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Purpose: Investigate risk factors for short term reactivation of retinopathy of prematurity (ROP) after intravitreal ranibizumab (IVR) therapy and determine safety and efficacy of repeat injections., Methods: Retrospective chart review study of patients screened for ROP as inpatients between 2013-2023 who received IVR within the UCLA healthcare system. Primary outcomes were rates and timing of short term ROP reactivation, defined as repeat worsening of ROP to stage 2 or 3 before 52 weeks postmenstrual age (PMA), as well as risk factors for reactivation. Other outcomes included adverse events and rates of reactivation after a second intravitreal injection., Results: 82 eyes of 43 patients received primary IVR 0.25mg/0.025cc for type 1 ROP. 13 patients (22 eyes) (30.2% of patients, 26.8% of eyes) developed short term reactivation an average of 7.2±1.7 weeks after treatment. Increased reactivation risk was associated with zone I disease (OR 6.23, 95% CI 1.35-28.7, p=0.019), lower PMA at 1st injection (OR 1.64, 95% CI 1.19-2.26; p=0.003), and lower gestational age at birth (OR 1.80, 95% CI 1.04-3.13, p=0.037). Of the 13 patients that received repeat injections, 5 required laser treatment for a second reactivation (11.6% of patients receiving IVR). No eyes developed retinal vascular occlusion, endophthalmitis or cataract., Conclusion: Repeat injections may be required after primary IVR for aggressive ROP. Repeat IVR treatment for ROP is effective and poses few ophthalmic adverse events, though additional reactivation remains a risk., Competing Interests: Financial Disclosures: The authors have no conflicts of interest to declare.

Purpose: Retinopathy of prematurity (ROP) results from postnatal hyperoxia exposure in premature infants and is characterized by aberrant neovascularization of retinal blood vessels. Epithelial membrane protein-2 (EMP2) regulates hypoxia-inducible factor (HIF)-induced vascular endothelial growth factor (VEGF) production in the ARPE-19 cell line and genetic knock-out of Emp2 in a murine oxygen-induced retinopathy (OIR) model attenuates neovascularization. We hypothesize that EMP2 blockade via intravitreal injection protects against neovascularization., Methods: Ex vivo choroid sprouting assay was performed, comparing media and human IgG controls versus anti-EMP2 antibody (Ab) treatment. In vivo, eyes from wild-type (WT) mice exposed to hyperoxia from postnatal (P) days 7 to 12 were treated with P12 intravitreal injections of control IgG or anti-EMP2 Abs. Neovascularization was assessed at P17 by flat mount imaging. Local and systemic effects of anti-EMP2 Ab treatment were assessed., Results: Choroid sprouts treated with 30 µg/mL of anti-EMP2 Ab demonstrated a 48% reduction in vessel growth compared to control IgG-treated sprouts. Compared to IgG-treated controls, WT OIR mice treated with 4 µg/g of intravitreal anti-EMP2 Ab demonstrated a 42% reduction in neovascularization. They demonstrated down-regulation of retinal gene expression in pathways related to vasculature development and up-regulation in genes related to fatty acid oxidation and tricarboxylic acid cycle respiratory electron transport, compared to controls. Anti-EMP2 Ab-treated OIR mice did not exhibit gross retinal histologic abnormalities, vision transduction abnormalities, or weight loss., Conclusions: Our results suggest that EMP2 blockade could be a local and specific treatment modality for retinal neovascularization in oxygen-induced retinopathies, without systemic adverse effects.

Glioblastoma is a highly aggressive neoplasm and the most common primary malignant brain tumor. Endothelial tissue plays a critical role in glioblastoma growth and progression, facilitating angiogenesis, cellular communication, and tumorigenesis. In this review, we present an up-to-date and comprehensive summary of the role of endothelial cells in glioblastomas, along with an overview of recent developments in glioblastoma therapies and tumor endothelial marker identification.

Importance: Preterm infants screened for retinopathy of prematurity (ROP) are at risk for heterogenous neurodevelopment outcomes that are difficult to predict., Objective: To characterize the potential association between socioeconomic and clinical risk factors and neurodevelopmental outcomes in a diverse, multicenter cohort of premature neonates screened for ROP., Design, Setting, and Participants: This was a retrospective cohort study using electronic medical records and US Census Bureau income data. This study was performed at academic (University of California, Los Angeles [UCLA] Mattel Children's Hospital and UCLA Santa Monica Hospital), community (Cedars-Sinai Medical Center), and LA county (Harbor-UCLA Medical Center) neonatal intensive care units. Participants included infants who met American Academy of Pediatrics guidelines for ROP screening and had records from at least 1 Bayley Scales of Infant and Toddler Development (BSID) neurodevelopment assessment between 0 and 36 months of adjusted age. Data analyses were conducted from January 1, 2011, to September 1, 2022., Exposures: Demographic and clinical information, proxy household income, and health insurance type were collected as risk factors., Main Outcomes and Measures: Neurodevelopmental outcomes in the cognitive, language, and motor domains measured via BSID were the primary outcomes., Results: A total of 706 infants (mean [SD] age, 28.6 [2.4] weeks; 375 male [53.1%]) met inclusion criteria. In a multivariable model, which included adjustments for birth weight, sex, insurance type, intraventricular hemorrhage (IVH), and age at assessment, public health insurance was associated with a 4-fold increased risk of moderate to severe neurodevelopmental impairment (NDI) in cognitive and language domains (cognitive, odds ratio [OR], 3.65; 95% CI, 2.28-5.86; P = 8.1 × 10-8; language, OR, 3.96; 95% CI, 2.61-6.02; P = 1.0 × 10-10) and a 3-fold increased risk in the motor domain (motor, OR, 2.60; 95% CI, 1.59-4.24; P = 1.4 × 10-4). In this adjusted model, clinical factors that were associated with an increased risk of moderate to severe NDI included lower birth weight, diagnosis of IVH, male sex, and older age at time of Bayley assessment. In unadjusted analyses, infants who received either laser or anti-VEGF treatment, compared with infants without treatment-requiring ROP, had lower BSID scores in multiple domains at 0 to 12 months, 12 to 24 months, and 24 to 36 months (DATA). In the multivariable model, treatment type was no longer associated with worse neurodevelopmental outcomes in any domain., Conclusions and Relevance: Study results suggest an association between public insurance type and NDI in a diverse population screened for ROP, indicating the complexities of neurodevelopment. This study also supports the early neurodevelopmental safety of anti-VEGF treatment, as anti-VEGF therapy was not found to be independently associated with worse NDI in any domain.

