High rates of placental inflammation among samples collected by the Multi-Omics for Mothers and Infants consortium.

BACKGROUND: The Multi-Omics for Mothers and Infants consortium aims to improve birth outcomes. Preterm birth is a major obstetrical complication globally and causes significant infant and childhood morbidity and mortality. OBJECTIVE: We analyzed placental samples (basal plate, placenta or chorionic villi, and the chorionic plate) collected by the 5 Multi-Omics for Mothers and Infants sites, namely The Alliance for Maternal and Newborn Health Improvement Bangladesh, The Alliance for Maternal and Newborn Health Improvement Pakistan, The Alliance for Maternal and Newborn Health Improvement Tanzania, The Global Alliance to Prevent Prematurity and Stillbirth Bangladesh, and The Global Alliance to Prevent Prematurity and Stillbirth Zambia. The goal was to analyze the morphology and gene expression of samples collected from preterm and uncomplicated term births. STUDY DESIGN: The teams provided biopsies from 166 singleton preterm (<37 weeks' gestation) and 175 term (≥37 weeks' gestation) deliveries. The samples were fixed in formalin and paraffin embedded. Tissue sections from these samples were stained with hematoxylin and eosin and subjected to morphologic analyses. Other placental biopsies (n=35 preterm, 21 term) were flash frozen, which enabled RNA purification for bulk transcriptomics. RESULTS: The morphologic analyses revealed a surprisingly high rate of inflammation that involved the basal plate, placenta or chorionic villi, and the chorionic plate. The rate of inflammation in chorionic villus samples, likely attributable to chronic villitis, ranged from 25% (Pakistan site) to 60% (Zambia site) of cases. Leukocyte infiltration in this location vs in the basal plate or chorionic plate correlated with preterm birth. Our transcriptomic analyses identified 267 genes that were differentially expressed between placentas from preterm vs those from term births (123 upregulated, 144 downregulated). Mapping the differentially expressed genes onto single-cell RNA sequencing data from human placentas suggested that all the component cell types, either singly or in subsets, contributed to the observed dysregulation. Consistent with the histopathologic findings, gene ontology analyses highlighted the presence of leukocyte infiltration or activation and inflammatory responses in both the fetal and maternal compartments. CONCLUSION: The relationship between placental inflammation and preterm birth is appreciated in developed countries. In this study, we showed that this link also exists in developing geographies. In addition, among the participating sites, we found geographic- and population-based differences in placental inflammation and preterm birth, suggesting the importance of local factors.

Declination of Treatment, Racial and Ethnic Disparity, and Overall Survival in US Patients With Breast Cancer.

Importance: Declining treatment negatively affects health outcomes among patients with cancer. Limited research has investigated national trends of and factors associated with treatment declination or its association with overall survival (OS) among patients with breast cancer. Objectives: To examine trends and racial and ethnic disparities in treatment declination and racial and ethnic OS differences stratified by treatment decision in US patients with breast cancer. Design, Setting, and Participants: This retrospective cross-sectional study used data for patients with breast cancer from the 2004 to 2020 National Cancer Database. Four treatment modalities were assessed: chemotherapy, hormone therapy (HT), radiotherapy, and surgery. The chemotherapy cohort included patients with stage I to IV disease. The HT cohort included patients with stage I to IV hormone receptor-positive disease. The radiotherapy and surgery cohorts included patients with stage I to III disease. Data were analyzed from March to November 2023. Exposure: Race and ethnicity and other sociodemographic and clinicopathologic characteristics. Main Outcomes and Measures: Treatment decision, categorized as received or declined, was modeled using logistic regression. OS was modeled using Cox regression. Models were controlled for year of initial diagnosis, age, sex, health insurance, median household income, facility type, Charlson-Deyo comorbidity score, histology, American Joint Committee on Cancer stage, molecular subtype, and tumor grade. Results: The study included 2 837 446 patients (mean [SD] age, 61.6 [13.4] years; 99.1% female), with 1.7% American Indian, Alaska Native, or other patients; 3.5% Asian or Pacific Islander patients; 11.2% Black patients; 5.6% Hispanic patients; and 78.0% White patients. Of 1 296 488 patients who were offered chemotherapy, 124 721 (9.6%) declined; 99 276 of 1 635 916 patients (6.1%) declined radiotherapy; 94 363 of 1 893 339 patients (5.0%) declined HT; and 15 846 of 2 590 963 patients (0.6%) declined surgery. Compared with White patients, American Indian, Alaska Native, or other patients (adjusted odds ratio [AOR], 1.47; 95% CI, 1.26-1.72), Asian or Pacific Islander patients (AOR, 1.29; 95% CI, 1.15-1.44), and Black patients (AOR, 2.01; 95% CI, 1.89-2.14) were more likely to decline surgery; American Indian, Alaska Native, or other patients (AOR, 1.13; 95% CI, 1.05-1.21) and Asian or Pacific Islander patients (AOR, 1.21; 95% CI, 1.16-1.27) were more likely to decline chemotherapy; and Black patients were more likely to decline radiotherapy (AOR, 1.05; 95% CI, 1.02-1.08). Asian or Pacific Islander patients (AOR, 0.81; 95% CI, 0.77-0.85), Black patients (AOR, 0.86; 95% CI, 0.83-0.89), and Hispanic patients (AOR, 0.66; 95% CI, 0.63-0.69) were less likely to decline HT. Furthermore, Black patients who declined chemotherapy had a higher mortality risk than White patients (adjusted hazard ratio [AHR], 1.07; 95% CI, 1.02-1.13), while there were no OS differences between Black and White patients who declined HT (AHR, 1.05; 95% CI, 0.97-1.13) or radiotherapy (AHR, 0.98; 95% CI, 0.92-1.04). Conclusions and Relevance: This cross-sectional study highlights racial and ethnic disparities in treatment declination and OS, suggesting the need for equity-focused interventions, such as patient education on treatment benefits and improved patient-clinician communication and shared decision-making, to reduce disparities and improve patient survival.

