StethAid: A Digital Auscultation Platform for Pediatrics.

(1) Background: Mastery of auscultation can be challenging for many healthcare providers. Artificial intelligence (AI)-powered digital support is emerging as an aid to assist with the interpretation of auscultated sounds. A few AI-augmented digital stethoscopes exist but none are dedicated to pediatrics. Our goal was to develop a digital auscultation platform for pediatric medicine. (2) Methods: We developed StethAid-a digital platform for artificial intelligence-assisted auscultation and telehealth in pediatrics-that consists of a wireless digital stethoscope, mobile applications, customized patient-provider portals, and deep learning algorithms. To validate the StethAid platform, we characterized our stethoscope and used the platform in two clinical applications: (1) Still's murmur identification and (2) wheeze detection. The platform has been deployed in four children's medical centers to build the first and largest pediatric cardiopulmonary datasets, to our knowledge. We have trained and tested deep-learning models using these datasets. (3) Results: The frequency response of the StethAid stethoscope was comparable to those of the commercially available Eko Core, Thinklabs One, and Littman 3200 stethoscopes. The labels provided by our expert physician offline were in concordance with the labels of providers at the bedside using their acoustic stethoscopes for 79.3% of lungs cases and 98.3% of heart cases. Our deep learning algorithms achieved high sensitivity and specificity for both Still's murmur identification (sensitivity of 91.9% and specificity of 92.6%) and wheeze detection (sensitivity of 83.7% and specificity of 84.4%). (4) Conclusions: Our team has created a technically and clinically validated pediatric digital AI-enabled auscultation platform. Use of our platform could improve efficacy and efficiency of clinical care for pediatric patients, reduce parental anxiety, and result in cost savings.

TGF-beta regulates T-cell neurokinin-1 receptor internalization and function.

Substance P (SP) is a proinflammatory mediator implicated in inflammatory bowel disease (IBD) and other inflammatory states. SP acts by stimulating the neurokinin-1 receptor (NK-1R) on T lymphocytes and other cell types, and regulates these cells in a complex interplay with multiple cytokines. The mechanisms of interaction among these inflammatory mediators are not yet fully understood. Here, we demonstrate that function of the NK-1R, a member of the G protein-coupled receptor (GPCR) superfamily, is modulated by TGF-beta. The latter acts not on a GPCR but via serine-threonine kinase-class receptors. By flow confocal image analysis, we demonstrate that TGF-beta delays SP-induced NK-1R internalization on mucosal T cells isolated from a mouse model of IBD and on granuloma T cells in murine schistosomiasis. Furthermore, luciferase reporter-gene assays revealed that NK-1R stimulation activates the nuclear factor of activated T cell- and activator protein-1-dependent signaling pathways, which are known triggers of effector T-cell cytokine production. TGF-beta markedly increases SP-induced activation of these signaling cascades, suggesting that delayed NK-1R internalization results in enhanced signaling. Providing a link to amplified immune function, SP and TGF-beta, when applied in combination, trigger a strong release of the proinflammatory cytokines IFN-gamma and IL17 from intestinal inflammatory T cells, whereas either agonist alone shows no effect. These observations establish precedent that members of two distinct receptor superfamilies can interact via a previously unrecognized mechanism, and reveal a paradigm of GPCR transregulation that is relevant to IBD and possibly other disease processes.

Asthma as a comorbidity in COVID-19 pediatric ICU admissions in a large metropolitan children's hospital.

RATIONALE: Children contribute to 5% of coronavirus disease of 2019 (COVID-19)-related hospitalizations in the United States. There is mounting evidence suggesting childhood asthma is a risk factor for severe disease. We hypothesized that asthma is associated with longer length of stay (LOS) and need for respiratory support among children admitted to pediatric intensive care unit (PICU) with COVID-19. METHODS: We reviewed 150 charts of children and young adults with a positive severe acute respiratory syndrome coronavirus 2polymerase chain reaction test admitted to the PICU at Children's National Hospital, Washington, DC between 2020 and 2021. We recorded demographics, anthropometrics, past medical history, clinical course, laboratory findings, imaging, medication usage, respiratory support, and outcomes. Functional Status Scale (FSS), which measures an Intensive Care Unitpatient's physical function, was used to characterize children with multiple comorbidities; FSS and obesity were included as covariates in multivariate analysis. Statistical analysis was performed using SPSS v25.0. RESULTS: Sixty-Eight patients ages 0-21 years met inclusion criteria. Median age was 14.9 years, 55.9% were female, median Body Mass Index percentile was 62, and 42.6% were African American. Compared with those without asthma, patients with asthma averaged longer LOS (20.7 vs. 10.2 days, p = 0.02), with longer PICU stay (15.9 vs. 7.6 days, p = 0.033) and prolonged maximum respiratory support (8.3 vs. 3.3 days, p = 0.016). Adjusted for obesity and poor physical function (FSS > 6), asthma remained a significant predictor of hospital LOS, PICU LOS, and days on maximum respiratory support. CONCLUSION: Asthma can cause severe disease with prolonged need for maximum respiratory support among children with COVID-19.