Purpose: Characterize clinical and socioeconomic factors that impact follow-up to complete retinal vascularization and subsequent pediatric ophthalmology follow-up in neonates with retinopathy of prematurity., Methods: Medical records of 402 neonates diagnosed with retinopathy of prematurity from neonatal intensive care units at the University of California, Los Angeles Mattel Children's Hospital and the University of California, Los Angeles Santa Monica Hospital, both academic medical centers, and the Harbor-University of California, Los Angeles Medical Center, a safety-net county hospital, were reviewed. Primary study outcomes were the rate of follow-up to complete retinal vascularization and adequate pediatric ophthalmology follow-up. Secondary outcome was the rate of nonretinal ocular comorbidity., Results: In whole-cohort analysis, 93.6% of neonates were followed to complete retinal vascularization, and 53.5% had adequate pediatric ophthalmology follow-up. Public insurance was associated with lower rates of pediatric ophthalmology follow-up (Odds ratio 0.66, 95% confidence interval 0.45-0.98, P = 0.04). Participants screened at the academic medical center had lower rates of pediatric ophthalmology follow-up compared with the safety-net county hospital (50.7% vs. 63.5%, P = 0.034). In subgroup analysis, academic medical center participants with public insurance were less likely to have pediatric ophthalmology follow-up than safety-net county hospital participants with public insurance (36.5% vs. 63.8%, P < 0.001) or those with private insurance at the academic medical center (36.5% vs. 59.2%, P< 0.001)., Conclusion: This study identified high follow-up rates to complete retinal vascularization, lower pediatric ophthalmology follow-up rates, and nonretinal ocular comorbidity at all hospitals. Insurance status relative to hospital type was identified as a risk factor for loss to follow-up. This demonstrates a need to further study health care disparities in retinopathy of prematurity infants.

Retinopathy of prematurity (ROP) is a leading cause of childhood blindness. ROP occurs in infants who are born very preterm. In ROP, retinal blood vessel development, which is prematurely arrested in preterm infants, is altered by perinatal exposures like oxygen and inflammation. Optimizing nutritional practices for preterm infants may mitigate the risk of ROP. In this article, we review the evidence that postnatal growth, hyperglycemia, polyunsaturated fatty acids, and breast milk provision may affect ROP risk. We also outline the current management strategies for ROP and describe the vision outcomes of children affected by ROP. [ Pediatr Ann . 2023;52(8):e303-e308.] .

Purpose: Determine whether prenatal maternal characteristics such as sociodemographic characteristics, comorbidities, or pregnancy complications affect retinopathy of prematurity (ROP) development., Methods: Medical records of 236 mother-infant dyads from our institution were reviewed, only including dyads in which infants were born at 30 weeks gestational age or earlier. The primary outcome measure was the risk of ROP (defined Stage 1 or greater in either eye) and its association with prenatal maternal variables., Results: Maternal Medicaid insurance, smoking during pregnancy, and chorioamnionitis were associated with an increased risk of ROP. For Medicaid insurance and chorioamnionitis, these risks were not appreciably altered by adjustment for potential confounders., Conclusion: These results suggest that several prenatal maternal factors may independently affect the risk of ROP in preterm infants. Validation of our findings could aid in the identification of infants at high risk for ROP based on prenatal clinical features.

Pathologic retinal neovascularization is a potentially blinding consequence seen in many common diseases including diabetic retinopathy, retinopathy of prematurity, and retinal vaso-occlusive diseases. This study investigates epithelial membrane protein 2 (EMP2) and its role as a possible modulator of angiogenesis in human retinal pigment epithelium (RPE) under hypoxic conditions. To study its effects, the RPE cell line ARPE-19 was genetically modified to either overexpress EMP2 or knock down its levels, and RNA sequencing and western blot analysis was performed to confirm the changes in expression at the RNA and protein level, respectively. Protein expression was evaluated under both normoxic conditions or hypoxic stress. Capillary tube formation assays with human umbilical vein endothelial cells (HUVEC) were used to evaluate functional responses. EMP2 expression was found to positively correlate with expression of pro-angiogenic factors HIF1α and VEGF at both mRNA and protein levels under hypoxic conditions. Mechanistically, EMP2 stabilized HIF1α expression through downregulation of von Hippel Lindau protein (pVHL). EMP2 mediated changes in ARPE-19 cells were also found to alter the secretion of a paracrine factor(s) in conditioned media that can regulate HUVEC migration and capillary tube formation in in vitro functional angiogenesis assays. This study identifies EMP2 as a potential mediator of angiogenesis in a human RPE cell line. EMP2 levels positively correlate with pro-angiogenic mediators HIF1α and VEGF, and mechanistically, EMP2 regulates HIF1α through downregulation of pVHL. This study supports further investigation of EMP2 as a promising novel target for therapeutic treatment of pathologic neovascularization in the retina., (© 2022. The Author(s).)

Purpose: Retinopathy of prematurity (ROP) can lead to blindness. Arachidonic acid (ARA) and docosahexaenoic acid (DHA) regulate retinal inflammation and angiogenesis. The aim of this study was to investigate red blood cell membrane (RBCM) ARA and DHA in preterm infants., Methods: This prospective observational study divided infants into groups by ROP severity and RBCM ARA and DHA means and terciles., Results: Although the mean ± SD RBCM ARA was different between groups (no ROP, 17.9% ± 0.7%, vs. type 2 ROP, 17.4% ± 0.8%, vs. type 1 ROP, 16.7% ± 1.0%; P < 0.001), the mean RBCM DHA was similar (P = 0.161). Infants with type 1 ROP were more likely to be in the lowest ARA and DHA terciles than in the highest (ARA, 44% vs. 5.6%; DHA, 22% vs. 5.6%). ARA and DHA declined over the first month of life in all ROP groups. At week 1, ARA was lower in the type 1 and type 2 ROP groups compared with the no-ROP group (18% ± 2% and 19% ± 3% vs. 21% ± 2%, respectively; P < 0.05 for all). At week 2, DHA and ARA were lower in the type I ROP group compared with the no-ROP group (3% ± 1% vs. 4% ± 1%, P = 0.03 and 16% ± 1% vs. 19% ± 1%, respectively; P < 0.01). A RBCM ARA% ≥ 17 was associated with a 45% reduction in any ROP. As the estimated 4-week ARA% mean increased by 1%, the odds of ROP decreased by 70% (odds ratio = 0.30; 95% confidence interval, 0.1-0.7)., Conclusions: Infants with severe ROP have lower ARA and DHA levels than infants without ROP. ARA and DHA may act synergistically to protect against ROP.

