Quantum Mechanics and the Metrics of General Relativity

A one-to-one correspondence is established between linearized space-time metrics of general relativity and the wave equations of quantum mechanics. Also, the key role of boundary conditions in distinguishing quantum mechanics from classical mechanics will emerge naturally from the procedure. Finally, we will find that the methodology will enable us to introduce not only test charges but also test masses by means of gauges.Comment: 24 pages, to be published in Foundation of Physics (IARD proc.

Applying mechanical philosophy to web science: The case of social machines

Social machines are a prominent focus of attention for those who work in the field of Web and Internet science. Although a number of online systems have been described as social machines, there is, as yet, little consensus as to the precise meaning of the term “social machine.” This presents a problem for the scientific study of social machines, especially when it comes to the provision of a theoretical framework that directs, informs, and explicates the scientific and engineering activities of the social machine community. The present paper outlines an approach to understanding social machines that draws on recent work in the philosophy of science, especially work in so-called mechanical philosophy. This is what might be called a mechanistic view of social machines. According to this view, social machines are systems whose phenomena are explained via an appeal to socio-technical mechanisms. We show how this account is able to accommodate a number of existing attempts to define the social machine concept, thereby yielding an important opportunity for theoretical integration

Use of proton pump inhibitors to treat persistent throat symptoms: Multicentre, double blind, randomised, placebo controlled trial

Objective. To assess the use of proton pump inhibitors (PPIs) to treat persistent throat symptoms. Design. Pragmatic, double blind, placebo controlled, randomised trial. Setting. Eight ear, nose, and throat outpatient clinics, United Kingdom. Participants. 346 patients aged 18 years or older with persistent throat symptoms who were randomised according to recruiting centre and baseline severity of symptoms (mild or severe): 172 to lansoprazole and 174 to placebo. Intervention. Random blinded allocation (1:1) to either 30 mg lansoprazole twice daily or matched placebo twice daily for 16 weeks. Main outcome measures. Primary outcome was symptomatic response at 16 weeks measured using the total reflux symptom index (RSI) score. Secondary outcomes included symptom response at 12 months, quality of life, and throat appearances. Results. Of 1427 patients initially screened for eligibility, 346 were recruited. The mean age of the study sample was 52.2 (SD 13.7) years, 196 (57%) were women, and 162 (47%) had severe symptoms at presentation; these characteristics were balanced across treatment arms. The primary analysis was performed on 220 patients who completed the primary outcome measure within a window of 14-20 weeks. Mean RSI scores were similar between treatment arms at baseline: lansoprazole 22.0 (95% confidence interval 20.4 to 23.6) and placebo 21.7 (20.5 to 23.0). Improvements (reduction in RSI score) were observed in both groups—score at 16 weeks: lansoprazole 17.4 (15.5 to19.4) and placebo 15.6 (13.8 to 17.3). No statistically significant difference was found between the treatment arms: estimated difference 1.9 points (95% confidence interval −0.3 to 4.2 points; P=0.096) adjusted for site and baseline symptom severity. Lansoprazole showed no benefits over placebo for any secondary outcome measure, including RSI scores at 12 months: lansoprazole 16.0 (13.6 to 18.4) and placebo 13.6 (11.7 to 15.5): estimated difference 2.4 points (−0.6 to 5.4 points). Conclusions. No evidence was found of benefit from PPI treatment in patients with persistent throat symptoms. RSI scores were similar between the lansoprazole and placebo groups after 16 weeks of treatment and at the 12 month follow-up

Trading Patterns and Market Integration in Overlapping Experimental Asset Markets

This paper examines trading patterns and market integration using laboratory asset markets. Our markets are designed to approximately correspond to the trading day for stocks cross-listed in markets in Europe and North America. Some of our markets feature timing restrictions so that participants cannot trade across markets except during a fully integrated overlap period. Comparison of markets with and without timing restrictions shows that restrictions reduce trading activity and shift transactions to the overlap period. When asset values are extreme, price discovery can be impeded when trading restrictions exist. The measurement of liquidity suggests that trading restrictions increase overall spreads

