Further delineation of the rare GDACCF (global developmental delay, absent or hypoplastic corpus callosum, dysmorphic facies syndrome): genotype and phenotype of 22 patients with ZNF148 mutations.

BACKGROUND: Pathogenic variants in the zinc finger protein coding genes are rare causes of intellectual disability and congenital malformations. Mutations in the ZNF148 gene causing GDACCF syndrome (global developmental delay, absent or hypoplastic corpus callosum, dysmorphic facies; MIM #617260) have been reported in five individuals so far. METHODS: As a result of an international collaboration using GeneMatcher Phenome Central Repository and personal communications, here we describe the clinical and molecular genetic characteristics of 22 previously unreported individuals. RESULTS: The core clinical phenotype is characterised by developmental delay particularly in the domain of speech development, postnatal growth retardation, microcephaly and facial dysmorphism. Corpus callosum abnormalities appear less frequently than suggested by previous observations. The identified mutations concerned nonsense or frameshift variants that were mainly located in the last exon of the ZNF148 gene. Heterozygous deletion including the entire ZNF148 gene was found in only one case. Most mutations occurred de novo, but were inherited from an affected parent in two families. CONCLUSION: The GDACCF syndrome is clinically diverse, and a genotype-first approach, that is, exome sequencing is recommended for establishing a genetic diagnosis rather than a phenotype-first approach. However, the syndrome may be suspected based on some recurrent, recognisable features. Corpus callosum anomalies were not as constant as previously suggested, we therefore recommend to replace the term 'GDACCF syndrome' with 'ZNF148-related neurodevelopmental disorder'.

Is laterality of congenital diaphragmatic hernia a reliable prognostic factor? French national cohort study.

OBJECTIVES: The objective of this study was to assess whether the laterality of congenital diaphragmatic hernia (CDH) was a prognostic factor for neonatal survival. METHODS: This was a cohort study using the French national database of the Reference Center for Diaphragmatic Hernias. The principal endpoint was survival after hospitalization in intensive care. We made a comparative study between right CDH and left CDH by univariate and multivariate analysis. Terminations and stillbirths were excluded from analyses of neonatal outcomes. RESULTS: A total of 506 CDH were included with 67 (13%) right CDH and 439 left CDH (87%). Rate of survival was 49% for right CDH and 74% for left CDH (P < .01). Multivariate analysis showed two factors significantly associated with mortality: thoracic herniation of liver (OR 2.27; IC 95% [1.07-4.76]; P = .03) and lung-to-head-ratio over under expected (OR 2.99; IC 95% [1.41-6.36]; P < .01). Side of CDH was not significantly associated with mortality (OR 1.87; IC 95% [0.61-5.51], P = .26). CONCLUSION: Rate of right CDH mortality is more important than left CDH. Nevertheless after adjusting for lung-to-head-ratio and thoracic herniation of liver, right CDH does not have a higher risk of mortality than left CDH.

Modelling and mapping the intra-urban spatial distribution of Plasmodium falciparum parasite rate using very-high-resolution satellite derived indicators.

