Background:Pulmonary stenosis (PS) is a common form of congenital heart disease (CHD) that impairs cardiopulmonary function and can be life-threatening in severe cases. As a complex polygenic disorder, the genetic basis of PS remains incompletely understood. Methods:Rare pathogenic single nucleotide variants (SNVs) were identified from whole-exome sequencing (WES) data of 185 sporadic PS patients and 100 healthy controls using multiple pathogenicity-filtering strategies. Gene-level burden test was performed, with complementary analysis using sequence kernel association test-optimal (SKAT-O). Three machine learning algorithms-least absolute shrinkage and selection operator (LASSO), random forest (RF), and extreme gradient boosting (XGBoost)-were applied to prioritize candidate genes. The overlap between machine learning-based selections and burden test results was systematically evaluated. Final candidate genes were further prioritized through protein-protein interaction (PPI) network analysis, and their expression in human pulmonary artery endothelial cells (HPAECs) was assessed by reverse transcription quantitative polymerase chain reaction (RT-qPCR). Results:Comparative analyses showed that different machine learning algorithms exhibited distinct feature selection patterns, with RF demonstrating the highest concordance with burden test results. A total of 17 candidate genes were prioritized (HAND2, SETD2, KDM6B, NCOR2, FLNB, NOTCH3, DNAH5, PLEC, COL5A1, KIF7, CLTCL1, XRN1, ITPR2, SCRIB, PYGB, IQGAP3, and SHC2). Conclusion:These findings indicate that machine learning can complement conventional gene-based analyses of WES data. This study provides a set of candidate genes associated with PS and offers a basis for further investigation of its genetic architecture.

Prenatal exposure to indoor volatile organic compounds (VOCs) poses a substantial yet underestimated threat to fetal brain development. We developed a realistic mouse model to investigate how gestational exposure to such formaldehyde-free paint VOCs mixture disrupts synaptic maturation and cognitive function in postnatal offspring, revealing a novel role for retinol metabolism. Pregnant C57BL/6 J mice inhaled filtered air (control; 0.15 ± 0.01 ppm) or VOCs (0.68 ± 0.06 ppm) from embryonic day 0-21. Exposed postnatal offspring showed deficits in exploratory behavior, recognition memory, and spatial learning, alongside neurodegeneration, reduced dendritic complexity, and lower levels of synaptic proteins (PSD-95, synaptophysin). We identified through transcriptomic and biochemical analyses significant retinol metabolism pathway enrichment, with downregulation of key genes (Aldh1a2, Crabp2) and their protein products. Our findings reveal that prenatal VOCs exposure disrupts synaptic development and cognition by interfering with retinol metabolism. This challenges the assumed safety of "low-VOCs" or "green" building materials in real-world scenarios. These results underscore the critical need to minimize maternal exposure to indoor air pollutants and to consider retinoid pathways as potential targets for intervention.

Many medical conditions are accompanied by severe pain. Acute pain refers to the experience of pain that lasts for only a few hours, whereas chronic pain is the ongoing emergence of pain signals over an extended period. Since ancient times, cannabis has been utilized for medical purposes. This article demonstrates the medicinal importance of cannabinoids through their analgesic and anti-inflammatory activities. Additionally, the mechanisms of cannabinoid-induced analgesia have been interpreted via preclinical investigations in animals. Cannabinoid extracts were formulated into gel and cream at concentrations of 2.5% and 5%. The cannabis cream showed the highest analgesic activity at 5% compared to methyl salicylate as a control. Moreover, cannabis gel produced a comparable anti-inflammatory effect at 5% against the standard diclofenac sodium. Molecular docking studies of all cannabinoids were performed to understand their modes of interaction and binding affinities with the cyclooxygenase II receptor. Additionally, molecular dynamics simulation studies were conducted for for both the ligand-free and cannabidiol-bound cyclooxygenase II to validate the in vivo and molecular docking results. During simulations, the stability of the protein was analyzed using root-mean-square deviation and root-mean-square fluctuation. The study of trajectories of the ligand-free and ligand-bound proteins was assessed using radius of gyration and solvent accessible surface area. Molecular mechanics/generalized Born surface area was used to evaluate the free energies of ligand binding. Dynamic cross-correlation matrix, principal component analysis and free energy landscape characterized the conformational changes and relative energies of them, which shows the existence of two metastable conformations in cyclooxygenase II, one of which is possibly the native state with catalytic activity. In conclusion, the data from this study support the use of medicinal cannabis in the management of pain. To mitigate the suffering of patients experiencing extreme pain, the rational use of cannabis-based drugs merits significant consideration.

