Timothy Thomas Cornell

All Publications

• SEQUENTIAL INTRAVENOUS AND INTRACEREBROVENTRICULAR GD2-CAR T-CELL THERAPY FOR H3K27M-MUTATED DIFFUSE MIDLINE GLIOMAS Monje, M., Mahdi, J., Majzner, R. G., Yeom, K., Schultz, L. M., Richards, R., Barsan, V., Song, K., Kamens, J., Baggott, C., Kunicki, M., Lim, A., Reschke, A., Mavroukakis, S., Egeler, E., Moon, J., Patel, S., Chinnasamy, H., Erickson, C., Jacobs, A., Duh, A. K., Rietberg, S. P., Tunuguntla, R., Klysz, D., Fowler, C., Green, S., Beebe, B., Carr, C., Fujimoto, M., Brown, A., Peterson, A. G., Mcintyre, C., Siddiqui, A., Lepori-Bui, N., Villar, K., Pham, K., Bove, R., Musa, E., Reynolds, W., Kuo, A., Prabhu, S., Rasmussen, L., Cornell, T. T., Partap, S., Fisher, P. G., Campen, C. J., Grant, G., Prolo, L., Ye, X., Sahaf, B., Davis, K. L., Feldman, S. A., Ramakrishna, S., Mackall, C. L. OXFORD UNIV PRESS INC. 2024

  View details for DOI 10.1093/neuonc/noae064.100

  View details for Web of Science ID 001252720000169

• EXCESS DAILY BLOOD COUNT SAMPLING IN CHILDREN: A PICU DATA COLLABORATIVE STUDY Shah, S., Dziorny, A., Flynn, A., Aczon, M., Farris, R., Horvat, C., Tawfik, D., Bennett, T., Cornell, T., Nishisaki, A., Kennedy, C., Sanchez-Pinto, L., Wetzel, R. LIPPINCOTT WILLIAMS & WILKINS. 2024

  View details for Web of Science ID 001131541101762

• Prevalence of burnout and its relation to the neuroendocrine system among pediatric residents during the early Covid-19 pandemic: A pilot feasibility study. Comprehensive psychoneuroendocrinology Tawfik, D. S., Rovnaghi, C., Profit, J., Cornell, T. T., Anand, K. J. 2023; 14: 100174

  Abstract

  Background: Measuring burnout relies on infrequent and subjective surveys, which often do not reflect the underlying factors or biological mechanisms that promote or prevent it. Burnout correlates with cortisol levels and dysregulation of the hypothalamic-pituitary-adrenal axis, but the chronology and strength of this relationship are unknown.Objective: To determine the prevalence and feasibility of studying burnout in pediatric residents using hair cortisol and hair oxytocin concentrations.Design: /Methods: Longitudinal observational cohort study of pediatric residents. We assessed burnout using the Stanford Professional Fulfillment Index and hair cortisol (HCC), and hair oxytocin concentrations (HOC) at four 3-month intervals from January 2020-January 2021. We evaluated test-retest reliability, sensitivity to change using Pearson product-moment correlations, and relationships between burnout and hair biomarkers using hierarchical mixed-effects linear regression.Results: 17 Pediatrics residents provided 78 wellness surveys and 54 hair samples. Burnout symptoms were present in 39 (50%) of the surveys, with 14 (82%) residents reporting burnout in at least one time point. The lowest (41%) and highest (60%) burnout prevalence occurred in 04/2020 and 01/2021, respectively. No significant associations between burnout scores and HCC (beta -0.01, 95%CI: 0.14-0.13), HOC (beta 0.06, 95%CI: 0.06-0.19), or the HCC:HOC ratio (beta -0.04, 95%CI: 0.09-0.02) were noted in separate analyses. Intra-individual changes in hair cortisol concentration were not associated with changes in burnout score.Conclusions: Burnout was prevalent among Pediatrics residents, with highest prevalence noted in January 2021. This pilot longitudinal study demonstrates the feasibility of evaluating burnout with stress and resilience biomarkers in Pediatrics residents.

  View details for DOI 10.1016/j.cpnec.2023.100174

  View details for PubMedID 36742128

• Drp1/p53 interaction mediates p53 mitochondrial localization and dysfunction in septic cardiomyopathy. Journal of molecular and cellular cardiology Mukherjee, R., Tetri, L. H., Li, S. J., Fajardo, G., Ostberg, N. P., Tsegay, K. B., Gera, K., Cornell, T. T., Bernstein, D., Mochly-Rosen, D., Haileselassie, B. 2023; 177: 28-37

  Abstract

  Previous studies have implicated p53-dependent mitochondrial dysfunction in sepsis induced end organ injury, including sepsis-induced myocardial dysfunction (SIMD). However, the mechanisms behind p53 localization to the mitochondria have not been well established. Dynamin-related protein 1 (Drp1), a mediator of mitochondrial fission, may play a role in p53 mitochondrial localization. Here we examined the role of Drp1/p53 interaction in SIMD using in vitro and murine models of sepsis.H9c2 cardiomyoblasts and BALB/c mice were exposed to lipopolysaccharide (LPS) to model sepsis phenotype. Pharmacologic inhibitors of Drp1 activation (ψDrp1) and of p53 mitochondrial binding (pifithrin μ, PFTμ) were utilized to assess interaction between Drp1 and p53, and the subsequent downstream impact on mitochondrial morphology and function, cardiomyocyte function, and sepsis phenotype.Both in vitro and murine models demonstrated an increase in physical Drp1/p53 interaction following LPS treatment, which was associated with increased p53 mitochondrial localization, and mitochondrial dysfunction. This Drp1/p53 interaction was inhibited by ΨDrp1, suggesting that this interaction is dependent on Drp1 activation. Treatment of H9c2 cells with either ΨDrp1 or PFTμ inhibited the LPS mediated localization of Drp1/p53 to the mitochondria, decreased oxidative stress, improved cellular respiration and ATP production. Similarly, treatment of BALB/c mice with either ΨDrp1 or PFTμ decreased LPS-mediated mitochondrial localization of p53, mitochondrial ROS in cardiac tissue, and subsequently improved cardiomyocyte contractile function and survival.Drp1/p53 interaction and mitochondrial localization is a key prodrome to mitochondrial damage in SIMD and inhibiting this interaction may serve as a therapeutic target.

