Pre-existing Immunocompromising Conditions and Outcomes of Acute COVID-19 Patients Admitted for Pediatric Intensive Care.

BACKGROUND: We aimed to determine if pre-existing immunocompromising conditions (ICCs) were associated with the presentation or outcome of patients with acute coronavirus disease 2019 (COVID-19) admitted for pediatric intensive care. METHODS: 55 hospitals in 30 U.S. states reported cases through the Overcoming COVID-19 public health surveillance registry. Patients <21 years admitted March 12, 2020-December 30, 2021 to the pediatric intensive care unit (PICU) or high acuity unit for acute COVID-19 were included. RESULTS: Of 1,274 patients, 105 (8.2%) had an ICC including 33 (31.4%) hematologic malignancies, 24 (22.9%) primary immunodeficiencies and disorders of hematopoietic cells, 19 (18.1%) nonmalignant organ failure with solid organ transplantation, 16 (15.2%) solid tumors and 13 (12.4%) autoimmune disorders. Patients with ICCs were older, had more underlying renal conditions, and had lower white blood cell and platelet counts than those without ICCs, but had similar clinical disease severity upon admission. In-hospital mortality from COVID-19 was higher (11.4% vs. 4.6%, p = 0.005) and hospitalization was longer (p = 0.01) in patients with ICCs. New major morbidities upon discharge were not different between those with and without ICC (10.5% vs 13.9%, p = 0.40). In patients with ICC, bacterial co-infection was more common in those with life-threatening COVID-19. CONCLUSIONS: In this national case series of patients <21 years of age with acute COVID-19 admitted for intensive care, existence of a prior ICCs were associated with worse clinical outcomes. Reassuringly, most patients with ICCs hospitalized in the PICU for severe acute COVID-19 survived and were discharged home without new severe morbidities.

Ataxia-Telangiectasia Mutated Loss-of-Function Displays Variant and Tissue-Specific Differences across Tumor Types.

PURPOSE: Mutations in the ATM gene are common in multiple cancers, but clinical studies of therapies targeting ATM-aberrant cancers have yielded mixed results. Refinement of ATM loss of function (LOF) as a predictive biomarker of response is urgently needed. EXPERIMENTAL DESIGN: We present the first disclosure and preclinical development of a novel, selective ATR inhibitor, ART0380, and test its antitumor activity in multiple preclinical cancer models. To refine ATM LOF as a predictive biomarker, we performed a comprehensive pan-cancer analysis of ATM variants in patient tumors and then assessed the ATM variant-to-protein relationship. Finally, we assessed a novel ATM LOF biomarker approach in retrospective clinical data sets of patients treated with platinum-based chemotherapy or ATR inhibition. RESULTS: ART0380 had potent, selective antitumor activity in a range of preclinical cancer models with differing degrees of ATM LOF. Pan-cancer analysis identified 10,609 ATM variants in 8,587 patient tumors. Cancer lineage-specific differences were seen in the prevalence of deleterious (Tier 1) versus unknown/benign (Tier 2) variants, selective pressure for loss of heterozygosity, and concordance between a deleterious variant and ATM loss of protein (LOP). A novel ATM LOF biomarker approach that accounts for variant classification, relationship to ATM LOP, and tissue-specific penetrance significantly enriched for patients who benefited from platinum-based chemotherapy or ATR inhibition. CONCLUSIONS: These data help to better define ATM LOF across tumor types in order to optimize patient selection and improve molecularly targeted therapeutic approaches for patients with ATM LOF cancers.

Screening for pediatric abusive head trauma: Are three variables enough?

BACKGROUND: The PediBIRN 4-variable clinical decision rule (CDR) detects abusive head trauma (AHT) with 96% sensitivity in pediatric intensive care (PICU) settings. Preliminary analysis of its performance in Pediatric Emergency Department settings found that elimination of its fourth predictor variable enhanced screening accuracy. OBJECTIVE: To compare the AHT screening performances of the "PediBIRN-4" CDR vs. the simplified 3-variable CDR in PICU settings. PARTICIPANTS AND SETTINGS: 973 acutely head-injured children <3 years hospitalized for intensive care across 18 sites between February 2011 and March 2021. METHODS: Retrospective, secondary analysis of the combined, prospective PediBIRN data sets. AHT definitional criteria and physicians' diagnoses were applied iteratively to sort patients into abusive vs. other head trauma cohorts. Outcome measures of CDR performance included sensitivity, specificity, predictive values, likelihood ratios, ROC AUC, and the correlation between each CDR's patient-specific estimates of AHT probability and the overall positive yield of patients' completed abuse evaluations. RESULTS: Applied accurately and consistently, both CDR's would have performed with sensitivity ≥93% and negative predictive value ≥91%. Eliminating the PediBIRN-4's fourth predictor variable resulted in significantly higher specificity (↑'d ≥19%), positive predictive value (↑'d ≥8%), and ROC AUC (↑'d ≥5%), but a 3% reduction in sensitivity. Both CDRs provided patient-specific estimates of abuse probability very strongly correlated with the positive yield of patients' completed abuse evaluations (Pearson's r = 0.95 and 0.91, p = .13). CONCLUSION: The PediBIRN 3-variable CDR performed with greater AHT screening accuracy than the 4-variable CDR. Both are good predictors of the results of patients' subsequent completed abuse evaluations.