Fluoride-related changes in the fetal cord blood proteome; a pilot study.

Background: Fluoride exposure during pregnancy has been associated with various effects on offspring, including changes in behavior and IQ. To provide clues to possible mechanisms by which fluoride affects human fetal development, we completed proteomic analyses of cord blood serum collected from second-trimester pregnant women residing in Northern California with either high or low fluoride exposure, as identified by maternal serum fluoride concentrations. Objective: To identify changes in cord blood proteins associated with maternal serum fluoride concentration in pregnant women living in Northern California. Methods: The proteomes of 19 archived second-trimester cord blood samples representing highest and lowest serum fluoride concentrations from a cohort of 48 women living in Northern California, previously analyzed for serum, urine and amniotic fluoride concentrations, were characterized by mass spectrometry. Proteins highly correlated to maternal serum fluoride concentrations were identified, and further compared in a group of samples from women with the highest serum fluoride to the group with the lowest maternal serum fluoride concentrations. Results: Nine cord blood proteins were significantly correlated with maternal serum fluoride concentrations. Six of these proteins, including apolipoprotein B-100, delta homolog 1, coagulation factor X, mimecan, plasma kallikrein, and vasorin, were significantly decreased in the cord blood from women with the highest serum fluoride levels. Conclusion: Changes in the relative amounts of second trimester cord blood proteins included proteins associated with the development of the fetal hematopoetic system.

Post-Civil War modernity and the nurse training movement: The "Experiment" of the Boston Training School for Nurses.

BACKGROUND/PURPOSE: This paper describes the origins of the Boston Training School for Nurses (1873), later named the Massachusetts General Hospital School of Nursing, and the role played by a Boston civic group, the Woman's Education Association, in its founding. METHODS: Social and political forces in the post-Civil War modern era and the challenges the founders encountered in establishing and managing a nursing school are delineated. DISCUSSION: Themes that highlight the significance of the Boston Training School's creation relative to the nurse training movement in America are identified. CONCLUSION: The long-term implications of the initial agreement for a 1-year experiment to train nurses in a formal educational setting are discussed.

Effect of neighborhood and individual-level socioeconomic factors on breast cancer screening adherence in a multi-ethnic study.

