Father's care uniquely influences male neurodevelopment.

Mammalian infants depend on parental care for survival, with numerous consequences for their behavioral development. We investigated the epigenetic and neurodevelopmental mechanisms mediating the impact of early biparental care on development of alloparenting behavior, or caring for offspring that are not one's own. We find that receiving high parental care early in life leads to slower epigenetic aging of both sexes and widespread male-specific differential expression of genes related to synaptic transmission and autism in the nucleus accumbens. Examination of parental care composition indicates that high-care fathers promote a male-specific increase in excitatory synapses and increases in pup retrieval behavior as juveniles. Interestingly, females raised by high-care fathers have the opposite behavioral response and display fewer pup retrievals. These results support the concept that neurodevelopmental trajectories are programmed by different features of early-life parental care and reveal that male neurodevelopmental processes are uniquely sensitive to care by fathers.

Premature infants with gestational age less than 25 weeks require increased ophthalmology resources for retinopathy of prematurity.

BACKGROUND: It is unclear how increasing survival of low gestational age (GA) infants affects ophthalmologic screening and treatment rates for retinopathy of prematurity (ROP). This study compared the examination and treatment rates of infants born at GA of <25 weeks and those born at GA of at least 25 weeks. METHODS: This was a retrospective study of patients who met institutional ROP screening criteria and were admitted to two neonatal intensive care units (NICUs) from January 2017 to June 2020. Variables analyzed were GA, birth weight, number of ophthalmology examinations, worst stage of ROP, presence of type 1 ROP, and comorbidities associated with ROP. The χ2, Fisher exact, and two-tailed t tests, as well as univariate and multivariable logistic regression, were used for statistical analysis. RESULTS: Compared to the GA≥25 group, the GA<25 group had a higher number of total exams (10 vs 4.3 [P < 0.001]), higher average worst stage of ROP (1.4 vs 0.3 [P < 0.001]) and higher rate of type 1 ROP (21% vs 1.4% [P < 0.001]), as well as higher mortality (37% vs 8.11% [P < 0. 001]). Multivariable logistic regression analysis controlling for GA, sepsis, and number of transfusions revealed that only GA was significantly associated with developing type 1 ROP. CONCLUSIONS: Infants with GA <25 weeks had more severe ROP and required significantly more ophthalmologic examinations than GA ≥25. It is important for ROP services to plan for this increased screening load, especially if the number of such lower-weight infants in their NICUs increases.

The time and financial ramifications of providing services for retinopathy of prematurity at a single inner-city institution in the United States: a pilot study.

BACKGROUND: Retinopathy of prematurity (ROP) is a sight-threatening disease that requires strict, scheduled screening and timely treatment. Examining infants in the neonatal intensive care unit (NICU) confers an added burden for ophthalmologists whose practices are predominantly outpatient. We sought to evaluate the time required for ROP services and to approximate compensation to better understand the implications of providing this crucial service. METHODS: The ROP coordinator tracked the time ophthalmologists spent providing ROP services at two NICUs (2018-2020). Estimated revenue was calculated using Medicaid Current Procedural Terminology codes. Total ophthalmologist time was from NICU arrival to departure; travel time was estimated as 45 minutes. RESULTS: The ophthalmologists cumulatively spent on average 98 and 108 hours yearly for screening only (SO) and screening plus treatment (ST), respectively; this increased to 164 and 181 hours yearly with travel time, respectively. Estimated annual Medicaid physician reimbursements were $15,246 ($156/hour) for SO and $19,184 for ST ($177/hour). Actual annual physician reimbursements were $39,655 ($405/hour) for SO and $53,385 for ST ($492/hour). With travel time, reimbursements decreased by about 40%. A hypothetical full-time ROP practice would generate annual physician salaries of $204,732 for SO and $232,807 for ST. With travel time, this decreases to $122,452 and $139,379, respectively. CONCLUSIONS: Performing ROP services requires substantial time, especially when including travel among facilities. This study highlights the extensive requirements for the critical task of decreasing ROP blindness.

Comparison of Visual Acuity Results Between ATS-HOTV and E-ETDRS Testing Methods in Children With Optic Pathway Gliomas.