BACKGROUND:Accurate detection of fetal cardiac time intervals is essential for diagnosing arrhythmias, yet conventional echocardiography cannot record fetal cardiac electrical activity. Fetal magnetocardiography (fMCG) offers precise, noninvasive detection, but clinical evidence remains limited. OBJECTIVE:This study aimed to evaluate the efficacy and safety of fMCG for detecting fetal cardiac magnetic signals, by comparison with fetal electrocardiography (fECG). METHODS:We conducted a 2-center, single-arm, prospective trial involving 342 pregnant women aged ≥18 years with gestational ages of >18 weeks. Each participant underwent both fECG and fMCG on the same day, with cardiac time intervals recorded. The primary end point was the detection rate of fetal cardiac waveforms reflecting atrial and ventricular rhythm relationships. RESULTS:In the full analysis set (n = 342), fMCG demonstrated a significantly higher detection rate for QRS complexes and RR intervals than fECG (87.98% vs 78.95%; P < .01), with a rate difference of 9.03% (95% confidence interval 3.50-14.56). Similar results were observed in the per-protocol set (n = 340; fMCG 87.94% vs fECG 79.41%; P < .01). Notably, only fMCG could reliably detect PR intervals (86.22%), P waves (86.22%), T waves (78.89%), and QT/corrected QT intervals (78.89%). Adverse events were rare (n = 1; 0.29%) and unrelated to the device. CONCLUSION:fMCG was superior to fECG in detecting RR and QRS signals. Moreover, fMCG uniquely enabled visualization of other intervals critical to arrhythmia diagnosis. It also exhibited a favorable safety profile, supporting its potential in fetal cardiac monitoring.

BackgroundPer- and polyfluoroalkyl substances (PFAS) exposure is associated with various health risks. However, limited research has explored their potential connection with congenital heart disease (CHD).ObjectiveThis study aimed to investigate the relationship between different types of PFAS and childhood CHD using a mixed analysis approach.MethodsA hospital-based case–control study was conducted involving 282 children with CHD and 282 control participants. Plasma samples were analyzed for 19 PFAS congeners. Logistic regression, Bayesian kernel-machine regression (BKMR), and weighted quantile sum (WQS) models were employed to assess the association between individual PFAS and PFAS mixtures with CHD risk.ResultsAnalysis of 564 subjects revealed higher plasma concentrations of various PFAS compounds in the CHD-group. Logistic regression identified significant associations between CHD risk and specific PFAS, notably 6:2 Chlorinated polyfluoroalkyl ether sulfonic acid (6:2 Cl-PFESA) (OR = 1.65; 95%CI: 1.40–1.94), 8:2 8:2 Cl-PFESA (OR = 1.69; 95%CI: 1.69–2.19), Perfluorobutanoic acid (PFBA) (OR = 2.68; 95%CI: 2.28–3.15), Perfluorobutane sulfonic acid (PFBS) (OR = 2.38; 95%CI: 1.77–3.22), Perfluorohexanoic acid (PFHxA) (OR = 2.62; 95%CI: 1.99–3.45), and Perfluorotetradecanoic acid (PFTeDA) (OR = 2.18; 95%CI: 1.81–2.63). BKMR analysis confirmed these findings. WQS analysis emphasized PFBA, 8:2 Cl-PFESA, PFHxA, and PFTeDA as key contributors to the association between PFAS mixture exposure and CHD risk.ConclusionExposure to PFAS mixtures was associated with an increased risk of CHD in children, with 6:2 Cl-PFESA, 8:2 ClPFESA, PFBA, PFHxA, and PFTeDA playing significant roles.