  View details for DOI 10.1016/j.yjmcc.2023.01.008

  View details for PubMedID 36841153

• DRP1/P53 INTERACTION PLAYS A KEY ROLE IN MITOCHONDRIAL DYSFUNCTION OF SEPTIC CARDIOMYOPATHY Tetri, L., Mukherjee, R., Li, S., Fajardo, G., Ostberg, N., Tsegay, K., Gera, K., Cornell, T., Bernstein, D., Mochly-Rosen, D., Haileselassie, B. LIPPINCOTT WILLIAMS & WILKINS. 2023: 617

  View details for Web of Science ID 000921450901535

• MITOCHONDRIAL FISSION & CELL-FREE MITOCHONDRIA MEDIATE CARDIAC DYSFUNCTION IN OBESITY CARDIOMYOPATHY Li, S., Chen, C., Ostberg, N., Tetri, L., Cornell, T., Mochly-Rosen, D., Haileselassie, B. LIPPINCOTT WILLIAMS & WILKINS. 2023: 50

  View details for Web of Science ID 000921450900100

• New and Progressive Medical Conditions After Pediatric Sepsis Hospitalization Requiring Critical Care. JAMA pediatrics Carlton, E. F., Gebremariam, A., Maddux, A. B., McNamara, N., Barbaro, R. P., Cornell, T. T., Iwashyna, T. J., Prosser, L. A., Zimmerman, J., Weiss, S., Prescott, H. C. 2022: e223554

  Abstract

  Importance: Children commonly experience physical, cognitive, or emotional sequelae after sepsis. However, little is known about the development or progression of medical conditions after pediatric sepsis.Objective: To quantify the development and progression of 4 common conditions in the 6 months after sepsis and to assess whether they differed after hospitalization for sepsis vs nonsepsis among critically ill children.Design, Setting, and Participants: This cohort study of 101 511 children (<19 years) with sepsis or nonsepsis hospitalization used a national administrative claims database (January 1, 2010, to June 30, 2018). Data management and analysis were conducted from April 1, 2020, to July 7, 2022.Exposures: Intensive care unit hospitalization for sepsis vs all-cause intensive care unit hospitalizations, excluding sepsis.Main Outcomes and Measures: Primary outcomes were the development of 4 target conditions (chronic respiratory failure, seizure disorder, supplemental nutritional dependence, and chronic kidney disease) within 6 months of hospital discharge. Secondary outcomes were the progression of the 4 target conditions among children with the condition before hospitalization. Outcomes were identified via diagnostic and procedural codes, durable medical equipment codes, and prescription medications. Differences in the development and the progression of conditions between pediatric patients with sepsis and pediatric patients with nonsepsis who survived intensive care unit hospitalization were assessed using logistic regression with matching weights.Results: A total of 5150 survivors of pediatric sepsis and 96 361 survivors of nonsepsis intensive care unit hospitalizations were identified; 2593 (50.3%) were female. The median age was 9.5 years (IQR, 3-15 years) in the sepsis cohort and 7 years (IQR, 2-13 years) in the nonsepsis cohort. Of the 5150 sepsis survivors, 670 (13.0%) developed a new target condition, and 385 of 1834 (21.0%) with a preexisting target condition had disease progression. A total of 998 of the 5150 survivors (19.4%) had development and/or progression of at least 1 condition. New conditions were more common among sepsis vs nonsepsis hospitalizations (new chronic respiratory failure: 4.6% vs 1.9%; odds ratio [OR], 2.54 [95% CI, 2.19-2.94]; new supplemental nutritional dependence: 7.9% vs 2.7%; OR, 3.17 [95% CI, 2.80-3.59]; and new chronic kidney disease: 1.1% vs 0.6%; OR, 1.65 [95% CI, 1.25-2.19]). New seizure disorder was less common (4.6% vs 6.0%; OR, 0.77 [95% CI, 0.66-0.89]). Progressive supplemental nutritional dependence was more common (1.5% vs 0.5%; OR, 2.95 [95% CI, 1.60-5.42]), progressive epilepsy was less common (33.7% vs 40.6%; OR, 0.74 [95% CI, 0.65-0.86]), and progressive respiratory failure (4.4% vs 3.3%; OR, 1.35 [95% CI, 0.89-2.04]) and progressive chronic kidney disease (7.9% vs 9.2%; OR, 0.84 [95% CI, 0.18-3.91]) were similar among survivors of sepsis vs nonsepsis admitted to an intensive care unit.Conclusions and Relevance: In this national cohort of critically ill children who survived sepsis, 1 in 5 developed or had progression of a condition of interest after sepsis hospitalization, suggesting survivors of pediatric sepsis may benefit from structured follow-up to identify and treat new or worsening medical comorbid conditions.