BACKGROUND: Although mammography can significantly reduce breast cancer mortality, many women do not receive their annual breast cancer screening. Differences in screening adherence exist by race/ethnicity, socioeconomic status (SES), and insurance status. However, more detailed investigations into the impact of neighborhood disadvantage and access to resources on screening adherence are lacking. METHODS: We comprehensively examined the effect of individual social, economic, and demographic factors (n = 34 variables), as well as neighborhood level SES (nSES) indicators (n = 10 variables) on breast cancer screening adherence across a multi-ethnic population (n = 472). In this cross-sectional study, participants were surveyed from 2017 to 2018. The data was analyzed using univariate regression and LASSO for variable reduction. Significant predictors were carried forward into final multivariable mixed-effect logistic regression models where odds ratios (OR), 95% confidence intervals and p-values were reported. RESULTS: Nineteen percent of participants were non-adherent to breast screening guidelines. Race/ethnicity was not associated with adherence; however, increasing age (OR = 0.97, 95%CI = 0.95-0.99, p = 0.01), renting a home (OR = 0.53, 95%CI = 0.30-0.94, p = 0.04), food insecurity (OR 0.46, 95%CI = 0.22-0.94, p = 0.01), and overcrowding (OR = 0.58, 95% CI = 0.32-0.94, p = 0.01) were significantly associated with lower breast cancer screening adherence. CONCLUSION: Socioeconomic indicators at the individual and neighborhood levels impact low breast cancer screening adherence and may help to inform future screening interventions.

Distinct transcriptional profiles of maternal and fetal placental macrophages at term are associated with gravidity.

Maternal intervillous monocytes (MIMs) and fetal Hofbauer cells (HBCs) are myeloid-derived immune cells at the maternal-fetal interface. Little is known regarding the molecular phenotypes and roles of these distinct monocyte/macrophage populations. Here, we used RNA sequencing to investigate the transcriptional profiles of MIMs and HBCs in six normal term pregnancies. Our analyses revealed distinct transcriptomes of MIMs and HBCs. Genes involved in differentiation and cell organization pathways were more highly expressed in MIMs vs. HBCs. In contrast, HBCs had higher expression of genes involved in inflammatory responses and cell surface receptor signaling. Maternal gravidity influenced monocyte programming, as expression of pro-inflammatory molecules was significantly higher in MIMs from multigravidas compared to primigravidas. In HBCs, multigravidas displayed enrichment of gene pathways involved in cell-cell signaling and differentiation. In summary, our results demonstrated that MIMs and HBCs have highly divergent transcriptional signatures, reflecting their distinct origins, locations, functions, and roles in inflammatory responses. Our data further suggested that maternal gravidity influences the gene signatures of MIMs and HBCs, potentially modulating the interplay between tolerance and trained immunity. The phenomenon of reproductive immune memory may play a novel role in the differential susceptibility of primigravidas to pregnancy complications.

Perfluorooctanoic acid induces transcriptomic alterations in second trimester human cytotrophoblasts.

Poly- and perfluroroalkylated substances (PFAS) are a major class of surfactants used in industry applications and consumer products. Despite efforts to reduce the usage of PFAS due to their environmental persistence, compounds such as perfluorooctanoic acid (PFOA) are widely detected in human blood and tissue. Although growing evidence supports that prenatal exposures to PFOA and other PFAS are linked to adverse pregnancy outcomes, the target organs and pathways remain unclear. Recent investigations in mouse and human cell lines suggest that PFAS may impact the placenta and impair trophoblast function. In this study, we investigated the effects of PFOA on cytotoxicity and the transcriptome in cultured second trimester human cytotrophoblasts (CTBs). We show that PFOA significantly reduces viability and induces cell death at 24 h, in a concentration-dependent manner. At subcytotoxic concentrations, PFOA impacted expression of hundreds of genes, including several molecules (CRH, IFIT1, and TNFSF10) linked with lipid metabolism and innate immune response pathways. Furthermore, in silico analyses suggested that regulatory factors such as peroxisome proliferator-activated receptor-mediated pathways may be especially important in response to PFOA. In summary, this study provides evidence that PFOA alters primary human CTB viability and gene pathways that could contribute to placental dysfunction and disease.

Proteomic analyses of primary human villous trophoblasts exposed to flame retardant BDE-47 using SWATH-MS.