Background: Congenital diaphragmatic hernia (CDH) is a cause of significant morbidity. CDH is the most common neonatal diagnosis requiring extracorporeal membrane oxygenation (ECMO)., Methods: We compared the different characteristics of ECMO and non-ECMO patients with CDH in a case-control study. Data were extracted from the Kids' Inpatient Database. Records from 2006 to 2016 were used. Patients <28 days of age were selected. CDH infants (n=9217) were stratified based on whether they were treated with ECMO (n=348) or not (n=8869). Demographic data and hospital characteristics were collected. Categorical variables were analyzed using χ 2 tests to determine associations between the ECMO-treated and non-ECMO-treated infants on demographic and clinical characteristics. Differences in hospitalization costs were analyzed using t-test. Multivariable logistic regression analyses were stratified by clinical and demographic characteristics to identify factors associated with ECMO. Significant variables were included in the model to determine predictors for ECMO., Results: The proportion of infants treated with ECMO was higher in White infants, and lower in Hispanics. The cost of hospitalization was higher with ECMO (p<0.0001). ECMO patients were more likely to be treated in their birth hospital (p<0.001), at an urban location (p<0.001) and more likely to have private insurance (p=0.011). After adjusting for confounders, odds of ECMO treatment remained lower in Hispanics (p=0.001) and self-payers (p=0.004)., Conclusion: There was a decrease in the proportion of CDH infants needing ECMO use in the USA from 2006 to 2016. Disparities exist in ECMO use and mortality between different ethnic groups and regions of the USA., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: To characterize visual outcomes in children screened for retinopathy of prematurity (ROP)., Design: Retrospective, interventional case series., Methods: Patients who received ROP screening examinations at UCLA Medical Centers and were followed with outpatient eye examinations at Stein Eye Institute and/or Doheny Eye Institute (Los Angeles, California) were included. Data were collected on birth characteristics, worst type of ROP, and ROP treatment. Adverse visual outcomes included myopia, strabismus, amblyopia, macular dragging, and optic atrophy. Snellen visual acuity was reported for children 4 years and older., Results: A total of 175 infants (350 eyes) were included for analysis (mean gestational age = 28.2 weeks and birth weight = 1059 g) from a screening population of 539 infants (1078 eyes, 32.4% follow-up) over a 9-year period. Fifteen eyes received primary anti-vascular endothelial growth factor (anti-VEGF) therapy, whereas 59 eyes received primary laser therapy. Primary anti-VEGF therapy, as compared with primary laser treatment, was associated with a decreased incidence of amblyopia (adjusted odds ratio [aOR] = 0.6-0.86, P < .0001) after controlling for gestational age and birth weight. The rates of optic atrophy (P = .79), strabismus (P = .98), and myopia (P = .93) were not different between anti-VEGF and laser treatment groups. Infants receiving anti-VEGF therapy had more posterior disease than laser-treated infants (P = .041). Infants receiving laser therapy were more likely to have severe myopia (aOR = 1.02-1.3, P = .023), amblyopia (aOR = 1.12-1.61, P = .002), and optic atrophy (aOR = 1.01-1.32, P = .045) than infants not treated., Conclusion: These findings add to the advantages of anti-VEGF treatment compared with primary laser treatment, particularly in posterior ROP., (Copyright © 2022. Published by Elsevier Inc.)

Objective: To characterize and quantify foveal development in treatment-naïve extremely preterm infants using optical coherence tomography., Methods: In this cross-sectional study, eyes treated for retinopathy of prematurity before imaging were excluded. Inner retinal thickness and outer retina thickness at foveal center and foveal rim were assessed. Extremely preterm (EPT, <28 weeks gestational age) eyes were compared with infants more than 28 weeks of gestation using a multivariable dimension reduction analysis (principal component analysis) and a bilinear factor mode analysis (partial least square discriminant analysis) to determine group intervariability. Further analyses were performed to investigate the effects of gestation on foveal development., Results: Twenty-six infants born at gestational ages ranging from 22 to 39 weeks were imaged between 32 and 80 weeks postmenstrual age. A principal component analysis and partial least squares discriminant analysis revealed that the foveal inner retina thickness was the main difference between EPT infants and non-EPT infants. This difference was reflected by comparing their inner retinal thickness over time (32-80 weeks postmenstrual age), which revealed a sustained thicker foveal inner retina for EPT infants when compared with non-EPT infants. The foveal pit seemed to be shallower in EPT infants when compared with non-EPT infants., Conclusions: Twenty-eight weeks of gestation seems to be a critical timepoint for foveal development; EPT infants had altered foveal inner retinal development throughout early postnatal development, which led to a thicker foveal inner retina and a shallower foveal pit soon after birth., Translational Relevance: Measuring untreated foveal parameters informs about the effects of prematurity on the fovea and provides a baseline when comparing with post-treatment foveal development.

Background: Alcohol use disorder (AUD) is a complex and chronic relapsing brain disease, which is often co-morbid with psychiatric disorders such as anxiety and depression. AUD phenotypes differ in men and women. Although genetic factors play an important role in its pathophysiology, epidemiologic evidence suggests that during prenatal development, individuals are more vulnerable to the negative effects of environmental factors that may predispose them to AUD later in life. We explored the effects of prenatal stress on the development of AUD phenotypes as well as anxiety- and depression-like behaviors using rat model., Methods: In this study, timed-pregnant Sprague Dawley dams were used. Dams in the control group were left undisturbed throughout gestation, whereas dams in stress groups were either subjected to protracted or acute restraint stress under bright light. At adulthood, the anxiety-like, ethanol drinking, and sucrose drinking behaviors were measured using the Light/Dark Box test and two-bottle free-choice procedure., Results: Compared to the control group, both the male and female offspring in the stress groups exhibited anxiety-like behavior and consumed significantly higher amounts of ethanol in which the acute stress group demonstrated the higher ethanol preference. Moreover, male but not female offspring from the stress groups had decreased sucrose preferences., Conclusion: These findings suggest that protracted and acute prenatal stress in late pregnancy can induce in anxiety-, depressive-like behaviors, and excessive ethanol intake in adult offspring., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Dong, Zhang, Chu and Pandey.)

Importance: Previous studies suggest that race or ethnicity may be associated with risk for developing retinopathy of prematurity (ROP). Little is known about how socioeconomic factors mediate the relationship between race or ethnicity and ROP outcomes., Objective: To evaluate how socioeconomic factors, in the context of race and ethnicity, are associated with ROP outcomes., Design, Setting, and Participants: This retrospective cohort study used US Census Bureau income data and electronic medical records from neonatal intensive care units at 4 hospitals, UCLA Mattel Children's Hospital, UCLA Santa Monica Hospital, Cedars-Sinai Medical Center, and Harbor-UCLA Medical Center. Eligible participants included neonates born at a gestational age (GA) of 30 weeks or less, birth weight less than 1500 g, or a GA at birth greater than 30 weeks but with an unstable clinical course. Participants were screened for ROP between January 1, 2010, and December 31, 2020., Exposures: Race and ethnicity data, GA, demographic and clinical information, proxy household income, and health insurance status were collected as risk factors., Main Outcomes and Measures: Diagnosis and severity of ROP were the main study outcomes. Severity was determined according to a classification system developed by the Early Treatment for Retinopathy of Prematurity Cooperative Group., Results: In a crude model, Hispanic neonates were more likely to be diagnosed with ROP (OR, 1.70; 95% CI, 1.20-2.42) and had more severe ROP (OR, 2.24; 95% CI, 1.21-4.15) compared with non-Hispanic White neonates; these associations were no longer found when adjusting for GA and socioeconomic factors (OR, 1.12; 95% CI, 0.68-1.82, and OR, 1.67; 95% CI, 0.80-3.52, for ROP diagnosis and severity, respectively). In a fully adjusted model, lower GA was the primary predictor of ROP incidence (OR, 0.52; 95% CI, 0.48-0.57; P < .001), and higher median household income was associated with higher GA (OR, 0.26; 95% CI, 0.09-0.43; P = .002)., Conclusions and Relevance: In this cohort study, GA was the primary driver of disparities in ROP outcomes in a heterogeneous population of neonates in Los Angeles, California. When examined in the context of socioeconomic factors, GA did not differ between racial and ethnic groups. Studies of disparities associated with race and ethnicity should consider these constructs in conjunction with other sociodemographic factors and social determinants of health.