  View details for DOI 10.1001/jamapediatrics.2022.3554

  View details for PubMedID 36215045

• GD2-CAR T cell therapy for H3K27M-mutated diffuse midline gliomas. Nature Majzner, R. G., Ramakrishna, S., Yeom, K. W., Patel, S., Chinnasamy, H., Schultz, L. M., Richards, R. M., Jiang, L., Barsan, V., Mancusi, R., Geraghty, A. C., Good, Z., Mochizuki, A. Y., Gillespie, S. M., Toland, A. M., Mahdi, J., Reschke, A., Nie, E., Chau, I. J., Rotiroti, M. C., Mount, C. W., Baggott, C., Mavroukakis, S., Egeler, E., Moon, J., Erickson, C., Green, S., Kunicki, M., Fujimoto, M., Ehlinger, Z., Reynolds, W., Kurra, S., Warren, K. E., Prabhu, S., Vogel, H., Rasmussen, L., Cornell, T. T., Partap, S., Fisher, P. G., Campen, C. J., Filbin, M. G., Grant, G., Sahaf, B., Davis, K. L., Feldman, S. A., Mackall, C. L., Monje, M. 2022

  Abstract

  Diffuse intrinsic pontine glioma (DIPG) and other H3K27M-mutated diffuse midline gliomas (DMG) are universally lethal paediatric central nervous system tumours1. We previously discovered that the disialoganglioside GD2 is highly expressed on H3K27M-mutant glioma cells and demonstrated promising preclinical efficacy of GD2-directed chimeric antigen receptor (CAR) T cells2, providing the rationale for a first-in-human Phase 1 clinical trial (NCT04196413). Because CAR T-cell-induced brainstem inflammation can result in obstructive hydrocephalus, increased intracranial pressure, and dangerous tissue shifts, neurocritical care precautions were incorporated. Here we present the clinical experience from the first four patients with H3K27M-mutant DIPG/DMG treated with GD2-CAR T cells (GD2-CART) at dose level 1 (1e6 GD2-CAR T cells/kg administered intravenously). Patients who exhibited clinical benefit were eligible for subsequent GD2-CAR T infusions administered intracerebroventricularly3. Toxicity was largely related to tumor location and reversible with intensive supportive care. On-target, off-tumor toxicity was not observed. Three of four patients exhibited clinical and radiographic improvement. Proinflammatory cytokines were increased in plasma and cerebrospinal fluid (CSF). Transcriptomic analyses of 65,598 single cells from CAR T cell products and CSF elucidate heterogeneity in response between subjects and administration routes. These early results underscore the promise of this approach for H3K27M+ DIPG/DMG therapy.

  View details for DOI 10.1038/s41586-022-04489-4

  View details for PubMedID 35130560

• Drp1/Fis1-Dependent Pathologic Fission and Associated Damaged Extracellular Mitochondria Contribute to Macrophage Dysfunction in Endotoxin Tolerance. Critical care medicine Mukherjee, R., Tompkins, C. A., Ostberg, N. P., Joshi, A. U., Massis, L. M., Vijayan, V., Gera, K., Monack, D., Cornell, T. T., Hall, M. W., Mochly-Rosen, D., Haileselassie, B. 1800

  Abstract

  OBJECTIVES: Recent publications have shown that mitochondrial dynamics can govern the quality and quantity of extracellular mitochondria subsequently impacting immune phenotypes. This study aims to determine if pathologic mitochondrial fission mediated by Drp1/Fis1 interaction impacts extracellular mitochondrial content and macrophage function in sepsis-induced immunoparalysis.DESIGN: Laboratory investigation.SETTING: University laboratory.SUBJECTS: C57BL/6 and BALB/C mice.INTERVENTIONS: Using in vitro and murine models of endotoxin tolerance (ET), we evaluated changes in Drp1/Fis1-dependent pathologic fission and simultaneously measured the quantity and quality of extracellular mitochondria. Next, by priming mouse macrophages with isolated healthy mitochondria (MC) and damaged mitochondria, we determined if damaged extracellular mitochondria are capable of inducing tolerance to subsequent endotoxin challenge. Finally, we determined if inhibition of Drp1/Fis1-mediated pathologic fission abrogates release of damaged extracellular mitochondria and improves macrophage response to subsequent endotoxin challenge.MEASUREMENTS AND MAIN RESULTS: When compared with naive macrophages (NMs), endotoxin-tolerant macrophages (ETM) demonstrated Drp1/Fis1-dependent mitochondrial dysfunction and higher levels of damaged extracellular mitochondria (Mitotracker-Green + events/50 muL: ETM = 2.42 * 106 ± 4,391 vs NM = 5.69 * 105 ± 2,478; p < 0.001). Exposure of NMs to damaged extracellular mitochondria (MH) induced cross-tolerance to subsequent endotoxin challenge, whereas MC had minimal effect (tumor necrosis factor [TNF]-alpha [pg/mL]: NM = 668 ± 3, NM + MH = 221 ± 15, and NM + Mc = 881 ± 15; p < 0.0001). Inhibiting Drp1/Fis1-dependent mitochondrial fission using heptapeptide (P110), a selective inhibitor of Drp1/Fis1 interaction, improved extracellular mitochondrial function (extracellular mitochondrial membrane potential, JC-1 [R/G] ETM = 7 ± 0.5 vs ETM + P110 = 19 ± 2.0; p < 0.001) and subsequently improved immune response in ETMs (TNF-alpha [pg/mL]; ETM = 149 ± 1 vs ETM + P110 = 1,150 ± 4; p < 0.0001). Similarly, P110-treated endotoxin tolerant mice had lower amounts of damaged extracellular mitochondria in plasma (represented by higher extracellular mitochondrial membrane potential, TMRM/MT-G: endotoxin tolerant [ET] = 0.04 ± 0.02 vs ET + P110 = 0.21 ± 0.02; p = 0.03) and improved immune response to subsequent endotoxin treatment as well as cecal ligation and puncture.CONCLUSIONS: Inhibition of Drp1/Fis1-dependent mitochondrial fragmentation improved macrophage function and immune response in both in vitro and in vivo models of ET. This benefit is mediated, at least in part, by decreasing the release of damaged extracellular mitochondria, which contributes to endotoxin cross-tolerance. Altogether, these data suggest that alterations in mitochondrial dynamics may play an important role in sepsis-induced immunoparalysis.

