Search

Hardware joined the battle against malware by introducing secure boot architectures, malware-aware processors, and trusted platform modules. Hardware performance indicators, power profiles, and side channel information can be leveraged at run-time via machine learning for continuous monitoring and protection. The explainability of these machine learning algorithms may play a crucial role in interpreting their results and avoiding false positives. In this paper, we present an eagle eye on the state of the art of these components: we examine secure architectures and malware-aware processors, such as those implemented in the RISC-V Instruction Set Architecture and Reduced Instruction Set Computer (RISC). We categorize hardware-assisted solutions increased by machine learning for classification. We survey recently proposed software-assisted and hardware-assisted explainability algorithms in our context. In the discussion, we suggest that (1) safe architectures that guarantee secure device boot are a must, (2) Side-channel approaches are challenging to integrate into embedded systems, yet they show promise in terms of efficiency, (3) malware-aware processors provide valuable features for malware detection software, and (4) Without explainability, malware detection software is error-prone and can be easily bypassed.

Corticosterone (CORT) inhibits development during early larval stages, but accelerates development in later stages in Bufo boreas. In contrast, studies from the literature suggest that COPT inhibits development in XENOPUS LAEVIS. We proposed that there is not a species difference in response to CORT, but rather differences in experimental design and the timing of hormone treatments. The current study tested the hypothesis that X. laevis would show similar dual responses to CORT depending on the stages during which they were treated. We initiated COPT treatments in X. laevis larvae at five stages (Nieuwkoop-Faber: 48, 52, 54, 56, and 58) with continued treatment throughout larval development. The higher dose (200 ng/mL) inhibited development when initiated at stages 48-56, but resulted in high mortality. CORT did not affect developmental rates when treatments began at stage 58, but there was an increase in mortality. The lower dose inhibited development when treatments began at stage 48, but had no effect at later stages. We conclude that CORT may be inhibitory throughout development. Ongoing studies examine the effects of COPT on pre- and prometamorphic (near stage 58) X. laevis larvae and the in vitro effects on development. This study was supported by an HHMI undergraduate grant and NSF grants (IBN-9513362 and IBN-9508996).

Abstract Background MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression implicated in multiple cellular processes. Cyclic stretch of alveoli is characteristic of mechanical ventilation, and is postulated to be partly responsible for the lung injury and inflammation in ventilator-induced lung injury. We propose that miRNAs may regulate some of the stretch response, and therefore hypothesized that miRNAs would be differentially expressed between cyclically stretched and unstretched rat alveolar epithelial cells (RAECs). Results RAECs were isolated and cultured to express type I epithelial characteristics. They were then equibiaxially stretched to 25% change in surface area at 15 cycles/minute for 1 hour or 6 hours, or served as unstretched controls, and miRNAs were extracted. Expression profiling of the miRNAs with at least 1.5-fold change over controls revealed 42 miRNAs were regulated (34 up and 8 down) with stretch. We validated 6 of the miRNAs using real-time PCR. Using a parallel mRNA array under identical conditions and publicly available databases, target genes for these 42 differentially regulated miRNAs were identified. Many of these genes had significant up- or down-regulation under the same stretch conditions. There were 362 down-regulated genes associated with up-regulated miRNAs, and 101 up-regulated genes associated with down-regulated miRNAs. Specific inhibition of two selected miRNAs demonstrated a reduction of the increased epithelial permeability seen with cyclic stretch. Conclusions We conclude that miRNA expression is differentially expressed between cyclically stretched and unstretched alveolar epithelial cells, and may offer opportunities for therapeutic intervention to ameliorate stretch-associated alveolar epithelial cell dysfunction.

Abstract Background In animals with heteromorphic sex chromosomes, dosage compensation of sex-chromosome genes is thought to be critical for species survival. Diverse molecular mechanisms have evolved to effectively balance the expressed dose of X-linked genes between XX and XY animals, and to balance expression of X and autosomal genes. Dosage compensation is not understood in birds, in which females (ZW) and males (ZZ) differ in the number of Z chromosomes. Results Using microarray analysis, we compared the male:female ratio of expression of sets of Z-linked and autosomal genes in two bird species, zebra finch and chicken, and in two mammalian species, mouse and human. Male:female ratios of expression were significantly higher for Z genes than for autosomal genes in several finch and chicken tissues. In contrast, in mouse and human the male:female ratio of expression of X-linked genes is quite similar to that of autosomal genes, indicating effective dosage compensation even in humans, in which a significant percentage of genes escape X-inactivation. Conclusion Birds represent an unprecedented case in which genes on one sex chromosome are expressed on average at constitutively higher levels in one sex compared with the other. Sex-chromosome dosage compensation is surprisingly ineffective in birds, suggesting that some genomes can do without effective sex-specific sex-chromosome dosage compensation mechanisms.

