A combinatorial panel for flow cytometry-based isolation of enteric nervous system cells from human intestine.

Efficient isolation of neurons and glia from the human enteric nervous system (ENS) is challenging because of their rare and fragile nature. Here, we describe a staining panel to enrich ENS cells from the human intestine by fluorescence-activated cell sorting (FACS). We find that CD56/CD90/CD24 co-expression labels ENS cells with higher specificity and resolution than previous methods. Surprisingly, neuronal (CD24, TUBB3) and glial (SOX10) selective markers appear co-expressed by all ENS cells. We demonstrate that this contradictory staining pattern is mainly driven by neuronal fragments, either free or attached to glial cells, which are the most abundant cell types. Live neurons can be enriched by the highest CD24 and CD90 levels. By applying our protocol to isolate ENS cells for single-cell RNA sequencing, we show that these cells can be obtained with high quality, enabling interrogation of the human ENS transcriptome. Taken together, we present a selective FACS protocol that allows enrichment and discrimination of human ENS cells, opening up new avenues to study this complex system in health and disease.

Minimally invasive surgical approach in children treated for oesophageal atresia is associated with attention problems at school age: a prospective cohort study.

The long-term neurodevelopment of children born with oesophageal atresia (OA) is unclear. Therefore, we assessed the neurocognitive domains and their predictors. Patients born with OA between February 2006 and December 2014, who were routinely seen at eight years as part of a structured prospective longitudinal follow-up program, were included. Main outcome measures were need for school support, performance in various neurocognitive domains and potential predictors of neurocognitive problems. We analysed data of 65 children with a mean (SD) age of 8.1 (0.2) years, of whom 89% with OA type C. Thirty-five (54%) surgical corrections were minimally invasive; the median (interquartile range) duration of exposure to anaesthetics in the first 24 months was 398 (296 - 710) minutes. Forty-four (68%) attended regular education without extra support and intelligence was within normal range (99-108). More than 50% had z-scores ≤ -2 on one or more neurocognitive domains, of which attention was the most frequently affected domain. The speed on the sustained attention task was significantly below normal (z-score -1.48 (2.12), p < .001), as was fluctuation of sustained attention (z-score -3.19 (3.80), p < .001). The minimally invasive approach and a lower socio-economic status (both p = 0.006) proved significant predictors for sustained attention problems in multivariable analyses.  Conclusion: Children who undergo minimally invasive surgery for OA correction are at risk for sustained attention problems at school age. Future studies unravelling the effects of perioperative events on neurodevelopment should lead to optimal surgical, anaesthesiological, and intensive care management in the neonatal period. What is Known: • School-aged children born with oesophageal atresia have normal intelligence but problems with sustained attention at eight years. What is New: • Oesophageal atresia patients, who undergo minimally invasive surgery or who have a background of lower socioeconomic status are at serious risk for sustained attention problems at school age. • Moreover, those who have been intubated for a longer period are at risk for stronger fluctuations in sustained attention.

Size matters: Large copy number losses in Hirschsprung disease patients reveal genes involved in enteric nervous system development.

Hirschsprung disease (HSCR) is a complex genetic disease characterized by absence of ganglia in the intestine. HSCR etiology can be explained by a unique combination of genetic alterations: rare coding variants, predisposing haplotypes and Copy Number Variation (CNV). Approximately 18% of patients have additional anatomical malformations or neurological symptoms (HSCR-AAM). Pinpointing the responsible culprits within a CNV is challenging as often many genes are affected. Therefore, we selected candidate genes based on gene enrichment strategies using mouse enteric nervous system transcriptomes and constraint metrics. Next, we used a zebrafish model to investigate whether loss of these genes affects enteric neuron development in vivo. This study included three groups of patients, two groups without coding variants in disease associated genes: HSCR-AAM and HSCR patients without associated anomalies (HSCR-isolated). The third group consisted of all HSCR patients in which a confirmed pathogenic rare coding variant was identified. We compared these patient groups to unaffected controls. Predisposing haplotypes were determined, confirming that every HSCR subgroup had increased contributions of predisposing haplotypes, but their contribution was highest in isolated HSCR patients without RET coding variants. CNV profiling proved that specifically HSCR-AAM patients had larger Copy Number (CN) losses. Gene enrichment strategies using mouse enteric nervous system transcriptomes and constraint metrics were used to determine plausible candidate genes located within CN losses. Validation in zebrafish using CRISPR/Cas9 targeting confirmed the contribution of UFD1L, TBX2, SLC8A1, and MAPK8 to ENS development. In addition, we revealed epistasis between reduced Ret and Gnl1 expression and between reduced Ret and Tubb5 expression in vivo. Rare large CN losses-often de novo-contribute to HSCR in HSCR-AAM patients. We proved the involvement of six genes in enteric nervous system development and Hirschsprung disease.