  View details for DOI 10.1097/CCM.0000000000005437

  View details for PubMedID 35067534

• Pediatric Organ Dysfunction Information Update Mandate (PODIUM) Contemporary Organ Dysfunction Criteria: Executive Summary. Pediatrics Bembea, M. M., Agus, M., Akcan-Arikan, A., Alexander, P., Basu, R., Bennett, T. D., Bohn, D., Brandao, L. R., Brown, A., Carcillo, J. A., Checchia, P., Cholette, J., Cheifetz, I. M., Cornell, T., Doctor, A., Eckerle, M., Erickson, S., Farris, R. W., Faustino, E. V., Fitzgerald, J. C., Fuhrman, D. Y., Giuliano, J. S., Guilliams, K., Gaies, M., Gorga, S. M., Hall, M., Hanson, S. J., Hartman, M., Hassinger, A. B., Irving, S. Y., Jeffries, H., Jouvet, P., Kannan, S., Karam, O., Khemani, R. G., Kissoon, N., Lacroix, J., Laussen, P., Leclerc, F., Lee, J. H., Leteurtre, S., Lobner, K., McKiernan, P. J., Menon, K., Monagle, P., Muszynski, J. A., Odetola, F., Parker, R., Pathan, N., Pierce, R. W., Pineda, J., Prince, J. M., Robinson, K. A., Rowan, C. M., Ryerson, L. M., Sanchez-Pinto, L. N., Schlapbach, L. J., Selewski, D. T., Shekerdemian, L. S., Simon, D., Smith, L. S., Squires, J. E., Squires, R. H., Sutherland, S. M., Ouellette, Y., Spaeder, M. C., Srinivasan, V., Steiner, M. E., Tasker, R. C., Thiagarajan, R., Thomas, N., Tissieres, P., Traube, C., Tucci, M., Typpo, K. V., Wainwright, M. S., Ward, S. L., Watson, R. S., Weiss, S., Whitney, J., Willson, D., Wynn, J. L., Yeyha, N., Zimmerman, J. J. 1800; 149 (Supplement_1): S1-S12

  Abstract

  Prior criteria for organ dysfunction in critically ill children were based mainly on expert opinion. We convened the Pediatric Organ Dysfunction Information Update Mandate (PODIUM) expert panel to summarize data characterizing single and multiple organ dysfunction and to derive contemporary criteria for pediatric organ dysfunction. The panel was composed of 88 members representing 47 institutions and 7 countries. We conducted systematic reviews of the literature to derive evidence-based criteria for single organ dysfunction for neurologic, cardiovascular, respiratory, gastrointestinal, acute liver, renal, hematologic, coagulation, endocrine, endothelial, and immune system dysfunction. We searched PubMed and Embase from January 1992 to January 2020. Study identification was accomplished using a combination of medical subject headings terms and keywords related to concepts of pediatric organ dysfunction. Electronic searches were performed by medical librarians. Studies were eligible for inclusion if the authors reported original data collected in critically ill children; evaluated performance characteristics of scoring tools or clinical assessments for organ dysfunction; and assessed a patient-centered, clinically meaningful outcome. Data were abstracted from each included study into an electronic data extraction form. Risk of bias was assessed using the Quality in Prognosis Studies tool. Consensus was achieved for a final set of 43 criteria for pediatric organ dysfunction through iterative voting and discussion. Although the PODIUM criteria for organ dysfunction were limited by available evidence and will require validation, they provide a contemporary foundation for researchers to identify and study single and multiple organ dysfunction in critically ill children.

  View details for DOI 10.1542/peds.2021-052888B

  View details for PubMedID 34970673

• FACTORS ASSOCIATED WITH PROLONGED DISCHARGE DELAYS IN A PEDIATRIC ICU Ostberg, N., Winter, S., Ling, J., Cornell, T., Scheinker, D. LIPPINCOTT WILLIAMS & WILKINS. 2022: 158

  View details for Web of Science ID 000777939300308

• PATHOGENIC AND POTENTIALLY PATHOGENIC INBORN ERRORS OF IMMUNITY VARIANTS IN PEDIATRIC SEVERE SEPSIS Kernan, K., Ghaloul-Gonzalez, L., Vockley, J., Lamb, J., Hollingshead, D., Sethi, R., Park, H., Carcillo, J., Berg, R., Wessel, D., Pollack, M., Meert, K., Hall, M., Newth, C., Lin, J., Doctor, A., Shanley, T., Cornell, T., Harrison, R., Collaborative Pediatric Critical LIPPINCOTT WILLIAMS & WILKINS. 2022: 723

  View details for Web of Science ID 000777939301674

• Immune System Dysfunction Criteria in Critically Ill Children: The PODIUM Consensus Conference. Pediatrics Hall, M. W., Carcillo, J. A., Cornell, T. 1800; 149 (Supplement_1): S91-S98

  Abstract

  CONTEXT: Immune system dysfunction is poorly represented in pediatric organ dysfunction definitions.OBJECTIVE: To evaluate evidence for criteria that define immune system dysfunction in critically ill children and associations with adverse outcomes and develop consensus criteria for the diagnosis of immune system dysfunction in critically ill children.DATA SOURCES: We conducted electronic searches of PubMed and Embase from January 1992 to January 2020, using medical subject heading terms and text words to define immune system dysfunction and outcomes of interest.STUDY SELECTION: Studies of critically ill children with an abnormality in leukocyte numbers or function that is currently measurable in the clinical laboratory in which researchers assessed patient-centered outcomes were included. Studies of adults or premature infants, animal studies, reviews and commentaries, case series (≤10 subjects), and studies not published in English with inability to determine eligibility criteria were excluded.DATA EXTRACTION: Data were abstracted from eligible studies into a standard data extraction form along with risk of bias assessment by a task force member.RESULTS: We identified the following criteria for immune system dysfunction: (1) peripheral absolute neutrophil count <500 cells/muL, (2) peripheral absolute lymphocyte count <1000 cells/muL, (3) reduction in CD4+ lymphocyte count or percentage of total lymphocytes below age-specific thresholds, (4) monocyte HLA-DR expression <30%, or (5) reduction in ex vivo whole blood lipopolysaccharide-induced TNFalpha production capacity below manufacturer-provided thresholds.LIMITATIONS: Many measures of immune system function are currently limited to the research environment.CONCLUSIONS: We present consensus criteria for the diagnosis of immune system dysfunction in critically ill children.

