Química receptor-sustrato y procesos de autoclasificación basados en metalociclos funcionalizados

Programa Oficial de Doutoramento en Química Ambiental e Fundamental. 5031V01[Resumen] Esta memoria se divide en tres partes diferenciadas, y comienza por el estudio de un metalociclo de Pd(II) dinuclear, derivado de 2,7-diazapirenio, como receptor de sustratos aromáticos en medio acuoso. La formación de los complejos de inclusión está favorecida por el establecimiento de interacciones π-π , C-H···π y efecto hidrofóbico. Los agregados obtenidos se han caracterizado mediante técnicas de RMN, mono y bidimensional, y difracción de Rayos X de monocristal. Se han estudiado también los parámetros termodinámicos y cinéticos del proceso de complejación. La segunda parte del trabajo se centra en la obtención de nuevos ligandos derivados de 4,4´-bipiridinio/2,7-diazapirenio con funcionalización diversa. El autoensamblaje de estos ligandos con centros metálicos de Pd(II) y Pt(II), conduce a una amplia gama de metalociclos funcionalizados, donde los grupos introducidos en los ligandos no interfieren en el proceso de autoensamblaje. Se estudia también, la capacidad de estos nuevos metalociclos funcionalizados como receptores de sustratos aromáticos en medio acuoso. Por último, se presenta el diseño de sistemas supramoleculares que conducen a la formación de pseudo[1]rotaxanos en medio acuoso, mediante el ensamblaje de diferentes ligandos complementarios, en forma y tamaño, con centros metálicos de Pd(II) y Pt(II). Los pseudo[1]rotaxanos obtenidos, resultan de un proceso de autoclasificación social integrativo, donde la formación de estas especies supone una ganancia entálpica y entrópica del sistema.[Resumo] Esta memoria divídese en tres partes diferenciadas, e comeza pola explotación dun metalociclo de Pd(II) dinuclear, derivado de 2,7-diazapirenio, como receptor de substratos aromáticos en medio acuoso. A formación dos complexos de inclusión está favorecida polo establecemento de interaccións π-π , C-H···π e polo efecto hidrofóbico. Os agregados obtidos foron caracterizados mediante técnicas de RMN, mono e bidimensional, así como difracción de Raios X de monocristal. Estudáronse tamén os parámetros termodinámicos e cinéticos do proceso de complexación. A segunda parte do traballo céntrase na obtención de novos ligandos derivados de 4,4´-bipiridinio/2,7-diazapirenio con diversa funcionalización. A autoensamblaxe de estes ligandos con centros metálicos de Pd(II) e Pt(II), conduce a unha ampla gama de metalociclos funcionalizados, onde os grupos introducidos nos ligandos non interfiren no proceso de autoensamblaxe. Estudouse tamén, a capacidade destes novos metalociclos funcionalizados como receptores de substratos aromáticos en medio acuoso. Por último, preséntase o deseño de sistemas supramoleculares que conducen á formación de pseudo[1]rotaxanos en medio acuoso, mediante a ensamblaxe de diferentes ligandos complementarios, en forma e tamaño, e centros metálicos de Pd(II) e Pt(II). Os pseudo[1]rotaxanos obtidos, resultan dun proceso de autoclasificación social integrativo, onde a formación destas especies supón unha ganancia entálpica e entrópica do sistema.[Abstract] This dissertation is divided in three parts. In the first part, we have studied the ability of a 2,7-diazapyrenium-based Pd(II) dinuclear metallacycle to complex aromatic guests in aqueous media. These inclusion complexes are favoured by π-π and C-H···π interactions as well as by the hydrophobic effect. All of these aggregates were characterized by 1D and 2D NMR and single crystal X-ray crystallography. Furthermore, the thermodynamic and kinetic parameters of the host-guest complexation have been also explored. The second part of this work is focused on the synthesis of new 4,4´-bipyridinium/2,7-diazapyrenium-based ligands owning several different functional groups. Self-assembly of these ligands with Pd(II) and Pt(II) metal centers, resulted in a series of a new functionalized metallacycles. The groups posed into the ligands do not interfere in the self-assembly processes. The ability of these new functionalized metallacycles to complex aromatic guests in water has been also studied. Finally, we have explored the synthesis of supramolecular systems designed to produce pseudo[1]rotaxanes in aqueous media. These supramolecules were obtained by assembly of ternary mixtures of complementary ligands and Pd(II) and Pt(II) centers. The pseudo[1]rotaxanes are the result of integrative social self-sorting, where, the formation of the species increases the enthalpic and entropic gain of the system