Children with Intestinal Failure are at Risk for Psychopathology and Trauma.

OBJECTIVES: The objective of this study is to assess the psychopathology and medical traumatic stress in children with intestinal failure (IF) and identify associated risk factors. METHODS: Two-center study, performed from September 2019 until April 2022 (partly during COVID-19 pandemic), including children (1.5-17 years) with IF, dependent on parenteral nutrition (PN) or weaned off PN, treated by a multidisciplinary IF-team. Psychopathology in children was evaluated with a semi-structured interview assessing psychiatric classifications and validated questionnaires assessing emotional (internalizing) and behavioral (externalizing) problems. Medical traumatic stress was assessed with a validated questionnaire. Problem scores were compared with normative data. Associations between clinical characteristics and outcomes were analyzed with linear regression analyses. RESULTS: Forty-one (of 111 eligible) children were included [median age 8.9 years (interquartile range, IQR 5.5-11.8), 54% female, 73% born preterm]. Median PN-duration was 17.3 months (IQR 6.9-54.0); 17 children (41%) were still PN-dependent. One third of the children met criteria for at least 1 psychiatric classification (compared with 14% in age-matched general population). Anxiety disorders and attention deficit hyperactivity disorder were most common. In school-aged children (n = 29, 6-17 years), significantly increased emotional problems were consistently reported by children ( P = 0.011), parents ( P < 0.001), and teachers ( P = 0.004). In preschool children (n = 12, 1.5-5 years), no significant differences with normative data were found. Subclinical or clinical emotional problems were reported in 19 children (46%). Medical traumatic stress was present in 14%, and 22% of children had received psychological help for trauma before. Lower gastrointestinal related quality of life was associated with more emotional problems, but not PN-duration. CONCLUSIONS: Children with IF, particularly school-aged children, are at risk for psychological problems which is reflected by the high rate of received psychotherapy and the high rate of emotional problems and psychiatric classifications.

Long-term neurodevelopment in children with resected congenital lung abnormalities.

To determine whether children who underwent resection of a congenital lung abnormality (CLA) are at higher risk for neurodevelopmental impairments than peers in the general population. The study population consisted of children born between 1999-2018 who underwent resection of a symptomatic CLA. Neurocognitive development (intelligence, memory, attention, visuospatial processing, executive functioning) and motor function of this population are monitored through our structured, prospective longitudinal follow-up program at the ages of 30 months, 5, 8, and 12 years. We compared study population scores with Dutch norm values using one-sample t-tests and one-sample binominal proportion tests. Forty-seven children were analyzed. The 8-year-olds showed significant impairments in sustained attention through the Dot Cancellation Test (mean z-scores -2.4; [-4.1; -0.8], p = 0.006 and -7.1; [-12.8; -1.4], p = 0.02 for execution speed and fluctuations respectively). Visuospatial memory was impaired at 8 years, though only in 1 out of 3 assessment tools (Rey Complex Figure Test z-scores (-1.0; [-1.5; -0.5], p < 0.001). Further neurocognitive outcomes were unimpaired at all tested ages. Regarding motor function outcomes, mean z-scores of total motor functioning were unimpaired across assessed ages. However, at 8 years, significantly more children than expected had definite motor problems (18% vs 5%, 95% CI [0.052; 0.403], p = 0.022).   Conclusion: This evaluation reveals impairment in some subtests of sustained attention, visuospatial memory and motor development. However, globally, normal neurodevelopmental outcomes were found throughout childhood. We recommend testing for neurodevelopmental impairments in children who underwent surgery for CLA only if associated morbidities are present or if caregivers express doubts about their daily functioning. What is Known: • In general, surgically managed CLA cases seldom suffer from long-term surgery-related morbidity and show favorable lung function. What is New: • Long-term neurocognitive and motor function outcome appear unimpaired within surgically managed CLA cases. We recommend testing for neurodevelopmental impairments in children who underwent surgery for CLA only if associated morbidities are present or if caregivers express doubts about their daily functioning.