Polybrominated diphenyl ethers (PBDEs) are a class of brominated flame retardants and recognized developmental toxicants that are detectable in placental tissues. Higher levels of in utero PBDE exposure have been associated with an increased risk of adverse birth outcomes. During pregnancy, cytotrophoblasts (CTBs) from the placenta play critical roles in the formation of the maternal-fetal interface via uterine invasion and vascular remodeling. The differentiation of these cells towards an invasive phenotype is crucial for proper placental development. We previously have shown that BDE-47 can impact CTB viability and hinder the ability of these cells to migrate and invade. To expand on potential toxicological mechanisms, we utilized quantitative proteomic approaches to identify changes in the global proteome of mid-gestation primary human CTBs after exposure to BDE-47. Using sequential window acquisition of all theoretical fragment-ion spectra (SWATH), we identified 3024 proteins in our CTB model of differentiation/invasion. Over 200 proteins were impacted as a function of BDE-47 exposure (1 µM and 5 µM) across the treatment period (15, 24, and 39 h). The differentially expressed molecules displayed time- and concentration-dependent changes in expression and were enriched in pathways associated with aggregatory and adhesive processes. Network analysis identified CYFIP1, a molecule previously unexplored in a placental context, to be dysregulated at BDE-47 concentrations previously seen to impact CTB migration/invasion. Our SWATH-MS dataset thus demonstrates BDE-47 impacts the global proteome of differentiating CTBs and serves as a valuable resource for further understanding of the relationship between environmental chemical exposures and placental development and function. AVAILABILITY OF DATA AND MATERIAL: Raw chromatograms are deposited on the MassIVE proteomic database (https://massive.ucsd.edu) under accession number MSV000087870. Normalized relative abundances are also available as Table S1.

Lipidomics Reveals Elevated Plasmalogens in Women with Obesity Who Develop Preeclampsia.

Objective: Preeclampsia (PE) is a prevalent pregnancy disorder worldwide with limited preventative treatments available. Obesity triples the risk for PE, yet only 10% of women with obesity develop PE. The factors that distinguish PE from uncomplicated pregnancies in the context of obesity have not been fully established. Methods: We studied a cohort of women with obesity throughout pregnancy to identify lipid mediators and/or biomarkers of PE. Blood samples were collected at each trimester and analyzed by both targeted lipidomics and standard lipid panels. Individual lipid species were compared by PE status at each trimester, as well as by self-identified race (Black vs. White) and fetal sex. Results: Standard lipid panels and clinical measurements revealed few differences between PE and uncomplicated pregnancies. Targeted lipidomics, however, identified plasmalogen, phosphatidylethanolamine, and free fatty acid species that were elevated in the third trimester of women with PE. Furthermore, race and trimester of pregnancy were considerable sources of plasma lipidomic variation in women with obesity. Conclusions: First and second trimester individual plasma lipid species do not predict the development of PE in obese women. In the third trimester, PE patients have elevated levels of plasmalogens-a class of lipoprotein-associated phospholipids that have been implicated in the response to oxidative stress.

Regionally distinct trophoblast regulate barrier function and invasion in the human placenta.

The human placenta contains two specialized regions: the villous chorion where gases and nutrients are exchanged between maternal and fetal blood, and the smooth chorion (SC) which surrounds more than 70% of the developing fetus but whose cellular composition and function is poorly understood. Here, we use single cell RNA-sequencing to compare the cell types and molecular programs between these two regions in the second trimester human placenta. Each region consists of progenitor cytotrophoblasts (CTBs) and extravillous trophoblasts (EVTs) with similar gene expression programs. While CTBs in the villous chorion differentiate into syncytiotrophoblasts, they take an alternative trajectory in the SC producing a previously unknown CTB population which we term SC-specific CTBs (SC-CTBs). Marked by expression of region-specific cytokeratins, the SC-CTBs form a stratified epithelium above a basal layer of progenitor CTBs. They express epidermal and metabolic transcriptional programs consistent with a primary role in defense against physical stress and pathogens. Additionally, we show that SC-CTBs closely associate with EVTs and secrete factors that inhibit the migration of the EVTs. This restriction of EVT migration is in striking contrast to the villous region where EVTs migrate away from the chorion and invade deeply into the decidua. Together, these findings greatly expand our understanding of CTB differentiation in these distinct regions of the human placenta. This knowledge has broad implications for studies of the development, functions, and diseases of the human placenta.

Bisphenol A replacement chemicals, BPF and BPS, induce protumorigenic changes in human mammary gland organoid morphology and proteome.

SignificanceBisphenol A (BPA), found in many plastic products, has weak estrogenic effects that can be harmful to human health. Thus, structurally related replacements-bisphenol S (BPS) and bisphenol F (BPF)-are coming into wider use with very few data about their biological activities. Here, we compared the effects of BPA, BPS, and BPF on human mammary organoids established from normal breast tissue. BPS disrupted organoid architecture and induced supernumerary branching. At a proteomic level, the bisphenols altered the abundance of common targets and those that were unique to each compound. The latter included proteins linked to tumor-promoting processes. These data highlighted the importance of testing the human health effects of replacements that are structurally related to chemicals of concern.

