SEraster: a rasterization preprocessing framework for scalable spatial omics data analysis.

MOTIVATION: Spatial omics data demand computational analysis but many analysis tools have computational resource requirements that increase with the number of cells analyzed. This presents scalability challenges as researchers use spatial omics technologies to profile millions of cells. RESULTS: To enhance the scalability of spatial omics data analysis, we developed a rasterization preprocessing framework called SEraster that aggregates cellular information into spatial pixels. We apply SEraster to both real and simulated spatial omics data prior to spatial variable gene expression analysis to demonstrate that such preprocessing can reduce computational resource requirements while maintaining high performance, including as compared to other down-sampling approaches. We further integrate SEraster with existing analysis tools to characterize cell-type spatial co-enrichment across length scales. Finally, we apply SEraster to enable analysis of a mouse pup spatial omics dataset with over a million cells to identify tissue-level and cell-type-specific spatially variable genes as well as spatially co-enriched cell types that recapitulate expected organ structures. AVAILABILITY AND IMPLEMENTATION: SEraster is implemented as an R package on GitHub (https://github.com/JEFworks-Lab/SEraster) with additional tutorials at https://JEF.works/SEraster.

A Panoramic View of Cell Population Dynamics in Mammalian Aging.

To elucidate the aging-associated cellular population dynamics throughout the body, here we present PanSci, a single-cell transcriptome atlas profiling over 20 million cells from 623 mouse tissue samples, encompassing a range of organs across different life stages, sexes, and genotypes. This comprehensive dataset allowed us to identify more than 3,000 unique cellular states and catalog over 200 distinct aging-associated cell populations experiencing significant depletion or expansion. Our panoramic analysis uncovered temporally structured, organ- and lineage-specific shifts of cellular dynamics during lifespan progression. Moreover, we investigated aging-associated alterations in immune cell populations, revealing both widespread shifts and organ-specific changes. We further explored the regulatory roles of the immune system on aging and pinpointed specific age-related cell population expansions that are lymphocyte-dependent. The breadth and depth of our 'cell-omics' methodology not only enhance our comprehension of cellular aging but also lay the groundwork for exploring the complex regulatory networks among varied cell types in the context of aging and aging-associated diseases.

Exploring the impact of prenatal perfluoroalkyl and polyfluoroalkyl substances exposure on blood pressure in early childhood: A longitudinal analysis.

Previous research investigating the correlation between prenatal exposure to per- and polyfluoroalkyl substances (PFAS) and subsequent blood pressure (BP) in offspring has yielded limited and contradictory findings. This study was conducted to investigate the potential relationship between maternal PFAS levels during pregnancy and subsequent BP in early childhood. A total of 129 expectant mothers from the Shanghai Birth Cohort were included in the study. Using high-performance liquid chromatography/tandem mass spectrometry, we measured ten PFAS compounds in maternal plasma throughout the pregnancy. When the children reached the age of 4, we examined their systolic BP (SBP) and diastolic BP (DBP), along with mean arterial pressure (MAP) and pulse pressure (PP). Data interpretation employed multiple linear and logistic regression models, complemented by Bayesian kernel machine regression (BKMR).We found that the majority of PFAS concentrations remained stable during pregnancy. The linear and BKMR models indicated a positive relationship between the PFAS mixture in maternal plasma and offspring's DBP and MAP, with perfluorohexanesulphonic acid (PFHxS) having the most significant influence (PFHxS and DBP [first trimester:ß=3.03, 95%CI: (1.01,5.05); second trimester: ß=2.35, 95%CI: (0.94,3.75); third trimester: ß=2.57, 95%CI:(0.80,4.34)]; MAP [first trimester:ß=2.55, 95%CI: (0.64,4.45); second trimester: ß=2.28, 95%CI: (0.95,3.61); third trimester: ß=2.35, 95%CI:(0.68,4.01)]). Logistic regression highlighted an increased risk of prehypertension and hypertension in offspring with higher maternal PFHxS concentrations during all three trimesters [first trimester: OR=2.53, 95%CI:(1.11,5.79), second trimester: OR=2.05, 95%CI:(1.11,3.78), third trimester: OR=3.08, 95%CI:(1.40,6.79)]. A positive correlation was identified between the half-lives of PFAS and the odds ratio (OR) of prehypertension and hypertension in childhood (ß=0.139, P=0.010). In conclusion, this research found maternal plasma PFAS concentrations to be positively associated with BP in offspring, with PFHxS showing the most significant influence. This correlation remained consistent throughout pregnancy, and this effect was proportional to the half-lives of PFAS.

