Detection of T wave peak for serial comparisons of JTp interval

Electrocardiogram (ECG) studies of drug-induced prolongation of the interval between the J point and the peak of the T wave (JTp interval) distinguished QT prolonging drugs that predominantly block the delayed potassium rectifier current from those affecting multiple cardiac repolarisation ion channel currents. Since the peak of the T wave depends on ECG lead, a “global” T peak requires to combine ECG leads into one-dimensional signal in which the T wave peak can be measured. This study aimed at finding the optimum one-dimensional representation of 12-lead ECGs for the most stable JTp measurements. Seven different one-dimensional representations were investigated including the vector magnitude of the orthogonal XYZ transformation, root mean square of all 12 ECG leads, and the vector magnitude of the 3 dominant orthogonal leads derived by singular value decomposition. All representations were applied to the representative waveforms of 660,657 separate 10-second 12-lead ECGs taken from repeated day-time Holter recordings in 523 healthy subjects aged 33.5±8.4 years (254 women). The JTp measurements were compared with the QT intervals and with the intervals between the J point and the median point of the area under the T wave one-dimensional representation (JT50 intervals) by means of calculating the residuals of the subject-specific curvilinear regression models relating the measured interval to the hysteresis-corrected RR interval of the underlying heart rate. The residuals of the regression models (equal to the intra-subject standard deviations of individually heart rate corrected intervals) expressed intra-subject stability of interval measurements. For both the JTp intervals and the JT50 intervals, the curvilinear regression residuals of measurements derived from the orthogonal XYZ representation were marginally but statistically significantly lower compared to the other representations. Using the XYZ representation, the residuals of the QT/RR, JTp/RR and JT50/RR regressions were 5.6±1.1 ms, 7.2±2.2 ms, and 4.9±1.2 ms, respectively (all statistically significantly different; p<0.0001). The study concludes that the orthogonal XYZ ECG representation might be proposed for future investigations of JTp and JT50 intervals. If the ability of classifying QT prolonging drugs is further confirmed for the JT50 interval, it might be appropriate to replace the JTp interval since it appears more stable

Sex differences in drug-induced changes in ventricular repolarization

Introduction: Heart rate corrected QT (QTc) interval prolongation is a predictor of drug-induced torsade de pointes, a potentially fatal ventricular arrhythmia that disproportionately affects women. This study assesses whether there are sex differences in the ECG changes induced by four different hERG potassium channel blocking drugs. Methods and results: Twenty-two healthy subjects (11 women) received a single oral dose of dofetilide, quinidine, ranolazine, verapamil and placebo in a double-blind 5-period crossover study. ECGs and plasma drug concentrations were obtained at pre-dose and at 15 time-points post-dose. Dofetilide, quinidine and ranolazine prolonged QTc. There were no sex differences in QTc prolongation for any drug, after accounting for differences in exposure. Sex differences in any ECG biomarker were observed only with dofetilide, which caused greater J-Tpeakc prolongation (p=0.045) but lesser Tpeak-Tend prolongation (p=0.006) and lesser decrease of T wave amplitude (p=0.003) in women compared to men. Conclusions: There were no sex differences in QTc prolongation for any of the studied drugs. Moreover, no systematic sex differences in other drug-induced ECG biomarker changes were observed in this study. This study suggests that the higher torsade risk in women compared to men is not due to a larger concentration-dependent QTc prolongation

Comprehensive T wave Morphology Assessment in a Randomized Clinical Study of Dofetilide, Quinidine, Ranolazine, and Verapamil

Background Congenital long QT syndrome type 2 (abnormal hERG potassium channel) patients can develop flat, asymmetric, and notched T waves. Similar observations have been made with a limited number of hERG-blocking drugs. However, it is not known how additional calcium or late sodium block, that can decrease torsade risk, affects T wave morphology. Methods and Results Twenty-two healthy subjects received a single dose of a pure hERG blocker (dofetilide) and 3 drugs that also block calcium or sodium (quinidine, ranolazine, and verapamil) as part of a 5-period, placebo-controlled cross-over trial. At pre-dose and 15 time-points post-dose, ECGs and plasma drug concentration were assessed. Patch clamp experiments were performed to assess block of hERG, calcium (L-type) and late sodium currents for each drug. Pure hERG block (dofetilide) and strong hERG block with lesser calcium and late sodium block (quinidine) caused substantial T wave morphology changes (P<0.001). Strong late sodium current and hERG block (ranolazine) still caused T wave morphology changes (P<0.01). Strong calcium and hERG block (verapamil) did not cause T wave morphology changes. At equivalent QTc prolongation, multichannel blockers (quinidine and ranolazine) caused equal or greater T wave morphology changes compared with pure hERG block (dofetilide). Conclusions T wave morphology changes are directly related to amount of hERG block; however, with quinidine and ranolazine, multichannel block did not prevent T wave morphology changes. A combined approach of assessing multiple ion channels, along with ECG intervals and T wave morphology may provide the greatest insight into drug-ion channel interactions and torsade de pointes risk

