Skipping the Line: Inequality in Access to Developmental-Behavioral Care.

CASE: The mother of an 18-month-old boy contacted the developmental and behavioral pediatrics clinic to request an evaluation because of concerns that her son is not using any words and only recently began walking. The child's mother became upset when she was notified that the clinic policy requires receipt of a formal request for evaluation from the primary care physician and that the first available appointment was in 9 months. Later that day, the child's grandmother contacted the clinic and reported that she is a member of the Donor Society affiliated with the university/medical system. Membership in the Donor Society is granted to individuals who have met specific philanthropic thresholds benefiting the university. One benefit to members of the Donor Society is the ability to access subspecialty medical services for themselves and their family members, across all disciplines, within 5 business days of their request.After confirming the details of the Donor Society promise with the philanthropic department of the hospital, a small committee of professionals within the clinic gathered to discuss the implications of this promised benefit to Donor Society members. This clinic is the only source for specialized, multidisciplinary developmental-behavioral health care that accepts public insurance within a 200-mile radius. The current waitlist for evaluation is 9 to 15 months depending on the reason for referral, and approximately 75% of patients on the waitlist receive some form of public assistance and/or live in a rural or underserved area. During the discussion, it was noted that there are 2 developmental-behavioral pediatric clinicians who practice within a cash-based private practice setting in the community. The waitlist for that practice was recently reported to be 3 to 6 months depending on the reason for evaluation, but that practice also requires a referral from the primary care physician before scheduling an initial evaluation.How would you recommend that the clinicians in the developmental and behavioral pediatrics clinic respond to the request to fulfill the promises made by the university to members of the Donor Society? How does a promise such as this one made to the Donor Society affect structural inequalities within the health care system and what strategies could be used to mitigate further inequalities that may result?

Screening for Anemia in Children with Down Syndrome.

OBJECTIVE: As part of the 2011 American Academy of Pediatrics (AAP) health supervision guidelines for children with Down syndrome (DS), annual screening for iron deficiency anemia is recommended between the ages of 1 and 18 years, but the evidence supporting this recommendation is limited. This study aimed to assess the prevalence of anemia in patients with DS between the ages of 1 and 18 years to provide additional evidence for the AAP 2011 guideline recommendations for annual hemoglobin and ferritin screening in patients with DS. METHODS: A retrospective cohort study was completed by obtaining data from the electronic health record (EHR) for patients meeting the following inclusion criterion: a diagnosis of DS in patients aged 1 to 18 years seen at our institution with hemoglobin drawn between July 2012 and 2016. Data were analyzed by the Fisher exact test and χ test. RESULTS: A total of 200 patients were identified. 22.5% had anemia, defined as a hemoglobin concentration less than 2 SDs for normed age. The National Health and Nutrition Examination Survey (2007-2010) reported prevalence of anemia for children aged 1 to 5 years is 3.2% when compared with 18.7% in our sample. Of the 45 children with anemia, 5% had a microcytic, 67.5% a normocytic, and 27.5% a macrocytic anemia. Only 10 received a diagnosis of anemia in the EHR. CONCLUSION: The prevalence of anemia in this cohort of children with DS is significantly higher than that in the general population, supporting the AAP guidelines for an annual screening until the age of 18 years.

Preventing elopement in children with autism spectrum disorder.

Reports of missing children with autism spectrum disorder (ASD) are common in the media, and elopement can lead to dire consequences. This study quantified the use of preventive measures that target elopement, plus identified child/family characteristics associated with elopement and the use of preventive measures. This cross-sectional study included 394 caregivers of children ages 2-17 years with ASD followed in an academic medical center's Developmental-Behavioral Pediatrics clinic. Details about elopement, preventive measure use, and sociodemographic characteristics were assessed via an investigator-designed, parent advocate-approved questionnaire, while pertinent clinical factors were extracted from patients' electronic health records. Two hundred and sixty-seven caregivers (68%) reported elopement by their child. Elopement risk was not associated with sociodemographic characteristics, nor with any specific comorbidity or neurobehavioral medication. Children with limited communication skills were more likely to have a history of elopement (OR 2.24, 95% CI 1.30-3.84; P = 0.004). The most common preventive measure used was lock(s) at top of doors (51%), while less than a quarter of families were using handicap permits, signs/visual markers, or tracking devices. Implementation of certain modifications was statistically associated with socioeconomic status and comorbidities of interest. In addition to supporting previous literature about the increased elopement risk in children with limited communication skills, this study is the first to reveal that caregiver use of numerous preventive measures varies widely. The associations noted with use of specific preventive measures can help guide recommendations for this dangerous comorbid symptom, and provide information needed for future studies to assess the efficacy of various preventive measures. Autism Res 2019, 12: 1139-1146. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Elopement, defined as leaving an area without permission and placing oneself in a potentially dangerous situation, is a behavior exhibited by many children with autism. There is little information about the use of various modifications that target elopement in the pediatric population. This study identifies child/family characteristics that were related to elopement and the use of modifications, and stresses the importance of counseling families of children with autism about elopement.