Viral lower respiratory tract infection (vLRTI) is a leading cause of hospitalization and death in children worldwide. Despite this, no studies have employed proteomics to characterize host immune responses to severe pediatric vLRTI in both the lower airway and systemic circulation. To address this gap, gain insights into vLRTI pathophysiology, and test a novel diagnostic approach, we assayed 1,305 proteins in tracheal aspirate (TA) and plasma from 62 critically ill children using SomaScan. We performed differential expression (DE) and pathway analyses comparing vLRTI (n=40) to controls with non-infectious acute respiratory failure (n=22), developed a diagnostic classifier using LASSO regression, and analyzed matched TA and plasma samples. We further investigated the impact of viral load and bacterial coinfection on the proteome. The TA signature of vLRTI was characterized by 200 DE proteins (P adj <0.05) with upregulation of interferons and T cell responses and downregulation of inflammation-modulating proteins including FABP and MIP-5. A nine-protein TA classifier achieved an AUC of 0.96 (95% CI 0.90-1.00) for identifying vLRTI. In plasma, the host response to vLRTI was more muted with 56 DE proteins. Correlation between TA and plasma was limited, although ISG15 was elevated in both compartments. In bacterial coinfection, we observed increases in the TNF-stimulated protein TSG-6, as well as CRP, and interferon-related proteins. Viral load correlated positively with interferon signaling and negatively with neutrophil-activation pathways. Taken together, our study provides fresh insight into the lower airway and systemic proteome of severe pediatric vLRTI, and identifies novel protein biomarkers with diagnostic potential., Competing Interests: DECLARATION OF INTERESTS The authors declare no conflicts of interest.

Background: Firearm injury is the leading cause of pediatric death in the United States (US), but few investigations have focused on the healthcare cost and burden of hospitalized survivors. We aimed to delineate the landscape of pediatric firearm hospitalizations, with a focus on sociodemographic characteristics and on acquired morbidity among survivors., Methods: We performed a retrospective cohort study of hospitalized children (<21 years old) with firearm injuries using the 2019 Kids' Inpatient Database, representing 80% of pediatric hospitalizations nationally., Results: There were 5998 hospitalizations with 5592 hospital survivors, giving a US population-adjusted hospitalization rate of 9.7 per 100,000 subjects <21 years. Black subjects (37.9 per 100,000) were admitted at higher rates than other races and ethnicities (3.8-6.2 per 100,000). Non-survivors were overrepresented in White subjects who were disproportionately victims of suicide. There were 199 new invasive medical devices placed (3.3% of hospitalized subjects), including 194 in 5592 survivors (3.5% of survivors): 87 tracheostomies, 30 feeding tubes, and 77 both. Suicide attempt was overrepresented as a cause of injury in subjects needing new devices. Charges and length of stay were longer for subjects needing new devices. Total charges for all hospitalized subjects exceeded $1.05 billion for 2019, $136 million (13%) of which represented the 3.3% of admissions needing new devices., Conclusions: Among pediatric firearm hospitalizations in 2019, Black children were overrepresented among assaults, and White children for suicide attempts. Suicide attempts were overrepresented among non-survivors, those requiring new devices, and contributed disproportionately to total hospital charges., Level of Evidence: Level 3., Competing Interests: Conflicts of interest Dr. Yehya reports consulting fees from AstraZeneca outside the scope of this study. The remaining authors declare no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Pediatric ARDS is associated with significant morbidity and mortality. High-quality data from clinical trials in children are limited due to numerous barriers to their design and execution. Here we describe the collaborative development of a master protocol as a tool to address some of these barriers and support the conduct of pediatric ARDS studies., Methods: Using PubMed, we performed a literature search of randomized controlled trials (RCTs) in pediatric ARDS to characterize the current state and evaluate potential benefit of harmonized master protocols. We used a multi-stakeholder, collaborative, and team science-oriented process to develop a master protocol template with links to common data elements (CDEs) for pediatric ARDS trials., Results: We identified 11 RCTs that enrolled between 14-200 total subjects per trial. Interventions included mechanical ventilation, prone positioning, corticosteroids, and surfactant. Studies displayed significant heterogeneity in ARDS definition, design, inclusion and exclusion criteria, and reported outcomes. Mortality was reported in 91% of trials and ventilator-free days in 73%. The trial heterogeneity made pooled analysis unfeasible. These findings underscore the need for a method to facilitate combined analysis of future trials through standardization of trial elements. As a potential solution, we developed a master protocol, iteratively revised with input from a multidisciplinary panel of experts and organized into 3 categories: instructions and general information, templated language, and a series of text options of common pediatric ARDS trial scenarios. Finally, we linked master protocol sections to relevant CDEs previously defined for pediatric ARDS and captured in a series of electronic case report forms., Conclusions: The majority of pediatric ARDS trials identified were small and heterogeneous in study design and outcome reporting. Using a master protocol template for pediatric ARDS trials with CDEs would support combining and comparing pediatric ARDS trial findings and increase the knowledge base., Competing Interests: Mr Miller discloses a relationship with Fisher and Paykel, S2N Health, MedEx Research, and Aerogen. Mr Miller is a section editor for Respiratory Care. The remaining authors have disclosed no conflicts of interest., (Copyright © 2024 by Daedalus Enterprises.)