Volatile organic compounds (VOCs) are widespread environmental pollutants associated with various health risks, including developmental toxicity. Our previous studies revealed a correlation between indoor VOCs exposure and an increased risk of congenital heart diseases (CHDs), which was confirmed by establishing a zebrafish exposure model. Metformin (MET), a classic hypoglycemic drug, has been identified to possess multiple properties. Based on previous research on the protective effects of metformin on air pollution, we propose a hypothesis of using metformin as protective agent against VOCs-induced developmental toxicity in zebrafish embryos and explore the underlying molecular mechanisms. The zebrafish embryos were exposed to the VOCs mixture (128 mg/L) alone or in combination with different concentrations of MET (0.5, 1.0 and 2.0 mg/mL) for 120 h. Toxicological indicators such as survival rate, hatching rate and morphological abnormalities (spinal curvature, yolk sac edema and body length reduction) were significantly alleviated by MET, especially in concentrations of 0.5 mg/mL. MET treatment effectively mitigated both cardiovascular impairments (pericardial edema and bradycardia) and neurodevelopmental deficits (locomotor activity). Transcriptomic profiling revealed MET-mediated modulation of apoptosis-related genes and cell cycle regulators. Pathway analyses identified significant enrichment in neurodevelopmental and cardiovascular functions, corroborated by acridine orange staining showing reduced apoptosis. Our findings demonstrate MET's anti-apoptotic protection against VOCs-induced developmental toxicity, suggesting its potential as a novel therapeutic intervention for pollution-related developmental disorders.

AIM:We sought to assess the degree to which environmental risk factors affect CHD prevalence using a case-control study. METHODS:A hospital-based study was conducted by collecting data from outpatients between January 2016 and January 2021, which included 31 CHD cases and 72 controls from eastern China. Risk ratios were estimated using univariate and multivariate logistic regression models and mediating effect analysis. RESULTS:Residential characteristics (usage of cement flooring, odds ratio = 17.04[1.954-148.574], P = 0.01; musty smell, odds ratio = 3.105[1.198-8.051], P = 0.02) and indoor total volatile organic compound levels of participants' room (odds ratio = 31.846[8.187-123.872, P < 0.001), benzene level (odds ratio = 7.370[2.289-23.726], P = 0.001) increased the risk of CHDs in offspring. And folic acid plays a masking effect, which mitigates the affection of the total volatile organic compound (indirect effect = -0.072[-0.138,-0.033]) and formaldehyde (indirect effect = -0.109[-0.381,-0.006]) levels on the incidence of CHDs. While food intake including milk (odds ratio = 0.396[0.16-0.977], P = 0.044), sea fish (odds ratio = 0.273[0.086-0.867], P = 0.028), and wheat (odds ratio = 0.390[0.154-0.990], P = 0.048) were all protective factors for the occurrence of CHDs. Factors including women reproductive history (history of conception control, odds ratio = 2.648[1.062-6.603], P = 0.037; history of threatened abortion, odds ratio = 2.632[1.005-6.894], P = 0.049; history of dysmenorrhoea (odds ratio = 2.720[1.075-6.878], P = 0.035); sleep status (napping habit during daytime, odds ratio = 0.856[0.355-2.063], P = 0.047; poor sleep quality, odds ratio = 3.180[1.037-9.754], P = 0.043); and work status (working time > 40h weekly, odds ratio = 2.882[1.172-7.086], P = 0.021) also influenced the CHDs incidence to differing degrees. CONCLUSION:Diet habits, nutrients intake, psychological status of pregnant women, and residential air quality were associated with fetal CHDs. Indoor total volatile organic compound content was significantly correlated with CHDs risk, and folic acid may serve as a masking factor that reduce the harmful effects of air pollutants.

Coronary artery disease (CAD) is a multigenic condition influenced by both nature and nurture (60% to 40%). Prognosis of CAD is based on familial patterns. This study examined and analyzed the susceptibility of CAD to genetic variants in various Pakistani families. A total of 50 families, 308 participants (79 affected and 229 unaffected were genotyped for NOS3 (rs1799983, rs2070744), PON1 (rs662), LPA-PLA2 (rs105193, rs1805017), APOE (rs429358, rs7412), PCSK9 (rs505151), MEF2A (rs325400), TNF (rs1800629) and LDLR (rs1122608, rs2228671) genes. The family-based association in CAD associated genes SNPs were NOS3 (rs1799983), PON1 (rs662), LPA-PLA2 (rs1805017), MEF2A (rs325400), and LDLR (rs1122608, rs222867) showed transmission within families p≤ 0.05 whereas NOS3 (rs2070744), APOE (rs429358, rs7412) and TNF (rs1800629) showed no association TDT asymptotic p-value >0.05. In DFAM and QFAM test NOS3 (rs1799983), PON1 (rs662), MEF2A (rs325400), and LDLR (rs1122608, rs222867) showed positive association p≤ 0.05 in both whereas NOS3 (rs2070744), APOE (rs429358, rs7412), LPA-PLA2 (rs1805017) and TNF (rs1800629) showed low risk of transmission asymptotic p-value >0.05 in DFAM but NOS3(rs2070744), APOE(rs7412), LPA-PLAG2(rs1805017) also showed association p≤ 0.05 whereas APOE (rs429358) and TNF (rs1800629) showed no association EMP1 p-value >0.05 in QFAM. In linkage analysis Chromosome 6 (Position 70.810): LOD = 3.16, Chromosome 7 (Position 107.190): LOD = 3.16, and chromosome 19 (Position 31.470): LOD = 3.90 also showed significant association with disease as p < 0.05. This discovery enhances the understanding about genetic variants of CAD and also facilitates early detection, targeted interventions, pattern of inheritance in population. This ultimately improving patient outcomes and guiding future research to highlight its significance as a potential diagnostic marker.

