MIS-C-Implications for the Pediatric Surgeon: An Algorithm for Differential Diagnostic Considerations.

BACKGROUND: multisystem inflammatory syndrome in children (MIS-C) is a new disease associated with a recent infection with severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). Affected children can present predominantly with abdominal symptoms, fever and high inflammatory parameters that might lead to a consult by the pediatric surgeon and an indication for surgery. METHODS: clinical data of three patients with MIS-C that underwent surgery were collected. Histopathological analysis of the appendix was performed. RESULTS: we present the clinical course of three children with fever, abdominal pain and vomiting for several days. Clinical examination and highly elevated inflammation markers led to indication for laparoscopy; appendectomy was performed in two patients. Because of intraoperative findings or due to lack of postoperative improvement, all patients were reevaluated and tested positive for MIS-C associated laboratory parameters and were subsequently treated with corticosteroids, intravenous immunoglobulins, acetyl salicylic acid and/or light molecular weight heparin. CONCLUSIONS: we discuss the implications of MIS-C as a new differential diagnosis and stress the importance of assessing the previous medical history, identifying patterns of symptoms and critically surveilling the clinical course. We implemented an algorithm for pediatric surgeons to consider MIS-C as a differential diagnosis for acute abdomen that can be integrated into the surgical workflow

Surgery and transplantation – Guidelines on Parenteral Nutrition, Chapter 18

In surgery, indications for artificial nutrition comprise prevention and treatment of catabolism and malnutrition. Thus in general, food intake should not be interrupted postoperatively and the re-establishing of oral (e.g. after anastomosis of the colon and rectum, kidney transplantation) or enteral food intake (e.g. after an anastomosis in the upper gastrointestinal tract, liver transplantation) is recommended within 24 h post surgery. To avoid increased mortality an indication for an immediate postoperatively artificial nutrition (enteral or parenteral nutrition (PN)) also exists in patients with no signs of malnutrition, but who will not receive oral food intake for more than 7 days perioperatively or whose oral food intake does not meet their needs (e.g. less than 60–80%) for more than 14 days. In cases of absolute contraindication for enteral nutrition, there is an indication for total PN (TPN) such as in chronic intestinal obstruction with a relevant passage obstruction e.g. a peritoneal carcinoma. If energy and nutrient requirements cannot be met by oral and enteral intake alone, a combination of enteral and parenteral nutrition is indicated. Delaying surgery for a systematic nutrition therapy (enteral and parenteral) is only indicated if severe malnutrition is present. Preoperative nutrition therapy should preferably be conducted prior to hospital admission to lower the risk of nosocomial infections. The recommendations of early postoperative re-establishing oral feeding, generally apply also to paediatric patients. Standardised operative procedures should be established in order to guarantee an effective nutrition therapy

Pharmacokinetics-Based Pediatric Dose Evaluation and Optimization Using Saliva - A Case Study.

Understanding pharmacokinetics (PK) in children is a prerequisite to determine optimal pediatric dosing. As plasma sampling in children is challenging, alternative PK sampling strategies are needed. In this case study we evaluated the suitability of saliva as alternative PK matrix to simplify studies in infants, investigating metamizole, an analgesic used off-label in infants. Six plasma and 6 saliva PK sample collections were scheduled after a single intravenous dose of 10 mg/kg metamizole. Plasma/saliva pharmacometric (PMX) modeling of the active metabolites 4-methylaminoantipyrine (4-MAA) and 4-aminoantipyrine (4-AA) was performed. Various reduced plasma sampling scenarios were evaluated by PMX simulations. Saliva and plasma samples from 25 children were included (age range, 5-70 months; weight range, 8.7-24.8 kg). Distribution of metamizole metabolites between plasma and saliva was without delay. Estimated mean (individual range) saliva/plasma fractions of 4-MAA and 4-AA were 0.32 (0.05-0.57) and 0.57 (0.25-0.70), respectively. Residual variability of 4-MAA (4-AA) in saliva was 47% (28%) versus 17% (11%) in plasma. A simplified sampling scenario with up to 6 saliva samples combined with 1 plasma sample was associated with similar PK parameter estimates as the full plasma sampling scenario. This case study with metamizole shows increased PK variability in saliva compared to plasma, compromising its suitability as single matrix for PK studies in infants. Nonetheless, rich saliva sampling can reduce the number of plasma samples required for PK characterization, thereby facilitating the conduct of PK studies to optimize dosing in pediatric patients

European consensus meeting of ARM-Net members concerning diagnosis and early management of newborns with anorectal malformations.

