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Structural features that enhance Li mobility in fast ion conductors with perovskite (Li3xLa2/3-xTiO3 series) and Nasicon structure (Li1+xTi2-xAlx (PO4)3 series) have been investigated. From the analysis of quadrupolar interactions, the local symmetry and exchange processes between structural sites occupied by lithium have been deduced to investigate local motions of lithium in conduction paths of analyzed compounds. The study of spin-lattice (T1) and spin-spin (T2) relaxation times made possible the analysis of the temperature dependence of Li residence times at structural sites. The comparison of these values with those deduced from conductivity (ac and dc-measurements) allowed the study of Li-motion mechanisms. The onset of long range motions requires the analysis of low frequency measurements (T2 relaxation and dc-conductivity). The non- Arrhenius behaviour, often observed in fast ion conductors, has been ascribed to order/disorder transitions. At increasing temperatures, Li motions become less correlated, producing the decrement of activation energy. In analyzed compounds, a direct measurement of diffusion coefficients has been obtained from NMR experiments performed with the pulse field gradient (PFG) technique. Finally, it is emphasized the importance of the vacancy percolation in conductivity processes.En esta presentación se analizan los rasgos estructurales que favorecen la movilidad de los iones litio en conductores con estructuras tipo perovskita (serie Li3xLa2/3-xTiO3 ) y Nasicon (serie Li1+xTi2-xAlx (PO4)3). El estudio de las interacciones cuadrupolares ha permitido deducir la simetría local y los procesos de intercambio entre sitios cristalinos ocupados por el litio. El estudio de la variación de los tiempos de relajación spin-red (T1) y spin-spin (T2) con la temperatura, ha permitido deducir los tiempos de residencia de los iones Li en los sitios estructurales. La comparación de estos valores con los deducidos a partir de las conductividades ac y dc, hace posible describir de un modo más preciso la dinámica de los iones. A temperaturas crecientes, los movimientos se vuelven menos correlacionados, produciéndose una disminución de la energía de activación. El análisis de los movimientos a larga distancia requiere medidas a baja frecuencia (medidas de T2 y conductividad-dc). Desviaciones de la conductividad del comportamiento Arrhenius, a menudo observadas en conductores iónicos rápidos, han sido adscritas a transiciones de orden-desorden en las que el movimiento de los iones se hace menos correlacionado. Una medida directa de los coeficientes de difusión ha sido obtenida con la técnica RMN de gradiente de campo pulsado (PFG). Finalmente se analiza la importancia de los fenómenos de percolación de vacantes en los procesos de conducción.

A structural and spectroscopic characterization of crystalline rods of Ce0.4Zr0.6O2 grown by the laser floating zone (LFZ) method is presented. A precursor rod of Ce0.4Zr0.6O2 composition was sintered at 1500 ºC in air atmosphere and then processed by the LFZ technique with a CO2 laser. The processed material was characterized by XRD, SEM and Raman spectroscopy. In the as-grown, dark-color processed rod, the Raman spectrum evolves radially from a t’-like one, corresponding to Ce0.37Zr0.63O2 composition, at the edge of the rod, to a very broad and weak, cubic-like one, at the center. The degree of cerium reduction and oxygen non-stoichiometry were determined through measurements of the electronic Raman spectrum of Ce3+. A strong Ce3+ signal was found at the core of the rod, indicating strong reduction, whereas no Ce3+ signal was detected at the edge. To restore oxygen and Ce4+ content a section of the fiber was reoxidized at 620 ºC for 24 h. A very homogeneous spectrum was found in the reoxidized sample, that was assigned to a t’-phase of composition Ce0.42Zr0.58O2.Presentamos una caracterización estructural y espectroscópica de fibras cristalinas de Ce0.4Zr0.6O2 crecidas mediante fusión zonal asistida por láser (LFZ). Una barra del material precursor, de composición Ce0.4Zr0.6O2, fue sinterizada a 1500 ºC en atmósfera de aire y después procesada por LFZ con un láser de CO2. El material procesado fue caracterizado por difracción de rayos X, microscopía electrónica de barrido y espectroscopía Raman. En la fibra recién procesada, de color gris oscuro, el espectro Raman varía radialmente desde un espectro de tipo t’, correspondiente a una composición Ce0.37Zr0.63O2, en el borde de la fibra, hasta un espectro muy ensanchado y débil, de aspecto cúbico, en el centro. El grado de reducción del cerio y la no estequiometría del oxígeno se determinaron a través de las medidas del Raman electrónico del Ce3+. La señal de Ce3+ era muy intensa en el centro de la fibra, lo que indica una fuerte reducción, mientras que no se detectó en el borde. Para restablecer el contenido de oxígeno y de Ce4+ una parte de la fibra fue reoxidada a 620 ºC durante 24 h. El espectro de la muestra reoxidada, de color amarillo pálido y muy homogénea, fue asignado a una fase t’ de composición Ce0.42Zr0.58O2.