This study utilized large-scale population data from the National Health and Nutrition Examination Survey (NHANES) to elucidate the relationship between the Klotho protein and metabolic syndrome along with its components. We further investigated the possible mediating effect of inflammation on these relationships. Our objective was to identify biomarkers for risk stratification and potential therapeutic targets for metabolic syndrome. This study enrolled 13,119 participants aged 40–79 years, spanning five NHANES cycles from 2007 to 2016, with complete information on metabolic syndrome and the Klotho protein. The definition of metabolic syndrome followed the criteria of the National Cholesterol Education Program-Adult Treatment Panel III. Survey-weighted logistic regression and subgroup analysis were used to explore the associations between serum Klotho protein levels and metabolic syndrome, along with its components. Mediation analysis was performed to investigate the mediating effects of inflammation-related markers, including white blood cells, neutrophils, lymphocytes, monocytes, the neutrophil-to-lymphocyte ratio (NLR), the platelet-to-lymphocyte ratio (PLR), the systemic immune-inflammation index (SII) and the monocyte-to-HDL ratio (MHR), with the aim of elucidating how the Klotho protein influences the onset and progression of metabolic syndrome. The study participants had an average age of 56.06 years (95

Congenital heart disease (CHD) is a common birth defect. Our previous studies suggest that indoor air pollution, especially total volatile organic compounds (TVOCs), may increase fetal CHD risk, whereas vitamin and folic acid (FA) supplements in early pregnancy might offer protection against CHD. However, limited research has explored whether FA or multivitamin supplementation can mitigate the effects of TVOCs exposure on CHD. We conducted a case-control study to investigate the association between maternal nutrient supplementation, household indoor air pollutant exposure during pregnancy, and CHD in offspring. Pregnant women with 22–30 gestational weeks were recruited from two hospitals in East China between January 2016 and March 2022. A comprehensive approach was used, incorporating questionnaires to collect nutrient supplement information, blood sample analysis to detect serum folate, vitamin B12, and homocysteine (HCY) concentrations, and field investigations to assess indoor benzene, toluene, xylene, formaldehyde, and TVOCs exposures. Logistic regression analysis was performed to identify CHD risk factors, and stratified analysis was used to evaluate the combined effects of nutrient supplementation and TVOCs on CHD. The study included 53 cases and 77 controls. Logistic regression analysis identified high maternal serum HCY (> 6.125 µmol/L) and high household TVOCs exposure (> 0.0165 mg/m³) as risk factors for CHD in offspring, with adjusted odds ratios of 2.98 (95

BackgroundThe existing evidence regarding the joint effect of heavy metals on blood pressure (BP) in children and adolescents is insufficient. Furthermore, the impact of factors such as body weight, fish consumption, and age on their association remains unclear.MethodsThe study utilized original data from the National Health and Nutrition Examination Survey, encompassing 2,224 children and adolescents with complete information on 12 urinary metals (barium, cadmium, cobalt, cesium, molybdenum, lead, antimony, thallium, tungsten, uranium, mercury and arsenic), BP, and core covariates. Various statistical methods, including weighted multiple logistic regression, linear regression, and Weighted Quantile Sum regression (WQS), were employed to evaluate the impact of mixed metal exposure on BP. Sensitivity analysis was conducted to confirm the primary analytical findings.ResultsThe findings revealed that children and adolescents with low-level exposure to lead (0.40 μg/L, 95%CI: 0.37, 0.42), mercury (0.38 μg/L, 95%CI: 0.35, 0.42) and molybdenum (73.66 μg/L, 95%CI: 70.65, 76.66) exhibited reduced systolic blood pressure (SBP) and diastolic blood pressure (DBP). Conversely, barium (2.39 μg/L, 95%CI: 2.25, 2.54) showed a positive association with increased SBP. A 25th percentile increase in the WQS index is significantly associated with a decrease in SBP of 0.67 mmHg (95%CI, −1.24, −0.10) and a decrease in DBP of 0.59 mmHg (95% CI, −1.06, −0.12), which remains statistically significant even after adjusting for weight. Furthermore, among individuals who consume fish, heavy metals have a more significant influence on SBP. A 25 percentile increase in the WQS index is significantly associated with a decrease of 3.30 mmHg (95% CI, −4.73, −1.87) in SBP, primarily attributed to mercury (27.61%), cadmium (27.49%), cesium (17.98%), thallium (8.49%). The study also identified a declining trend in SBP among children aged 10–17, whereas children aged 11–18 exhibited lower levels of systolic and diastolic blood pressure, along with a reduced risk of hypertension.ConclusionSome heavy metals demonstrate an inverse association with the BP of children and adolescents, particularly notable in groups with fish consumption and older children and adolescents. Future studies are warranted to validate these findings and delve deeper into the interplay of heavy metals.