  View details for DOI 10.1542/peds.2021-052888N

  View details for PubMedID 34970674

• GD2 CAR T cells mediate clinical activity and manageable toxicity in children and young adults with DIPG and H3K27M-mutated diffuse midline gliomas. Majzner, R. G., Ramakrishna, S., Mochizuki, A., Patel, S., Chinnasamy, H., Yeom, K., Schultz, L., Richards, R., Campen, C., Reschke, A., Mahdi, J., Toland, A., Baggott, C., Mavroukakis, S., Egeler, E., Moon, J., Landrum, K., Erickson, C., Rasmussen, L., Barsan, V., Tamaresis, J. S., Marcy, A., Kunicki, M., Fujimoto, M., Ehlinger, Z., Kurra, S., Cornell, T., Partap, S., Fisher, P., Grant, G., Vogel, H., Sahaf, B., Davis, K., Feldman, S., Mackall, C. L., Monje, M. AMER ASSOC CANCER RESEARCH. 2021

  View details for Web of Science ID 000680263501014

• SINGLE CELL RNA SEQUENCING FROM THE CSF OF SUBJECTS WITH H3K27M+DIPG/DMG TREATED WITH GD2 CAR T-CELLULAR THERAPY Mochizuki, A., Ramakrishna, S., Good, Z., Patel, S., Chinnasamy, H., Yeom, K., Schultz, L., Richards, R., Campen, C., Reschke, A., Mahdi, J., Toland, A., Baggot, C., Mavroukakis, S., Egeler, E., Moon, J., Landrum, K., Erickson, C., Rasmussen, L., Barsan, V., Tamaresis, J., Marcy, A., Kunicki, M., Celones, M., Ehlinger, Z., Kurra, S., Cornell, T., Partap, S., Fisher, P., Grant, G., Vogel, H., Davis, K., Feldman, S., Sahaf, B., Majzner, R., Mackall, C., Monje, M. OXFORD UNIV PRESS INC. 2021: 39

  View details for DOI 10.1093/neuonc/noab090.158

  View details for Web of Science ID 000671540600159

• GD2 CAR T-CELLS MEDIATE CLINICAL ACTIVITY AND MANAGEABLE TOXICITY IN CHILDREN AND YOUNG ADULTS WITH H3K27M-MUTATED DIPG AND SPINAL CORD DMG Majzner, R., Ramakrishna, S., Mochizuki, A., Patel, S., Chinnasamy, H., Yeom, K., Schultz, L., Richards, R., Campen, C., Reschke, A., Mahdi, J., Martin, A., Toland, S., Baggott, C., Mavroukakis, S., Egeler, E., Moon, J., Landrum, K., Erickson, C., Rasmussen, L., Barsan, V., Tamaresis, J., Marcy, A., Kunicki, M., Fujimoto, M., Ehlinger, Z., Kurra, S., Cornell, T., Partap, S., Fisher, P., Grant, G., Vogel, H., Sahaf, B., Davis, K., Feldman, S., Mackall, C., Monje, M. OXFORD UNIV PRESS INC. 2021: 49-50

  View details for DOI 10.1093/neuonc/noab090.200

  View details for Web of Science ID 000671540600201

• Quantifying Pediatric Intensive Care Unit Staffing Levels at a Pediatric Academic Medical Center: A Mixed Methods Approach. Journal of nursing management Ostberg, N., Ling, J., Winter, S. G., Som, S., Vasilakis, C., Shin, A. Y., Cornell, T. T., Scheinker, D. 2021

  Abstract

  AIM: Identify, simulate, and evaluate the formal and informal patient-level and unit-level factors that nurse managers use to determine the number of nurses for each shift.BACKGROUND: Nurse staffing schedules are commonly set based on metrics such as midnight census that do not account for seasonality or midday turnover, resulting in last-minute adjustments or inappropriate staffing levels.METHODS: Staffing schedules at a pediatric intensive care unit (PICU) were simulated based on nurse-to-patient assignment rules from interviews with nursing management. Multivariate regression modeled the discrepancies between scheduled and historical staffing levels and constructed rules to reduce these discrepancies. The primary outcome was the median difference between simulated and historical staffing levels.RESULTS: Nurse-to-patient ratios underestimated staffing by a median of 1.5 nurses per shift. Multivariate regression identified patient turnover as the primary factor accounting for this difference and subgroup analysis revealed that patient age and weight were also important. New rules reduced the difference to a median of 0.07 nurses per shift.CONCLUSION: Measurable, predictable indicators of patient acuity and historical trends may allow for schedules that better match demand.IMPLICATIONS FOR NURSING MANAGEMENT: Data-driven methods can quantify what drives unit demand and generate nurse schedules that require fewer last-minute adjustments.

