Ability of a novel shock index that incorporates invasive hemodynamics to predict mortality in patients with ST-elevation myocardial infarction.

OBJECTIVE: To determine whether the use of invasively measured hemodynamics improves the prognostic ability of a shock index (SI). BACKGROUND: SI such as Admission-SI, Age-SI, Modified SI (MSI), and Age-MSI predict short-term mortality in ST-elevation myocardial infarction (STEMI). METHODS: Single-center study of 510 patients who underwent primary percutaneous coronary intervention. STEMI SI was defined as age × heart rate (HR) divided by coronary perfusion pressure (CPP). RESULTS: The mean age was 62 ± 14 years, 66% were males with hypertension (69%), tobacco use (38%), diabetes (28%) and chronic kidney disease (6%). The mean HR, systolic blood pressure (SBP), and CPP were 81 ± 18 bpm, 124 ± 28 mmHg, and 52.8 ± 16.3 mmHg, respectively. Patients with STEMI SI ≥182 (n = 51) were more likely to experience a cardiac arrest in the catheterization laboratory (9.8% vs. 2.0%; p = .001), require mechanical circulatory support (47.1% vs. 8.5%; p < .0001) and be treated with vasopressors (56.9% vs. 10.7%; p < .0001) compared to STEMI SI < 182 (n = 459). After multivariate adjustment, patients with STEMI SI ≥182 were 10, 10.1 and 4.8 times more likely to die during hospitalization, at 30 days and at 5 years, respectively. The C statistic of STEMI SI was 0.870, similar to GRACE score (AUC = 0.902; p = .29) and TIMI STEMI score (AUC = 0.895; p = .36). CONCLUSION: STEMI SI is an easy to calculate risk score that identifies STEMI patients at high risk of in-hospital death.

Pediatric oral food challenges in the outpatient setting: A single-center experience.

Background: Oral food challenge (OFC) is the criterion standard for diagnosing food allergy (FA). It is important to have parameters to aid in selecting ideal OFC candidates. Objective: We sought to characterize outcomes and predictors of OFCs for common food allergens. Methods: We completed a retrospective chart review of all OFCs for IgE-mediated FA performed at Duke University pediatric allergy clinics from June 2017 through May 2022. Patients were deemed eligible for milk, egg, and nut OFC if testing revealed a specific IgE level not exceeding 2 kU/L and a skin prick test (SPT) resulting in a wheal size not exceeding 5 mm. Different parameters were followed for selecting candidates for baked challenge. Results: A total of 663 OFCs were conducted on 510 patients (59% male). The most common foods challenged were peanut (26%), plain egg (23%), baked egg (8%), and milk (8%), with pass rates of 84%, 88%, 62%, and 84%, respectively. Of the patients who failed OFC, 84% had objective symptoms, 23% had multisystemic reactions, and 15% required epinephrine. Although the presence of a personal or family history of atopy or prior failed OFC was not associated with outcomes, a history of anaphylaxis (regardless of the trigger) was associated with increased risk of failure. Conclusion: Although there are no established consensus guidelines, our study provides a benchmark illustrating that cutoffs of a specific IgE level not exceeding 2 kU/L and SPT finding not exceeding 5 mm result in a failure rate of approximately 13% for nonbaked milk, nonbaked egg, and nuts. The high rate of failed baked egg OFCs is likely related to selection bias, but our results illustrate the low negative predictive value of ovomucoid.

Congenital lobar emphysema in monozygotic twins.

Congenital lobar emphysema (CLE) is caused by airway defects resulting in air trapping and hyperinflation of the affected lobe. Case reports of families affected with CLE imply a genetic etiology. However, the genetic contributions have not been well-described. We present a case of CLE in a monozygotic twin brother with respiratory distress diagnosed with right upper lobe (RUL) CLE and treated with a lobectomy. His asymptomatic twin brother was screened prophylactically, found to have RUL CLE and subsequently underwent a lobectomy. Our report provides further evidence supporting the genetic predisposition and potential benefit of early screening for CLE in comparable scenarios.

Usefulness of a Novel Risk Score to Predict In-Hospital Mortality in Patients ≥ 60 Years of Age with ST Elevation Myocardial Infarction.