Exposure to pesticides and risk of colorectal cancer: A systematic review and meta-analysis.

Colorectal cancer (CRC) is a widespread malignancy worldwide, and its relationship with pesticide exposure remains inconclusive. This study aims to elucidate the relationship between pesticide exposure and the risk of colon, rectal, or CRC, focusing on specific pesticide groups. We conducted an extensive literature search for peer-reviewed studies published up to March 31, 2023. Summary risk ratios (RR) and their corresponding 95% confidence intervals (CI) were calculated using stratified random-effects meta-analyses, taking into account different types of exposure and outcomes, and various exposed populations and pesticide subgroups. This approach aimed to address the substantial heterogeneity observed across the literature. We also assessed heterogeneity and potential small-study effects to ensure the robustness of our findings. From the 50 studies included in this review, 33 contributed to the meta-analysis. Our results indicate a significant association between herbicide exposure and colon cancer in both lifetime-days (LDs) (RR = 1.20; 95% CI = 1.01-1.42) and intensity-weighted lifetime-days (IWLDs) (RR = 1.29, 95% CI = 1.12-1.49) exposure. Similarly, insecticide exposure was associated with an increased risk of colon cancer in IWLDs (RR = 1.32; 95% CI = 1.02-1.70) exposure, and rectal cancer in any versus never exposure (RR = 1.21; 95% CI = 1.07-1.36), IDs (RR = 1.86; 95% CI = 1.30-2.67) and IWLDs (RR = 1.70; 95% CI = 1.03-2.83) exposure. While these findings suggest significant associations of herbicide and insecticide exposure with colon and rectal cancer, respectively, further research is needed to explore the impact of other pesticide groups and deepen our understanding of pesticide exposure. These results have important implications for policymakers and regulators, underscoring the need for stricter supervision and regulation of pesticide use to mitigate CRC risk.

Exposure to volatile organic compounds induces cardiovascular toxicity that may involve DNA methylation.

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.

Highly dispersed amorphous nano-selenium functionalized carbon nanofiber aerogels for high-efficient uptake and immobilization of Hg(II) ions.

Owing to the strong Hg-Se interaction, Se-containing materials are promising for the uptake and immobilization of Hg(II) ions; compared with metal selenides or selenized compounds, elemental Se contains the highest ratio of Se. However, it remains a challenge to fully expose all the potential Se binding sites and achieve high utilization efficiency of elemental Se. Through rational design on the structure, dispersity, and size of materials, Se/CNF aerogels composed of abundant well-dispersed and amorphous nano-Se have been prepared and applied for the high-efficient uptake and immobilization of Hg(II) ions. The well-dispersion of nano-Se increases the exposure of Se sites, the amorphous structure benefits the easy cleavage of Se-Se bonds, the 3D porous networks of aerogels permit fast ions transport and easy operation. Benefiting from the combination effect of strong Hg-Se interaction and sufficient exposure of Se-enriched sites, the Se/CNF aerogels demonstrate strong binding ability (Kd = 3.8 ×105 mL·g-1), high capacity (943.4 mg·g-1), and preeminent selectivity (αMHg > 100) towards highly toxic Hg(II) ions. Notably, the utilization efficiency of Se in Se/CNF aerogels is as high as 99.5%. Moreover, the strong Hg-Se interaction and extraordinary stability of HgSe could minimize the environmental impact of the spent Se/CNF adsorbents after its disposal.

