Pediatric Neurogastroenterology and Motility Services in North America: Neurogastroenterology and Motility Survey Report.

ABSTRACT: To characterize the current availability and scope of pediatric neurogastroenterology and motility (PNGM) services in North America (NA), the NASPGHAN-NGM committee distributed a self-reporting survey through the NASPGHAN bulletin board and mailing listserv, to compile a list of NA centers offering PNGM services, PNGM training, and the types of diagnostic and therapeutic PNGM procedures and services. We received responses that 54 centers in NA offer some form of PNGM services. Previously, the NASPGHAN website had last updated information from 2015 listing 36 centers in the USA and 2 in Canada. The American Neurogastroenterology and Motility Society (ANMS) website had 16 PNGM centers listed in NA in 2021. Neither of these resources capture additional information regarding training, research, advanced diagnostics, and therapeutics, and all available PNGM services. Our data highlights the growth in the field of PNGM services, and the variability of their distribution throughout the continent.

A Guide to Establishing a Pediatric Neurogastroenterology and Motility Program.

ABSTRACT: The purpose of this document is to provide guidance for establishing a pediatric neurogastroenterology and motility (PNGM) program, including considerations for personnel, equipment, and physical space requirements, and business planning, from members of the neurogastroenterology and motility (NGM) Committee of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) who have developed PNGM programs at various institutions. A business plan defining the needs for required personnel, dedicated physical space, procedures, clinical care, and equipment storage is a prerequisite. Thoughtful logistical planning should address provider schedules, clinical visits, procedure coordination, and prior authorization processes. A business-plan outlining equipment purchase with projected costs, revenue generation, and goals for future growth is desirable for obtaining institutional support, which is imperative to building a successful PNGM program.

Healthcare Burden and Cost in Children with Anorectal Malformation During the First 5 Years of Life.

OBJECTIVE: To identify cumulative 5-year healthcare costs and healthcare days in children with anorectal malformation (ARM) and to compare the cumulative 5-year healthcare costs and healthcare days in children with ARM with 3 control cohorts: healthy, premature, and congenital heart disease (CHD). STUDY DESIGN: We performed a retrospective case-control study using the Truven MarketScan database of commercial claims encounters between 2008 and 2017. The ARM, CHD, and premature cohorts were identified using a targeted list of International Classification of Diseases 9th or 10th Revision diagnosis and Current Procedural Terminology codes. The healthy cohort included patients without ARM, preterm birth, or CHD. RESULTS: We identified 664 children with ARM, 3356 children with heart disease, 63 190 children who were born preterm, and 2947 healthy patients. At 5 years, the total healthcare costs of children with ARM ($273K, 95% CI $168K-$378K) were similar to the premature cohort ($246K, 95% CI $237K-$255K) and lower than the CHD cohort ($466K, 95% CI $401K-$530K, P < .001). Total healthcare days were similar in children with ARM (158 days, 95% CI 117-198) and prematurity (141 days, 95% CI 137-144) but lower than CHD (223 days, 95% CI 197-250, P = .02). In ARM, outpatient care (126 days, 95% CI 93-159) represented the largest contribution to total healthcare days. CONCLUSIONS: Children with ARM accumulate similar healthcare costs to children with prematurity and comparable healthcare days to children with CHD and prematurity in the first 5 years of life. Outpatient care represents the majority of healthcare days in children with ARM, identifying this as a target for quality improvement and demonstrating the long-term impact of this condition.

Novel Quantitative Trait Loci for Grain Cadmium Content Identified in Hard White Spring Wheat.

Cadmium (Cd) is a heavy metal that can cause a variety of adverse effects on human health, including cancer. Wheat comprises approximately 20% of the human diet worldwide; therefore, reducing the concentrations of Cd in wheat grain will have significant impacts on the intake of Cd in food products. The tests for measuring the Cd content in grain are costly, and the content is affected significantly by soil pH. To facilitate breeding for low Cd content, this study sought to identify quantitative trait loci (QTL) and associated molecular markers that can be used in molecular breeding. One spring wheat population of 181 doubled haploid lines (DHLs), which was derived from a cross between two hard white spring wheat cultivars "UI Platinum" (UIP) and "LCS Star" (LCS), was assessed for the Cd content in grain in multiple field trials in Southeast Idaho, United States. Three major QTL regions, namely, QCd.uia2-5B, QCd.uia2-7B, and QCd.uia2-7D, were identified on chromosomes 5B, 7B, and 7D, respectively. All genes in these three QTL regions were identified from the NCBI database. However, three genes related to the uptake and transport of Cd were used in the candidate gene analysis. The sequences of TraesCS5B02G388000 (TaHMA3) in the QCd.uia2-5B region and TraesCS7B02G320900 (TaHMA2) and TraesCS7B02G322900 (TaMSRMK3) in the QCd.uia2-7B region were compared between UIP and LCS. TaHMA2 on 7B is proposed for the first time as a candidate gene for grain Cd content in wheat. A KASP marker associated with this gene was developed and it will be further validated in near-isogenic lines via a gene-editing system in future studies.