The structures of microcline perthites collected from granitic pegmatites have been studied at different observation scales using optical microscopy (OM), X-ray diffraction (XRD), 27Al MASS-NMR spectroscopy, and electron microprobe (EMPA) with Na mappings. Pegmatite perthites are identified as complex systems. During the cooling process, K-rich feldspars display two separated genetic periods of recrystallization, each one with variable intensity along different samples. During the first period, in the mineral structure a progressive construction of macrostructural pseudo-periodic patterns is produced. These regular patterns emerge due to a combined mechanism of non-ergodic Si/Al local ordering and a global cooperative effect of the crystal structure. From the incoherent Na/K interfaces arise transformation fronts (avalanches) which can coalesce longitudinally and juxtapose transversally to self-assemble into irregular domains. Finally, they can evolve up to create regular twin-domains (Albite and Pericline laws) as the crystal unit of the macrostructural building. This selforganization process is activated when the system is open to water circulation acting as a catalyst of Al/Si ordering in the feldspar lattice linked with an external stimulation by shear tectonic stress. During the second period the structural patterns, previously created, are destroyed by (i) relaxation and deformation twinning mechanisms, (ii) coarsening of twin-domains produced by dissolution-precipitation due to aqueous fluids interactions at low temperature, (iii) reorientation of Periclinelaw twin-domains to the Albite-law orientation.Se han estudiado estructuras de feldespatos potásicos triclínicos (microclinas) intercrecidos con feldespatos sódicos en texturas pertíticas procedentes de pegmatitas graníticas a diferentes escalas de observación, mediante microscopía de luz transmitida (MLT), difracción de rayos-X (DRX), resonancia magnética nuclear de alta resolución del núcleo 27Al (RMN), y mapas químicos de contenido en Na por microsonda electrónica (ME). Las pertitas pegmatíticas son sistemas complejos en cuyos feldespatos potásicos se han identificado dos periodos genéticos independientes de recristalización durante el enfriamiento geológico. En el primer periodo, en la estructura mineral se produce la construcción gradual de patrones macroscópicos regulares pseudoperiódicos, como consecuencia del efecto combinado de un ordenamiento local no-ergódico en la distribución Si/Al y de un efecto cooperativo global de la estructura del cristal. Desde las interfases incoherentes con el feldespato sódico surgen frentes de transformación a modo de avalanchas que pueden coalescer longitudinalmente y yuxtaponerse transversalmente para auto-ensamblarse, y finalmente evolucionar hasta formar dominios-macla (leyes Albita y Periclina), como unidad cristalina de construcción de la macroestructura. Estos procesos de auto-organización se activan cuando el sistema está abierto a la circulación de moléculas de agua catalizadoras para el ordenamiento de la red, al tiempo que existe una estimulación externa por tensiones tectónicas de cizalla. Durante el segundo periodo se destruyen los patrones estructurales creados previamente, por: (i) maclados de relajación y deformación, (ii) engrosamientos de dominios por disolución-reprecipitación debidos a interacciones con fluidos acuosos a baja temperatura, (iii) reorientaciones de dominiosmacla según ley Periclina hacia orientaciones de ley Albita.