La visión caleidoscópica en el arte plástico y la animación experimental. La movilidad basada en la reiteración simétrica, fragmentación y reintegración

[ES] En esta tesis doctoral se aborda el concepto de la visión caleidoscópica con el fin de reflexionar en esta idea, asumiendo esta mirada en un sentido amplio, es decir, más allá de lo que se observa en un caleidoscopio. En concreto, el objeto de estudio determina la repercusión de esta polivisión caleidoscópica en el arte plástico y animación basada en la movilidad, reiteración simétrica, fragmentación y reintegración. De igual manera, asumiendo este principio se profundiza en la dinámica caleidoscópica, al subvertir los órdenes con la variación de algún elemento. De modo que se expone lo significativo de las disposiciones más singulares de los patrones, incorporando elementos de modificación o ruptura en la desintegración del lenguaje caleidoscópico con la finalidad de desestructurar o deconstruir la distribución de la red al alterar la simetría; o algún componente que visibilice estructuras menos lineales como alternativas a los patrones continuos, uniformes y cerrados, y en este caso se plantea un descentramiento y una abertura mayor. Se verificará en los procesos creativos un conjunto de obras en un contexto contemporáneo puede generar diversas lecturas y facetas que estimulen la creatividad. Por lo tanto, esta repercusión se analizará mediante obras plásticas y filmes de animación significativas, además, es relevante precisar que se analizará a través de métodos alternativos que pueden alterar la estructura convencional. Del mismo modo, se hará un recorrido y contextualización de esta visión en un orden conceptual y formal, junto a una exposición de juguetes ópticos vinculados a la imagen refleja entre los que se encuentra el caleidoscopio, con el fin de analizar la evolución del objeto y de la óptica del mismo, pasando por pequeños y grandes artefactos, analizando los elementos comunes que la conforman y también las diferencias, hasta ver en la actualidad la confluencia de esta óptica con los artefactos de gran formato. Este enfoque tiene el propósito de abrir la mirada y permitir una comprensión más amplia, interconectada y diversa, lo cual expresa aspectos de evolución. A la vez, se puede señalar, cómo finalmente esta óptica en la actualidad se lleva hacia la instalación o intervención artística con innovaciones a la par, es posible verificar cómo no es solo una visión en el arte, sino que esta idea de crecimiento se extiende, a la vida, al relacionarse con el entorno como un tejido de patrones en interacción. En este sentido, se sigue el concepto de "extimidad" (extimité), acuñado por Jacques Lacan en el siglo XX ya que, expresa la interrelación entre exterior e interior en un juego de inversión, donde lo íntimo pasa al exterior y viceversa. Esta noción en la tesis se extrapola al arte del caleidoscopio porque exterioriza algo que está en el interior y también en la visión caleidoscópica, donde se determina una sincronía entre el mundo externo e interno que transmite dicha visión.[CA] En aquesta tesi doctoral s'aborda el concepte de la visió calidoscòpica amb la finalitat de reflexionar-hi, i s'assumeix aquesta mirada en un sentit ampli, és a dir, més enllà del que s'observa en un calidoscopi. En concret, l'objecte d'estudi determina la repercussió d'aquesta polivisió calidoscòpica en l'art plàstic i l'animació basada en la mobilitat, reiteració simètrica, fragmentació i reintegració. D'igual manera, assumint aquest principi s'aprofundeix en la dinàmica calidoscòpica, en subvertir els ordres amb la variació d'algun element; així s'exposa el significatiu de les disposicions més singulars dels patrons, incorporant elements de modificació o ruptura en la desintegració del llenguatge calidoscòpic amb la finalitat de desestructurar o desconstruir la distribució de la xarxa en alterar la simetria; o algun component que visibilitze estructures menys lineals com a alternatives als patrons continus, uniformes i tancats, i en aquest cas es planteja un descentrament i una obertura major. Es verificaran en els processos creatius un conjunt d'obres [que] en un context contemporani poden generar diverses lectures i facetes que estimulen la creativitat. Per tant, aquesta repercussió s'analitzarà mitjançant obres plàstiques i films d'animació significatives. A més, és rellevant precisar que s'analitzarà a través de mètodes alternatius que poden alterar l'estructura convencional. De la mateixa manera, es farà un recorregut i contextualització d'aquesta visió en un ordre conceptual i formal, al costat