Purpose: To evaluate whether choroidal thickness (CT) using arm-mounted optical coherence tomography (OCT) in infants screened for retinopathy of prematurity (ROP) correlates with oxygen exposure in neonates., Methods: OCT images were obtained in infants screened for ROP in a single level IV neonatal intensive care unit. CT was measured at three different locations: the subfoveal center and 1.5 mm from the fovea center in each direction. Correlation and regression analyses were performed to determine the relationship between clinical factors and CT. Clinical factors included gestational age, birth weight, presence of bronchopulmonary dysplasia (BPD), and fraction of inspired oxygen (FiO2) at defined time points: 30 weeks postmenstrual age (PMA), 36 weeks PMA, and on day of imaging., Results: Mean subfoveal, nasal, and temporal choroidal thicknesses CT (SFCT, NCT, and TCT, respectively) were 228.0 ± 51.4 µm, 179.7 ± 50.3 µm, and 186.4 ± 43.8 µm, respectively. SFCT was found to be significantly thicker than NCT and TCT (P < 0.0001 and P = 0.0002, respectively), but no significant difference was found between NCT and TCT (P = 0.547). Compared with infants without BPD, infants with BPD had thinner SFCT and NCT (P = 0.01 and P = 0.0008, respectively). Birth weight was positively correlated with SFCT (r = 0.39, P = 0.01) and NCT (r = 0.33, P = 0.045) but not TCT. Gestational age and ROP stage were not significantly associated with CT. SFCT was found to be significantly thinner with higher average FiO2 supplementation levels at 30 weeks PMA (r = -0.51, P = 0.01) but not at 36 weeks PMA. Regression analysis revealed that FiO2 at 30 weeks PMA was an independent predictor of SFCT in infants screened for ROP (P = 0.01)., Conclusions: Early postnatal exposure (<32 weeks PMA) to higher oxygen supplementation in premature neonates statistically predicts choroidal thinning.

Purpose: To evaluate the relationship between retinopathy of prematurity (ROP) severity and neurodevelopmental outcomes in premature neonates at 0-36 months corrected age. Methods: A retrospective chart review was performed on 228 neonates screened for ROP at the UCLA Mattel Children's Hospital between 2011 and 2018. Demographic information, clinical outcomes, ROP severity (no ROP, type 1 ROP, type 2 ROP), and Bayley-III neurodevelopmental scores were collected. Infants were grouped into corrected age cohorts (0-12, 12-24, and 24-36 months) to assess neurodevelopmental outcomes with increasing age. Within each age cohort, ANOVA and Chi-Square testing were used to detect differences in birth characteristics and neurodevelopmental scores between infants with type 1 ROP, type 2 ROP, or no ROP. Univariable analyses assessed the relationship between ROP severity and neurodevelopmental outcomes within each age cohort. A multivariable analysis was then performed to determine if ROP severity remained significantly associated with worse neurodevelopmental scores after controlling for birth weight (BW), intraventricular hemorrhage grade (IVH), health insurance type, male sex, and age at Bayley testing. Results: Without controlling for factors associated with prematurity, neonates with type 1 ROP had poorer cognition ( p = 0.001) and motor ( p = 0.006) scores at ages 0-12 months and poorer cognition ( p = 0.01), language ( p = 0.04) and motor ( p = 0.04) scores at ages 12-24 months than infants without ROP, but no significant differences were detected at ages 24-36 months. After adjusting for BW, IVH, insurance type, male sex, and age at Bayley testing, ROP severity was no longer associated with worse neurodevelopmental scores in any domain. Conclusion: This study emphasizes that poorer neurodevelopmental outcomes in preterm neonates are most likely related to lower birthweight, associated co-morbidities of prematurity, and socioeconomic factors such as health insurance, not severity of ROP itself., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Altendahl, Sim, Kokhanov, Gundlach, Tsui and Chu.)

In type 1 endometrial cancer, unopposed estrogen stimulation is thought to lead to endometrial hyperplasia which precedes malignant progression. Recent data from our group and others suggest that ALDH activity mediates stemness in endometrial cancer, but while aldehyde dehydrogenase 1 (ALDH1) has been suggested as a putative cancer stem cell marker in several cancer types, its clinical and prognostic value in endometrial cancer remains debated. The aim of this study was to investigate the clinical value of ALDH1 expression in endometrial hyperplasia and to determine its ability to predict progression to endometrial cancer. Interrogation of the TCGA database revealed upregulation of several isoforms in endometrial cancer, of which the ALDH1 isoforms collectively constituted the largest group. To translate its expression, a tissue microarray was previously constructed which contained a wide sampling of benign and malignant endometrial samples. The array contained a metachronous cohort of samples from individuals who either developed or did not develop endometrial cancer. Immunohistochemical staining was used to determine the intensity and frequency of ALDH1 expression. While benign proliferative and secretory endometrium showed very low levels of ALDH1, slightly higher expression was observed within the stratum basalis. In disease progression, cytoplasmic ALDH1 expression showed a step-wise increase between endometrial hyperplasia, atypical hyperplasia, and endometrial cancer. ALDH1 was also shown to be an early predictor of EC development, suggesting that it can serve as an independent prognostic indicator of patients with endometrial hyperplasia with or without atypia who would progress to cancer (p = 0.012).

Epithelial membrane protein 2 (EMP2) is a tetraspan membrane protein that has been revealed in cancer and placental models to mediate a number of vascular responses. Recently, Emp2 modulation has been shown to have an immunologic effect on uterine NK cell recruitment in the mouse placenta. Given the importance of immune cell populations on both placental vascularization and maternal immune tolerance of the developing fetus, we wanted to better characterize the immunologic effects of Emp2 at the placental-fetal interface. We performed flow cytometry of WT and Emp2 KO C57Bl/6 mouse uterine horns at GD12.5 to characterize immune cell populations localized to the various components of the maternal-fetal interface. We found that Emp2 KO decidua and placenta showed an elevated overall percentage of CD45+ cells compared to WT. Characterization of CD45+ cells in the decidua of Emp2 KO dams revealed an increase in NK cells, whereas in the placenta, Emp2 KO dams showed an increased percentage of M1 macrophages (with an increased ratio of M1/M2 macrophages). Given the differences detected in uNK cell populations in the decidua, we further characterized the interaction between Emp2 genetic KO and NK cell deletion via anti-asialo GM1 antibody injections. While the double knock-out of Emp2 and NK cells did not alter individual pup birthweight, it significantly reduced total litter weight and size by ∼50 %. In conclusion, Emp2 appears to regulate uNK and macrophage cell populations in pregnancy., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Emerging infectious diseases, including Ebola, chikungunya, Zika, and dengue, may have significant impacts on maternal-fetal dyads and neonatal outcomes. Pregnant women infected with Ebola demonstrate high mortality and very low evidence of neonatal survival. Maternal chikungunya infection can result in high rates of perinatal transmission, and infected neonates demonstrate variable disease severity. Dengue can be transmitted to neonates via vertical transmission or perinatal transmission. Zika is characterized by mild disease in pregnant women, but congenital infection can be severe. Treatment largely is supportive for these diseases, and vaccine development remains under way, with promising recent advances, notably for Ebola., (Copyright © 2021 Elsevier Inc. All rights reserved.)

With over 400 reported disorders, the skeletal dysplasias represent a myriad of molecularly-based skeletal abnormalities. Arising from errors in skeletal development, the clinical spectrum of disease evolves through an affected individual's life. The naming and grouping of these disorders are ever-changing, but the fundamentals of diagnosis remain the same and are accomplished through a combination of prenatal ultrasonography and postnatal physical examination, radiography, and genetic analysis. Although some disorders are lethal in the perinatal and neonatal periods, other disorders allow survival into infancy, childhood, and even adulthood with relatively normal lives. The foundation of management for an affected individual is multidisciplinary care. Medical advances have offered new insights into reducing common morbidities through pharmacologic means. This review summarizes the normal skeletal development and discusses the 3 most common skeletal dysplasias that can affect the newborn., (Copyright © 2021 by the American Academy of Pediatrics.)

