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.

Optimized spatial information for 1990, 2000, and 2010 U.S. census microdata.

We report on the successful completion of a project to upgrade the positional accuracy of every response to the 1990, 2000, and 2010 U.S. decennial censuses. The resulting data set, called Optimized Spatial Census Information Linked Across Time (OSCILAT), resides within the restricted-access data warehouse of the Federal Statistical Research Data Center (FSRDC) system where it is available for use with approval from the U.S. Census Bureau. OSCILAT greatly improves the accuracy and completeness of spatial information for older censuses conducted prior to major quality improvements undertaken by the Bureau. Our work enables more precise spatial and longitudinal analysis of census data and supports exact tabulations of census responses for arbitrary spatial units, including tabulating responses from 1990, 2000, and 2010 within 2020 block boundaries for precise measures of change over time for small geographic areas.

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.

Harmonizing Disparate Data across Time and Place: The Integrated Spatio-Temporal Aggregate Data Series.

In this article, the authors describe a new data infrastructure project being developed at the Minnesota Population Center. The Integrated Spatio-Temporal Aggregate Data Series (ISTADS) will make it easier for researchers to use publicly available aggregate data for the United States over a time span that covers virtually the entire life of the nation: 1790-2012. In addition to facilitating access and ease of use, ISTADS will facilitate the use of these various data sets in mapping and spatial analysis.

Across the Rural-Urban Universe: Two Continuous Indices of Urbanization for U.S. Census Microdata.

Microdata from U.S. decennial censuses and the American Community Survey are a key resource for social science and policy analysis, enabling researchers to investigate relationships among all reported characteristics for individual respondents and their households. To protect privacy, the Census Bureau restricts the detail of geographic information in public use microdata, and this complicates how researchers can investigate and account for variations across levels of urbanization when analyzing microdata. One option is to focus on metropolitan status, which can be determined exactly for most microdata records and approximated for others, but a binary metro/nonmetro classification is still coarse and limited on its own, emphasizing one aspect of rural-urban variation and discounting others. To address these issues, we compute two continuous indices for public use microdata-average tract density and average metro/micro-area population-using population-weighted geometric means. We show how these indices correspond to two key dimensions of urbanization-concentration and size-and we demonstrate their utility through an examination of disparities in poverty throughout the rural-urban universe. Poverty rates vary across settlement types in nonlinear ways: rates are lowest in moderately dense parts of major metro areas, and rates are higher in both low- and high-density areas, as well as in smaller commuting systems. Using the two indices also reveals that correlations between poverty and demographic characteristics vary considerably across settlement types. Both indices are now available for recent census microdata via IPUMS USA (https://usa.ipums.org).

Reduced turnaround times through multi-sectoral community collaboration during the first surge of SARS-CoV-2 and associated effect on patient care and hospital operations.

BACKGROUND: In March 2020, an influx of admissions in COVID-19 positive patients threatened to overwhelm healthcare facilities in East Baton Rouge Parish, Louisiana. Exacerbating this problem was an overall shortage of diagnostic testing capability at that time, resulting in a delay in time-to-result return. An improvement in diagnostic testing availability and timeliness was necessary to improve the allocation of resources and ultimate throughput of patients. The management of a COVID-19 positive patient or patient under investigation requires infection control measures that can quickly consume personal protective equipment (PPE) stores and personnel available to treat these patients. Critical shortages of both PPE and personnel also negatively impact care in patients admitted with non-COVID-19 illnesses. METHODS: A multisectoral partnership of healthcare providers, facilities and academicians created a molecular diagnostic lab within an academic research facility dedicated to testing inpatients and healthcare personnel for SARS-CoV-2. The purpose of the laboratory was to provide a temporary solution to the East Baton Rouge Parish healthcare community until individual facilities were self-sustaining in testing capabilities. We describe the partnership and the impacts of this endeavor by developing a model derived from a combination of data sources, including electronic health records, hospital operations, and state and local resources. FINDINGS: Our model demonstrates two important principles: the impact of reduced turnaround times (TAT) on potential differences in inpatient population numbers for COVID-19 and savings in PPE attributed to the more rapid TAT.

The µ-opioid receptor variant N190K is unresponsive to peptide agonists yet can be rescued by small-molecule drugs.