Introduction: In the United States (US), racial and socioeconomic disparities have been implicated in pediatric intensive care unit (PICU) admissions and outcomes, with higher rates of critical illness in more deprived areas. The degree to which this persists despite insurance coverage is unknown. We investigated whether disparities exist in PICU admission and mortality according to socioeconomic position and race in children receiving Medicaid., Methods: Using Medicaid data from 2007-2014 from 23 US states, we tested the association between area level deprivation and race on PICU admission (among hospitalized children) and mortality (among PICU admissions). Race was categorized as Black, White, other and missing. Patient-level ZIP Code was used to generate a multicomponent variable describing area-level social vulnerability index (SVI). Race and SVI were simultaneously tested for associations with PICU admission and mortality., Results: The cohort contained 8,914,347 children (23·0% Black). There was no clear trend in odds of PICU admission by SVI; however, children residing in the most vulnerable quartile had increased PICU mortality (aOR 1·12 (95%CI 1·04-1·20; p = 0·0021). Black children had higher odds of PICU admission (aOR 1·04; 95% CI 1·03-1·05; p < 0·0001) and higher mortality (aOR 1·09; 95% CI 1·02-1·16; p = 0·0109) relative to White children. Substantial state-level variation was apparent, with the odds of mortality in Black children varying from 0·62 to 1·8., Conclusion: In a Medicaid cohort from 2007-2014, children with greater socioeconomic vulnerability had increased odds of PICU mortality. Black children were at increased risk of PICU admission and mortality, with substantial state-level variation. Our work highlights the persistence of sociodemographic disparities in outcomes even among insured children., (© 2024. The Author(s).)

Competing Interests: Dr. Keim disclosed that Timpel Medical loans a medical device to his institution. Dr. Yehya’s institution received funding from the National Institutes of Health; he received funding from AstraZeneca. Dr. Pinto has disclosed that he does not have any potential conflicts of interest.

Background: Mechanical power is a summary variable quantifying the risk of ventilator-induced lung injury. The original mechanical power equation was developed using square flow ventilation. However, most children are ventilated using decelerating flow. It is unclear whether mechanical power differs according to mode of flow delivery. This study compared mechanical power in children with acute respiratory distress syndrome who received both square and decelerating flow ventilation., Methods: This was a secondary analysis of a prospectively enrolled cohort of pediatric acute respiratory distress syndrome. Patients were ventilated on decelerating flow and then placed in square flow and allowed to stabilize. Ventilator metrics from both modes were collected within 24 h of acute respiratory distress syndrome onset. Paired t tests were used to compare differences in mechanical power between the modes., Results: This study enrolled 185 subjects with a median oxygenation index of 9.5 (interquartile range, 7 to 13) and median age of 8.3 yr (interquartile range, 1.8 to 14). Mechanical power was lower in square flow mode (mean, 0.46 J · min-1 · kg-1; SD, 0.25; 95% CI, 0.42 to 0.50) than in decelerating flow mode (mean, 0.49 J · min-1 · kg-1; SD, 0.28; 95% CI, 0.45 to 0.53) with a mean difference of 0.03 J · min-1 · kg-1 (SD, 0.08; 95% CI, 0.014 to 0.038; P < 0.001). This result remained statistically significant when stratified by age of less than 2 yr in square flow compared to decelerating flow and also when stratified by age of 2 yr or greater in square flow compared to decelerating flow. The elastic contribution in square flow was 70%, and the resistive contribution was 30%., Conclusions: Mechanical power was marginally lower in square flow than in decelerating flow, although the clinical significance of this is unclear. Upward of 30% of mechanical power may go toward overcoming resistance, regardless of age. This is nearly three-fold greater resistance compared to what has been reported in adults., (Copyright © 2024 American Society of Anesthesiologists. All Rights Reserved.)

