Using the National Birth Defects Prevention Network (NBDPN) annual data report, U.S. national prevalence estimates for major birth defects are developed based on birth cohort 2010-2014.
Data from 39 ...U.S. population-based birth defects surveillance programs (16 active case-finding, 10 passive case-finding with case confirmation, and 13 passive without case confirmation) were used to calculate pooled prevalence estimates for major defects by case-finding approach. Fourteen active case-finding programs including at least live birth and stillbirth pregnancy outcomes monitoring approximately one million births annually were used to develop national prevalence estimates, adjusted for maternal race/ethnicity (for all conditions examined) and maternal age (trisomies and gastroschisis). These calculations used a similar methodology to the previous estimates to examine changes over time.
The adjusted national birth prevalence estimates per 10,000 live births ranged from 0.62 for interrupted aortic arch to 16.87 for clubfoot, and 19.93 for the 12 critical congenital heart defects combined. While the birth prevalence of most birth defects studied remained relatively stable over 15 years, an increasing prevalence was observed for gastroschisis and Down syndrome. Additionally, the prevalence for atrioventricular septal defect, tetralogy of Fallot, omphalocele, and trisomy 18 increased in this period compared to the previous periods. Active case-finding programs generally had higher prevalence rates for most defects examined, most notably for anencephaly, anophthalmia/microphthalmia, trisomy 13, and trisomy 18.
National estimates of birth defects prevalence provide data for monitoring trends and understanding the impact of these conditions. Increasing prevalence rates observed for selected conditions warrant further examination.
Treating biliary atresia in newborns earlier can delay or prevent the need for liver transplant; however, treatment typically occurs later because biliary atresia is difficult to detect during its ...early stages.
To determine the diagnostic yield of newborn screening for biliary atresia with direct or conjugated bilirubin measurements and to evaluate the association of screening implementation with clinical outcomes.
A cross-sectional screening study of 124 385 infants born at 14 Texas hospitals between January 2015 and June 2018; and a pre-post study of 43 infants who underwent the Kasai portoenterostomy as treatment for biliary atresia at the region's largest pediatric hepatology center before (January 2008-June 2011) or after (January 2015-June 2018) screening implementation. Final follow-up occurred on July 15, 2019.
Two-stage screening with direct or conjugated bilirubin measurements. In stage 1, all newborns were tested within the first 60 hours of life, with a positive screening result defined as bilirubin levels exceeding derived 95th percentile reference intervals. In stage 2, infants who had a positive screening result in stage 1 were retested at or before the 2-week well-child visit, with a positive screening result defined as bilirubin levels greater than the stage 1 result or greater than 1 mg/dL.
The primary outcomes of the screening study were sensitivity, specificity, positive predictive value, and negative predictive value based on infants testing positive in both stages. The reference standard was biliary atresia diagnosed at the region's pediatric hepatology centers. The primary outcome of the pre-post study was the age infants underwent the Kasai portoenterostomy for treatment of biliary atresia.
Of 124 385 newborns in the screening study, 49.2% were female, 87.6% were of term gestational age, 70.0% were white, and 48.1% were Hispanic. Screening identified the 7 known infants with biliary atresia with a sensitivity of 100% (95% CI, 56.1%-100.0%), a specificity of 99.9% (95% CI, 99.9%-99.9%), a positive predictive value of 5.9% (95% CI, 2.6%-12.2%), and a negative predictive value of 100.0% (95% CI, 100.0%-100.0%). In the pre-post study, 24 infants were treated before screening implementation and 19 infants were treated after screening implementation (including 6 of 7 from the screening study, 7 from screening at nonstudy hospitals, and 6 from referrals because of clinical symptoms). The age infants underwent the Kasai portoenterostomy was significantly younger after screening was implemented (mean age, 56 days SD, 19 days before screening implementation vs 36 days SD, 22 days after screening implementation; between-group difference, 19 days 95% CI, 7-32 days; P = .004).