Perfluoroalkyl substances in umbilical cord blood and blood pressure in offspring: a prospective cohort study.

BACKGROUND: Humans are widely exposed to perfluoroalkyl substances (PFAS), which have been found to be associated with various adverse birth outcomes. As blood pressure (BP) is an important parameter reflecting cardiovascular health in early life, it is necessary to investigate the association of PFAS exposure during early lifetime and BP in childhood. Therefore, we investigated the potential association between PFAS levels in umbilical cord blood and BP of the offspring at 4 years of age in a prospective cohort study. METHODS: PFAS in umbilical cord blood samples after birth were measured with high-performance liquid chromatography/tandem mass spectrometry in the Shanghai Birth Cohort. BP was measured at 4 years of age in the offspring. Multiple linear regression model was used to investigate the association between individual PFAS level and BP of the offspring. Bayesian kernel machine regression (BKMR) was used to analyze the relationship between the PFAS mixture and BP of the offspring, while weighted quantile sum (WQS) regression was utilized for sensitivity analysis. RESULTS: A total of 129 mother-child pairs were included in our analysis. In multiple linear regressions, we observed that long-chain PFAS, mainly including perfluorooctane sulfonate (PFOS), perfluorodecanoic acid (PFDA) and perfluoroundecanoic acid (PFUA), was negatively associated with systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial blood pressure (MAP). BKMR showed that an increase in umbilical cord blood PFAS mixture levels was significantly associated with a decrease in SBP, DBP and MAP [Estimated differences (SD): -0.433 (0.161); -0.437 (0.176); -0.382 (0.179), respectively]. The most important component in the association with SBP, DBP, and MAP was PFUA. PFDoA was found to be positively associated with SBP, DBP and MAP in both models. Sensitivity analysis with WQS regression showed consistent results. CONCLUSION: Our findings suggested that umbilical blood PFAS exposure was negatively associated with BP in offspring at 4 years of age, including SBP, DBP, and MAP.

Persistent organic pollutants exposure and risk of autism spectrum disorders: A systematic review and meta-analysis.

Accumulating number of epidemiological studies has recently proposed that improvement in the risk of autism spectrum disorders (ASD) is associated with persistent organic pollutants (POPs) exposure. However, evidence from current researches is limited and inconsistent. Thus, we conducted a systematic review and meta-analysis to investigate the potential associations comprehensively. We systematically and extensively searched two electronic databases (PubMed and EMBASE) from inception to July 3, 2022 and an updated search was performed before submission. Summary odds ratios (ORs) and 95% confidence intervals (CIs) were derived from stratified random-effects meta-analyses by type of exposure and outcome. We also tested the potential heterogeneity across studies, conducted sensitivity analysis and evaluated publication bias. A total of 20 studies were finally included in our study. Meta-analytical effect estimates indicated a positive association between prenatal exposure to PCB-138, PCB-153 and PCB-170 and an increased risk of ASD, with OR of 1.89 (95% CI = 1.21-2.95, I2 = 0%), 1.61 (95% CI = 1.05-2.47, I2 = 0%) and 1.46 (95% CI = 1.03-2.06, I2 = 0%) respectively. In contrast, PFDA was found inversely associated with the risk of ASD (OR = 0.70, 95% CI = 0.52-0.94, I2 = 0%). The level of evidence supporting a link between ASD risk and exposure to PCB-138, PCB-153, PCB-170, and PFDA was respectively categorized as low, low, moderate, and low. In summary, this systematic review and meta-analysis suggest that exposure to PCB-138, PCB-153, and PCB-170 correlates with a heightened risk of ASD, with evidence levels rated as "low", "low", and "moderate", respectively. In contrast, PFDA exposure appears to be inversely associated with ASD risk, with a "low" level of supporting evidence. However, due to the limited number of studies available for each exposure and outcome pairing, these results should be interpreted with caution. Sufficiently powered studies are needed to validate our findings.

The Association between Maternal Urinary Phthalate Concentrations and Blood Pressure in Pregnancy: A Systematic Review and Meta-Analysis.