Neonates with ambiguous genitalia have various clinical presentations, etiologies, and outcomes, ranging from benign to life-threatening. This review provides a summary of these findings. Some diagnoses may lead to delayed sex assignment. A systematic approach to the evaluation of disorders of sex development can allow for timely treatment and family counseling., (Copyright © 2021 by the American Academy of Pediatrics.)

The purpose of this paper was to perform a scoping review examining the occupational therapy peer-reviewed literature regarding the LGBTQIA+ community to (a) determine what types of scholarship have been generated and (b) whether the association between LGBTQIA+ self-identification and homelessness has been identified and addressed in occupational therapy practice. A database search of seven peer-reviewed, health care publication indexes, with 19 key search terms was performed. The database search targeted articles published prior to January 2020. Fifty-three articles were identified within the occupational therapy literature and addressing the LGBTQIA+ community. The majority of this literature (n = 40) was exploratory studies through which researchers sought to better understand the unique needs of subgroups within the LGBTQIA+ community. Only three articles addressed the link between LGBTQIA+ self-identification and homelessness with no articles that addressed evaluation and intervention of the factors predisposing this population to homelessness. As occupational therapists have a unique skill set that could be used to help LGBTQIA+ community members transition from and remain free from homelessness, occupational therapy researchers must develop and assess interventions that target these factors. Occupational therapy educators should develop and assess curricular programming to heighten student comfort and preparedness in service delivery to this community.

Objective: This study aimed to describe two cases of acute respiratory distress syndrome (ARDS) secondary to novel coronavirus disease 2019 (COVID-19) in pregnant women requiring extracorporeal membrane oxygenation (ECMO), and resulting in premature delivery., Study Design: The clinical course of two women hospitalized with ARDS due to COVID-19 care in our intensive care (ICU) is summarized; both participants provided consent to be included in this case series., Results: Both women recovered with no clinical sequelae. Neonatal outcomes were within the realm of expected for prematurity with the exception of coagulopathy. There was no vertical transmission to the neonates., Conclusion: This case series highlights that ECMO is a feasible treatment in the pregnant woman with severe COVID-19 and that delivery can be performed safely on ECMO with no additional risk to the fetus. While ECMO carries its natural risks, it should be considered a viable option during pregnancy and the postpartum period., Key Points: · COVID-19 may present with a more severe course in pregnancy.. · ECMO may be used in pregnant woman with severe COVID-19.. · Delivery can be performed on ECMO without added fetal risk.., Competing Interests: None declared., (Thieme. All rights reserved.)

Introduction: Murine models provide microvascular insights into the 3-D network disarray seen in retinopathy and cardiovascular diseases. Light-sheet fluorescence microscopy (LSFM) has emerged to capture retinal vasculature in 3-D, allowing for assessment of the progression of retinopathy and the potential to screen new therapeutic targets in mice. We hereby coupled LSFM, also known as selective plane illumination microscopy, with topological quantification, to characterize the retinal vascular plexuses undergoing preferential obliteration. Method and Result: In postnatal mice, we revealed the 3-D retinal microvascular network in which the vertical sprouts bridge the primary (inner) and secondary (outer) plexuses, whereas, in an oxygen-induced retinopathy (OIR) mouse model, we demonstrated preferential obliteration of the secondary plexus and bridging vessels with a relatively unscathed primary plexus. Using clustering coefficients and Euler numbers, we computed the local versus global vascular connectivity. While local connectivity was preserved ( p > 0.05, n = 5 vs. normoxia), the global vascular connectivity in hyperoxia-exposed retinas was significantly reduced ( p < 0.05, n = 5 vs. normoxia). Applying principal component analysis (PCA) for auto-segmentation of the vertical sprouts, we corroborated the obliteration of the vertical sprouts bridging the secondary plexuses, as evidenced by impaired vascular branching and connectivity, and reduction in vessel volumes and lengths ( p < 0.05, n = 5 vs. normoxia). Conclusion: Coupling 3-D LSFM with topological quantification uncovered the retinal vasculature undergoing hyperoxia-induced obliteration from the secondary (outer) plexus to the vertical sprouts. The use of clustering coefficients, Euler's number, and PCA provided new network insights into OIR-associated vascular obliteration, with translational significance for investigating therapeutic interventions to prevent visual impairment., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19), is highly contagious and can cause serious respiratory illness and other clinical manifestations. The aim of this review is to summarize the clinical presentation, diagnosis, and outcomes of COVID-19 in pregnant women and neonates, who may be especially vulnerable to the effects of COVID-19, and to discuss what is known about potential maternal-fetal and maternal-neonatal transmission of SARS-CoV-2., (Copyright © 2020 by the American Academy of Pediatrics.)

Low birthweight and decreased postnatal weight gain are known predictors of worse retinopathy of prematurity (ROP) but the role of prenatal growth patterns in ROP remains inconclusive. To distinguish small for gestational age (SGA) from intrauterine growth restriction (IUGR) as independent predictors of ROP, we performed a retrospective cohort study of patients who received ROP screening examinations at a level IV neonatal intensive care unit over a 7-year period. Data on IUGR and SGA status, worst stage of and need for treatment for ROP, and postnatal growth was obtained. 343 infants were included for analysis (mean gestational age = 28.6 weeks and birth weight = 1138.2 g). IUGR infants were more likely to have a worse stage of ROP and treatment-requiring ROP (both p < 0.0001) compared to non-IUGR infants. IUGR infants were more likely to be older at worst stage of ROP (p < 0.0001) and to develop postnatal growth failure (p = 0.01) than non-IUGR infants. Independent of postnatal growth failure status, IUGR infants had a 4-5 × increased risk of needing ROP treatment (p < 0.001) compared to non-IUGR infants. SGA versus appropriate for gestational age infants did not demonstrate differences in retinopathy outcomes, age at worst ROP stage, or postnatal growth failure. These findings emphasize the importance of prenatal growth on ROP development.

Cystoid macular edema (CME) has been reported in the neonatal period associated with preterm birth; however, its pathogenesis remains unclear and is likely multifactorial. The authors report the case of a preterm infant imaged using optical coherence tomography (OCT), which revealed severe CME that regressed after laser treatment. Because laser for retinopathy of prematurity aims to reduce vascular endothelial growth factor (VEGF) levels, this case considers the possibility of VEGF-mediated CME pathogenesis. Further, the authors provide additional evidence of the value of OCT for noninvasive visualization of the preterm retina; the modality provides an effective way to evaluate and monitor progression of CME. [Ophthalmic Surg Lasers Imaging Retina. 2020;51:472-475.]., (Copyright 2020, SLACK Incorporated.)

Mycoplasma species (spp.) can be commensals or opportunistic pathogens of the urogenital tract, and they can be commonly isolated from amniotic fluid, placenta, and fetal/neonatal tissue or blood in mothers delivering prematurely or their preterm infants. Although the presence of Mycoplasma spp. has been associated with adverse maternal-fetal outcomes such as preterm birth and maternal chorioamnionitis, it is less clear whether vertical transmission to the neonate results in colonization or active infection/inflammation. Moreover, the presence of Mycoplasma spp. in neonatal blood, cerebrospinal fluid, or tissue has been variably associated with increased risk of neonatal comorbidities, especially bronchopulmonary dysplasia (BPD). Although the treatment of the mother or neonate with antibiotics is effective in eradicating ureaplasma, it is not clear that the treatment is effective in reducing the incidence of major morbidities of the preterm neonate (eg, BPD). In this article, we review the animal and clinical data for ureaplasma-related complications and treatment strategies. [Pediatr Ann. 2020;49(7):e305-e312.]., (Copyright 2020, SLACK Incorporated.)