  View details for DOI 10.1111/jonm.13346

  View details for PubMedID 33894027

• Acute kidney injury after in-hospital cardiac arrest. Resuscitation Mah, K. E., Alten, J. A., Cornell, T. T., Selewski, D. T., Askenazi, D. n., Fitzgerald, J. C., Topjian, A. n., Page, K. n., Holubkov, R. n., Slomine, B. S., Christensen, J. R., Dean, J. M., Moler, F. W. 2021

  Abstract

  Determine 1) frequency and risk factors for acute kidney injury (AKI) after in-hospital cardiac arrest (IHCA) in the Therapeutic Hypothermia after Pediatric Cardiac Arrest In-Hospital (THAPCA-IH) trial and associated outcomes; 2) impact of temperature management on post-IHCA AKI.Secondary analysis of THAPCA-IH; a randomized controlled multi-national trial at 37 children's hospitals.Serum creatinine (Cr) within 24 h of randomization.Prevalence of severe AKI defined by Stage 2 or 3 Kidney Disease Improving Global Outcomes Cr criteria. 12-month survival with favorable neurobehavioral outcome. Analyses stratified by entire cohort and cardiac subgroup. Risk factors and outcomes compared among cohorts with and without severe AKI.Subject randomization: 159 to hypothermia, 154 to normothermia. Overall, 80% (249) developed AKI (any stage), and 66% (207) developed severe AKI. Cardiac patients (204, 65%) were more likely to develop severe AKI (72% vs 56%,p = 0.006). Preexisting cardiac or renal conditions, baseline lactate, vasoactive support, and systolic blood pressure were associated with severe AKI. Comparing hypothermia versus normothermia, there were no differences in severe AKI rate (63% vs 70%,p = 0.23), peak Cr, time to peak Cr, or freedom from mortality or severe AKI (p = 0.14). Severe AKI was associated with decreased hospital survival (48% vs 65%,p = 0.006) and decreased 12-month survival with favorable neurobehavioral outcome (30% vs 53%,p < 0.001).Severe post-IHCA AKI occurred frequently especially in those with preexisting cardiac or renal conditions and peri-arrest hemodynamic instability. Severe AKI was associated with decreased survival with favorable neurobehavioral outcome. Hypothermia did not decrease incidence of severe AKI post-IHCA.

  View details for DOI 10.1016/j.resuscitation.2020.12.023

  View details for PubMedID 33450335

• THE PEDIATRIC ICU DATA COLLABORATIVE Bennett, T., Flynn, A., Sanchez-Pinto, L., Farris, R., Kennedy, C., Cornell, T., Dziorny, A., Nishisaki, A., Shah, S., Horvat, C., Wetzel, R. LIPPINCOTT WILLIAMS & WILKINS. 2021: 262

  View details for Web of Science ID 000672597101118

• Clinician Accuracy in Identifying and Predicting Organ Dysfunction in Critically Ill Children. Critical care medicine Carlton, E. F., Close, J., Paice, K., Dews, A., Gorga, S. M., Sturza, J., Barbaro, R. P., Cornell, T. T., Prescott, H. C. 2020

  Abstract

  OBJECTIVES: To determine clinician accuracy in the identification and prediction of multiple organ dysfunction syndrome.DESIGN: Prospective cohort study.SETTING: University of Michigan's C.S. Mott Children's Hospital PICU.PATIENTS: Patients admitted to the PICU with an anticipated PICU length of stay greater than 48 hours.INTERVENTIONS: None.MEASUREMENTS AND MAIN RESULTS: For each patient, the clinical team (attending, fellow, resident/nurse practitioner) was surveyed regarding existing and anticipated organ dysfunction. The primary outcomes were clinicians' accuracy at identifying multiple organ dysfunction syndrome and predicting new or progressive multiple organ dysfunction syndrome, compared to the objective assessment of multiple organ dysfunction syndrome using Proulx criteria. We also measured sensitivity, specificity, negative and positive predictive values, and negative and positive likelihood ratios of clinician assessments. We tested for differences in accuracy by clinician type using chi-square tests. Clinicians rated their confidence in prediction on a 5-point Likert scale. There were 476 eligible PICU admissions, for whom 1,218 surveys were completed. Multiple organ dysfunction syndrome was present in 89 patients (18.7%) at enrollment, and new or progressive multiple organ dysfunction syndrome occurred in 39 (8.2%). Clinicians correctly identified multiple organ dysfunction syndrome with 79.9% accuracy and predicted additional organ dysfunction with 82.6% accuracy. However, the positive and negative likelihood ratios for new or progressive multiple organ dysfunction syndrome prediction were 3.0 and 0.7, respectively, indicating a weak relationship between the clinician prediction and development of new or progressive multiple organ dysfunction syndrome. The positive predictive value of new or progressive multiple organ dysfunction syndrome prediction was just 22.1%. We found no differences in accuracy by clinician type for either identification of multiple organ dysfunction syndrome (80.2% vs 78.2% vs 81.0%; p = 0.57) or prediction of new or progressive multiple organ dysfunction syndrome (84.8% vs 82.8% vs 80.3%; p = 0.26) for attendings, fellows, and residents/nurse practitioners, respectively. There was a weak correlation between the confidence and accuracy of prediction (pairwise correlation coefficient, 0.26; p < 0.001).CONCLUSIONS: PICU clinicians correctly identified multiple organ dysfunction syndrome and predicted new or progressive multiple organ dysfunction syndrome with 80% accuracy. However, only 8% of patients developed new or progressive multiple organ dysfunction syndrome, so accuracy was largely due to true negative predictions. The positive predictive value for new or progressive multiple organ dysfunction syndrome prediction was just 22%. Accuracy did not differ by clinician type, but was correlated with self-rated confidence and was higher for negative predictions.