Background: Studies on breastfeeding promotion and support interventions suggest some economic benefits. This study assessed the direct and indirect costs of a multicomponent breastfeeding promotion and support intervention during the first two years of the infant's life., Methods: This is a cost-benefit analysis of data generated from a randomized controlled trial that investigated whether provision of a multicomponent breastfeeding promotion and support intervention to Lebanese mothers in the first six months postpartum would improve breastfeeding rates compared to standard obstetric and pediatric care. Data of 339 participants on sociodemographics, mother and infant health, infant nutrition, direct and indirect costs of the intervention were used to assess the benefit-cost ratio (BCR) of the intervention at one, six, 12, and 24 months as primary outcome. Secondary outcomes included overall costs of infant nutrition and infant-mother dyad health costs during the first two years. Multiple linear regression models explored the effect of the intervention on the overall infant nutrition cost and mother-infant health costs. Similar regression models investigated the association between cost variables and infant nutrition types (exclusive breastfeeding, mixed feeding, artificial milk). Intention to treat analyses were conducted using SPSS (version 24). Statistical significance was set at a p-value below 0.05., Results: The prevalence of Exclusive/Predominant breastfeeding among participants declined from 51.6% in the first month to 6.6% at the end of second year. The multicomponent breastfeeding intervention incurred 485 USD more in costs than the control group during the first six months but was cost-efficient at one year (incremental net benefits of 374 USD; BCR = 2.44), and two years (incremental net benefits of 472 USD; BCR = 2.82). In adjusted analyses, the intervention was significantly associated with fewer infant illness visits in the first year (p = 0.045). Stratified analyses by the infant nutrition type revealed that infants who were on Exclusive/Predominant, or Any Breastfeeding had significantly more favorable health outcomes at different time points during the first two years (p<0.05) compared to infants receiving Artificial Milk only, with health benefits being highest in the Exclusive/Predominant breastfeeding group. Moreover, Exclusive/Predominant and Any Breastfeeding had significantly lower costs of infant illness visits, hospitalizations, and infant medications during the two years (p<0.05) but had additional cost for maternal non-routine doctor visits due to breastfeeding (all p values <0.05). Whereas the overall cost (direct and indirect) during the first six months was significantly lower for the Exclusive/Predominant breastfeeding infants (p = 0.001), they were similar in infants on Mixed Feeding or Artificial Milk., Conclusions: Breastfeeding is associated with significant economic and infant health benefits in the first two years. In the context of the current economic crisis in Lebanon, this study provides further evidence to policymakers on the need to invest in national breastfeeding promotion and support interventions., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Basbous et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Acute kidney injury (AKI) is a common complication of critical illness and associated with high morbidity and mortality. Optimal timing of continuous kidney replacement therapy (CKRT) in children is unknown. We aimed to measure the association between timing of initiation and mortality., Methods: This is a single-center retrospective cohort study of pediatric patients receiving CKRT from 2013 to 2019. The primary exposure, time to CKRT initiation, was measured from onset of stage 3 AKI during hospitalization (defined using Kidney Disease: Improving Global Outcomes creatinine and urine output criteria) and analyzed as both a continuous and categorical variable. The primary outcome was ICU mortality., Results: Ninety-nine patients met criteria for analysis. Overall mortality was 39% (39/99). Median time from stage 3 AKI onset to CKRT initiation was 1.5 days in survivors and 5.5 days in nonsurvivors (p < 0.001). In multivariable analysis, increased time to CKRT initiation was independently associated with mortality [OR 1.02 per hour (95% CI 1.01-1.04), p < 0.001]. Longer time to CKRT initiation was associated with higher odds of mortality in ascending time intervals. Patients started on CKRT > 2 days compared to < 2 days after stage 3 AKI onset had higher mortality (65% vs. 5%, p < 0.001), longer median ICU length of stay (25 vs. 12 d, p < 0.001), longer median CKRT duration (11 vs. 5 d, p < 0.001), and fewer AKI-free days (0 vs. 14 d, p < 0.001)., Conclusions: Longer time to initiation of CKRT after development of severe AKI is independently associated with mortality. Consideration of early CKRT in this high-risk population may be a strategy to reduce mortality and improve recovery of kidney function. However, there remains significant heterogeneity in the definition of early versus late initiation and the optimal timing of CKRT remains unknown., (© 2024. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Objectives: The Pediatric Acute Respiratory Distress Syndrome Biomarker Risk Model (PARDSEVERE) used age and three plasma biomarkers measured within 24 hours of pediatric acute respiratory distress syndrome (ARDS) onset to predict mortality in a pilot cohort of 152 patients. However, longitudinal performance of PARDSEVERE has not been evaluated, and it is unclear whether the risk model can be used to prognosticate after day 0. We, therefore, sought to determine the test characteristics of PARDSEVERE model and population over the first 7 days after ARDS onset., Design: Secondary unplanned post hoc analysis of data from a prospective observational cohort study carried out 2014-2019., Setting: University-affiliated PICU., Patients: Mechanically ventilated children with ARDS., Interventions: None., Measurements and Main Results: Between July 2014 and December 2019, 279 patients with ARDS had plasma collected at day 0, 266 at day 3 (11 nonsurvivors, two discharged between days 0 and 3), and 207 at day 7 (27 nonsurvivors, 45 discharged between days 3 and 7). The actual prevalence of mortality on days 0, 3, and 7, was 23% (64/279), 14% (38/266), and 13% (27/207), respectively. The PARDSEVERE risk model for mortality on days 0, 3, and 7 had area under the receiver operating characteristic curve (AUROC [95% CI]) of 0.76 (0.69-0.82), 0.68 (0.60-0.76), and 0.74 (0.65-0.83), respectively. The AUROC data translate into prevalence thresholds for the PARDSEVERE model for mortality (i.e., using the sensitivity and specificity values) of 37%, 27%, and 24% on days 0, 3, and 7, respectively. Negative predictive value (NPV) was high throughout (0.87-0.90 for all three-time points)., Conclusions: In this exploratory analysis of the PARDSEVERE model of mortality risk prediction in a population longitudinal series of data from days 0, 3, and 7 after ARDS diagnosis, the diagnostic performance is in the "acceptable" category. NPV was good. A major limitation is that actual mortality is far below the prevalence threshold for such testing. The model may, therefore, be more useful in cohorts with higher mortality rates (e.g., immunocompromised, other countries), and future enhancements to the model should be explored., Competing Interests: Drs. Whitney and Varisco received support for article research from the National Institutes of Health (NIH). Dr. Varisco received funding from Society of Critical Care Medicine Discovery Award 2020 (R01HL141229). Dr. Raby received support for article research from the NIH (R01HL130974, R01HL118455, P01HL132825, P01HL114501, R01HL118455, RK08HL155892, U01AI160087, U19AI095219, and U01TR001810); he received funding from Chan Zuckerberg Initiative 2022-316770, UpToDate, and royalties as Genetics Section Editor. Dr. Yehya’s institution received funding from the National Heart, Lung, and Blood Institute and the NIH (K23HL136688 and R01HL148054); he received funding from AstraZeneca. Ms. Johnson has disclosed that she does not have any potential conflicts of interest., (Copyright © 2024 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Sepsis is the leading cause of death of hospitalized children worldwide. Despite the established link between immune dysregulation and mortality in pediatric sepsis, it remains unclear which host immune factors contribute causally to adverse sepsis outcomes. Identifying modifiable pathobiology is an essential first step to successful translation of biologic insights into precision therapeutics. We designed a prospective, longitudinal cohort study of 88 critically ill pediatric patients with multiple organ dysfunction syndrome (MODS), including patients with and without sepsis, to define subphenotypes associated with targetable mechanisms of immune dysregulation. We first assessed plasma proteomic profiles and identified shared features of immune dysregulation in MODS patients with and without sepsis. We then employed consensus clustering to define three subphenotypes based on protein expression at disease onset and identified a strong association between subphenotype and clinical outcome. We next identified differences in immune cell frequency and activation state by MODS subphenotype and determined the association between hyperinflammatory pathway activation and cellular immunophenotype. Using single cell transcriptomics, we demonstrated STAT3 hyperactivation in lymphocytes from the sickest MODS subgroup and then identified an association between STAT3 hyperactivation and T cell immunometabolic dysregulation. Finally, we compared proteomics findings between patients with MODS and patients with inborn errors of immunity that amplify cytokine signaling pathways to further assess the impact of STAT3 hyperactivation in the most severe patients with MODS. Overall, these results identify a potentially pathologic and targetable role for STAT3 hyperactivation in a subset of pediatric patients with MODS who have high severity of illness and poor prognosis.