Knots in Charged Polymers

The interplay of topological constraints and Coulomb interactions in static and dynamic properties of charged polymers is investigated by numerical simulations and scaling arguments. In the absence of screening, the long-range interaction localizes irreducible topological constraints into tight molecular knots, while composite constraints are factored and separated. Even when the forces are screened, tight knots may survive as local (or even global) equilibria, as long as the overall rigidity of the polymer is dominated by the Coulomb interactions. As entanglements involving tight knots are not easy to eliminate, their presence greatly influences the relaxation times of the system. In particular, we find that tight knots in open polymers are removed by diffusion along the chain, rather than by opening up. The knot diffusion coefficient actually decreases with its charge density, and for highly charged polymers the knot's position appears frozen.Comment: Revtex4, 9 pages, 9 eps figure

Comparative analysis of macroalgae supplementation on the rumen microbial community: Asparagopsis taxiformis inhibits major ruminal methanogenic, fibrolytic, and volatile fatty acid-producing microbes in vitro

Seaweeds have received a great deal of attention recently for their potential as methane-suppressing feed additives in ruminants. To date, Asparagopsis taxiformis has proven a potent enteric methane inhibitor, but it is a priority to identify local seaweed varieties that hold similar properties. It is essential that any methane inhibitor does not compromise the function of the rumen microbiome. In this study, we conducted an in vitro experiment using the RUSITEC system to evaluate the impact of three red seaweeds, A. taxiformis, Palmaria mollis, and Mazzaella japonica, on rumen prokaryotic communities. 16S rRNA sequencing showed that A. taxiformis had a profound effect on the microbiome, particularly on methanogens. Weighted Unifrac distances showed significant separation of A. taxiformis samples from the control and other seaweeds (p < 0.05). Neither P. mollis nor M. japonica had a substantial effect on the microbiome (p > 0.05). A. taxiformis reduced the abundance of all major archaeal species (p < 0.05), leading to an almost total disappearance of the methanogens. Prominent fiber-degrading and volatile fatty acid (VFA)-producing bacteria including Fibrobacter and Ruminococcus were also inhibited by A. taxiformis (p < 0.05), as were other genera involved in propionate production. The relative abundance of several other bacteria including Prevotella, Bifidobacterium, Succinivibrio, Ruminobacter, and unclassified Lachnospiraceae were increased by A. taxiformis suggesting that the rumen microbiome adapted to an initial perturbation. Our study provides baseline knowledge of microbial dynamics in response to seaweed feeding over an extended period and suggests that feeding A. taxiformis to cattle to reduce methane may directly, or indirectly, inhibit important fiber-degrading and VFA-producing bacteria

Is group cognitive behaviour therapy for postnatal depression evidence-based practice? A systematic review

Background: There is evidence that psychological therapies including cognitive behaviour therapy (CBT) may be effective in reducing postnatal depression (PND) when offered to individuals. In clinical practice, this is also implemented in a group therapy format, which, although not recommended in guidelines, is seen as a cost-effective alternative. To consider the extent to which group methods can be seen as evidence-based, we systematically review and synthesise the evidence for the efficacy of group CBT compared to currently used packages of care for women with PND, and we discuss further factors which may contribute to clinician confidence in implementing an intervention. Methods: Seventeen electronic databases were searched. All full papers were read by two reviewers and a third reviewer was consulted in the event of a disagreement on inclusion. Selected studies were quality assessed, using the Cochrane Risk of Bias Tool, were data extracted by two reviewers using a standardised data extraction form and statistically synthesised where appropriate using the fixed-effect inverse-variance method. Results: Seven studies met the inclusion criteria. Meta-analyses showed group CBT to be effective in reducing depression compared to routine primary care, usual care or waiting list groups. A pooled effect size of d = 0.57 (95% CI 0.34 to 0.80, p < 0.001) was observed at 10–13 weeks post-randomisation, reducing to d = 0.28 (95% CI 0.03 to 0.53, p = 0.025) at 6 months. The non-randomised comparisons against waiting list controls at 10–13 weeks was associated with a larger effect size of d = 0.94 (95% CI 0.42 to 1.47, p < 0.001). However due to the limitations of the available data, such as ill-specified definitions of the CBT component of the group programmes, these results should be interpreted with caution. Conclusions: Although the evidence available is limited, group CBT was shown to be effective. We argue, therefore, that there is sufficient evidence to implement group CBT, conditional upon routinely collected outcomes being benchmarked against those obtained in trials of individual CBT, and with other important factors such as patient preference, clinical experience, and information from the local context taken into account when making the treatment decision

