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Objective: To evaluate the effectiveness of patient education, physician counseling, and point-of-care (POC) testing on improving adherence to lipid screening national guidelines in a general pediatric cardiology practice (2017-2023)., Study Design: Regional primary care providers were surveyed regarding lipid screening practices. Key drivers were categorized (physician, patient, and system) with corresponding interventions. Pediatric cardiologists started offering lipid screening during regular visits by providing families with preventive cardiovascular education materials and lab phlebotomy testing. System redesign included educational posters, clinical intake protocol, physician counseling, electronic health record integration, and POC testing. Run charts and statistical process control charts measured screening rates and key processes., Results: The primary care survey response rate was 32% (95/294); 97% supported pediatric cardiologists conducting routine lipid screening. Pediatric cardiology mean baseline lipid screening rate was 0%, increased to 7% with patient education, and to 61% after system redesign including POC testing. Screening rates among 1467 patients were similar across age groups (P = .98). More patients received lipid screening by POC (91.7%) compared with phlebotomy (8.3%). Lipid abnormalities detected did not differ by screening methodology (P = .49)., Conclusion: Patient education, counseling, and POC testing improved adherence to national lipid screening guidelines, providing a possible model for primary care implementation., Competing Interests: Declaration of Competing Interest The authors have no relevant conflicts of interest. Funding/Support: Children's Miracle Network., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Outpatient cardiologists provide longitudinal care for Fontan patients. As these patients age, they face mounting morbidities, necessitating challenging conversations about prognosis and goals of care. We created a novel survey to evaluate cardiologists' attitudes surrounding risk counseling for patients/caregivers. Cardiologists were recruited during concomitant outpatient enrollment of individuals with Fontan operation > age 10. Physician demographic data, expectations of timing in discussing adverse event risk, and perceived barriers were collected. Barriers were analyzed using a thematic approach. 40 cardiologists (9 institutions) responded regarding 155 patients (mean age 21.2 years, SD 7.7). Physicians were mostly male (58%) with mean practice of 21 years post-fellowship (SD 12). Most felt the time was right to have a conversation with patient (55%) and family (62%), and majority thought patient (53%) and family (75%) were ready for such a conversation. Most had previously discussed prognosis with patient (72%) and family (75%). Providers were inclined to discuss risk with caregivers earlier (mean patient age 9 years, SD 11) than patients (mean patient age 17 years, SD 6.4). Nevertheless, 42% of physicians perceived significant barriers and provided 58 narrative comments categorized into 4 major themes: (1) Patient-related (53.4%), including cognitive limitations and mental health; (2) Provider-related (16.4%), including lack of familiarity, preservation of happiness, and discomfort; (3) Family related (12.3%), including protection/denial and psychosocial stressors; (4) Other (26%), including social barriers. Experienced cardiologists are willing to have difficult conversations; nearly half reported largely patient-related barriers. Facilitating these conversations is critical for the adolescent/young adult with Fontan physiology., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Understanding the structure-property relationship is crucial for designing materials with desired properties. The past few years have witnessed remarkable progress in machine-learning methods for this connection. However, substantial challenges remain, including the generalizability of models and prediction of properties with materials-dependent output dimensions. Here we present the virtual node graph neural network to address the challenges. By developing three virtual node approaches, we achieve Γ-phonon spectra and full phonon dispersion prediction from atomic coordinates. We show that, compared with the machine-learning interatomic potentials, our approach achieves orders-of-magnitude-higher efficiency with comparable to better accuracy. This allows us to generate databases for Γ-phonon containing over 146,000 materials and phonon band structures of zeolites. Our work provides an avenue for rapid and high-quality prediction of phonon band structures enabling materials design with desired phonon properties. The virtual node method also provides a generic method for machine-learning design with a high level of flexibility., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: It is unknown how well cardiologists predict which Fontan patients are at risk for major adverse events (MAEs)., Objectives: The purpose of this study was to examine the accuracy of cardiologists' ability to identify the "good Fontan" patient, free from MAE within the following year, and compare that predicted risk cohort to patients who experienced MAE., Methods: This prospective, multicenter study included patients ≥10 years with lateral tunnel or extracardiac Fontan. The cardiologist was asked the yes/no "surprise" question: would you be surprised if your patient has a MAE in the next year? After 12 months, the cardiologist was surveyed to assess MAE. Agreement between cardiologist predictions of MAE and observed MAE was determined using the simple kappa coefficient. Multivariable generalized linear mixed effects models were performed to identify factors associated with MAE., Results: Overall, 146 patients were enrolled, and 99/146 (68%) patients w`ere predicted to be a "good Fontan." After 12 months, 17 (12%) experienced a MAE. The simple kappa coefficient of cardiologists' prediction was 0.17 (95% CI: 0.02-0.32), suggesting prediction of MAE was 17% better than random chance. In the multivariable cardiologist-predicted MAE (N = 47) model, diuretic/beta-blocker use ( P  ≤ 0.001) and systolic dysfunction ( P  = 0.005) were associated with MAE. In the observed multivariable MAE (N = 17) model, prior unplanned cardiac admission ( P  = 0.006), diuretic/beta-blocker use ( P  = 0.028), and ≥moderate atrioventricular valve regurgitation ( P  = 0.049) were associated with MAE., Conclusions: Cardiologists are marginally able to predict which Fontan patients are at risk for MAE over a year. There was overlap between factors associated with a cardiologist's prediction of risk and observed MAE, namely the use of diuretic/beta-blocker., Competing Interests: This project was supported by a grant from the New England Congenital Cardiology Research Foundation, Boston, Massachusetts, USA. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Aim: Numerous studies have shown that H 2 S serves as an acute oxygen sensor in a variety of cells. We hypothesize that H 2 S also serves in extended oxygen sensing., Methods: Here, we compare the effects of extended exposure (24-48 hours) to varying O 2 tensions on H 2 S and polysulphide metabolism in human embryonic kidney (HEK 293), human adenocarcinomic alveolar basal epithelial (A549), human colon cancer (HTC116), bovine pulmonary artery smooth muscle, human umbilical-derived mesenchymal stromal (stem) cells and porcine tracheal epithelium (PTE) using sulphur-specific fluorophores and fluorometry or confocal microscopy., Results: All cells continuously produced H 2 S in 21% O 2 and H 2 S production was increased at lower O 2 tensions. Decreasing O 2 from 21% to 10%, 5% and 1% O 2 progressively increased H 2 S production in HEK293 cells and this was partially inhibited by a combination of inhibitors of H 2 S biosynthesis, aminooxyacetate, propargyl glycine and compound 3. Mitochondria appeared to be the source of much of this increase in HEK 293 cells. H 2 S production in all other cells and PTE increased when O 2 was lowered from 21% to 5% except for HTC116 cells where 1% O 2 was necessary to increase H 2 S, presumably reflecting the hypoxic environment in vivo. Polysulphides (H 2 S n , where n = 2-7), the key signalling metabolite of H 2 S also appeared to increase in many cells although this was often masked by high endogenous polysulphide concentrations., Conclusion: These results show that cellular H 2 S is increased during extended hypoxia and they suggest this is a continuously active O 2 -sensing mechanism in a variety of cells., (© 2019 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.)

