-up. The median follow-up time for the 166 hospitalized survivors was 88.5 (2190) months. Moderate or above new aortic valve regurgitation (NAR; in this article, NAR represents moderate or greater reflux unless otherwise specified) occurred in 19 cases (11.45%), and aortic root dilation (ARD) occurred in 28 cases (16.87%). Late right ventricular outflow tract obstruction (RVOTO) occurred in 33 cases (19.88%). There were 18 patients (10.84%) who underwent late re-intervention, and the most common indication for intervention was RVOTO, followed by recurrent aortic coarctation in patients undergoing concurrent arch repair and NAR or ARD. Receiver operating characteristics analysis found that NAR had the strongest predictive power for ARD, followed by RVOTO, followed by bicuspid native pulmonary valve (BPV), and aorto-pulmonary diameter mismatch (APDMM) was the weakest. Multivariate analysis showed that APDMM, previous pulmonary artery banding (PAB), and mild NAR at discharge were independent risk factors for late NAR and ARD. Low surgical weight was an independent risk factor specific to NAR, and BPV was an independent risk factor specific to ARD. Older surgical age and ARD were independent risk factors for late RVOTO. Older surgical age, operation before 2014, late RVOTO, and late ARD were independent risk factors for late intervention. No reintervention events for coronary dysfunction were found in the late stage, but one patient occurred myocardial infarction due to coronary embolism after reoperation. CONCLUSION: Early and late survival rates after ASO in TGA patients have been remarkably improved in recent decades. Increased rates of NAR, ARD, recurrent coarctation of the aorta, and RVOTO as children age are major future outcomes of concern and may imply more late reinterventions. Careful follow-up of neo-aortic valve and root function is imperative, especially in patients with APDMM, previous PAB, mild NAR at discharge, low surgical weight, and BPV structures.

Function of PHEX mutations p.Glu145* and p.Trp749Arg in families with X-linked hypophosphatemic rickets by the negative regulation mechanism on FGF23 promoter transcription.

X-linked hypophosphatemic rickets (XLH) is characterized by increased circulating fibroblast growth factor 23 (FGF23) concentration caused by PHEX (NM_000444.5) mutations. Renal tubular resorption of phosphate is impaired, resulting in rickets and impaired bone mineralization. By phenotypic-genetic linkage analysis, two PHEX pathogenic mutations were found in two XLH families: c.433 G > T, p.Glu145* in exon 4 and c.2245 T > C, p.Trp749Arg in exon 22. Immunofluorescence showed that the localization of p.Glu145* and p.Trp749Arg mutant and secretory PHEX (secPHEX) changed, with decreased expression. In a HEK293T cell model co-transfected with PHEX, secPHEX, and FGF23, wild-type PHEX, secPHEX, and FGF23 proteins were distributed in the cell membrane or endoplasmic reticulum, while the mutant was located in the nuclear membrane and cytoplasm. qPCR of p.Glu145* revealed decreased PHEX and secPHEX mRNA expression in cells, with no difference in mRNA expression of p.Trp749Arg. Both mutations decreased intracellular PHEX endopeptidase activity. Western blot analysis showed decrease in mutant and secPHEX protein expression and no FGF23 protein expression in single-transfected PHEX and secPHEX cells. In cells co-transfected with FGF23, PHEX and secPHEX mutation promoted FGF23 expression. Dual-luciferase reporter gene was used to detect the effect of PHEX on FGF23 promoter. The dual-luciferase reporter gene showed that after PHEX overexpression, the activity of mutant firefly luciferase was significantly higher than that of wild type. The regulatory mechanism between PHEX and FGF23 is still unclear, but we found that PHEX is a direct transcriptional inhibitor of FGF23 and affects the expression of FGF23. This study verified the pathogenicity of the two variants and revealed the possible regulatory mechanism between PHEX and FGF23.

Prognosis and related risk factors analysis of total anomalous pulmonary venous connection correction.