Phthalates are commonly found in a wide range of environments and have been linked to several negative health outcomes. While earlier research indicated a potential connection between phthalate exposure and blood pressure (BP) during pregnancy, the results of these studies remain inconclusive. The objective of this meta-analysis was to elucidate the relationship between phthalate exposure and BP in pregnancy. A comprehensive literature search was carried out with PubMed, EMBASE, and Web of Science, and pertinent studies published up until 5 March 2023 were reviewed. Random-effects models were utilized to consolidate the findings of continuous outcomes, such as diastolic and systolic BP, as well as the binary outcomes of hypertensive disorders of pregnancy (HDP). The present study included a total of 10 studies. First-trimester MBP exposure exhibited a positive association with mean systolic and diastolic BP during both the second and third trimesters (ß = 1.05, 95% CI: 0.27, 1.83, I2 = 93%; ß = 0.40, 95% CI: 0.05, 0.74, I2 = 71%, respectively). Second-trimester monobenzyl phthalate (MBzP) exposure was positively associated with systolic and diastolic BP in the third trimester (ß = 0.57, 95% CI: 0.01, 1.13, I2 = 0; ß = 0.70, 95% CI: 0.27, 1.13, I2 = 0, respectively). Conversely, first-trimester mono-2-ethylhexyl phthalate (MEHP) exposure demonstrated a negative association with mean systolic and diastolic BP during the second and third trimesters (ß = -0.32, 95% CI: -0.60, -0.05, I2 = 0; ß = -0.32, 95% CI: -0.60, -0.05, I2 = 0, respectively). Additionally, monoethyl phthalate (MEP) exposure was found to be associated with an increased risk of HDP (OR = 1.12, 95% CI: 1.02, 1.23, I2 = 26%). Our study found that several phthalate metabolites were associated with increased systolic and diastolic BP, as well as the risk of HDP across pregnancies. Nevertheless, given the limited number of studies analyzed, additional research is essential to corroborate these findings and elucidate the molecular mechanisms linking phthalates to BP changes during pregnancy.

The association of gestational age and birthweight with blood pressure, cardiac structure, and function in 4 years old: a prospective birth cohort study.

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 [ß = - 0.41, 95% CI: (- 0.76, - 0.07)] and mean arterial pressure [ß = - 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 [ß = - 1.02, 95% CI: (- 1.76, - 0.27)] and shorten fraction [ß = 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.

Association of Maternal Glucose Concentrations During Pregnancy With Cardiovascular Alterations in Early Childhood: A Prospective Birth Cohort Study.

BACKGROUND: Maternal hyperglycemia has been associated with cardiovascular disease risks in offspring. Previous studies were mostly conducted to test this association in pregnancies with (pre)gestational diabetes mellitus. However, the association may not be limited to populations with diabetes only. OBJECTIVES: The aim of this study was to assess the association between gestational glucose concentrations in women without (pre)gestational diabetes mellitus and childhood cardiovascular alterations at the age of 4 y. METHODS: Our study was based on the Shanghai Birth Cohort. Briefly, among 1016 nondiabetic mothers (age: 30.8 ± 3.42 y; BMI: 21.3 ± 2.94) and their offsprings (age: 4.41 ± 0.22 y; BMI: 15.0 ± 1.56; 53.0% males), results of maternal 1-h oral OGTT between 24 and 28 gestational weeks were obtained. Childhood blood pressure (BP) measurement, echocardiography, and vascular ultrasound were performed at 4 y old. Linear regression and binary logistic regression were conducted to test the association between maternal glucose and childhood cardiovascular outcomes. RESULTS: Compared with children from mothers with glucose concentrations in the lowest quartile, children from mothers in the highest quartile had higher BP (systolic: 97.0 ± 7.41 compared with 98.9 ± 7.82 mmHg, P = 0.006; diastolic: 56.8 ± 5.83 compared with 57.9 ± 6.03 mmHg, P = 0.051) and lower left ventricular ejection fraction (92.5 ± 9.15 compared with 90.8 ± 9.16 %, P = 0.046). Also, higher maternal OGTT 1-h glucose concentrations across the full range were associated with higher childhood BP (systolic: ß: 0.56; 95% CI: 0.19, 0.93; diastolic: ß: 0.36; 95% CI: 0.05, 0.66). Logistic regression showed, compared with children from mothers in the lowest quartile, children from mothers in the highest quartile had a 58% (OR=1.58; 95% CI: 1.01, 2.47) higher odds of elevated systolic BP (≥90th percentile). CONCLUSIONS: In a population without (pre)gestational diabetes mellitus, higher maternal OGTT 1-h glucose were associated with childhood cardiovascular structure and function alterations. Further studies are needed to assess whether interventions to reduce gestational glucose will mitigate subsequent cardiometabolic risks in offspring.