Background: Systemic corticosteroid use in acute respiratory failure has yielded uncertain benefits, partially because of off-target side effects. Inhaled corticosteroids (ICSs) confer localized antiinflammatory benefits and may protect adults with direct lung injury (DLI) from developing respiratory failure. To our knowledge, this relationship has not been studied in children., Research Question: Do children with DLI who are prescribed ICSs before hospitalization have lower odds of progressing to respiratory failure?, Study Design and Methods: This retrospective, single-center cohort identified children seeking treatment at the ED with DLI and medication records before hospitalization. The primary outcome was intubation; secondary outcomes included noninvasive respiratory support (NRS). We tested the association of ICSs with intubation and NRS, adjusting for confounders. We stratified analyses on history of asthma and performed a sensitivity analysis adjusting for systemic corticosteroid use to account for status asthmaticus., Results: Of 35,220 patients, 17,649 patients (50%) were prescribed ICSs. Intubation occurred in 169 patients (73 patients receiving ICSs) and NRS was used in 3,582 patients (1,336 patients receiving ICS). ICS use was associated with lower intubation (adjusted OR, 0.46; 95% CI, 0.31-0.67) and NRS (aOR, 0.45; 95% CI, 0.40-0.49). The association between ICS and NRS differed according to history of asthma ( P = .04 for interaction), with ICS exposure remaining protective only for patients with a history of asthma. Results held true in sensitivity analyses., Interpretation: ICS use prior to hospitalization may protect children with DLI from progressing to respiratory failure, with possible differential efficacy according to history of asthma.