A Proposal for Integrated Efficacy-to-Effectiveness (E2E) Clinical Trials

We propose an “efficacy-to-effectiveness” (E2E) clinical trial design, in which an effectiveness trial would commence seamlessly upon completion of the efficacy trial. Efficacy trials use inclusion/exclusion criteria to produce relatively homogeneous samples of participants with the target condition, conducted in settings that foster adherence to rigorous clinical protocols. Effectiveness trials use inclusion/exclusion criteria that generate heterogeneous samples that are more similar to the general patient spectrum, conducted in more varied settings, with protocols that approximate typical clinical care. In E2E trials, results from the efficacy trial component would be used to design the effectiveness trial component, to confirm and/or discern associations between clinical characteristics and treatment effects in typical care, and potentially to test new hypotheses. An E2E approach may improve the evidentiary basis for selecting treatments, expand understanding of the effectiveness of treatments in subgroups with particular clinical features, and foster incorporation of effectiveness information into regulatory processes.National Center for Research Resources (U.S.) (Grant UL1 RR025752)National Center for Advancing Translational Sciences (U.S.) (Grant UL1 TR000073

COVID-19: Rapid antigen detection for SARS-CoV-2 by lateral flow assay: A national systematic evaluation of sensitivity and specificity for mass-testing

Background Lateral flow device (LFD) viral antigen immunoassays have been developed around the world as diagnostic tests for SARS-CoV-2 infection. They have been proposed to deliver an infrastructure-light, cost-economical solution giving results within half an hour. Methods LFDs were initially reviewed by a Department of Health and Social Care team, part of the UK government, from which 64 were selected for further evaluation from 1st August to 15th December 2020. Standardised laboratory evaluations, and for those that met the published criteria, field testing in the Falcon-C19 research study and UK pilots were performed (UK COVID-19 testing centres, hospital, schools, armed forces). Findings 4/64 LFDs so far have desirable performance characteristics (orient Gene, Deepblue, Abbott and Innova SARS-CoV-2 Antigen Rapid Qualitative Test). All these LFDs have a viral antigen detection of >90% at 100,000 RNA copies/ml. 8951 Innova LFD tests were performed with a kit failure rate of 5.6% (502/8951, 95% CI: 5.1–6.1), false positive rate of 0.32% (22/6954, 95% CI: 0.20–0.48). Viral antigen detection/sensitivity across the sampling cohort when performed by laboratory scientists was 78.8% (156/198, 95% CI 72.4–84.3). Interpretation Our results suggest LFDs have promising performance characteristics for mass population testing and can be used to identify infectious positive individuals. The Innova LFD shows good viral antigen detection/sensitivity with excellent specificity, although kit failure rates and the impact of training are potential issues. These results support the expanded evaluation of LFDs, and assessment of greater access to testing on COVID-19 transmission. Funding Department of Health and Social Care. University of Oxford. Public Health England Porton Down, Manchester University NHS Foundation Trust, National Institute of Health Research

“Supposing that truth is a woman, what then?” The Lie Detector, The Love Machine and the Logic of Fantasy

One of the consequences of the public outcry over the 1929 St Valentine’s Day massacre was the establishment of a Scientific Crime Detection Laboratory at Northwestern University. The photogenic “Lie Detector Man”, Leonarde Keeler, was the Laboratory’s poster boy and his instrument the jewel in the crown of forensic science. The press often depicted Keeler gazing at a female suspect attached to his “sweat box”; a galvanometer electrode in her hand, a sphygmomanometer cuff on her arm and a rubber pneumograph tube strapped across her breasts. Keeler’s fascination with the deceptive charms of the female body was one he shared with his fellow lie detector pioneers, all of whom met their wives – and in William Marston’s case his mistress too – through their engagement with the instrument. Marston employed his own “Love Meter”, as the press dubbed it, to prove that “brunettes react far more violently to amatory stimuli than blondes”. In this paper I draw on the psychoanalytic concepts of fantasy and pleasure to argue that the female body played a pivotal role in establishing the lie detector’s reputation as an infallible and benign mechanical technology of truth