A randomised, placebo controlled trial of extra-oesophageal reflux treatment in the management of upper respiratory symptoms [TOPPITS:Trial of Proton Pump Inhibitors in Throat Symptoms]

Background. Persistent throat symptoms, such as throat clearing, globus sensation, voice change and catarrh are extremely common. On very limited evidence, they are increasingly attributed to “laryngopharyngeal reflux (LPR)” and treated with proton pump inhibitors (PPIs) in primary and secondary care. Methods. A double blind placebo controlled UK multicentre phase III trial randomly allocated adults with persistent throat symptoms 1:1 to either 30 mg of Lansoprazole or matched placebo twice daily for 16 weeks, stratified by centre and symptom severity. The primary outcome was patient-reported symptomatic response, measured by the total Reflux Symptom Index (RSI) score at the end of therapy. Secondary outcomes included safety, further symptoms and quality of life measures at 12-months. Results. 346 participants were randomised from 8 UK centres: mean (sd) age 52 (13), 196 (57%) female, 162 (47%) severe symptoms, balanced across randomised groups. Mean RSI scores (95% CI) were similar at baseline- Lansoprazole: 22.0 (20.4, 23.6), placebo: 21.7 (20.5, 23.0). Improvements (reduction in score) were observed in both groups at 16-weeks: Lansoprazole: 17.4 (15.5, 19.4), placebo: 15.6 (13.8, 17.3) (p=0.096 adjusted by site, severity). There was no statistically significant difference between randomised groups. No significant differences were observed in the secondary outcome measures. Conclusions. TOPPITS is the largest, definitive trial to assess PPI effectiveness for persistent throat symptoms. It found no advantage of Lansoprazole over placebo in a range of outcomes. The near routine use of PPIs for throat symptoms should be discontinued

Do Pregnant Women and Those at Risk of Developing Post-Natal Depression Consume Lower Amounts of Long Chain Omega-3 Polyunsaturated Fatty Acids?

The aims were to compare intakes of long chain omega-3 polyunsaturated fatty acid (LC n-3 PUFA) in pregnant and non-pregnant women in Australia and to compare these intakes to the Australian National Nutrition Survey of 1995 (NNS95) [1] and to determine if the LC n-3 PUFA intakes differed in women who may be ‘at risk’ compared with women ‘not at risk’ of developing post-natal depression (PND). A validated LC n-3 PUFA food frequency questionnaire and pregnant women’s Edinburgh Postnatal Depression Scale (EPDS) scores were used. LC n-3 PUFA intakes were comparable to the NNS95 but did not differ due to pregnancy or whether or not a woman is at risk of developing PND

Ranolazine as an Alternative Therapy to Flecainide for SCN5A V411M Long QT Syndrome Type 3 Patients