  View details for DOI 10.1097/CCM.0000000000004555

  View details for PubMedID 32804793

• New Medical Device Acquisition During Pediatric Severe Sepsis Hospitalizations. Critical care medicine Carlton, E. F., Donnelly, J. P., Hensley, M. K., Cornell, T. T., Prescott, H. C. 2020

  Abstract

  Severe sepsis is a significant cause of healthcare utilization and morbidity among pediatric patients. However, little is known about how commonly survivors acquire new medical devices during pediatric severe sepsis hospitalization. We sought to determine the rate of new device acquisition (specifically, tracheostomy placement, gastrostomy tube placement, vascular access devices, ostomy procedures, and amputation) among children surviving hospitalizations with severe sepsis. For contextualization, we compare this to rates of new device acquisition among three comparison cohorts: 1) survivors of all-cause pediatric hospitalizations; 2) matched survivors of nonsepsis infection hospitalizations; and 3) matched survivors of all-cause nonsepsis hospitalization with similar organ dysfunction.Observational cohort study.Nationwide Readmission Database (2016), including all-payer hospitalizations from 27 states.Eighteen-thousand two-hundred ten pediatric severe sepsis hospitalizations; 532,738 all-cause pediatric hospitalizations; 16,173 age- and sex-matched nonsepsis infection hospitalizations; 15,025 organ dysfunction matched all-cause nonsepsis hospitalizations; and all with live discharge.Among 18,210 pediatric severe sepsis hospitalizations, 1,024 (5.6%) underwent device placement. Specifically, 3.5% had new gastrostomy, 3.1% new tracheostomy, 0.6% new vascular access devices, 0.4% new ostomy procedures, and 0.1% amputations. One-hundred forty hospitalizations (0.8%) included two or more new devices. After applying the Nationwide Readmissions Database sampling weights, there were 55,624 pediatric severe sepsis hospitalizations and 1,585,194 all-cause nonsepsis hospitalizations with live discharge in 2016. Compared to all-cause pediatric hospitalizations, severe sepsis hospitalizations were eight-fold more likely to involve new device acquisition (6.4% vs 0.8%; p < 0.001). New device acquisition was also higher in severe sepsis hospitalizations compared with matched nonsepsis infection hospitalizations (5.1% vs 1.2%; p < 0.01) and matched all-cause hospitalizations with similar organ dysfunction (4.7% vs 2.8%; p < 0.001).In this nationwide, all-payer cohort of U.S. pediatric severe sepsis hospitalizations, one in 20 children surviving severe sepsis experienced new device acquisition. The procedure rate was nearly eight-fold higher than all-cause, nonsepsis pediatric hospitalizations, and four-fold higher than matched nonsepsis infection hospitalizations.

  View details for DOI 10.1097/CCM.0000000000004272

  View details for PubMedID 32108704

• Cardiac Dysfunction Identified by Strain Echocardiography Is Associated With Illness Severity in Pediatric Sepsis. Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies Patel, M. D., Mariano, K. n., Dunbar, T. n., Cornell, T. T., Punn, R. n., Haileselassie, B. n. 2020

  Abstract

  Sepsis-induced myocardial dysfunction has been associated with illness severity and mortality in pediatrics. Although early sepsis-induced myocardial dysfunction diagnosis could aid in hemodynamic management, current echocardiographic metrics for assessing biventricular function are limited in detecting early impairment. Strain echocardiography is a validated quantitative measure that can detect subtle perturbations in left ventricular and right ventricular function. This investigation evaluates the utility of strain echocardiography in pediatric sepsis and compares with to conventional methods.Retrospective, observational study comparing left ventricular and right ventricular strain. Strain was compared with ejection fraction and fractional shortening and established sepsis severity of illness markers.Tertiary care medical-surgical PICU from July 2013 to January 2018.Seventy-nine septic children and 28 healthy controls.None.Compared with healthy controls, patients with severe sepsis demonstrated abnormal left ventricular strain (left ventricular longitudinal strain: -13.0% ± 0.72; p = 0.04 and left ventricular circumferential strain: -16.5% ± 0.99; p = 0.046) and right ventricular (right ventricular longitudinal strain = -14.3% ± 6.3; p < 0.01) despite normal fractional shortening (36.0% ± 1.6 vs 38.1% ± 1.1; p = 0.5129) and ejection fraction (60.7% ± 2.2 vs 65.3% ± 1.5; p = 0.33). There was significant association between depressed left ventricular longitudinal strain and increased Vasotrope-Inotrope Score (r = 0.52; p = 0.034). Worsening left ventricular circumferential strain was correlated with higher lactate (r = 0.31; p = 0.03) and higher Pediatric Risk of Mortality-III score (r = 0.39; p < 0.01). Depressed right ventricular longitudinal strain was associated with elevated pediatric multiple organ dysfunction score (r = 0.44; p < 0.01) CONCLUSIONS:: Compared with healthy children, pediatric septic patients demonstrated abnormal left ventricular and right ventricular strain concerning for early signs of cardiac dysfunction. This was despite having normal ejection fraction and fractional shortening. Abnormal strain was associated with abnormal severity of illness markers. Strain echocardiography may have utility as an early indicator of sepsis-induced myocardial dysfunction in pediatric sepsis.

  View details for DOI 10.1097/PCC.0000000000002247

  View details for PubMedID 32084099

• Characteristics of Pediatric Extracorporeal Membrane Oxygenation Programs in the United States and Canada. ASAIO journal (American Society for Artificial Internal Organs : 1992) Troy, L. n., Su, F. n., Kilbaugh, T. n., Rasmussen, L. n., Kuo, T. n., Jett, E. n., Cornell, T. n., Berg, M. n., Haileselassie, B. n. 2020

