Copy number variations in 375 patients with oesophageal atresia and/or tracheoesophageal fistula

Oesophageal atresia (OA) with or without tracheoesophageal fistula (TOF) are rare anatomical congenital malformations whose cause is unknown in over 90% of patients. A genetic background is suggested, and among the reported genetic defects are copy number variations (CNVs). We hypothesized that CNVs contribute to OA/TOF development. Quantifying their prevalence could aid in genetic diagnosis and clinical care strategies. Therefore, we profiled 375 patients in a combined Dutch, American and German cohort via genomic microarray and compared the CNV profiles with their unaffected parents and published control cohorts. We identified 167 rare CNVs containing genes (frequency<0.0005 in our in-house cohort). Eight rare CNVs - in six patients - were de novo, including one CNV previously associated with oesophageal disease. (hg19 chr7:g.(143820444-143839360)-(159119486-159138663)del) 1.55% of isolated OA/TOF patients and 1.62% of patients with additional congenital anomalies had de novo CNVs. Furthermore, three (15q13.3, 16p13.3 and 22q11.2) susceptibility loci were identified based on their overlap with known OA/TOF-associated CNV syndromes and overlap with loci in published CNV association case-control studies in developmental delay. Our study suggests that CNVs contribute to OA/TOF development. In addition to the identified likely deleterious de novo CNVs, we detected 167 rare CNVs. Although not directly disease-causing, these CNVs might be of interest, as they can act as a modifier in a multiple hit model, or as the second hit in a recessive condition

Standardized postnatal management of infants with congenital diaphragmatic hernia in Europe: The CDH EURO Consortium Consensus - 2015 Update

In 2010, the congenital diaphragmatic hernia (CDH) EURO Consortium published a standardized neonatal treatment protocol. Five years later, the number of participating centers has been raised from 13 to 22. In this article the relevant literature is updated, and consensus has been reached between the members of the CDH EURO Consortium. Key updated recommendations are: (1) planned delivery after a gestational age of 39 weeks in a high-volume tertiary center; (2) neuromuscular blocking agents to be avoided during initial treatment in the delivery room; (3) adapt treatment to reach a preductal saturation of between 80 and 95% and postductal saturation >70%; (4) target PaCO2 to be between 50 and 70 mm Hg; (5) conventional mechanical ventilation to be the optimal initial ventilation strategy, and (6) intravenous sildenafil to be considered in CDH patients with severe pulmonary hypertension. This article represents the current opinion of all consortium members in Europe for the optimal neonatal treatment of CDH

Two versus five days of antibiotics after appendectomy for complex acute appendicitis (APPIC): Study protocol for a randomized controlled trial

Background: Acute appendicitis is one of the most common indications for emergency surgery. In patients with a complex appendicitis, prolonged antibiotic prophylaxis is recommended after appendectomy. There is no consensus regarding the optimum duration of antibiotics. Guidelines propose 3 to 7 days of treatment, but shorter courses may be as effective in the prevention of infectious complications. At the same time, the global issue of increasing antimicrobial resistance urges for optimization of antibiotic strategies. The aim of this study is to determine whether a short course (48 h) of postoperative antibiotics is non-inferior to current standard practice of 5 days. Methods: Patients of 8 years and older undergoing appendectomy for acute complex appendicitis - defined as a gangrenous and/or perforated appendicitis or appendicitis in presence of an abscess - are eligible for inclusion. Immunocompromised or pregnant patients are excluded, as well as patients with a contraindication to the study antibiotics. In total, 1066 patients will be randomly allocated in a 1:1 ratio to the experimental treatment arm (48 h of postoperative intravenously administered (IV) antibiotics) or the control arm (5 days of postoperative IV antibiotics). After discharge from the hospital, patients participate in a productivity-cost-questionnaire at 4 weeks and a standardized telephone follow-up at 90 days after appendectomy. The primary outcome is a composite endpoint of infectious complications, including intra-abdominal abscess (IAA) and surgical site infection (SSI), and mortality within 90 days after appendectomy. Secondary outcomes include IAA, SSI, restart of antibiotics, length of hospital stay (LOS), reoperation, percutaneous drainage, readmission rate, and cost-effectiveness. The non-inferiority margin for the difference in the primary endpoint rate is set at 7.5% (one-sided test at α 0.025). Both per-protocol and intention-to-treat analyses will be performed. Discussion: This trial will provide evidence on whether 48 h of postoperative antibiotics is non-inferior to a standard course of 5 days of antibiotics. If non-inferiority is established, longer intravenous administration following appendectomy for complex appendicitis can be abandoned, and guidelines need to be adjusted accordingly

Automated control for investigation of the insufflation-ventilation interaction in experimental laparoscopy.

