Prognostic Role of Androgen Receptor in Triple Negative Breast Cancer: A Multi-Institutional Study

Background: Androgen Receptor (AR) has emerged as a potential therapeutic target for AR-positive triple-negative breast cancer (TNBC). However, conflicting reports regarding AR’s prognostic role in TNBC are putting its usefulness in question. Some studies conclude that AR positivity indicates a good prognosis in TNBC whereas others suggest the opposite, and some show that AR status has no significant bearing on the patients’ prognosis. Methods: We evaluated the prognostic value of AR in resected primary tumors from TNBC patients from six international cohorts {US (n=420), UK (n=239), Norway (n=104), Ireland (n=222), Nigeria (n=180), and India (n=242); total n=1407}. All TNBC samples were stained with the same anti-AR antibody using the same immunohistochemistry protocol, and samples with ≥1% of AR-positive nuclei were deemed AR-positive TNBCs. Results: AR status shows population-specific patterns of association with patients’ overall survival after controlling for age, grade, population, and chemotherapy. We found AR-positive status to be a marker of good prognosis in US and Nigerian cohorts, a marker of poor prognosis in Norway, Ireland and Indian cohorts, and neutral in UK cohort. Conclusion: AR status, on its own, is not a reliable prognostic marker. More research to investigate molecular subtype composition among the different cohorts is warranted

Nematode and Arthropod Genomes Provide New Insights into the Evolution of Class 2 B1 GPCRs

Nematodes and arthropods are the most speciose animal groups and possess Class 2 B1 G-protein coupled receptors (GPCRs). Existing models of invertebrate Class 2 B1 GPCR evolution are mainly centered on Caenorhabditis elegans and Drosophila melanogaster and a few other nematode and arthropod representatives. The present study reevaluates the evolution of metazoan Class 2 B1 GPCRs and orthologues by exploring the receptors in several nematode and arthropod genomes and comparing them to the human receptors. Three novel receptor phylogenetic clusters were identified and designated cluster A, cluster B and PDF-R-related cluster. Clusters A and B were identified in several nematode and arthropod genomes but were absent from D. melanogaster and Culicidae genomes, whereas the majority of the members of the PDF-R-related cluster were from nematodes. Cluster A receptors were nematode and arthropod-specific but shared a conserved gene environment with human receptor loci. Cluster B members were orthologous to human GCGR, PTHR and Secretin members with which they probably shared a common origin. PDF-R and PDF-R related clusters were present in representatives of both nematodes and arthropods. The results of comparative analysis of GPCR evolution and diversity in protostomes confirm previous notions that C. elegans and D. melanogaster genomes are not good representatives of nematode and arthropod phyla. We hypothesize that at least four ancestral Class 2 B1 genes emerged early in the metazoan radiation, which after the protostome-deuterostome split underwent distinct selective pressures that resulted in duplication and deletion events that originated the current Class 2 B1 GPCRs in nematode and arthropod genomes.This work was supported by the Portuguese Foundation for Science and Technology (FCT) project PTDC/BIA-BCM/114395/2009, by the European Regional Development Fund through COMPETE and FCT under the project ‘‘PEst-C/MAR/LA0015/2011.’’ RCF is in receipt of an FCT grant (SFRH/BPD/89811/2012) and JCRC is supported by auxiliary research contract FCT Pluriannual funds attributed to CCMAR. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Validation and Opportunities of Electrocardiographic Imaging: From Technical chievements to Clinical Applications