The Rodin-Ohno hypothesis that two enzyme superfamilies descended from one ancestral gene: an unlikely scenario for the origins of translation that will not be dismissed

Background Because amino acid activation is rate-limiting for uncatalyzed protein synthesis, it is a key puzzle in understanding the origin of the genetic code. Two unrelated classes (I and II) of contemporary aminoacyl-tRNA synthetases (aaRS) now translate the code. Observing that codons for the most highly conserved, Class I catalytic peptides, when read in the reverse direction, are very nearly anticodons for Class II defining catalytic peptides, Rodin and Ohno proposed that the two superfamilies descended from opposite strands of the same ancestral gene. This unusual hypothesis languished for a decade, perhaps because it appeared to be unfalsifiable. Results The proposed sense/antisense alignment makes important predictions. Fragments that align in antiparallel orientations, and contain the respective active sites, should catalyze the same two reactions catalyzed by contemporary synthetases. Recent experiments confirmed that prediction. Invariant cores from both classes, called Urzymes after Ur = primitive, authentic, plus enzyme and representing ~20% of the contemporary structures, can be expressed and exhibit high, proportionate rate accelerations for both amino-acid activation and tRNA acylation. A major fraction (60%) of the catalytic rate acceleration by contemporary synthetases resides in segments that align sense/antisense. Bioinformatic evidence for sense/antisense ancestry extends to codons specifying the invariant secondary and tertiary structures outside the active sites of the two synthetase classes. Peptides from a designed, 46-residue gene constrained by Rosetta to encode Class I and II ATP binding sites with fully complementary sequences both accelerate amino acid activation by ATP ~400 fold. Conclusions Biochemical and bioinformatic results substantially enhance the posterior probability that ancestors of the two synthetase classes arose from opposite strands of the same ancestral gene. The remarkable acceleration by short peptides of the rate-limiting step in uncatalyzed protein synthesis, together with the synergy of synthetase Urzymes and their cognate tRNAs, introduce a new paradigm for the origin of protein catalysts, emphasize the potential relevance of an operational RNA code embedded in the tRNA acceptor stems, and challenge the RNA-World hypothesis. Reviewers This article was reviewed by Dr. Paul Schimmel (nominated by Laura Landweber), Dr. Eugene Koonin and Professor David Ardell

Implications of individual QT/RR profiles - Part 1: Inaccuracies and problems of population-specific QT/heart rate corrections

Introduction Universal QT correction formulas are potentially problematic in corrected QT (QTc) interval comparisons at different heart rates. Instead of individual-specific corrections, population-specific corrections are occasionally used based on QT/RR data pooled from all study subjects. Objective To investigate the performance of individual-specific and population-specific corrections, a statistical modeling study was performed using QT/RR data of 523 healthy subjects. Methods In each subject, full drug-free QT/RR profiles were available, characterized using non-linear regression models. In each subject, 50 baseline QT/RR readings represented baseline data of standard QT studies. Using these data, linear and log-linear heart rate corrections were optimized for each subject and for different groups of ten and 50 subjects. These corrections were applied in random combinations of heart rate changes between − 10 and + 25 beats per minute (bpm) and known QTc interval changes between − 25 and + 25 ms. Results Both the subject-specific and population-specific corrections based on the 50 baseline QT/RR readings tended to underestimate/overestimate the QTc interval changes when heart rate was increasing/decreasing, respectively. The result spread was much wider with population-specific corrections, making the estimates of QTc interval changes practically unpredictable. Conclusion Subject-specific heart rate corrections based on limited baseline drug-free data may lead to inconsistent results and, in the presence of underlying heart rate changes, may potentially underestimate or overestimate QTc interval changes. The population-specific corrections lead to results that are much more influenced by the combination of individual QT/RR patterns than by the actual QTc interval changes. Subject-specific heart rate corrections based on full profiles derived from drug-free baseline recordings with wide QT/RR distribution should be used when studying drugs expected to cause heart rate changes