BACKGROUND: The rapid and often uncontrolled rural-urban migration in Sub-Saharan Africa is transforming urban landscapes expected to provide shelter for more than 50% of Africa's population by 2030. Consequently, the burden of malaria is increasingly affecting the urban population, while socio-economic inequalities within the urban settings are intensified. Few studies, relying mostly on moderate to high resolution datasets and standard predictive variables such as building and vegetation density, have tackled the topic of modeling intra-urban malaria at the city extent. In this research, we investigate the contribution of very-high-resolution satellite-derived land-use, land-cover and population information for modeling the spatial distribution of urban malaria prevalence across large spatial extents. As case studies, we apply our methods to two Sub-Saharan African cities, Kampala and Dar es Salaam. METHODS: Openly accessible land-cover, land-use, population and OpenStreetMap data were employed to spatially model Plasmodium falciparum parasite rate standardized to the age group 2-10 years (PfPR2-10) in the two cities through the use of a Random Forest (RF) regressor. The RF models integrated physical and socio-economic information to predict PfPR2-10 across the urban landscape. Intra-urban population distribution maps were used to adjust the estimates according to the underlying population. RESULTS: The results suggest that the spatial distribution of PfPR2-10 in both cities is diverse and highly variable across the urban fabric. Dense informal settlements exhibit a positive relationship with PfPR2-10 and hotspots of malaria prevalence were found near suitable vector breeding sites such as wetlands, marshes and riparian vegetation. In both cities, there is a clear separation of higher risk in informal settlements and lower risk in the more affluent neighborhoods. Additionally, areas associated with urban agriculture exhibit higher malaria prevalence values. CONCLUSIONS: The outcome of this research highlights that populations living in informal settlements show higher malaria prevalence compared to those in planned residential neighborhoods. This is due to (i) increased human exposure to vectors, (ii) increased vector density and (iii) a reduced capacity to cope with malaria burden. Since informal settlements are rapidly expanding every year and often house large parts of the urban population, this emphasizes the need for systematic and consistent malaria surveys in such areas. Finally, this study demonstrates the importance of remote sensing as an epidemiological tool for mapping urban malaria variations at large spatial extents, and for promoting evidence-based policy making and control efforts.

Predictors of the Performance of Early Antireflux Surgery in Esophageal Atresia.

OBJECTIVE: To identify predictors of and factors associated with the performance of antireflux surgery during the first year of life in children born with esophageal atresia. STUDY DESIGN: All patients were included in a French registry for esophageal atresia. All 38 multidisciplinary French centers completed questionnaires about perinatal characteristics and one-year outcome for children born with esophageal atresia. RESULTS: Of 835 infants with esophageal atresia born in France from 2010 to 2014, 682 patients, excluding those with long-gap esophageal atresia, were included. Three patients had type I, 669 had type III, and 10 had type IV esophageal atresia. Fifty-three children (7.8%) received fundoplication during the first year of life. The median age at the time of the end-to-end esophageal anastomosis was 1.1 day (range 0-15). Multivariate analysis identified three perioperative factors that predicted the need for early antireflux surgery: anastomotic tension (P = .004), associated malformations (P = .019), and low birth weight (P = .018). Six other factors, measured during the first year of life, were associated with the need for antireflux surgery: gastroesophageal reflux (P < .001), anastomotic stricture (P < .001), gastrostomy (P < .001), acute life-threatening event (P = .002), respiratory complications (P = .045), and poor nutritional status (P < .001). CONCLUSIONS: Gastroesophageal reflux disease, low birth weight, poor nutrition, and surgical anastomosis difficulties predicted the performance of antireflux surgery in the first year of life in infants with esophageal atresia.

The Belgian MicroArray Prenatal (BEMAPRE) database: A systematic nationwide repository of fetal genomic aberrations.

OBJECTIVE: With the replacement of karyotyping by chromosomal microarray (CMA) in invasive prenatal diagnosis, new challenges have arisen. By building a national database, we standardize the classification and reporting of prenatally detected copy number variants (CNVs) across Belgian genetic centers. This database, which will link genetic and ultrasound findings with postnatal development, forms a unique resource to investigate the pathogenicity of variants of uncertain significance and to refine the phenotypic spectrum of pathogenic and susceptibility CNVs. METHODS: The Belgian MicroArray Prenatal (BEMAPRE) consortium is a collaboration of all genetic centers in Belgium. We collected data from all invasive prenatal procedures performed between May 2013 and July 2016. RESULTS: In this three-year period, 13 266 prenatal CMAs were performed. By national agreement, a limited number of susceptibility CNVs and no variants of uncertain significance were reported. Added values for using CMA versus conventional karyotyping were 1.8% in the general invasive population and 2.7% in cases with an ultrasound anomaly. Of the reported CNVs, 31.5% would have remained undetected with non-invasive prenatal test as the first-tier test. CONCLUSION: The establishment of a national database for prenatal CNV data allows for a uniform reporting policy and the investigation of the prenatal and postnatal genotype-phenotype correlation.

Outcome of long gap esophageal atresia at 6 years: A prospective case control cohort study.

