Accuracy and Interpretation of Transcutaneous Carbon Dioxide Monitoring in Critically Ill Children.

OBJECTIVES: Transcutaneous carbon dioxide (Tcco2) monitoring can noninvasively assess ventilation by estimating carbon dioxide (CO2) levels in the blood. We aimed to evaluate the accuracy of Tcco2 monitoring in critically ill children by comparing it to the partial pressure of arterial carbon dioxide (Paco2). In addition, we sought to determine the variation between Tcco2 and Paco2 acceptable to clinicians to modify patient care and to determine which patient-level factors may affect the accuracy of Tcco2 measurements. DESIGN: Retrospective observational cohort study. SETTING: Single, quaternary care PICU from July 1, 2012, to August 1, 2020. PATIENTS: Included participants were admitted to the PICU and received noninvasive ventilation support (i.e., continuous or bilevel positive airway pressure), conventional mechanical ventilation, or high-frequency oscillatory or percussive ventilation with Tcco2 measurements obtained within 15 minutes of Paco2 measurement. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Three thousand four hundred seven paired arterial blood gas and Tcco2 measurements were obtained from 264 patients. Bland-Altman analysis revealed a bias of -4.4 mm Hg (95% CI, -27 to 18.3 mm Hg) for Tcco2 levels against Paco2 levels on the first measurement pair for each patient, which fell within the acceptable range of ±5 mm Hg stated by surveyed clinicians, albeit with wide limits of agreement. The sensitivity and specificity of Tcco2 to diagnose hypercarbia were 93% and 71%, respectively. Vasoactive-Infusion Score (VIS), age, and self-identified Black/African American race confounded the relationship between Tcco2 with Paco2 but percent fluid overload, weight-for-age, probe location, and severity of illness were not significantly associated with Tcco2 accuracy. CONCLUSIONS: Tcco2 monitoring may be a useful adjunct to monitor ventilation in children with respiratory failure, but providers must be aware of the limitations to its accuracy.

Cilia-related gene signature in the nasal mucosa correlates with disease severity and outcomes in critical respiratory syncytial virus bronchiolitis.

Background: Respiratory syncytial virus (RSV) can cause life-threatening respiratory failure in infants. We sought to characterize the local host response to RSV infection in the nasal mucosa of infants with critical bronchiolitis and to identify early admission gene signatures associated with clinical outcomes. Methods: Nasal scrape biopsies were obtained from 33 infants admitted to the pediatric intensive care unit (PICU) with critical RSV bronchiolitis requiring non-invasive respiratory support (NIS) or invasive mechanical ventilation (IMV), and RNA sequencing (RNA-seq) was performed. Gene expression in participants who required shortened NIS ( 3 days), and IMV was compared. Findings: Increased expression of ciliated cell genes and estimated ciliated cell abundance, but not immune cell abundance, positively correlated with duration of hospitalization in infants with critical bronchiolitis. A ciliated cell signature characterized infants who required NIS for > 3 days while a basal cell signature was present in infants who required NIS for

Age-related Differences in the Nasal Mucosal Immune Response to SARS-CoV-2.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected more than 180 million people since the onset of the pandemic. Despite similar viral load and infectivity rates between children and adults, children rarely develop severe illness. Differences in the host response to the virus at the primary infection site are among the mechanisms proposed to account for this disparity. Our objective was to investigate the host response to SARS-CoV-2 in the nasal mucosa in children and adults and compare it with the host response to respiratory syncytial virus (RSV) and influenza virus. We analyzed clinical outcomes and gene expression in the nasal mucosa of 36 children with SARS-CoV-2, 24 children with RSV, 9 children with influenza virus, 16 adults with SARS-CoV-2, and 7 healthy pediatric and 13 healthy adult controls. In both children and adults, infection with SARS-CoV-2 led to an IFN response in the nasal mucosa. The magnitude of the IFN response correlated with the abundance of viral reads, not the severity of illness, and was comparable between children and adults infected with SARS-CoV-2 and children with severe RSV infection. Expression of ACE2 and TMPRSS2 did not correlate with age or presence of viral infection. SARS-CoV-2-infected adults had increased expression of genes involved in neutrophil activation and T-cell receptor signaling pathways compared with SARS-CoV-2-infected children, despite similar severity of illness and viral reads. Age-related differences in the immune response to SARS-CoV-2 may place adults at increased risk of developing severe illness.