QTL mapping for grain yield and three yield components in a population derived from two high-yielding spring wheat cultivars.

KEY MESSAGE: Four genomic regions on chromosomes 4A, 6A, 7B, and 7D were discovered, each with multiple tightly linked QTL (QTL clusters) associated with two to three yield components. The 7D QTL cluster was associated with grain yield, fertile spikelet number per spike, thousand kernel weight, and heading date. It was located in the flanking region of FT-D1, a homolog gene of Arabidopsis FLOWERING LOCUS T, a major gene that regulates wheat flowering. Genetic manipulation of yield components is an important approach to increase grain yield in wheat (Triticum aestivum). The present study used a mapping population comprised of 181 doubled haploid lines derived from two high-yielding spring wheat cultivars, UI Platinum and LCS Star. The two cultivars and the derived population were assessed for six traits in eight field trials primarily in Idaho in the USA. The six traits were grain yield, fertile spikelet number per spike, productive tiller number per unit area, thousand kernel weight, heading date, and plant height. Quantitative Trait Locus (QTL) analysis of the six traits was conducted using 14,236 single-nucleotide polymorphism (SNP) markers generated from the wheat 90 K SNP and the exome and promoter capture arrays. Of the 19 QTL detected, 14 were clustered in four chromosomal regions on 4A, 6A, 7B and 7D. Each of the four QTL clusters was associated with multiple yield component traits, and these traits were often negatively correlated with one another. As a result, additional QTL dissection studies are needed to optimize trade-offs among yield component traits for specific production environments. Kompetitive allele-specific PCR markers for the four QTL clusters were developed and assessed in an elite spring wheat panel of 170 lines, and eight of the 14 QTL were validated. The two parents contain complementary alleles for the four QTL clusters, suggesting the possibility of improving grain yield via genetic recombination of yield component loci.

Incidence and Prevalence of Pediatric Eosinophilic Esophagitis in Utah Based on a 5-Year Population-Based Study.

BACKGROUND & AIMS: Eosinophilic esophagitis (EoE) is often detected in children and is considered to be a rare disease, with prevalence values reported to be below 60 cases per 100,000 persons. To determine whether the incidence of EoE in children in Utah exceeds estimates from regional reports, we calculated incidence and prevalence values over a 5-year period. METHODS: Using consensus guidelines for the diagnosis of EoE, we reviewed pathology records from the Intermountain Healthcare pathology database, from July 1, 2011 through June 31, 2016. We collected data on 10,619 pediatric patients with available esophageal biopsy results, and identified cases of esophageal eosinophilia (>14 eosinophils in a high-power microscopy field in an endoscopic biopsy). An EoE case required the presence of esophageal eosinophilia, symptoms of esophageal dysfunction, and the absence of co-morbid conditions that may cause esophageal eosinophilia. Annual pediatric EoE incidence and prevalence values were calculated per 100,000 children, based on averaged pediatric population estimates from census figures of Utah in 2010 and 2016. RESULTS: We identified 1281 unique pediatric patients who met criteria for esophageal eosinophilia. Of those, 1060 patients met criteria for newly diagnosed EoE. Over the 5-year period studied, the average annual pediatric EoE incidence in Utah was 24 cases per 100,000 children. The prevalence in year 5 of the study was 118 cases per 100,000 children. CONCLUSION: In a population-based study of children in Utah, we found the incidence and prevalence of pediatric EoE to be higher than previously reported. This could be due to the prominence of EoE risk factors in this region, as well as Utah's searchable medical record system that allows for reliable case ascertainment. Further studies of this type could increase disease awareness, prompting early referral to pediatric gastroenterologists and trials to strengthen evidence-based, algorithmic approaches to EoE diagnosis and treatment in children.

