Increased platelet counts are associated with female sex and asthma severity.

Background: Significant sex differences occur in asthma phenotypes across the lifespan. Platelet activation is associated with a steroid-refractory asthma phenotype.

Objective: We sought to test the hypothesis that higher platelet counts in females are associated with increased prevalence and severity of asthma compared with males.

Elexacaftor/Tezacaftor/Ivacaftor Supports Treatment for CF with ΔI1023-V1024-CFTR.

Cystic Fibrosis (CF) is a common genetic disease in the United States, resulting from mutations in the gene. CFTR modulators, particularly Elexacaftor/Tezacaftor/Ivacaftor (ETI), have significantly improved clinical outcomes for patients with CF. However, many CFTR mutations are not eligible for CFTR modulator therapy due to their rarity.

External validation and update of the pediatric asthma risk score as a passive digital marker for childhood asthma using integrated electronic health records.

Background: In the search for practical prognostic decision support, numerous childhood asthma prediction tools (including a recent Pediatric Asthma Risk Score [PARS]) with modest prognostic accuracy have been developed, however, the prognostic utility of these tools using existing electronic health records (EHR) in clinical settings is unknown. To test the hypothesis that childhood asthma can be predicted using EHR, we sought to externally validate and update the PARS as a passive digital marker (PDM) for asthma risk.

Methods: Using a retrospective, population-based observational study design, children born between 2010 and 2017 who were consecutively enrolled at any of the pediatric healthcare institutions that contribute EHR data to the Indiana Network of Patient Care (INPC) databases were included in our analyses.

Development of an asthma health-care burden score as a measure of severity and predictor of remission in SARP III and U-BIOPRED: results from two major longitudinal asthma cohorts.

Background: Current asthma guidelines, including those of the European Respiratory Society (ERS) and American Thoracic Society (ATS), suboptimally predict asthma remission, disease severity, and health-care utilisation. We aimed to establish a novel approach to assess asthma severity based on asthma health-care burden data.

Methods: We analysed prospectively collected data from the Severe Asthma Research Program III (SARP III; USA) and the European Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED; 11 European countries) to calculate a composite burden score based on asthma exacerbations and health-care utilisation, which was modified to include the use of short-acting beta agonists (SABAs) to reflect asthma symptom burden.

A matched analysis of the use of high flow nasal cannula for pediatric severe acute asthma.

Rationale: The high-flow nasal cannula (HFNC) device is commonly used to treat pediatric severe acute asthma. However, there is little evidence regarding its effectiveness in real-world practice.

Objectives: We sought to compare the physiologic effects and clinical outcomes for children treated for severe acute asthma with HFNC versus matched controls.

Identification of severe acute pediatric asthma phenotypes using unsupervised machine learning.

Rationale: More targeted management of severe acute pediatric asthma could improve clinical outcomes.

Objectives: To identify distinct clinical phenotypes of severe acute pediatric asthma using variables obtained in the first 12 h of hospitalization.

Methods: We conducted a retrospective cohort study in a quaternary care children's hospital from 2014 to 2022.

Asthma Inception: Epidemiologic Risk Factors and Natural History Across the Life Course.

Asthma is a descriptive label for an obstructive inflammatory disease in the lower airways manifesting with symptoms including breathlessness, cough, difficulty in breathing, and wheezing. From a clinician's point of view, asthma symptoms can commence at any age, although most patients with asthma-regardless of their age of onset-seem to have had some form of airway problems during childhood. Asthma inception and related pathophysiologic processes are therefore very likely to occur early in life, further evidenced by recent lung physiologic and mechanistic research.

NOVEL ECHOCARDIOGRAM ANALYSIS OF CARDIAC DYSFUNCTION IS ASSOCIATED WITH MORTALITY IN PEDIATRIC SEPSIS.

Objectives: The objective of our study was to semiautomatically generate echocardiogram indices in pediatric sepsis using novel algorithms and determine which indices were associated with mortality. We hypothesized that strain and diastolic indices would be most associated with mortality. Design: Retrospective cohort study of children with sepsis from 2017 to 2022.

In Vivo Analysis of Tissue S-Nitrosothiols in Pediatric Sepsis.

S-nitrosothiols are endogenous, bioactive molecules. S-nitrosothiols are implicated in many diseases, including sepsis. It is currently cumbersome to measure S-nitrosothiols clinically.

Antigen stasis and airway nitrosative stress in human primary ciliary dyskinesia.

Nasal nitric oxide (nNO) is low in most patients with primary ciliary dyskinesia (PCD). Decreased ciliary motion could lead to antigen stasis, increasing oxidant production and NO oxidation in the airways. This could both decrease gas phase NO and increase nitrosative stress.