Newborn screening with direct or conjugated bilirubin measurements detected all known infants with biliary atresia in the study population, although the 95% CI around the sensitivity estimate was wide and the study design did not ensure complete ascertainment of false-negative results. Research is needed in larger populations to obtain more precise estimates of diagnostic yield and to better understand the clinical outcomes and cost-effectiveness of this screening approach.
To evaluate speech understanding outcomes in a large adult cohort who demonstrated poor hearing performance with well fit hearing aids in the unilateral and bilateral or bimodal listening conditions ...at preimplant, 3-, 6- and 12-months.
Post-linguistically deafened adults (N = 100) with bilateral moderate-to-profound sensorineural hearing loss and limited functional benefit from well fit bilateral hearing aids.
A multicenter, prospective, repeated-measures, within-subject controlled study was conducted. All subjects were implanted with a Slim Modiolar cochlear implant and were required to use bimodal stimulation (cochlear implant and hearing aid in contralateral ear) for 6-months postimplant and optionally to 12-months. Evaluations included: speech recognition for monosyllabic consonant-nucleus-consonant (CNC) words in quiet; AzBio sentences in coincident noise (at +5 and +10 dB signal-to-noise ratio (SNR)), in implant ear and bimodal conditions. All speech tests were performed at preimplant and 6-months postimplant for primary endpoint outcomes, and a subset of speech tests at 3- and 12-months.
In the implant ear only, at 3-, 6- and 12-months postimplant, 84%, 93% and 97% of subjects respectively, demonstrated significantly improved monosyllabic word scores in quiet compared to preimplant hearing aid scores (p < 0.05). At 12-months, a mean gain of 51% points, for monosyllabic words and 32% points for sentences in noise was observed (p < 0.001).
In the bimodal condition, at 6-months postimplant, 87% of subjects demonstrated significantly improved monosyllabic word scores in quiet compared to preimplant bilateral hearing aid scores (p < 0.05). At 6-months, a mean gain of 40% points, for monosyllabic words was observed (p < 0.001). Speech scores for sentences in noise significantly improved for the bimodal condition at 6- and 12-months (p < 0.001).
In addition to speech scores for the implanted ear, bimodal condition scores demonstrated further increments, especially for sentences in noise at 6- and 12-months (p < 0.001).
Results support that bimodal hearing is superior to bilateral hearing aids in this cohort of bilateral moderate-to-profound adult hearing aid users. Our study cohort demonstrated significant improvements for speech scores for the cochlear implant (CI) ear only and bimodal conditions compared to the baseline preimplant unilateral and bilateral hearing aid conditions respectively. The greatest gain in performance was in the first three months of device use with incremental improvement through 12 months. These findings indicate that when hearing aids fit to National Acoustics Laboratory (NAL-1) targets do not provide the necessary audibility needed for speech recognition, referral for CI-candidacy evaluation is strongly recommended.
Trial registration: Clintrial.govNCT03007472. Registered 01/02/2017, https://clinicaltrials.gov/ct2/show/NCT03007472?term=clinical+evaluation+of+the+nucleus+CI532&draw=2&rank=2.
Langerhans cell histiocytosis (LCH) is a clonal disorder with elusive etiology, characterized by the accumulation of CD207(+) dendritic cells (DCs) in inflammatory lesions. Recurrent BRAF-V600E ...mutations have been reported in LCH. In this study, lesions from 100 patients were genotyped, and 64% carried the BRAF-V600E mutation within infiltrating CD207(+) DCs. BRAF-V600E expression in tissue DCs did not define specific clinical risk groups but was associated with increased risk of recurrence. Strikingly, we found that patients with active, high-risk LCH also carried BRAF-V600E in circulating CD11c(+) and CD14(+) fractions and in bone marrow (BM) CD34(+) hematopoietic cell progenitors, whereas the mutation was restricted to lesional CD207(+) DC in low-risk LCH patients. Importantly, BRAF-V600E expression in DCs was sufficient to drive LCH-like disease in mice. Consistent with our findings in humans, expression of BRAF-V600E in BM DC progenitors recapitulated many features of the human high-risk LCH, whereas BRAF-V600E expression in differentiated DCs more closely resembled low-risk LCH. We therefore propose classification of LCH as a myeloid neoplasia and hypothesize that high-risk LCH arises from somatic mutation of a hematopoietic progenitor, whereas low-risk disease arises from somatic mutation of tissue-restricted precursor DCs.