[EN] The prolongation of the QT interval represents the main feature of the long QT syndrome (LQTS), a life-threatening genetic disease. The heterozygous SCN5A V411M mutation of the human sodium channel leads to a LQTS type 3 with severe proarrhythmic effects due to an increase in the late component of the sodium current (INaL). The two sodium blockers flecainide and ranolazine are equally recommended by the current 2015 ESC guidelines to treat patients with LQTS type 3 and persistently prolonged QT intervals. However, awareness of pro-arrhythmic effects of flecainide in LQTS type 3 patients arose upon the study of the SCN5A E1784K mutation. Regarding SCN5A V411M individuals, flecainide showed good results albeit in a reduced number of patients and no evidence supporting the use of ranolazine has ever been released. Therefore, we ought to compare the effect of ranolazine and flecainide in a SCN5A V411M model using an in-silico modeling and simulation approach. We collected clinical data of four patients. Then, we fitted four Markovian models of the human sodium current (INa) to experimental and clinical data. Two of them correspond to the wild type and the heterozygous SCN5A V411M scenarios, and the other two mimic the effects of flecainide and ranolazine on INa. Next, we inserted them into three isolated cell action potential (AP) models for endocardial, midmyocardial and epicardial cells and in a one-dimensional tissue model. The SCN5A V411M mutation produced a 15.9% APD90 prolongation in the isolated endocardial cell model, which corresponded to a 14.3% of the QT interval prolongation in a one-dimensional strand model, in keeping with clinical observations. Although with different underlying mechanisms, flecainide and ranolazine partially countered this prolongation at the isolated endocardial model by reducing the APD90 by 8.7 and 4.3%, and the QT interval by 7.2 and 3.2%, respectively. While flecainide specifically targeted the mutation-induced increase in peak INaL, ranolazine reduced it during the entire AP. Our simulations also suggest that ranolazine could prevent early afterdepolarizations triggered by the SCN5A V411M mutation during bradycardia, as flecainide. We conclude that ranolazine could be used to treat SCN5A V411M patients, specifically when flecainide is contraindicated.This work was partially supported by Fondo Europeo de Desarrollo Regional (FEDER, "Union Europea, Una forma de hacer Europa") with the Ministerio de Economia y Competitividad (DPI2015-69125-R), Direccion General de Politica Cientifica de la Generalitat Valenciana (PROMETEO/2020/043) and Instituto de Salud Carlos III (La Fe Biobank PT17/0015/0043), as well as by Vicerrectorado de Investigacion, Innovacion y Transferencia de la Universitat Politecnica de Valencia with Ayuda a Primeros Proyectos de Investigacion (PAID-06-18), and by Memorial Nacho Barbera.Cano, J.; Zorio, E.; Mazzanti, A.; Arnau, MÁ.; Trenor Gomis, BA.; Priori, SG.; Saiz Rodríguez, FJ.... (2020). Ranolazine as an Alternative Therapy to Flecainide for SCN5A V411M Long QT Syndrome Type 3 Patients. Frontiers in Pharmacology. 