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Item AARC and PALISI Clinical Practice Guideline: Pediatric Critical Asthma(Mary Ann Liebert, Inc., 2025) White, Benjamin R.; Miller, Andrew G.; Baker, Joyce; Basnet, Sangita; Carroll, Christopher L.; Craven, Hannah J.; Dalabih, Abdallah; Fitzpatrick, Anne M.; Glogowski, Joel; Irazuzta, Jose Enrique; Kapuscinski, Christine A.; Lenox, Jesslyn; Lovinsky-Desir, Stephanie; Maue, Danielle K.; Moody, Gerald; Newth, Christopher; Rehder, Kyle J.; Sochet, Anthony A.; Said, Sana J.; Willis, L. Denise; Whipple, Elizabeth C.; Goodfellow, Lynda; Abu-Sultaneh, SamerTo address the lack of guidance for clinicians in their care of children with critical asthma, a multidisciplinary team of medical providers used Grading of Recommendations, Assessment, Development, and Evaluation methodology to make the following recommendations: 1. We suggest the use of continuous inhaled short-acting β agonist (SABA) over frequent intermittent SABA in children treated for critical asthma. (Conditional recommendation, very low certainty of evidence) 2. We suggest the use of either high- or low-dose continuous inhaled SABA regimens in children treated for critical asthma. (Conditional recommendation, very low certainty of evidence) 3. We suggest the use of either dexamethasone or methylprednisolone (or an equivalent dose of prednisone/prednisolone) for children treated for critical asthma. (Conditional recommendation, very low certainty of evidence) 4. We suggest the use of intravenous (IV) magnesium (intermittent or continuous) as an adjunct therapy in children treated for critical asthma. (Conditional recommendation, low certainty of evidence) 5. We cannot recommend for or against the use of IV methylxanthines as an adjunct therapy in children treated for critical asthma. (Conditional recommendation, very low certainty of evidence) 6. We suggest the use of an IV SABA infusion as an adjunct therapy in children treated for critical asthma. (Conditional recommendation, low certainty of evidence) 7. We cannot recommend for or against the application of high-flow nasal cannula versus conventional oxygen therapy in children presenting with critical asthma with persistent hypoxemia and/or respiratory distress. (Conditional recommendation, very low certainty of evidence) 8. We suggest the use of bi-level positive airway pressure over conventional oxygen therapy in children presenting with critical asthma with persistent hypoxemia and/or respiratory distress. (Conditional recommendation, very low certainty of evidence) 9. We cannot recommend for or against the application of bi-level positive airway pressure over high-flow nasal cannula for children hospitalized with critical asthma with persistent hypoxemia and/or respiratory distress. (Conditional recommendation, very low certainty of evidence) 10. We cannot recommend for or against the application of heliox in children treated for critical asthma. (Conditional recommendation, very low certainty of evidence) 11. We suggest the use of a dedicated protocol or pathway for managing children treated for critical asthma. (Conditional recommendation, low certainty of evidence).Item What Can Twins Teach Us About Malaria Epidemiology?(Oxford, 2023-01) John, Chandy C.; Pediatrics, School of MedicineItem Wide Institutional Variability in the Treatment of Pediatric Critical Asthma: A Multicenter Retrospective Study(Wolters Kluwer, 2024-01) Rogerson, Colin M.; Hogan, Alexander H.; Waldo, Briana; White, Benjamin R.; Carroll, Christopher L.; Shein, Steven L.; Pediatrics, School of MedicineOBJECTIVES: Children with status asthmaticus refractory to first-line therapies of systemic corticosteroids and inhaled beta-agonists often receive additional treatments. Because there are no national guidelines on the use of asthma therapies in the PICU, we sought to evaluate institutional variability in the use of adjunctive asthma treatments and associations with length of stay (LOS) and PICU use. DESIGN: Multicenter retrospective cohort study. SETTING: Administrative data from the Pediatric Health Information Systems (PHIS) database. PATIENTS: All inpatients 2–18 years old were admitted to a PHIS hospital between 2013 and 2021 with a diagnostic code for asthma. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: This study included 213,506 inpatient encounters for asthma, of which 29,026 patient encounters included care in a PICU from 39 institutions. Among these PICU encounters, large variability was seen across institutions in both the number of adjunctive asthma therapies used per encounter (min: 0.6, median: 1.7, max: 2.5, p < 0.01) and types of adjunctive asthma therapies (aminophylline, ipratropium, magnesium, epinephrine, and terbutaline) used. The center-level median hospital LOS ranged from 1 (interquartile range [IQR]: 1, 3) to 4 (3, 6) days. Among all the 213,506 inpatient encounters for asthma, the range of asthma admissions that resulted in PICU admission varied between centers from 5.2% to 47.3%. The average number of adjunctive therapies used per institution was not significantly associated with hospital LOS (p = 0.81) nor the percentage of encounters with PICU admission (p = 0.47). CONCLUSIONS: Use of adjunctive therapies for status asthmaticus varies widely among large children’s hospitals and was not associated with hospital LOS or the percentage of encounters with PICU admission. Wide variance presents an opportunity for standardizing care with evidence-based guidelines to optimize outcomes and decrease adverse treatment effects and hospital costs.Item Rho kinases in cardiovascular physiology and pathophysiology: the effect of fasudil(Wolters Kluwer, 2013) Shi, Jianjian; Wei, Lei; Pediatrics, School of MedicineRho kinase (ROCK) is a major downstream effector of the small GTPase RhoA. ROCK family, consisting of ROCK1 and ROCK2, plays central roles in the organization of actin cytoskeleton and is involved in a wide range of fundamental cellular functions, such as contraction, adhesion, migration, proliferation, and apoptosis. Due to the discovery of effective inhibitors, such as fasudil and Y27632, the biological roles of ROCK have been extensively explored with particular attention on the cardiovascular system. In many preclinical models of cardiovascular diseases, including vasospasm, arteriosclerosis, hypertension, pulmonary hypertension, stroke, ischemia-reperfusion injury, and heart failure, ROCK inhibitors have shown a remarkable efficacy in reducing vascular smooth muscle cell hypercontraction, endothelial dysfunction, inflammatory cell recruitment, vascular remodeling, and cardiac remodeling. Moreover, fasudil has been used in the clinical trials of several cardiovascular diseases. The continuing utilization of available pharmacological inhibitors and the development of more potent or isoform-selective inhibitors in ROCK signaling research and in treating human diseases are escalating. In this review, we discuss the recent molecular, cellular, animal, and clinical studies with a focus on the current understanding of ROCK signaling in cardiovascular physiology and diseases. We particularly note that emerging evidence suggests that selective targeting ROCK isoform based on the disease pathophysiology may represent a novel therapeutic approach for the disease treatment including cardiovascular diseases.Item ST2 as a Marker for Risk of Therapy-Resistant Graft-versus-Host Disease and Death(Massachusetts Medical Society, 2013) Vander Lugt, Mark T.; Braun, Thomas M.; Hanash, Samir; Ritz, Jerome; Ho, Vincent T.; Antin, Joseph H.; Zhang, Qing; Wong, Chee-Hong; Wang, Hong; Chin, Alice; Gomez, Aurélie; Harris, Andrew C.; Levine, John E.; Choi, Sung W.; Couriel, Daniel; Reddy, Pavan; Ferrara, James L. M.; Paczesny, Sophie; Pediatrics, School of MedicineBackground: No plasma biomarkers are associated with the response of acute graft-versus-host disease (GVHD) to therapy after allogeneic hematopoietic stem-cell transplantation. Methods: We compared 12 biomarkers in plasma obtained a median of 16 days after therapy initiation from 10 patients with a complete response by day 28 after therapy initiation and in plasma obtained from 10 patients with progressive GVHD during therapy. The lead biomarker, suppression of tumorigenicity 2 (ST2), was measured at the beginning of treatment for GVHD in plasma from 381 patients and during the first month after transplantation in three independent sets totaling 673 patients to determine the association of this biomarker with treatment-resistant GVHD and 6-month mortality after treatment or transplantation. Results: Of the 12 markers, ST2 had the most significant association with resistance to GVHD therapy and subsequent death without relapse. As compared with patients with low ST2 values at therapy initiation, patients with high ST2 values were 2.3 times as likely to have treatment-resistant GVHD (95% confidence interval [CI], 1.5 to 3.6) and 3.7 times as likely to die within 6 months after therapy (95% CI, 2.3 to 5.9). Patients with low ST2 values had lower mortality without relapse than patients with high ST2 values, regardless of the GVHD grade (11% vs. 31% among patients with grade I or II GVHD and 14% vs. 67% among patients with grade III or IV GVHD, P<0.001 for both comparisons). Plasma ST2 values at day 14 after transplantation were associated with 6-month mortality without relapse, regardless of the intensity of the conditioning regimen. Conclusions: ST2 levels measured at the initiation of therapy for GVHD and during