Disparities in Vision Screening in Primary Care for Young Children With Autism Spectrum Disorder.

OBJECTIVES: To determine the rate of vision screening among children with and without autism spectrum disorder (ASD), the rate of photoscreening compared with visual acuity screening, and the effect of demographic factors on vision screening for children with ASD. METHODS: Data from well visits for 3- to 5-year-olds between January 2016 and December 2019 were collected via PEDSnet. Billing codes for vision screening were a proxy for the completion of vision screening. χ2 analysis examined the relationship of age, sex, race, ethnicity, region, and socioeconomic status to vision screening rate and rate of photoscreening versus visual acuity screening. Multivariate logistic regression assessed factors that impacted the odds of vision screening. RESULTS: We analyzed 63 829 well-child visits. Children with ASD were less likely to have a vision screening (36.5%) compared with children without ASD (59.9%). The lowest rates of screening occurred during the 3-year visit. Of those with ASD, Black children had a lower screening rate (27.6%) than white (39.7%) and other/multiracial children (39.8%). The use of photoscreening was higher in Hispanic children, increasing the overall rate of vision screening greater than non-Hispanic children. Practice region influenced the rates of vision screening for children with ASD because of more photoscreening. CONCLUSIONS: Children with ASD are less likely to receive vision screening at well visits compared with typically developing children. This disparity was greatest among younger children and Black children. One practice region used more photoscreening and had higher rates of screening. Photoscreening is a useful tool to decrease disparity, especially among high-risk patient groups.

Oxidative stress induces club cell proliferation and pulmonary fibrosis in Atp8b1 mutant mice.

Atp8b1 (ATPase, aminophospholipid transporter, class I, type 8B, member 1) is a cardiolipin transporter in the apical membrane of lung epithelial cells. While the role of Atp8b1 in pneumonia-induced acute lung injury (ALI) has been well studied, its potential role in oxidative stress-induced ALI is poorly understood. We herein show that Atp8b1G308V/G308V mice under hyperoxic conditions display exacerbated cell apoptosis at alveolar epithelium and aberrant proliferation of club cells at bronchiolar epithelium. This hyperoxia-induced ambivalent response in Atp8b1G308V/G308V lungs was followed by patchy distribution of non-uniform interstitial fibrosis at late recovery phase under normoxia. Since this club cell abnormality is commonly observed between Atp8b1G308V/G308V lungs under hyperoxic conditions and IPF lungs, we characterized this mouse fibrosis model focusing on club cells. Intriguingly, subcellular morphological analysis of IPF lungs, using transmission electron microscopy (TEM), revealed that metaplastic bronchiolar epithelial cells in fibrotic lesions and deformed type II alveolar epithelial cells (AECs) in alveoli with mild fibrosis, have common morphological features including cytoplasmic vacuolation and dysmorphic lamellar bodies. In conclusion, the combination of Atp8b1 mutation and hyperoxic insult serves as a novel platform to study unfocused role of club cells in IPF.

Reduction of serum 25-hydroxyvitamin D concentrations with intravenous lipid emulsion in a dog.

The recommended daily allowance of vitamin D has been increased. Toxicosis in pets may increase as a result. A dog ingested ~ 200 000 IU of vitamin D, serum concentrations were above the reference range (RR) and decreased to the RR after lipid treatment. This is the first known report of lipid treatment for hypervitaminosis D.

Réduction des concentrations sériques de 25-hydroxyvitamine D à l'aide d'une émulsion intraveineuse de lipides chez un chien. L'apport quotidien recommandé de vitamine D a été accru. La toxicose chez les animaux de compagnie peut augmenter en raison de cette hausse. Un chien a ingéré ~ 200 000 UI de vitamine D, les concentrations sériques étaient supérieures à la fourchette de référence (FR) et a chuté à la FR après le traitement aux lipides. Il s'agit du premier rapport connu de traitement aux lipides pour la toxicose à l'hypervitaminose D.(Traduit par Isabelle Vallières).