BACKGROUND DATA: EA is the most frequent congenital esophageal malformation. Long gap EA remains a therapeutic challenge for pediatric surgeons. A case case-control prospective study from a multi-institutional national French data base was performed to assess the outcome, at age of 1 and 6 years, of long gap esophageal atresia (EA) compared with non-long gap EA/tracheo-esophageal fistula (TEF). The secondary aim was to assess whether initial treatment (delayed primary anastomosis of native esophagus vs. esophageal replacement) influenced mortality and morbidity at ages 1 and 6 years. METHODS: A multicentric population-based prospective study was performed and included all patients who underwent EA surgery in France from January 1, 2008 to December 31, 2010. A comparative study was performed with non-long gap EA/TEF patients. Morbidity at birth, 1 year, and 6 years was assessed. RESULTS: Thirty-one patients with long gap EA were compared with 62 non-long gap EA/TEF patients. At age 1 year, the long gap EA group had longer parenteral nutrition support and longer hospital stay and were significantly more likely to have complications both early post-operatively and before age 1 year compared with the non-long gap EA/TEF group. At 6 years, digestive complications were more frequent in long gap compared to non-long gap EA/TEF patients. Tracheomalacia was the only respiratory complication that differed between the groups. Spine deformation was less frequent in the long gap group. There were no differences between conservative and replacement groups at ages 1 and 6 years except feeding difficulties that were more common in the native esophagus group. CONCLUSIONS: Long gap strongly influenced digestive morbidity at age 6 years.

Different Fecal Microbiota in Hirschsprung's Patients With and Without Associated Enterocolitis.

Background and Objectives: Patients with Hirschsprung's disease are at risk of developing Hirschsprung-associated enterocolitis, especially in the first 2 years of life. The pathophysiology of this inflammatory disease remains unclear, and intestinal dysbiosis has been proposed in the last decade. The primary objective of this study was to evaluate in a large cohort if Hirschsprung-associated enterocolitis was associated with alterations of fecal bacterial composition compared with HD without enterocolitis in different age groups. Methods: We analyzed the fecal microbiota structure of 103 Hirschsprung patients from 3 months to 16 years of age, all of whom had completed definitive surgery for rectosigmoid Hirschsprung. 16S rRNA gene sequencing allowed us to compare the microbiota composition between Hirschsprung's disease patients with (HAEC group) or without enterocolitis (HD group) in different age groups (0-2, 2-6, 6-12, and 12-16 years). Results: Richness and diversity increased with age group but did not differ between HD and HAEC patients, irrespective of the age group. Relative abundance of Actinobacteria was lower in HAEC than in HD patients under 2 years of age (-66%, P = 0.045). Multivariate analysis by linear models (MaAsLin) considering sex, medications, birth mode, breast-feeding, and the Bristol stool scale, as well as surgery parameters, highlighted Flavonifractor plautii and Eggerthella lenta, as well as Ruminococcus gnavus group, as positively associated with Hirschsprung-associated enterocolitis in the 0-2 years age group. Conclusion: Hirschsprung-associated enterocolitis was associated with features of intestinal dysbiosis in infants (0-2 years) but not in older patients. This could explain the highest rate of enterocolitis in this age group. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT02857205, MICROPRUNG, NCT02857205, 02/08/2016.

COVID-19 in Europe: Dataset at a sub-national level.

The COVID-19 pandemic has hit humanity, straining health care systems, economies, and governments worldwide. In one of the responses to the pandemic, a big global effort has been mounted to collect, analyze, and make data publicly available. However, many of the existing COVID-19 public datasets are (i) aggregated at country level, and (ii) tend not to bring the COVID-19-specific data coupled with socio-demographic, economic, public policy, health, pollution and environmental factors, all of which may be key elements to study the transmission of the SARS-CoV-2 and its severity. To aid the evaluation of the determinants and impact of the COVID-19 pandemic at a large scale, we present here a new dataset with socio-demographic, economic, public policy, health, pollution and environmental factors for the European Union at the small regions level (NUTS3). The database is freely accessible at http://dx.doi.org/10.17632/2ghxnrkr9p.4. This dataset can help to monitor the COVID-19 mortality and infections at the sub-national level and enable analysis that may inform future policymaking.

