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PLoS Computational Biology Oct 2020Genome-wide association studies (GWAS) have primarily identified trait-associated loci in the non-coding genome. Colocalization analyses of SNP associations from GWAS...
Genome-wide association studies (GWAS) have primarily identified trait-associated loci in the non-coding genome. Colocalization analyses of SNP associations from GWAS with expression quantitative trait loci (eQTL) evidence enable the generation of hypotheses about responsible mechanism, genes and tissues of origin to guide functional characterization. Here, we present a web-based colocalization browsing and testing tool named LocusFocus (https://locusfocus.research.sickkids.ca). LocusFocus formally tests colocalization using our established Simple Sum method to identify the most relevant genes and tissues for a particular GWAS locus in the presence of high linkage disequilibrium and/or allelic heterogeneity. We demonstrate the utility of LocusFocus, following up on a genome-wide significant locus from a GWAS of meconium ileus (an intestinal obstruction in cystic fibrosis). Using LocusFocus for colocalization analysis with eQTL data suggests variation in ATP12A gene expression in the pancreas rather than intestine is responsible for the GWAS locus. LocusFocus has no operating system dependencies and may be installed in a local web server. LocusFocus is available under the MIT license, with full documentation and source code accessible on GitHub at https://github.com/naim-panjwani/LocusFocus.
Topics: Computational Biology; Cystic Fibrosis; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Internet; Linkage Disequilibrium; Molecular Sequence Annotation; Polymorphism, Single Nucleotide; Quantitative Trait Loci; Software
PubMed: 33090994
DOI: 10.1371/journal.pcbi.1008336 -
Journal of Pediatric Surgery Nov 2022Patients with Hirschsprung disease (HD) mostly undergo surgery around the age of three to six months. While awaiting surgery, therapy to treat the obstruction such as...
BACKGROUND
Patients with Hirschsprung disease (HD) mostly undergo surgery around the age of three to six months. While awaiting surgery, therapy to treat the obstruction such as transanal irrigation (TAI) or laxatives is applied. The aim of this study was to gain insight in the prevalence and severity of complications occurring while awaiting surgery and to identify patient characteristics associated with the development of these complications.
METHODS
This study retrospectively analyzed data of patients with HD operated in our center between 2000 and 2021. Complications emerging while awaiting surgery were graded using Clavien-Dindo (CD). Patient characteristics as predictor of a complication were tested using logistic regression analysis.
RESULTS
Twenty-two of 132 (17%) included patients (preoperative treatment: 94% TAI; 2% laxatives; 2% other therapy) developed 45 complications while awaiting surgery, including predominantly major complications (91%). Bowel perforation occurred most frequently (n = 9, 7%) wherefrom six caused by TAI (5%), including three patients with total colon aganglionosis (TCA) (2%) counting one life-threatening and one lethal perforation. The other perforations were caused by meconium ileus (n = 2) and Hirschsprung associated enterocolitis (HAEC) (n = 1). Other frequent complications were: sepsis (5%), ileus (4%) and persistent obstruction (4%). Predictive factor for developing complication was TCA (OR 9.905, CI 2.994-32.772, p < 0.001).
CONCLUSION
We found a complication rate of 17% in patients while awaiting surgery, reporting bowel perforation most frequently. We found this complication in patients with TCA being highly dangerous causing one life-threatening and one lethal perforation. Therefore, we advise in patients with (suspected) TCA to limit the time awaiting surgery.
LEVEL OF EVIDENCE
level III.
Topics: Enterocolitis; Hirschsprung Disease; Humans; Infant; Intestinal Perforation; Laxatives; Postoperative Complications; Retrospective Studies; Risk Factors
PubMed: 35354528
DOI: 10.1016/j.jpedsurg.2022.02.022 -
Cureus Mar 2021Interstitial obstruction in newborn infants can be caused by several factors such as malrotation, meconium plug syndrome, meconium ileus, Hirschsprung's disease, atresia...
Interstitial obstruction in newborn infants can be caused by several factors such as malrotation, meconium plug syndrome, meconium ileus, Hirschsprung's disease, atresia and stenosis. Neonates who have been diagnosed with an interstitial obstruction are in need of immediate treatment; otherwise, they can deteriorate rapidly. Surgery remains the mainstay of treatment in most cases. Pediatric gastrointestinal tumours are very rare, especially in newborn infants. Their management is usually different as compared to adults. We present the case of a newborn infant who was born with interstitial obstruction. At the 31 weeks scan, a significant dilation of the small bowel was observed and the diagnosis of interstitial obstruction was made. When born, the newborn was transferred to a specialised unit and underwent a laparotomy. The findings were consistent with a tumour causing the obstruction; the histology reported this tumour as benign lymphoid hyperplasia. Pseudolymphoma is a very rare cause of fetal interstitial obstruction, and it should be considered in the differential diagnosis.