Arthrogryposis multiplex congenita (AMC) is a complex, etiologically diverse, clinical descriptor identified in a variety of diagnoses characterized by multiple congenital joint contractures. The root cause of AMC is decreased fetal movement in-utero, whether resulting from maternal or pregnancy influences, nervous system pathology, or an underlying genetic abnormality. Prenatal diagnosis via ultrasonography can be challenging and may require additional imaging techniques or studies. After birth, these infants may require assistance breathing and feeding depending on the underlying diagnosis. Physical therapy and surgical intervention of the contractures are the mainstays of therapy, and outcomes can be good when intervention is provided in a timely manner. Those infants with syndromic causes of arthrogryposis are more likely to have poor outcomes; therefore, determining the underlying etiology for AMC is important as this can influence counseling regarding individual prognosis as well as future pregnancies. [Pediatr Ann. 2020;49(7):e299-e304.]., (Copyright 2020, SLACK Incorporated.)

Objectives: To evaluate the utility of tracheal aspirates in suspected pneumonia in intubated neonates and to measure the burden of antibiotic use associated with a positive tracheal aspirate culture., Design: Retrospective cohort study between January 2016 and December 2017., Setting: A level IV neonatal intensive care unit (NICU)., Patients: Intubated patients with a tracheal aspirate culture., Methods: Data on temporally associated clinical measures of illness, laboratory and radiographic testing, and clinical demographic information were analyzed., Results: Positive tracheal aspirate cultures were associated with lower birth weight and a normal immature to total neutrophil ratio (I/T ratio). Positive tracheal aspirates were not significantly associated with clinical, laboratory, or radiographic markers used in clinical practice to screen for infection. Despite the lack of positive clinical associations, a positive tracheal aspirate culture was associated with increased risk of prolonged antibiotic exposure., Conclusion: These findings suggest that positive tracheal aspirates do not always represent clinical infection and may result in unnecessary antibiotic exposure.

Purpose: To assess the feasibility of imaging extremely low birth weight infants, defined as infants born weighing less than 1000 g or before 27 weeks of gestational age, with an arm-mounted optical coherence tomography angiography (OCTA) device., Methods: Cross-sectional case series conducted at a single site in-patient academic center. Subjects included infants who had been born premature and met ROP screening criteria. Birth history such as gestational age and birth weight were collected. Subjects were imaged with OCTA in a supine position during ROP screening and treatment. Segmental errors were manually corrected and FAZ area was calculated from the superficial and deep capillary plexus (SCP, DCP) layers. Main outcomes measures were foveal avascular zone (FAZ) area, ROP stage and treatment., Results: Seven ELBW infants were included with an average gestational age of 25 weeks (range = 23-4/7 to 26 weeks) and average postmenstrual age of 54.7 weeks (range = 43-80 weeks) at the time of imaging. Average birth weight was 615 g (range 500-680 grams). Thirteen eyes had ROP treatment including primary laser, anti-vascular endothelial growth factor injection with delayed laser, and scleral buckle. Six infants were imaged under general anesthesia and one infant was imaged without sedation. Average FAZ area was 0.17 mm 2 (range = 0.03 mm 2 -0.37 mm 2 ) in the SCP and 0.04 mm 2 (range 0 mm 2 -0.09 mm 2 ) in the DCP. FAZ area correlated positively to the ratio of outer retinal layer thickness to inner retinal layer thickness at the foveal center in the SCP and DCP (r 2  = 0.48, p = 0.02; r 2  = 0.46, p = 0.02) and negatively with inner retinal layer thickness in the SCP (r 2  = 0.56, p = 0.008)., Conclusions and Importance: Arm-mounted OCTA was feasible in ELBW infants and provided information about the developing fovea. Measurement of FAZ area and retinal thickness using this modality may be used to study the effects of ELBW, peripheral ROP and ROP treatment on foveal development., Competing Interests: None of the authors have any financial disclosures., (© 2020 The Authors.)

Purpose: Retinopathy of prematurity (ROP) is a leading cause of childhood blindness. ROP occurs as a consequence of postnatal hyperoxia exposure in premature infants, resulting in vasoproliferation in the retina. The tetraspan protein epithelial membrane protein-2 (EMP2) is highly expressed in the retinal pigment epithelium (RPE) in adults, and it controls vascular endothelial growth factor (VEGF) production in the ARPE-19 cell line. We, therefore, hypothesized that Emp2 knockout (Emp2 KO) protects against neovascularization in murine oxygen-induced retinopathy (OIR)., Methods: Eyes were obtained from wildtype (WT) and Emp2 KO mouse pups at P7, P12, P17, and P21 after normoxia or hyperoxia (P7-P12) exposure. Following hyperoxia exposure, RNA sequencing was performed using the retina/choroid layers obtained from WT and Emp2 KO at P17. Retinal sections from P7, P12, P17, and P21 were evaluated for Emp2, hypoxia-inducible factor 1α (Hif1α), and VEGF expression. Whole mount images were generated to assess vaso-obliteration at P12 and neovascularization at P17., Results: Emp2 KO OIR mice demonstrated a decrease in pathologic neovascularization at P17 compared with WT OIR mice through evaluation of retinal vascular whole mount images. This protection was accompanied by a decrease in Hif1α at P12 and VEGFA expression at P17 in Emp2 KO animals compared with the WT animals in OIR conditions. Collectively, our results suggest that EMP2 enhances the effects of neovascularization through modulation of angiogenic signaling., Conclusions: The protection of Emp2 KO mice against pathologic neovascularization through attenuation of HIF and VEGF upregulation in OIR suggests that hypoxia-induced upregulation of EMP2 expression in the neuroretina modulates HIF-mediated neuroretinal VEGF expression.

Iron deficiency is common worldwide and is associated with adverse pregnancy outcomes. The increasing prevalence of indiscriminate iron supplementation during pregnancy also raises concerns about the potential adverse effects of iron excess. We examined how maternal iron status affects the delivery of iron to the placenta and fetus. Using mouse models, we documented maternal homeostatic mechanisms that protect the placenta and fetus from maternal iron excess. We determined that under physiological conditions or in iron deficiency, fetal and placental hepcidin did not regulate fetal iron endowment. With maternal iron deficiency, critical transporters mediating placental iron uptake (transferrin receptor 1 [TFR1]) and export (ferroportin [FPN]) were strongly regulated. In mice, not only was TFR1 increased, but FPN was surprisingly decreased to preserve placental iron in the face of fetal iron deficiency. In human placentas from pregnancies with mild iron deficiency, TFR1 was increased, but there was no change in FPN. However, induction of more severe iron deficiency in human trophoblast in vitro resulted in the regulation of both TFR1 and FPN, similar to what was observed in the mouse model. This placental adaptation that prioritizes placental iron is mediated by iron regulatory protein 1 (IRP1) and is important for the maintenance of mitochondrial respiration, thus ultimately protecting the fetus from the potentially dire consequences of generalized placental dysfunction.