[EN] Electrocardiographic imaging (ECGI) reconstructs the electrical activity of the heart from a dense array of body-surface electrocardiograms and a patient-specific heart-torso geometry. Depending on how it is formulated, ECGI allows the reconstruction of the activation and recovery sequence of the heart, the origin of premature beats or tachycardia, the anchors/hotspots of re-entrant arrhythmias and other electrophysiological quantities of interest. Importantly, these quantities are directly and non-invasively reconstructed in a digitized model of the patient's three-dimensional heart, which has led to clinical interest in ECGI's ability to personalize diagnosis and guide therapy. Despite considerable development over the last decades, validation of ECGI is challenging. Firstly, results depend considerably on implementation choices, which are necessary to deal with ECGI's ill-posed character. Secondly, it is challenging to obtain (invasive) ground truth data of high quality. In this review, we discuss the current status of ECGI validation as well as the major challenges remaining for complete adoption of ECGI in clinical practice. Specifically, showing clinical benefit is essential for the adoption of ECGI. Such benefit may lie in patient outcome improvement, workflow improvement, or cost reduction. Future studies should focus on these aspects to achieve broad adoption of ECGI, but only after the technical challenges have been solved for that specific application/pathology. We propose 'best' practices for technical validation and highlight collaborative efforts recently organized in this field. Continued interaction between engineers, basic scientists, and physicians remains essential to find a hybrid between technical achievements, pathological mechanisms insights, and clinical benefit, to evolve this powerful technique toward a useful role in clinical practice.This study received financial support from the Hein Wellens Fonds, the Cardiovascular Research and Training Institute (CVRTI), the Nora Eccles Treadwell Foundation, the National Institute of General Medical Sciences of the National Institutes of Health (P41GM103545), the National Institutes of Health (NIH HL080093), the French government as part of the Investments of the Future program managed by the National Research Agency (ANR-10-IAHU-04), from the VEGA Grant Agency in Slovakia (2/0071/16), from the Slovak Research and Development Agency (APVV-14-0875), the Fondo Europeo de Desarrollo Regional (FEDER), the Instituto de Salud Carlos III (PI17/01106) and from Conselleria d'Educacio, Investigacio, Cultura i Esport de la Generalitat Valenciana (AICO/2018/267) and NIH grant (HL125998) and National Science Foundation (ACI-1350374).Cluitmans, M.; Brooks, D.; Macleod, RS.; Dossel, O.; Guillem Sánchez, MS.; Van Dam, P.; Svehlikova, J.... (2018). Validation and Opportunities of Electrocardiographic Imaging: From Technical chievements to Clinical Applications. Frontiers in Physiology. 9. https://doi.org/10.3389/fphys.2018.01305S9Andrews, C. M., Srinivasan, N. T., Rosmini, S., Bulluck, H., Orini, M., Jenkins, S., … Rudy, Y. (2017). Electrical and Structural Substrate of Arrhythmogenic Right Ventricular Cardiomyopathy Determined Using Noninvasive Electrocardiographic Imaging and Late Gadolinium Magnetic Resonance Imaging. Circulation: Arrhythmia and Electrophysiology, 10(7). doi:10.1161/circep.116.005105Aras, K., Good, W., Tate, J., Burton, B., Brooks, D., Coll-Font, J., … MacLeod, R. (2015). Experimental Data and Geometric Analysis Repository—EDGAR. Journal of Electrocardiology, 48(6), 975-981. doi:10.1016/j.jelectrocard.2015.08.008Austen, W., Edwards, J., Frye, R., Gensini, G., Gott, V., Griffith, L., … Roe, B. (1975). A reporting system on patients evaluated for coronary artery disease. Report of the Ad Hoc Committee for Grading