Pharmacological characterization of human incretin receptor missense variants.

Glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are gut-derived incretin hormones that regulate blood glucose levels. In addition to their widely accepted insulinotropic role, there is evidence that GLP-1 modulates feeding behavior and GIP regulates lipid metabolism, thereby promoting postprandial fat deposition. In this study, we investigated whether naturally occurring polymorphisms in the GLP-1 receptor (GLP-1R) and the GIP receptor (GIP-R) affect the pharmacological properties of these proteins. After transient expression of the receptors in human embryonic kidney 293 cells, basal and ligand-induced cAMP production were assessed by use of luciferase reporter gene assays. Our data reveal that the wild-type GIP-R displays a considerable degree of ligand-independent activity. In comparison, the GIP-R variants C46S, G198C, R316L, and E354Q show a marked decrease in basal signaling that may, at least in part, be explained by reduced cell surface expression. When stimulated with GIP, the C46S and R316L mutants display significantly reduced potency (>1000 and 25- fold, respectively) compared with wild type. Complementary competition binding assays further demonstrate that the C46S variant fails to bind radio-iodinated GIP, whereas all other GIP-R mutants maintain normal ligand affinity. In contrast to the GIP-R, the wild-type GLP-1R lacks constitutive activity. Furthermore, none of the 10 GLP-1R missense mutations showed an alteration in pharmacological properties versus wild type. The extent to which abnormalities in GIP-R function may lead to physiological changes or affect drug sensitivity in selected populations (e.g., obese, diabetic individuals) remains to be further investigated.

Two naturally occurring mutations in the type 1 melanin-concentrating hormone receptor abolish agonist-induced signaling.

The melanin-concentrating hormone (MCH) receptor type 1 (MCHR1) is a seven-transmembrane domain protein that modulates orexigenic activity of MCH, the corresponding endogenous peptide agonist. MCH antagonists are being explored as a potential treatment for obesity. In the current study, we examined the pharmacological impact of 11 naturally occurring mutations in the human MCHR1. Wild-type and mutant receptors were transiently expressed in human embryonic kidney 293 cells. MCHR1-mediated, Gα(i)-dependent signaling was monitored by using luciferase reporter gene assays. Two mutants, R210H and P377S, failed to respond to MCH. Five other variants showed significant alterations in MCH efficacy, ranging from 44 to 142% of the wild-type value. At each of the MCH-responsive mutants, agonist potency and inhibition by (S)-methyl 3-((3-(4-(3-acetamidophenyl)piperidin-1-yl)propyl)carbamoyl)-4-(3,4-difluorophenyl)-6-(methoxymethyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (SNAP-7941), an established MCHR1 small-molecule antagonist, were similar to wild type. To explore the basis for inactivity of the R210H and P377S mutants, we examined expression levels of these receptors. Assessment by enzyme-linked immunosorbent assay revealed that cell surface expression of both nonfunctional receptors was comparable with wild type. Overnight treatment with SNAP-7941, followed by washout of antagonist, enhanced MCH induced signaling by the wild-type receptor and restored MCH responsiveness of the P377S but not the R210H variant. It is of note that the two loss-of-function mutants were identified in markedly underweight individuals, raising the possibility that a lean phenotype may be linked to deficient MCHR1 signaling. Formal association studies with larger cohorts are needed to explore the extent to which signaling-deficient MCHR1 variants influence the maintenance of body weight.

Peripheral Eosinophilia Found in Pediatric Enterobius vermicularis Infections.

Enterobius vermicularis, the common pinworm, is well known in North America as a parasitic infection, mainly affecting children. It is a very contagious organism, and it is responsible for a high number of infections in the United States each year. A rise in eosinophilia is linked to most parasitic infections. However, the correlation between eosinophilia and enterobiasis infections is not well documented in the literature. In this article, we present 3 cases involving patients seen for pediatric gastroenterology consultation with concern for inflammatory bowel disease. As part of their evaluation, each patient was found to have eosinophilia of unknown significance with an ultimate diagnosis of pinworm infections made by endoscopy. Their illness presentation did not include classic enterobiasis symptoms such as rectal pruritus or nighttime irritability. These cases support a link between eosinophilia and enterobiasis that may be instructive for pediatric providers seeing patients with eosinophilia for which there is no readily apparent underlying cause.

Search for alpha-helical propensity in the receptor-bound conformation of glucagon-like peptide-1.

To elucidate the receptor-bound conformation of glucagon-like peptide-1 (GLP-1), a series of conformationally constrained GLP-1 analogues were synthesized by introducing lactam bridges between Lys(i) and Glu(i)(+4) to form alpha-helices at various positions. The activity and affinity of these analogues to GLP-1 receptors suggested that the receptor-bound conformation comprises two alpha-helical segments between residues 11-21 and 23-34. It is notable that the N-terminal alpha-helix is extended to Thr(11), and that Gly(22) plays a pivotal role in arranging the two alpha-helices. Based on these findings, a highly potent bicyclic GLP-1 analogue was synthesized which is the most conformationally constrained GLP-1 analogue reported to date.