Eighty six microclines with perthitic texture from seven granitic pegmatites have been collected and studied by X-ray diffraction (XRD), X-ray fluorescence (XRF) and optical microscopy (OM). The statistical distribution of the structural state of the microclines shows a tendency to bimodality and also the coexistence of different triclinicities. Pegmatitic microclines are better described when considered as complex crystals and not as heterogeneous pseudomorphic assemblages after sanidine transformation, because the structural state is organized following structural patterns around the interfase with Na-feldspar veins in macroperthitic texture. This tendency to bimodality allows to distinguish among disordered and ordered microclines linked with static and dynamic genetic regimes of solid state evolution on cooling. The static regime produces limited reequilibration since a surface re-crystallization process of regions with high local Si/Al order occurs along boundaries. The ordering is located next to circulation surfaces because the catalyst aqueous fluids have mainly a channeled motion. The dynamic regime is adaptative and important volumes are re-equilibrated by bulk re-crystallization give rise to an ordered microcline. This behavior can be explained considering that a volumetric flow of catalyst water molecules promote global Si/Al ordering. A transitional regime can be distinguished by partial penetration of water through the structures.Se han muestreado y estudiado ochenta y seis microclinas con textura pertítica procedentes de siete pegmatitas graníticas por difracción de rayos-X (DRX), fluorescencia de rayos-X (FRX) y microscopía óptica de luz transmitida (MLT). La tendencia hacia la bimodalidad estructural y la coexistencia de multitud de estados estructurales se describe considerando las microclinas pegmatíticas no como pseudomorfos heterogéneos sino como cristales complejos. Según ésta descripción, los estados estructurales no están distribuidos al azar sino que están organizados según patrones estructurales en torno a las interfases con el feldespato sódico en venas macropertíticas. La tendencia a la bimodalidad en el estado estructural permite distinguir entre microclinas desordenadas y ordenadas, cuyo origen se puede correlacionar con una dualidad en su evolución al estado sólido según un régimen genético estático y otro dinámico durante el enfriamiento. El régimen estático produce un re-equilibrado limitado porque la recristalización de regiones con mayor orden Si/Al es superficial. El ordenamiento Si/Al está localizado en las proximidades de las superficies con circulación acanalada de fluidos acuosos catalizadores de las transformaciones estructurales. El régimen dinámico es adaptativo y el re-equilibrado es extenso operando por recristalización global. Este comportamiento se explica por el flujo volumétrico de las moléculas de agua catalizadoras del re-equilibrado. La penetración parcial del agua a través de la estructura produce un régimen transicional entre los dos anteriores.