Objective: To investigate the echocardiographic features, consistency of diagnosis between fetal and postnatal periods and postnatal clinical outcomes of fetal pulmonary valve stenosis (PS) with different degrees. Methods: This study was a retrospective cohort study comprising 108 cases of fetal PS diagnosed during the fetal period and followed up postnatally at Xinhua Hospital, Shanghai Jiaotong University School of Medicine from November 2012 to February 2023. Echocardiographic characteristics, including morphological and hemodynamic features were collected for all fetuses who were then were followed up to at least 6 months after birth. One-way analysis of variance and Kruskal-Wallis test were used to compare the differences in the echocardiographic features among fetuses with different degrees of PS. Subsequently, McNemar test was used to assess the consistency of diagnosis between the fetal and postnatal periods. Furthermore, Logistic regression analysis was applied to explore the risk factors for neonatal intervention in fetuses with moderate PS and the receiver operating characteristic (ROC) curve was utilized to ascertain the optimal cut-off value for continuous variables. Results: The age of the mothers of the 108 fetuses at the initial assessment was (30.8±4.0) years, and the gestational age was 26.5 (24.6, 30.0) weeks. The fetuses were categorized into mild (17 cases), moderate (49 cases), and severe groups (42 cases) based on the initial echocardiographic features. Mild PS was characterized by valve thickening and hyperechogenicity combined with systolic flow acceleration or dilation of main pulmonary artery. Moderate PS exhibited both restricted valve motion and a colorful blood flow pattern at the valve orifice. The peak flow velocities of fetuses with moderate and critical PS were notably higher than those in the mild group ((2.66±0.86) and (2.77±1.30) vs. (1.43±0.59)m/s, F=14.52, P<0.001). In critical PS, all cases showed retrograde ductal flow, with a significantly higher proportion of a small right ventricle compared to the mild and moderate PS (42.9% (18/42) vs. 0 and 2.0% (1/49), χ2=31.73, P<0.001). The proportion of severe tricuspid regurgitation was also higher (35.7% (15/42) vs. 0 and 10.2% (5/49), χ2=36.94, P<0.001). Compared to mild and severe PS, the consistency of diagnosis between fetal and postnatal periods in moderate PS was lower (40.8% (20/49) vs.13/17 and 80.3% (35/42), χ2=12.45, P=0.006). The systolic flow velocity was identified as an independent risk factor for neonatal intervention in fetuses with moderate PS (OR=7.21, 95%CI2.11-24.62). A flow velocity of ≥2.18 m/s in second trimester and ≥3.15 m/s in third trimester indicated the necessity of neonatal intervention for fetal moderate PS. Among the 108 fetuses, 68 underwent surgical intervention and all survived. Additionally, 39 fetuses were regularly followed up. A sole non-surgical fatality occurred, leading to a 6-month survival rate of 99.1% (107/108). Conclusions: Various degrees of fetal PS demonstrate distinctive morphological and hemodynamic alterations in echocardiography. The disparity in severity between the postnatal and fetal stages requires ongoing monitoring for fetal PS. The prognosis for fetal PS is generally favorable.

