Environmental Determinants of Post-Discharge Acute Respiratory Illness among Preterm Infants with Bronchopulmonary Dysplasia.

OBJECTIVE: To analyze the association of components of the Centers for Disease Control and Prevention (CDC) Environmental Justice Index (EJI) with respiratory health outcomes among infants with bronchopulmonary dysplasia (BPD) within one year after discharge from the neonatal intensive care unit. METHODS: This was a retrospective cohort study of a cohort of preterm infants with BPD. Multivariable logistic regression models estimated associations of EJI and its components with medically attended acute respiratory illness, defined as an ED visit or inpatient readmission, within one year of discharge from the neonatal intensive care unit. A mediation analysis was conducted to evaluate how environmental injustice may contribute to racial disparities in acute respiratory illness. RESULTS: Greater EJI was associated with an increased risk of medically attended respiratory illness (per EJI standard deviation increment, aOR 1.38, 95% CI: 1.12-1.69). Of the index's components, the Environmental Burden Module's Air pollution domain had the greatest association (aOR 1.44, 95% CI: 1.44-2.61). With respect to individual indicators within the EJI, Diesel Particulate Matter (DSLPM) and Air Toxic Cancer Risk (ATCR) demonstrated the strongest relationship (aOR 2.06, 95% CI: 1.57-2.71 and aOR 2.10, 95% CI: 1.59-2.78, respectively). Among non-Hispanic Black infants, 63% experienced a medically attended acute respiratory illness as compared to 18% of non-Hispanic White infants. DSLPM mediated 39% of the Black-White disparity in medically attended acute respiratory illness (p = 0.004). CONCLUSIONS: Environmental exposures, particularly air pollution, are associated with post-discharge respiratory health outcomes among preterm infants with BPD after adjusting for clinical, demographic, and social vulnerability risk factors. Certain types of air pollutants, namely, DSLPM, are more greatly associated with acute respiratory illness. Environmental exposures may contribute to racial disparities in medically attended acute respiratory illness among infants with BPD.

Place-Based Strategies Addressing Neighborhood Environments to Improve Perinatal and Preterm Infant Outcomes.

Preterm birth (defined as birth <37 weeks of gestation) is a significant health concern globally, with lasting implications for individuals, families, and society. In the United States, high preterm birth rates among Black and low-income populations likely result from differences in environmental exposures. Structural racism and economic disadvantage have led to unequal distribution of polluting industrial sites and roadways across society as well as differential access to health-promoting resources which contribute to preterm birth risk. Once born, preterm infants remain at risk for numerous environmentally responsive adverse health outcomes that affect growth and development throughout childhood and adulthood. In this commentary, we describe associations of neighborhood environments with pregnancy and preterm infant health outcomes and propose strategies to address harmful exposures that affect families across the lifespan.

Addressing Maternal Mortality in the US-A Pediatrics Responsibility.

This Viewpoint suggests that pediatricians' contact with the maternal-infant dyad postpartum presents an opportunity to address the US maternal mortality crisis and its inequities.

Associations of DNA Methylation Mortality Risk Markers with Congenital Microcephaly from Zika Virus: A Study of Brazilian Children Less than 4 Years of Age.

BACKGROUND: Zika virus (ZIKV)-associated congenital microcephaly is an important contributor to pediatric death, and more robust pediatric mortality risk metrics are needed to help guide life plans and clinical decision making for these patients. Although common etiologies of pediatric and adult mortality differ, early life health can impact adult outcomes-potentially through DNA methylation. Hence, in this pilot study, we take an early step in identifying pediatric mortality risk metrics by examining associations of ZIKV infection and associated congenital microcephaly with existing adult DNA methylation-based mortality biomarkers: GrimAge and Zhang's mortality score (ZMS). METHODS: Mortality measures were calculated from previously published HumanMethylationEPIC BeadChip data from 44 Brazilian children aged 5-40 months (18 with ZIKV-associated microcephaly; 7 normocephalic, exposed to ZIKV in utero; and 19 unexposed controls). We used linear models adjusted for chronological age, sex, methylation batch and white blood cell proportions to evaluate ZIKV and mortality marker relationships. RESULTS: We observed significant decreases in GrimAge-component plasminogen activator inhibitor-1 [PAI-1; ß = -2453.06 pg/ml, 95% confidence interval (CI) -3652.96, -1253.16, p = 0.0002], and ZMS-site cg14975410 methylation (ß = -0.06, 95% CI -0.09, -0.03, p = 0.0003) among children with microcephaly compared to controls. PAI-1 (ß = -2448.70 pg/ml, 95% CI -4384.45, -512.95, p = 0.01) and cg14975410 (ß = 0.01, 95% CI -0.04, 0.06, p = 0.64) results in comparisons of normocephalic, ZIKV-exposed children to controls were not statistically significant. CONCLUSION: Our results suggest that elements of previously-identified adult epigenetic markers of mortality risk are associated with ZIKV-associated microcephaly, a known contributor to pediatric mortality risk. These findings may provide insights for efforts aimed at developing pediatric mortality markers.

Proteasome inhibition rescues clinically significant unstable variants of the mismatch repair protein Msh2.

MSH2 is required for DNA mismatch repair recognition in eukaryotes. Deleterious mutations in human MSH2 account for approximately half of the alleles associated with a common hereditary cancer syndrome. Previously, we characterized clinically identified MSH2 missense mutations, using yeast as a model system, and found that the most common cause of defective DNA mismatch repair was low levels of the variant Msh2 proteins. Here, we show that increased protein turnover is responsible for the reduced cellular levels. Increasing gene dosage of more than half of the missense alleles fully restored function. A titration experiment revealed that raising the expression level of one variant to less than wild-type levels restored mismatch repair, suggesting that overexpression is not always required to regain function. We found that the ubiquitin-mediated proteasome degradation pathway is the major mechanism for increased turnover of the Msh2 variants and identified the primary ubiquitin ligase as San1. Deletion of San1 restored protein levels for all but one variant, but did not elevate wild-type Msh2 levels. The unstable variants interacted with San1, whereas wild-type Msh2 did not. Additionally, san1Δ suppressed the mismatch repair defect of unstable variants. Of medical significance, the clinically approved drug Bortezomib partially restored protein levels and mismatch repair function for low-level variants and reversed the resistance to cisplatin, a common chemotherapeutic. Our results provide the foundation for an innovative therapeutic regime for certain mismatch-repair-defective cancers that are refractory to conventional chemotherapies.