Discovery of 6-[(3S,4S)-4-Amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-3-(2,3-dichlorophenyl)-2-methyl-3,4-dihydropyrimidin-4-one (IACS-15414), a Potent and Orally Bioavailable SHP2 Inhibitor.

Src homology 2 (SH2) domain-containing phosphatase 2 (SHP2) plays a role in receptor tyrosine kinase (RTK), neurofibromin-1 (NF-1), and Kirsten rat sarcoma virus (KRAS) mutant-driven cancers, as well as in RTK-mediated resistance, making the identification of small-molecule therapeutics that interfere with its function of high interest. Our quest to identify potent, orally bioavailable, and safe SHP2 inhibitors led to the discovery of a promising series of pyrazolopyrimidinones that displayed excellent potency but had a suboptimal in vivo pharmacokinetic (PK) profile. Hypothesis-driven scaffold optimization led us to a series of pyrazolopyrazines with excellent PK properties across species but a narrow human Ether-à-go-go-Related Gene (hERG) window. Subsequent optimization of properties led to the discovery of the pyrimidinone series, in which multiple members possessed excellent potency, optimal in vivo PK across species, and no off-target activities including no hERG liability up to 100 µM. Importantly, compound 30 (IACS-15414) potently suppressed the mitogen-activated protein kinase (MAPK) pathway signaling and tumor growth in RTK-activated and KRASmut xenograft models in vivo.

Mammary-specific expression of Trim24 establishes a mouse model of human metaplastic breast cancer.

Conditional overexpression of histone reader Tripartite motif containing protein 24 (TRIM24) in mouse mammary epithelia (Trim24COE) drives spontaneous development of mammary carcinosarcoma tumors, lacking ER, PR and HER2. Human carcinosarcomas or metaplastic breast cancers (MpBC) are a rare, chemorefractory subclass of triple-negative breast cancers (TNBC). Comparison of Trim24COE metaplastic carcinosarcoma morphology, TRIM24 protein levels and a derived Trim24COE gene signature reveals strong correlation with human MpBC tumors and MpBC patient-derived xenograft (PDX) models. Global and single-cell tumor profiling reveal Met as a direct oncogenic target of TRIM24, leading to aberrant PI3K/mTOR activation. Here, we find that pharmacological inhibition of these pathways in primary Trim24COE tumor cells and TRIM24-PROTAC treatment of MpBC TNBC PDX tumorspheres decreased cellular viability, suggesting potential in therapeutically targeting TRIM24 and its regulated pathways in TRIM24-expressing TNBC.

A Cluster Randomized Trial to Reduce Missed Abusive Head Trauma in Pediatric Intensive Care Settings.

OBJECTIVE: To estimate the impact of the PediBIRN (Pediatric Brain Injury Research Network) 4-variable clinical decision rule (CDR) on abuse evaluations and missed abusive head trauma in pediatric intensive care settings. STUDY DESIGN: This was a cluster randomized trial. Participants included 8 pediatric intensive care units (PICUs) in US academic medical centers; PICU and child abuse physicians; and consecutive patients with acute head injures <3 years (n = 183 and n = 237, intervention vs control). PICUs were stratified by patient volumes, pair-matched, and randomized equally to intervention or control conditions. Randomization was concealed from the biostatistician. Physician-directed, cluster-level interventions included initial and booster training, access to an abusive head trauma probability calculator, and information sessions. Outcomes included "higher risk" patients evaluated thoroughly for abuse (with skeletal survey and retinal examination), potential cases of missed abusive head trauma (patients lacking either evaluation), and estimates of missed abusive head trauma (among potential cases). Group comparisons were performed using generalized linear mixed-effects models. RESULTS: Intervention physicians evaluated a greater proportion of higher risk patients thoroughly (81% vs 73%, P = .11) and had fewer potential cases of missed abusive head trauma (21% vs 32%, P = .05), although estimated cases of missed abusive head trauma did not differ (7% vs 13%, P = .22). From baseline (in previous studies) to trial, the change in higher risk patients evaluated thoroughly (67%→81% vs 78%→73%, P = .01), and potential cases of missed abusive head trauma (40%→21% vs 29%→32%, P = .003), diverged significantly. We did not identify a significant divergence in the number of estimated cases of missed abusive head trauma (15%→7% vs 11%→13%, P = .22). CONCLUSIONS: PediBIRN-4 CDR application facilitated changes in abuse evaluations that reduced potential cases of missed abusive head trauma in PICU settings. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03162354.