Vedolizumab Antagonizes MAdCAM-1-Dependent Human Placental Cytotrophoblast Adhesion and Invasion In Vitro.

BACKGROUND: Anti-α4ß7 (Vedolizumab) treats inflammatory bowel disease (IBD) by blocking the interaction between integrin α4ß7 on leukocytes and mucosal addressin cell-adhesion molecule-1 (MAdCAM-1) on the gut endothelium. Women with IBD often require continuing biologic therapy during pregnancy to avoid disease flare. To date, there have been no reports of an increase in adverse events with Vedolizumab use during pregnancy. Notably, integrins play a major role in human placental development during pregnancy. It is unknown whether Vedolizumab disrupts placental cell (cytotrophoblast) invasion and/or adhesion by blocking interactions with MAdCAM-1. We therefore investigated human placental expression of MAdCAM-1, the role of MAdCAM-1/α4ß7 interactions in cytotrophoblast invasion/adhesion in vitro, and whether Vedolizumab administration in vivo alters the placental structure. METHODS: Histological sections of placentas from normal pregnancies were evaluated for MAdCAM-1 expression by immunofluorescence. The impacts of Vedolizumab or anti-integrin ß7 on human cytotrophoblast invasion and adhesion were assessed. Histology results from term placentas of 2 patients with IBD receiving Vedolizumab were compared to those of untreated healthy controls. RESULTS: Placental MAdCAM-1 expression was predominantly associated with invading extravillous cytotrophoblasts at the maternal-fetal interface. Treatment of isolated primary cytotrophoblasts with Vedolizumab or anti-integrin ß7 significantly reduced Matrigel invasion, adherence to a MAdCAM-1-coated substrate, and interactions with HuT-78 cells. Placentas from 2 Vedolizumab-treated patients with IBD exhibited pronounced pathologic features as compared to healthy control specimens. CONCLUSIONS: This study revealed a previously unrecognized role for α4ß7 and MAdCAM-1 in human placentation. More clinical and histological data from Vedolizumab-treated pregnant patients will be necessary to determine whether this medication poses any risk to the mother and fetus.

SARS-CoV-2 BNT162b2 vaccine-induced humoral response and reactogenicity in individuals with prior COVID-19 disease.

BACKGROUNDMost individuals with prior COVID-19 disease manifest long-term protective immune responses against reinfection. Accordingly, we tested the hypothesis that humoral immune and reactogenicity responses to a SARS-CoV-2 mRNA vaccine differ in individuals with and without prior COVID-19 disease.METHODSHealth care workers (n = 61) with (n = 30) and without (n = 31) prior COVID-19 disease received two 30 µg doses of Pfizer BNT162b2 vaccine 3 weeks apart. Serum IgG antibody against the spike receptor-binding domain; serum neutralizing activity; and vaccine reactogenicity were assessed longitudinally every 2 weeks for 56 days after the first injection.RESULTSThe COVID-19 group manifested more rapid increases in spike IgG antibody and serum neutralizing activity after the first vaccine dose but showed little or no increase after the second dose compared with the infection-naive group. In fact, spike IgG was at its maximum level after the first dose in 36% of the COVID-19 group versus 0% of the infection-naive group. Peak IgG antibody levels were lower but appeared to fall more slowly in the COVID-19 group versus the infection-naive group. Finally, adverse systemic reactions, e.g., fever, headache, and malaise, were more frequent and lasted longer after both the first and second injection in the COVID-19 group than in the infection-naive group.CONCLUSIONIndividuals with prior COVID-19 disease demonstrate a robust, accelerated humoral immune response to the first dose but an attenuated response to the second dose of BNT162b2 vaccine compared with controls. The COVID-19 group also experienced greater reactogenicity. Humoral responses and reactogenicity to BNT162b2 differ qualitatively and quantitatively in individuals with prior COVID-19 disease compared with infection-naive individuals.FUNDINGThis work was supported by Temple University institutional funds.

'Who is going to put their life on the line for a dollar? That's crazy': community perspectives of financial compensation in clinical research.