11:1-19. https://doi.org/10.3389/fphar.2020.580481S11911Abdelsayed, M., Peters, C. H., & Ruben, P. C. (2015). Differential thermosensitivity in mixed syndrome cardiac sodium channel mutants. The Journal of Physiology, 593(18), 4201-4223. doi:10.1113/jp270139Ackerman, M. J., Priori, S. G., Willems, S., Berul, C., Brugada, R., Calkins, H., … Zipes, D. P. (2011). HRS/EHRA Expert Consensus Statement on the State of Genetic Testing for the Channelopathies and Cardiomyopathies. Heart Rhythm, 8(8), 1308-1339. doi:10.1016/j.hrthm.2011.05.020Aliot, E., Capucci, A., Crijns, H. J., Goette, A., & Tamargo, J. (2010). Twenty-five years in the making: flecainide is safe and effective for the management of atrial fibrillation. Europace, 13(2), 161-173. doi:10.1093/europace/euq382Andrikopoulos, G. K. (2015). Flecainide: Current status and perspectives in arrhythmia management. World Journal of Cardiology, 7(2), 76. doi:10.4330/wjc.v7.i2.76Belardinelli, L., Liu, G., Smith-Maxwell, C., Wang, W.-Q., El-Bizri, N., Hirakawa, R., … Shryock, J. C. (2012). A Novel, Potent, and Selective Inhibitor of Cardiac Late Sodium Current Suppresses Experimental Arrhythmias. Journal of Pharmacology and Experimental Therapeutics, 344(1), 23-32. doi:10.1124/jpet.112.198887Bengel, P., Ahmad, S., & Sossalla, S. (2017). Inhibition of Late Sodium Current as an Innovative Antiarrhythmic Strategy. Current Heart Failure Reports, 14(3), 179-186. doi:10.1007/s11897-017-0333-0Blich, M., Khoury, A., Suleiman, M., Lorber, A., Gepstein, L., & Boulous, M. (2019). Specific Therapy Based on the Genotype in a Malignant Form of Long QT3, Carrying the V411M Mutation. International Heart Journal, 60(4), 979-982. doi:10.1536/ihj.18-705Bohnen, M. S., Peng, G., Robey, S. H., Terrenoire, C., Iyer, V., Sampson, K. J., & Kass, R. S. (2017). Molecular Pathophysiology of Congenital Long QT Syndrome. Physiological Reviews, 97(1), 89-134. doi:10.1152/physrev.00008.2016Britton, O. J., Bueno-Orovio, A., Van Ammel, K., Lu, H. R., Towart, R., Gallacher, D. J., & Rodriguez, B. (2013). Experimentally calibrated population of models predicts and explains intersubject variability in cardiac cellular electrophysiology. Proceedings of the National Academy of Sciences, 110(23), E2098-E2105. doi:10.1073/pnas.1304382110Caballero, R., Dolz-Gaiton, P., Gomez, R., Amoros, I., Barana, A., Gonzalez de la Fuente, M., … Delpon, E. (2010). Flecainide increases Kir2.1 currents by interacting with cysteine 311, decreasing the polyamine-induced rectification. Proceedings of the National Academy of Sciences, 107(35), 15631-15636. doi:10.1073/pnas.1004021107Carrasco, J. I., Izquierdo, I., Medina, P., Arnau, M. Á., Salvador, A., & Zorio, E. (2012). Flecainide, a Therapeutic Option in a Patient With Long QT Syndrome Type 3 Caused by the Heterozygous V411M Mutation in the SCN5A Gene. Revista Española de Cardiología (English Edition), 65(11), 1058-1059. doi:10.1016/j.rec.2012.03.013Chadda, K. R., Jeevaratnam, K., Lei, M., & Huang, C. L.-H. (2017). Sodium channel biophysics, late sodium current and genetic arrhythmic syndromes. Pflügers Archiv - European Journal of Physiology, 469(5-6), 629-641. doi:10.1007/s00424-017-1959-1Chang, K. C., Dutta, S., Mirams, G. R., Beattie, K. A., Sheng, J., Tran, P. N., … Li, Z. (2017). Uncertainty Quantification Reveals the Importance of Data Variability and Experimental Design Considerations for in Silico Proarrhythmia Risk Assessment. Frontiers in Physiology, 8. doi:10.3389/fphys.2017.00917Chorin, E., Hu, D., Antzelevitch, C., Hochstadt, A., Belardinelli, L., Zeltser, D., … Viskin, S. (2016). Ranolazine for Congenital Long-QT Syndrome Type III. Circulation: Arrhythmia and Electrophysiology, 9(10). doi:10.1161/circep.116.004370Colquhoun, D., Dowsland, K. A., Beato, M., & Plested, A. J. R. (2004). How to Impose Microscopic Reversibility in Complex Reaction Mechanisms. Biophysical Journal, 86(6), 3510-3518. doi:10.1529/biophysj.103.038679Crumb, W. J., Vicente, J., Johannesen, L., & Strauss, D. G. (2016). An evaluation of 30 clinical drugs against the comprehensive in vitro