17ß-Estradiol protects the esophageal epithelium from IL-13-induced barrier dysfunction and remodeling.

BACKGROUND: The incidence of eosinophilic esophagitis (EoE) is greater in male than female subjects, and the underlying molecular basis for this sex bias remains unclear. OBJECTIVE: We sought to delineate the contribution of the sex hormone estrogen to the EoE phenotype and esophageal epithelial barrier function and remodeling. METHODS: We performed demographic and incidence analyses of EoE in male and female subjects from a single-center pediatric cohort. Estrogen-responsive gene expression analyses and estrogen receptor (ESR) immunofluorescence staining of esophageal biopsy specimens from patients with EoE and control subjects were performed. The effect of 17ß-estradiol (E2) on IL-13-induced signaling pathways, gene expression, and esophageal epithelial architecture and barrier function in a primary human esophageal keratinocyte cell (EPC2) culture system (EPC2-air-liquid interface) was examined. RESULTS: We observed a male predominance in patients with EoE. Analyses of RNA sequencing data sets revealed a significant dysregulation of the estrogen-responsive gene network and expression of ESR1 and ESR2 in esophageal biopsy specimens from patients with EoE compared with control subjects. IL-13 stimulation of EPC2-air-liquid interface cells led to altered cellular architecture with induced dilation of intercellular spaces and barrier dysfunction. Pretreatment of EPC2s with E2 prior to IL-13 exposure abrogated IL-13-induced architectural changes and esophageal barrier dysfunction. Mechanistically, E2-protective effects were dependent on ESR2 and associated with diminishing of IL-13-induced tyrosine kinase 2 and signal transducer and activator of transcription 6 phosphorylation and EoE-dysregulated gene expression. CONCLUSIONS: Estrogen-responsive genes are modified in patients with EoE compared with control subjects. E2 attenuated IL-13-induced architectural changes and esophageal epithelial barrier dysfunction through inhibition of the IL-13/tyrosine kinase 2/signal transducer and activator of transcription 6 pathway via ESR2-dependent process. Estrogen hormone signaling may protect against development of EoE in female subjects.

QTL identification and KASP marker development for productive tiller and fertile spikelet numbers in two high-yielding hard white spring wheat cultivars.

Selecting high-yielding wheat cultivars with more productive tillers per unit area (PTN) combined with more fertile spikelets per spike (fSNS) is difficult. QTL mapping of these traits may aid understanding of this bottleneck and accelerate precision breeding for high yield via marker-assisted selection. PTN and fSNS were assessed in four to five trials from 2015 to 2017 in a doubled haploid population derived from two high-yielding cultivars "UI Platinum" and "SY Capstone." Two QTL for PTN (QPTN.uia-4A and QPTN.uia-6A) and four QTL for fSNS (QfSNS.uia-4A, QfSNS.uia-5A, QfSNS.uia-6A, and QfSNS.uia-7A) were identified. The effects of the QTL were primarily additive and, therefore, pyramiding of multiple QTL may increase PTN and fSNS. However, the two QTL for PTN were positioned in the flanking regions for the two QTL for fSNS on chromosomes 4A and 6A, respectively, suggesting either possible pleiotropic effect of the same QTL or tightly linked QTL and explaining the difficulty of selecting both high PTN and fSNS in phenotypic selection. Kompetitive allele-specific PCR (KASP) markers for all identified QTL were developed and validated in a recombinant inbred line (RIL) population derived from the same two cultivars. In addition, KASP markers for three of the QTL (QPTN.uia-6A, QfSNS.uia-6A, and QfSNS.uia-7A) were further validated in a diverse spring wheat panel, indicating their usefulness under different genetic backgrounds. These KASP markers could be used by wheat breeders to select high PTN and fSNS.

Solute carrier family 9, subfamily A, member 3 (SLC9A3)/sodium-hydrogen exchanger member 3 (NHE3) dysregulation and dilated intercellular spaces in patients with eosinophilic esophagitis.