The µ-opioid receptor (MOR) plays an important role in modulating analgesia, feeding behavior, and a range of autonomic functions. In the current study, we investigated the degree to which 13 naturally occurring missense mutations affect the pharmacological properties of the human MOR. After expression of each receptor in human embryonic kidney 293 cells, signaling (Gα(i/o)-mediated) induced by peptide agonists was assessed using luciferase reporter gene assays. Multiple mutants (S66F, S147C, R260H, R265C, R265H, and S268P) show a significant reduction in agonist potency. At the N190K variant, agonist-mediated signaling was essentially absent. Enzyme-linked immunosorbent assay, microscopic analysis, and radioligand binding assays revealed that this mutant shows markedly reduced cell-surface expression, whereas all other receptor variants were expressed at normal levels. Surface expression of the N190K variant could be increased by incubation with the alkaloid agonist buprenorphine or with either naltrexone or naloxone, structurally related MOR antagonists. We were surprised to find that both putative antagonists, despite being inactive at the wild-type MOR, triggered a concentration-dependent increase in N190K receptor-mediated signaling. In contrast, peptidic ligands failed to promote expression or rescue function of the N190K mutant. Subsequent analysis of the N190K variant in an ethnically diverse cohort identified this isoform in a subgroup of African Americans. Taken together, our studies reveal that the N190K mutation leads to severe functional alterations and, in parallel, changes the response to established MOR ligands. The extent to which this mutation results in physiological abnormalities or affects drug sensitivity in selected populations (e.g., those with chronic pain or addiction) remains to be investigated.

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.

Bicomponent Trend Maps: A Multivariate Approach to Visualizing Geographic Time Series.

The most straightforward approaches to temporal mapping cannot effectively illustrate all potentially significant aspects of spatio-temporal patterns across many regions and times. This paper introduces an alternative approach, bicomponent trend mapping, which employs a combination of principal component analysis and bivariate choropleth mapping to illustrate two distinct dimensions of long-term trend variations. The approach also employs a bicomponent trend matrix, a graphic that illustrates an array of typical trend types corresponding to different combinations of scores on two principal components. This matrix is useful not only as a legend for bicomponent trend maps but also as a general means of visualizing principal components. To demonstrate and assess the new approach, the paper focuses on the task of illustrating population trends from 1950 to 2000 in census tracts throughout major U.S. urban cores. In a single static display, bicomponent trend mapping is not able to depict as wide a variety of trend properties as some other multivariate mapping approaches, but it can make relationships among trend classes easier to interpret, and it offers some unique flexibility in classification that could be particularly useful in an interactive data exploration environment.

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.

Hybrid Areal Interpolation of Census Counts from 2000 Blocks to 2010 Geographies.

To measure population changes in areas where census unit boundaries do not align across time, a common approach is to interpolate data from one census's units to another's. This article presents a broad assessment of areal interpolation models for estimating counts of 2000 characteristics in 2010 census units throughout the United States. We interpolate from 2000 census block data using 4 types of ancillary data to guide interpolation: 2010 block densities, imperviousness data, road buffers, and water body polygons. We test 8 binary dasymetric (BD) models and 8 target-density weighting (TDW) models, each using a unique combination of the 4 ancillary data types, and derive 2 hybrid models that blend the best-performing BD and TDW models. The most accurate model is a hybrid that generally gives high weight to TDW (allocating 2000 data in proportion to 2010 densities) but gives increasing weight to a BD model (allocating data uniformly within developed land near roads) in proportion to the estimated 2000-2010 rate of change within each block. Although for most 2010 census units, this hybrid model's estimates differ little from the simplest model's estimates, there are still many areas where the estimates differ considerably. Estimates from the final model, along with lower and upper bounds for each estimate, are publicly available for over 1,000 population and housing characteristics at 10 geographic levels via the National Historical Geographic Information System (NHGIS - http://nhgis.org).

Practically Saline.

Introduction. In December 2014, the Food and Drug Administration issued a recall of all Wallcur simulation products due to reports of their use in clinical practice. We present a case of septic shock and multiorgan failure after the accidental intravenous infusion of a nonsterile Wallcur simulation product. Case. The patient presented with symptoms of rigors and dyspnea occurring immediately after infusion of Wallcur Practi-0.9% saline. Initial laboratory evidence was consistent with severe septic shock and multiorgan dysfunction. His initial lactic acid level was 9 mmol/L (reference range = 0.5-2.2), and he had evidence of acute kidney injury and markers of disseminated intravascular coagulation. All 4 blood culture bottles isolated multidrug-resistant Empedobacter brevis. The patient recovered from his illness and was discharged with ciprofloxacin therapy per susceptibilities. Discussion. This patient represents the first described case of severe septic shock associated with the infusion of a Wallcur simulation product. Intravenous inoculation of a nonsterile fluid is rare and exposes the patient to unusual environmental organisms, toxins, or unsafe fluid characteristics such as tonicity. During course of treatment, we identified the possible culprit to be a multidrug-resistant isolate of Empedobacter brevis. We also discuss the systemic failures that led to this outbreak.