Objective: Intrauterine growth restriction (IUGR) is a complication of pregnancy that has both short- and long-term sequelae for affected mothers and offspring. The pathophysiology of disease stems from poor nutrient and oxygen provision to the fetus, resulting in increased oxidative stress within the placenta. As the milieu within the local microenvironment alters macrophage differentiation, we hypothesized that macrophage plasticity may be altered in placentas associated with IUGR, and that macrophages would show hallmarks of lipid peroxidation including altered aldehyde metabolism., Methods: In human placentas taken from normal pregnancies resulting in appropriate-for-gestational-age (AGA) newborns and placentas associated with IUGR, placental macrophages were evaluated by immunohistochemistry and shown in IUGR to resemble pro-inflammatory activated M1-type macrophages. To link oxidative stress to macrophages, the expression of aldehyde dehydrogenase (ALDHs) isozymes ALDH1, ALDH2, and ALDH3 was assessed., Results: All three isozymes displayed preferential staining for distinct cellular populations within the term human placenta. ALDH1 and ALDH2 were strongly expressed in placental Hofbauer and decidual stromal cells. ALDH3, in contrast, was present in extravillous trophoblasts. Comparing AGA and IUGR-associated placentas, ALDH1 and ALDH2 trended to have greater expression in macrophage populations but lower expression in decidual cell populations in IUGR-associated placentas. ALDH3 had higher expression in IUGR-associated placentas but localized specifically to extravillous trophoblast populations., Conclusion: Therefore, we speculate that specific ALDH isozymes have cell-specific functions related to differentiation, inflammation, or oxidative stress responses that are altered in IUGR-associated term human placentas. This family of isozymes may be a novel method to identify human placentas affected by placental insufficiency/IUGR., (Copyright © 2019. Published by Elsevier Ltd.)

Intrauterine growth restriction (IUGR) enhances risk for adult onset cardiovascular disease (CVD). The mechanisms underlying IUGR are poorly understood, though inadequate blood flow and oxygen/nutrient provision are considered common endpoints. Based on evidence in humans linking IUGR to adult CVD, we hypothesized that in murine pregnancy, maternal late gestational hypoxia (LG-H) exposure resulting in IUGR would result in (1) placental transcriptome changes linked to risk for later CVD, and 2) adult phenotypes of CVD in the IUGR offspring. After subjecting pregnant mice to hypoxia (10.5% oxygen) from gestational day (GD) 14.5 to 18.5, we undertook RNA sequencing from GD19 placentas. Functional analysis suggested multiple changes in structural and functional genes important for placental health and function, with maximal dysregulation involving vascular and nutrient transport pathways. Concordantly, a ~10% decrease in birthweights and ~30% decrease in litter size was observed, supportive of placental insufficiency. We also found that the LG-H IUGR offspring exhibit increased risk for CVD at 4 months of age, manifesting as hypertension, increased abdominal fat, elevated leptin and total cholesterol concentrations. In summary, this animal model of IUGR links the placental transcriptional response to the stressor of gestational hypoxia to increased risk of developing cardiometabolic disease.

Inherent genetic programming and environmental factors affect fetal growth in utero. Epidemiologic data in growth-altered fetuses, either intrauterine growth restricted (IUGR) or large for gestational age (LGA), demonstrate that these newborns are at increased risk of cardiometabolic disease in adulthood. There is growing evidence that the in utero environment leads to epigenetic modification, contributing to eventual risk of developing heart disease or diabetes. In this study, we used reduced representation bisulfite sequencing to examine genome-wide DNA methylation variation in placental samples from offspring born IUGR, LGA, and appropriate for gestational age (AGA) and to identify differential methylation of genes important for conferring risk of cardiometabolic disease. We found that there were distinct methylation signatures for IUGR, LGA, and AGA groups and identified over 500 differentially methylated genes (DMGs) among these group comparisons. Functional and gene network analyses revealed expected relationships of DMGs to placental physiology and transport, but also identified novel pathways with biologic plausibility and potential clinical importance to cardiometabolic disease. Specific loci for DMGs of interest had methylation patterns that were strongly associated with anthropometric presentations. We further validated altered gene expression of these specific DMGs contributing to vascular and metabolic diseases (SLC36A1, PTPRN2, CASZ1, IL10), thereby establishing transcriptional effects toward assigning functional significance. Our results suggest that the gene expression and methylation state of the human placenta are related and sensitive to the intrauterine environment, as it affects fetal growth patterns. We speculate that these observed changes may affect risk for offspring in developing adult cardiometabolic disease.

Retinopathy of prematurity (ROP) is a condition seen in premature infants that is characterized by abnormal retinal blood vessel growth incited by relative hyperoxia and followed by hypoxia. It can have severe consequences ranging from high myopia to blindness. This article reviews recent "hot" topics related to ROP, specifically the changing incidence of ROP worldwide, the advent of predictive algorithms for screening for ROP, the emerging data behind efficacy of anti-vascular endothelial growth factor treatments for ROP, and advanced retinal imaging in children who were born premature. [Pediatr Ann. 2017;46(11):e415-e422.]., (Copyright 2017, SLACK Incorporated.)

Congenital hyperinsulinism is a rare disorder that commonly presents in the immediate postnatal period as persistent hypoglycemia. The condition is frequently resistant to medical therapies, and the genetic mutations implicated in the disorder can be predictive of response to therapy. Evaluation of hypoglycemia in the illustrative case presented in this article led to genetic testing identifying recessive mutations in the potassium channel subunits of the beta-islet pancreatic cells. Potassium channel defects are often refractory to medical therapies, so near-total pancreatectomy is usually indicated; however, genetic mutations leading to metabolic dysregulation within the beta-islet pancreatic cells are usually responsive to medical therapy. Aggressive treatment of hypoglycemia in the setting of congenital hyperinsulinism is important to prevent long-term neurologic sequelae secondary to hypoglycemia-induced brain injury. [Pediatr Ann. 2017;46(11):e409-e414.]., (Copyright 2017, SLACK Incorporated.)

Epithelial membrane protein-2 (EMP2) is a tetraspan protein predicted to regulate placental development. Highly expressed in secretory endometrium and trophectoderm cells, previous studies suggest that it may regulate implantation by orchestrating the surface expression of integrins and other membrane proteins. In order to test the role of EMP2 in pregnancy, mice lacking EMP2 (Emp2 -/- ) were generated. Emp2 -/- females are fertile but have reduced litter sizes when carrying Emp2 -/- but not Emp2 +/- fetuses. Placentas of Emp2 -/- fetuses exhibit dysregulation in pathways related to neoangiogenesis, coagulation, and oxidative stress, and have increased fibrin deposition and altered vasculature. Given that these findings often occur due to placental insufficiency resulting in an oxygen-poor environment, the expression of hypoxia-inducible factor-1 alpha (HIF-1α) was examined. Placentas from Emp2 -/- fetuses had increased total HIF-1α expression in large part through an increase in uterine NK (uNK) cells, demonstrating a unique interplay between uNK cells and trophoblasts modulated through EMP2. To determine if these results translated to human pregnancy, placentas from normal, term deliveries or those complicated by placental insufficiency resulting in intrauterine growth restriction (IUGR) were stained for EMP2. EMP2 was significantly reduced in both villous and extravillous trophoblast populations in IUGR placentas. Experiments in vitro using human trophoblast cells lines indicate that EMP2 modulates angiogenesis by altering HIF-1α expression. Our results reveal a novel role for EMP2 in regulating trophoblast function and vascular development in mice and humans, and suggest that it may be a new biomarker for placental insufficiency. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd., (Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