Spatio-temporal data on the air pollutant nitrogen dioxide derived from Sentinel satellite for France.

Monitoring of air pollution is an important task in public health. Availability of data is often hindered by the paucity of the ground monitoring station network. We present here a new spatio-temporal dataset collected and processed from the Sentinel 5P remote sensing platform. As an example application, we applied the full workflow to process measurements of nitrogen dioxide (NO2) collected over the territory of mainland France from May 2018 to June 2019. The data stack generated is daily measurements at a 4 × 7 km spatial resolution. The supplementary Python code package used to collect and process the data is made publicly available. The dataset provided in this article is of value for policy-makers and health assessment.

Analysis of enteric nervous system and intestinal epithelial barrier to predict complications in Hirschsprung's disease.

In Hirschsprung's disease (HSCR), postoperative course remains unpredictable. Our aim was to define predictive factors of the main postoperative complications: obstructive symptoms (OS) and Hirschsprung-associated enterocolitis (HAEC). In this prospective multicentre cohort study, samples of resected bowel were collected at time of surgery in 18 neonates with short-segment HSCR in tertiary care hospitals. OS and HAEC were noted during postoperative follow-up. We assessed the enteric nervous system and the intestinal epithelial barrier (IEB) in ganglionic segments by combining immunohistochemical, proteomic and transcriptomic approaches, with functional ex vivo analysis of motility and para/transcellular permeability. Ten HSCR patients presented postoperative complications (median follow-up 23.5 months): 6 OS, 4 HAEC (2 with OS), 2 diarrhoea (without OS/HAEC). Immunohistochemical analysis showed a significant 41% and 60% decrease in median number of nNOS-IR myenteric neurons per ganglion in HSCR with OS as compared to HSCR with HAEC/diarrhoea (without OS) and HSCR without complications (p = 0.0095; p = 0.002, respectively). Paracellular and transcellular permeability was significantly increased in HSCR with HAEC as compared to HSCR with OS/diarrhoea without HAEC (p = 0.016; p = 0.009) and HSCR without complications (p = 0.029; p = 0.017). This pilot study supports the hypothesis that modulating neuronal phenotype and enhancing IEB permeability may treat or prevent postoperative complications in HSCR.

A suite of global, cross-scale topographic variables for environmental and biodiversity modeling.

Topographic variation underpins a myriad of patterns and processes in hydrology, climatology, geography and ecology and is key to understanding the variation of life on the planet. A fully standardized and global multivariate product of different terrain features has the potential to support many large-scale research applications, however to date, such datasets are unavailable. Here we used the digital elevation model products of global 250 m GMTED2010 and near-global 90 m SRTM4.1dev to derive a suite of topographic variables: elevation, slope, aspect, eastness, northness, roughness, terrain roughness index, topographic position index, vector ruggedness measure, profile/tangential curvature, first/second order partial derivative, and 10 geomorphological landform classes. We aggregated each variable to 1, 5, 10, 50 and 100 km spatial grains using several aggregation approaches. While a cross-correlation underlines the high similarity of many variables, a more detailed view in four mountain regions reveals local differences, as well as scale variations in the aggregated variables at different spatial grains. All newly-developed variables are available for download at Data Citation 1 and for download and visualization at http://www.earthenv.org/topography.

Tunica vaginalis flap for urethrocutaneous fistula repair after proximal and mid-shaft hypospadias surgery: A 12-year experience.