Our objective was to comprehensively evaluate the risk of a broad range of birth defects among offspring of women with diabetes, overall and stratified by pregestational versus gestational diagnosis, ...using the phenome-wide association (PheWAS) methodology.
We performed a registry linkage study of all live births (>6,500,000) and birth defects cases (>290,000) in Texas, 1999–2015. We ascertained diabetes from birth and fetal death certificates. We calculated prevalence rate ratios (PRR) for phenotypes with ≥10 cases among exposed offspring (n = 130).
Diabetes was associated with the prevalence of any defect (PRR 1.40, 95% confidence interval CI 1.38–1.42), multiple defects (PRR 1.86, 95% CI 1.81–1.91), and 60 specific phenotypes, including novel (hypospadias, mitral stenosis) and previously reported phenotypes (renal a-/dysgenesis, spinal anomalies). Pregestational diabetes was a stronger risk factor for any defect (PRR 2.00, 95% CI 1.93–2.07), multiple defects (PRR 3.27, 95% CI 3.11–3.44), and the 60 specific phenotypes evaluated. Gestational diabetes was associated with any defect (PRR 1.21, 95% CI 1.19–1.23) and 47 specific birth defects phenotypes, although associations were weaker than for pregestational diabetes.
The PheWAS is an efficient way to identify risk factors for disease using population-based registry data. Pregestational diabetes is associated with a broader range of phenotypes than previously reported. Because diabetes is diagnosed in 1% of women prior to pregnancy and 6%–9% during pregnancy, our results highlight a significant public health concern.
Langerhans cell histiocytosis (LCH) is a myeloproliferative disorder characterized by lesions composed of pathological CD207+ dendritic cells with an inflammatory infiltrate. BRAFV600E remains the ...only recurrent mutation reported in LCH. In order to evaluate the spectrum of somatic mutations in LCH, whole exome sequencing was performed on matched LCH and normal tissue samples obtained from 41 patients. Lesions from other histiocytic disorders, juvenile xanthogranuloma, Erdheim-Chester disease, and Rosai-Dorfman disease were also evaluated. All of the lesions from histiocytic disorders were characterized by an extremely low overall rate of somatic mutations. Notably, 33% (7/21) of LCH cases with wild-type BRAF and none (0/20) with BRAFV600E harbored somatic mutations in MAP2K1 (6 in-frame deletions and 1 missense mutation) that induced extracellular signal-regulated kinase (ERK) phosphorylation in vitro. Single cases of somatic mutations of the mitogen-activated protein kinase (MAPK) pathway genes ARAF and ERBB3 were also detected. The ability of MAPK pathway inhibitors to suppress MAPK kinase and ERK phosphorylation in cell culture and primary tumor models was dependent on the specific LCH mutation. The findings of this study support a model in which ERK activation is a universal end point in LCH arising from pathological activation of upstream signaling proteins.
•Recurrent somatic mutations in MAP2K1 were identified in 33% of LCH lesions with wild-type BRAF. The mutant MAPK kinase 1 proteins activate ERK.•The ability of MAPK pathway inhibitors to suppress MAPK kinase and ERK phosphorylation in vitro was dependent on the specific LCH mutation.
Abstract
Background
Several cancer-susceptibility syndromes are reported to underlie pediatric rhabdomyosarcoma (RMS); however, to our knowledge there have been no systematic efforts to characterize ...the heterogeneous genetic etiologies of this often-fatal malignancy.
