Melanin protects the skin and eyes from the harmful effects of UV irradiation, protects neural cells from toxic insults, and is required for sound conduction in the inner ear. Aberrant regulation of melanogenesis underlies skin disorders (melasma and vitiligo), neurologic disorders (Parkinson's disease), auditory disorders (Waardenburg's syndrome), and opthalmologic disorders (age related macular degeneration). Much of the core synthetic machinery driving melanin production has been identified; however, the spectrum of gene products participating in melanogenesis in different physiological niches is poorly understood. Functional genomics based on RNA-mediated interference (RNAi) provides the opportunity to derive unbiased comprehensive collections of pharmaceutically tractable single gene targets supporting melanin production. In this study, we have combined a high-throughput, cell-based, one-well/one-gene screening platform with a genome-wide arrayed synthetic library of chemically synthesized, small interfering RNAs to identify novel biological pathways that govern melanin biogenesis in human melanocytes. Ninety-two novel genes that support pigment production were identified with a low false discovery rate. Secondary validation and preliminary mechanistic studies identified a large panel of targets that converge on tyrosinase expression and stability. Small molecule inhibition of a family of gene products in this class was sufficient to impair chronic tyrosinase expression in pigmented melanoma cells and UV-induced tyrosinase expression in primary melanocytes. Isolation of molecular machinery known to support autophagosome biosynthesis from this screen, together with in vitro and in vivo validation, exposed a close functional relationship between melanogenesis and autophagy. In summary, these studies illustrate the power of RNAi-based functional genomics to identify novel genes, pathways, and pharmacologic agents that impact a biological phenotype and operate outside of preconceived mechanistic relationships.

Objective To describe social disparities in early intervention service use and provider-reported outcomes. Methods Secondary data analysis of administrative data to ascertain EI service use of all EI and discipline-specific services and child and family characteristics. Adjusted logistic regression models estimated the odds of receiving each type of core EI service. Adjusted median regression models estimated differences in EI intensity for each type of core EI service. Adjusted ordinal regression models estimated the association between each type of EI therapy service and provider estimates of children’s global functional improvement. Results Children with a diagnosis (b=0.8 SE=0.2) and those whose caregiver had 12 years of education or less (b=0.6 SE=0.3) had higher EI intensity. Black, non-Hispanic (BNH) children had nearly 75% lower odds of receiving physical therapy (PT) [OR=0.3, 95%CI:0.1, 0.7] and greater odds of receiving speech therapy [OR=3.4, 95%CI:1.3, 9.3] than their white, non-Hispanic (WNH) peers. BNH who received PT received about an hour less per month (b=−0.7 SE=0.4) than their WNH peers. Hispanic children [b=1.0 SE=0.3)] and those with higher family income (b=0.7 SE=0.3) received greater intensity of PT compared to their peers who are WNH and from low-income families. Publically insured children had lower intensity of OT (b=−0.5 SE=0.3) and ST (b=−0.6 SE=0.3). Greater intensity of EI services was not associated with greater provider perceived improvement. Conclusions Results suggest disparities, by race and family income, in receipt of EI therapy services. These findings highlight opportunities to customize and coordinate care for improved EI access and care quality.

Key Points Question What is the timeliness and service intensity of children enrolled in early intervention, and is service intensity associated with greater gains in function? Findings In this cohort study, more than half of the study children received delayed early intervention access and most received low-intensity early intervention services. An additional hour per month of early intervention services was associated with a 3-point gain in functional outcomes. Meaning Linking clinical and early intervention records could help integrate data to track early intervention–eligible children and improve early intervention timeliness, service intensity, and outcomes.

BackgroundElectronic patient-reported outcomes (e-PROs) may provide valid and feasible options for obtaining family input on their child’s functioning for care planning and outcome monitoring, but they have not been adopted into early intervention (EI). The purpose of this pilot study was to evaluate the feasibility of implementing technology-based functional assessment into EI practice and to examine child, family, service, and environmental correlates of caregiver-reported child functioning in the home.MethodsIn a cross-sectional design, eight individual EI providers participated in a 90-min technology-based functional assessment training to recruit participants and a 60-min semi-structured focus group post data collection. Participants completed the Young Children’s Participation and Environment Measure (YC-PEM) home section online and Pediatric Evaluation of Disability Inventory Computer Adaptive Test (PEDI-CAT) via iPad. Participants’ EI service use data were obtained from administrative records.ResultsA total of 37 caregivers of children between 6 and 35 months old (mean age = 19.4, SD = 7.7) enrolled, a rate of 44% (37/84) in 2.5 months. Providers suggested expanding staff training, gathering data during scheduled evaluations, and providing caregivers and providers with access to assessment summaries. Caregivers wanted their child’s participation to change in 56% of home activities. Lower caregiver education and higher EI intensity were related to less child involvement in home activities.ConclusionsImplementing technology-based functional assessment is feasible with modifications, and these data can be useful for highlighting child, family, and EI service correlates of caregiver-reported child functioning that merit further study. Feasibility results informed protocol modifications related to EI provider training, timing of data collection, and management of EI service use data extraction, as preparation for a subsequent scale-up study that is underway.

Background: Early Intervention (EI) is a federally mandated, state-administered system of care for children with developmental delays and disabilities under the age of three. Gaps exist in the process of accessing EI through pediatric primary care, and low rates of EI access are well documented and disproportionately affect poor and minority children. The aims of this paper are to examine child characteristics associated with gaps in EI (1) referral, (2) access and (3) service use. To our knowledge, this is the first study to leverage linked safety net health system pediatric primary care and EI records data to follow EI-referred children longitudinally to understand EI service use gaps from EI referral to EI service utilization. Methods: In a retrospective cohort design (14,710 children with developmental disability or delay), we linked pediatric primary care records between a large, integrated safety net health system in metro Denver and its corresponding EI program (2014-2016). Using adjusted marginal effects [ME, (95% CI)], we estimated gaps in EI referral, access, and service type (i.e., physical [PT], occupational [OT], speech therapy [ST] and developmental intervention [DI]). Analyses accounted for child characteristics including socio-demographics, diagnosis, condition severity, and baseline function. Results: Only 18.7% of EI-eligible children (N = 2726) received a referral; 26% of those (N = 722) received services for a net enrollment rate of 5% among EI-eligible children. Having the most severe developmental condition was positively associated with EI referral [ME = 0.334 [0.249, 0.420]) and Individualized Family Services Plan (IFSP) receipt [ME = 0.156 [0.088, 0.223]). Children less likely to be EI-referred were Black, non-Hispanic (BNH) [ME =-0.029 (− 0.054, − 0.004)] and had a diagnosed condition ([ME = − 0.046 (− 0.087, − 0.005)]. Children with a diagnosis and those with higher income were more likely to receive PT or OT. Higher baseline cognitive and adaptive skills were associated with lower likelihood of PT [ME =-0.029 (− 0.054, − 0.004)], OT [ME =-0.029 (− 0.054, − 0.004)], and ST [ME =-0.029 (− 0.054, − 0.004)]. Conclusions: We identified and characterized gaps in EI referral, access, and service use in an urban safety-net population of children with high rates of developmental delay. Interventions are needed to improve integrated systems of care affecting primary care and EI processes and coordination.