proarrhythmia assay (CiPA) proposed ion channel panel. Journal of Pharmacological and Toxicological Methods, 81, 251-262. doi:10.1016/j.vascn.2016.03.009Dutta, S., Chang, K. C., Beattie, K. A., Sheng, J., Tran, P. N., Wu, W. W., … Li, Z. (2017). Optimization of an In silico Cardiac Cell Model for Proarrhythmia Risk Assessment. Frontiers in Physiology, 8. doi:10.3389/fphys.2017.00616Elkins, R. C., Davies, M. R., Brough, S. J., Gavaghan, D. J., Cui, Y., Abi-Gerges, N., & Mirams, G. R. (2013). Variability in high-throughput ion-channel screening data and consequences for cardiac safety assessment. Journal of Pharmacological and Toxicological Methods, 68(1), 112-122. doi:10.1016/j.vascn.2013.04.007Ficker, E., Jarolimek, W., Kiehn, J., Baumann, A., & Brown, A. M. (1998). Molecular Determinants of Dofetilide Block of HERG K + Channels. Circulation Research, 82(3), 386-395. doi:10.1161/01.res.82.3.386Grandi, E., Pasqualini, F. S., & Bers, D. M. (2010). A novel computational model of the human ventricular action potential and Ca transient. Journal of Molecular and Cellular Cardiology, 48(1), 112-121. doi:10.1016/j.yjmcc.2009.09.019Guo, D., & Jenkinson, S. (2019). Simultaneous assessment of compound activity on cardiac Nav1.5 peak and late currents in an automated patch clamp platform. Journal of Pharmacological and Toxicological Methods, 99, 106575. doi:10.1016/j.vascn.2019.04.001Hegyi, B., Bányász, T., Izu, L. T., Belardinelli, L., Bers, D. M., & Chen-Izu, Y. (2018). β-adrenergic regulation of late Na+ current during cardiac action potential is mediated by both PKA and CaMKII. Journal of Molecular and Cellular Cardiology, 123, 168-179. doi:10.1016/j.yjmcc.2018.09.006Horne, A. J., Eldstrom, J., Sanatani, S., & Fedida, D. (2011). A novel mechanism for LQT3 with 2:1 block: A pore-lining mutation in Nav1.5 significantly affects voltage-dependence of activation. Heart Rhythm, 8(5), 770-777. doi:10.1016/j.hrthm.2010.12.041Horvath, B., Banyasz, T., Jian, Z., Hegyi, B., Kistamas, K., Nanasi, P. P., … Chen-Izu, Y. (2013). Dynamics of the late Na+ current during cardiac action potential and its contribution to afterdepolarizations. Journal of Molecular and Cellular Cardiology, 64, 59-68. doi:10.1016/j.yjmcc.2013.08.010Horváth, B., Hézső, T., Szentandrássy, N., Kistamás, K., Árpádffy-Lovas, T., Varga, R., … Nánási, P. P. (2020). Late sodium current in human, canine and guinea pig ventricular myocardium. Journal of Molecular and Cellular Cardiology, 139, 14-23. doi:10.1016/j.yjmcc.2019.12.015KAUFMAN, E. S. (2008). Use of Ranolazine in Long-QT Syndrome Type 3. Journal of Cardiovascular Electrophysiology, 19(12), 1294-1295. doi:10.1111/j.1540-8167.2008.01255.xLancaster, M. C., & Sobie, E. (2016). Improved Prediction of Drug-Induced Torsades de Pointes Through Simulations of Dynamics and Machine Learning Algorithms. Clinical Pharmacology & Therapeutics, 100(4), 371-379. doi:10.1002/cpt.367Li, Z., Dutta, S., Sheng, J., Tran, P. N., Wu, W., Chang, K., … Colatsky, T. (2017). Improving the In Silico Assessment of Proarrhythmia Risk by Combining hERG (Human Ether-à-go-go-Related Gene) Channel–Drug Binding Kinetics and Multichannel Pharmacology. Circulation: Arrhythmia and Electrophysiology, 10(2). doi:10.1161/circep.116.004628Liu, H., Atkins, J., & Kass, R. S. (2003). Common Molecular Determinants of Flecainide and Lidocaine Block of Heart Na+ Channels. Journal of General Physiology, 121(3), 199-214. doi:10.1085/jgp.20028723Liu, H., Tateyama, M., Clancy, C. E., Abriel, H., & Kass, R. S. (2002). Channel Openings Are Necessary but not Sufficient for Use-dependent Block of