the first month after transplantation improved risk stratification for treatment-resistant GVHD and death without relapse after transplantation.Item Graft-versus-Host Disease Biomarkers: Omics and Personalized Medicine(Springer, 2013) Paczesny, Sophie; Raiker, Nisha; Brooks, Sam; Mumaw, Christy; Pediatrics, School of MedicineAllogeneic hematopoietic stem cell transplantation (allo-HSCT) is the most effective form of tumor immunotherapy available to date and the frequency of transplants continues to increase worldwide. However, while allo-HSCT usually induces a beneficial graft-versus leukemia effect, a major source of morbidity and mortality following allo-HSCT is graft-versus-host disease (GVHD). Currently available diagnostic and staging tools frequently fail to identify those at higher risk for GVHD morbidity, treatment unresponsiveness, and death. Furthermore, there are shortcomings in the risk stratification of patients before GVHD clinical signs develop. In parallel, recent years have been characterized by an explosive evolution of omics technologies, largely due to technological advancements in chemistry, engineering, and bioinformatics. Building on these opportunities, plasma biomarkers have been identified and validated as promising diagnostic and prognostic tools for acute GVHD. This review summarizes current information on the types of GVHD biomarkers, the omics tools used to identify them, the biomarkers currently validated as acute GVHD markers, and future recommendations for incorporating biomarkers into new grading algorithms for risk-stratifying patients and creating more personalized treatment courses. Future directions will include randomized evaluations of these biomarkers in multicenter prospective studies while extending on the need for biomarkers of chronic GVHD.Item Signaling mechanisms of glucose-induced F-actin remodeling in pancreatic islet β cells(Springer Nature, 2013-08-23) Kalwat, Michael A.; Thurmond, Debbie C.; Pediatrics, School of MedicineThe maintenance of whole-body glucose homeostasis is critical for survival, and is controlled by the coordination of multiple organs and endocrine systems. Pancreatic islet β cells secrete insulin in response to nutrient stimuli, and insulin then travels through the circulation promoting glucose uptake into insulin-responsive tissues such as liver, skeletal muscle and adipose. Many of the genes identified in human genome-wide association studies of diabetic individuals are directly associated with β cell survival and function, giving credence to the idea that β-cell dysfunction is central to the development of type 2 diabetes. As such, investigations into the mechanisms by which β cells sense glucose and secrete insulin in a regulated manner are a major focus of current diabetes research. In particular, recent discoveries of the detailed role and requirements for reorganization/remodeling of filamentous actin (F-actin) in the regulation of insulin release from the β cell have appeared at the forefront of islet function research, having lapsed in prior years due to technical limitations. Recent advances in live-cell imaging and specialized reagents have revealed localized F-actin remodeling to be a requisite for the normal biphasic pattern of nutrient-stimulated insulin secretion. This review will provide an historical look at the emergent focus on the role of the actin cytoskeleton and its regulation of insulin secretion, leading up to the cutting-edge research in progress in the field today.Item Human Papillomavirus Vaccine Communication: Perspectives of 11–12 Year-Old Girls, Mothers, and Clinicians(Elsevier, 2013) Kowalczyk Mullins, Tanya L.; Griffioen, Anne M.; Glynn, Susan; Zimet, Gregory D.; Rosenthal, Susan L.; Fortenberry, J. Dennis; Kahn, Jessica A.; Pediatrics, School of MedicineObjectives: Because little is known about the content of human papillomavirus (HPV) vaccine-related discussions with young adolescent girls in clinical settings, we explored communication between 11- and 12 year-old girls, mothers, and clinicians regarding HPV vaccines and concordance in reports of maternal and clinician communication. Methods: We conducted individual interviews with 33 girls who had received the quadrivalent HPV vaccine in urban and suburban clinical settings, their mothers, and their clinicians. Data were analyzed using qualitative methods. Results: From the perspectives of both girls and mothers, clinicians and parents were the preferred sources of HPV vaccine information for girls. Vaccine efficacy and risks/benefits of vaccination were the most commonly reported desired and actual topics of discussion by mothers, girls, and clinicians. Clinician recommendation of vaccination was reported by nearly one-fifth of girls and nearly half