Allosteric SHP2 Inhibitor, IACS-13909, Overcomes EGFR-Dependent and EGFR-Independent Resistance Mechanisms toward Osimertinib.

Src homology 2 domain-containing phosphatase (SHP2) is a phosphatase that mediates signaling downstream of multiple receptor tyrosine kinases (RTK) and is required for full activation of the MAPK pathway. SHP2 inhibition has demonstrated tumor growth inhibition in RTK-activated cancers in preclinical studies. The long-term effectiveness of tyrosine kinase inhibitors such as the EGFR inhibitor (EGFRi), osimertinib, in non-small cell lung cancer (NSCLC) is limited by acquired resistance. Multiple clinically identified mechanisms underlie resistance to osimertinib, including mutations in EGFR that preclude drug binding as well as EGFR-independent activation of the MAPK pathway through alternate RTK (RTK-bypass). It has also been noted that frequently a tumor from a single patient harbors more than one resistance mechanism, and the plasticity between multiple resistance mechanisms could restrict the effectiveness of therapies targeting a single node of the oncogenic signaling network. Here, we report the discovery of IACS-13909, a specific and potent allosteric inhibitor of SHP2, that suppresses signaling through the MAPK pathway. IACS-13909 potently impeded proliferation of tumors harboring a broad spectrum of activated RTKs as the oncogenic driver. In EGFR-mutant osimertinib-resistant NSCLC models with EGFR-dependent and EGFR-independent resistance mechanisms, IACS-13909, administered as a single agent or in combination with osimertinib, potently suppressed tumor cell proliferation in vitro and caused tumor regression in vivo. Together, our findings provide preclinical evidence for using a SHP2 inhibitor as a therapeutic strategy in acquired EGFRi-resistant NSCLC. SIGNIFICANCE: These findings highlight the discovery of IACS-13909 as a potent, selective inhibitor of SHP2 with drug-like properties, and targeting SHP2 may serve as a therapeutic strategy to overcome tumor resistance to osimertinib.

Protecting children from iatrogenic harm during COVID19 pandemic.

Critical care management of patients with COVID-19 has been influenced by a mixture of public, media and societal pressure, as well as clinical and anecdotal observations from many prominent researchers and key opinion leaders. These factors may have affected the principles of evidence-based medicine and encouraged the widespread use of non-tested pharmacological and aggressive respiratory support therapies, even in intensive care units (ICUs). The COVID-19 pandemic has predominantly affected adult populations, while children appear to be relatively spared of severe disease. Notwithstanding, paediatric intensive care (PICU) clinicians may already have been influenced by changes in practices of adult ICUs, and these changes may pose unintended consequences to the vulnerable population in the PICU. In this article, we analyse several potential iatrogenic causes of the detrimental effects of the current pandemic to children and highlight the risks underlying a sudden change of clinical practice.

Assessing Frequency of Respiratory Complications in Children Undergoing Adenotonsillectomy.