Development of a simulator for training of fetoscopic myelomeningocele surgery.

OBJECTIVE: To develop a realistic simulation model for laparotomy-assisted fetoscopic spina bifida aperta (SBa) surgery, to be used for training purposes and preoperative planning. METHODS: The predefined general requirement was a realistic model of an exteriorized uterus, allowing all neurosurgical steps of the intervention. The uterus was modelled using ultrasound and MRI images of a 25 weeks' gravid uterus, consisting of flexible polyurethane foam coated with pigmented silicone. The fetal model, contained an opening on the dorsal side for a customizable spinal insert with all the aspects of a SBa, including a cele, placode, and myofascial and skin layer. The model was assessed in a series of validation experiments. RESULTS: Production costs are low, uterus and fetus are reusable. Placental localization and the level and size of the spinal defect are adjustable, enabling case-specific adaptations. All aspects of the simulator were scored close to realistic or higher for both appearance and functional capacities. CONCLUSIONS: This innovative model provides an excellent training opportunity for centers that are starting a fetoscopic SBa repair program. It is the first simulation model with adjustable spinal defect and placental localisation. Further objective validation is required, but the potential for using this model in preoperative planning is promising.

Development and validation of a condition-specific quality of life instrument for adults with esophageal atresia: the SQEA questionnaire.

The importance of multidisciplinary long-term follow-up for adults born with esophageal atresia (EA) is increasingly recognized. Hence, a valid, condition-specific instrument to measure health-related quality of life (HRQoL) becomes imperative. This study aimed to develop and validate such an instrument for adults with EA. The Specific Quality of life in Esophageal atresia Adults (SQEA) questionnaire was developed through focus group-based item generation, pilot testing, item reduction and a multicenter, nationwide field test to evaluate the feasibility, reliability (internal and retest) and validity (structural, construct, criterion and convergent), in compliance with the consensus-based standards for the selection of health measurement instruments guidelines. After pilot testing (n = 42), items were reduced from 144 to 36 questions. After field testing (n = 447), three items were discarded based on item-response theory results. The final SQEA questionnaire (33 items) forms a unidimensional scale generating an unweighted total score. Feasibility, internal reliability (Cronbach's alpha 0.94) and test-retest agreement (intra-class coefficient 0.92) were good. Construct validity was discriminative for esophageal replacement (P < 0.001), dysphagia (P < 0.001) and airway obstruction (P = 0.029). Criterion validity showed a good correlation with dysphagia (area under the receiver operating characteristic 0.736). SQEA scores correlated well with other validated disease-specific HRQoL scales such as the GIQLI and SGRQ, but poorly with the more generic RAND-36. Overall, this first condition-specific instrument for EA adults showed satisfactory feasibility, reliability and validity. Additionally, it shows discriminative ability to detect disease burden. Therefore, the SQEA questionnaire is both a valid instrument to assess the HRQoL in EA adults and an interesting signaling tool, enabling clinicians to recognize more severely affected patients.

Cognitive Outcomes in Children With Conditions Affecting the Small Intestine: A Systematic Review and Meta-analysis.