Ancestry of the Timorese: age-related macular degeneration associated genotype and allele sharing among human populations from throughout the world.

We observed that the third leading cause of blindness in the world, age-related macular degeneration (AMD), occurs at a very low documented frequency in a population-based cohort from Timor-Leste. Thus, we determined a complete catalog of the ancestry of the Timorese by analysis of whole exome chip data and haplogroup analysis of SNP genotypes determined by sequencing the Hypervariable I and II regions of the mitochondrial genome and 17 genotyped YSTR markers obtained from 535 individuals. We genotyped 20 previously reported AMD-associated SNPs in the Timorese to examine their allele frequencies compared to and between previously documented AMD cohorts of varying ethnicities. For those without AMD (average age > 55 years), genotype and allele frequencies were similar for most SNPs with a few exceptions. The major risk allele of HTRA1 rs11200638 (10q26) was at a significantly higher frequency in the Timorese, as well as 3 of the 5 protective CFH (1q32) SNPs (rs800292, rs2284664, and rs12066959). Additionally, the most commonly associated AMD-risk SNP, CFH rs1061170 (Y402H), was also seen at a much lower frequency in the Korean and Timorese populations than in the assessed Caucasian populations (C ~7 vs. ~40%, respectively). The difference in allele frequencies between the Timorese population and the other genotyped populations, along with the haplogroup analysis, also highlight the genetic diversity of the Timorese. Specifically, the most common ancestry groupings were Oceanic (Melanesian and Papuan) and Eastern Asian (specifically Han Chinese). The low prevalence of AMD in the Timorese population (2 of 535 randomly selected participants) may be due to the enrichment of protective alleles in this population at the 1q32 locus.

Genetic variants associated with severe retinopathy of prematurity in extremely low birth weight infants.

PURPOSE: To determine genetic variants associated with severe retinopathy of prematurity (ROP) in a candidate gene cohort study of US preterm infants. METHODS: Preterm infants in the discovery cohort were enrolled through the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network, and those in the replication cohort were from the University of Iowa. All infants were phenotyped for ROP severity. Because of differences in the durations of enrollment between cohorts, severe ROP was defined as threshold disease in the discovery cohort and as threshold disease or type 1 ROP in the replication cohort. Whole genome amplified DNA from stored blood spot samples from the Neonatal Research Network biorepository was genotyped using an Illumina GoldenGate platform for candidate gene single nucleotide polymorphisms (SNPs) involving angiogenic, developmental, inflammatory, and oxidative pathways. Three analyses were performed to determine significant epidemiologic variables and SNPs associated with levels of ROP severity. Analyses controlled for multiple comparisons, ancestral eigenvalues, family relatedness, and significant epidemiologic variables. Single nucleotide polymorphisms significantly associated with ROP severity from the discovery cohort were analyzed in the replication cohort and in meta-analysis. RESULTS: Eight hundred seventeen infants in the discovery cohort and 543 in the replication cohort were analyzed. Severe ROP occurred in 126 infants in the discovery and in 14 in the replication cohort. In both cohorts, ventilation days and seizure occurrence were associated with severe ROP. After controlling for significant factors and multiple comparisons, two intronic SNPs in the gene BDNF (rs7934165 and rs2049046, P < 3.1 × 10(-5)) were associated with severe ROP in the discovery cohort and were not associated with severe ROP in the replication cohort. However, when the cohorts were analyzed together in an exploratory meta-analysis, rs7934165 increased in associated significance with severe ROP (P = 2.9 × 10(-7)). CONCLUSIONS: Variants in BDNF encoding brain-derived neurotrophic factor were associated with severe ROP in a large candidate gene study of infants with threshold ROP.