In laparoscopic surgery the abdominal cavity is insufflated with pressurized carbon dioxide gas to create workspace. This pressure is exerted through the diaphragm onto the lungs, competing with ventilation and hampering it. In clinical practice the difficulty of optimizing this balance can lead to the application of harmfully high pressures. This study set out to create a research platform for the investigation of the complex interaction between insufflation and ventilation in an animal model. The research platform was constructed to incorporate insufflation, ventilation and relevant hemodynamic monitoring devices, controlling insufflation and ventilation from a central computer. The core of the applied methodology is the fixation of physiological parameters by applying closed-loop control of specific ventilation parameters. For accurate volumetric measurements the research platform can be used in a CT scanner. An algorithm was designed to keep blood carbon dioxide and oxygen values stable, minimizing the effect of fluctuations on vascular tone and hemodynamics. This design allowed stepwise adjustment of insufflation pressure to measure the effects on ventilation and circulation. A pilot experiment in a porcine model demonstrated adequate platform performance. The developed research platform and protocol automation have the potential to increase translatability and repeatability of animal experiments on the biomechanical interactions between insufflation and ventilation

Quality of life in adulthood after resection of a sacrococcygeal teratoma in childhood : A Dutch multicentre study

Objective Children treated for sacrococcygeal teratoma (SCT) may experience functional sequelae later in life. It is not known whether SCT and associated problems affect the patient's general quality of life (QoL). In a national survey, we evaluated general QoL in adults treated for SCT during childhood and compared the results to reference values for the Dutch population. Design The records of patients aged ≥18 years treated for an SCT in one of the six paediatric surgical centres in the Netherlands from 1970 to 1993 were retrospectively reviewed; patient characteristics were retrieved from medical records. General QoL was evaluated using the Short Form 36 Health Survey (SF-36). The means of the eight SF-36 domain scores of patients treated for SCT were compared to reference values for the Dutch population (n=757, aged 18-43 years). Linear regression analysis was used to adjust for differences in baseline characteristics between both groups. Results 46 of 51 patients treated for SCT during childhood (90.2%), with a mean age of 26.3 years (range 18.3-41.1), returned completed SF-36 questionnaires. Their scores on all SF-36 subcategories were equivalent to those of the Dutch reference population. No significant differences in the scores of the SF-36 subcategories were found after linear regression analysis adjusting for differences in age, sex and living status between both groups. Conclusions The long-term QoL of patients treated for SCT during childhood does not differ from that of the general population. Moreover, patients do not show impairment in social, physical or emotional functioning in adulthood

The incidence of associated abnormalities in patients with sacrococcygeal teratoma

Gross genetic causes for SCT are unknown; however, it might be associated with other abnormalities. We assessed the incidence of associated abnormalities in a large national cohort of neonates with SCT and aimed to identify predictive risk factors. The medical records were reviewed of 235 consecutive neonates with SCT treated at the six pediatric surgical centers in the Netherlands from 1970 to 2010. Potential risk factors for associated abnormalities analyzed included sex, gestational age, tumor-volume/histology and Altman-classification. In 76 patients (32.3%) at least one associated abnormality was diagnosed, with hydronephrosis as the most common (16.2%) and hip dysplasia in 4.3%. Multiple abnormalities were documented for 21 (9.0%). Prematurity and Altman type IV SCT were associated with an increased risk of any associated abnormality. No association between increased tumor-volume and hydronephrosis or hip dysplasia was found. Patients with type IV Altman SCT had a fourfold risk of suffering from hydronephrosis compared to Altman type I SCT. SCT was associated with other abnormalities in one-third of children. Some were tumor-related while others were related to prematurity or occurred sporadically. In contrast to clinically obvious anomalies, hip dysplasia or hydronephrosis might be latently present with more subtle clinical presentation. We therefore suggest renal- and hip-ultrasound in all patients, certainly those with Altman type IV SCT. Level II (retrospective study

Investigation for cystic fibrosis in infants with jejunoileal atresia in the Netherlands: a 35-year experience with 114 cases.

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Evaluation of Gastroesophageal Reflux in Children Born with Esophageal Atresia Using pH and Impedance Monitoring

Objectives To evaluate acid and non-acid gastroesophageal reflux in infants and school-aged children with esophageal atresia (EA) using pH-impedance (pH-MII) monitoring. Methods Between 2012-2017, all 24-hour pH-MII studies performed in infants (≥18 months) and 8-year olds with EA were included. Anti-acid therapy was discontinued before study. Exclusion criteria were: isolated tracheoesophageal fistula; esophageal replacement therapy; tube feeding; and monitoring <18 hours. Automatically detected retrograde bolus movements (RBM) were manually reviewed and modified/deleted if necessary. Results We included 57 children (51% male; 2% isolated EA; 44% thoracoscopic EA repair): 24 infants (median age 0.6 years) and 33 school-aged children (median age 8.2 years). Of the automatically detected 3,313 RBM, 1,292 were manually deleted from the tracings: 52% of non-acid RBM and 8% of acid RBM (mainly misinterpreted swallows or one event recognized as several events). In infants, median reflux index (RI;pH<4) was 2.6% (abnormal in n=2), median RBM was 61 (62% non-acid, 58% mixed) and median of the mean BCT was 11 seconds. In older children, median RI was 0.3% (abnormal in n=4), median RBM was 21 (64% non-acid; 75% mixed) and median of the mean BCT was 13 seconds. Conclusions Most children with EA off medication have a normal RI, yet experience a significant number of non-acid RBM. After manual revision of the tracings a high percentage of RBM was deleted. Our data show that automated impedance analysis software needs refinement for use in infants and children with EA and question the need for standard antiacid therapy in these patients