Objective:To summarize the outcomes of different types of pulmonary atresia in neonates treated by ductus arteriosus stenting.Methods:This study was a retrospective cohort study. A total of 19 neonates who had pulmonary atresia treated by ductus arteriosus stenting in Xinhua Hospital, Shanghai Jiao Tong University School of Medicine from April 2014 to June 2021 were included. They were divided into the intact ventricular septum (PA-IVS) group and the ventricular septal defect (PA-VSD) group. Ductus arteriosus stents were implanted by different approaches. These children were followed up regularly at the 1, 3, 6, and 12 months after the surgery and annually since then to evaluate the outcome. Independent sample t-test was used for the statistical analysis. Results:There were 12 children in PA-IVS group and 7 in PA-VSD group. All of them were full term in fants. The gestational age of the PA-IVS group and the PA-VSD group was (38.8±1.1) and (37.7±1.8) weeks, the birth weights were (3.2±0.4) and (3.4±1.1) kg, and the age at operation was (10±9) and (12±7) days, respectively, without significant difference (all P>0.05). Among the 12 children with PA-IVS, 9 had stents successfully implanted through the femoral artery and 3 through the femoral vein. Of the 7 children with PA-VSD, 2 had the stents successfully implanted via the femoral artery and 2 failed, and the remaining 3 had stents successfully implanted via the left carotid artery. There was no postoperative thromboembolism, arteriovenous fistula, pseudoaneurysm or other vascular complications. Five children with PA-VSD who had successful operations were followed up at 6 months of age. They all had the operation for pulmonary atresia, repair of the ventricular septal defect, removal of arterial duct stents, and ligation of the arterial duct. All children survived without any stent displacement or stenosis and biventricular circulation was achieved during the follow-up. Conclusions:Ductus arteriosous stenting can be the first-stage treatment for children with PA-IVS and PA-VSD. In addition to the traditional femoral vein and femoral artery approach, the carotid artery can be used as a route for stent placement.

Objective. The aim of this study is to investigate the predictive value of fetal and neonatal echocardiographic parameters for neonatal coarctation repair in fetuses suspected of coarctation of the aorta (CoA), establish a prediction model for neonatal coarctation repair, and verify its predictive effectiveness and clinical applicability. Methods. From September 2017 to September 2022, fetuses suspected with CoA were enrolled. They were divided into two groups based on the need for neonatal coarctation repair. Fetal and neonatal echocardiographic parameters and clinical characteristics were collected retrospectively. Univariate and multivariate logistic regressions were applied to select significant predictors, which were further used to establish the nomogram prediction model. The area under the curve (AUC) of the receiver operating characteristic (ROC) was employed to quantify its discrimination ability. The calibration curve was drawn for internal verification, and the decision curve analysis (DCA) and clinical impact curve (CIC) were used to evaluate the clinical applicability of the prediction model. Results. This study included 50 infants suspected of CoA prenatally, of which 16 (32%) received aortic coarctation repair in the neonatal period and 34 (68%) did not. Multivariable logistic regression analysis revealed that the fetal echocardiographic parameter aortic isthmus/ductus arteriosus (AoI/DA) diameter ratio and the neonatal echocardiographic parameters such as the distance from left common carotid to left subclavian artery (LCSA) and the diameter of distal transverse aortic arch (DTAA) were independent predictors for neonatal coarctation repair. The ROC curve of the model showed excellent predictive value (AUC = 0.943). The calibration curve of the prediction model exhibited good fitness. The DCA and CIC demonstrated that the model had good clinical utility. Conclusion. The prediction model, which combines the fetal echocardiographic parameter AoI/DA diameter ratio and the neonatal echocardiographic parameters distance of LCSA and DTAA diameter, has an exceptional level of clinical value and prediction accuracy.

Background: Sepsis is the second-leading cause of death in neonates. We established a predictive nomogram to identify critically ill neonates early and reduce the time to treatment. Methods: It is a retrospective case-control study based on the MIMIC-III database. The study population comprised 924 neonates diagnosed with sepsis. Results: Neonates with sepsis included in the MIMIC-III database were enrolled, including 880 surviving neonates and 44 neonates who died. In the derivation dataset, stepwise regression and the Lasso algorithm were employed to select predictive variables, and the neonatal sequential organ failure assessment score (nSOFA) was calculated simultaneously. Bootstrap resampling was utilized to perform internal validation. The results indicated that the Lasso algorithm displayed superior discrimination, sensitivity, and specificity relative to stepwise regression and nSOFA scores. After 500 bootstrap resampling tests, the area under the receiver operating characteristic curve (AUC) of the Lasso algorithm was 0.912 (95% CI: 0.870-0.977). The nomogram based on the Lasso algorithm outperformed stepwise regression and nSOFA scores in terms of calibration and the clinical net benefit. This nomogram can assist in prognosticating neonatal severe sepsis and aid in guiding clinical practice while concurrently improving patient outcomes. Conclusions: The established nomogram revealed that jaundice, corticosteroid use, weight, serum calcium, inotropes and base excess are all important predictors of 28-day mortality in neonates with sepsis. This nomogram can facilitate the early identification of neonates with severe sepsis. However, it still requires further modification and external validation to make it widely available.