OBJECTIVES: The aim of the study was to assess cognitive outcomes in children with intestinal failure (IF) and children at high risk of IF with conditions affecting the small intestine requiring parenteral nutrition. METHODS: EMBASE, Cochrane, Web of Science, Google Scholar, MEDLINE, and PsycINFO were searched from inception to October 2020. Studies were included constituting original data on developmental quotient (DQ), intelligence quotient (IQ) and/or severe developmental delay/disability (SDD) rates assessed with standardized tests. We used appropriate standardized tools to extract data and assess study quality. We performed random effects meta-analyses to estimate pooled means of DQ/IQ and pooled SDD rates (general population mean for DQ/IQ: 100, for percentage with SDD: 1.8%) for 4 groups: IF, surgical necrotizing enterocolitis (NEC), abdominal wall defects (AWD), and midgut malformations (MM). Associations of patient characteristics with DQ/IQ were evaluated with meta-regressions. RESULTS: Thirty studies met the inclusion criteria. The pooled mean DQ/IQ for IF, NEC, AWD, and MM were 86.8, 83.3, 96.6, and 99.5, respectively. The pooled SDD rates for IF, NEC, AWD and MM were 28.6%, 32.8%, 8.5%, and 3.7%, respectively. Meta-regressions indicated that lower gestational age, longer hospital stay, and higher number of surgeries but not parenteral nutrition duration, were associated with lower DQ/IQ. CONCLUSIONS: Adverse developmental outcomes are common in children with IF and NEC, and to a much lesser extent in children with AWD and MM. It is important to monitor cognitive development in children with conditions affecting the small intestine and to explore avenues for prevention and remediation.

A novel method for monitoring abdominal compliance to optimize insufflation pressure during laparoscopy.

BACKGROUND: Abdominal compliance describes the ease of expansion of the abdominal cavity. Several studies highlighted the importance of monitoring abdominal compliance (Cab) during the creation of laparoscopic workspace to individualize the insufflation pressure. The lack of validated clinical monitoring tools for abdominal compliance prevents accurate tailoring of insufflation pressure. Oscillometry, also known as the forced oscillation technique (FOT), is currently used to measure respiratory mechanics and has the potential to be adapted for monitoring abdominal compliance. This study aimed to define, develop and evaluate a novel approach which can monitor abdominal compliance during laparoscopy using endoscopic oscillometry. MATERIALS AND METHODS: Endoscopic oscillometry was evaluated in a porcine model for laparoscopy. A custom-built insufflator was developed for applying an oscillatory pressure signal superimposed onto a mean intra-abdominal pressure. This insufflator was used to measure the abdominal compliance at insufflation pressures ranging from 5 to 20 hPa (3.75 to 15 mmHg). The measurements were compared to the static abdominal compliance, which was measured simultaneously with computed tomography imaging. RESULTS: Endoscopic oscillometry recordings and CT images were obtained in 10 subjects, resulting in 76 measurement pairs for analysis. The measured dynamic Cab ranged between 0.0216 and 0.261 L/hPa while the static Cab based on the CT imaging ranged between 0.0318 and 0.364 L/hPa. The correlation showed a polynomial relation and the adjusted R-squared was 97.1%. CONCLUSIONS: Endoscopic oscillometry can be used to monitor changes in abdominal compliance during laparoscopic surgery, which was demonstrated in this study with a comparison with CT imaging in a porcine laparoscopy model. Use of this technology to personalize the insufflation pressure could reduce the risk of applying excessive pressure and limit the drawbacks of insufflation.

Prenatal stomach position and volume in relation to postnatal outcomes in left-sided congenital diaphragmatic hernia.

OBJECTIVE: To examine the association between prenatal stomach position (SP) grade and stomach volume (SV) and the need for pulmonary hypertension (PH) treatment after birth in prenatally diagnosed left-sided congenital diaphragmatic hernia (CDH), live born >34 weeks. METHODS: In retrospect, SP grade and SV were determined in fetuses with isolated left-sided CDH from 19 weeks gestational age (GA) onwards at three different time periods (≤24 weeks' GA: US1, 24-30 weeks' GA: US2; ≥30 weeks' GA: US3). Primary outcome was need for treatment of PH after birth. Secondary analyses included the predictive value of SP and SV for other respiratory outcomes and postnatal defect size. RESULTS: A total of 101 fetuses were included. SP grade was significantly associated with need for treatment of PH (US1, US2, and US3: p < 0.02). Also, prenatal SP grade was positively associated with defect size and development of chronic lung disease (CLD) in survivors. No association was found between SV and respiratory morbidities or postnatal defect size. CONCLUSION: SP grade in left-sided CDH fetuses is associated with an increased need for PH treatment, a larger postnatal defect size and CLD in survivors. We consider SP determination a valuable contribution to the prenatal assessment of left-sided CDH.

Recommendations for endoscopic surveillance after esophageal atresia repair in adults.