Importance: A recent study showed an association between high hospital-level noninvasive positive pressure ventilation (NIPPV) use and in-hospital cardiac arrest (IHCA) in children with bronchiolitis., Objectives: We aimed to determine if patient-level exposure to NIPPV in children with bronchiolitis was associated with IHCA., Design, Setting and Participants: Retrospective cohort study at a single-center quaternary PICU in North America including children with International Classification of Diseases primary or secondary diagnoses of bronchiolitis in the Virtual Pediatric Systems database., Main Outcomes and Measures: The primary exposure was NIPPV and the primary outcome was IHCA., Measurements and Main Results: Of 4698 eligible ICU admissions with bronchiolitis diagnoses, IHCA occurred in 1.2% (57/4698). At IHCA onset, invasive mechanical ventilation (IMV) was the most frequent level of respiratory support (65%, 37/57), with 12% (7/57) receiving NIPPV. Patients with IHCA had higher Pediatric Risk of Mortality-III scores (3 [0-8] vs. 0 [0-2]; p < 0.001), more frequently had a complex chronic condition (94.7% vs. 46.2%; p < 0.001), and had higher mortality (21.1% vs. 1.0%; p < 0.001) compared with patients without IHCA. Return of spontaneous circulation (ROSC) was achieved in 93% (53/57) of IHCAs; 79% (45/57) survived to hospital discharge. All seven children without chronic medical conditions and with active bronchiolitis symptoms at the time of IHCA achieved ROSC, and 86% (6/7) survived to discharge. In multivariable analysis restricted to patients receiving NIPPV or IMV, NIPPV exposure was associated with lower odds of IHCA (adjusted odds ratio [aOR], 0.07; 95% CI, 0.03-0.18) compared with IMV. In secondary analysis evaluating categorical respiratory support in all patients, compared with IMV, NIPPV was associated with lower odds of IHCA (aOR, 0.35; 95% CI, 0.14-0.87), whereas no difference was found for minimal respiratory support (none/nasal cannula/humidified high-flow nasal cannula [aOR, 0.56; 95% CI, 0.23-1.36])., Conclusions and Relevance: Cardiac arrest in children with bronchiolitis is uncommon, occurring in 1.2% of bronchiolitis ICU admissions. NIPPV use in children with bronchiolitis was associated with lower odds of IHCA., Competing Interests: Dr. Shepard’s participation in this project was supported by the Pediatric Hospital Epidemiology and Outcomes Research Training program, the National Institutes of Health, and the National Institute of Child Health and Human Development-funded postdoctoral fellowship (T32 HD060550). The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Objectives: Describing our institution's off-label use of gabapentin to treat irritability after superior cavopulmonary connection surgery and its impact on subsequent opiate and benzodiazepine requirements., Methods: This is a single-center retrospective cohort study including infants who underwent superior cavopulmonary connection operation between 2011 and 2019., Results: Gabapentin was administered in 74 subjects (74/323, 22.9%) during the observation period, with a median (IQR) starting dose of 5.7 (3.3, 15.0) mg/kg/day and a maximum dose of 10.7 (5.5, 23.4) mg/kg/day. Infants who underwent surgery in 2015-19 were more likely to receive gabapentin compared with those who underwent surgery in 2011-14 (p < 0.0001). Infants prescribed gabapentin were younger at surgery (137 versus 146 days, p = 0.007) and had longer chest tube durations (1.8 versus 0.9 days, p < 0.001), as well as longer postoperative intensive care (5.8 versus 3.1 days, p < 0.0001) and hospital (11.5 versus 7.0 days, p < 0.0001) lengths of stays. The year of surgery was the only predisposing factor associated with gabapentin administration in multivariate analysis. In adjusted linear regression, infants prescribed gabapentin on postoperative day 0-4 (n = 64) had reduced benzodiazepine exposure in the following 3 days (-0.29 mg/kg, 95% CI -0.52 - -0.06, p = 0.01) compared with those not prescribed gabapentin, while no difference was seen in opioid exposure (p = 0.59)., Conclusions: Gabapentin was used with increasing frequency during the study period. There was a modest reduction in benzodiazepine requirements associated with gabapentin administration and no reduction in opioid requirements. A randomised controlled trial could better assess gabapentin's benefits postoperatively in children with congenital heart disease.