Abstract Background Current evidence relating birthweight and gestational age to cardiovascular risk is conflicting. Whether these factors have independent or interactive impacts on cardiovascular parameters during early childhood remains unclear. The goal of this study was to explore whether there were any independent and interactive effects of gestational age and birthweight on blood pressure, left ventricle (LV) structure, and function in 4 years old. Methods This study included 1194 children in the Shanghai Birth Cohort from 2013 to 2016. Information about the mothers and children was recorded at time of birth using a questionnaire. Follow-up measurements, including anthropometric, blood pressure, and echocardiography, were taken between 2018 and 2021, when the children were 4 years old. Multiple linear or logistic regressions and restricted cubic spline were used to explore the association of birthweight and gestational age with cardiovascular measurements. Results Gestational age had a significant negative correlation with both systolic blood pressure [β = − 0.41, 95% CI: (− 0.76, − 0.07)] and mean arterial pressure [β = − 0.36, 95%CI: (− 0.66, − 0.07)]. The risk of prehypertension decreased with increased gestational age [OR = 0.54, 95% CI: (0.32, 0.93)]. The relationship between birthweight with blood pressure was U-shape (P for non-linear < 0.001). The wall thickness, volume, mass, and cardiac output of LV increased with birthweight, though the ejection fraction [β = − 1.02, 95% CI: (− 1.76, − 0.27)] and shorten fraction [β = 0.72, 95% CI: (− 1.31, − 0.14)] decreased with birthweight. The risk of LV hypertrophy was not associated with birthweight [OR = 1.59, 95% CI: (0.68, 3.73)]. Conclusions In this study, we found different associations of birthweight and gestational age with cardiovascular measurements in the offspring at 4 years old. Gestational age influenced blood pressure independent of birthweight. Heart size and function at 4 years old was influenced mostly by birthweight and not by gestational age.

Volatile organic compounds (VOCs) are common air pollutants and water contaminants. We previously found maternal exposure to VOCs was associated with offspring congenital heart disease (CHD). However, little information is available about the effects of VOCs on cardiovascular development at embryonic stage and the underlying mechanism remains unclear. In this study, we aimed to investigate the effects of a mixture of six VOCs on cardiovascular development in zebrafish embryos. Embryos were exposed to different concentrations of VOCs mixture (32 mg/L, 64 mg/L and 128 mg/L) for 96 h, cardiovascular abnormalities including elongated heart shape, increased distance between sinus venosus and bulbus arteriosus, slowed circulation and altered heart rate were observed in a dose- and time-dependent manner. Meanwhile, VOCs exposure increased global DNA methylation levels in embryos. Analysis identified hundreds of differentially methylated sites and the enrichment of differentially methylated sites on cardiovascular development. Two differentially methylated-associated genes involved in MAPK pathway, hgfa and ntrk1, were identified to be the potential genes mediating the effects of VOCs. By enzyme-linked immunosorbent assay, altered human serum hgf and ntrk1 levels were detected in abnormal pregnancies exposed to higher VOCs levels with fetal CHD. For the first time, our study revealed exposure to VOCs induced severe cardiovascular abnormalities in zebrafish embryos. The toxicity might result from alterations in DNA methylation and corresponding expression levels of genes involved in MAPK pathway. Our study provides important information for the risk of VOCs exposure on embryonic cardiovascular development.