of Coronary Artery Disease, Council on Cardiovascular Surgery, American Heart Association. Circulation, 51(4), 5-40. doi:10.1161/01.cir.51.4.5Bayley, R. H., & Berry, P. M. (1962). The electrical field produced by the eccentric current dipole in the nonhomogeneous conductor. American Heart Journal, 63(6), 808-820. doi:10.1016/0002-8703(62)90065-0Bear, L. R., Huntjens, P. R., Walton, R. D., Bernus, O., Coronel, R., & Dubois, R. (2018). Cardiac electrical dyssynchrony is accurately detected by noninvasive electrocardiographic imaging. Heart Rhythm, 15(7), 1058-1069. doi:10.1016/j.hrthm.2018.02.024Bear, L. R., LeGrice, I. J., Sands, G. B., Lever, N. A., Loiselle, D. S., Paterson, D. J., … Smaill, B. H. (2018). How Accurate Is Inverse Electrocardiographic Mapping? Circulation: Arrhythmia and Electrophysiology, 11(5). doi:10.1161/circep.117.006108Berger, T., Fischer, G., Pfeifer, B., Modre, R., Hanser, F., Trieb, T., … Hintringer, F. (2006). Single-Beat Noninvasive Imaging of Cardiac Electrophysiology of Ventricular Pre-Excitation. Journal of the American College of Cardiology, 48(10), 2045-2052. doi:10.1016/j.jacc.2006.08.019Berger, T., Pfeifer, B., Hanser, F. F., Hintringer, F., Fischer, G., Netzer, M., … Seger, M. (2011). Single-Beat Noninvasive Imaging of Ventricular Endocardial and Epicardial Activation in Patients Undergoing CRT. PLoS ONE, 6(1), e16255. doi:10.1371/journal.pone.0016255Dubois, R., Pashaei, A., Duchateau, J., & Vigmond, E. (2016). Evaluation of Combined Noninvasive Electrocardiographic Imaging and Phase Mapping approach for Atrial Fibrillation: A Simulation Study. 2016 Computing in Cardiology Conference (CinC). doi:10.22489/cinc.2016.037-540Duchateau, J., Potse, M., & Dubois, R. (2017). Spatially Coherent Activation Maps for Electrocardiographic Imaging. IEEE Transactions on Biomedical Engineering, 64(5), 1149-1156. doi:10.1109/tbme.2016.2593003Erem, B., Brooks, D. H., van Dam, P. M., Stinstra, J. G., & MacLeod, R. S. (2011). Spatiotemporal estimation of activation times of fractionated ECGs on complex heart surfaces. 2011 Annual International Conference of the IEEE Engineering in Medicine and Biology Society. doi:10.1109/iembs.2011.6091455Erem, B., van Dam, P. M., & Brooks, D. H. (2014). Identifying Model Inaccuracies and Solution Uncertainties in Noninvasive Activation-Based Imaging of Cardiac Excitation Using Convex Relaxation. IEEE Transactions on Medical Imaging, 33(4), 902-912. doi:10.1109/tmi.2014.2297952Erkapic, D., & Neumann, T. (2015). Ablation of Premature Ventricular Complexes Exclusively Guided by Three-Dimensional Noninvasive Mapping. Cardiac Electrophysiology Clinics, 7(1), 109-115. doi:10.1016/j.ccep.2014.11.010Everett, T. H., Lai-Chow Kok, Vaughn, R. H., Moorman, R., & Haines, D. E. (2001). Frequency domain algorithm for quantifying atrial fibrillation organization to increase defibrillation efficacy. IEEE Transactions on Biomedical Engineering, 48(9), 969-978. doi:10.1109/10.942586Faes, L., & Ravelli, F. (2007). A morphology-based approach to the evaluation of atrial fibrillation organization. IEEE Engineering in Medicine and Biology Magazine, 26(4), 59-67. doi:10.1109/memb.2007.384097Fitzpatrick, A. P., Gonzales, R. P., Lesh, M. D., odin, G. W., Lee, R. J., & Scheinman, M. M. (1994). New algorithm for the localization of accessory atrioventricular connections using a baseline electrocardiogram. Journal of the American College of Cardiology, 23(1), 107-116. doi:10.1016/0735-1097(94)90508-8Geselowitz, D. B. (1989). On the theory of the electrocardiogram. Proceedings of the IEEE, 77(6), 857-876. doi:10.1109/5.29327Geselowitz, D. B. (1992). Description of cardiac sources in anisotropic cardiac muscle. Journal of Electrocardiology, 25, 65-67. doi:10.1016/0022-0736(92)90063-6Ghanem, R. N., Jia, P., Ramanathan, C., Ryu, K., Markowitz, A., & Rudy, Y. (2005). Noninvasive