d'una exposició de joguets òptics vinculats a la imatge reflexa entre els quals hi ha el calidoscopi, amb la finalitat d'analitzar l'evolució de l'objecte i la seua l'òptica. Passarem per petits i grans artefactes i analitzarem els elements comuns que la conformen i també les diferències, fins a veure en l'actualitat la confluència d'aquesta òptica amb els artefactes de gran format. Aquest enfocament té el propòsit d'obrir la mirada i permetre una comprensió més àmplia, interconnectada i diversa, la qual cosa expressa aspectes d'evolució. Així mateix, es pot assenyalar com finalment aquesta òptica en l'actualitat porta cap a la instal·lació o intervenció artística amb innovacions i alhora, i és possible verificar com no és només una visió en l'art, sinó que la idea de creixement s'estén, a la vida, en relacionar-se amb l'entorn com un teixit de patrons en interacció. En aquest sentit, se segueix el concepte d'extimitat" (extimité), encunyat per Jacques Lacan en el segle XX ja que, expressa la interrelació entre exterior/interior i viceversa, en un joc d'inversió, on l'íntim passa a l'exterior i tots dos estan implicats. Aquesta noció en la tesi, s'extrapola a l'art del calidoscopi perquè exterioritza alguna cosa que està a l'interior i també en la visió calidoscòpica, on es determina una sincronia entre el món extern i intern que transmet la visió.[EN] This doctoral thesis explores and reflects on the concept of the kaleidoscopic view, assuming this gaze in a broad sense; that is, beyond what is observed in a kaleidoscope. Specifically, the object of study determines the repercussions of this kaleidoscopic polyvision in plastic art and animation, with an image shaped by mobility, symmetrical reiteration, fragmentation and reintegration. Moreover, the kaleidoscopic dynamics are intensified by subverting the orders through the variation of certain elements. In this way, the significance of the most unique patterns is exposed, incorporating elements of modification or rupture in the disintegration of the kaleidoscopic language, with the aim of deconstructing the arrangement of the network by altering the symmetry. Similarly, the focus is shifted to less linear structures as alternatives to the continuous, uniform, closed patterns, through a decentring and greater opening. In the creative processes, a set of works in a contemporary context can generate multiple facets and diverse readings that stimulate creativity. Therefore, this repercussion will be analysed through significant works of plastic art and animation films, and applying alternative methods that can alter the conventional structure. Furthermore, there will be a conceptual and formal exploration and contextualisation of this vision, together with a discussion of optical toys linked to the reflex image, including the kaleidoscope. By so doing, the evolution of the object and its optics are analysed, passing through small and large artefacts, examining both the common elements and the differences, until we reach the confluence of these optics in the present-day large-format artefacts. This approach is intended to open the gaze and allow for a broader, interconnected and diverse understanding, incorporating aspects of evolution. At the same time, it is shown how this optic is nowadays is ultimately applied to installations or innovative artistic intervention. At the same time, it can be seen that it is not only a vision in art, but also the idea of growth extends out to life, relating to the environment as a series of woven, interacting patterns. In this sense, the concept of "extimacy" (extimité), a term coined by Jacques Lacan in the 20th century, is applied, as it expresses the interrelationship between exterior/interior in a game of inversion, where the intimate passes to the exterior and vice versa. In the thesis, this notion is extrapolated to the art of the kaleidoscope because it externalises something that is inside, and within the kaleidoscopic view there is a synchrony between the external and internal world that conveys this vision.Quiero mostrar gratitud a las entidades financiadoras que han dado soporte a esta investigación por la ayuda de una FPI: Ministerio de Economía y Empresa, Gobierno de España y al Fondo Social Europeo por la cofinanciación recibida en la convocatoria: Ayuda para contrato predoctoral para la formación de Doctores.Rama Sotos, T. (2021). La visión caleidoscópica en el arte plástico y la animación experimental. La movilidad basada en la reiteración simétrica, fragmentación y reintegración [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/175740TESI

