In a large health system in the United States, investigators examined whether mortality, receipt of mechanical ventilation, and patient acuity changed over time among adult patients with COVID-19–related critical illness admitted to intensive care units.

Hemin is released from hemoglobin after CNS hemorrhage and is present at high micromolar concentrations in intracranial hematomas. This highly reactive compound is potentially cytotoxic via a variety of oxidative and nonoxidative mechanisms. However, despite its clinical relevance, little is known of its effect on neuronal cells. In this study, we tested the hypotheses that hemin is toxic to human neurons at physiologically relevant concentrations and that its toxicity is iron dependent and oxidative. A homogeneous population of neuron-like cells was produced by sequential treatment of SH-SY5Y cells with retinoic acid and brain-derived neurotrophic factor, using the protocol of Encinas et al. Hemin exposure for 24 hr resulted in cell death that progressively increased between 3 and 30 microM (EC(50) approximately 10 microM); protoporphyrin IX, the iron-free congener of hemin, was not toxic. Cell death commenced at 14 hr and was preceded by a marked increase in cellular reactive oxygen species (ROS). Most injury and ROS production were prevented by concomitant treatment with an equimolar concentration of the lipid-soluble iron chelator phenanthroline; the water-soluble chelator deferoxamine was also effective at concentrations of 0.1 mM or higher. Heme oxygenase-2 was constitutively expressed by these cells, and heme oxygenase-1 was induced by hemin. Heme oxygenase inhibition attenuated ROS generation and reduced injury by about one-third. Cell death was also prevented with the sulfhydryl reducing agents glutathione and mercaptoethanol. Nuclear morphology in the hours prior to cell lysis revealed a predominantly homogenous staining pattern; the percentage of fragmented nuclei was increased only at 4 hr and then accounted for only 1.45% +/- 0.25% of cells. The general caspase inhibitor zVAD-fmk had no effect on cell viability. These results suggest that hemin is toxic to human neuron-like cells at concentrations that are less than 3% of those observed in intracranial hematomas. In this model, its toxicity is iron dependent, oxidative, and predominantly necrotic.

Since randomized coronary revascularization trials in stable CAD have shown no reduced MI or mortality, the threshold of quantitative myocardial perfusion severity was analyzed for association with reduced death, MI or stroke after revascularization within 90 days after PET. In a prospective long-term cohort of stable CAD, regional, artery specific, quantitative myocardial perfusion by positron emission tomography (PET), coronary revascularization within 90 days after PET and all cause death, myocardial infarction and stroke (DMS) at 9 years follow-up, mean 3.0 ± 2.3 years, were analyzed by multivariate Cox regression models and propensity analysis. For 3774 sequential rest-stress PET scans, regional, artery specific, severely reduced Coronary Flow Capacity (CFC) (CFR ≤ 1.27 and stress perfusion ≤ 0.83 cc/min/g) associated with 60% increased hazard ratio for major adverse cardiovascular events (MACE) and 30% increased hazard of DMS that was significantly reduced by 54% associated with revascularization within 90 days after PET ( = 0.0369), compared to moderate or mild CFC, CFR, other PET metrics or medical treatment alone. Depending on severity threshold for statistical certainty, up to 19% of this clinical cohort had CFC severity associated with reduced DMS after revascularization. Coronary Flow Capacity by PET provides objective, regional, artery specific, size-severity physiologic quantification of CAD severity associated with high risk of death, MI and stroke that is significantly reduced after revascularization within 90 days after PET, an association not seen for moderate to mild perfusion abnormalities or medical treatment alone.

Recreational consumption of synthetic cannabinoid receptor agonists (SCRAs) is a growing crisis in public health in many parts of the world. AMB-FUBINACA is a member of this class of drugs and is responsible for a large proportion of SCRA-related toxicity both in New Zealand and internationally. Strikingly, little is currently known about the mechanisms by which SCRAs exert toxic effects or whether their activity through the CB 1 cannabinoid receptor (the mediator of cannabinoid-related psychoactivity) is sufficient to explain clinical observations. The current study therefore set out to perform a basic molecular pharmacology characterization of AMB-FUBINACA (in comparison to traditional research cannabinoids CP55,940, WIN55,212-2, and Δ 9 -THC) in fundamental pathways of receptor activity, including cAMP inhibition, pERK activation, ability to drive CB 1 internalization, and ability to induce translocation of β-arrestins-1 and -2. Activity pathways were then compared by operational analysis to indicate whether AMB-FUBINACA may be a biased ligand. Results revealed that AMB-FUBINACA is highly efficacious and potent in all pathways assayed. However, surprisingly, bias analysis suggested that Δ 9 -THC, not AMB-FUBINACA, may be a biased ligand, with it being less active in both arrestin pathways than predicted by the activity of the other ligands tested. These data may help predict molecular characteristics of SCRAs. However, more research is required to determine whether these molecular effects manifest in toxicity at tissue/system level.