  Abstract

  The aim of this study was to evaluate the current infrastructure and practice characteristics of pediatric extracorporeal membrane oxygenation (ECMO) programs. A 40-question survey of center-specific demographics, practice structure, program experience, and support network utilized to cannulate and maintain a pediatric patient on ECMO was designed via a web-based survey tool. The survey was distributed to pediatric ECMO programs in the United States and Canada. Of the 101 centers that were identified to participate, 41 completed the survey. The majority of responding centers are university affiliated (73%) and have an intensive care unit (ICU) with 15-25 beds (58%). Extracorporeal membrane oxygenation has been offered for >10 years in 85% of the centers. The median number of total cannulations per center in 2017 was 15 (interquartile range [IQR] = 5-30), with the majority occurring in the cardiovascular intensive care unit (median = 13, IQR = 5-25). Fifty-seven percent of responding centers offer ECPR, with a median number of four cases per year (IQR = 2-7). Most centers cannulate in an operating room or ICU; 11 centers can cannulate in the pediatric ED. Sixty-three percent of centers have standardized protocols for postcannulation management. The majority of protocols guide anticoagulation, sedation, or ventilator management; left ventricle decompression and reperfusion catheter placement are the least standardized procedures. The majority of pediatric ECMO centers have adopted the infrastructure recommendations from the Extracorporeal Life Support Organization. However, there remains broad variability of practice characteristics and organizational infrastructure for pediatric ECMO centers across the United States and Canada.

  View details for DOI 10.1097/MAT.0000000000001311

  View details for PubMedID 33181543

• The American College of Critical Care Medicine Clinical Practice Parameters for Hemodynamic Support of Pediatric and Neonatal Septic Shock: Executive Summary PEDIATRIC CRITICAL CARE MEDICINE Davis, A. L., Carcillo, J. A., Aneja, R. K., Deymann, A. J., Lin, J. C., Nguyen, T. C., Okhuysen-Cawley, R. S., Relvas, M. S., Rozenfeld, R. A., Skippen, P. W., Stojadinovic, B. J., Williams, E. A., Yeh, T. S., Balamuth, F., Brierley, J., de Caen, A. R., Cheifetz, I. M., Choong, K., Conway, E., Cornell, T., Doctor, A., Dugas, M., Feldman, J. D., Fitzgerald, J. C., Flori, H. R., Fortenberry, J. D., Graciano, A., Greenwald, B. M., Hall, M. W., Han, Y., Hernan, L. J., Irazuzta, J. E., Iselin, E., van der Jagt, E. W., Jeffries, H. E., Kache, S., Katyal, C., Kissoon, N., Kon, A. A., Kutko, M. C., MacLaren, G., Maul, T., Mehta, R., Odetola, F., Parbuoni, K., Paul, R., Peters, M. J., Ranjit, S., Reuter-Rice, K. E., Schnitzler, E. J., Scott, H. F., Torres, A., Weingarten-Abrams, J., Weiss, S. L., Zimmerman, J. J., Zuckerberg, A. L. 2017; 18 (9): 884–90

  View details for PubMedID 28723883

• American College of Critical Care Medicine Clinical Practice Parameters for Hemodynamic Support of Pediatric and Neonatal Septic Shock CRITICAL CARE MEDICINE Davis, A. L., Carcillo, J. A., Aneja, R. K., Deymann, A. J., Lin, J. C., Nguyen, T. C., Okhuysen-Cawley, R. S., Relvas, M. S., Rozenfeld, R. A., Skippen, P. W., Stojadinovic, B. T., Williams, E. A., Yeh, T. S., Balamuth, F., Brierley, J., de Caen, A. R., Cheifetz, I. M., Choong, K., Conway, E., Cornell, T., Doctor, A., Dugas, M., Feldman, J. D., Fitzgerald, J. C., Flori, H. R., Fortenberry, J. D., Graciano, A. L., Greenwald, B. M., Hall, M. W., Han, Y. Y., Hernan, L. J., Irazurta, J. E., Iselin, E., van der Jagt, E. W., Jeffries, H. E., Kache, S., Katyal, C., Kissoon, N. T., Kon, A. A., Kutko, M. C., MacLaren, G., Maul, T., Mehta, R., Odetola, F., Parbuoni, K., Paul, R., Peters, M. J., Ranjit, S., Reuter-Rice, K. E., Schnitzler, E. J., Scott, H. F., Torres, A., Weingarten-Abrams, J., Weiss, S. L., Zimmerman, J. J., Zuckerberg, A. L. 2017; 45 (6): 1061-1093

  Abstract

  The American College of Critical Care Medicine provided 2002 and 2007 guidelines for hemodynamic support of newborn and pediatric septic shock. Provide the 2014 update of the 2007 American College of Critical Care Medicine "Clinical Guidelines for Hemodynamic Support of Neonates and Children with Septic Shock."Society of Critical Care Medicine members were identified from general solicitation at Society of Critical Care Medicine Educational and Scientific Symposia (2006-2014). The PubMed/Medline/Embase literature (2006-14) was searched by the Society of Critical Care Medicine librarian using the keywords: sepsis, septicemia, septic shock, endotoxemia, persistent pulmonary hypertension, nitric oxide, extracorporeal membrane oxygenation, and American College of Critical Care Medicine guidelines in the newborn and pediatric age groups.The 2002 and 2007 guidelines were widely disseminated, translated into Spanish and Portuguese, and incorporated into Society of Critical Care Medicine and American Heart Association/Pediatric Advanced Life Support sanctioned recommendations. The review of new literature highlights two tertiary pediatric centers that implemented quality improvement initiatives to improve early septic shock recognition and first-hour compliance to these guidelines. Improved compliance reduced hospital mortality from 4% to 2%. Analysis of Global Sepsis Initiative data in resource rich developed and developing nations further showed improved hospital mortality with compliance to first-hour and stabilization guideline recommendations.The major new recommendation in the 2014 update is consideration of institution-specific use of 1) a "recognition bundle" containing a trigger tool for rapid identification of patients with septic shock, 2) a "resuscitation and stabilization bundle" to help adherence to best practice principles, and 3) a "performance bundle" to identify and overcome perceived barriers to the pursuit of best practice principles.

  View details for DOI 10.1097/CCM.0000000000002425

  View details for PubMedID 28509730