PubMed: 33842123
DOI: 10.7759/cureus.13746 -
Genes Sep 2020The goal was to study the phenotypic manifestations of c.3844T>C (p.Trp1282Arg, W1282R) variant, a CF-causing mutation, in patients from the Russian Federation. Clinical...
The goal was to study the phenotypic manifestations of c.3844T>C (p.Trp1282Arg, W1282R) variant, a CF-causing mutation, in patients from the Russian Federation. Clinical manifestations and complications (the age at CF diagnosis, sweat test, pancreatic status, lung function, microbial infection, body mass index (BMI), the presence of meconium ileus (MI), diabetes, and severe liver disease) were compared in four groups: group 1-patients carrying c.3844T>C and severe class I or II variant in trans; group 2-3849+10kbC>T/F508del patients; group 3-F508del/F508del patients; and group 4-patients with W1282R and "mild" variant in trans. Based on the analyses, W1282R with class I or II variant in trans appears to cause at least as severe CF symptoms as F508del homozygotes as reflected in the early age of diagnosis, high sweat chloride concentration, insufficient pancreatic function, and low lung function, in contrast to 3849+10kbC-T/F508del compound heterozygotes having milder clinical phenotypes. The W1282R pathogenic variant is seemed to lead to severe disease phenotype with pancreatic insufficiency similarly to the F508del homozygous genotype.
Topics: Adolescent; Adult; Child; Child, Preschool; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Genotype; Homozygote; Humans; Infant; Mutation; Phenotype; Russia; Young Adult
PubMed: 32992607
DOI: 10.3390/genes11101137 -
The Journal of Maternal-fetal &... Sep 2020Temporary enterostomies are life-saving in neonatal surgery, however, causing loss of fluid electrolyte, delays in distal bowel adaptation and thus delayed growth of...
Temporary enterostomies are life-saving in neonatal surgery, however, causing loss of fluid electrolyte, delays in distal bowel adaptation and thus delayed growth of newborns. In this study, we aimed to present the method and clinical results of distal stoma refeeding in premature and mature neonates. Between January 2012 and December 2017, records of newborn patients who underwent enterostomy and distal stoma refeeding were retrospectively analyzed. Premature and full term neonates who had distal stoma refeeding were evaluated by stoma indications, resection status, duration of total parenteral nutrition use, time of stoma closure operation and surgery findings. Distal stoma refeeding was performed to 23 newborns in study period. Surgical diagnosis of newborns were meconium ileus, focal intestinal perforation, volvulus, necrotizing enterocolitis, ileal atresia, jejunal atresia, and gastroschisis. The bowel resection was performed in 14 patients. Stoma closure was done on the average day 77th. Total parenteral nutrition was given average 28 d and no total parenteral nutrition complication was seen. The stoma closure operations were performed easily. Distal stoma refeeding is safe and successful method. The success of distal stoma refeeding depends on expert team, time, and equipment.
Topics: Enterocolitis, Necrotizing; Enterostomy; Feasibility Studies; Humans; Infant, Newborn; Parenteral Nutrition, Total; Retrospective Studies
PubMed: 30585079
DOI: 10.1080/14767058.2018.1563593 -
Pediatric Surgery International Sep 2020We aim to evaluate the diagnostic performance and relationship between clinical characteristics, imaging findings, and final diagnosis for the neonatal contrast enema...
PURPOSE
We aim to evaluate the diagnostic performance and relationship between clinical characteristics, imaging findings, and final diagnosis for the neonatal contrast enema (CE).
METHODS
Retrospective 10-year review of all neonatal CEs including imaging findings, clinical information, indication, and final diagnosis from discharge summaries, surgical reports, and pathology (reference standard). Two blinded pediatric radiologists reinterpreted 366 CEs for obstruction, microcolon, rectosigmoid index (RSI), serrations, meconium, ileal cut-off, transition zone, diagnosis, and level of confidence. CE diagnostic performance was calculated versus reference standard.