Maternal plasma perfluoroalkyl substances concentrations in early pregnancy and cardiovascular development in offspring: A prospective cohort study.

BACKGROUND: High maternal plasma perfluoroalkyl substances (PFAS) concentrations 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 plasma PFAS concentrations 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 957 children from the Shanghai Birth Cohort aged at 4 years old. Maternal plasma concentrations of PFAS were measured at mean gestational age of 14.4 (SD:1.8) weeks. The joint associations between PFAS mixture concentrations and cardiovascular parameters were analyzed using a Bayesian kernel machine regression (BKMR). The potential association of individual PFAS chemicals concentrations was explored using multiple linear regression. RESULTS: In BKMR analyses, carotid intima media thickness (cIMT), interventricular septum thickness in diastole and systole, posterior wall thicknesses in diastole and systole, and relative wall thickness were significantly lower when all log10-transformed PFAS were fixed at 75th percentile in comparison to at their 50th percentile[Estimated overall Risk:-0.31 (95%CI: -0.42, -0.20), -0.09 (95%CI: -0.11, -0.07), -0.21 (95%CI: -0.26, -0.16), -0.09 (95%CI: -0.11, -0.07), -0.07 (95%CI: -0.10, -0.04) and -0.005 (95%CI: -0.006, -0.004)].Furthermore, maternal plasma concentrations of individual short-chain PFAS was associated with a decrease in left ventricular wall thickness, intraventricular septum thickness and enlarged chamber volume, and long-chain with a decrease in cIMT. CONCLUSIONS: Our findings suggest that maternal plasma PFAS concentrations during early pregnancy was adversely associated with cardiovascular development in offspring, including thinner cardiac wall thickness and cIMT.

Different Associations of Systolic Blood Pressure and Body Mass Index With Cardiac Structure and Function in Young Children.

BACKGROUND: Both elevated systolic blood pressure (SBP) and excess weight can lead to early cardiovascular organ damage in children. In this study, we investigated whether there is a difference in the associations of SBP and body mass index (BMI) with cardiovascular structure and function in 4-year-old children. METHODS: In 1474 children (52.3% males) from the Shanghai Birth Cohort, physical examination and echocardiography were performed. Standardized linear regression models were used to evaluate the associations of BMI Z score and SBP Z score with cardiovascular parameters and to compare the strengths of these associations. RESULTS: The incidence of SBP elevation significantly increased in overweight children. SBP was positively related to heart rate, left ventricular (LV) ejection fraction and fraction shortening (ß=1.824 [95% CI, 1.014-2.634], 0.579 [0.294-0.864], and 0.480 [0.257-0.704], respectively). BMI Z score was positively associated with LV mass index (ß=1.225 [0.863-1.587]) and the risk of LV hypertrophy (odds ratio=1.428 [1.157-1.761]) but negatively related to measures of systolic function, including LV ejection fraction, LV fraction short, and global longitudinal strain (ß=-0.417 [-0.735 to -0.099], -0.302 [-0.551 to -0.053], and -0.392 [-0.621 to -0.163], respectively). No noteworthy additive or multiplicative interactions between BMI and SBP were detected. CONCLUSIONS: Elevations in both BMI and SBP were related to cardiac structure and function in children as young as 4 years old. Elevated SBP was associated with increased heart rate and LV ejection at the early stage of BP elevation. BMI showed a closer relationship with left heart diameters and geometry than SBP.