Importance: While disparities in consent rates for research have been reported in multiple adult and pediatric settings, limited data informing enrollment in pediatric intensive care unit (PICU) research are available. Acute care settings such as the PICU present unique challenges for study enrollment, given the highly stressful and emotional environment for caregivers and the time-sensitive nature of the studies., Objective: To determine whether race and ethnicity, language, religion, and Social Deprivation Index (SDI) were associated with disparate approach and consent rates in PICU research., Design, Setting, and Participants: This retrospective cohort study was performed at the Children's Hospital of Philadelphia PICU between July 1, 2011, and December 31, 2021. Participants included patients eligible for studies requiring prospective consent. Data were analyzed from February 2 to July 26, 2022., Exposure: Exposures included race and ethnicity (Black, Hispanic, White, and other), language (Arabic, English, Spanish, and other), religion (Christian, Jewish, Muslim, none, and other), and SDI (composite of multiple socioeconomic indicators)., Main Outcomes and Measures: Multivariable regressions separately tested associations between the 4 exposures (race and ethnicity, language, religion, and SDI) and 3 outcomes (rates of approach among eligible patients, consent among eligible patients, and consent among those approached). The degree to which reduced rates of approach mediated the association between lower consent in Black children was also assessed., Results: Of 3154 children included in the study (median age, 6 [IQR, 1.9-12.5] years; 1691 [53.6%] male), rates of approach and consent were lower for Black and Hispanic families and those of other races, speakers of Arabic and other languages, Muslim families, and those with worse SDI. Among children approached for research, lower consent odds persisted for those of Black race (unadjusted odds ratio [OR], 0.73 [95% CI, 0.55-0.97]; adjusted OR, 0.68 [95% CI, 0.49-0.93]) relative to White race. Mediation analysis revealed that 51.0% (95% CI, 11.8%-90.2%) of the reduced odds of consent for Black individuals was mediated by lower probability of approach., Conclusions and Relevance: In this cohort study of consent rates for PICU research, multiple sociodemographic factors were associated with lower rates of consent, partly attributable to disparate rates of approach. These findings suggest opportunities for reducing disparities in PICU research participation.

BACKGROUNDThe molecular signature of pediatric acute respiratory distress syndrome (ARDS) is poorly described, and the degree to which hyperinflammation or specific tissue injury contributes to outcomes is unknown. Therefore, we profiled inflammation and tissue injury dynamics over the first 7 days of ARDS, and associated specific biomarkers with mortality, persistent ARDS, and persistent multiple organ dysfunction syndrome (MODS).METHODSIn a single-center prospective cohort of intubated pediatric patients with ARDS, we collected plasma on days 0, 3, and 7. Nineteen biomarkers reflecting inflammation, tissue injury, and damage-associated molecular patterns (DAMPs) were measured. We assessed the relationship between biomarkers and trajectories with mortality, persistent ARDS, or persistent MODS using multivariable mixed effect models.RESULTSIn 279 patients (64 [23%] nonsurvivors), hyperinflammatory cytokines, tissue injury markers, and DAMPs were higher in nonsurvivors. Survivors and nonsurvivors showed different biomarker trajectories. IL-1α, soluble tumor necrosis factor receptor 1, angiopoietin 2 (ANG2), and surfactant protein D increased in nonsurvivors, while DAMPs remained persistently elevated. ANG2 and procollagen type III N-terminal peptide were associated with persistent ARDS, whereas multiple cytokines, tissue injury markers, and DAMPs were associated with persistent MODS. Corticosteroid use did not impact the association of biomarker levels or trajectory with mortality.CONCLUSIONSPediatric ARDS survivors and nonsurvivors had distinct biomarker trajectories, with cytokines, endothelial and alveolar epithelial injury, and DAMPs elevated in nonsurvivors. Mortality markers overlapped with markers associated with persistent MODS, rather than persistent ARDS.FUNDINGNIH (K23HL-136688, R01-HL148054).