RESULTS
Diagnoses included Hirschsprung disease (HD) (15.8%), small left colon syndrome (14.8%), small intestinal atresia/colonic atresia (SIA/CA) (12.6%), meconium ileus (MI) (4.4%), and normal (48.9%). CE had a moderate specificity (87.7%) and low sensitivity (65.5%) for HD; abnormal RSI and serrations showed high specificities (90.3%, 97.4%) but low sensitivities (46.6%, 17.2%). CE showed high specificity (97.4%) and low sensitivity (56.3%) for MI blinded to cystic fibrosis status. Microcolon was specific (96.6%) but not sensitive (68.8%) for MI. CE showed highest PPV (73.1%) (specificity 95.6%, sensitivity 82.6%) for SIA/CA. Microcolon with an abrupt cut-off was specific (99.1%) but not sensitive (41.3%) for atresias.
CONCLUSION
Neonatal CE demonstrates high specificities and low to moderate sensitivities across all diagnoses, with lowest performance in HD.
CLINICAL TRIAL REGISTRATION
None.
Topics: Barium Enema; Colon; Female; Humans; Infant, Newborn; Intestinal Atresia; Intestinal Obstruction; Intestine, Small; Male; Reproducibility of Results; Retrospective Studies
PubMed: 32572600
DOI: 10.1007/s00383-020-04701-4 -
European Journal of Pediatrics Mar 2023We aimed to evaluate cutoff values of immunoreactive trypsinogen (IRT)/IRT and determine relationship between IRT values and clinical characteristics of children with...
We aimed to evaluate cutoff values of immunoreactive trypsinogen (IRT)/IRT and determine relationship between IRT values and clinical characteristics of children with cystic fibrosis (CF). This study is cross-sectional study. Data of children with positive newborn screening (NBS) between 2015 and 2021 were evaluated in three pediatric pulmonology centers. Age at admission, sex, gestational age, presence of history of meconium ileus, parental consanguinity, sibling with CF, and doll-like face appearance, first and second IRT values, sweat chloride test, fecal elastase, fecal fat, biochemistry results, and age at CF diagnosis were recorded. Sensitivity and specificity of IRT cutoff values were evaluated. Of 815 children with positive NBS, 58 (7.1%) children were diagnosed with CF. Median values of first and second IRT were 157.2 (103.7-247.6) and 113.0 (84.0-201.5) μg/L. IRT values used in current protocol, sensitivity was determined as 96.6%, specificity as 17.2% for first IRT, and 96.6% sensitivity, 20.5% specificity for second IRT. Positive predictive value (PPV) was determined as 7.1%. When cutoff value for first IRT was estimated as 116.7 μg/L, sensitivity was 69.0% and specificity was 69.6%, and when cutoff value was set to 88.7 μg/L for second IRT, sensitivity was 69.0% and specificity was 69.0%. Area under curve was 0.757 for first and 0.763 for second IRT (p < 0.001, p < 0.001, respectively). PPV was calculated as 4.3%. Conclusion: Although sensitivity of CF NBS is high in our country, its PPV is significantly lower than expected from CF NBS programs. False-positive NBS results could have been overcome by revising NBS strategy. What is Known: • Although immunoreactive trypsinogen elevation is a sensitive test used in cystic fibrosis newborn screening, its specificity is low. • In countries although different algorithms are used, all strategies begin with the measurement of immunoreactive trypsinogen in dried blood spots. What is New: • In our study, it was shown that use of the IRT/IRT protocol for cystic fibrosis newborn screening is not sufficient for the cut-off values determined by the high number of patients. • Newborn screening strategy should be reviewed to reduce false positive newborn screening results.
Topics: Infant, Newborn; Child; Humans; Cystic Fibrosis; Neonatal Screening; Cystic Fibrosis Transmembrane Conductance Regulator; Trypsinogen; Cross-Sectional Studies; Sensitivity and Specificity
PubMed: 36565324
DOI: 10.1007/s00431-022-04766-4 -
Pediatric Pulmonology Nov 2020To investigate and summarize the clinical and genetic characteristics of Chinese cystic fibrosis (CF) patients to improve clinicians' understanding and decrease the...
OBJECTIVES
To investigate and summarize the clinical and genetic characteristics of Chinese cystic fibrosis (CF) patients to improve clinicians' understanding and decrease the rates of misdiagnosis and missed diagnoses in China.
METHODS
The EMBASE, Cochrane Library, PubMed and SinoMed databases were searched for studies involving Chinese CF patients from January 1975 to August 2019.