Electrocardiographic Imaging (ECGI): Comparison to intraoperative mapping in patients. Heart Rhythm, 2(4), 339-354. doi:10.1016/j.hrthm.2004.12.022Ghosh, S., Rhee, E. K., Avari, J. N., Woodard, P. K., & Rudy, Y. (2008). Cardiac Memory in Patients With Wolff-Parkinson-White Syndrome. Circulation, 118(9), 907-915. doi:10.1161/circulationaha.108.781658Ghosh, S., Silva, J. N. A., Canham, R. M., Bowman, T. M., Zhang, J., Rhee, E. K., … Rudy, Y. (2011). Electrophysiologic substrate and intraventricular left ventricular dyssynchrony in nonischemic heart failure patients undergoing cardiac resynchronization therapy. Heart Rhythm, 8(5), 692-699. doi:10.1016/j.hrthm.2011.01.017Grace, A., Verma, A., & Willems, S. (2017). Dipole Density Mapping of Atrial Fibrillation. European Heart Journal, 38(1), 5-9. doi:10.1093/eurheartj/ehw585Dorset, D. L. (1996). Electron crystallography. Acta Crystallographica Section B Structural Science, 52(5), 753-769. doi:10.1107/s0108768196005599Haissaguerre, M., Hocini, M., Denis, A., Shah, A. J., Komatsu, Y., Yamashita, S., … Dubois, R. (2014). Driver Domains in Persistent Atrial Fibrillation. Circulation, 130(7), 530-538. doi:10.1161/circulationaha.113.005421HAISSAGUERRE, M., HOCINI, M., SHAH, A. J., DERVAL, N., SACHER, F., JAIS, P., & DUBOIS, R. (2013). Noninvasive Panoramic Mapping of Human Atrial Fibrillation Mechanisms: A Feasibility Report. Journal of Cardiovascular Electrophysiology, 24(6), 711-717. doi:10.1111/jce.12075Han, C., Pogwizd, S. M., Killingsworth, C. R., & He, B. (2011). Noninvasive imaging of three-dimensional cardiac activation sequence during pacing and ventricular tachycardia. Heart Rhythm, 8(8), 1266-1272. doi:10.1016/j.hrthm.2011.03.014Bin He, Guanglin Li, & Xin Zhang. (2003). Noninvasive imaging of cardiac transmembrane potentials within three-dimensional myocardium by means of a realistic geometry anisotropic heart model. IEEE Transactions on Biomedical Engineering, 50(10), 1190-1202. doi:10.1109/tbme.2003.817637Bin He, & Dongsheng Wu. (2001). Imaging and visualization of 3-D cardiac electric activity. IEEE Transactions on Information Technology in Biomedicine, 5(3), 181-186. doi:10.1109/4233.945288Horáček, B. M., Sapp, J. L., Penney, C. J., Warren, J. W., & Wang, J. J. (2011). Comparison of epicardial potential maps derived from the 12-lead electrocardiograms with scintigraphic images during controlled myocardial ischemia. Journal of Electrocardiology, 44(6), 707-712. doi:10.1016/j.jelectrocard.2011.08.009Horáček, B. M., Wang, L., Dawoud, F., Xu, J., & Sapp, J. L. (2015). Noninvasive electrocardiographic imaging of chronic myocardial infarct scar. Journal of Electrocardiology, 48(6), 952-958. doi:10.1016/j.jelectrocard.2015.08.035Jamil-Copley, S., Vergara, P., Carbucicchio, C., Linton, N., Koa-Wing, M., Luther, V., … Kanagaratnam, P. (2015). Application of Ripple Mapping to Visualize Slow Conduction Channels Within the Infarct-Related Left Ventricular Scar. Circulation: Arrhythmia and Electrophysiology, 8(1), 76-86. doi:10.1161/circep.114.001827Janssen, A. M., Potyagaylo, D., Dössel, O., & Oostendorp, T. F. (2017). Assessment of the equivalent dipole layer source model in the reconstruction of cardiac activation times on the basis of BSPMs produced by an anisotropic model of the heart. Medical & Biological Engineering & Computing, 56(6), 1013-1025. doi:10.1007/s11517-017-1715-xKnecht, S., Sohal, M., Deisenhofer, I., Albenque, J.-P., Arentz, T., Neumann, T., … Rostock, T. (2017). Multicentre evaluation of non-invasive biatrial mapping for persistent atrial fibrillation ablation: the AFACART study. EP Europace, 19(8), 1302-1309. doi:10.1093/europace/euw168Kuck, K.