BACKGROUND: Endoscopic surveillance of adults with esophageal atresia is advocated, but the optimal surveillance strategy remains uncertain. This study aimed to provide recommendations on appropriate starting age and intervals of endoscopic surveillance in adults with esophageal atresia. METHODS: Participants underwent standardized upper endoscopies with biopsies. Surveillance intervals of 3-5 years were applied, depending on age and histopathological results. Patient's age and time to development of (pre)malignant lesions were calculated. RESULTS: A total of 271 patients with esophageal atresia (55% male; median age at baseline endoscopy 26.7 (range 15.6-68.5) years; colon interposition n = 17) were included. Barrett's esophagus was found in 19 (7%) patients (median age 32.3 (17.8-56.0) years at diagnosis). Youngest patient with a clinically relevant Barrett's esophagus was 20.9 years. Follow-up endoscopies were performed in 108 patients (40%; median follow-up time 4.6 years). During surveillance, four patients developed Barrett's esophagus but no dysplasia or cancer was found. One 45-year-old woman with a colon interposition developed an adenoma with high-grade dysplasia which was radically removed. Two new cases of esophageal carcinoma were diagnosed in patients (55 and 66 years old) who were not under surveillance. One of them had been curatively treated for esophageal carcinoma 13 years ago. CONCLUSIONS: This study shows that endoscopic screening of patients with esophageal atresia, including those with a colon interposition, can be started at 20 years of age. Up to the age of 40 years a surveillance interval of 10 years appeared to be safe. Endoscopic surveillance may also be warranted for patients after curative esophageal cancer treatment.

Neurocardiovascular coupling in congenital diaphragmatic hernia patients undergoing different types of surgical treatment.

BACKGROUND: The effect of peri-operative management on the neonatal brain is largely unknown. Triggers for perioperative brain injury might be revealed by studying changes in neonatal physiology peri-operatively. OBJECTIVE: To study neonatal pathophysiology and cerebral blood flow regulation peri-operatively using the neuro-cardiovascular graph. DESIGN: Observational, prospective cohort study on perioperative neuromonitoring. Neonates were included between July 2018 and April 2020. SETTING: Multicentre study in two high-volume tertiary university hospitals. PATIENTS: Neonates with congenital diaphragmatic hernia were eligible if they received surgical treatment within the first 28 days of life. Exclusion criteria were major cardiac or chromosomal anomalies, or syndromes associated with altered cerebral perfusion or major neurodevelopmental impairment. The neonates were stratified into different groups by type of peri-operative management. INTERVENTION: Each patient was monitored using near-infrared spectroscopy and EEG in addition to the routine peri-operative monitoring. Neurocardiovascular graphs were computed off-line. MAIN OUTCOME MEASURES: The primary endpoint was the difference in neurocardiovascular graph connectivity in the groups over time. RESULTS: Thirty-six patients were included. The intraoperative graph connectivity decreased in all patients operated upon in the operation room (OR) with sevoflurane-based anaesthesia ( P  < 0.001) but remained stable in all patients operated upon in the neonatal intensive care unit (NICU) with midazolam-based anaesthesia. Thoracoscopic surgery in the OR was associated with the largest median connectivity reduction (0.33 to 0.12, P  < 0.001) and a loss of baroreflex and neurovascular coupling. During open surgery in the OR, all regulation mechanisms remained intact. Open surgery in the NICU was associated with the highest neurovascular coupling values. CONCLUSION: Neurocardiovascular graphs provided more insight into the effect of the peri-operative management on the pathophysiology of neonates undergoing surgery. The neonate's clinical condition as well as the surgical and the anaesthesiological approach affected the neonatal physiology and CBF regulation mechanisms at different levels. TRIAL REGISTRATION: NL6972, URL: https://www.trialre-gister.nl/trial/6972 .

Remote ischemic conditioning in necrotizing enterocolitis: study protocol of a multi-center phase II feasibility randomized controlled trial.