RESULTS
In total, 113 Chinese patients, including 53 males and 60 females, were reported. Nineteen patients had a family history of CF. The median age at diagnosis was 8.7 years. Among Chinese CF patients, 70.8% had bronchiectasis, 9.7% had a hemoptysis history, 33.6% had clubbed fingers, 17.7% had allergic bronchopulmonary aspergillosis, and 29.2% had chronic diarrhea; the incidence of malnutrition was 52.2%. Five patients had jaundice, 26 patients had hepatomegaly, and 9 patients had meconium ileus in the neonatal period, and the incidence of liver cirrhosis was 5.3%. The predominant organism in airways was Pseudomonas aeruginosa, followed by Staphylococcus aureus. Seventy-nine patients underwent the sweat test, and all of them were positive, with an average chloride ion level of 122.2 mmol/L. Eighty-eight Chinese CF patients underwent genetic testing, and 74 CF transmembrane conductance regulator (CFTR) gene mutations were reported. The most common gene mutation was c.2909G→A. One Phe508del gene mutation was observed.
CONCLUSION
The common clinical manifestations and CFTR gene mutations in Chinese CF patients are different from those in Caucasian patients. The age at CF diagnosis in China is relatively old, suggesting that the CF incidence in China may be seriously underestimated.
Topics: Asian People; Bacterial Infections; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans
PubMed: 32716133
DOI: 10.1002/ppul.24980 -
European Journal of Pediatric Surgery... Jan 2021With the advances of neonatology, the survival rate for "live-born periviable fetuses" weighing < 300 g, a subgroup of extremely low birth weight (BW) infants, has...
With the advances of neonatology, the survival rate for "live-born periviable fetuses" weighing < 300 g, a subgroup of extremely low birth weight (BW) infants, has improved over the past 10 years. Meconium-related ileus (MRI) represents an early postnatal hazard, and, if medical evacuation fails, a surgical challenge in such immature babies. We report the interdisciplinary management of surgically treated MRI in a newborn with a BW of 273 g. According to the worldwide database held by the University of Iowa, he is registered as the tiniest male newborn in Europe. The boy was born in the 25th gestational week by cesarean section after a triplet pregnancy with twin-twin transfusion syndrome, him being the donor. He had a BW of 273 g, whereas his brothers had a BW of 740 g and 722 g. Cardiopulmonary stabilization and ventilation were successful. He developed MRI unresponsive to medical treatment. On day 14 of life, a minilaparotomy was performed in the right lower quadrant to externalize a loop of the distal ileum in a no-touch technique. Despite the small diameter of only 2 mm, a standard loop ileostomy could be fashioned. There were no intra- or postoperative abdominal complications. Bowel function and weight gain were adequate and the ileostomy was closed electively 5 months later at a body weight of 3.5 kg. In summary, minilaparotomy and loop ileostomy placement were effective to treat surgical MRI in Europe's tiniest male newborn. With the advances of neonatology, pediatric surgery reaches new frontiers as well.
PubMed: 33680707
DOI: 10.1055/s-0040-1721406 -
Nutrition in Clinical Practice :... Dec 2021Children with cystic fibrosis (CF) are at risk of altered body composition (BC). Newborn screening (NBS) may lead to improved BC outcomes. We investigated BC and its...
BACKGROUND
Children with cystic fibrosis (CF) are at risk of altered body composition (BC). Newborn screening (NBS) may lead to improved BC outcomes. We investigated BC and its relationship with lung function in prepubertal children diagnosed with CF by NBS. Secondary aims explored predictors of fat-free mass (FFM) and lung function.
METHODS
Thirty-seven screened (non-meconium ileus) children with CF (20 boys) born 2007-2012 had a dual-energy x-ray absorptiometry scan at 5-8 years to determine whole-body (WB) and appendicular BC. Anthropometry was performed and routine spirometry recorded. Results were converted to z-scores, height-adjusted (fat mass index [FMI] and FFM index [FFMI]) and compared with population mean values. Predictors of forced expiratory volume in 1 second (FEV ) were assessed using linear regression.
RESULTS
Height, body mass index (BMI), and FEV were within normal limits, however, weight and BC were significantly low compared with reference data (weight, P = .03; WB FMI, P = .001; WB FFMI, P = .009). Gender differences were detected, with lower appendicular BC in boys and lower weight, BMI, and BC in girls. The association between FEV and WB FFMI (r = 0.38; P = .02) was stronger than with BMI (r = 0.29; P = .08). WB FFMI was the only significant predictor of FEV in a multivariable model (95% CI, 0.11-0.99; P = .016).
CONCLUSION
In this NBS CF population, gender differences in growth and BC were apparent despite preserved lung function. These results support BC assessment in prepubertal children, particularly girls, with an opportunity to direct interventions to optimize FFM.
Topics: Absorptiometry, Photon; Body Composition; Body Mass Index; Child; Cystic Fibrosis; Female; Humans; Infant, Newborn; Lung; Male; Neonatal Screening
PubMed: 33301217
DOI: 10.1002/ncp.10604