-H., Schaumann, A., Eckardt, L., Willems, S., Ventura, R., Delacrétaz, E., … Hansen, P. S. (2010). Catheter ablation of stable ventricular tachycardia before defibrillator implantation in patients with coronary heart disease (VTACH): a multicentre randomised controlled trial. The Lancet, 375(9708), 31-40. doi:10.1016/s0140-6736(09)61755-4Identification of Rotors during Human Atrial Fibrillation Using Contact Mapping and Phase Singularity Detection: Technical Considerations. (2017). IEEE Transactions on Biomedical Engineering, 64(2), 310-318. doi:10.1109/tbme.2016.2554660Leong, K. M. W., Ng, F. S., Yao, C., Roney, C., Taraborrelli, P., Linton, N. W. F., … Varnava, A. M. (2017). ST-Elevation Magnitude Correlates With Right Ventricular Outflow Tract Conduction Delay in Type I Brugada ECG. Circulation: Arrhythmia and Electrophysiology, 10(10). doi:10.1161/circep.117.005107Chenguang Liu, Eggen, M. D., Swingen, C. M., Iaizzo, P. A., & Bin He. (2012). Noninvasive Mapping of Transmural Potentials During Activation in Swine Hearts From Body Surface Electrocardiograms. IEEE Transactions on Medical Imaging, 31(9), 1777-1785. doi:10.1109/tmi.2012.2202914MacLeod, R. S., Ni, Q., Punske, B., Ershler, P. R., Yilmaz, B., & Taccardi, B. (2000). Effects of heart position on the body-surface electrocardiogram. Journal of Electrocardiology, 33, 229-237. doi:10.1054/jelc.2000.20357Metzner, A., Wissner, E., Tsyganov, A., Kalinin, V., Schlüter, M., Lemes, C., … Kuck, K.-H. (2017). Noninvasive phase mapping of persistent atrial fibrillation in humans: Comparison with invasive catheter mapping. Annals of Noninvasive Electrocardiology, 23(4), e12527. doi:10.1111/anec.12527Modre, R., Tilg, B., Fischer, G., Hanser, F., Messnarz, B., Seger, M., … Roithinger, F. X. (2003). Atrial Noninvasive Activation Mapping of Paced Rhythm Data. Journal of Cardiovascular Electrophysiology, 14(7), 712-719. doi:10.1046/j.1540-8167.2003.02558.xNarayan, S. M., Krummen, D. E., Shivkumar, K., Clopton, P., Rappel, W.-J., & Miller, J. M. (2012). Treatment of Atrial Fibrillation by the Ablation of Localized Sources. Journal of the American College of Cardiology, 60(7), 628-636. doi:10.1016/j.jacc.2012.05.022NG, J., KADISH, A. H., & GOLDBERGER, J. J. (2007). Technical Considerations for Dominant Frequency Analysis. Journal of Cardiovascular Electrophysiology, 18(7), 757-764. doi:10.1111/j.1540-8167.2007.00810.xOosterhoff, P., Meijborg, V. M. F., van Dam, P. M., van Dessel, P. F. H. M., Belterman, C. N. W., Streekstra, G. J., … Oostendorp, T. F. (2016). Experimental Validation of Noninvasive Epicardial and Endocardial Activation Imaging. Circulation: Arrhythmia and Electrophysiology, 9(8). doi:10.1161/circep.116.004104Oster, H. S., Taccardi, B., Lux, R. L., Ershler, P. R., & Rudy, Y. (1997). Noninvasive Electrocardiographic Imaging. Circulation, 96(3), 1012-1024. doi:10.1161/01.cir.96.3.1012Oster, H. S., Taccardi, B., Lux, R. L., Ershler, P. R., & Rudy, Y. (1998). Electrocardiographic Imaging. Circulation, 97(15), 1496-1507. doi:10.1161/01.cir.97.15.1496PEDRÓN-TORRECILLA, J., RODRIGO, M., CLIMENT, A. M., LIBEROS, A., PÉREZ-DAVID, E., BERMEJO, J., … GUILLEM, M. S. (2016). Noninvasive Estimation of Epicardial Dominant High-Frequency Regions During Atrial Fibrillation. Journal of Cardiovascular Electrophysiology, 27(4), 435-442. doi:10.1111/jce.12931Ploux, S., Lumens, J., Whinnett, Z., Montaudon, M., Strom, M., Ramanathan, C., … Bordachar, P. (2013). Noninvasive Electrocardiographic Mapping to Improve Patient Selection for Cardiac Resynchronization Therapy. Journal of the American College of Cardiology, 61(24), 2435-2443. doi:10.1016/j.jacc.2013.01.093Potyagaylo, D., Segel, M., Schulze, W. H. W., & Dössel, O. (2013). Noninvasive Localization of Ectopic Foci: A New Optimization Approach for Simultaneous Reconstruction of Transmembrane Voltages and Epicardial Potentials. Lecture Notes in Computer Science, 166-173. doi:10.1007/978-3-642-38899-6_20Punshchykova, O., Švehlíková, J., Tyšler, M., Grünes, R., Sedova, K., Osmančík, P., … Kneppo, P. (2016). Influence