Characteristics of Mussels-Derived Carbon Dots and Their Applications in Bio-Imaging and Detection of Riboflavin.

A simple and green strategy has been demonstrated for the synthesis of carbon dots (CDs) from mussels. The chemical structure and optical properties of mussels-derived CDs prepared at different reaction temperatures (140, 160, and 180 °C) were evaluated. The average size of synthesized fluorescent CDs decreased from 2.06 to 1.30 nm as reaction temperatures increased from 140 to 180 °C. The fluorescence quantum yield of CDs could reach up to 15.20%. The surface of CDs was rich in functional groups such as -OH, -NH2, and -COOH, providing CDs with good water solubility and biocompatibility. Furthermore, the mussel-derived CDs have been successfully applied in bio-imaging for onion endothelium cells, HepG2 cells, and zebrafish. In addition, CDs could be employed as a biosensor for riboflavin detection. Therefore, mussels are a promising carbon resource for preparing N-doped CDs for bio-imaging and monitoring riboflavin.

Associations of maternal gestational diabetes mellitus with alterations in cardiovascular system in early childhood.

AIMS: The association of maternal gestational diabetes mellitus (GDM) with childhood cardiovascular alterations is not well established. This study aims to test the hypothesis that prenatal exposure to GDM is associated with vascular and cardiac alterations in early childhood. METHODS: In a population-based prospective cohort among 1094 mothers and their offspring, GDM was diagnosed according to the International Association of Diabetes and Pregnancy Study Groups criteria. Childhood blood pressure (BP) measurement, echocardiography and vascular ultrasound were performed using standardised methods at 4 years old. The associations between maternal GDM and childhood cardiovascular outcomes were modelled using linear regression and binary logistic regression. Mediation analysis was conducted to test the potential mediators. RESULTS: Maternal GDM was associated with higher systolic BP (SBP; ß, 1.20; [0.11, 2.28]), lower left ventricular end-diastolic diameter (LVEDD; ß, -0.36; [-0.71, -0.01]), lower end-diastolic volume (EDV; ß, -1.42; [-2.71, -0.13]) and increased risk of high blood pressure (HBP, OR = 1.522; 95% CI, 1.023 to 2.264) in offspring at the age of 4 years. After stratification by sex, the association remained strong only in male offspring (SBP: ß, 1.94; [0.37, 3.51]; LVEDD: ß, -0.60; [-1.09, -0.12]; EDV: ß, -2.09; [-3.86, -0.31]; HBP: OR = 1.797; 95% CI, 1.063 to 3.037) and was independent of maternal and child characteristics. However, carotid intima-media thickness (cIMT) was not associated with maternal GDM. Mediation analysis showed that the effects on childhood cardiovascular alterations were attributable mostly to the direct effects of maternal GDM. CONCLUSIONS: Our results provide evidence that maternal GDM is associated with offspring cardiovascular adaptations at preschool age. Further studies are needed to replicate our results and the long-term effect of these adaptations on later cardiovascular risks needs further investigation.

Predisposition to atrioventricular septal defects may be caused by SOX7 variants that impair interaction with GATA4.