Combined Intrathoracic and Subcutaneous Splenosis Discovered 51 Years after Abdominal Trauma.

Splenosis is a rare condition that results from the autotransplantation of splenic parenchyma into unexpected locations such as the abdomen or subcutaneous tissue. In the presence of coexisting injury to the diaphragm intrathoracic transplantation can occur emerging as single or multiple pleural-based masses. This occurs after traumatic rupture of the spleen and is usually asymptomatic, only to be discovered incidentally on routine thoracic or abdominal imaging. To our knowledge this is the third documented case of combined intrathoracic and subcutaneous splenosis found in English literature. This occurred in a 71-year-old male involved in a motor vehicle accident at age 19 requiring urgent splenectomy. He has a significant cigarette smoking history and was referred to our hospital for further evaluation of an abnormality seen on shoulder X-ray.

Food Particle Aspiration Associated with Hemorrhagic Shock: A Diagnostic Dilemma.

The hemodynamic compromise caused by a large aspirated food particle in the airway can become the focus of medical attention and a distraction from rare but fatal Heimlich maneuver related injuries after an incident of food aspiration. We herein present a case of an 84-year-old man who was brought to the emergency department after an episode of choking at a restaurant followed by several failed Heimlich maneuver attempts. Despite relieving the airway obstruction by extracting a large piece of steak from the airway, the patient remained hypotensive and required continued hemodynamic support. Repeated laboratory tests within 24 hrs of aspiration showed a significant decline in the hemoglobin level. A computed tomography (CT) scan of the abdomen and pelvis showed a lacerated liver with a large subcapsular hematoma draining into the pelvis. Conclusion. Hepatic rupture is a rare complication of Heimlich maneuver; this paper represents the second case report in the literature. It emphasizes the necessity of early identification and surveillance of fatal Heimlich maneuver complications in a high risk population.

Iatrogenic Cushing syndrome and secondary adrenal insufficiency related to concomitant triamcinolone and ritonavir administration: a case report and review.

Triamcinolone is a long-acting glucocorticoid medication that can be responsible for transient suppression of the hypothalamic­pituitary­adrenal (HPA) axis. This physiologic alteration may persist for weeks after repeated or even single localized injection of this agent. However, when this glucocorticoid agent is given to patients receiving the HIV protease inhibitor (PI) ritonavir (RTV),inhibition of their shared cytochrome P450 3A4 degradation pathway leads to an increased bioavailability of triamcinolone, with subsequent heightening and prolongation of the glucocorticoid serum levels. In those instances, iatrogenic Cushing syndrome may ensue. The authors encountered such an event in an HIV-infected patient on chronic treatment with an antiretroviral regimen containing RTV. The patient's clinical presentation and laboratory investigations confirmed a diagnosis of Cushing syndrome and secondary adrenal insufficiency. This was believed to have occurred in close association following cervical vertebral column facet joint injections with triamcinolone acetonide for cephalagia deemed related to cervical spine disease. The discontinuation of the RTV-boosted PI therapy alone, promoting the clearance of the elevated triamcinolone serum levels and restoration of HPAhomeostasis, proved successful in this patient. For this case, the authors review the published English medical literature relating to this uncommon phenomenon.

Iatrogenic Cushing syndrome and secondary adrenal insufficiency related to concomitant triamcinolone and ritonavir administration: a case report and review.

Triamcinolone is a long-acting glucocorticoid medication that can be responsible for transient suppression of the hypothalamic­pituitary­adrenal (HPA) axis. This physiologic alteration may persist for weeks after repeated or even single localized injection of this agent. However, when this glucocorticoid agent is given to patients receiving the HIV protease inhibitor (PI) ritonavir (RTV),inhibition of their shared cytochrome P450 3A4 degradation pathway leads to an increased bioavailability of triamcinolone, with subsequent heightening and prolongation of the glucocorticoid serum levels. In those instances, iatrogenic Cushing syndrome may ensue. The authors encountered such an event in an HIV-infected patient on chronic treatment with an antiretroviral regimen containing RTV. The patient's clinical presentation and laboratory investigations confirmed a diagnosis of Cushing syndrome and secondary adrenal insufficiency. This was believed to have occurred in close association following cervical vertebral column facet joint injections with triamcinolone acetonide for cephalagia deemed related to cervical spine disease. The discontinuation of the RTV-boosted PI therapy alone, promoting the clearance of the elevated triamcinolone serum levels and restoration of HPAhomeostasis, proved successful in this patient. For this case, the authors review the published English medical literature relating to this uncommon phenomenon.