INTRODUCTION: Fistulas are a common complication of hypospadias surgery; they are more frequent after mid-shaft and posterior hypospadias repair. Surgical treatment of fistula still remains challenging with a significant failure rate. The basic principle is to add layers between skin and neourethra in order to decrease the incidence of recurrent urethrocutaneous fistula (UCF). We report our experience of UCF repair using a vascularized tunica vaginalis flap (TVF) after posterior and mid-shaft hypospadias surgery. MATERIAL AND METHODS: A retrospective review of all patients operated on using TVF for UCF in our institution between December 2005 and July 2017 was performed. RESULTS: Among 36 cases, TVF was used at a first attempt in 22 patients; 14 children had a prior attempt to close the fistula, and four of them had two surgeries before TVF repair. UCF was respectively penoscrotal (n = 3, 8%), posterior (n = 19, 53%), midshaft (n = 9, 25%) and anterior (n = 5, 14%). The size of the fistula was more than 5 mm in 26 patients. The UCF was treated successfully in every case after one single procedure. In the three children with two fistulas, both fistulas were successfully treated by the same TVF. After an average follow-up time of 45 months there was no recurrence of the initial UCF. In four cases of undescended testis, it was possible to dissect the flap through an inguinal incision and perform an orchydopexy in the same time. One patient presented a testicular atrophy after undescended testis surgery. DISCUSSION: Area review of published series shows excellent results in UCF repair including recurrent fistula (Table). TVF can aspire to some advantages with regard to a dartos flap (DF). First of all, a nearly 2.5-fold lower incidence of fistula after fistula repair with TVF than with DF (5.1% vs. 12.2%) has been shown. Secondly, TVF allows treating multiple fistulas, and can also be brought to the anterior part of the penis until the balano preputial furrow, allowing curing anterior fistula. Furthermore, it doesn't lead to aesthetic complications such as penile rotation or distal skin necrosis, which can occur during DF procedures. CONCLUSION: TVF is a simple and reproductive technique for UCF repair, with a high success rate. The risk of testicular atrophy has to be considered in case of associated undescended testis surgery, and careful attention must be given to the TVF dissection. This technique should be considered as first choice treatment for any UCF.

[Severe thrombopenia as single sign of hemophagocytosis in a patient with cirrhosis and lethal infection of ascitis fluid by Escherichia coli]. / Thrombopénie sévère d'aggravation rapide comme seul signe d'une hémophagocytose chez un malade atteint de cirrhose avec infection léthale du liquide d'ascite par Escherichia coli.

Hemophagocytosis is defined by a systemic macrophages activation, phagocyting the blood elements. This syndrome can be primary or secondary to multiple causes such as neoplasia or infections. We report here the first case of a hemophagocytosis caused by an Escherichia coli infection of ascitis fluid.

Position Paper of INoEA Working Group on Long-Gap Esophageal Atresia: For Better Care.

INoEA is the International Network of Esophageal Atresia and consists of a broad spectrum of pediatric specialties and patient societies. The working group on long-gap esophageal atresia (LGEA) set out to develop guidelines regarding the definition of LGEA, the best diagnostic and treatment strategies, and highlight the necessity of experience and communication in the management of these challenging patients. Review of the literature and expert discussion concluded that LGEA should be defined as any esophageal atresia (EA) that has no intra-abdominal air, realizing that this defines EA with no distal tracheoesophageal fistula (TEF). LGEA is considerably more complex than EA with distal TEFs and should be referred to a center of expertise. The first choice is to preserve the native esophagus and pursue primary repair, delayed primary anastomosis, or traction/growth techniques to achieve anastomosis. A cervical esophagostomy should be avoided if possible. Only if primary anastomosis is not possible, replacement techniques should be used. Jejunal interposition is proposed as the best option among the major EA centers. In light of the infrequent occurrence of LGEA and the technically demanding techniques involved to achieve esophageal continuity, it is strongly advised to develop regional or national centers of expertise for the management and follow-up of these very complex patients.

Failure of First-Line Antibiotics in Nonoperative Management of Appendiceal Mass, toward a Second-Line Instead of Surgery?