A new method for the geometrical and optical characterization of non-uniform thin isotropic dielectric films deposited onto a transparent substrate, has been developed. The algorithm is based on using the two envelopes of the optical reflection spectrum taken at normal incidence. The method allows determining the average thickness and the refractive index of the films with accuracies better than 1 %. The formulation is not only valid in the case of wedge-shaped thin films, but also for films showing a significant surface roughness. In the latter, the amplitude of the surface roughness can be estimated. Amorphous As40S60 thin films have been deposited by spin coating onto glass substrates, from a solution of the bulk material in n-propylamine. Indications of the surface roughness in these films were found from total reflectance measurements (specular + diffuse), by using a integrating sphere, and also from mechanical measurements, by using a profilometer. The latter technique provided a value for the average surface roughness of 20 ± 4 nm, which is in excellent agreement with that optically determined value of 17.4 ± 0.4 nm.Se ha desarrollado un nuevo método para la caracterización geométrica y óptica de láminas dieléctricas isótropas con espesor variable, depositadas sobre un substrato transparente. Este método está basado en el uso de las dos envolventes de los espectros de reflexión, obtenidos en incidencia normal, y permite determinar el espesor medio y el índice de refracción de estas láminas, con precisiones mejores que el 1 %. La formulación contempla la posibilidad de ser aplicable, no sólo en el caso de láminas cuyo espesor varíe linealmente a lo largo del área cubierta por el haz luminoso de medida, sino en aquellas que presenten un rugosidad significativa en su superficie y, en tal caso, permite determinar la amplitud de la rugosidad promedio. Así, se han preparado láminas delgadas amorfas de composición química As40S60 mediante el centrifugado de una disolución de este compuesto calcogenuro en n-propilamina. La rugosidad superficial de estas láminas se ha puesto de manifiesto a partir de las medidas de la reflectancia total (especular + difusa), haciendo uso de una esfera integradora, así como a través de medidas mecánicas de espesores, usando un perfilómetro. Esta última técnica proporcionó un valor para la amplitud media de la rugosidad de 20 ± 4 nm. El acuerdo entre este valor y el calculado mediante el presente método de caracterización óptica, 17.4 ± 0.4 nm, es excelente.

Background: A lesion-level risk prediction for acute coronary syndrome (ACS) needs better characterization., Objectives: This study sought to investigate the additive value of artificial intelligence-enabled quantitative coronary plaque and hemodynamic analysis (AI-QCPHA)., Methods: Among ACS patients who underwent coronary computed tomography angiography (CTA) from 1 month to 3 years before the ACS event, culprit and nonculprit lesions on coronary CTA were adjudicated based on invasive coronary angiography. The primary endpoint was the predictability of the risk models for ACS culprit lesions. The reference model included the Coronary Artery Disease Reporting and Data System, a standardized classification for stenosis severity, and high-risk plaque, defined as lesions with ≥2 adverse plaque characteristics. The new prediction model was the reference model plus AI-QCPHA features, selected by hierarchical clustering and information gain in the derivation cohort. The model performance was assessed in the validation cohort., Results: Among 351 patients (age: 65.9 ± 11.7 years) with 2,088 nonculprit and 363 culprit lesions, the median interval from coronary CTA to ACS event was 375 days (Q1-Q3: 95-645 days), and 223 patients (63.5%) presented with myocardial infarction. In the derivation cohort (n = 243), the best AI-QCPHA features were fractional flow reserve across the lesion, plaque burden, total plaque volume, low-attenuation plaque volume, and averaged percent total myocardial blood flow. The addition of AI-QCPHA features showed higher predictability than the reference model in the validation cohort (n = 108) (AUC: 0.84 vs 0.78; P < 0.001). The additive value of AI-QCPHA features was consistent across different timepoints from coronary CTA., Conclusions: AI-enabled plaque and hemodynamic quantification enhanced the predictability for ACS culprit lesions over the conventional coronary CTA analysis. (Exploring the Mechanism of Plaque Rupture in Acute Coronary Syndrome Using Coronary Computed Tomography Angiography and Computational Fluid Dynamics II [EMERALD-II]; NCT03591328)., Competing