OBJECTIVES: To determine the frequency of respiratory complications in children admitted to the ICU after adenotonsillectomy and to identify factors associated with the risk of respiratory complications in this cohort. DESIGN: Retrospective observational study. SETTING: PICU. PATIENT POPULATION: All children admitted to the ICU following adenotonsillectomy from September 30, 2009, to March 30, 2014. MEASUREMENTS AND MAIN RESULTS: Of the 165 children included in the study, 150 (91%) received no respiratory support other than oxygen in the first 2 hours postoperatively. Of the 15 who required support following 2 hours, 14 required nasopharyngeal airways, one required invasive mechanical ventilation, and seven required supplemental oxygen for more than 2 hours. None of the children who received respiratory support for less than 2 hours required subsequent ICU level care. When comparing those who received support for more than 2 hours to those who did not, there were no differences in clinical characteristics except that those who received support were more likely to have chronic neurologic disease including autism, seizures, or cerebral palsy (odds ratio, 3.7; 95% CI, 1.1-11.9; p = 0.04). Intraoperative events were not predictive of need for respiratory support. Most of the children (n = 117/165 or 71%) had sleep studies preoperatively. Abnormal sleep studies (apnea-hypopnea index > 20 [n = 68] or oxygen saturation nadir < 80% [n = 48]) were not associated with need for postoperative respiratory support. CONCLUSIONS: Most children admitted to the ICU following adenotonsillectomy in this population required no support after 2 hours. Preoperative factors such as obesity and abnormal sleep studies were not predictive of need for postoperative respiratory support. Need for respiratory support at 2 hours may be a useful criterion for need for ICU level care in this population.

Risk Factors for Delayed Enteral Nutrition in Critically Ill Children.

OBJECTIVE: Delayed enteral nutrition, defined as enteral nutrition started 48 hours or more after admission to the PICU, is associated with an inability to achieve full enteral nutrition and worse outcomes in critically ill children. We reviewed nutritional practices in six medical-surgical PICUs and determined risk factors associated with delayed enteral nutrition in critically ill children. DESIGN: Retrospective cross-sectional study using medical records as source of data. SETTING: Six medical-surgical PICUs in northeastern United States. PATIENTS: Children less than 21 years old admitted to the PICU for 72 hours or more excluding those awaiting or recovering from abdominal surgery. MEASUREMENTS AND MAIN RESULTS: A total of 444 children with a median age of 4.0 years were included in the study. Enteral nutrition was started at a median time of 20 hours after admission to the PICU. There was no significant difference in time to start enteral nutrition among the PICUs. Of those included, 88 children (19.8%) had delayed enteral nutrition. Risk factors associated with delayed enteral nutrition were noninvasive (odds ratio, 3.37; 95% CI, 1.69-6.72) and invasive positive-pressure ventilation (odds ratio, 2.06; 95% CI, 1.15-3.69), severity of illness (odds ratio for every 0.1 increase in pediatric index of mortality 2 score, 1.39; 95% CI, 1.14-1.71), procedures (odds ratio, 3.33; 95% CI, 1.67-6.64), and gastrointestinal disturbances (odds ratio, 2.05; 95% CI, 1.14-3.68) within 48 hours after admission to the PICU. Delayed enteral nutrition was associated with failure to reach full enteral nutrition while in the PICU (odds ratio, 4.09; 95% CI, 1.97-8.53). Nutrition consults were obtained in less than half of the cases, and none of the PICUs used tools to assure the adequacy of energy and protein nutrition. CONCLUSIONS: Institutions in this study initiated enteral nutrition for a high percentage of patients by 48 hours of admission. Noninvasive positive-pressure ventilation was most strongly associated with delay enteral nutrition. A better understanding of these risk factors and assessments of nutritional requirements should be explored in future prospective studies.

Validation of a clinical prediction rule for pediatric abusive head trauma.

BACKGROUND AND OBJECTIVE: To reduce missed cases of pediatric abusive head trauma (AHT), Pediatric Brain Injury Research Network investigators derived a 4-variable AHT clinical prediction rule (CPR) with sensitivity of .96. Our objective was to validate the screening performance of this AHT CPR in a new, equivalent patient population. METHODS: We conducted a prospective, multicenter, observational, cross-sectional study. Applying the same inclusion criteria, definitional criteria for AHT, and methods used in the completed derivation study, Pediatric Brain Injury Research Network investigators captured complete clinical, historical, and radiologic data on 291 acutely head-injured children <3 years of age admitted to PICUs at 14 participating sites, sorted them into comparison groups of abusive and nonabusive head trauma, and measured the screening performance of the AHT CPR. RESULTS: In this new patient population, the 4-variable AHT CPR demonstrated sensitivity of .96, specificity of .46, positive predictive value of .55, negative predictive value of .93, positive likelihood ratio of 1.67, and negative likelihood ratio of 0.09. Secondary analysis revealed that the AHT CPR identified 98% of study patients who were ultimately diagnosed with AHT. CONCLUSIONS: Four readily available variables (acute respiratory compromise before admission; bruising of the torso, ears, or neck; bilateral or interhemispheric subdural hemorrhages or collections; and any skull fractures other than an isolated, unilateral, nondiastatic, linear, parietal fracture) identify AHT with high sensitivity in young, acutely head-injured children admitted to the PICU.