Concentrations of thromboxane metabolites in feline urine.

OBJECTIVE To determine the predominant thromboxane (TX) metabolite in urine of healthy cats, evaluate whether the method of sample collection would impact concentration of that metabolite, and propose a reference interval for that metabolite in urine of healthy cats. ANIMALS 17 cats (11 purpose-bred domestic shorthair cats, 5 client-owned domestic shorthair cats, and 1 client-owned Persian cat). PROCEDURES All cats were deemed healthy on the basis of results for physical examination, a CBC, serum biochemical analysis, urinalysis, and measurement of prothrombin time and activated partial thromboplastin time. Voided and cystocentesis urine samples (or both) were collected. Aliquots of urine were stored at -80°C until analysis. Concentrations of TXB2, 11-dehydroTXB2, and 2,3 dinorTXB2 were measured with commercially available ELISA kits. Urinary creatinine concentration was also measured. RESULTS 11-dehydroTXB2 was the most abundant compound, representing (mean ± SD) 59 ± 18% of the total amount of TX detected. In all samples, the concentration of 11-dehydroTXB2 was greater than that of 2,3 dinorTXB2 (mean, 4.2 ± 2.7-fold as high). Mean concentration of 11-dehydroTXB2 for the 17 cats was 0.57 ± 0.47 ng/mg of creatinine. A reference interval (based on the 5% to 95% confidence interval) of 0.10 to 2.1 ng of 11-dehydroTXB2/mg of creatinine was proposed for healthy cats. CONCLUSIONS AND CLINICAL RELEVANCE In this study, 11-dehydroTXB2 was the major TX metabolite in feline urine. Measurement of this metabolite may represent a noninvasive, convenient method for monitoring in vivo platelet activation in cats at risk for thromboembolism.

Intravenous Lipid Emulsion Therapy for Bromethalin Toxicity in a Dog.

Bromethalin is a central nervous system toxin currently incorporated into several different rodenticides. In 2008, the EPA requested that manufacturers phase out second-generation anticoagulant rodenticides. In response, manufacturers began to increase production of bromethalin-based rodenticides. It is likely that pet exposure to bromethalin will increase in the future. Bromethalin has no known antidote and tends to deposit in fat. Intravenous lipid emulsions (ILEs) are being used with increasing frequency in both human and veterinary medicine to treat numerous acute systemic toxicities. A 4 yr old spayed female Pit bull terrier was presented following witnessed ingestion of bromethalin rodenticide by the owners. Decontamination was unsuccessful and ILE was started. Serum was frozen at -80°C before and 1 hr after completion of ILE. In rats, the half-life of desmethylbromethalin, the toxic metabolite, has been reported at 5.6 days and 6 days, and it is likely to be similar in dogs. The only intervention between the pre-lipid serum sample and the post-lipid serum sample was the administration of ILE, and the serum desmethylbromethalin levels were reduced by 75% (from 4 ppb to 1 ppb) during this time. To the authors' knowledge, this is the first report describing treatment of bromethalin ingestion with ILE.

Copy number variation analysis identifies novel CAKUT candidate genes in children with a solitary functioning kidney.

Copy number variations associate with different developmental phenotypes and represent a major cause of congenital anomalies of the kidney and urinary tract (CAKUT). Because rare pathogenic copy number variations are often large and contain multiple genes, identification of the underlying genetic drivers has proven to be difficult. Here we studied the role of rare copy number variations in 80 patients from the KIMONO study cohort for which pathogenic mutations in three genes commonly implicated in CAKUT were excluded. In total, 13 known or novel genomic imbalances in 11 of 80 patients were absent or extremely rare in 23,362 population controls. To identify the most likely genetic drivers for the CAKUT phenotype underlying these rare copy number variations, we used a systematic in silico approach based on frequency in a large data set of controls, annotation with publicly available databases for developmental diseases, tolerance and haploinsufficiency scores, and gene expression profile in the developing kidney and urinary tract. Five novel candidate genes for CAKUT were identified that showed specific expression in the human and mouse developing urinary tract. Among these genes, DLG1 and KIF12 are likely novel susceptibility genes for CAKUT in humans. Thus, there is a significant role of genomic imbalance in the determination of kidney developmental phenotypes. Additionally, we defined a systematic strategy to identify genetic drivers underlying rare copy number variations.