Interests: Funding Support and Author Disclosures This study received funding from HeartFlow Inc. The company performed the computational fluid dynamics, and artificial intelligence quantitative coronary plaque analysis but was not involved in the study design, collection, analysis, and interpretation of data; the writing of this paper; or the decision to submit it for publication. Dr Koo has received institutional research grants from Abbott, Philips, and HeartFlow Inc. Dr Nam has received institutional research grants from Abbott and Genoss. Dr Merkely has received direct personal payments for speaker fees or studies from Abbott, AstraZeneca, Biotronik, Boehringer Ingelheim, CSL Behring, Daiichi Sankyo, DUKE Clinical Institute, Medtronic, and Novartis and institutional grants from Abbott, AstraZeneca, Biotronik, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, CSL Behring, Daiichi Sankyo, DUKE Clinical Institute, Eli Lilly, Medtronic, Novartis, Terumo, and VIFOR Pharma. Dr de Bruyne has received institutional unrestricted research grants from Abbott, Boston Scientific, and Biotronik; has received consulting fees from Abbott, Opsens, and Boston Scientific; and is a shareholder for Siemens, GE, Bayer, Philips, HeartFlow Inc, Edwards Life Sciences, Sanofi, and Omega Pharma. Dr Ko has equity in Artrya and has received honoraria from Medtronic, Abbott Vascular, and Canon Medical. Dr Leipsic is a consultant for and holds stock options in HeartFlow Inc and modest personal core lab fees from Arineta. Dr Shah has received honoraria as a speaker for HeartFlow Inc. Dr Bax has received unrestricted research grants from Abbott and Edwards Lifesciences to the Department of Cardiology, Leiden University Medical Center, the Netherlands. Dr Shaw has received honoraria from HeartFlow Inc and Elucid Imaging. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

The ubiquitin E2 variant domain of TSG101 (TSG101-UEV) plays a pivotal role in protein sorting and virus budding by recognizing PTAP motifs within ubiquitinated proteins. Disrupting TSG101-UEV/PTAP interactions has emerged as a promising strategy for the development of novel host-oriented antivirals with a broad spectrum of action. Nonetheless, finding inhibitors with good properties as therapeutic agents remains a challenge since the key determinants of binding affinity and specificity are still poorly understood. Here we present a detailed thermodynamic, structural, and dynamic characterization viral PTAP Late domain recognition by TSG101-UEV, combining isothermal titration calorimetry, X-ray diffraction structural studies, molecular dynamics simulations, and computational analysis of intramolecular communication pathways. Our analysis highlights key contributions from conserved hydrophobic contacts and water-mediated hydrogen bonds at the PTAP binding interface. We have identified additional electrostatic hotspots adjacent to the core motif that modulate affinity. Using competitive phage display screening we have improved affinity by 1-2 orders of magnitude, producing novel peptides with low micromolar affinities that combine critical elements found in the best natural binders. Molecular dynamics simulations revealed that optimized peptides engage new pockets on the UEV domain surface. This study provides a comprehensive view of the molecular forces directing TSG101-UEV recognition of PTAP motifs, revealing that binding is governed by conserved structural elements yet tuneable through targeted optimization. These insights open new venues to design inhibitors targeting TSG101-dependent pathways with potential application as novel broad-spectrum antivirals., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Abstract: Selecting the most suitable alternative donor becomes challenging in severe aplastic anemia (SAA) when a matched sibling donor (MSD) is unavailable. We compared outcomes in patients with SAA undergoing stem cell transplantation (SCT) from matched unrelated donors (MUD) (n = 1106), mismatched unrelated donors (MMUD) (n = 340), and haploidentical donors (Haplo) (n = 206) registered in the European Society for Blood and Marrow Transplantation database (2012-2021). For Haplo SCT, only those receiving posttransplant cyclophosphamide for graft-versus-host disease (GVHD) prophylaxis were included. Median age was 20 years, and the median time from diagnosis to transplantation 8.7 months. Compared with MUD, MMUD (hazard ratio [HR], 2.93; 95% confidence interval [CI], 1.52-5.6) and Haplo (HR, 5.15; 95% CI, 2.5-10.58) showed significantly higher risks of primary graft failure. MUD had lower rates of acute GVHD compared with