Understanding the Role of Endothelial Cells in Glioblastoma: Mechanisms and Novel Treatments.

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.

PRENATAL MATERNAL CHARACTERISTICS ASSOCIATED WITH RETINOPATHY OF PREMATURITY.

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.

A MULTICENTER STUDY OF RETINOPATHY OF PREMATURITY FOLLOW-UP ADHERENCE.

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.

Maternal-Neonatal Dyad Outcomes of Maternal COVID-19 Requiring Extracorporeal Membrane Support: A Case Series.

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..

The Association between LGBTQIA+ Self-Identification and Factors Facilitating Homelessness: A Scoping Review of the Occupational Therapy Peer-Reviewed Literature.

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.

Epithelial membrane protein 2 (EMP2) deficiency alters placental angiogenesis, mimicking features of human placental insufficiency.

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.

Intrauterine Growth Restriction: Hungry for an Answer.

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.

Cardiovascular dysfunction in adult mice following postnatal intermittent hypoxia.

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.

Hypotension following patent ductus arteriosus ligation: the role of adrenal hormones.

OBJECTIVE: To test the hypothesis that an impaired adrenal response to stress might play a role in the hypotension that follows patent ductus arteriosus (PDA) ligation. STUDY DESIGN: We performed a multicenter study of infants born at <32 weeks' gestation who were about to undergo PDA ligation. Serum adrenal steroids were measured 3 times: before and after a cosyntropin (1.0 µg/kg) stimulation test (performed before the ligation), and at 10-12 hours after the ligation. A standardized approach for diagnosis and treatment of postoperative hypotension was followed at each site. A modified inotrope score (1 × dopamine [µg/kg/min] + 1 × dobutamine) was used to monitor the catecholamine support an infant received. Infants were considered to have catecholamine-resistant hypotension if their greatest inotrope score was >15. RESULTS: Of 95 infants enrolled, 43 (45%) developed hypotension and 14 (15%) developed catecholamine-resistant hypotension. Low postoperative cortisol levels were not associated with the overall incidence of hypotension after ligation. However, low cortisol levels were associated with the refractoriness of the hypotension to catecholamine treatment. In a multivariate analysis: the OR for developing catecholamine-resistant hypotension was OR 36.6, 95% CI 2.8-476, P = .006. Low cortisol levels (in infants with catecholamine-resistant hypotension) were not attributable to adrenal immaturity or impairment; their cortisol precursor concentrations were either low or unchanged, and their response to cosyntropin was similar to infants without catecholamine-resistant hypotension. CONCLUSION: Infants with low cortisol concentrations after PDA ligation are likely to develop postoperative catecholamine-resistant hypotension. We speculate that decreased adrenal stimulation, rather than an impaired adrenal response to stimulation, may account for the decreased production.

Epithelial Membrane Protein 2 (EMP2) Blockade Attenuates Pathological Neovascularization in Murine Oxygen-Induced Retinopathy.

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.

Retinopathy of Prematurity: The Role of Nutrition.

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.].

Neurodevelopmental Outcomes in Infants Screened for Retinopathy of Prematurity.

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.

The nonimpact of gestational age on neurodevelopmental outcome for ventilated survivors born at 23-28 weeks of gestation.

AIM: It has long been known that survival of preterm infants strongly depends upon birth weight and gestational age. This study addresses a different question - whether the gestational maturity improves neurodevelopmental outcomes for ventilated infants born at 23-28 weeks who survive to neonatal intensive care unit (NICU) discharge. METHODS: We performed a prospective cohort study of 199 ventilated infants born between 23 and 28 weeks of gestation. Neurodevelopmental impairment was determined using the Bayley Scales of Infant Development-II at 24 months. RESULTS: As expected, when considered as a ratio of all births, both survival and survival without neurodevelopmental impairment were strongly dependent on gestational age. However, the percentage of surviving infants who displayed neurodevelopmental impairment did not vary with gestational age for any level of neurodevelopmental impairment (MDI or PDI <50, <60, <70). Moreover, as a higher percentage of ventilated infants survived to NICU discharge at higher gestational ages, but the percentage of neurodevelopmental impairment in NICU survivors was unaffected by gestational age, the percentage of all ventilated births who survived with neurodevelopmental impairment rose - not fell - with increasing gestation age. CONCLUSION: For physicians, parents and policy-makers whose primary concern is the presence of neurodevelopmental impairment in infants who survive the NICU, reliance on gestational age appears to be misplaced.

Acute and Protracted Prenatal Stress Produce Mood Disorder-Like and Ethanol Drinking Behaviors in Male and Female Adult Offspring.

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.

ECMO utilization in infants with congenital diaphragmatic hernia in the USA.

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 χ2 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.

Characterization of Foveal Development in Treatment-Naïve Extremely Preterm Infants.

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.

Decreased Levels of Erythrocyte Membrane Arachidonic and Docosahexaenoic Acids Are Associated With Retinopathy of Prematurity.

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.

Association Between Social Determinants of Health and Retinopathy of Prematurity Outcomes.

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.

Real-World Visual Outcomes of Laser and Anti-VEGF Treatments for Retinopathy of Prematurity.

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.

Epithelial membrane protein 2 (EMP2) regulates hypoxia-induced angiogenesis in the adult retinal pigment epithelial cell lines.

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.