BACKGROUND: Financial compensation of research participants has been standard practice for centuries, however, there is an ongoing debate among researchers and ethicists regarding the ethical nature of this practice. While these debates develop ethical arguments and theories, they fail to incorporate input from those most affected by financial compensation: potential research participants. METHODS: To identify attitudes surrounding clinical research, participants of a long-standing cohort completed a one-time interview. Open-ended questions stimulated a participant-driven discussion surrounding medical research. Following a grounded theory methodology, 58 semistructured interview transcripts were coded, focusing on attitudes surrounding financial compensation of research participants. RESULTS: Of the interviews coded, the majority of participants identified as Black/African American (n=44) and were women (n=40). Five major themes emerged. In support of financial compensation, participants felt that study participants should be compensated for time, effort and risk. However, participants were concerned that compensation may differentially impact low-income populations and entice them to hide potentially harmful side effects. Participants also mentioned that financial compensation may invalidate study results if participants knowingly provide false information to subvert inclusion/exclusion criteria. CONCLUSION: The emergence of both positive and negative themes reiterates the complicated issue of providing financial compensation for study participation. While compensation as a motivator for research participation raises ethical concerns, participants discussed weighing the benefits with the risks in order to make an informed decision. To avoid paternalistic behaviours, research staff must allow potential research participants to review the available information and make the decision that best reflects their wishes.

RNA profiling of laser microdissected human trophoblast subtypes at mid-gestation reveals a role for cannabinoid signaling in invasion.

Human placental architecture is complex. Its surface epithelium, specialized for transport, forms by fusion of cytotrophoblast progenitors into multinucleated syncytiotrophoblasts. Near the uterine surface, these progenitors assume a different fate, becoming cancer-like cells that invade its lining and blood vessels. The latter process physically connects the placenta to the mother and shunts uterine blood to the syncytiotrophoblasts. Isolation of trophoblast subtypes is technically challenging. Upon removal, syncytiotrophoblasts disintegrate and invasive cytotrophoblasts are admixed with uterine cells. We used laser capture to circumvent these obstacles. This enabled isolation of syncytiotrophoblasts and two subpopulations of invasive cytotrophoblasts from cell columns and the endovascular compartment of spiral arteries. Transcriptional profiling revealed numerous genes, the placental or trophoblast expression of which was not known, including neurotensin and C4ORF36. Using mass spectrometry, discovery of differentially expressed mRNAs was extended to the protein level. We also found that invasive cytotrophoblasts expressed cannabinoid receptor 1. Unexpectedly, screening agonists and antagonists showed that signals from this receptor promote invasion. Together, these results revealed previously unseen gene expression patterns that translate to the protein level. Our data also suggested that endogenous and exogenous cannabinoids can affect human placental development.

Global proteomic analyses of human cytotrophoblast differentiation/invasion.

During human pregnancy, cytotrophoblasts (CTBs) from the placenta differentiate into specialized subpopulations that play crucial roles in proper fetal growth and development. A subset of these CTBs differentiate along an invasive pathway, penetrating the decidua and anchoring the placenta to the uterus. A crucial hurdle in pregnancy is the ability of these cells to migrate, invade and remodel spiral arteries, ensuring adequate blood flow to nourish the developing fetus. Although advances continue in describing the molecular features regulating the differentiation of these cells, assessment of their global proteomic changes at mid-gestation remain undefined. Here, using sequential window acquisition of all theoretical fragment-ion spectra (SWATH), which is a data-independent acquisition strategy, we characterized the protein repertoire of second trimester human CTBs during their differentiation towards an invasive phenotype. This mass spectrometry-based approach allowed identification of 3026 proteins across four culture time points corresponding to sequential stages of differentiation, confirming the expression dynamics of established molecules and offering new information into other pathways involved. The availability of a SWATH CTB global spectral library serves as a beneficial resource for hypothesis generation and as a foundation for further understanding CTB differentiation dynamics.

Effect of Neighborhood and Individual-Level Socioeconomic Factors on Colorectal Cancer Screening Adherence.