Background Conservative approach for complicated appendicitis has been gradually adopted in children to decrease postoperative morbidity. The first aim of this study was to assess the efficacy of a second-line antibiotics enlarged on Pseudomonas aeruginosa and Enterococcus in case of poor clinical outcome after initial conservative approach for appendiceal mass and abscess. The second aim of this study was to identify predictive factors of failure of first-line antibiotics. Methods We performed a prospective review of all the cases of appendiceal mass or abscess managed at our institution between November 2007 and September 2011 after implementation of a conservative protocol including a second-line antibiotics in case of poor initial clinical outcome. Results A total of 64 consecutive patients were included. We observed a success in 46 patients after the first-line antibiotics and in 14 of the remaining patients after the second-line. The only predictive factor of failure of the first-line antibiotics was a shorter duration of symptoms before admission (p = 0.02). Laparoscopic appendectomy was performed in all the cases (emergency or interval procedure) with six postoperative complications and two conversions to open surgery. Conclusions A gradual adapted antibiotherapy in nonoperative management of appendiceal abscess and mass is effective. We found no relevant predictive factor of failure of the first-line antibiotics.

Trisomy rescue mechanism: the case of concomitant mosaic trisomy 14 and maternal uniparental disomy 14 in a 15-year-old girl.

Maternal uniparental disomy of chromosome 14 (upd(14)mat) is responsible for a Prader-Willi-like syndrome with precocious puberty. Although upd(14) is often hypothesized to result from trisomy rescue mechanism, T14 cell lines are usually not found with postnatal cytogenetic investigations. We report the coexistence of both chromosomal abnormalities in a 15-year-old girl.

Laparoscopic management of congenital duodenal atresia or stenosis: A single-center early experience.

BACKGROUND: The background is to review our experience with laparoscopic repair of congenital duodenal atresia or stenosis (CDAS) and compare postoperative outcome with a group control of laparotomy repair. METHODS: Retrospective chart review of all cases of CDAS undergoing laparoscopic surgery at our institution between July 2013 and May 2014 and comparison with a group control of open operation performed between 2007 and 2010. Data were compared using Fisher's exact test for qualitative values and Mann-Whitney test for quantitative values. P values less than 0,05 were considered statistically significant. RESULTS: Ten consecutive cases were identified in laparoscopic group (7 duodenoduodenostomy and 3 duodenojejunostomy) and 19 cases in laparotomy group (16 duodenoduodenostomy and 3 web excision). Median birth weight was lower in laparoscopic group (2125 grams Vs 2777 grams p=0,04). In laparoscopic group, there was no conversion and no intraoperative complication. Median duration of surgery was 90minutes (80-150). In both groups, the surgical morbidity rate was 10%. Median time to initiation of oral feeding was significatively shorter in laparotomy group (8days Vs 4 p=0,009). Median time to full oral feeding and length of stay were shorter in laparotomy but not statistically different. (36days Vs 16,5 p=0,14 and 45,5days Vs 25,5 p=0,09 respectively) After a median follow up of 149,5days (24-355) in laparoscopic group, 8 children had a full oral intake. Five children had a weight below the 10th percentile. CONCLUSION: The laparoscopic approach for CDAS is safe and reproducible with outcomes similar to open repair even in the beginning of a learning curve for pediatric surgeons with appropriate laparoscopic skills. In this small series, laparoscopy did not appear to decrease time to full oral intake or length of stay. Larger studies are suggested to provide more conclusive results.

Developmental delay and facial dysmorphism in a child with an 8.9 Mb de novo interstitial deletion of 3q25.1-q25.32: Genotype-phenotype correlations of chromosome 3q25 deletion syndrome.

Interstitial deletions of the long arm of chromosome 3 are rare and detailed genotype-phenotype correlations are not well established. We report on the clinical, cytogenetic and molecular findings of a 5-year-old patient with a de novo interstitial deletion from 3q25.1 to 3q25.32. Clinical features include relative microcephaly, developmental delay and facial dysmorphism with a coarse face, ptosis, synophrys, epicanthic folds, broad nasal bridge, long philtrum, large mouth with full lips, dysplastic and low-set ears. Revealed by conventional banding techniques, the deleted region of 8.9 Mb was confirmed by fluorescent in situ hybridization (FISH) analyses and array comparative genomic hybridization (array-CGH). To our knowledge, this is the smallest interstitial deletion reported in the 3q25 region. The phenotype of our patient is compared with the 10 previously reported cases implicating the 3q25 region.