Filsafat Barat dan Timur, Sejarah Filsafat dan Retorika Serta Teori Kebenaran

Filsafat menggunakan metode bertanya sebagai alat untuk mencari jawaban, dan objeknya adalah segala hal yang dapat diperdebatkan. Filsafat mencoba memahami makna dan nilai dalam alam semesta, yang hanya dapat diakses oleh manusia melalui pikiran dan pemahaman. Sejarah filsafat telah melalui berbagai periode, termasuk Zaman Yunani kuno, Zaman Kegelapan, Zaman Pencerahan, zaman modern awal, zaman modern, dan masa pos modern. Setiap periode ini memiliki perkembangan filsafatnya sendiri. Ada juga berbagai teori pengetahuan yang mencoba menjelaskan bagaimana pengetahuan diperoleh, termasuk empirisme, rasionalisme, konstruktivisme, dan lainnya. Pendekatan terhadap kebenaran juga bervariasi, dengan teori koherensi, korespondensi, pragmatisme, dan lainnya yang berusaha memahami sifat kebenaran

Milling the Mistletoe: Nanotechnological Conversion of African Mistletoe (Loranthus micranthus) Intoantimicrobial Materials

Nanosizing represents a straight forward technique to unlock the biological activity of complex plant materials. The aim of this study was to develop herbal nanoparticles with medicinal value from dried leaves and stems of Loranthus micranthus with the aid of ball-milling, high speed stirring, and high-pressure homogenization techniques. The milled nanoparticles were characterized using laser diffraction analysis, photon correlation spectroscopy analysis, and light microscopy. The average size of leaf nanoparticles was around 245 nm and that of stem nanoparticles was around 180 nm. The nanoparticles were tested for their antimicrobial and nematicidal properties against a Gram-negative bacterium Escherichia coli, a Gram-positive bacterium Staphylococcus carnosus, fungi Candida albicans and Saccharomyces cerevisiae, and a nematode Steinernemafeltiae. The results show significant activities for both leaf and (particularly) stem nanoparticles of Loranthus micranthus on all organisms tested, even at a particle concentration as low as 0.01% (w/w). The results observed indicate that nanoparticles (especially of the stem) of Loranthus micranthus could serve as novel antimicrobial agents with wide-ranging biomedical applications

Unveiling and Revealing the Mirror: Mobile Reverberations in Patrick Bokanowski's Animated Films

[EN] Abstract The principal focus of this article is to provide an analysis of some of the most significant works by the independent filmmaker Patrick Bokanowski and the methodology he uses to create those animated films. It addresses Bokanowski¿s technique of filming on various kinds of reflective surfaces as a strategy for transforming the image through optical deformation and thereby expressing his subjective vision in films and animation. He explores the practical application of creating reverberation as visual echoes, as well as the use of unusual reflections that appear in mirrors and other more unstable reflective surfaces, such as liquid mercury, and the refraction occurring in sculpted lenses, glass or water. The aim of said strategy is the pure expression of subjective experience, with the director using a camera as if it were an entirely free-moving paintbrush that inspires creativity and breaks loose from automatic camera movements. Accordingly, this study examines the dynamic, expressive potential of the language of catoptrics, taking as paradigmatic examplestwo of Bokanowski's short films: La Plage (1992) and Au bord du lac (1994). Our analyses of these films are aimed at demonstrating how the artist manages to bring about qualitative, transformative changes of forms and space by reflecting images on mirrors, ripples in mercury and movements of water, and by combining these elements. The system developed by Bokanowski successfully transports us to an ever-changing, poetic universe and breaks new ground in the field of animation.The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article. This work was supported by the Spanish Ministry of Economy, Industry and Competitiveness, and was co-financed by the European Social Fund in the call for applications for Predoctoral Scholarships for Doctoral Training: [BES 2014-069330], within the framework of the R&D&I project: Alternative Strategies for the Creation of Animated Images Based on Its Essence: The Dynamic Expression [HAR2013-41708-P].Tamara Rama-Sotos; Lloret Ferrándiz, MC. (2019). Unveiling and Revealing the Mirror: Mobile Reverberations in Patrick Bokanowski's Animated Films. Animation. 14(2):1-19. https://doi.org/10.1177/1746847719856997S119142Bokanowski P (1992) Réflexions Optiques. Paris: In Bref, n.11, 34–38.Bokanowski P (2017a) Incandescent Material, Notes on the Cinematic Image. Published in booklet included in: Un Rêve Solaire DVD 2018. Paris: Re:Voir, 3–7.Buchan, S. (2013). Pervasive Animation. doi:10.4324/978020315257