Immune response to SARS-CoV-2 in the nasal mucosa in children and adults.

RATIONALE: Despite similar viral load and infectivity rates between children and adults infected with SARS-CoV-2, children rarely develop severe illness. Differences in the host response to the virus at the primary infection site are among the proposed mechanisms. OBJECTIVES: To investigate the host response to SARS-CoV-2, respiratory syncytial virus (RSV), and influenza virus (IV) in the nasal mucosa in children and adults. METHODS: Clinical outcomes and gene expression in the nasal mucosa were analyzed in 36 children hospitalized with SARS-CoV-2 infection, 24 children with RSV infection, 9 children with IV infection, 16 adults with mild to moderate SARS-CoV-2 infection, and 7 healthy pediatric and 13 healthy adult controls. RESULTS: In both children and adults, infection with SARS-CoV-2 leads to an interferon response in the nasal mucosa. The magnitude of the interferon response correlated with the abundance of viral reads and was comparable between symptomatic children and adults infected with SARS-CoV-2 and symptomatic children infected with RSV and IV. Cell type deconvolution identified an increased abundance of immune cells in the samples from children and adults with a viral infection. Expression of ACE2 and TMPRSS2 - key entry factors for SARS-CoV-2 - did not correlate with age or presence or absence of viral infection. CONCLUSIONS: Our findings support the hypothesis that differences in the immune response to SARS-CoV-2 determine disease severity, independent of viral load and interferon response at the primary infection primary site.

In vivo manipulation of the extracellular matrix induces vascular regression in a basal chordate.

We investigated the physical role of the extracellular matrix (ECM) in vascular homeostasis in the basal chordate Botryllus schlosseri, which has a large, transparent, extracorporeal vascular network encompassing an area >100 cm2 We found that the collagen cross-linking enzyme lysyl oxidase is expressed in all vascular cells and that in vivo inhibition using ß-aminopropionitrile (BAPN) caused a rapid, global regression of the entire network, with some vessels regressing >10 mm within 16 h. BAPN treatment changed the ultrastructure of collagen fibers in the vessel basement membrane, and the kinetics of regression were dose dependent. Pharmacological inhibition of both focal adhesion kinase (FAK) and Raf also induced regression, and levels of phosphorylated FAK in vascular cells decreased during BAPN treatment and FAK inhibition but not Raf inhibition, suggesting that physical changes in the vessel ECM are detected via canonical integrin signaling pathways. Regression is driven by apoptosis and extrusion of cells through the basal lamina, which are then engulfed by blood-borne phagocytes. Extrusion and regression occurred in a coordinated manner that maintained vessel integrity, with no loss of barrier function. This suggests the presence of regulatory mechanisms linking physical changes to a homeostatic, tissue-level response.

Wnt affects symmetry and morphogenesis during post-embryonic development in colonial chordates.

BACKGROUND: Wnt signaling is one of the earliest and most highly conserved regulatory pathways for the establishment of the body axes during regeneration and early development. In regeneration, body axes determination occurs independently of tissue rearrangement and early developmental cues. Modulation of the Wnt signaling in either process has shown to result in unusual body axis phenotypes. Botryllus schlosseri is a colonial ascidian that can regenerate its entire body through asexual budding. This processes leads to an adult body via a stereotypical developmental pathway (called blastogenesis), without proceeding through any embryonic developmental stages. RESULTS: In this study, we describe the role of the canonical Wnt pathway during the early stages of asexual development. We characterized expression of three Wnt ligands (Wnt2B, Wnt5A, and Wnt9A) by in situ hybridization and qRT-PCR. Chemical manipulation of the pathway resulted in atypical budding due to the duplication of the A/P axes, supernumerary budding, and loss of the overall cell apical-basal polarity. CONCLUSIONS: Our results suggest that Wnt signaling is used for equivalent developmental processes both during embryogenesis and asexual development in an adult organism, suggesting that patterning mechanisms driving morphogenesis are conserved, independent of embryonic, or regenerative development.