MMUD and Haplo (grade 2-4: 13%, 22%, and 19%, respectively; P < .001; grade 3-4: 5%, 9%, and 7%, respectively; P = .028). The 3-year nonrelapse mortality rate was 14% for MUD, 19% for MMUD, and 27% for Haplo (P < .001), whereas overall survival and GVHD and relapse-free survival (GRFS) rates were 81% and 73% for MUD, 74% and 65% for MMUD, and 63% and 54% for Haplo, respectively (P < .001). In addition to donor type, multivariable analysis identified other factors associated with GRFS such as patient age, performance status, and interval between diagnosis and transplantation. For patients with SAA lacking an MSD, our findings support MUDs as the preferable alternative donor option. However, selecting between an MMUD and Haplo donor remains uncertain and requires further exploration., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Newborn bloodspot screening (NBS) for cystic fibrosis (CF) is important for early diagnosis and treatment. However, screening can lead to false-positive results leading to unnecessary follow-up tests and distress. This study evaluated the 11-year performance of the Swiss CF-NBS programme, estimated optimal cut-offs for immunoreactive trypsinogen (IRT), and examined how simulated algorithms would change performance., Methods: The Swiss CF-NBS is based on an IRT-DNA algorithm with a second IRT (IRT-2) as safety net. We analysed data from 2011 to 2021, covering 959,006 IRT-1 analyses and 282 children with CF. We studied performance based on European Cystic Fibrosis Society (ECFS) standards including sensitivity, specificity, positive predictive value (PPV), false negative rate, and second heel-prick tests; identified optimal IRT cut-offs using receiver operating characteristics (ROC) curves; and calculated performance for simulated algorithms with different cut-offs for IRT-1, IRT-2, and safety net., Results: The Swiss CF-NBS showed excellent sensitivity (96 %, 10 false negative cases) but moderate PPV (25 %). Optimal IRT-1 and IRT-2 cut-offs were identified at 2.7 (>99th percentile) and 5.9 (>99.8th percentile) z-scores, respectively. Analysis of simulated algorithms showed that removing the safety net from the current algorithm could increase PPV to 30 % and eliminate >200 second heel-prick tests per year, while keeping sensitivity at 95 %., Conclusion: The Swiss CF-NBS program performed well over 11 years but did not achieve the ECFS standards for PPV (≥30 %). Modifying or removing the safety net could improve PPV and reduce unnecessary follow-up tests while maintaining the ECFS standards for sensitivity., Competing Interests: Declaration of competing interest No conflict of interest to declare for any of the authors., (Copyright © 2024. Published by Elsevier B.V.)

The high disease burden of influenza virus poses a significant threat to human health. Optimized diagnostic technologies that combine speed, sensitivity, and specificity with minimal equipment requirements are urgently needed to detect the many circulating species, subtypes, and variants of influenza at the point of need. Here, we introduce such a method using Streamlined Highlighting of Infections to Navigate Epidemics (SHINE), a clustered regularly interspaced short palindromic repeats (CRISPR)-based RNA detection platform. Four SHINE assays were designed and validated for the detection and differentiation of clinically relevant influenza species (A and B) and subtypes (H1N1 and H3N2). When tested on clinical samples, these optimized assays achieved 100% concordance with quantitative RT-PCR. Duplex Cas12a/Cas13a SHINE assays were also developed to detect two targets simultaneously. This study demonstrates the utility of this duplex assay in discriminating two alleles of an oseltamivir resistance (H275Y) mutation as well as in simultaneously detecting influenza A and human RNAse P in patient samples. These assays have the potential to expand influenza detection outside of clinical laboratories for enhanced influenza diagnosis and surveillance., Competing Interests: Disclosure Statement J.A.