Toward 68Ga and 64Cu Positron Emission Tomography Probes: Is H2dedpa-N,N′-pram the Missing Link for dedpa Conjugation?

[Abstract] H2dedpa-N,N′-pram (H2L1), a new chelator derived from the hexadentate ligand 1,2-bis[[(6-carboxypyridin-2-yl)methyl]amino]ethane (H2dedpa), which incorporates 3-propylamine chains anchored to the secondary amines of the ethylenediamine core of the latter, has emerged as a very promising scaffold for preparing 68Ga- and 64Cu-based positron emission tomography probes. This new platform is cost-effective and easy to prepare, and the two pendant primary amines make it versatile for the preparation of bifunctional chelators by conjugation and/or click chemistry. Reported herein, we have also included the related H2dedpa-N,N′-prpta (H2L2) platform as a simple structural model for its conjugated systems. X-ray crystallography confirmed that the N4O2 coordination sphere provided by the dedpa2– core is maintained at both Ga(III) and Cu(II). The complex formation equilibria were deeply investigated by a thorough multitechnique approach with potentiometric, NMR spectrometric, and UV–vis spectrophotometric titrations, revealing effective chelation. The thermodynamic stability of the Ga(III) complexes at physiological relevant conditions is slightly higher than that of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), the common and clinically approved chelator used in the clinic [pGa = 19.5 (dedpa-N,N′-pram) and 20.8 (dedpa-N,N′-prpta) versus 18.5 (DOTA) at identical conditions], and significantly higher for the Cu(II) complexes [pCu = 21.96 (dedpa-N,N′-pram) and 22.8 (dedpa-N,N′-prpta) versus 16.2 (DOTA)], which are even more stable than that of the parent ligand dedpa2– (pCu = 18.5) and that of 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) (pCu = 18.5). This high stability found for Cu(II) complexes is related to the conversion of the secondary amines of the ethylenediamine core of dedpa2– into tertiary amines, whereby the architecture of the new H2L1 chelator is doubly optimal in the case of this metal ion: high accessibility of the primary amine groups and their incorporation via the secondary amines, which contributes to a significant increase in the stability of the metal complex. Quantitative labeling of both chelators with both radionuclides ([68Ga]Ga3+ and [64Cu]Cu2+) was observed within 15 min at room temperature with concentrations as low as 10–5 M. Furthermore, serum stability studies confirmed a high radiochemical in vitro stability of all systems and therefore confirmed H2L1 as a promising and versatile chelator for further radiopharmaceutical in vivo studies.We thank NSERC for PGS-D and UBC for Four Year Fellowships (to L.S.), the NSERC CREATE IsoSiM training program at TRIUMF (to L.S.), as well as NSERC Discovery Grants (to C.O. and P.S.). TRIUMF receives additional funding via a contribution agreement with the National Research Council of Canada. M.d.G.J.-P. gratefully acknowledges the technical assistance of T. R. Masvikeni. C.P.-B., T.R., A.d.B., and T.R.-B. are grateful to the Spanish Ministry of Science and Innovation (CTQ2016-74862-P) and Xunta de Galicia (ED431B 2022/40) for financial support. C.P.-B. also thanks Xunta de Galicia for a Ph.D. fellowship. We also appreciate the help of Dr. A. Llamas (Unidade de Raios X RIAIDT at University of Santiago de Compostela, Spain) for useful crystallographic discussions. Funding for open access charge provided by Universidade da Coruña/CISUG.Xunta de Galicia; ED431B 2022/4