Collection and characterization of semen from green iguanas (Iguana iguana).

OBJECTIVE: To determine an efficient method for the collection of semen samples by means of electroejaculation, characterize spermatozoa quality and quantity, and determine the effect of refrigerated storage on motility of spermatozoa obtained from green iguanas (Iguana iguana). ANIMALS: 18 adult green iguanas. PROCEDURES: Green iguanas were anesthetized, and semen samples were obtained by means of electroejaculation. Up to 3 series of electrostimulations were performed; the procedure was stopped after a semen sample was obtained. Various semen sample variables were evaluated. RESULTS: Semen samples were obtained from 16 iguanas; most (n = 10) iguanas produced a semen sample after the second series of electrostimulations. Median semen sample volume was 0.05 mL. Mean spermatozoa concentration was 2 69.0 × 10(6) spermatozoa/mL. Median percentage of motile spermatozoa was 78%. The only morphological abnormality of spermatozoa was bent tails (mean percentage in a semen sample, 5.7%). Spermatozoa motility decreased significantly during refrigeration (4°C); median percentage motility after 24, 48, and 72 hours of refrigeration was 60%, 33%, and 0%, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Results of this study suggested electroejaculation can be performed to collect semen samples from green iguanas, characteristics of iguana semen samples are similar to those for semen samples obtained from other reptiles, and motility of iguana spermatozoa decreases during refrigeration within 48 to 72 hours.

Mutations in DSTYK and dominant urinary tract malformations.

BACKGROUND: Congenital abnormalities of the kidney and the urinary tract are the most common cause of pediatric kidney failure. These disorders are highly heterogeneous, and the etiologic factors are poorly understood. METHODS: We performed genomewide linkage analysis and whole-exome sequencing in a family with an autosomal dominant form of congenital abnormalities of the kidney or urinary tract (seven affected family members). We also performed a sequence analysis in 311 unrelated patients, as well as histologic and functional studies. RESULTS: Linkage analysis identified five regions of the genome that were shared among all affected family members. Exome sequencing identified a single, rare, deleterious variant within these linkage intervals, a heterozygous splice-site mutation in the dual serine-threonine and tyrosine protein kinase gene (DSTYK). This variant, which resulted in aberrant splicing of messenger RNA, was present in all affected family members. Additional, independent DSTYK mutations, including nonsense and splice-site mutations, were detected in 7 of 311 unrelated patients. DSTYK is highly expressed in the maturing epithelia of all major organs, localizing to cell membranes. Knockdown in zebrafish resulted in developmental defects in multiple organs, which suggested loss of fibroblast growth factor (FGF) signaling. Consistent with this finding is the observation that DSTYK colocalizes with FGF receptors in the ureteric bud and metanephric mesenchyme. DSTYK knockdown in human embryonic kidney cells inhibited FGF-stimulated phosphorylation of extracellular-signal-regulated kinase (ERK), the principal signal downstream of receptor tyrosine kinases. CONCLUSIONS: We detected independent DSTYK mutations in 2.3% of patients with congenital abnormalities of the kidney or urinary tract, a finding that suggests that DSTYK is a major determinant of human urinary tract development, downstream of FGF signaling. (Funded by the National Institutes of Health and others.).

Presumed reactive polyarthritis and granulomatous vasculitis in a Mississippi sandhill crane (Grus canadensis pulla).