BACKGROUND: Eosinophilic esophagitis (EoE) is characterized by histopathologic modifications of esophageal tissue, including eosinophil-rich inflammation, basal zone hyperplasia, and dilated intercellular spaces (DIS). The underlying molecular processes that drive the histopathologic features of EoE remain largely unexplored. OBJECTIVE: We sought to investigate the involvement of solute carrier family 9, subfamily A, member 3 (SLC9A3) in esophageal epithelial intracellular pH (pHi) and DIS formation and the histopathologic features of EoE. METHODS: We examined expression of esophageal epithelial gene networks associated with regulation of pHi in the EoE transcriptome of primary esophageal epithelial cells and an in vitro esophageal epithelial 3-dimensional model system (EPC2-ALI). Molecular and cellular analyses and ion transport assays were used to evaluate the expression and function of SLC9A3. RESULTS: We identified altered expression of gene networks associated with regulation of pHi and acid-protective mechanisms in esophageal biopsy specimens from pediatric patients with EoE (healthy subjects, n = 6; patients with EoE, n = 10). The most dysregulated gene central to regulating pHi was SLC9A3. SLC9A3 expression was increased within the basal layer of esophageal biopsy specimens from patients with EoE, and expression positively correlated with disease severity (eosinophils/high-power field) and DIS (healthy subjects, n = 10; patients with EoE, n = 10). Analyses of esophageal epithelial cells revealed IL-13-induced, signal transducer and activator of transcription 6-dependent SLC9A3 expression and Na+-dependent proton secretion and that SLC9A3 activity correlated positively with DIS formation. Finally, we showed that IL-13-mediated, Na+-dependent proton secretion was the primary intracellular acid-protective mechanism within the esophageal epithelium and that blockade of SLC9A3 transport abrogated IL-13-induced DIS formation. CONCLUSIONS: SLC9A3 plays a functional role in DIS formation, and pharmacologic interventions targeting SLC9A3 function may suppress the histopathologic manifestations in patients with EoE.

Genome-Wide Association Mapping of Fusarium Head Blight Resistance in Spring Wheat Lines Developed in the Pacific Northwest and CIMMYT.

Fusarium head blight (FHB) is a destructive disease of wheat in humid and semihumid areas of the world. It has emerged in the Pacific Northwest (PNW) in recent years because of changing climate and crop rotation practices. Our objectives in the present study were to identify and characterize quantitative trait loci (QTL) associated with FHB resistance in spring wheat lines developed in the PNW and the International Maize and Wheat Improvement Center. In total, 170 spring wheat lines were evaluated in field and greenhouse trials in 2015 and 2016. Fourteen lines showing consistent resistance in multiple environments were identified. These lines are valuable resources in wheat variety improvement of FHB resistance because they have no Sumai 3 or Sumai 3-related background. The 170 lines were genotyped using a high-density Illumina 90K single-nucleotide polymorphisms (SNP) assay and 10 other non-SNP markers. A genome-wide association analysis was conducted with a mixed model (Q+K). Consistent, significant SNP associations with multiple traits were found on chromosomes 1B, 2B, 4B, 5A, 5B, and 6A. The locus on chromosome 5B for reduced deoxynivalenol content may be novel. The identified QTL are being validated in additional mapping studies and the identified resistant lines are being used in variety development for FHB resistance and facilitated by marker-assisted selection.

Immunosuppression in pediatric liver transplant recipients: Unique aspects.

Pediatric liver transplantation has experienced improved outcomes over the last 50 years. This can be attributed in part to establishing optimal use of immunosuppressive agents to achieve a balance between minimizing the risks of allograft rejection and infection. The management of immunosuppression in children is generally more complex and can be challenging when compared with the use of these agents in adult liver transplant patients. Physiologic differences in children alter the pharmacokinetics of immunosuppressive agents, which affects absorption, distribution, metabolism, and drug excretion. Children also have a longer expected period of exposure to immunosuppression, which can impact growth, risk of infection (bacterial, viral, and fungal), carcinogenesis, and likelihood of nonadherence. This review discusses immunosuppressive options for pediatric liver transplant recipients and the unique issues that must be addressed when managing this population. Further advances in the field of tolerance and accommodation are needed to relieve the acute and cumulative burden of chronic immunosuppression in children. Liver Transplantation 23 244-256 2017 AASLD.

Lower Newborn Bone Mineral Content Associated With Maternal Use of Tenofovir Disoproxil Fumarate During Pregnancy.