A Dynamic Model of Interactions of Ca^(2+), Calmodulin, and Catalytic Subunits of Ca^(2+)/Calmodulin-Dependent Protein Kinase II

During the acquisition of memories, influx of Ca^(2+) into the postsynaptic spine through the pores of activated N-methyl-D-aspartate-type glutamate receptors triggers processes that change the strength of excitatory synapses. The pattern of Ca^(2+) influx during the first few seconds of activity is interpreted within the Ca^(2+)-dependent signaling network such that synaptic strength is eventually either potentiated or depressed. Many of the critical signaling enzymes that control synaptic plasticity, including Ca^(2+)/calmodulin-dependent protein kinase II (CaMKII), are regulated by calmodulin, a small protein that can bind up to 4 Ca^(2+) ions. As a first step toward clarifying how the Ca^(2+)-signaling network decides between potentiation or depression, we have created a kinetic model of the interactions of Ca^(2+), calmodulin, and CaMKII that represents our best understanding of the dynamics of these interactions under conditions that resemble those in a postsynaptic spine. We constrained parameters of the model from data in the literature, or from our own measurements, and then predicted time courses of activation and autophosphorylation of CaMKII under a variety of conditions. Simulations showed that species of calmodulin with fewer than four bound Ca^(2+) play a significant role in activation of CaMKII in the physiological regime, supporting the notion that processing ofCa^(2+) signals in a spine involves competition among target enzymes for binding to unsaturated species of CaM in an environment in which the concentration of Ca^(2+) is fluctuating rapidly. Indeed, we showed that dependence of activation on the frequency of Ca^(2+) transients arises from the kinetics of interaction of fluctuating Ca^(2+) with calmodulin/CaMKII complexes. We used parameter sensitivity analysis to identify which parameters will be most beneficial to measure more carefully to improve the accuracy of predictions. This model provides a quantitative base from which to build more complex dynamic models of postsynaptic signal transduction during learning

Who is who? Gamification Proposal for Learning Psychology

[EN] Gamification is a powerful strategy in the field of education; since it contributes to improve attentional processes, to stimulate motivation and to enhance mechanisms for significative learning. The present work shows an innovation project based on the basic principles of gamification whose objective is to consolidate knowledge about the most relevant authors in the field of Learning Psychology, using a methodology that combines theoretical (search of information in sources of high academic rigor on a previously selected author) and practical components (classroom adaptation of the game "Who's who?"), aimed at delving into their life and work. The activity was evaluated through ad hoc satisfaction surveys, addressed to students and teachers, obtaining high rates in all cases (recommendation to other classmates, knowledge acquired and course content). From the findings, it is clear the usefulness and viability of applying playful strategies in the classroom to favor the conquest of the competences contemplated in the academic curriculum.[ES] La gamificación es una estrategia poderosa en el ámbito de la educación; pues contribuye a canalizar los procesos atencionales, estimular la motivación y potenciar mecanismos con los que dotar de significatividad al aprendizaje. El presente trabajo muestra un proyecto de innovación basado en los principios básicos de la gamificación que tiene como objetivo general consolidar el conocimiento sobre autores de mayor relevancia en el campo de la Psicología del Aprendizaje, utilizando para ello una metodología que aúna componentes teóricos (búsqueda de información en fuentes de elevado rigor académico sobre algún autor previamente seleccionado) y prácticos (adaptación en el aula del clásico juego “¿quién es quién?”) dirigida a profundizar en su vida y obra. La actividad se evaluó mediante encuestas de satisfacción ad hoc, dirigidas tanto al alumnado participante como al profesorado, obteniéndose índices altos en todos los casos (recomendación a otros compañeros y compañeras, conocimientos adquiridos y contenidos del curso). De los hallazgos se desprende la utilidad y viabilidad de aplicar estrategias lúdicas en el aula para favorecer la conquista de las competencias contempladas en el currículum académico.Cabedo Peris, J.; Alhambra Borrás, T.; Duque Moreno, A.; Rama Galdón, E.; Hita Yáñez, E.; Martínez Sierra, R.; Ródenas González, F.... (2023). ¿Quién es quién? Propuesta de gamificación para psicología del aprendizaje. Editorial Universitat Politècnica de València. 1097-1109. https://doi.org/10.4995/INRED2023.2023.166661097110

