Testing the Prognostic Accuracy of the Updated Pediatric Sepsis Biomarker Risk Model

Background We previously derived and validated a risk model to estimate mortality probability in children with septic shock (PERSEVERE; PEdiatRic SEpsis biomarkEr Risk modEl). PERSEVERE uses five biomarkers and age to estimate mortality probability. After the initial derivation and validation of PERSEVERE, we combined the derivation and validation cohorts (n = 355) and updated PERSEVERE. An important step in the development of updated risk models is to test their accuracy using an independent test cohort. Objective To test the prognostic accuracy of the updated version PERSEVERE in an independent test cohort. Methods Study subjects were recruited from multiple pediatric intensive care units in the United States. Biomarkers were measured in 182 pediatric subjects with septic shock using serum samples obtained during the first 24 hours of presentation. The accuracy of PERSEVERE 28-day mortality risk estimate was tested using diagnostic test statistics, and the net reclassification improvement (NRI) was used to test whether PERSEVERE adds information to a physiology-based scoring system. Results Mortality in the test cohort was 13.2%. Using a risk cut-off of 2.5%, the sensitivity of PERSEVERE for mortality was 83% (95% CI 62–95), specificity was 75% (68–82), positive predictive value was 34% (22–47), and negative predictive value was 97% (91–99). The area under the receiver operating characteristic curve was 0.81 (0.70–0.92). The false positive subjects had a greater degree of organ failure burden and longer intensive care unit length of stay, compared to the true negative subjects. When adding PERSEVERE to a physiology-based scoring system, the net reclassification improvement was 0.91 (0.47–1.35; p<0.001). Conclusions The updated version of PERSEVERE estimates mortality probability reliably in a heterogeneous test cohort of children with septic shock and provides information over and above a physiology-based scoring system

A new pathway of glucocorticoid action for asthma treatment through the regulation of PTEN expression

<p>Abstract</p> <p>Background</p> <p>"Phosphatase and tensin homolog deleted on chromosome 10" (PTEN) is mostly considered to be a cancer-related gene, and has been suggested to be a new pathway of pathogenesis of asthma. The purpose of this study was to investigate the effects of the glucocorticoid, dexamethasone, on PTEN regulation.</p> <p>Methods</p> <p>OVA-challenged mice were used as an asthma model to investigate the effect of dexamethasone on PTEN regulation. Immunohistochemistry was used to detect expression levels of PTEN protein in lung tissues. The human A549 cell line was used to explore the possible mechanism of action of dexamethasone on human PTEN regulation <it>in vitro</it>. A luciferase reporter construct under the control of PTEN promoter was used to confirm transcriptional regulation in response to dexamethasone.</p> <p>Results</p> <p>PTEN protein was found to be expressed at low levels in lung tissues in asthmatic mice; but the expression was restored after treatment with dexamethasone. In A549 cells, human PTEN was up-regulated by dexamethasone treatment. The promoter-reporter construct confirmed that dexamethasone could regulate human PTEN transcription. Treatment with the histone deacetylase inhibitor, TSA, could increase PTEN expression in A549 cells, while inhibition of histone acetylase (HAT) by anacardic acid attenuated dexamethasone-induced PTEN expression.</p> <p>Conclusions</p> <p>Based on the data a new mechanism is proposed where glucocorticoids treat asthma partly through up-regulation of PTEN expression. The <it>in vitro </it>studies also suggest that the PTEN pathway may be involved in human asthma.</p

Identification of pediatric septic shock subclasses based on genome-wide expression profiling

<p>Abstract</p> <p>Background</p> <p>Septic shock is a heterogeneous syndrome within which probably exist several biological subclasses. Discovery and identification of septic shock subclasses could provide the foundation for the design of more specifically targeted therapies. Herein we tested the hypothesis that pediatric septic shock subclasses can be discovered through genome-wide expression profiling.</p> <p>Methods</p> <p>Genome-wide expression profiling was conducted using whole blood-derived RNA from 98 children with septic shock, followed by a series of bioinformatic approaches targeted at subclass discovery and characterization.</p> <p>Results</p> <p>Three putative subclasses (subclasses A, B, and C) were initially identified based on an empiric, discovery-oriented expression filter and unsupervised hierarchical clustering. Statistical comparison of the three putative subclasses (analysis of variance, Bonferonni correction, <it>P </it>< 0.05) identified 6,934 differentially regulated genes. K-means clustering of these 6,934 genes generated 10 coordinately regulated gene clusters corresponding to multiple signaling and metabolic pathways, all of which were differentially regulated across the three subclasses. Leave one out cross-validation procedures indentified 100 genes having the strongest predictive values for subclass identification. Forty-four of these 100 genes corresponded to signaling pathways relevant to the adaptive immune system and glucocorticoid receptor signaling, the majority of which were repressed in subclass A patients. Subclass A patients were also characterized by repression of genes corresponding to zinc-related biology. Phenotypic analyses revealed that subclass A patients were younger, had a higher illness severity, and a higher mortality rate than patients in subclasses B and C.</p> <p>Conclusion</p> <p>Genome-wide expression profiling can identify pediatric septic shock subclasses having clinically relevant phenotypes.</p

Understanding genomics - Implications for the emergency medicine physician and the treatment of asthma

TARGET AUDIENCE: Physicians, nurse practitioners, and physician assistants who evaluate and care for children with minor illnesses. Specialists including pediatricians, emergency physicians, pediatric emergency physicians, family practitioners, and pediatric nurse practitioners will find this information particularly useful. LEARNING OBJECTIVES: After completion of this article, the reader will be able to: 1. Explain the role of single-nucleotide polymorphisms and haplotypes in the development of asthma and asthma exacerbations. 2. Describe what is currently known about how environmental influences interact with genotype to produce an asthmatic phenotype. 3. Describe the 3 possible effects of a single-nucleotide polymorphism or haplotype on pharmacology in the context of asthma

Toward early identification of acute lung injury in the emergency department

BACKGROUND: There are no studies evaluating the epidemiology of pediatric acute lung injury (ALI) in the emergency department (ED), where early identification and interventions are most likely to be helpful. The purpose of this study was to describe the epidemiology of the ALI precursor acute hypoxemic respiratory failure (AHRF) in the ED. METHODS: We analyzed 11,664 pediatric patient records from 16 EDs. Records were selected if oxygen saturation (SpO(2)) was recorded during the visit. Virtual partial pressure of oxygen (pO(2)) was calculated from SpO(2), thus allowing calculation of ratios of pO(2) to fraction of inspired oxygen (FiO(2)) (PFRs). Patients with a PFR < 300 were classified as having AHRF. Univariate analyses and logistic regression were used to test the association of clinical factors with the presence of AHRF and intubation. RESULTS: AHRF criteria (ie, PFR < 300) were met in 121 (2.9%) of the 4,184 patients with an oxygenation measurement. The following variables were independently associated with ALI: higher Pediatric Risk of Admission II score (adjusted odds ratio [95% confidence interval (CI)] = 1.12 [1.08–1.16]; p < .001), higher heart rate (1.02 [1.01–1.03]; p = .009), a positive chest radiograph (2.35 [1.02–5.43]; p = .045), and lower temperature (0.49 [0.36–0.68]; p < .001). The final model had an R(2) = .20. CONCLUSION: We found nonintubated AHRF to be prevalent in the ED. The low R(2) for the regression model for AHRF underscores the lack of criteria for early identification of patients with respiratory compromise. Our findings represent an important first step toward establishing the true incidence of ALI in the pediatric ED