of Torso Model Complexity on the Noninvasive Localization of Ectopic Ventricular Activity. Measurement Science Review, 16(2), 96-102. doi:10.1515/msr-2016-0013RAMANATHAN, C., & RUDY, Y. (2001). Electrocardiographic Imaging: II. Effect of Torso Inhomogeneities on Noninvasive Reconstruction of Epicardial Potentials, Electrograms, and Isochrones. Journal of Cardiovascular Electrophysiology, 12(2), 241-252. doi:10.1046/j.1540-8167.2001.00241.xReddy, V. Y., Reynolds, M. R., Neuzil, P., Richardson, A. W., Taborsky, M., Jongnarangsin, K., … Josephson, M. E. (2007). Prophylactic Catheter Ablation for the Prevention of Defibrillator Therapy. New England Journal of Medicine, 357(26), 2657-2665. doi:10.1056/nejmoa065457Rodrigo, M., Climent, A. M., Liberos, A., Fernández-Avilés, F., Berenfeld, O., Atienza, F., & Guillem, M. S. (2017). Technical Considerations on Phase Mapping for Identification of Atrial Reentrant Activity in Direct- and Inverse-Computed Electrograms. Circulation: Arrhythmia and Electrophysiology, 10(9). doi:10.1161/circep.117.005008ROTEN, L., PEDERSEN, M., PASCALE, P., SHAH, A., ELIAUTOU, S., SCHERR, D., … HAÏSSAGUERRE, M. (2012). Noninvasive Electrocardiographic Mapping for Prediction of Tachycardia Mechanism and Origin of Atrial Tachycardia Following Bilateral Pulmonary Transplantation. Journal of Cardiovascular Electrophysiology, 23(5), 553-555. doi:10.1111/j.1540-8167.2011.02250.xRudy, Y. (2013). Noninvasive Electrocardiographic Imaging of Arrhythmogenic Substrates in Humans. Circulation Research, 112(5), 863-874. doi:10.1161/circresaha.112.279315Ghosh, S., Avari, J. N., Rhee, E. K., Woodard, P. K., & Rudy, Y. (2008). Noninvasive electrocardiographic imaging (ECGI) of epicardial activation before and after catheter ablation of the accessory pathway in a patient with Ebstein anomaly. Heart Rhythm, 5(6), 857-860. doi:10.1016/j.hrthm.2008.03.011Rudy, Y., Plonsey, R., & Liebman, J. (1979). The effects of variations in conductivity and geometrical parameters on the electrocardiogram, using an eccentric spheres model. Circulation Research, 44(1), 104-111. doi:10.1161/01.res.44.1.104SALINET, J. L., TUAN, J. H., SANDILANDS, A. J., STAFFORD, P. J., SCHLINDWEIN, F. S., & NG, G. A. (2013). Distinctive Patterns of Dominant Frequency Trajectory Behavior in Drug-Refractory Persistent Atrial Fibrillation: Preliminary Characterization of Spatiotemporal Instability. Journal of Cardiovascular Electrophysiology, 25(4), 371-379. doi:10.1111/jce.12331Dalu, Y. (1978). Relating the multipole moments of the heart to activated parts of the epicardium and endocardium. Annals of Biomedical Engineering, 6(4), 492-505. doi:10.1007/bf02584552Sánchez, C., Bueno-Orovio, A., Pueyo, E., & Rodríguez, B. (2017). Atrial Fibrillation Dynamics and Ionic Block Effects in Six Heterogeneous Human 3D Virtual Atria with Distinct Repolarization Dynamics. Frontiers in Bioengineering and Biotechnology, 5. doi:10.3389/fbioe.2017.00029Sanders, P., Berenfeld, O., Hocini, M., Jaïs, P., Vaidyanathan, R., Hsu, L.-F., … Haïssaguerre, M. (2005). Spectral Analysis Identifies Sites of High-Frequency Activity Maintaining Atrial Fibrillation in Humans. Circulation, 112(6), 789-797. doi:10.1161/circulationaha.104.517011Sapp, J. L., Bar-Tal, M., Howes, A. J., Toma, J. E., El-Damaty, A., Warren, J. W., … Horáček, B. M. (2017). Real-Time Localization of Ventricular Tachycardia Origin From the 12-Lead Electrocardiogram. JACC: Clinical Electrophysiology, 3(7), 687-699. doi:10.1016/j.jacep.2017.02.024Sapp, J. L., Dawoud, F., Clements, J. C., & Horáček, B. M. (2012). Inverse Solution Mapping of Epicardial Potentials. Circulation: Arrhythmia and Electrophysiology, 5(5), 1001-1009. doi:10.1161/circep.111.970160Sapp, J. L., Wells, G. A., Parkash, R., Stevenson, W. G., Blier, L., Sarrazin, J.