Numerous algorithms are available to predict short-term mortality in ST elevation myocardial infarction (STEMI) but none are focused on elderly patients or include invasive hemodynamics. A simplified risk score (LASH score) including left ventricular end diastolic pressure > 20 mm Hg, age > 75 years, systolic blood pressure < 100 mm Hg and heart rate > 100 bpm was tested in a retrospective, single-center study of 346 patients ≥ 60 years old who underwent primary percutaneous coronary intervention (PPCI). The median age was 70 years [IQR: 64, 79], 60.1% were men, and 77.8% identified as White. In-hospital all-cause mortality was 10.1%. Patients with a LASH score ≥ 3 (n = 34) had an in-hospital mortality rate of 44.1% compared to 6.4% for LASH score ≤ 2 (p < 0.0001). The odds ratio for in-hospital mortality for patients with LASH score ≥ 3 was 13.2 (95% CI 5.3-33.1) compared to patients with a LASH score ≤ 2 when adjusted for sex, cardiac arrest, heart failure, and prior cerebrovascular event. The LASH score had an area under the ROC curve for predicting in-hospital mortality of 0.795 [CI 0.716-0.872], as compared to TIMI-STEMI (0.881, CI 0.829-0.931; p = 0.01), GRACE (0.849, CI 0.778-0.920; p = 0.19), shock index (0.769, CI 0.667-0.871; p = 0.51) and modified shock index (0.765, CI 0.716-0.873; p = 0.48). In summary, a simplified, easy to calculate risk score that incorporates age and invasive hemodynamics predicts in-hospital mortality in patients ≥ 60 years old undergoing PPCI for STEMI.

Doxorubicin Exposure Causes Subacute Cardiac Atrophy Dependent on the Striated Muscle-Specific Ubiquitin Ligase MuRF1.

Background Anthracycline chemotherapeutics, such as doxorubicin, are used widely in the treatment of numerous malignancies. The primary dose-limiting adverse effect of anthracyclines is cardiotoxicity that often presents as heart failure due to dilated cardiomyopathy years after anthracycline exposure. Recent data from animal studies indicate that anthracyclines cause cardiac atrophy. The timing of onset and underlying mechanisms are not well defined, and the relevance of these findings to human disease is unclear. Methods and Results Wild-type mice were sacrificed 1 week after intraperitoneal administration of doxorubicin (1-25 mg/kg), revealing a dose-dependent decrease in cardiac mass ( R2=0.64; P<0.0001) and a significant decrease in cardiomyocyte cross-sectional area (336±29 versus 188±14 µm2; P<0.0001). Myocardial tissue analysis identified a dose-dependent upregulation of the ubiquitin ligase, MuRF1 (muscle ring finger-1; R2=0.91; P=0.003) and a molecular profile of muscle atrophy. To investigate the determinants of doxorubicin-induced cardiac atrophy, we administered doxorubicin 20 mg/kg to mice lacking MuRF1 (MuRF1-/-) and wild-type littermates. MuRF1-/- mice were protected from cardiac atrophy and exhibited no reduction in contractile function. To explore the clinical relevance of these findings, we analyzed cardiac magnetic resonance imaging data from 70 patients in the DETECT-1 cohort and found that anthracycline exposure was associated with decreased cardiac mass evident within 1 month and persisting to 6 months after initiation. Conclusions Doxorubicin causes a subacute decrease in cardiac mass in both mice and humans. In mice, doxorubicin-induced cardiac atrophy is dependent on MuRF1. These findings suggest that therapies directed at preventing or reversing cardiac atrophy might preserve the cardiac function of cancer patients receiving anthracyclines.

Tracking GPCR biosynthesis and degradation using a nonradioactive pulse chase methodology.

The ß2-adrenergic receptor (ß2AR) is a prototypical member of the G protein-coupled receptor (GPCR) superfamily of proteins and is one of the best-characterized GPCRs due to its role in several important physiological systems. Because of limited availability of high quality antibodies against GPCRs, much of the work done on ß2AR took advantage of heterologous expression systems. Overexpressed proteins may overwhelm the cellular regulatory machinery leading potentially to responses distinct from the native protein. To address this issue we generated a stable cell line with a tetracycline-inducible ß2AR tagged with a FLAG epitope, such that we are able to control the quantity of receptor produced. This allows us to induce a discrete pulse of FLAG-ß2AR transcription and translation allowing us to follow the complete life cycle of the protein from synthesis as an immature protein to degradation. We show that such limited pulses of receptor expression lead to signaling phenotypes that more closely reflect endogenous signaling events.

Cellular and subcellular context determine outputs from signaling biosensors.

The use of biosensors either individually or as part of panels has now become a common technique to capturing signaling events in living cells. Such biosensors have become particularly important for probing biased signaling and allostery in G protein-coupled receptor drug screening efforts. However, assumptions about the portability of such biosensors between cell types may lead to misinterpretation of drug effects on specific signaling pathways in a given cellular context. Further, the output of a particular biosensor may be different depending on where it is localized in a cell. Here, we discuss strategies to mitigate these concerns which should feed into future biosensor design and usage.