Methods
We performed exome-sequencing on germline DNA from 615 patients with newly diagnosed RMS consented through the Children’s Oncology Group. We compared the prevalence of cancer predisposition variants in 63 autosomal-dominant cancer predisposition genes in these patients with population controls (n = 9963). All statistical tests were 2-sided.
Results
We identified germline cancer predisposition variants in 45 RMS patients (7.3%; all FOXO1 fusion negative) across 15 autosomal dominant genes, which was statistically significantly enriched compared with controls (1.4%, P = 1.3 × 10–22). Specifically, 73.3% of the predisposition variants were found in predisposition syndrome genes previously associated with pediatric RMS risk, such as Li-Fraumeni syndrome (TP53) and neurofibromatosis type I (NF1). Notably, 5 patients had well-described oncogenic missense variants in HRAS (p.G12V and p.G12S) associated with Costello syndrome. Also, genetic etiology differed with histology, as germline variants were more frequent in embryonal vs alveolar RMS patients (10.0% vs 3.0%, P = .02). Although patients with a cancer predisposition variant tended to be younger at diagnosis (P = 9.9 × 10–4), 40.0% of germline variants were identified in those older than 3 years of age, which is in contrast to current genetic testing recommendations based on early age at diagnosis.
Conclusions
These findings demonstrate that genetic risk of RMS results from germline predisposition variants associated with a wide spectrum of cancer susceptibility syndromes. Germline genetic testing for children with RMS should be informed by RMS subtypes and not be limited to only young patients.
Glioblastoma multiforme (GBM) and single brain metastasis (MET) are the 2 most common malignant brain tumors that can appear similar on anatomic imaging but require vastly different treatment ...strategy. The purpose of our study was to determine whether the peak height and the percentage of signal intensity recovery derived from dynamic susceptibility-weighted contrast-enhanced (DSC) perfusion MR imaging could differentiate GBM and MET.
Forty-three patients with histopathologic diagnosis of GBM (n=27) or MET (n=16) underwent DSC perfusion MR imaging in addition to anatomic MR imaging before surgery. Regions of interest were drawn around the nonenhancing peritumoral T2 lesion (PTL) and the contrast-enhancing lesion (CEL). T2* signal intensity-time curves acquired during the first pass of gadolinium contrast material were converted to the changes in relaxation rate to yield T2* relaxivity (Delta R2*) curve. The peak height of maximal signal intensity drop and the percentage of signal intensity recovery at the end of first pass were measured for each voxel in the PTL and CEL regions of the tumor.
The average peak height for the PTL was significantly higher (P=.04) in GBM than in MET. The average percentage of signal intensity recovery was significantly reduced in PTL (78.4% versus 82.8%; P=.02) and in CEL (62.5% versus 80.9%, P<.01) regions of MET compared with those regions in the GBM group.
The findings of our study show that the peak height and the percentage of signal intensity recovery derived from the Delta R2* curve of DSC perfusion MR imaging can differentiate GBM and MET.
Cochlear implantation as an approved clinical therapy ushered in an exciting era of innovation for the treatment of hearing loss. The U.S. Food and Drug Administration approved the use of cochlear ...implants as a treatment option for adults with profound sensorineural hearing loss in 1985. The landscape for treating adults and children with significant hearing loss has changed dramatically over the last three decades. The purpose of this paper is to examine the evolving regulatory process and changes to clinical care. A significant emerging trend in cochlear implantation is the consideration of steroids to preserve hearing during and following surgery. This parallels the quest for hearing preservation in noise-induced hearing disorders, especially considering the current interest in biological drug therapies in this population. The future will likely usher in an era of combination therapeutics utilizing drugs and cochlear implantation. For over 30+ years and following regulatory compliance, the Rocky Mountain Ear Center has developed an extensive candidacy and outcome assessment protocol. This systematic approach evaluates both unaided and aided auditory performance during candidacy stages and post-implantation. Adjunctive measures of cognition and quality-of-life augment the auditory assessment in specific populations. Practical insights into lessons learned have directed further clinical research and have resulted in beneficial changes to clinical care.
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