Atrioventricular septal defects (AVSD) are a complicated subtype of congenital heart defects for which the genetic basis is poorly understood. Many studies have demonstrated that the transcription factor SOX7 plays a pivotal role in cardiovascular development. However, whether SOX7 single nucleotide variants are involved in AVSD pathogenesis is unclear. To explore the potential pathogenic role of SOX7 variants, we recruited a total of 100 sporadic non-syndromic AVSD Chinese Han patients and screened SOX7 variants in the patient cohort by targeted sequencing. Functional assays were performed to evaluate pathogenicity of nonsynonymous variants of SOX7. We identified three rare SOX7 variants, c.40C > G, c.542G > A, and c.743C > T, in the patient cohort, all of which were found to be highly conserved in mammals. Compared to the wild type, these SOX7 variants had increased mRNA expression and decreased protein expression. In developing hearts, SOX7 and GATA4 were highly expressed in the region of atrioventricular cushions. Moreover, SOX7 overexpression promoted the expression of GATA4 in human umbilical vein endothelial cells. A chromatin immunoprecipitation assay revealed that SOX7 could directly bind to the GATA4 promoter and luciferase assays demonstrated that SOX7 activated the GATA4 promoter. The SOX7 variants had impaired transcriptional activity relative to wild-type SOX7. Furthermore, the SOX7 variants altered the ability of GATA4 to regulate its target genes. In conclusion, our findings showed that deleterious SOX7 variants potentially contribute to human AVSD by impairing its interaction with GATA4. This study provides novel insights into the etiology of AVSD and contributes new strategies to the prenatal diagnosis of AVSD.

Sex-Disparity in the Association Between Birthweight and Cardiovascular Parameters in 4-Year-Old Children: A Chinese Cohort Study.

Background: Sex-related differences in cardiovascular parameters have been well documented in adults, and the impact of birthweight on cardiovascular health in later life has been acknowledged. However, data was limited regarding the association between birthweight and cardiovascular outcomes at an early age, and the sex-disparity in the association remained unclear. Objective: To investigate the association between birthweight and cardiovascular parameters in 4-year-old children. Furthermore, to explore whether sex-disparity exist in this association or in cardiovascular risk. Methods: Follow-up data from the Shanghai Birth Cohort (SBC) was analyzed. Detailed perinatal information including both maternal and offspring datum were recorded. Blood pressure, echocardiography, and anthropometry assessment were conducted during the follow-up of 4-year-old children. Linear regression models were used to analyze the association between birthweight and left ventricle (LV) structure and function changes in each sex and birthweight category. Multivariable logistic regression models were used to compare risk of left ventricular hypertrophy (LVH) in different birthweight subgroups. Results: Overall, macrosomia was significantly associated with thickened LV posterior wall thickness in systole [LVPWs, (ß = 0.26, 95% CI: 0.06, 0.45)] and diastole [LVPWd, (ß = 0.18, 95% CI: 0.06, 0.30)], and thickened interventricular septal thickness in diastole [IVSd, (ß = 0.16, 95% CI: 0.05, 0.28)]. Boys with macrosomia showed a higher left ventricle mass index [LVMI, (ß = 1.29, 95% CI: 0.14, 2.43)], thickened LVPWs (ß = 0.30, 95% CI: 0.05, 0.56) and LVPWd (ß = 0.21, 95% CI: 0.06, 0.36), and thickened IVSd (ß = 0.23, 95% CI: 0.09, 0.36). However, no significant association of structural changes was found in girls. Furthermore, an increased risk of LVH was found solely in macrosomic boys (OR = 2.79, 95% CI: 1.17, 6.63). Conclusion: Children with macrosomia developed cardiovascular changes as early as 4 years of age. Macrosomia was associated with LV structural changes and higher LVH risk in pre-school-aged boys, while no association was found in girls.

Growth patterns in early childhood and cardiovascular structure and function at 4 years old: A prospective cohort study.

BACKGROUND AND AIMS: Childhood overweight and obesity are lifetime risk factors for cardiovascular disease but the relationship between dynamic body mass index (BMI) change and cardiovascular structure and function in early childhood remains unclear. METHODS AND RESULTS: This cohort study consisted 525 participants with 6 distinct representative growth patterns to examine the associations between BMI growth patterns and subsequent cardiovascular structure and function at age 4. BMIs were obtained at birth, 2 and 4 years old. Cardiovascular assessments were performed, including blood pressure (BP), cardiac geometric parameters, left ventricular (LV) function, speckle-tracking, integrated backscatter analysis and carotid intima-media thickness. Compared to the stable normal BMI pattern, children with the stable overweight (OW) pattern had significantly greater LV anatomic parameters in fully adjusted models. Children with the catch-up (CU) pattern revealed a uniform trend and had poorer strain. LV diameters and integrated backscatter signals were larger for those with BMI gain and lose pattern. Children with BMI lose pattern showed improved tendency involving LV mass index and BP. Both OW and CU patterns were associated with high systolic BP [odds ratio (95% CI): OW: 3.67 (1.08, 12.47); CU: 4.24 (1.75, 10.28)]. Compared to static BMI measurements at birth, 2 and 4 years old, dynamic BMI growth patterns were more predictive of cardiovascular structure and function at 4. CONCLUSIONS: Children with overweight-related BMI growth patterns in early childhood experienced undesirable cardiovascular functional or structural changes as early as 4 years old, indicating that early intervention is needed and potentially beneficial.