-F., … Tang, A. S. L. (2016). Ventricular Tachycardia Ablation versus Escalation of Antiarrhythmic Drugs. New England Journal of Medicine, 375(2), 111-121. doi:10.1056/nejmoa1513614Schulze, W. H. W., Chen, Z., Relan, J., Potyagaylo, D., Krueger, M. W., Karim, R., … Dössel, O. (2016). ECG imaging of ventricular tachycardia: evaluation against simultaneous non-contact mapping and CMR-derived grey zone. Medical & Biological Engineering & Computing, 55(6), 979-990. doi:10.1007/s11517-016-1566-xShah, D. C., Jaïs, P., Haïssaguerre, M., Chouairi, S., Takahashi, A., Hocini, M., … Clémenty, J. (1997). Three-dimensional Mapping of the Common Atrial Flutter Circuit in the Right Atrium. Circulation, 96(11), 3904-3912. doi:10.1161/01.cir.96.11.3904Shome, S., & Macleod, R. (s. f.). Simultaneous High-Resolution Electrical Imaging of Endocardial, Epicardial and Torso-Tank Surfaces Under Varying Cardiac Metabolic Load and Coronary Flow. Lecture Notes in Computer Science, 320-329. doi:10.1007/978-3-540-72907-5_33SIMMS, H. D., & GESELOWITZ, D. B. (1995). Computation of Heart Surface Potentials Using the Surface Source Model. Journal of Cardiovascular Electrophysiology, 6(7), 522-531. doi:10.1111/j.1540-8167.1995.tb00425.xSvehlikova, J., Teplan, M., & Tysler, M. (2018). Geometrical constraint of sources in noninvasive localization of premature ventricular contractions. Journal of Electrocardiology, 51(3), 370-377. doi:10.1016/j.jelectrocard.2018.02.013Tsyganov, A., Wissner, E., Metzner, A., Mironovich, S., Chaykovskaya, M., Kalinin, V., … Kuck, K.-H. (2018). Mapping of ventricular arrhythmias using a novel noninvasive epicardial and endocardial electrophysiology system. Journal of Electrocardiology, 51(1), 92-98. doi:10.1016/j.jelectrocard.2017.07.018Umapathy, K., Nair, K., Masse, S., Krishnan, S., Rogers, J., Nash, M. P., & Nanthakumar, K. (2010). Phase Mapping of Cardiac Fibrillation. Circulation: Arrhythmia and Electrophysiology, 3(1), 105-114. doi:10.1161/circep.110.853804Van Dam, P. M., Oostendorp, T. F., Linnenbank, A. C., & van Oosterom, A. (2009). Non-Invasive Imaging of Cardiac Activation and Recovery. Annals of Biomedical Engineering, 37(9), 1739-1756. doi:10.1007/s10439-009-9747-5Van Oosterom, A. (2001). Genesis of the T wave as based on an equivalent surface source model. Journal of Electrocardiology, 34(4), 217-227. doi:10.1054/jelc.2001.28896Van Oosterom, A. (2002). Solidifying the solid angle. Journal of Electrocardiology, 35(4), 181-192. doi:10.1054/jelc.2002.37176Van Oosterom, A. (2004). ECGSIM: an interactive tool for stu

A community-based, bionic leg rehabilitation program for patients with chronic stroke: clinical trial protocol

Stroke is a major global health problem whereby many survivors have unmet needs concerning mobility during recovery. As such, the use of robotic assisted devices (i.e., a bionic leg) within a community-setting may be an important adjunct to normal physiotherapy in chronic stroke survivors. This study will be a dual-centre, randomized, parallel group clinical trial to investigate the impact of a community based, training program using a bionic leg on biomechanical, cardiovascular and functional outcomes in stroke survivors. Following a baseline assessment which will assess gait, postural sway, vascular health (blood pressure, arterial stiffness) and functional outcomes (6-minute walk), participants will be randomized to a 10-week program group, incorporating either: i) physiotherapy plus community-based bionic leg training program, ii) physiotherapy only, or iii) usual care control. The training program will involve participants engaging in a minimum of 1 hour per day of bionic leg activities at home. Follow up assessment, identical to baseline, will occur after 10-weeks, 3 and 12 months post intervention. Given the practical implications of the study, the clinical significance of using the bionic leg will be assessed for each outcome variable. The potential improvements in gait, balance, vascular health and functional status may have a meaningful impact on patients’ quality of life. The integration of robotic devices within home-based rehabilitation programs may prove to be a cost effective, practical and beneficial resource for stroke survivors