Cardiac Na+ Channels by Flecainide. Journal of General Physiology, 120(1), 39-51. doi:10.1085/jgp.20028558Lu, H. R., Vlaminckx, E., & Gallacher, D. J. (2008). Choice of cardiac tissue in vitro plays an important role in assessing the risk of drug-induced cardiac arrhythmias in human: Beyond QT prolongation. Journal of Pharmacological and Toxicological Methods, 57(1), 1-8. doi:10.1016/j.vascn.2007.06.005Makielski, J. C. (2016). Late sodium current: A mechanism for angina, heart failure, and arrhythmia. Trends in Cardiovascular Medicine, 26(2), 115-122. doi:10.1016/j.tcm.2015.05.006Makita, N., Behr, E., Shimizu, W., Horie, M., Sunami, A., Crotti, L., … Roden, D. M. (2008). The E1784K mutation in SCN5A is associated with mixed clinical phenotype of type 3 long QT syndrome. Journal of Clinical Investigation. doi:10.1172/jci34057Maltsev, V. A., Sabbah, H. N., Higgins, R. S. D., Silverman, N., Lesch, M., & Undrovinas, A. I. (1998). Novel, Ultraslow Inactivating Sodium Current in Human Ventricular Cardiomyocytes. Circulation, 98(23), 2545-2552. doi:10.1161/01.cir.98.23.2545Moreno, J. D., & Clancy, C. E. (2012). Pathophysiology of the cardiac late Na current and its potential as a drug target. Journal of Molecular and Cellular Cardiology, 52(3), 608-619. doi:10.1016/j.yjmcc.2011.12.003Moreno, J. D., Lewis, T. J., & Clancy, C. E. (2016). Parameterization for In-Silico Modeling of Ion Channel Interactions with Drugs. PLOS ONE, 11(3), e0150761. doi:10.1371/journal.pone.0150761Moreno, J. D., Yang, P.-C., Bankston, J. R., Grandi, E., Bers, D. M., Kass, R. S., & Clancy, C. E. (2013). Ranolazine for Congenital and Acquired Late I Na -Linked Arrhythmias. Circulation Research, 113(7). doi:10.1161/circresaha.113.301971Moreno, J. D., Zhu, Z. I., Yang, P.-C., Bankston, J. R., Jeng, M.-T., Kang, C., … Clancy, C. E. (2011). A Computational Model to Predict the Effects of Class I Anti-Arrhythmic Drugs on Ventricular Rhythms. Science Translational Medicine, 3(98). doi:10.1126/scitranslmed.3002588Moss, A. J., Windle, J. R., Hall, W. J., Zareba, W., Robinson, J. L., McNitt, S., … Manalan, A. S. (2005). Safety and Efficacy of Flecainide in Subjects with Long QT-3 Syndrome (DeltaKPQ Mutation): A Randomized, Double-Blind, Placebo-Controlled Clinical Trial. Annals of Noninvasive Electrocardiology, 10(s4), 59-66. doi:10.1111/j.1542-474x.2005.00077.xMOSS, A. J., ZAREBA, W., SCHWARZ, K. Q., ROSERO, S., MCNITT, S., & ROBINSON, J. L. (2008). Ranolazine Shortens Repolarization in Patients with Sustained Inward Sodium Current Due to Type-3 Long-QT Syndrome. Journal of Cardiovascular Electrophysiology, 19(12), 1289-1293. doi:10.1111/j.1540-8167.2008.01246.xO’Hara, T., Virág, L., Varró, A., & Rudy, Y. (2011). Simulation of the Undiseased Human Cardiac Ventricular Action Potential: Model Formulation and Experimental Validation. PLoS Computational Biology, 7(5), e1002061. doi:10.1371/journal.pcbi.1002061Paul, A. A., Witchel, H. J., & Hancox, J. C. (2002). Inhibition of the current of heterologously expressed HERG potassium channels by flecainide and comparison with quinidine, propafenone and lignocaine. British Journal of Pharmacology, 136(5), 717-729. doi:10.1038/sj.bjp.0704784Penniman, J. R., Kim, D. C., Salata, J. J., & Imredy, J. P. (2010). Assessing use-dependent inhibition of the cardiac Na± current (INa) in the PatchXpress automated patch clamp. Journal of Pharmacological and Toxicological Methods, 62(2), 107-118. doi:10.1016/j.vascn.2010.06.007Postema, P. G., De Jong, J. S. S. G., Van der Bilt, I. A. C., & Wilde, A. A. M. (2008). Accurate electrocardiographic assessment of the QT interval: Teach the tangent. Heart Rhythm, 5(7), 1015-1018. doi:10.1016/j.hrthm.2008.03.037Priori, S. G., Blomström-Lundqvist, C., Mazzanti, A., Blom, N., Borggrefe, M., Camm, J., … Van Veldhuisen, D. J. (2015). 