Background: Prenatal exposure to perfluoroalkyl substances (PFAS) has been associated with adverse birth outcomes, but data on early childhood cardiovascular health is limited. This study aimed to assess the potential association between maternal PFAS exposure during early pregnancy and cardiovascular development in offspring.Material and methods: Cardiovascular development was assessed through blood pressure measurement, echocardiography and carotid ultrasound examinations among 782 children from the Shanghai Birth Cohort aged at 4 years. Levels of PFAS were measured in maternal blood during early pregnancy. The joint associations between PFAS mixture and cardiovascular parameters were analyzed using a Bayesian kernel machine regression. Principal component analysis was used to reduce dimensionality of the PFAS data and to summarize two principal components (PCs). The potential association of exposure to the two PCs or individual PFAS chemicals was explored using multiple linear regression.Results: Exposure to PFAS mixture was negatively associated with cardiovascular development measures, after adjusting for potential confounders. Carotid intima media thickness (cIMT), interventricular septum thickness in diastole and systole, and relative wall thickness were significantly -0.38mm (95% confidence interval: -0.50, -0.26mm), -0.06mm (-0.08, -0.04mm), -0.10mm (-0.14, -0.06mm), and -0.005 (-0.006, -0.004) lower, respectively, when all log-transformed PFAS were fixed at 75th percentile in comparison to at their 50th percentile. The mothed of PCA then yielded two PCs of PFAS, and a consistent negative association was found between cardiovascular parameters with PC1, which was heavily weighted by long-chain PFAS. In addition, exposure to individual PFAS chemical was also inversely related to cardiovascular development. Exposure to individual short-chain PFAS was associated with a decrease in left ventricular wall thickness, and long-chain with a decrease in interventricular septum thickness.Conclusions: Our findings suggest that maternal exposure to PFAS during early pregnancy was negatively associated with cardiovascular development in offspring, including thinner cardiac wall thickness and cIMT.

ObjectivesCongenital ventricular aneurysms or diverticulum (VA/VD) are rare cardiac anomalies with lack prenatal evaluation data. The present study aimed to provide the prenatal characteristics and outcomes from a tertiary center and the use of new techniques to evaluate the shape and contractility of these fetuses. MethodsTen fetuses were diagnosed with VA or VD, and 30 control fetuses were enrolled. Fetal echocardiography was performed to make the diagnosis. The prenatal echo characteristics and follow-up data were carefully reviewed. The shape and contractility measurements of the four-chamber view (4CV) and both ventricles were measured and computed using fetal fetal heart quantification (HQ). ResultsA total of 10 fetuses were enrolled, including 4 cases of left ventricular diverticulum, 5 cases of left ventricular aneurysm, and 1 case of right ventricular aneurysm (RVA). Four cases chose to terminate the pregnancy. The RVA was associated with a perimembranous ventricular septal defect. Two cases had fetal arrhythmia, and one case had pericardial effusion. After birth, one case underwent surgical resection at five years old. The 4CV global sphericity index (SI) of free-wall located ventricular outpouching (VO) was significantly lower than the apical ones and the control group (p < 0.01). Four of five apical left VOs had significant higher (>95th centile) SI in base segments, and three of four left VOs in the free-wall had significant lower (< 5th centile) SI in the majority of 24 segments. Compared to the control group, the left ventricle (LV) global longitudinal strain, ejection fraction, and fractional area change were significantly decreased (p < 0.01), while the LV cardiac output of the cases was in the normal range. The transverse fraction shortening of the affected segments of ventricles was significantly lower than the other ventricle segments (p < 0.01). ConclusionsFetal HQ is a promising technique to evaluate the shape and contractility of congenital ventricular aneurysm and diverticulum.

Background::Intrauterine valvuloplasty is an innovative therapy, which promotes ventricular growth and function in some congenital heart diseases (CHDs). The technique remains challenging and can only be performed in a few centers. This study aimed to assess the feasibility and mid-term outcomes of fetal cardiac intervention (FCI) in fetuses with critical CHD in an experienced tertiary center.Methods::Five fetal aortic valvuloplasty (FAV) or fetal pulmonary valvuloplasty (FPV) procedures were performed in our fetal heart center between August 2018 and May 2022. Technical success was defined as crossing the aortic or pulmonary valve and balloon inflation, followed by evidence of increased blood flow across the valve and/or new regurgitation. Follow-up clinical records and echocardiography were obtained during the prenatal and postnatal periods.Results::Five fetuses received FAV or FPV, including critical aortic stenosis ( n = 2) and pulmonary atresia with intact ventricular septum ( n = 3). The mean maternal age was 33.0 ± 2.6 years. The median gestational age (GA) at diagnosis was 24 weeks (range, 22-26 weeks). The median GA at intervention was 29 weeks (range, 28-32 weeks). All five cases underwent successful or partially successful procedures. One patient had pulmonary valve perforation without balloon dilation. No procedure-related deaths or significant complications occurred. However, one neonatal death occurred due to heart and renal failure. The median follow-up period was 29.5 months (range, 8.0-48.0 months). The four surviving patients had achieved biventricular circulation, exhibited improved valve, and ventricular development at the last follow-up visit. Conclusion::Intrauterine FCI could be performed safely with good prognosis in critical CHD.