PURPOSE: Remote ischemic conditioning (RIC) is a maneuver involving brief cycles of ischemia reperfusion in an individual's limb. In the early stage of experimental NEC, RIC decreased intestinal injury and prolonged survival by counteracting the derangements in intestinal microcirculation. A single-center phase I study demonstrated that the performance of RIC was safe in neonates with NEC. The aim of this phase II RCT was to evaluate the safety and feasibility of RIC, to identify challenges in recruitment, retainment, and to inform a phase III RCT to evaluate efficacy. METHODS: RIC will be performed by trained research personnel and will consist of four cycles of limb ischemia (4-min via cuff inflation) followed by reperfusion (4-min via cuff deflation), repeated on two consecutive days post randomization. The primary endpoint of this RCT is feasibility and acceptability of recruiting and randomizing neonates within 24 h from NEC diagnosis as well as masking and completing the RIC intervention. RESULTS: We created a novel international consortium for this trial and created a consensus on the diagnostic criteria for NEC and protocol for the trial. The phase II multicenter-masked feasibility RCT will be conducted at 12 centers in Canada, USA, Sweden, The Netherlands, UK, and Spain. The inclusion criteria are: gestational age < 33 weeks, weight ≥ 750 g, NEC receiving medical treatment, and diagnosis established within previous 24 h. Neonates will be randomized to RIC (intervention) or no-RIC (control) and will continue to receive standard management of NEC. We expect to recruit and randomize 40% of eligible patients in the collaborating centers (78 patients; 39/arm) in 30 months. Bayesian methods will be used to combine uninformative prior distributions with the corresponding observed proportions from this trial to determine posterior distributions for parameters of feasibility. CONCLUSIONS: The newly established NEC consortium has generated novel data on NEC diagnosis and defined the feasibility parameters for the introduction of a novel treatment in NEC. This phase II RCT will inform a future phase III RCT to evaluate the efficacy and safety of RIC in early-stage NEC.

SOX2 and SOX21 in Lung Epithelial Differentiation and Repair.

The lung originates from the ventral foregut and develops into an intricate branched structure of airways, alveoli, vessels and support tissue. As the lung develops, cells become specified and differentiate into the various cell lineages. This process is controlled by specific transcription factors, such as the SRY-related HMG-box genes SOX2 and SOX21, that are activated or repressed through intrinsic and extrinsic signals. Disturbances in any of these processes during the development of the lung may lead to various pediatric lung disorders, such as Congenital Diaphragmatic Hernia (CDH), Congenital Pulmonary Airway Malformation (CPAM) and Broncho-Pulmonary Dysplasia (BPD). Changes in the composition of the airways and the alveoli may result in reduced respiratory function and eventually lead to chronic lung disorders. In this concise review, we describe different intrinsic and extrinsic cellular processes required for proper differentiation of the epithelium during development and regeneration, and the influence of the microenvironment on this process with special focus on SOX2 and SOX21.

Ontogeny of Small Intestinal Drug Transporters and Metabolizing Enzymes Based on Targeted Quantitative Proteomics.

Most drugs are administered to children orally. An information gap remains on the protein abundance of small intestinal drug-metabolizing enzymes (DMEs) and drug transporters (DTs) across the pediatric age range, which hinders precision dosing in children. To explore age-related differences in DMEs and DTs, surgical leftover intestinal tissues from pediatric and adult jejunum and ileum were collected and analyzed by targeted quantitative proteomics for apical sodium-bile acid transporter, breast cancer resistance protein (BCRP), monocarboxylate transporter 1 (MCT1), multidrug resistance protein 1 (MDR1), multidrug resistance-associated protein (MRP) 2, MRP3, organic anion-transporting polypeptide 2B1, organic cation transporter 1, peptide transporter 1 (PEPT1), CYP2C19, CYP3A4, CYP3A5, UDP glucuronosyltransferase (UGT) 1A1, UGT1A10, and UGT2B7. Samples from 58 children (48 ileums, 10 jejunums, age range: 8 weeks to 17 years) and 16 adults (8 ileums, 8 jejunums) were analyzed. When comparing age groups, BCRP, MDR1, PEPT1, and UGT1A1 abundance was significantly higher in adult ileum as compared with the pediatric ileum. Jejunal BCRP, MRP2, UGT1A1, and CYP3A4 abundance was higher in the adults compared with children 0-2 years of age. Examining the data on a continuous age scale showed that PEPT1 and UGT1A1 abundance was significantly higher, whereas MCT1 and UGT2B7 abundance was lower in adult ileum as compared with the pediatric ileum. Our data contribute to the deeper understanding of the ontogeny of small intestinal drug-metabolizing enzymes and drug transporters and shows DME-, DT-, and intestinal location-specific, age-related changes. SIGNIFICANCE STATEMENT: This is the first study that describes the ontogeny of small intestinal DTs and DMEs in human using liquid chromatography with tandem mass spectrometry-based targeted quantitative proteomics. The current analysis provides a detailed picture about the maturation of DT and DME abundances in the human jejunum and ileum. The presented results supply age-related DT and DME abundance data for building more accurate PBPK models that serve to support safer and more efficient drug dosing regimens for the pediatric population.