Purpose: To determine if visual acuity (VA) outcomes are comparable using the amblyopia treatment study HOTV protocol (ATS-HOTV) and electronic Early Treatment of Diabetic Retinopathy Study (E-ETDRS) protocol in children with optic pathway gliomas (OPGs). Methods: Children enrolled in a prospective study of OPGs were eligible if they completed both the ATS-HOTV and E-ETDRS during the same visit. The contribution of age, testing order, having neurofibromatosis type 1, visual field loss, and circumpapillary retinal nerve fiber layer thickness to VA difference were assessed using generalized estimating equations to account for the intereye correlation. Results: Forty-eight children (median age, 10.3 years; range, 5.2-17.1 years; 49% female) met inclusion criteria and contributed 93 study eyes at their initial visit. Eleven patients (22 eyes) had more than one study visit, permitting longitudinal evaluation. ATS-HOTV measures of VA were higher than E-ETDRS at the initial (0.13 ± 0.36 vs. 0.23 ± 0.39 logarithm of the minimum angle of resolution [logMAR], P < 0.001) and all visits (0.13 ± 0.34 vs. 0.21 ± 0.36 logMAR, P < 0.001). VA remained significantly higher with ATS-HOTV regardless of test order, but the mean difference between tests was most profound when tested with ATS-HOTV first compared to E-ETDRS first (P < 0.001). Conclusions: VA results differ significantly between the ATS-HOTV and E-ETDRS testing methods in children with OPGs. Given the wide range of ages and testing ability of children, one VA testing method should be used throughout longitudinal OPG clinical trials. Translational Relevance: It is imperative that age-appropriate VA testing methods are standardized across all pediatric OPG clinical trials.

Changes in institutional oxygen saturation targets are associated with an increased rate of severe retinopathy of prematurity.

PURPOSE: To evaluate the effect of changes in institutional peripheral oxygen saturation (SpO2) targets, made in response to recent randomized trials, on risk of developing severe retinopathy of prematurity (ROP). METHODS: This study was a secondary analysis of data from 21 North American hospitals during the periods 2006-2012 and 2015-2017. Hospitals were categorized based on whether or not SpO2 targets were increased between the two study periods. Severe ROP (type 1, type 2, or zone III stage 3+) rates were compared within and between groups. Generalized mixed effect models with random intercepts were used to account for within-center clustering and to calculate odds ratios (aOR) adjusted by birth weight (BW) and gestational age (GA), using patient-level data. RESULTS: A total of 8,142 infants underwent ROP examinations at 21 hospitals during the two study periods: 5,716 in 2006-2012 (mean BW, 1109 ± 369 g; GA, 28.0 ± 2.6; 11.6% severe ROP); 2,426 in 2015-2017 (mean BW, 1086 ± 347 g; GA, 28.0 ± 2.8; 12.8% severe ROP). Fourteen hospitals increased SpO2 targets, and 7 hospitals did not. Hospitals that increased targets had a 3% increase in severe ROP (from 12% to 15%; aOR = 1.25; 95% CI, 1.01-1.55; P = 0.044); hospitals without SpO2 changes had a 2% decrease (from 11% to 9%; aOR = 0.72; 95% CI, 0.52-1.00; P = 0.049). The difference in change of severe ROP between groups of hospitals was significant (P = 0.005). CONCLUSIONS: Increases in institutional SpO2 targets in response to recent randomized trials were associated with increased severe ROP. Hospitals considering increasing their SpO2 targets should anticipate increases in rates of severe ROP and manage screening and treatment resources accordingly.

Implementation of telemedicine screening for retinopathy of prematurity in rural areas in Guatemala.

PURPOSE: To report findings of a telemedicine retinopathy of prematurity (ROP) screening program in six neonatal units in rural areas of Guatemala, using a portable, noncontact, 40° field digital fundus camera (Pictor Plus) operated by trained technicians. METHODS: National ROP Program Guidelines screening criteria were used: gestational age <36 weeks and/or birth weight (BW) <2000 g, or GA <36 weeks but BW ≥2000 g, with qualifying medical history. Retinal images were obtained by two technicians and graded by ophthalmologists experienced in ROP. Infants with signs of pre-plus or plus disease in one or both eyes were referred for clinical examination. Screening was stopped when retinal vessels in anterior zone II were normal on two successive evaluations or the infant had reached 45 week's postmenstrual age. RESULTS: A total of 418 of 1,890 eligible infants (22.1%) were screened. Mean GA was 33.9 ± 2.2 weeks (range, 27-36), and mean BW 1728.3 ± 379.3 g (range, 840-2830 g). Thirty-three infants (8.6%) developed plus or pre-plus disease, and 19 (58%) underwent ophthalmologic examination. Fifteen infants were confirmed with type 1 ROP, and 14 were treated. Mean GA of treated infants treated was 33.6 ± 3.0 weeks (range, 32-34.9), and mean BW was 1,646 ± 245.8 g (range, 1100-1774.1 g). CONCLUSIONS: Imaging with a noncontact fundus camera can facilitate detection of treatable ROP in countries with limited resources. Strengthening the health systems, including motivation and continued training of neonatal intensive care personnel is essential to improve and maintain program effectiveness. Reasons for, and interventions to address the low uptake of screening need to be explored to extend coverage of ROP screening to district hospitals in Guatemala.

