Cardiogenic Shock Intravascular Cooling Trial (CHILL-SHOCK).

BACKGROUND: Cardiogenic shock (CS) is complicated by high mortality rates. Targeted temperature control (TTC) has been proposed as an adjunct therapy in CS. This study aims to examine the safety of TTC in patients presenting with CS. METHODS AND RESULTS: In this open-label, randomized controlled pilot trial, 20 patients with hemodynamic criteria for CS were assigned to standard of care plus TTC vs standard of care alone. The primary outcome was a composite safety outcome, including well-described complications of TTC. Secondary outcomes included mortality at 90 days, invasive hemodynamic and echocardiographic parameters, electrocardiographic measurements, and inotrope dosing. There were no significant differences in the composite analysis of prespecified safety outcomes (3 events in the TTC group vs 0 events in the control group; P = 0.24). Patients randomized to TTC demonstrated a statistically significant increase in cardiac index and cardiac power index compared to the control group at 48-96 hours after randomization (3.6 [3.1, 3.9] L/min/m2 vs 2.6 [2.5, 3.15] L/min/m2; P = 0.029 and 0.61 [0.55, 0.7] W/m2 vs 0.53 [0.435, 0.565] W/m2; P = 0.029, respectively). CONCLUSION: TTC may be a safe adjunct therapy for patients presenting with CS and may yield improvement in specific hemodynamic parameters.

Pretreatment of tamarind pericarp to increase antioxidant availability and its application in a functional food.

Diverse researchers have considered by-products of food and agricultural processing industries as a source of antioxidants. Tamarind (Tamarindus indica) is a leguminous tree, native from tropical Africa bearing edible fruit. The fruit is composed of 30% pulp, 40% seed, and 30% pericarp. Currently, tamarind pericarp is a waste from tamarind processing (approximately 54,400 tons of pericarp in 2012 worldwide) and is contributing to environmental contamination. This research aimed to determine the effect of maceration, microwaves, and ultrasound on the increase in the antioxidant availability in tamarind pericarp and its incorporation as a functional ingredient in cookies (5 and 10% substitution). Antioxidant content, antioxidant activity, proximate, and sensorial analysis of the cookies were conducted. The microwave method was the best pretreatment compared with sonication and maceration since it showed 1.3-fold higher amounts of phenolic compounds and 1.2-fold higher antioxidant capacity. The 10% substitution of tamarind pericarp powder in cookies, significantly increased the fiber content (four-fold) and phenolic compounds content (2.6-fold) and the product presented good acceptance in a sensorial test. Thus, tamarind pericarp powder could be considered as an antioxidant and fiber source and could be used as a functional ingredient in food products.

Phase 1 Open-Label Study of Omigapil in Patients With LAMA2- or COL6-Related Dystrophy.

Background and Objectives: Omigapil is a small molecule which inhibits the GAPDH-Siah1-mediated apoptosis pathway. Apoptosis is a pathomechanism underlying the congenital muscular dystrophy subtypes LAMA2-related dystrophy (LAMA2-RD) and COL6-related dystrophy (COL6-RD). Studies of omigapil in the (dyw/dyw) LAMA2-RD mouse model demonstrated improved survival, and studies in the (dy2J/dy2J) LAMA2-RD mouse model and the (Col6a1-/-) COL6-RD mouse model demonstrated decreased apoptosis. Methods: A phase 1 open-label, sequential group, ascending oral dose, cohort study of omigapil in patients with LAMA2-RD or COL6-RD ages 5-16 years was performed (1) to establish the pharmacokinetic (PK) profile of omigapil at a range of doses, (2) to evaluate the safety and tolerability of omigapil at a range of doses, and (3) to establish the feasibility of conducting disease-relevant clinical assessments. Patients were enrolled in cohorts of size 4, with each patient receiving 4 weeks of vehicle run-in and 12 weeks of study drug (at daily doses ranging from 0.02 to 0.08 mg/kg). PK data from each cohort were analyzed before each subsequent dosing cohort was enrolled. A novel, adaptive dose-finding method (stochastic approximation with virtual observation recursion) was used to allow for dose escalation/reduction between cohorts based on PK data. Results: Twenty patients were enrolled at the NIH (LAMA2-RD: N = 10; COL6-RD: N = 10). Slightly greater than dose-proportional increases in systemic exposure to omigapil were seen at doses 0.02-0.08 mg/kg/d. The dose which achieved patient exposure within the pre-established target area under the plasma concentration-vs-time curve (AUC0-24h) range was 0.06 mg/kg/d. In general, omigapil was safe and well tolerated. No consistent changes were seen in the disease-relevant clinical assessments during the duration of the study. Discussion: This study represents the thus far only clinical trial of a therapeutic small molecule for LAMA2-RD and COL6-RD, completed with an adaptive trial design to arrive at dose adjustments. The trial met its primary end point and established that the PK profile of omigapil is suitable for further development in pediatric patients with LAMA2-RD or COL6-RD, the most common forms of congenital muscular dystrophy. While within the short duration of the study disease-relevant clinical assessments did not demonstrate significant changes, this study establishes the feasibility of performing interventional clinical trials in these rare disease patient populations. Classification of Evidence: This study provides Class IV evidence of omigapil in a dose-finding phase 1 study. Trial Registration Information: Clinical Trials NCT01805024.

Left Ventricular Pressure Ratio Predicts In-Hospital Outcomes in Hospitalized Heart Failure With Reduced Ejection Fraction.

BACKGROUND: Given the risk of hemodynamic compromise in heart failure with reduced ejection fraction (HFrEF) patients undergoing left heart catheterization (LHC), there is a need for a simple parameter that can predict clinical outcomes. We hypothesize that left ventricular pressure ratio (LVPR), calculated as left ventricle systolic/left ventricle end-diastolic pressure, is a strong predictor of hemodynamic collapse in these patients. METHODS: Retrospective analysis of consecutive hospitalized HFrEF patients undergoing combined LHC and right heart catheterization (RHC) at a single institution from 2015-2017 was performed. LVPR was compared with standard RHC hemodynamic variables. The primary outcome was in-hospital escalation of therapy, defined as ≥40 mm Hg drop in systolic blood pressure (SBP), SBP ≤90 mm Hg for ≥15 minutes, start or escalation of vasoactive medications, cardiopulmonary resuscitation, or in-hospital death. Receiver-operating characteristic (ROC) analysis and Kaplan-Meier survival analysis were performed for prediction of the primary outcome. RESULTS: A total of 176 patients were included in this study. ROC analysis determined an optimal cut-off value of ≤3.96, which correlated with an area under the curve (AUC) of 0.65 (sensitivity, 45.9%; specificity, 83.2%; correctly classified, 64.9%). AUC was similar to other variables obtained using RHC. In-hospital survival free of escalation of therapy was lower in the low LVPR group vs the high LVPR group (0% vs 33%, respectively; P<.01). CONCLUSION: LVPR is an easily measured index obtained during LHC that can risk stratify hospitalized patients with HFrEF at the time of LHC.