Rationale: The epidemiology, management, and outcomes of acute respiratory distress syndrome (ARDS) differ between children and adults, with lower mortality rates in children despite comparable severity of hypoxemia. However, the relationship between age and mortality is unclear. Objective: We aimed to define the association between age and mortality in ARDS, hypothesizing that it would be nonlinear. Methods: We performed a retrospective cohort study using data from two pediatric ARDS observational cohorts ( n  = 1,236), multiple adult ARDS trials ( n  = 5,547), and an adult observational ARDS cohort ( n  = 1,079). We aligned all datasets to meet Berlin criteria. We performed unadjusted and adjusted logistic regression using fractional polynomials to assess the potentially nonlinear relationship between age and 90-day mortality, adjusting for sex, Pa O 2 /Fi O 2 , immunosuppressed status, year of study, and observational versus randomized controlled trial, treating each individual study as a fixed effect. Measurements and Main Results: There were 7,862 subjects with median ages of 4 years in the pediatric cohorts, 52 years in the adult trials, and 61 years in the adult observational cohort. Most subjects (43%) had moderate ARDS by Berlin criteria. Ninety-day mortality was 19% in the pediatric cohorts, 33% in the adult trials, and 67% in the adult observational cohort. We found a nonlinear relationship between age and mortality, with mortality risk increasing at an accelerating rate between 11 and 65 years of age, after which mortality risk increased more slowly. Conclusions: There was a nonlinear relationship between age and mortality in pediatric and adult ARDS.

Objectives: To characterize immunocompromised-associated pediatric acute respiratory distress syndrome (I-PARDS) and contrast it to PARDS., Design: This is a secondary analysis of the 2016-2017 PARDS incidence and epidemiology (PARDIE) study, a prospective observational, cross-sectional study of children with PARDS., Setting: Dataset of 145 PICUs across 27 countries., Patients: During 10 nonconsecutive weeks (from May 2016 to June 2017), data about immunocompromising conditions (ICCs, defined as malignancy, congenital/acquired immunodeficiency, posttransplantation, or diseases requiring immunosuppression) were collected., Interventions: None., Measurements and Main Results: Of 708 subjects, 105 (14.8%) had ICC. Before the development of I-PARDS, those with ICC were more likely to be hospitalized (70% vs. 35%, p < 0.001), have more at-risk for PARDS ( p = 0.046), and spent more hours at-risk (20 [interquartile range, IQR: 8-46] vs. 11 [IQR: 4-33], [ p = 0.002]). Noninvasive ventilation (NIV) use was more common in those with ICC ( p < 0.001). Of those diagnosed with PARDS on NIV ( n = 161), children with ICC were more likely to be subsequently intubated ( n = 28/40 [70%] vs n = 53/121 [44%], p = 0.004). Severe PARDS was more common (32% vs 23%, p < 0.001) in I-PARDS. Oxygenation indices were higher at diagnosis and had less improvement over the first 3 days of PARDS ( p < 0.001). Children with I-PARDS had greater nonpulmonary organ dysfunction. Adjusting for Pediatric Risk of Mortality IV and oxygenation index, children with I-PARDS had a higher severity of illness-adjusted PICU mortality (adjusted hazard ratio: 3.0 [95% CI, 1.9-4.7] p < 0.001) and were less likely to be extubated alive within 28 days (subdistribution hazard ratio: 0.47 [95% CI, 0.31-0.71] p < 0.001)., Conclusions: I-PARDS is a unique subtype of PARDS associated with hospitalization before diagnosis and increased: time at-risk for PARDS, NIV use, hypoxia, nonpulmonary organ dysfunction, and mortality. The opportunity for early detection and intervention seems to exist. Dedicated study in these patients is imperative to determine if targeted interventions will benefit these unique patients with the ultimate goal of improving outcomes., Competing Interests: Dr. Bhalla received funding from nonhealthcare stocks. Drs. Bhalla and Rowan received support for article research from the National Institutes of Health (NIH). Dr. Emeriaud’s institution received funding from Maquet and Fonds de recherche du Québec - Santé. Dr. Fitzgerald’s institution received funding from the NIH. Dr. Thomas received funding from Bayer. Dr. Yehya received funding from AstraZeneca. Dr. Rowan’s institution received funding from the NIH (K23HL150244). The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)