Gastrostomy and Tracheostomy After Complete Repair of Tetralogy of Fallot in Children With 22q11.2 Deletion Syndrome.

OBJECTIVES: Caring for a child with gastrostomy and/or tracheostomy can cause measurable parental stress. It is generally known that children with 22q11.2 deletion syndrome are at greater risk of requiring gastrostomy or tracheostomy after heart surgery, although the magnitude of that risk after complete repair of tetralogy of Fallot has not been described. We sought to determine the degree to which 22q11.2 deletion is associated with postoperative gastrostomy and/or tracheostomy after repair of tetralogy of Fallot. DESIGN: Retrospective cohort study. SETTING: Pediatric Health Information System. PATIENTS: Children undergoing complete repair of tetralogy of Fallot (ventricular septal defect closure and relief of right ventricular outflow tract obstruction) from 2003 to 2016. Patients were excluded if they had pulmonary atresia, other congenital heart defects, and/or genetic diagnoses other than 22q11.2 deletion. MEASUREMENTS AND MAIN RESULTS: Two groups were formed on the basis of 22q11.2 deletion status. Outcomes were postoperative tracheostomy and postoperative gastrostomy. Bivariate analysis and Kaplan-Meier analysis at 150 days postoperatively were performed. There were 4,800 patients, of which 317 (7%) had a code for 22q11.2 deletion. There were no significant differences between groups for age at surgery or sex. Patients with 22q11.2 deletion had significantly higher rates of gastrostomy (18% vs 5%; p < 0.001) and higher rates of tracheostomy (7% vs 1%; p < 0.001); there was no difference for mortality. Kaplan-Meier analyses also showed higher rates of gastrostomy (p = 0.024) and tracheostomy (p = 0.037). CONCLUSIONS: The present study establishes rates of postoperative gastrostomy and tracheostomy in children with 22q11.2 deletion after complete repair of tetralogy of Fallot. These data are useful to clinicians for providing families with preoperative counseling.

Platelet Glycoprotein VI Haplotypes and the Presentation of Paediatric Sepsis.

Sepsis triggers a complex series of pathophysiologic events involving inflammatory responses and coagulation abnormalities. While circulating blood platelets are well-characterized for their contributions to coagulation, increasingly platelet-dependent effects on inflammation are being recognized. Here, we focus on the platelet membrane receptor, glycoprotein VI (GPVI), and its role in platelet microparticle (pMP) release. The GPVI receptor is a platelet-specific collagen membrane receptor that, upon ligand binding, facilitates the release of pMPs. As membrane-bound platelet fragments of less than 1 µm, pMPs are known to have both pro-inflammatory and pro-coagulant properties. Thus, pMPs are potentially impacting sepsis at multiple stages of the inflammatory response. Studies are presented documenting the impact of the most common GPVI haplotypes, GPVIa and GPVIb, on pMP levels and release in healthy individuals (n = 49). The GPVIa haplotype corresponds to an approximately twofold increase in circulating pMPs as a percentage of total microparticles in healthy individuals along with a heightened in vitro release of pMPs. Additionally, patients admitted to a paediatric intensive care unit (ICU) (n = 73) with an initial diagnosis of sepsis were recruited and their GPVI haplotypes determined. Septic patients of the GPVIa haplotype (n = 59) were statistically more likely to present with a diagnosis of severe sepsis or septic shock, as compared with GPVIb individuals (n = 14). Independent disease classification via PELOD-2 and Pediatric Risk of Mortality III scores confirmed individuals with the GPVIa haplotype were more likely to have significant organ failure. Thus, GPVI haplotypes influence pMP levels in the circulation and are predictive of sepsis severity when presenting to the ICU.

Reirradiation of recurrent medulloblastoma: does clinical benefit outweigh risk for toxicity?

BACKGROUND: Patients with recurrent medulloblastoma (MB) have a dismal prognosis. There has been a reluctance to use radiation in the salvage therapy regimens for these patients because of concerns about toxicity and unknown efficacy. Comparing survival outcomes and toxicities in relapsed patients treated with and without radiation may help to define its role. METHODS: A retrospective review was conducted that included 38 patients with recurrent MB treated with similar risk-adapted therapy at initial diagnosis; reirradiation was a component of salvage therapy in 14. Overall survival (OS) and toxicity were evaluated according to the use of radiation, prior risk stratification, and other factors. RESULTS: For relapsed standard-risk patients, the use of additional irradiation resulted in a statistically significant improvement in OS from initial diagnosis (P = .036), with 5- and 10-year OS rates of 55% ± 14% and 33% ± 16% versus 46% ± 14% and 0% for reirradiated patients versus others, respectively. Similar improvement was observed in high-risk patients (P = .003). There was an association between the use of additional irradiation and an increased rate of necrosis as determined by neuroimaging (P = .0468). CONCLUSIONS: The use of irradiation as a component of salvage therapy for relapsed MB may prolong survival. The benefit appears to be greatest for relapsed standard-risk patients.

Host DNA repair proteins in response to Pseudomonas aeruginosa in lung epithelial cells and in mice.

Although DNA repair proteins in bacteria are critical for pathogens' genome stability and for subverting the host defense, the role of host DNA repair proteins in response to bacterial infection is poorly defined. Here, we demonstrate, for the first time, that infection with the Gram-negative bacterium Pseudomonas aeruginosa significantly altered the expression and enzymatic activity of 8-oxoguanine DNA glycosylase (OGG1) in lung epithelial cells. Downregulation of OGG1 by a small interfering RNA strategy resulted in severe DNA damage and cell death. In addition, acetylation of OGG1 is required for host responses to bacterial genotoxicity, as mutations of OGG1 acetylation sites increased Cockayne syndrome group B (CSB) protein expression. These results also indicate that CSB may be involved in DNA repair activity during infection. Furthermore, OGG1 knockout mice exhibited increased lung injury after infection with P. aeruginosa, as demonstrated by higher myeloperoxidase activity and lipid peroxidation. Together, our studies indicate that P. aeruginosa infection induces significant DNA damage in host cells and that DNA repair proteins play a critical role in the host response to P. aeruginosa infection, serving as promising targets for the treatment of this condition and perhaps more broadly Gram-negative bacterial infections.