Extending Hui-Walter framework to correlated outcomes with application to diagnosis tests of an eye disease among premature infants.

Diagnostic accuracy, a measure of diagnostic tests for correctly identifying patients with or without a target disease, plays an important role in evidence-based medicine. Diagnostic accuracy of a new test ideally should be evaluated by comparing to a gold standard; however, in many medical applications it may be invasive, costly, or even unethical to obtain a gold standard for particular diseases. When the accuracy of a new candidate test under evaluation is assessed by comparison to an imperfect reference test, bias is expected to occur and result in either overestimates or underestimates of its true accuracy. In addition, diagnostic test studies often involve repeated measurements of the same patient, such as the paired eyes or multiple teeth, and generally lead to correlated and clustered data. Using the conventional statistical methods to estimate diagnostic accuracy can be biased by ignoring the within-cluster correlations. Despite numerous statistical approaches have been proposed to tackle this problem, the methodology to deal with correlated and clustered data in the absence of a gold standard is limited. In this article, we propose a method based on the composite likelihood function to derive simple and intuitive closed-form solutions for estimates of diagnostic accuracy, in terms of sensitivity and specificity. Through simulation studies, we illustrate the relative advantages of the proposed method over the existing methods that simply treat an imperfect reference test as a gold standard in correlated and clustered data. Compared with the existing methods, the proposed method can reduce not only substantial bias, but also the computational burden. Moreover, to demonstrate the utility of this approach, we apply the proposed method to the study of National-Eye-Institute-funded Telemedicine Approaches to Evaluating of Acute-Phase Retinopathy of Prematurity (e-ROP), for estimating accuracies of both the ophthalmologist examination and the image evaluation.

International Classification of Retinopathy of Prematurity, Third Edition.

PURPOSE: The International Classification of Retinopathy of Prematurity is a consensus statement that creates a standard nomenclature for classification of retinopathy of prematurity (ROP). It was initially published in 1984, expanded in 1987, and revisited in 2005. This article presents a third revision, the International Classification of Retinopathy of Prematurity, Third Edition (ICROP3), which is now required because of challenges such as: (1) concerns about subjectivity in critical elements of disease classification; (2) innovations in ophthalmic imaging; (3) novel pharmacologic therapies (e.g., anti-vascular endothelial growth factor agents) with unique regression and reactivation features after treatment compared with ablative therapies; and (4) recognition that patterns of ROP in some regions of the world do not fit neatly into the current classification system. DESIGN: Review of evidence-based literature, along with expert consensus opinion. PARTICIPANTS: International ROP expert committee assembled in March 2019 representing 17 countries and comprising 14 pediatric ophthalmologists and 20 retinal specialists, as well as 12 women and 22 men. METHODS: The committee was initially divided into 3 subcommittees-acute phase, regression or reactivation, and imaging-each of which used iterative videoconferences and an online message board to identify key challenges and approaches. Subsequently, the entire committee used iterative videoconferences, 2 in-person multiday meetings, and an online message board to develop consensus on classification. MAIN OUTCOME MEASURES: Consensus statement. RESULTS: The ICROP3 retains current definitions such as zone (location of disease), stage (appearance of disease at the avascular-vascular junction), and circumferential extent of disease. Major updates in the ICROP3 include refined classification metrics (e.g., posterior zone II, notch, subcategorization of stage 5, and recognition that a continuous spectrum of vascular abnormality exists from normal to plus disease). Updates also include the definition of aggressive ROP to replace aggressive-posterior ROP because of increasing recognition that aggressive disease may occur in larger preterm infants and beyond the posterior retina, particularly in regions of the world with limited resources. ROP regression and reactivation are described in detail, with additional description of long-term sequelae. CONCLUSIONS: These principles may improve the quality and standardization of ROP care worldwide and may provide a foundation to improve research and clinical care.

Neurodevelopmental outcome of preterm infants enrolled in myo-inositol randomized controlled trial.

