Sexually dimorphic DNA methylation and gene expression patterns in human first trimester placenta.

BACKGROUND: Fetal sex and placental development impact pregnancy outcomes and fetal-maternal health, but the critical timepoint of placenta establishment in first trimester is understudied in human pregnancies. METHODS: Pregnant subjects were recruited in late first trimester (weeks 10-14) at time of chorionic villus sampling, a prenatal diagnostic test. Leftover placenta tissue was collected and stored until birth outcomes were known, then DNA and RNA were isolated from singleton, normal karyotype pregnancies resulting in live births. DNA methylation was measured with the Illumina Infinium MethylationEPIC BeadChip array (n = 56). Differential methylation analysis compared 25 females versus 31 males using a generalized linear model on 743,461 autosomal probes. Gene expression sex differences were analyzed with RNA-sequencing (n = 74). An integrated analysis was performed using linear regression to correlate gene expression and DNA methylation in 51 overlapping placentas. RESULTS: Methylation analysis identified 151 differentially methylated probes (DMPs) significant at false discovery rate < 0.05, including 89 (59%) hypermethylated in females. Probe cg17612569 (GABPA, ATP5J) was the most significant CpG site, hypermethylated in males. There were 11 differentially methylated regions affected by fetal sex, with transcription factors ZNF300 and ZNF311 most significantly hypermethylated in males and females, respectively. RNA-sequencing identified 152 genes significantly sexually dimorphic at false discovery rate < 0.05. The 151 DMPs were associated with 18 genes with gene downregulation (P < 0.05) in the direction of hypermethylation, including 2 genes significant at false discovery rate < 0.05 (ZNF300 and CUB and Sushi multiple domains 1, CSMD1). Both genes, as well as Family With Sequence Similarity 228 Member A (FAM228A), showed significant correlation between DNA methylation and sexually dimorphic gene expression, though FAM228A DNA methylation was less sexually dimorphic. Comparison with other sex differences studies found that cg17612569 is male-hypermethylated across gestation in placenta and in human blood up to adulthood. CONCLUSIONS: Overall, sex dimorphic differential methylation with associated differential gene expression in the first trimester placenta is small, but there remain significant genes that may be regulated through methylation leading to differences in the first trimester placenta.

Fetal sex and placenta development affect pregnancy outcomes for both the fetus and mother throughout pregnancy, including risk of miscarriages, preterm birth, preeclampsia, and other outcomes. Epigenetics, the "overlay" of regulatory signals on DNA which affects how DNA is read, is not well understood in early pregnancy when critical placenta developments are happening that affect the rest of pregnancy. Here, we use leftover placenta biopsy samples (n = 56) donated by Cedars-Sinai patients with informed consent to learn about first trimester human placenta DNA methylation differences due to fetal sex. Out of the total 743,461 sites analyzed, we identified 151 sites significantly affected by fetal sex after correcting p-values to reduce false positives (false discovery rate < 0.05). We also performed an analysis to look at multiple sites and identified 11 regions across the genome with significant DNA methylation changes due to fetal sex. Furthermore, because DNA methylation is a regulatory mark on DNA which typically dampens gene expression, we also compared the DNA methylation sex differences to placental RNA-sequencing gene expression analysis using the same tissue from a mostly overlapping patient group (n = 74 total sequenced, n = 51 overlap). We identify 18 genes which show both significant DNA methylation differences and gene expression changes. The most significant gene was transcription factor ZNF300 with higher DNA methylation in males and reduced gene expression in males (and thus higher gene expression in females). This study identifies some sex differences that continue until later pregnancy and others that are unique to first trimester.

Time Course of Mechanical Ventilation Driving Pressure Levels in Pediatric Acute Respiratory Distress Syndrome: Outcomes in a Prospective, Multicenter Cohort Study From Colombia, 2018-2022.

OBJECTIVES: High driving pressure (DP, ratio of tidal volume (V t ) over respiratory system compliance) is a risk for poor outcomes in patients with pediatric acute respiratory distress syndrome (PARDS). We therefore assessed the time course in level of DP (i.e., 24, 48, and 72 hr) after starting mechanical ventilation (MV), and its association with 28-day mortality. DESIGN: Multicenter, prospective study conducted between February 2018 and December 2022. SETTING: Twelve tertiary care PICUs in Colombia. PATIENTS: One hundred eighty-four intubated children with moderate to severe PARDS. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The median (interquartile range [IQR]) age of the PARDS cohort was 11 (IQR 3-24) months. A total of 129 of 184 patients (70.2%) had a pulmonary etiology leading to PARDS, and 31 of 184 patients (16.8%) died. In the first 24 hours after admission, the plateau pressure in the nonsurvivor group, compared with the survivor group, differed (28.24 [IQR 24.14-32.11] vs. 23.18 [IQR 20.72-27.13] cm H 2 O, p < 0.01). Of note, children with a V t less than 8 mL/kg of ideal body weight had lower adjusted odds ratio (aOR [95% CI]) of 28-day mortality (aOR 0.69, [95% CI, 0.55-0.87]; p = 0.02). However, we failed to identify an association between DP level and the oxygenation index (aOR 0.58; 95% CI, 0.21-1.58) at each of time point. In a diagnostic exploratory analysis, we found that DP greater than 15 cm H 2 O at 72 hours was an explanatory variable for mortality, with area under the receiver operating characteristic curve of 0.83 (95% CI, 0.74-0.89); there was also increased hazard for death with hazard ratio 2.5 (95% CI, 1.07-5.92). DP greater than 15 cm H 2 O at 72 hours was also associated with longer duration of MV (10 [IQR 7-14] vs. 7 [IQR 5-10] d; p = 0.02). CONCLUSIONS: In children with moderate to severe PARDS, a DP greater than 15 cm H 2 O at 72 hours after the initiation of MV is associated with greater odds of 28-day mortality and a longer duration of MV. DP should be considered a variable worth monitoring during protective ventilation for PARDS.

Breast cancer knowledge, attitude and screening behaviors among Hispanics in South Texas colonias.

This study examines breast cancer knowledge, attitudes and screening behaviors of Hispanic women living in the South Texas colonias of Maverick and Val Verde Counties. We used the Health Belief Model to analyze the effects of HBM constructs on clinical breast exam (CBE) and mammogram screening. Using a multistage systematic sampling approach we interviewed women living within these colonias. Logistic regression analysis was used to predict CBE and mammography screening behaviors. The results indicate that knowledge, susceptibility, barriers and source of health information were statistically significant in predicting CBE among these women. In addition, background variables such as marital status and health insurance were also significant in predicting CBE. Findings further indicate that source of health information, barriers, and health insurance significantly predicts mammography screening behaviors. Results suggest that for women living in colonias along the South Texas Border socio-demographic variables play a significant role in CBE and mammography utilization.