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. European Heart Journal, 36(41), 2793-2867. doi:10.1093/eurheartj/ehv316Rivolta, I., Abriel, H., Tateyama, M., Liu, H., Memmi, M., Vardas, P., … Kass, R. S. (2001). Inherited Brugada and Long QT-3 Syndrome Mutations of a Single Residue of the Cardiac Sodium Channel Confer Distinct Channel and Clinical Phenotypes. Journal of Biological Chemistry, 276(33), 30623-30630. doi:10.1074/jbc.m104471200Romero, L., Cano, J., Gomis-Tena, J., Trenor, B., Sanz, F., Pastor, M., & Saiz, J. (2018). In Silico QT and APD Prolongation Assay for Early Screening of Drug-Induced Proarrhythmic Risk. Journal of Chemical Information and Modeling, 58(4), 867-878. doi:10.1021/acs.jcim.7b00440Romero, L., Trenor, B., Yang, P.-C., Saiz, J., & Clancy, C. E. (2015). In silico screening of the impact of hERG channel kinetic abnormalities on channel block and susceptibility to acquired long QT syndrome. Journal of Molecular and Cellular Cardiology, 87, 271-282. doi:10.1016/j.yjmcc.2015.08.015Rudy, Y., & Silva, J. R. (2006). Computational biology in the study of cardiac ion channels and cell electrophysiology. Quarterly Reviews of Biophysics, 39(1), 57-116. doi:10.1017/s0033583506004227Saint, D. A. (2008). The cardiac persistent sodium current: an appealing therapeutic target? British Journal of Pharmacology, 153(6), 1133-1142. doi:10.1038/sj.bjp.0707492Smallwood, J., Robertson, D., & Steinberg, M. (1989). Electrophysiological effects of flecainide enantiomers in canine Purkinje fibres. Naunyn-Schmiedeberg’s Archives of Pharmacology, 339(6). doi:10.1007/bf00168654Sobie, E. A. (2009). Parameter Sensitivity Analysis in Electrophysiological Models Using Multivariable Regression. Biophysical Journal, 96(4), 1264-1274. doi:10.1016/j.bpj.2008.10.056Soltis, A. R., & Saucerman, J. J. (2010). Synergy between CaMKII Substrates and β-Adrenergic Signaling in Regulation of Cardiac Myocyte Ca2+ Handling. Biophysical Journal, 99(7), 2038-2047. doi:10.1016/j.bpj.2010.08.016Trenor, B., Cardona, K., Gomez, J. F., Rajamani, S., Ferrero, J. M., Belardinelli, L., & Saiz, J. (2012). Simulation and Mechanistic Investigation of the Arrhythmogenic Role of the Late Sodium Current in Human Heart Failure. PLoS ONE, 7(3), e32659. doi:10.1371/journal.pone.0032659Yang, P.-C., DeMarco, K. R., Aghasafari, P., Jeng, M.-T., Dawson, J. R. D., Bekker, S., … Clancy, C. E. (2020). A Computational Pipeline to Predict Cardiotoxicity. Circulation Research, 126(8), 947-964. doi:10.1161/circresaha.119.316404Yang, P.-C., El-Bizri, N., Romero, L., Giles, W. R., Rajamani, S., Belardinelli, L., & Clancy, C. E. (2016). A computational model predicts adjunctive pharmacotherapy for cardiac safety via selective inhibition of the late cardiac Na current. Journal of Molecular and Cellular Cardiology, 99, 151-161. doi:10.1016/j.yjmcc.2016.08.011Yang, P., Moreno, J. D., Miyake, C. Y., Vaughn‐Behrens, S. B., Jeng, M., Grandi, E., … Clancy, C. E. (2015). In silico prediction of drug therapy in catecholaminergic polymorphic ventricular tachycardia. The Journal of Physiology, 594(3), 567-593. doi:10.1113/jp271282Zhu, W., Mazzanti, A., Voelker, T. L., Hou, P., Moreno, J. D., Angsutararux, P., … Silva, J. R. (2019). Predicting Patient Response to the Antiarrhythmic Mexiletine Based on Genetic Variation. Circulation Research, 124(4), 539-552. doi:10.1161/circresaha.118.31405