OBJECTIVE: This study evaluates the 24-month follow-up for the NICHD Neonatal Research Network (NRN) Inositol for Retinopathy Trial. STUDY DESIGN: Bayley Scales of Infants Development-III and a standardized neurosensory examination were performed in infants enrolled in the main trial. Moderate/severe NDI was defined as BSID-III Cognitive or Motor composite score <85, moderate or severe cerebral palsy, blindness, or hearing loss that prevents communication despite amplification were assessed. RESULTS: Primary outcome was determined for 605/638 (95%). The mean gestational age was 25.8 ± 1.3 weeks and mean birthweight was 805 ± 192 g. Treatment group did not affect the risk for the composite outcome of death or survival with moderate/severe NDI (60% vs 56%, p = 0.40). CONCLUSIONS: Treatment group did not affect the risk of death or survival with moderate/severe NDI. Despite early termination, this study represents the largest RCT of extremely preterm infants treated with myo-inositol with neurodevelopmental outcome data.

Associations between visual function and magnitude of refractive error for emmetropic to moderately hyperopic 4- and 5-year-old children in the Vision in Preschoolers - Hyperopia in Preschoolers Study.

PURPOSE: To evaluate associations between visual function and the level of uncorrected hyperopia in 4- and 5-year-old children without strabismus or amblyopia. METHODS: Children with spherical equivalent (SE) cycloplegic refractive error of -0.75 to +6.00 on eligibility testing for the Vision in Preschoolers-Hyperopia in Preschoolers (VIP-HIP) study were included. Children were grouped as emmetropic (<1D SE myopia or hyperopia), low hyperopic (+1 to <+3D SE) or moderate hyperopic (+3 to +6D SE). Children with anisometropia or astigmatism (≥1D), amblyopia or strabismus were excluded. Visual functions assessed were monocular distance visual acuity (VA) and binocular near VA with crowded HOTV charts, accommodative lag using the Monocular Estimation Method and near stereoacuity by 'Preschool Assessment of Stereopsis with a Smile'. Visual functions were compared as continuous measures among refractive error groups. RESULTS: 554 children (mean age 58 months) were included in the analysis. Mean SE (SD) {N} for emmetropia, low and moderate hyperopia were +0.52D (0.49) {N = 270}, +2.18D (0.57) {N = 171} and +3.95D (0.78) {N = 113}, respectively. There was a consistent trend of poorer visual function with increasing hyperopia (p < 0.001). Although all children had age-normal distance VA, logMAR (Snellen) VA of 0.00 (6/6) or better was achieved (distance, near) among more emmetropic (52%, 26%) and low hyperopic (47%, 15%) children than moderate hyperopes (25%, 9%). Mean (SD) distance logMAR VA declined from emmetropic 0.05 (0.10), to low hyperopic 0.06 (0.10) to moderately hyperopic children 0.12 (0.11) (p < 0.001); A mild progressive decrease in near VA also was observed from the emmetropic 0.13 (0.11) to low hyperopic 0.15 (0.10) to moderate hyperopic 0.19 (0.11) groups, (p < 0.001). Accommodative responses showed an increased lag with increasing hyperopia (ρ = 0.50, p < 0.001). Median near stereoacuity for emmetropes, low and moderate hyperopes was 40, 60 and 120 sec arc, respectively. The percentage of these groups with no reduced near visual functions was 83%, 61%, and 34%, respectively. CONCLUSIONS: Decreasing visual function was associated with increasing hyperopia in 4- and 5-year-olds without strabismus or amblyopia. As hyperopia with reduced visual function has been associated with early literacy deficits, near visual function should be evaluated in these children.

Genetic, epigenetic, and environmental factors controlling oxytocin receptor gene expression.