of mothers. The most common concordant messages were related to efficacy of the vaccine, with concordance in 70% of triads. The most common discordant messages were related to sexual health. Approximately half of clinicians (16) reported discussing sexual health, but only 5 mothers (15%) and 4 girls (12%) reported this. Triads recruited from suburban (vs. urban) practices had higher degrees of concordance in reported vaccination communication. Conclusions: HPV vaccine efficacy and safety are important topics for clinicians to discuss with both girls and mothers; educating mothers is important because parents are a preferred source of vaccine-related information for girls. Because girls may be missing important vaccine-related messages, they should be encouraged to actively engage in vaccine discussions.Item Promoting Use of Booster Seats in Rural Areas Through Community Sports Programs(Wiley, 2013) Aitken, Mary E.; Miller, Beverly K.; Anderson, Byron L.; Swearingen, Christopher J.; Monroe, Kathy W.; Daniels, Dawn; O'Neil, Joseph; Scherer, L. R. "Tres"; Hafner, John; Mullins, Samantha H.; Pediatrics, School of MedicineBackground: Booster seats reduce mortality and morbidity for young children in car crashes, but use is low, particularly in rural areas. This study targeted rural communities in 4 states using a community sports-based approach. Objective: The Strike Out Child Passenger Injury (Strike Out) intervention incorporated education about booster seat use in children ages 4-7 years within instructional baseball programs. We tested the effectiveness of Strike Out in increasing correct restraint use among participating children. Methods: Twenty communities with similar demographics from 4 states participated in a nonrandomized, controlled trial. Surveys of restraint use were conducted before and after baseball season. Intervention communities received tailored education and parents had direct consultation on booster seat use. Control communities received only brochures. Results: One thousand fourteen preintervention observation surveys for children ages 4-7 years (Intervention Group [I]: N = 511, Control [C]: N = 503) and 761 postintervention surveys (I: N = 409, C: N = 352) were obtained. For 3 of 4 states, the intervention resulted in increases in recommended child restraint use (Alabama +15.5%, Arkansas +16.1%, Illinois +11.0%). Communities in 1 state (Indiana) did not have a positive response (-9.2%). Overall, unadjusted restraint use increased 10.2% in intervention and 1.7% in control communities (P = .02). After adjustment for each state in the study, booster seat use was increased in intervention communities (Cochran-Mantel-Haenszel odds ratio 1.56, 95% confidence interval [1.16-2.10]). Conclusions: A tailored intervention using baseball programs increased appropriate restraint use among targeted rural children overall and in 3 of 4 states studied. Such interventions hold promise for expansion into other sports and populations.Item Hepatocyte Growth Factor Signaling in Intrapancreatic Ductal Cells Drives Pancreatic Morphogenesis(Public Library of Science, 2013) Anderson, Ryan M.; Delous, Marion; Bosch, Justin A.; Ye, Lihua; Robertson, Morgan A.; Hesselson, Daniel; Stainier, Didier Y. R.; Pediatrics, School of MedicineIn a forward genetic screen for regulators of pancreas development in zebrafish, we identified donut(s908) , a mutant which exhibits failed outgrowth of the exocrine pancreas. The s908 mutation leads to a leucine to arginine substitution in the ectodomain of the hepatocyte growth factor (HGF) tyrosine kinase receptor, Met. This missense mutation impedes the proteolytic maturation of the receptor, its trafficking to the plasma membrane, and diminishes the phospho-activation of its kinase domain. Interestingly, during pancreatogenesis, met and its hgf ligands are expressed in pancreatic epithelia and mesenchyme, respectively. Although Met signaling elicits mitogenic and migratory responses in varied contexts, normal proliferation rates in donut mutant pancreata together with dysmorphic, mislocalized ductal cells suggest that met primarily functions motogenically in pancreatic tail formation. Treatment with PI3K and STAT3 inhibitors, but not with MAPK inhibitors, phenocopies the donut pancreatic defect, further indicating that Met signals through migratory pathways during pancreas development. Chimera analyses showed that Met-deficient cells were excluded from the duct, but not acinar, compartment in the pancreatic tail. Conversely, wild-type intrapancreatic duct and "tip cells" at the leading edge of the growing pancreas rescued the donut phenotype. Altogether, these results reveal a novel and essential role for HGF signaling in the intrapancreatic ducts during exocrine morphogenesis.