A 1.5-year-old female Mississippi sandhill crane (Grus canadensis pulla) was presented and managed for a polyarthritis of the intertarsal and tarsophalangeal articulations. Results of aerobic bacterial cultures, Mycoplasma species culture, and polymerase chain reaction testing of articular fluid did not identify any causative organisms. Results of radiographs and cytologic examination of articular fluid were consistent with an inflammatory, nonerosive polyarthritis. The arthritis did not improve with systemic anti-inflammatory and antibiotic treatment and with joint lavage. A large necrotic granulomatous mass was detected on the right shoulder area from which Staphylococcus aureus and Enterococcus species were isolated as opportunistic pathogens. Two days after surgical resection of the mass, the distal polyarthritis resolved. Histopathologic examination of the mass was consistent with granulomatous vasculitis with abscess formation of unknown origin. In this crane, the unresponsiveness to standard therapy, the presence of an infected and inflammatory mass, and the resolution of the polyarthritis after the resection of the mass strongly supported a diagnosis of reactive immune-mediated nonerosive polyarthritis. Analysis of this case suggests that immune-mediated idiopathic arthritis should be a differential diagnosis of distal polyarthritis in cranes and that an inciting source remote from the joints should be investigated in case of lack of response to standard therapy.

Copy-number disorders are a common cause of congenital kidney malformations.

We examined the burden of large, rare, copy-number variants (CNVs) in 192 individuals with renal hypodysplasia (RHD) and replicated findings in 330 RHD cases from two independent cohorts. CNV distribution was significantly skewed toward larger gene-disrupting events in RHD cases compared to 4,733 ethnicity-matched controls (p = 4.8 × 10(-11)). This excess was attributable to known and novel (i.e., not present in any database or in the literature) genomic disorders. All together, 55/522 (10.5%) RHD cases harbored 34 distinct known genomic disorders, which were detected in only 0.2% of 13,839 population controls (p = 1.2 × 10(-58)). Another 32 (6.1%) RHD cases harbored large gene-disrupting CNVs that were absent from or extremely rare in the 13,839 population controls, identifying 38 potential novel or rare genomic disorders for this trait. Deletions at the HNF1B locus and the DiGeorge/velocardiofacial locus were most frequent. However, the majority of disorders were detected in a single individual. Genomic disorders were detected in 22.5% of individuals with multiple malformations and 14.5% of individuals with isolated urinary-tract defects; 14 individuals harbored two or more diagnostic or rare CNVs. Strikingly, the majority of the known CNV disorders detected in the RHD cohort have previous associations with developmental delay or neuropsychiatric diseases. Up to 16.6% of individuals with kidney malformations had a molecular diagnosis attributable to a copy-number disorder, suggesting kidney malformations as a sentinel manifestation of pathogenic genomic imbalances. A search for pathogenic CNVs should be considered in this population for the diagnosis of their specific genomic disorders and for the evaluation of the potential for developmental delay.

Exome sequencing identified MYO1E and NEIL1 as candidate genes for human autosomal recessive steroid-resistant nephrotic syndrome.

To identify gene loci associated with steroid-resistant nephrotic syndrome (SRNS), we utilized homozygosity mapping and exome sequencing in a consanguineous pedigree with three affected siblings. High-density genotyping identified three segments of homozygosity spanning 33.6 Mb on chromosomes 5, 10, and 15 containing 296 candidate genes. Exome sequencing identified two homozygous missense variants within the chromosome 15 segment; an A159P substitution in myosin 1E (MYO1E), encoding a podocyte cytoskeletal protein; and an E181K substitution in nei endonuclease VIII-like 1 (NEIL1), encoding a base-excision DNA repair enzyme. Both variants disrupt highly conserved protein sequences and were absent in public databases, 247 healthy controls, and 286 patients with nephrotic syndrome. The MYO1E A159P variant is noteworthy, as it is expected to impair ligand binding and actin interaction in the MYO1E motor domain. The predicted loss of function is consistent with the previous demonstration that Myo1e inactivation produces nephrotic syndrome in mice. Screening 71 additional patients with SRNS, however, did not identify independent NEIL1 or MYO1E mutations, suggesting larger sequencing efforts are needed to uncover which mutation is responsible for the phenotype. Our findings demonstrate the utility of exome sequencing for rapidly identifying candidate genes for human SRNS.