The ARM-Net (anorectal malformation network) consortium held a consensus meeting in which the classification of ARM and preoperative workup were evaluated with the aim of improving monitoring of treatment and outcome. The Krickenbeck classification of ARM and preoperative workup suggested by Levitt and Peña, used as a template, were discussed, and a collaborative consensus was achieved. The Krickenbeck classification is appropriate in describing ARM for clinical use. The preoperative workup was slightly modified. In males with a visible fistula, no cross-table lateral X-ray is needed and an anoplasty or (mini-) posterior sagittal anorectoplasty can directly be performed. In females with a small vestibular fistula (Hegar size 5 mm, and in the meantime, gentle painless dilatations can be performed. In both male and female perineal fistula and either a low birth weight (<2,000 g) or severe associated congenital anomalies, prolonged preoperative painless dilatations might be indicated to decrease perioperative morbidity caused by general anesthesia. The Krickenbeck classification is appropriate in describing ARM for clinical use. Some minor modifications to the preoperative workup by Levitt and Peña have been introduced in order to refine terminology and establish a comprehensive preoperative workup

Whole exome resequencing reveals recessive mutations in TRAP1 in individuals with CAKUT and VACTERL association

Congenital abnormalities of the kidney and urinary tract (CAKUT) account for approximately half of children with chronic kidney disease and they are the most frequent cause of end-stage renal disease in children in the US. However, its genetic etiology remains mostly elusive. VACTERL association is a rare disorder that involves congenital abnormalities in multiple organs including the kidney and urinary tract in up to 60% of the cases. By homozygosity mapping and whole exome resequencing combined with high-throughput mutation analysis by array-based multiplex PCR and next-generation sequencing, we identified recessive mutations in the gene TNF receptor-associated protein 1 (TRAP1) in two families with isolated CAKUT and three families with VACTERL association. TRAP1 is a heat shock protein 90-related mitochondrial chaperone possibly involved in antiapoptotic and endoplasmic reticulum-stress signaling. Trap1 is expressed in renal epithelia of developing mouse kidney E13.5 and in the kidney of adult rats, most prominently in proximal tubules and in thick medullary ascending limbs of Henle’s loop. Thus, we identified mutations in TRAP1 as highly likely causing CAKUT or CAKUT in VACTERL association

No association between the common calcium-sensing receptor polymorphism rs1801725 and irritable bowel syndrome

Background The calcium-sensing receptor (CaSR) is a calcium (Ca2+) sensitive G protein-coupled receptor implicated in various biological processes. In particular, it regulates Ca2+/Mg2+- homeostasis and senses interstitial Ca2+ levels and thereby controls downstream signalling cascades. Due to its expression in the gut epithelium, the enteric nervous system and smooth muscles and its key function in regulation and coordination of muscular contraction and secretion, it represents an excellent candidate gene to be investigated in the pathophysiology of irritable bowel syndrome (IBS). Disturbed CaSR structure and function may impact gastrointestinal regulation of muscular contraction, neuronal excitation and secretion and consequently contribute to symptoms seen in IBS, such as disordered defecation as well as disturbed gut motility and visceral sensitivity. Methods We have therefore genotyped the functional CASR SNP rs1801725 in three case control samples from the UK, Belgium and the USA. Results Genotype frequencies showed no association in the three genotyped case–control samples, neither with IBS nor with IBS subtypes. Conclusions Although we could not associate the SNP to any of the established bowel symptom based IBS subtypes we cannot rule out association to altered Ca2+ levels and disturbed secretion and gut motility which were unfortunately not assessed in the patients genotyped. This underlines the necessity of a more detailed phenotyping of IBS patients and control individuals in future studies

A complementary study approach unravels novel players in the pathoetiology of Hirschsprung disease

Hirschsprung disease (HSCR, OMIM 142623) involves congenital intestinal obstruction caused by dysfunction of neural crest cells and their progeny during enteric nervous system (ENS) development. HSCR is a multifactorial disorder; pathogenetic variants accounting for disease phenotype are identified only in a minority of cases, and the identification of novel disease-relevant genes remains challenging. In order to identify and to validate a potential disease-causing relevance of novel HSCR candidate genes, we established a complementary study approach, combining whole exome sequencing (WES) with transcriptome analysis of murine embryonic ENS-related tissues, literature and databas