BACKGROUND: Fetal bone effects of maternal tenofovir use have not been well studied. We sought to compare whole-body bone mineral content (BMC) of newborns exposed vs not exposed to tenofovir in utero. METHODS: We enrolled participants from April 2011 to June 2013 at 14 US clinical sites. Singleton infants of women with human immunodeficiency virus (HIV) infection who took tenofovir in late pregnancy (tenofovir-exposed) or no tenofovir during pregnancy (tenofovir-unexposed) were enrolled during late pregnancy or within 72 hours of birth. Infants born before 36 weeks gestation or with confirmed HIV infection were excluded. Whole-body BMC was measured in the first month of life and compared with that of the tenofovir-exposed and tenofovir-unexposed newborns, unadjusted and adjusted for covariates. RESULTS: Seventy-four tenofovir-exposed and 69 tenofovir-unexposed infants had evaluable BMC measurements. Tenofovir-exposed mothers were more likely to be married (31% vs 22%; P = .04) and to use boosted protease inhibitors (84% vs 62%; P = .004). Tenofovir-exposed newborns did not differ from unexposed newborns on mean gestational age (38.2 vs 38.1 weeks) or mean length (-0.41 vs -0.18) or weight (-0.71 vs -0.48) Z-scores. The mean (standard deviation) BMC of tenofovir-exposed infants was 12% lower than for unexposed infants (56.0 [11.8] vs 63.8 [16.6] g; P = .002). The adjusted mean bone mineral content was 5.3 g lower (95% confidence interval, -9.5, -1.2; P = .013) in the tenofovir-exposed infants. CONCLUSIONS: Maternal tenofovir use is associated with significantly lower neonatal BMC. The duration and clinical significance of this finding should be evaluated in longitudinal studies. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov NCT01310023.

AR42, a novel histone deacetylase inhibitor, as a potential therapy for vestibular schwannomas and meningiomas.

Neurofibromatosis type 2 (NF2) is an autosomal-dominant disease that results in the formation of bilateral vestibular schwannomas (VSs) and multiple meningiomas. Treatment options for NF2-associated tumors are limited, and to date, no medical therapies are FDA approved. The ideal chemotherapeutic agent would inhibit both VS and meningiomas simultaneously. The objectives of this study are (1) to test the efficacy of AR42, a novel histone deacetylase inhibitor, to inhibit VS and meningioma growth and (2) to investigate this drug's mechanisms of action. Primary cultures of human VS and meningioma cells were established. Nf2-deficient mouse schwannoma and benign human meningioma Ben-Men-1 cells were also cultured. Cells were treated with AR42, and the drug's effects on proliferation and the cell cycle were analyzed using a methanethiosulfonate assay and flow cytometry, respectively. Human phospho-kinase arrays and Western blots were used to evaluate the effects of AR42 on intracellular signaling. The in vivo efficacy of AR42 was investigated using schwannoma xenografts. Tumor volumes were quantified using high-field, volumetric MRI, and molecular target analysis was performed using immunohistochemistry. AR42 inhibited the growth of primary human VS and Nf2-deficient mouse schwannoma cells with a half maximal inhibitory concentration (IC(50)) of 500 nM and 250-350 nM, respectively. AR42 also inhibited primary meningioma cells and the benign meningioma cell line, Ben-Men-1, with IC(50) values of 1.5 µM and 1.0 µM, respectively. AR42 treatment induced cell-cycle arrest at G(2) and apoptosis in both VS and meningioma cells. Also, AR42 exposure decreased phosphorylated Akt in schwannoma and meningioma cells. In vivo treatment with AR42 inhibited the growth of schwannoma xenografts, induced apoptosis, and decreased Akt activation. The potent growth inhibitory activity of AR42 in schwannoma and meningioma cells suggests that AR42 should be further evaluated as a potential treatment for NF2-associated tumors.

Impacts of abstinence education on teen sexual activity, risk of pregnancy, and risk of sexually transmitted diseases.

This paper examines the impacts of four abstinence-only education programs on adolescent sexual activity and risks of pregnancy and sexually transmitted diseases (STDs). Based on an experimental design, the impact analysis uses survey data collected in 2005 and early 2006 from more than 2,000 teens who had been randomly assigned to either a program group that was eligible to participate in one of the four programs or a control group that was not. The findings show no significant impact on teen sexual activity, no differences in rates of unprotected sex, and some impacts on knowledge of STDs and perceived effectiveness of condoms and birth control pills