OBJECTIVE: This study was performed to analyze the surgical outcomes of our center biventricular correction with total anomalous pulmonary venous connection (TAPVC) and to explore the risk factors associated with postoperative mortality and postoperative pulmonary venous obstruction (PVO). METHODS: In total, 104 patients diagnosed with TAPVC and underwent biventricular correction from January 1, 2009 to December 31, 2021, in Beijing Children's Hospital Affiliated with Capital Medical University were included. The primary endpoints were early and late postoperative mortality and postoperative pulmonary vein obstruction. RESULTS: Multivariable analysis indicated that prolonged cardiopulmonary bypass (CPB) time was the only independent risk factor for early postoperative mortality. Emergency surgery, preoperative moderate, and severe pulmonary hypertension (PH), and prolonged CPB time were independent risk factors for postoperative PVO. According to ROC curve analysis, the cut-off value of CPB time for predicting early mortality was 148 min (AUC = 0.916, 95% CI 0.811-1.000). CONCLUSION: In the past 12 years, with surgical technique and perioperative management advancement, the prognosis of children treated with TAPVC biventricular correction in our center has generally improved. However, surgical repair remains challenging, and early mortality remains high in children with prolonged CPB time during surgery. Postoperative PVO often occurs in children who underwent emergency surgery, combined with moderate and severe PH and prolonged CPB time.

Analysis of a Family with Brugada Syndrome and Sudden Cardiac Death Caused by a Novel Mutation of SCN5A.

Background: Brugada syndrome is a hereditary cardiac disease associated with mutations in ion channel genes. The clinical features include ventricular fibrillation, syncope, and sudden cardiac death. A family with Brugada syndrome with sudden cardiac death was analyzed to locate the associated mutation in the SCN5A gene. Methods and Results: Three generations of a Han Chinese family with Brugada syndrome were recruited in the study; their clinical phenotype data were collected and DNA samples extracted from the peripheral blood. Next-generation sequencing was carried out in the proband, and candidate genes and mutations were screened using the full exon capture technique. The family members who participated in the survey were tested for possible mutations using Sanger sequencing. Six family members were diagnosed with Brugada syndrome, including four asymptomatic patients. A newly discovered heterozygous mutation in the proband was located in exon 25 of SCN5A (NM_000335.5) at c.4313dup(p.Trp1439ValfsTer32). Among the surviving family members, only those with a Brugada wave on their electrocardiogram carried the c.4313dup(p.Trp1439ValfsTer32) variant. Bioinformatics prediction revealed that the frameshift of the c.4313dup (p.Trp1439ValfsTer32) mutant led to a coding change of 32 amino acids, followed by a stop codon, resulting in a truncated protein product. Conclusion: The newly discovered mutation site c.4313dup(p.Trp1439ValfsTer32) in exon 25 of SCN5A may be the molecular genetic basis of the family with Brugada syndrome.

A novel compound heterozygous variant linked to hematuria in a family with hereditary factor VII deficiency.

BACKGROUND: Hereditary factor VII deficiency (FVIID) is a rare congenital autosomal recessive bleeding disorder. In clinical manifestations, its onset is caused by variant of the F7 gene (NM_019616) with strong heterogeneity. We identified a family with hematuria caused by a novel F7 compound heterozygous variant and investigated the FVIID-dependent mechanism impacted by these variants. METHODS: Coagulation factors in the proband were functionally verified. We located pathogenic variants in relevant genes using next-generation sequencing after target enrichment and verified them by Sanger sequencing. We examined the coagulation activity and secretion pattern of recombinant FVII variants expressed in cells and observed their location and stability by immunofluorescence. RESULTS: We found a missense variant c.1207G>A (p.Gly403Ser) and a frameshift variant c.154_155del (p.Arg53fs) in the F7 gene of the proband. FVII activity tests showed that the variants significantly decreased its presence in the cell culture supernatant. Moreover, the R53fs mutant lacked the FVII functional domain and had no detectable activity. Immunofluorescence indicated that the p.Gly403Ser variant was distributed to the cell membrane and cytoplasm, whereas the FVII R53fs variant was not detected. Deficient FVII protein function and severe coagulation disorder are the likely causes of hematuria and other bleeding symptoms in the proband. CONCLUSIONS: The newly discovered F7 gene variants enrich the spectrum of hereditary FVII deficiency and provide a new foundation for the diagnosis and treatment of this type of coagulation disorder.

