BackgroundResting conventional 12-lead ECG has low sensitivity for detection of coronary artery disease (CAD) and left ventricular hypertrophy (LVH) and low positive predictive value (PPV) for prediction of left ventricular systolic dysfunction (LVSD). We hypothesized that a ~5-min resting 12-lead advanced ECG test ("A-ECG") that combined results from both the advanced and conventional ECG could more accurately screen for these conditions than strictly conventional ECG.MethodsResults from nearly every conventional and advanced resting ECG parameter known from the literature to have diagnostic or predictive value were first retrospectively evaluated in 418 healthy controls and 290 patients with imaging-proven CAD, LVH and/or LVSD. Each ECG parameter was examined for potential inclusion within multi-parameter A-ECG scores derived from multivariate regression models that were designed to optimally screen for disease in general or LVSD in particular. The performance of the best retrospectively-validated A-ECG scores was then compared against that of optimized pooled criteria from the strictly conventional ECG in a test set of 315 additional individuals.ResultsCompared to optimized pooled criteria from the strictly conventional ECG, a 7-parameter A-ECG score validated in the training set increased the sensitivity of resting ECG for identifying disease in the test set from 78% (72-84%) to 92% (88-96%) (P < 0.0001) while also increasing specificity from 85% (77-91%) to 94% (88-98%) (P < 0.05). In diseased patients, another 5-parameter A-ECG score increased the PPV of ECG for LVSD from 53% (41-65%) to 92% (78-98%) (P < 0.0001) without compromising related negative predictive value.ConclusionResting 12-lead A-ECG scoring is more accurate than strictly conventional ECG in screening for CAD, LVH and LVSD.
Acute coronary artery occlusion is detected with higher sensitivity using high-frequency QRS analysis compared with conventional assessment of ST segments. This result suggests that analysis of HF-QRS could provide an adjunctive tool with high sensitivity for detecting acute myocardial ischemia.
This review considers antiviral nucleoside analog (NA) drugs, including ribavirin, favipiravir, and molnupiravir, which induce genome error catastrophe in SARS‐CoV or SARS‐CoV‐2 via lethal mutagenesis as a mode of action. In vitro data indicate that molnupiravir may be 100 times more potent as an antiviral agent than ribavirin or favipiravir. Molnupiravir has recently demonstrated efficacy in a phase 3 clinical trial. Because of its anticipated global use, its relative potency, and the reported in vitro “host” cell mutagenicity of its active principle, β‐d‐N4‐hydroxycytidine, we have reviewed the development of molnupiravir and its genotoxicity safety evaluation, as well as the genotoxicity profiles of three congeners, that is, ribavirin, favipiravir, and 5‐(2‐chloroethyl)‐2′‐deoxyuridine. We consider the potential genetic risks of molnupiravir on the basis of all available information and focus on the need for additional human genotoxicity data and follow‐up in patients treated with molnupiravir and similar drugs. Such human data are especially relevant for antiviral NAs that have the potential of permanently modifying the genomes of treated patients and/or causing human teratogenicity or embryotoxicity. We conclude that the results of preclinical genotoxicity studies and phase 1 human clinical safety, tolerability, and pharmacokinetics are critical components of drug safety assessments and sentinels of unanticipated adverse health effects. We provide our rationale for performing more thorough genotoxicity testing prior to and within phase 1 clinical trials, including human PIG‐A and error corrected next generation sequencing (duplex sequencing) studies in DNA and mitochondrial DNA of patients treated with antiviral NAs that induce genome error catastrophe via lethal mutagenesis.
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