Despite the effectiveness of screenings in reducing colorectal cancer (CRC) mortality, ~25% of US adults do not adhere to screening guidelines. Prior studies associate socioeconomic status (SES) with low screening adherence and suggest that neighborhood deprivation can influence CRC outcomes. We comprehensively investigated the effect of neighborhood SES circumstances (nSES), individual SES, and race/ethnicity on adherence to CRC screening in a multiethnic cross-sectional study. Participant surveys assessing 32 individual-level socioeconomic and healthcare access measures were administered from 2017 to 2018. Participant data were joined with nine nSES measures from the US Census at the census tract level. Univariate, LASSO, and multivariable mixed-effect logistic regression models were used for variable reduction and evaluation of associations. The total study population included 526 participants aged 50-85; 29% of participants were non-adherent. In the final multivariable model, age (p = 0.02) and Non-Hispanic Black race (p = 0.02) were associated with higher odds of adherence. Factors associated with lower adherence were home rental (vs. ownership) (p = 0.003), perception of low healthcare quality (p = 0.006), no routine checkup within two years (p = 0.002), perceived discrimination (p = 0.02), and nSES deprivation (p = 0.02). After comprehensive variable methods were applied, socioeconomic indicators at the neighborhood and individual level were found to contribute to low CRC screening adherence.

Human placental cytotrophoblast epigenome dynamics over gestation and alterations in placental disease.

The human placenta and its specialized cytotrophoblasts rapidly develop, have a compressed lifespan, govern pregnancy outcomes, and program the offspring's health. Understanding the molecular underpinnings of these behaviors informs development and disease. Profiling the extraembryonic epigenome and transcriptome during the 2nd and 3rd trimesters revealed H3K9 trimethylation overlapping deeply DNA hypomethylated domains with reduced gene expression and compartment-specific patterns that illuminated their functions. Cytotrophoblast DNA methylation increased, and several key histone modifications decreased across the genome as pregnancy advanced. Cytotrophoblasts from severe preeclampsia had substantially increased H3K27 acetylation globally and at genes that are normally downregulated at term but upregulated in this syndrome. In addition, some cases had an immature pattern of H3K27ac peaks, and others showed evidence of accelerated aging, suggesting subtype-specific alterations in severe preeclampsia. Thus, the cytotrophoblast epigenome dramatically reprograms during pregnancy, placental disease is associated with failures in this process, and H3K27 hyperacetylation is a feature of severe preeclampsia.

Outcomes of Premature Ventricular Contraction-Cardiomyopathy in the Veteran Population: A Secondary Analysis of the CHF-STAT Study.

OBJECTIVES: This study sought to assess the rate and outcomes of premature ventricular contractions (PVC)-cardiomyopathy from the CHF-STAT (Survival Trial of Antiarrhythmic Therapy in Congestive Heart Failure) trial, a population with cardiomyopathy (left ventricular [LV] ejection fraction of <40%) and frequent PVCs (>10 PVCs per hour). BACKGROUND: PVCs are associated with heart failure and PVC-cardiomyopathy. The prevalence of PVC-cardiomyopathy and outcome benefits of PVC suppression are not clear. METHODS: A secondary analysis of the CHF-STAT study was performed to compare the rate of successful PVC suppression (≥80% PVC reduction), LV recovery (defined as improvement in LV ejection fraction of ≥10% points), and PVC-cardiomyopathy between amiodarone and placebo groups at 6 months. PVC-cardiomyopathy was defined if both PVC reduction of ≥80% and LV ejection fraction improvement of ≥10% were present at 6 months. Cardiac events (death or resuscitated cardiac arrest) were compared between PVC-cardiomyopathy versus non-PVC-cardiomyopathy during a 5-year follow-up. RESULTS: The rates of successful PVC suppression and LV recovery were significantly higher in the amiodarone (72% and 39%, respectively) when compared to the placebo group (12% and 16%, respectively; p < 0.001), regardless of cardiomyopathy etiology. PVC-cardiomyopathy was present in 29% and 1.8% of patients in the amiodarone and placebo groups, respectively (p < 0.001). Similar PVC-cardiomyopathy rates were found in ischemic (24% amiodarone vs. 2% placebo; p < 0.001) and nonischemic populations (41% amiodarone vs. 1.5% placebo; p < 0.001). Death and resuscitated cardiac arrest were significantly lower in patients with PVC-cardiomyopathy and those treated with amiodarone. CONCLUSIONS: The overall prevalence of PVC-cardiomyopathy in the CHF-STAT study was significant regardless of ischemic substrate (29%, overall population; 41%, nonischemic cardiomyopathy). Treatment of PVC-cardiomyopathy with amiodarone is likely to improve survival in this high-risk population.