Longitudinal Health Status and Quality of Life After Esophageal Atresia Repair.

OBJECTIVES: To longitudinally evaluate self-reported and proxy-reported health status (HS) and quality of life (QoL) of school-aged children born with esophageal atresia (EA). METHODS: We obtained Pediatric Quality of Life Inventory (HS) and DUX-25 (QoL) questionnaires from children born with EA between 1999 and 2011 at 8 and/or 12 years old. Children completed self-reports during neuropsychological assessments in a prospective longitudinal follow-up program. Parents filled out proxy-reports at home. Total and subscale scores were evaluated longitudinally and compared with sex-specific reference norms. RESULTS: In total, 110 participants (62% boys) were included. Self-reported HS improved significantly between 8 and 12 years for both boys (mean difference [md] 4.35, effect size [ES] 0.54, P = 0.009) and girls (md 3.26, ES 0.63, P = 0.004). Proxy-reported HS tended to improve over time, while self-reported and proxy-reported QoL tended to decline. Self-reported HS at 8 years was below normal for both boys (md -5.44, ES -0.35, P < 0.001) and girls (md -7.61, ES -0.32, P < 0.001). Girls' self-reported QoL was below normal at 8 (md -5.00, ES -0.18, P = 0.019) and 12 years (md -10.50, ES -0.26, P = 0.001). Parents reported normal HS at both ages, whereas they rated the QoL of their daughters below normal at 12 years (md -10.00, ES -0.16, P = 0.022). All above results are total scores. CONCLUSIONS: Self-reported and proxy-reported HS of children with EA improved between 8 and 12 years, while their QoL tended to decline. We recommend to consider HS and QoL as two separate concepts and to measure both simultaneously and longitudinally when evaluating the burden of disease.

A clinical guideline for structured assessment of CT-imaging in congenital lung abnormalities.

OBJECTIVES: To develop a clinical guideline for structured assessment and uniform reporting of congenital lung abnormalities (CLA) on Computed Tomography (CT)-scans. MATERIALS AND METHODS: A systematic literature search was conducted for articles describing CT-scan abnormalities of congenital pulmonary airway malformation (CPAM), bronchopulmonary sequestration (BPS), congenital lobar emphysema (CLE) and bronchogenic cyst (BC). A structured report using objective features of CLA was developed after consensus between a pediatric pulmonologist, radiologist and surgeon. RESULTS: Of 1581 articles identified, 158 remained after title-abstract screening by two independent reviewers. After assessing full-texts, we included 28 retrospective cohort-studies. Air-containing cysts and soft tissue masses are described in both CPAM and BPS while anomalous arterial blood supply is only found in BPS. Perilesional low-attenuation areas, atelectasis and mediastinal shift may be found in all aforementioned abnormalities and can also be seen in CLE as a cause of a hyperinflated lobe. We have developed a structured report, subdivided into five sections: Location & Extent, Airway, Lesion, Vascularization and Surrounding tissue. CONCLUSIONS: CT-imaging findings in CLA are broad and nomenclature is variable. Overlap is seen between and within abnormalities, possibly due to definitions often being based on pathological findings, which is an unsuitable approach for CT imaging. We propose a structured assessment of CLA using objective radiological features and uniform nomenclature to improve reporting.

An international survey on anastomotic stricture management after esophageal atresia repair: considerations and advisory statements.