Instantaneous Wave-Free Ratio for the Assessment of Intermediate Left Main Coronary Artery Stenosis: Correlations With Fractional Flow Reserve/Intravascular Ultrasound and Prognostic Implications: The iLITRO-EPIC07 Study

Background: There is little information available on agreement between fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR) in left main coronary artery (LMCA) intermediate stenosis. Besides, several meta-analyses support the use of FFR to guide LMCA revascularization, but limited information is available on iFR in this setting. Our aims were to establish the concordance between FFR and iFR in intermediate LMCA lesions, to evaluate with intravascular ultrasound (IVUS) in cases of FFR/iFR discordance, and to prospectively validate the safety of deferring revascularization based on a hybrid decision-making strategy combining iFR and IVUS. Methods: Prospective, observational, multicenter registry with 300 consecutive patients with intermediate LMCA stenosis who underwent FFR and iFR and, in case of discordance, IVUS and minimal lumen area measurements. Primary clinical end point was a composite of cardiovascular death, LMCA lesion-related nonfatal myocardial infarction, or unplanned LMCA revascularization. Results: FFR and iFR had an agreement of 80% (both positive in 67 and both negative in 167 patients); in case of disagreement (31 FFR+/iFR- and 29 FFR-/iFR+) minimal lumen area was & GE;6 mm(2) in 8.7% of patients with FFR+ and 14.6% with iFR+. Among the 300 patients, 105 (35%) underwent revascularization and 181 (60%) were deferred according to iFR and IVUS. At a median follow-up of 20 months, major adverse cardiac events incidence was 8.3% in the defer group and 13.3% in the revascularization group (hazard ratio, 0.71 [95% CI 0.30-1.72]; P=0.45). Conclusions: In patients with intermediate LMCA stenosis, a physiology-guided treatment decision is feasible either with FFR or iFR with moderate concordance between both indices. In case of disagreement, the use of IVUS may be useful to indicate revascularization. Deferral of revascularization based on iFR appears to be safe in terms of major adverse cardiac events

Rationale and design of the Concordance study between FFR and iFR for the assessment of lesions in the left main coronary artery. The ILITRO-EPIC-07 Trial

Introduction and objectives: Patients with left main coronary artery (LMCA) stenosis have been excluded from the trials that support the non-inferiority of the instantaneous wave-free ratio (iFR) compared to the fractional flow reserve (FFR) in the decision-making process of coronary revascularization. This study proposes to prospectively assess the concordance between the two indices in LMCA lesions and to validate the iFR cut-off value of 0.89 for clinical use. Methods: National, prospective, and observational multicenter registry of 300 consecutive patients with intermediate lesions in the LMCA (angiographic stenosis, 25% to 60%. A pressure gudiewire study and determination of the RFF and the iFR will be performed: in the event of a negative concordant result (FFR > 0.80/iFR > 0.89), no treatment will be performed; in case of a positive concordant result (FFR 0.80/iFR 0.89), an intravascular echocardiography will be performed and revascularization will be delayed if the minimum lumen area is > 6 mm(2). The primary clinical endpoint will be a composite of cardiovascular death, LMCA lesion-related non-fatal infarction or need for revascularization of the LMCA lesion at 12 months. Conclusions: Confirm that an iFR-guided decision-making process in patients with intermediate LMCA stenosis is clinically safe and would have a significant clinical impact. Also, justify its systematic use when prescribing treatment in these potentially high-risk patients