BACKGROUND: The neuropeptide oxytocin regulates mammalian social behavior. Disruptions in oxytocin signaling are a feature of many psychopathologies. One commonly studied biomarker for oxytocin involvement in psychiatric diseases is DNA methylation at the oxytocin receptor gene (OXTR). Such studies focus on DNA methylation in two regions of OXTR, exon 3 and a region termed MT2 which overlaps exon 1 and intron 1. However, the relative contribution of exon 3 and MT2 in regulating OXTR gene expression in the brain is currently unknown. RESULTS: Here, we use the prairie vole as a translational animal model to investigate genetic, epigenetic, and environmental factors affecting Oxtr gene expression in a region of the brain that has been shown to drive Oxtr related behavior in the vole, the nucleus accumbens. We show that the genetic structure of Oxtr in prairie voles resembles human OXTR. We then studied the effects of early life experience on DNA methylation in two regions of a CpG island surrounding the Oxtr promoter: MT2 and exon 3. We show that early nurture in the form of parental care results in DNA hypomethylation of Oxtr in both MT2 and exon 3, but only DNA methylation in MT2 is associated with Oxtr gene expression. Network analyses indicate that CpG sites in the 3' portion of MT2 are most highly associated with Oxtr gene expression. We also identify two novel SNPs in exon 3 of Oxtr in prairie voles and a novel alternative transcript originating from the third intron of the gene. Expression of the novel alternative transcript is associated with genotype at SNP KLW2. CONCLUSIONS: These results identify putative regulatory features of Oxtr in prairie voles which inform future studies examining OXTR in human social behaviors and disorders. These studies indicate that in prairie voles, DNA methylation in MT2, particularly in the 3' portion, is more predictive of Oxtr gene expression than DNA methylation in exon 3. Similarly, in human temporal cortex, we find that DNA methylation in the 3' portion of MT2 is associated with OXTR expression. Together, these results suggest that among the CpG sites studied, DNA methylation of MT2 may be the most reliable indicator of OXTR gene expression. We also identify novel features of prairie vole Oxtr, including SNPs and an alternative transcript, which further develop the prairie vole as a translational model for studies of OXTR.

Early angiographic signs of retinopathy of prematurity requiring treatment.

BACKGROUND/OBJECTIVES: Fluorescein angiography (FA) has been a pivotal tool to study the pathophysiology of retinopathy of prematurity (ROP) in vivo. We examined the course of ROP using FA in order to assess the predictive value of angiographic features. SUBJECTS/METHODS: This is an observational retrospective cohort multi-center study of eyes screened for ROP with binocular indirect ophthalmoscope and with FA. All infants undergoing screening examination for ROP who had retinal vasculature limited to Zone I and posterior Zone II vascularization underwent FA between 31 and 34 weeks postmenstrual age. RetCam fundus imaging and video digital fluorescein angiography were performed in the neonatal intensive care units. Masked grading of the FA images was retrospectively conducted by two ROP expert ophthalmologists. Ten criteria that describe retinovascular and choroidal features on FA were used to assess their predictive value for development of treatment-requiring ROP. RESULTS: A total of 98 eyes of 56 patients were included for this study. FAs of eyes of premature infants show a wide range of features either at the junction between the vascular and avascular retina and posteriorly to that. Among the angiographic features evaluated, leakage, shunts and hyperfluorescent lesions at the junction between vascular and avascular zone were predictive of the development of treatment-requiring ROP (p < 0.05), but findings in the posterior vascularized retina were not. CONCLUSIONS: FA can add to our understanding of the evolution of vascular abnormalities in the course of ROP and can help predict which eyes will go on to treatment.

Progression from preplus to plus disease in the Telemedicine Approaches to Evaluating Acute-Phase Retinopathy of Prematurity (e-ROP) Study: incidence, timing, and predictors.

PURPOSE: To determine the incidence of and timing and predictors for progression from pre-plus to plus disease, based on evaluation of images. METHODS: Two trained readers independently evaluated posterior pole images of infants from 13 North American centers for pre-plus/plus disease, stage, and zone of retinopathy of prematurity (ROP). Discrepancies between readers were adjudicated. To be eligible for analysis, eyes had to have at least two imaging sessions, the earlier one with pre-plus disease. RESULTS: Of 681 eyes of 444 infants with pre-plus first detected at mean postmenstrual age (PMA) of 35.5 ± 2.1 weeks, 54 (7.9%) progressed to plus disease at a mean PMA of 37.6 ± 2.4 weeks with the mean interval for progression of 2.7 weeks (range, 0.4-8.9 weeks). Progression rate was higher for eyes with larger number of quadrants of pre-plus (44% for eyes with four quadrants vs 4% with one quadrant [P < 0.0001]), earlier PMA with pre-plus (18% for 32 weeks' PMA vs 3% for PMA of >37 weeks [P = 0.02]), higher ROP stage (12% for stage 3, 2.5% for no ROP [P < 0.0001]), lower ROP zone (24% for zone I, 6% for zone II or no ROP [P < 0.0001]) at the time of first pre-plus detection. CONCLUSIONS: Based on image evaluation, 8% of eyes progressed from pre-plus to plus disease at a mean interval of 3 weeks. Pre-plus in multiple quadrants, higher stages of ROP, and lower zones of ROP were associated with higher risk of progression. Image evaluation for pre-plus may help in the identification of high-risk eyes for developing plus disease.