Association of Maternal Gestational Weight Gain With Left Ventricle Geometry and Function in Offspring at 4 Years of Age: A Prospective Birth Cohort Study.

Background: Maternal gestational weight gain (GWG) may be associated with cardiovascular diseases in the offspring from childhood to adulthood. We aimed to investigate the association between maternal GWG and the left ventricle (LV) geometry and function in the offspring, and explore the influence of the intrauterine environment on early childhood cardiac change. Methods: Data of 981 mother-offspring pairs from the Shanghai Birth Cohort was used. Maternal pre-pregnancy weight and height, weight in the first trimester (≤ 12 weeks), and before delivery were measured. The echocardiography, blood pressure, and anthropometry assessment were evaluated in the offspring at 4 years of age. Results: Interventricular septal thickness during diastole had a significantly positive correlation with total GWG [ß = 0.009, (0.001, 0.017)]. In the second and third trimesters, LV mass index [ß = 0.149, (0.015,0.282)], interventricular septal thickness in systole [ß = 0.027, (0.011,0.043)], and in diastole [ß = 0.014, (0.005,0.023)] were positively associated with GWG. The risks of eccentric [OR = 1.115, (1.232, 1.010)] and concentric hypertrophy [OR = 1.133, (1.259,1.018)] increased with the elevation of maternal GWG. Conclusions: This study suggested that the excessive maternal GWG was associated with the thickening of the interventricular septum in the offspring, especially during the second and third trimesters. Excessive GWG in the second and third trimesters was a risk factor for LV eccentric and concentric hypertrophy in the offspring.

Anti-CLL1 Chimeric Antigen Receptor T-Cell Therapy in Children with Relapsed/Refractory Acute Myeloid Leukemia.

PURPOSE: The survival rate of children with refractory/relapsed acute myeloid leukemia (R/R-AML) by salvage chemotherapy is minimal. Treatment with chimeric antigen receptor T cells (CAR T) has emerged as a novel therapy to improve malignancies treatment. C-type lectin-like molecule 1 (CLL1) is highly expressed on AML stem cells, blast cells, and monocytes, but not on normal hematopoietic stem cells, indicating the therapeutic potential of anti-CLL1 CAR T in AML treatment. This study aimed to test the safety and efficacy of CAR T-cell therapy in R/R-AML. PATIENTS AND METHODS: Four pediatric patients with R/R-AML were enrolled in the ongoing phase I/II anti-CLL1 CAR T-cell therapy trial. The CAR design was based on an apoptosis-inducing gene, FKBP-caspase 9, to establish a safer CAR (4SCAR) application. Anti-CLL1 CAR was transduced into peripheral blood mononuclear cells of the patients via lentivector 4SCAR, followed by infusion into the recipients after lymphodepletion chemotherapy. Cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, and other adverse events were documented. Treatment response was evaluated by morphology and flow cytometry-based minimal residual disease assays. RESULTS: Three patients with R/R-AML achieved complete remission and minimal residual disease negativity, while the other patient remained alive for 5 months. All these patients experienced low-grade and manageable adverse events. CONCLUSIONS: On the basis of our single-institution experience, autologous anti-CLL1 CAR T-cell therapy has the potential to be a safe and efficient alternative treatment for children with R/R-AML, and therefore requires further investigation.