Population genetic structure of traditional populations in the Peruvian Central Andes and implications for South American population history.

Molecular-based characterizations of Andean peoples are traditionally conducted in the service of elucidating continent-level evolutionary processes in South America. Consequently, genetic variation among "western" Andean populations is often represented in relation to variation among "eastern" Amazon and Orinoco River Basin populations. This west-east contrast in patterns of population genetic variation is typically attributed to large-scale phenomena, such as dual founder colonization events or differing long-term microevolutionary histories. However, alternative explanations that consider the nature and causes of population genetic diversity within the Andean region remain underexplored. Here we examine population genetic diversity in the Peruvian Central Andes using data from the mtDNA first hypervariable region and Y-chromosome short tandem repeats among 17 newly sampled populations and 15 published samples. Using this geographically comprehensive data set, we first reassessed the currently accepted pattern of western versus eastern population genetic structure, which our results ultimately reject: mtDNA population diversities were lower, rather than higher, within Andean versus eastern populations, and only highland Y-chromosomes exhibited significantly higher within-population diversities compared with eastern groups. Multiple populations, including several highland samples, exhibited low genetic diversities for both genetic systems. Second, we explored whether the implementation of Inca state and Spanish colonial policies starting at about ad 1400 could have substantially restructured population genetic variation and consequently constitute a primary explanation for the extant pattern of population diversity in the Peruvian Central Andes. Our results suggest that Peruvian Central Andean population structure cannot be parsimoniously explained as the sole outcome of combined Inca and Spanish policies on the region's population demography: highland populations differed from coastal and lowland populations in mtDNA genetic structure only; highland groups also showed strong evidence of female-biased gene flow and/or effective sizes relative to other Peruvian ecozones. Taken together, these findings indicate that population genetic structure in the Peruvian Central Andes is considerably more complex than previously reported and that characterizations of and explanations for genetic variation may be best pursued within more localized regions and defined time periods.

Fructokinase, Fructans, Intestinal Permeability, and Metabolic Syndrome: An Equine Connection?

Fructose is a simple sugar present in honey and fruit, but can also exist as a polymer (fructans) in pasture grasses. Mammals are unable to metabolize fructans, but certain gram positive bacteria contain fructanases and can convert fructans to fructose in the gut. Recent studies suggest that fructose generated from bacteria, or directly obtained from the diet, can induce both increased intestinal permeability and features of metabolic syndrome, especially the development of insulin resistance. The development of insulin resistance is driven in part by the metabolism of fructose by fructokinase C in the liver, which results in oxidative stress in the hepatocyte. Similarly, the metabolism of fructose in the small bowel by intestinal fructokinase may lead to increased intestinal permeability and endotoxemia. While speculative, these observations raise the possibility that the mechanism by which fructans induce laminitis could involve intestinal and hepatic fructokinase. Further studies are indicated to determine the role of fructanases, fructose and fructokinase in equine metabolic syndrome and laminitis.

Comparative genomic and phylogenetic approaches to characterize the role of genetic recombination in mycobacterial evolution.

The genus Mycobacterium encompasses over one hundred named species of environmental and pathogenic organisms, including the causative agents of devastating human diseases such as tuberculosis and leprosy. The success of these human pathogens is due in part to their ability to rapidly adapt to their changing environment and host. Recombination is the fastest way for bacterial genomes to acquire genetic material, but conflicting results about the extent of recombination in the genus Mycobacterium have been reported. We examined a data set comprising 18 distinct strains from 13 named species for evidence of recombination. Genomic regions common to all strains (accounting for 10% to 22% of the full genomes of all examined species) were aligned and concatenated in the chromosomal order of one mycobacterial reference species. The concatenated sequence was screened for evidence of recombination using a variety of statistical methods, with each proposed event evaluated by comparing maximum-likelihood phylogenies of the recombinant section with the non-recombinant portion of the dataset. Incongruent phylogenies were identified by comparing the site-wise log-likelihoods of each tree using multiple tests. We also used a phylogenomic approach to identify genes that may have been acquired through horizontal transfer from non-mycobacterial sources. The most frequent associated lineages (and potential gene transfer partners) in the Mycobacterium lineage-restricted gene trees are other members of suborder Corynebacterinae, but more-distant partners were identified as well. In two examined cases of potentially frequent and habitat-directed transfer (M. abscessus to Segniliparus and M. smegmatis to Streptomyces), observed sequence distances were small and consistent with a hypothesis of transfer, while in a third case (M. vanbaalenii to Streptomyces) distances were larger. The analyses described here indicate that whereas evidence of recombination in core regions within the genus is relatively sparse, the acquisition of genes from non-mycobacterial lineages is a significant feature of mycobacterial evolution.