BACKGROUND: Endoscopic dilatation is the first-line treatment of stricture formation after esophageal atresia (EA) repair. However, there is no consensus on how to perform these dilatation procedures which may lead to a large variation between centers, countries and doctor's experience. This is the first cross-sectional study to provide an overview on differences in endoscopic dilatation treatment of pediatric anastomotic strictures worldwide. METHODS: An online questionnaire was sent to members of five pediatric medical networks, experienced in treating anastomotic strictures in children with EA. The main outcome was the difference in endoscopic dilatation procedures in various centers worldwide, including technical details, dilatation approach (routine or only in symptomatic patients), and adjuvant treatment options. Descriptive statistics were performed with SPSS. RESULTS: Responses from 115 centers from 32 countries worldwide were analyzed. The preferred approach was balloon dilatation (68%) with a guidewire (66%), performed by a pediatric gastroenterologist (n = 103) or pediatric surgeon (n = 48) in symptomatic patients (68%). In most centers, hydrostatic pressure was used for balloon dilatation. The insufflation duration was standardized in 59 centers with a median duration of 60 (range 5-300) seconds. The preferred first-line adjunctive treatments in case of recurrent strictures were intralesional steroids and topical mitomycin C, in respectively 47% and 31% of the centers. CONCLUSIONS: We found a large variation in stricture management in children with EA, which confirms the current lack of consensus. International networks for rare diseases are required for harmonizing and comparing the procedures, for which we give several suggestions.

Long-term neurodevelopment in children born with esophageal atresia: a systematic review.

BACKGROUND: Although the survival rate of esophageal atresia (EA) has increased to over 90%, the risk of functional long-term neurodevelopmental deficits is uncertain. Studies on long-term outcomes of children with EA show conflicting results. Therefore, we provide an overview of the current knowledge on the long-term neurodevelopmental outcome of children with EA. METHODS: We performed a structured literature search in Embase, Medline Ovid, Web of Science, Cochrane CENTRAL, and Google scholar on November 8, 2020 with the keywords 'esophageal atresia', 'long-term outcome', 'motor development', 'cognitive development', and 'neurodevelopment'. RESULTS: The initial search identified 945 studies, of which 15 were included. Five of these published outcomes of multiple tests or tested at multiple ages. Regarding infants, one of six studies found impaired neurodevelopment at 1 year of age. Regarding preschoolers, two of five studies found impaired neurodevelopment; the one study assessing cognitive development found normal cognitive outcome. Both studies on motor function reported impairment. Regarding school-agers, the one study on neurodevelopmental outcome reported impairment. Cognitive impairment was found in two out of four studies, and motor function was impaired in both studies studying motor function. CONCLUSIONS: Long-term neurodevelopment of children born with EA has been assessed with various instruments, with contrasting results. Impairments were mostly found in motor function, but also in cognitive performance. Generally, the long-term outcome of these children is reason for concern. Structured, multidisciplinary long-term follow-up programs for children born with EA would allow to timely detect neurodevelopmental impairments and to intervene, if necessary.

Associations of perioperative characteristics with motor function in preschool children born with esophageal atresia.

BACKGROUND: Children born with esophageal atresia experience long-term neurodevelopmental deficits, with unknown origin. AIMS: To find associations between perioperative variables during primary esophageal atresia repair and motor function at age 5 years. METHODS: This ambidirectional cohort study included children born with esophageal atresia who consecutively had been operated on in the Erasmus MC-Sophia Children's Hospital, University Medical Center, Rotterdam, from January 2007 through June 2013. The perioperative data of this cohort were collected retrospectively; the motor function data prospectively. RESULTS: After exclusion of patients with syndromal congenital diseases (n = 8) and lost to follow-up (n = 10), the data of 53 children were included. The mean (SD) total motor function impairment z-score at 5 years of age was -0.66 (0.99), significantly below normal (p < .001). In multivariable linear regression analysis, number of postoperative days endotracheal intubation (B = -0.211, 95% CI: -0.389 to -0.033, p = .021) was negatively associated with motor outcome, whereas high blood pressure (B = 0.022, 95% CI 0.001 to 0.042, p = .038) was positively associated. Preoperative nasal oxygen supplementation versus room air (B = 0.706, 95% CI: 0.132 to 1.280, p = .016) was positively associated with motor outcome, which we cannot explain. CONCLUSIONS: Motor function in 5-year-old esophageal atresia patients was impaired and negatively associated with the number of postoperative days of endotracheal intubation and positively associated with high blood pressure. Prospective studies with critical perioperative monitoring and monitoring during stay at the intensive care unit are recommended.