Review and Analysis of Two Gitelman Syndrome Pedigrees Complicated with Proteinuria or Hashimoto's Thyroiditis Caused by Compound Heterozygous SLC12A3 Mutations.

Gitelman syndrome (GS) is an autosomal recessive inherited salt-losing renal tubular disease, which is caused by a pathogenic mutation of SLC12A3 encoding thiazide-sensitive Na-Cl cotransporter, which leads to disturbance of sodium and chlorine reabsorption in renal distal convoluted tubules, resulting in phenotypes such as hypovolemia, renin angiotensin aldosterone system (RAAS) activation, hypokalemia, and metabolic alkalosis. In this study, two GS families with proteinuria or Hashimoto's thyroiditis were analyzed for genetic-phenotypic association. Sanger sequencing revealed that two probands carried SLC12A3 compound heterozygous mutations, and proband A carried two pathogenic mutations: missense mutation Arg83Gln, splicing mutation, or frameshift mutation NC_000016.10:g.56872655_56872667 (gcggacatttttg>accgaaaatttt) in exon 8. Proband B carries two missense mutations: novel Asp839Val and Arg904Gln. Both probands manifested hypokalemia, hypomagnesemia, hypocalcinuria, metabolic alkalosis, and RAAS activation; in addition, the proband A exhibited decreased urinary chloride, phosphorus, and increased magnesium ions excretion, complicated with Hashimoto's Thyroiditis, while the proband B exhibited enhanced urine sodium excretion and proteinuria. The older sister of proband B with GS also had Hashimoto's thyroiditis. Electron microscopy revealed swelling and vacuolar degeneration of glomerular epithelial cells, diffuse proliferation of mesangial cells and matrix, accompanied by a small amount of low-density electron-dense deposition, and segmental fusion of epithelial cell foot processes in proband B. Light microscopy showed mild mesangial hyperplasia in the focal segment of the glomerulus, hyperplasia, and hypertrophy of juxtaglomerular apparatus cells, mild renal tubulointerstitial lesions, and one glomerular sclerosis. So, long-term hypokalemia of GS can cause kidney damage and may also be susceptible to thyroid disease.

Surgical correction for scimitar syndrome by right thoracotomy and direct anastomosis in children.

IMPORTANCE: Scimitar syndrome (SS) is a rare type of congenital heart disease characterized by total or partial anomalous venous drainage of the right lung to the inferior vena cava. However, the surgical repair techniques for SS vary according to patients' anatomical and pathological features. OBJECTIVE: This study was performed to analyze the mid-term results of a less invasive surgical correction technique for SS in children. METHODS: Eleven patients with SS who underwent surgical repair from January 2012 to March 2020 were retrospectively analyzed. The anomalous scimitar vein (SV) was directly reimplanted to the left atrium, and the concomitant atrial septal defect was simultaneously repaired with cardiopulmonary bypass. RESULTS: Three male and eight female patients were included in the study. Their mean age was 3.1 ± 1.3 years, and their mean body weight was 12.8 ± 3.0 kg. Most patients had symptoms, such as upper respiratory tract infection, dyspnea, and recurrent pneumonia, and two patients had pulmonary hypertension. None of the 11 patients who underwent direct SV reimplantation by right thoracotomy developed bleeding, arrhythmia, heart failure, or perioperative death, and no patients required reoperation during a mean follow-up period of 36.6 ± 15.2 months. Postoperative echocardiography revealed no restenosis or obstruction of the anastomosis in any patients. INTERPRETATION: Surgical repair for SS by right thoracotomy and direct anastomosis of the SV to the posterior wall of the left atrium is safe and effective, with good long-term patency of the reimplanted SV and a low mortality rate.