Hypoxia releases S-nitrosocysteine from carotid body glomus cells-relevance to expression of the hypoxic ventilatory response.

We have provided indirect pharmacological evidence that hypoxia may trigger release of the S-nitrosothiol, S-nitroso-L-cysteine (L-CSNO), from primary carotid body glomus cells (PGCs) of rats that then activates chemosensory afferents of the carotid sinus nerve to elicit the hypoxic ventilatory response (HVR). The objective of this study was to provide direct evidence, using our capacitive S-nitrosothiol sensor, that L-CSNO is stored and released from PGCs extracted from male Sprague Dawley rat carotid bodies, and thus further pharmacological evidence for the role of S-nitrosothiols in mediating the HVR. Key findings of this study were that 1) lysates of PGCs contained an S-nitrosothiol with physico-chemical properties similar to L-CSNO rather than S-nitroso-L-glutathione (L-GSNO), 2) exposure of PGCs to a hypoxic challenge caused a significant increase in S-nitrosothiol concentrations in the perfusate to levels approaching 100 fM via mechanisms that required extracellular Ca, 3) the dose-dependent increases in minute ventilation elicited by arterial injections of L-CSNO and L-GSNO were likely due to activation of small diameter unmyelinated C-fiber carotid body chemoafferents, 4) L-CSNO, but not L-GSNO, responses were markedly reduced in rats receiving continuous infusion (10 μmol/kg/min, IV) of both S-methyl-L-cysteine (L-SMC) and S-ethyl-L-cysteine (L-SEC), 5) ventilatory responses to hypoxic gas challenge (10% O, 90% N) were also due to the activation of small diameter unmyelinated C-fiber carotid body chemoafferents, and 6) the HVR was markedly diminished in rats receiving L-SMC plus L-SEC.

Erythrocytic metabolism of ATLX-0199: An agent that increases minute ventilation.

Both L- and D-isomers of S-nitrosocysteine (CSNO) can bind to the intracellular domain of voltage-gated potassium channels in vitro. CSNO binding inhibits these channels in the carotid body, leading to increased minute ventilation in vivo. However, only the l-isomer is active in vivo because it requires the l-amino acid transporter (LAT) for transmembrane transport.

Defining and Promoting Pediatric Pulmonary Health: Developing Biomarkers for Pulmonary Health.

Children with inherited and/or acquired respiratory disorders often arrive in adolescence and adulthood with diminished lung function that might have been detected and prevented had better mechanisms been available to identify and to assess progression of disease. Fortunately, advances in genetic assessments, low-cost diagnostics, and minimally- invasive novel biomarkers are being developed to detect and to treat respiratory diseases before they give rise to loss of life or lung function. This paper summarizes the Developing Biomarkers for Pulmonary Health sessions of the National Heart, Lung, and Blood Institute- sponsored 2021 Defining and Promoting Pediatric Pulmonary Health workshop.

Effects of pH alteration on respiratory syncytial virus in human airway epithelial cells.

Background: Respiratory syncytial virus (RSV) is a leading cause of respiratory distress and hospitalisation in the paediatric population. Low airway surface pH impairs antimicrobial host defence and worsens airway inflammation. Inhaled Optate safely raises airway surface pH in humans and raises intracellular pH in primary human airway epithelial cells (HAECs) .

Asthma innovations from the first International Collaborative Asthma Network forum.

Background: Many patients have uncontrolled asthma despite available treatments. Most of the new asthma therapies have focused on type 2 (T2) inflammation, leaving an unmet need for innovative research into mechanisms of asthma beyond T2 and immunity. An international group of investigators developed the International Collaborative Asthma Network (ICAN) with the goal of sharing innovative research on disease mechanisms, developing new technologies and therapies, organising pilot studies and engaging early-stage career investigators from across the world.

Genetic analyses of chr11p15.5 region identify - associated with asthma-related phenotypes.

Objective: Genome-wide association studies (GWASs) have identified single nucleotide polymorphisms (SNPs) in chr11p15.5 region associated with asthma and idiopathic interstitial pneumonias (IIPs). We sought to identify functional genes for asthma by combining SNPs and mRNA expression in bronchial epithelial cells (BEC) in the Severe Asthma Research Program (SARP).

Investigations of a combination of atopic status and age of asthma onset identify asthma subphenotypes.

Objective: Subphenotypes of asthma may be determined by age onset and atopic status. We sought to characterize early or late onset atopic asthma with fungal or non-fungal sensitization (AAFS or AANFS) and non-atopic asthma (NAA) in children and adults in the Severe Asthma Research Program (SARP). SARP is an ongoing project involving well-phenotyped patients with mild to severe asthma.