Whole-body tissue stabilization and selective extractions via tissue-hydrogel hybrids for high-resolution intact circuit mapping and phenotyping

To facilitate fine-scale phenotyping of whole specimens, we describe here a set of tissue fixation-embedding, detergent-clearing and staining protocols that can be used to transform excised organs and whole organisms into optically transparent samples within 1–2 weeks without compromising their cellular architecture or endogenous fluorescence. PACT (passive CLARITY technique) and PARS (perfusion-assisted agent release in situ) use tissue-hydrogel hybrids to stabilize tissue biomolecules during selective lipid extraction, resulting in enhanced clearing efficiency and sample integrity. Furthermore, the macromolecule permeability of PACT- and PARS-processed tissue hybrids supports the diffusion of immunolabels throughout intact tissue, whereas RIMS (refractive index matching solution) grants high-resolution imaging at depth by further reducing light scattering in cleared and uncleared samples alike. These methods are adaptable to difficult-to-image tissues, such as bone (PACT-deCAL), and to magnified single-cell visualization (ePACT). Together, these protocols and solutions enable phenotyping of subcellular components and tracing cellular connectivity in intact biological networks

Predictors of Enhancing Human Physical Attractiveness: Data from 93 Countries

People across the world and throughout history have gone to great lengths to enhance their physical appearance. Evolutionary psychologists and ethologists have largely attempted to explain this phenomenon via mating preferences and strategies. Here, we test one of the most popular evolutionary hypotheses for beauty-enhancing behaviors, drawn from mating market and parasite stress perspectives, in a large cross-cultural sample. We also test hypotheses drawn from other influential and non-mutually exclusive theoretical frameworks, from biosocial role theory to a cultural media perspective. Survey data from 93,158 human participants across 93 countries provide evidence that behaviors such as applying makeup or using other cosmetics, hair grooming, clothing style, caring for body hygiene, and exercising or following a specific diet for the specific purpose of improving ones physical attractiveness, are universal. Indeed, 99% of participants reported spending \u3e10 min a day performing beauty-enhancing behaviors. The results largely support evolutionary hypotheses: more time was spent enhancing beauty by women (almost 4 h a day, on average) than by men (3.6 h a day), by the youngest participants (and contrary to predictions, also the oldest), by those with a relatively more severe history of infectious diseases, and by participants currently dating compared to those in established relationships. The strongest predictor of attractiveness-enhancing behaviors was social media usage. Other predictors, in order of effect size, included adhering to traditional gender roles, residing in countries with less gender equality, considering oneself as highly attractive or, conversely, highly unattractive, TV watching time, higher socioeconomic status, right-wing political beliefs, a lower level of education, and personal individualistic attitudes. This study provides novel insight into universal beauty-enhancing behaviors by unifying evolutionary theory with several other complementary perspectives