Placental insufficiency leading to intrauterine growth restriction (IUGR) demonstrates perturbed gene expression affecting placental angiogenesis and nutrient transfer from mother to fetus. To understand the post-transcriptional mechanisms underlying such placental gene expression changes, our objective was to identify key non-coding microRNAs that express biological function. To this end, we initially undertook microarrays targeting microRNAs in a small sub-set of placentas of appropriate (AGA) versus small for gestational age (SGA) weight infants, and observed up-regulation of 97 miRs and down-regulation of 44 miRs in SGA versus AGA. In a larger cohort of samples (AGA, n = 21; SGA, n = 11; IUGR subset, n = 5), we validated by qRT-PCR differential expression of three specific microRNAs (miR-10b, -363 and -149) that target genes mediating angiogenesis and nutrient transfer. Validation yielded an increase in miR-10b and -363 expression of ~2.5-fold (p<0.02 each) in SGA versus AGA, and of ~3-fold (p<0.005) in IUGR versus AGA, with no significant change despite a trending increase in miR-149. To further establish a cause-and-effect paradigm, employing human HTR8 trophoblast cells, we assessed the effect of nutrient deprivation on miR expression and inhibition of endogenous miRs on target gene expression. In-vitro nutrient deprivation (~50%) increased the expression of miR-10b and miR-149 by 1.5-fold (p<0.02) while decreasing miR-363 (p<0.0001). Inhibition of endogenous miRs employing antisense sequences against miR-10b, -363 and -149 revealed an increase respectively in the expression of the target genes KLF-4 (transcription factor which regulates angiogenesis), SNAT1 and 2 (sodium coupled neutral amino acid transporters) and LAT2 (leucine amino acid transporter), which translated into a similar change in the corresponding proteins. Finally to establish functional significance we performed dual-luciferase reporter assays with 3'-insertion of miR-10b alone and observed a ~10% reduction in the 5'-luciferase activity versus the control. Lastly, we further validated by microarray and employing MirWalk software that the pathways and target genes identified by differentially expressed miRs in SGA/IUGR compared to AGA are consistent in a larger cohort. We have established the biological significance of various miRs that target common transcripts mediating pathways of importance, which are perturbed in the human IUGR placenta.

Intrauterine growth restriction (IUGR) affects up to 10% of pregnancies and often results in short- and long-term sequelae for offspring. The mechanisms underlying IUGR are poorly understood, but it is known that healthy placentation is essential for nutrient provision to fuel fetal growth, and is regulated by immunologic inputs. We hypothesized that in pregnancy, maternal food restriction (FR) resulting in IUGR would decrease the overall immunotolerant milieu in the placenta, leading to increased cellular stress and death. Our specific objectives were to evaluate (1) key cytokines (eg, IL-10) that regulate maternal-fetal tolerance, (2) cellular processes (autophagy and endoplasmic reticulum [ER] stress) that are immunologically mediated and important for cellular survival and functioning, and (3) the resulting IUGR phenotype and placental histopathology in this animal model. After subjecting pregnant mice to mild and moderate FR from gestational day 10 to 19, we collected placentas and embryos at gestational day 19. We examined RNA sequencing data to identify immunologic pathways affected in IUGR-associated placentas and validated messenger RNA expression changes of genes important in cellular integrity. We also evaluated histopathologic changes in vascular and trophoblastic structures as well as protein expression changes in autophagy, ER stress, and apoptosis in the mouse placentas. Several differentially expressed genes were identified in FR compared with control mice, including a considerable subset that regulates immune tolerance, inflammation, and cellular integrity. In summary, maternal FR decreases the anti-inflammatory effect of IL-10 and suppresses placental autophagic and ER stress responses, despite evidence of dysregulated vascular and trophoblast structures leading to IUGR., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Intrauterine growth restriction (IUGR) has been defined in several ways, but in general describes a condition in which the fetus exhibits poor growth in utero. This complication of pregnancy poses a significant public health burden as well as increased morbidity and mortality for the offspring. In human IUGR, alteration in fetal glucose and insulin homeostasis occurs in an effort to conserve energy and survive at the expense of fetal growth in an environment of inadequate nutrient provision. Several animal models of IUGR have been utilized to study the effects of IUGR on fetal glucose handling, as well as the postnatal reprogramming of energy metabolite handling, which may be unmasked in adulthood as a maladaptive propensity for cardiometabolic disease. This developmental programming may be mediated in part by epigenetic modification of essential regulators of glucose homeostasis. Several pharmacological therapies and nonpharmacological lifestyle modifications have shown early promise in mitigating the risk for or severity of adult metabolic phenotypes but still require further study of unanticipated and/or untoward side effects., (©2016 Int. Union Physiol. Sci./Am. Physiol. Soc.)

In recent decades, with advances in neonatal intensive care, extremely premature infants are now surviving into adulthood. Epidemiologic data on the health of these ex-premature infants have begun to reveal a concerning motif-that is, prematurity, in and of itself, seems to be a risk factor for cardiovascular and metabolic disease in later adulthood. The mechanisms underlying this increased risk are unclear, but it is believed that both adverse fetal environment and postnatal exposures for a premature infant likely contribute to the developmental programming of disease by altering the normal trajectory of maturation and aging of multiple organ systems. This article specifically focuses on perinatal factors that may affect risk for cardiovascular disease., (Copyright 2015, SLACK Incorporated.)

Necrotizing enterocolitis in full-term infants is relatively rare. When seen, it is usually associated with perinatal asphyxia, sepsis, or specific forms of congenital heart disease. It can also be associated with endocrinopathies. In this review, a full-term infant was found to have necrotizing enterocolitis and persistent hypoglycemia. Evaluation for hypoglycemia revealed pan-hypopituitarism, and magnetic resonance imaging confirmed this diagnosis. Timely evaluation and early initiation of hormone replacement therapy is essential to minimize long-term morbidities and mortality associated with pan-hypopituitarism., (Copyright 2015, SLACK Incorporated.)

Background: Ex-premature infants are at higher risk for hypertension and cardiovascular disease as adults, although the mechanisms underlying such increased risks are unknown. We hypothesize that postnatal exposure to intermittent hypoxia (IH) leads to cardiovascular dysfunction in adulthood with alterations of the renin-angiotensin pathway., Methods: Neonatal mice were exposed to IH for 4 wk. At the age of 3 mo, various cardiovascular measurements were obtained., Results: IH-exposed mice exhibited higher systolic blood pressure, impaired baroreflex responses, and decreased heart rate variability. Furthermore, IH-exposed mice manifested evidence of endothelial dysfunction, as shown by reduced reperfusion indices after tail vessel occlusion and impaired vasodilatory responses to acetylcholine. CD31(+) endothelial cells isolated from mesenteric arteries of IH-exposed mice expressed higher levels of angiotensin-converting enzyme and reactive oxygen species; plasma angiotensin-II levels were also significantly higher in these animals. In addition, DNA methylation patterns of the Ace1 and the Agt genes in these cells were congruent with their expression patterns., Conclusion: Our results suggest that exposures to postnatal IH alter the normal development of the renin-angiotensin system and promote the occurrence of cardiovascular dysfunction during adulthood in mice.