Systems biology-based analysis implicates a novel role for vitamin D metabolism in the pathogenesis of age-related macular degeneration.

Vitamin D has been shown to have anti-angiogenic properties and to play a protective role in several types of cancer, including breast, prostate and cutaneous melanoma. Similarly, vitamin D levels have been shown to be protective for risk of a number of conditions, including cardiovascular disease and chronic kidney disease, as well as numerous autoimmune disorders such as multiple sclerosis, inflammatory bowel diseases and type 1 diabetes mellitus. A study performed by Parekh et al. was the first to suggest a role for vitamin D in age-related macular degeneration (AMD) and showed a correlation between reduced serum vitamin D levels and risk for early AMD. Based on this study and the protective role of vitamin D in diseases with similar pathophysiology to AMD, we examined the role of vitamin D in a family-based cohort of 481 sibling pairs. Using extremely phenotypically discordant sibling pairs, initially we evaluated the association of neovascular AMD and vitamin D/sunlight-related epidemiological factors. After controlling for established AMD risk factors, including polymorphisms of the genes encoding complement factor H (CFH) and age-related maculopathy susceptibility 2/HtrA serine peptidase (ARMS2/HTRA1), and smoking history, we found that ultraviolet irradiance was protective for the development of neovascular AMD (p = 0.001). Although evaluation of serum vitamin D levels (25-hydroxyvitamin D [25(OH)D]) was higher in unaffected individuals than in their affected siblings, this finding did not reach statistical significance. Based on the relationship between ultraviolet irradiance and vitamin D production, we employed a candidate gene approach for evaluating common variation in key vitamin D pathway genes (the genes encoding the vitamin D receptor [VDR]; cytochrome P450, family 27, subfamily B, polypeptide 1 [CYP27B1]; cytochrome P450, family 24, subfamily A, polypeptide 1 [CYP24A1]; and CYP27A1) in this same family-based cohort. Initial findings were then validated and replicated in the extended family cohort, an unrelated case-control cohort from central Greece and a prospective nested case-control population from the Nurse's Health Study and Health Professionals Follow-Up Studies, which included patients with all subtypes of AMD for a total of 2,528 individuals. Single point variants in CYP24A1 (the gene encoding the catabolising enzyme of the vitamin D pathway) were demonstrated to influence AMD risk after controlling for smoking history, sex and age in all populations, both separately and, more importantly, in a meta-analysis. This is the first report demonstrating a genetic association between vitamin D metabolism and AMD risk. These findings were also supplemented with expression data from human donor eyes and human retinal cell lines. These data not only extend previous biological studies in the AMD field, but further emphasise common antecedents between several disorders with an inflammatory/immunogenic component such as cardiovascular disease, cancer and AMD.

Inferring population continuity versus replacement with aDNA: a cautionary tale from the Aleutian Islands.

In The Aleutian and Commander Islands and Their Inhabitants (Philadelphia: Wistar Institute of Anatomy and Biology, 1945), Hrdlicka proposed a population replacement event in the Aleutian Islands approximately 1,000 years ago based on a perceived temporal shift in cranial morphology. However, the archaeological record indicates cultural, and presumed population, continuity for more than 4,000 years. We use mtDNA haplogroup data in the series of prehistoric eastern Aleutian samples (n = 86) studied craniometrically by Hrdlicka to test alternative hypotheses regarding population continuity or replacement in the region. This molecular characterization, in conjunction with direct dating of individual specimens, provided increased resolution for hypothesis testing. Results indicate an apparent shift in mtDNA haplogroup frequencies in the eastern Aleutians approximately 1,000 years ago, in concert with changes in mortuary practices and isotopic signatures reflecting resource acquisition strategies. The earliest Aleut populations were characterized by a high frequency of haplogroup A, as are most modern populations of the North American arctic. Later prehistoric peoples in the Aleutians were characterized by a high frequency of haplogroup D and a correspondingly lower frequency of haplogroup A, a pattern typified by modern Aleut populations.