Use of a massive transfusion protocol with hemostatic resuscitation for severe intraoperative bleeding in a child.

Use of a defined massive transfusion (MT) protocol for severe intraoperative bleeding in a pediatric patient has never been described. Herein we present a case whereby use of hemostatic resuscitation delineated in an MT protocol optimally treated hemorrhage resulting from a large tumor during right hepatectomy. The MT protocol principles, benefits, and postoperative course of the patient are described.

Use of dexmedetomidine for sedation of children hospitalized in the intensive care unit.

BACKGROUND: Dexmedetomidine is a potentially useful sedative for hospitalized children, but there is little published data regarding its safety, dosage, or efficacy. OBJECTIVE: To report our experience with dexmedetomidine for the sedation of hospitalized children. DESIGN: Retrospective case series. SETTING: Pediatric ICU of a university-affiliated children's hospital. PATIENTS: We retrospectively examined data from the medical records of all children who received dexmedetomidine for sedation between December 2003 and October 2005. INTERVENTION: None. RESULTS: Dexmedetomidine was administered 74 times to 60 children (median age 1.5 years, range 0.1-17.2 years). The most common indications for ICU admission were respiratory distress/failure (53%), status-postcorrective cardiac surgery (19%), and other postoperative patients (18%). In 53% of cases dexmedetomidine was used to supplement ongoing sedation judged inadequate and in 41% of cases it was used as a bridge to extubation while other sedatives were weaned or discontinued. Among all the children, the median dose to maintain adequate sedation was 0.7 microg/kg per hour (range 0.2-2.5 microg/kg per hour), with a median duration of therapy of 23 hours (range 3-451 hours). Most children (80%) experienced no adverse effects from the sedation, with hypotension (9%), hypertension (8%), and bradycardia (3%) the most common adverse events. For 93% of children who experienced a side effect, it resolved either without treatment or by withholding the infusion. CONCLUSIONS: In this cohort of children hospitalized in the ICU, dexmedetomidine appeared to be effective and to have few adverse effects. Dexmedetomidine may have a potentially useful role to play in sedating hospitalized children.

Inhaled prostacyclin following surgical repair of congenital heart disease--a pilot study.

BACKGROUND: The development of additional therapies for the treatment of pulmonary hypertension would be a significant advancement in the treatment of congenital heart disease. Recently, studies have found inhaled prostacyclin (PGI2) is an effective pulmonary vasodilator, comparable with nitric oxide. In this prospective interventional pilot study, we examined the physiologic effects of inhaled PGI2 in children with congenital heart disease and pulmonary hypertension. METHODS: Six children (median age 6 months, range 5 to 21 months) with congenital heart disease and preoperative pulmonary hypertension (mean pulmonary artery pressure [MPAP] greater than 50% systemic) received a 15-minute course of inhaled PGI2 intraoperatively postrepair. The inhaled PGI2 was delivered by aerosolizing the IV formulation (Flolan, Glaxo-Wellcome) to achieve a dose of 50 ng/kg/min. Physiologic parameters measured during the medication period were compared with measurements taken during two 15-minute baseline periods before and after the medication period. RESULTS: Inhaled PGI2 significantly reduced the mean pulmonary artery pressure from 25 +/- 3 to 21 +/- 3 (p < 0.01) and improved the PaO2/FiO2 ratio from 275 +/- 181 to 433 +/- 285 (p = 0.01). There were no significant changes in systemic blood pressure, heart rate, or cardiac index. CONCLUSIONS: Children with congenital heart disease and pulmonary hypertension may benefit from inhaled PGI2. Inhaled PGI2 reduced pulmonary blood pressures and improved oxygenation in this small study. PGI2 acts through cyclic adenosine monophosphate mediated pulmonary vasodilation, a mechanism different from nitric oxide. In children with inadequate response to nitric oxide, inhaled PGI2 may be a useful alternative pulmonary vasodilator.

Inhaled prostacyclin for term infants with persistent pulmonary hypertension refractory to inhaled nitric oxide.

We report the use of inhaled prostacyclin (PGI(2)) in 4 neonates with persistent pulmonary hypertension and hypoxemia refractory to inhaled nitric oxide. Oxygenation rapidly improved after inhalation of PGI(2) in all infants. The condition of one infant subsequently deteriorated, and alveolar capillary dysplasia was found at autopsy. The surviving infants were discharged with normal oxygen saturations in room air.