The G protein-coupled receptor (GPCR) CXCR4 is a co-receptor for HIV and is involved in cancers and autoimmune diseases. We characterized five purine or quinazoline core polyamine pharmacophores used for targeting CXCR4 dysregulation in diseases. All were neutral antagonists for wild-type CXCR4 and two were biased antagonists with effects on β-arrestin-2 only at high concentrations. These compounds displayed various activities for a constitutively active mutant (CAM). We use the IT1t-CXCR4 crystal structure and molecular dynamics (MD) simulations to develop two hypotheses for the activation of the N119 3.35 A CAM. The N119 3.35 A mutation facilitates increased coupling of TM helices III and VI. IT1t deactivates the CAM by disrupting the coupling between TM helices III and VI, mediated primarily by residue F87 2.53 . Mutants of F87 2.53 in N119 3.35 A CXCR4 precluded constitutive signaling and prevented inverse agonism. This work characterizes CXCR4 ligands and provides a mechanism for N119 3.35 A constitutive activation., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

An emerging number of non-chemokine mediators are found to bind to classical chemokine receptors and to elicit critical biological responses. Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine that exhibits chemokine-like activities through non-cognate interactions with the chemokine receptors CXCR2 and CXCR4, in addition to activating the type II receptor CD74. Activation of the MIF-CXCR2 and -CXCR4 axes promotes leukocyte recruitment, mediating the exacerbating role of MIF in atherosclerosis and contributing to the wealth of other MIF biological activities. Although the structural basis of the MIF-CXCR2 interaction has been well studied and was found to engage a pseudo-ELR and an N-like loop motif, nothing is known about the regions of CXCR4 and MIF that are involved in binding to each other. Using a genetic strain of Saccharomyces cerevisiae that expresses a functional CXCR4 receptor, site-specific mutagenesis, hybrid CXCR3/CXCR4 receptors, pharmacological reagents, peptide array analysis, chemotaxis, fluorescence spectroscopy, and circular dichroism, we provide novel molecular information about the structural elements that govern the interaction between MIF and CXCR4. The data identify similarities with classical chemokine-receptor interactions but also provide evidence for a partial allosteric agonist compared with CXCL12 that is possible due to the two binding sites of CXCR4., (© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.)

The question addressed in this study was whether exogenous insulin can enhance the rate of assimilation of blood glucose after prolonged hypovolemia when homeostasis is waning. Twenty-three well-fed mongrel dogs were maintained at a mean arterial blood pressure of 50 mm Hg by bleeding. Periodic analyses were made of arterial and venous plasma concentration of glucose, femoral blood flow, arterial plasma concentration of insulin, and hematocrit. At the onset of physiologic deterioration signaled by the need to reinfuse 50 ml of shed blood to maintain 50 mm Hg blood pressure, dogs received either 10 ml saline (control; n=15) or 10 ml saline containing 2 units insulin (treated; n=8). Administration of 2 units of insulin to eight of the dogs caused a significantly faster decline of blood glucose than that observed in saline-treated animals. Despite the more rapid decline in plasma concentration of glucose in animals that received insulin, there was no significant difference in glucose uptake between the two groups of animals. The hemoconcentration reflected by a rising hematocrit that develops when hypovolemia persists was accentuated by the administration of insulin without supplementary fluids. The absence of any effect of insulin on glucose uptake in the hindlimb in the late phase of hypovolemic shock suggests that the accelerated decline in arterial glucose levels may be due to inhibitory effects of insulin on hepatic glucose release. These results are not consistent with the resistance of plasma glucose to insulin in the late phases of hypovolemic shock.