-S., P.C.S., and C.M. are inventors on a pending patent application held by the Broad Institute (international patent application number PCT/US2021/049145), which covers the SHINE technology. P.C.S. is a cofounder of, shareholder in, and consultant to Sherlock Biosciences, Inc., and Delve Bio, as well as a board member of and shareholder in Danaher Corp. C.M. is a cofounder of Carver Biosciences, a startup company developing Cas13-based antivirals, and holds equity in Carver Biosciences., (Copyright © 2024 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Abstract: There is a paucity of information on how to select the most appropriate unrelated donor (UD) in hematopoietic stem cell transplantation (HSCT) using posttransplant cyclophosphamide (PTCy). We retrospectively analyzed the characteristics of 10/10 matched UDs (MUDs) and 9/10 mismatched UDs (MMUDs) that may affect transplant outcomes in patients with acute myeloid leukemia (AML) in first or second complete remission (CR1 or CR2). The primary end point was leukemia-free survival (LFS). Overall, 1011 patients were included with a median age of 54 years (range, 18-77). Donors had a median age of 29 years (range, 18-64); 304 (30%) were females, of which 150 (15% of the whole group) were donors to male recipients, and 621 (61%) were MUDs; 522 (52%) had negative cytomegalovirus (CMV-neg) serostatus, of which 189 (19%) were used for CMV-neg recipients. Donor age older than 30 years had a negative impact on relapse (hazard ratio [HR], 1.38; 95% confidence interval [CI], 1.06-1.8), LFS (HR, 1.4; 95% CI, 1.12-1.74), overall survival (HR 1.45; 95% CI, 1.14-1.85) and graft-versus-host disease (GVHD) free, relapse-free survival (HR, 1.29; 95% CI, 1.07-1.56). In addition, CMV-neg donors for CMV-neg recipients were associated with improved LFS (HR, 0.74; 95% CI, 0.55-0.99). The use of MMUD and female donors for male recipients did not significantly impact any transplant outcomes. For patients undergoing HSCT from a UD with PTCy for AML, donor age <30 years significantly improves survival. In this context, donor age might be prioritized over HLA match considerations. In addition, CMV-neg donors are preferable for CMV-neg recipients. However, further research is needed to validate and refine these recommendations., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

The standard of care for the first-line management of metastatic urothelial carcinoma has been recently challenged, with the combination of pembrolizumab and enfortumab vedotin (P-EV) strongly arising as a practice-changing option from classical platinum-based chemotherapies. With this paradigm shift on the horizon new questions, including the most suitable second line of treatment for these patients, and the role that the molecular characterization of these tumours will have when selecting these therapies will inevitably arise. Furthermore, after the negative results of the Keynote 361 and IMvigor 130 trials, the combination of nivolumab with platinum-based chemotherapy followed by nivolumab maintenance (Nivo GC-Nivo) has also shown positive results when compared with chemotherapy alone. Translational studies at a molecular, cellular, and functional level will be key to better explain these discordant results. In this Current Perspective, we discuss the potential impact of these results in clinical practice and propose specific guidance for prospective translational research., Competing Interests: Disclosure M.D.F. has received grants fees from “Fundación Cris contra el Cáncer”, travel fees from Astellas, AstraZeneca, Pfizer, Pierre Fabre, Roche, Bristol Meiers Squibb, Novartis, MSD, Janssen, MERK, Ipsen and Bayer Pharmamar, and speakers’ bureau from Janssen, Pierre Fabre and Roche. All outside the submitted work. G.V. has received speaker's fees from MSD, GSK, Pfizer and Pierre Fabre, and has held an advisory role with AstraZeneca. All outside of the submitted work. J.L.P.G. has received research grants and support from Astellas, Amgen, BMS, MSD, Novartis, Roche, Seattle Genetics, speakers’ bureau and advisory boards from Astellas, MSD, Roche, and travel support from BMS, MSD, Roche, Merck. All outside the submitted work. The rest of authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: Treatment of malignant midface tumors is a surgical challenge with an increased difficulty to obtain free surgical margins. The computer assisted surgery (CAS) and intraoperative navigation (ION) can be very helpful in complex midface resections. The main objective of this paper is to evaluate if the ION could improve the rate of free surgical margins in locally advanced midface malignancies., Materials and Methods: A retrospective cohort study was performed including 40 patients with a locally advanced malignant midface tumor (T4a/b) surgically treated from September 2016 to September 2022. Patients were divided in two groups, a control group included 20 patients operated on without ION and the study group included 20 patients treated with Navigation assisted surgery. A systematic analysis was performed comparing surgical margins in both groups., Results: Squamous cell carcinoma was the most common histological type. Oral cavity was the most common primary location. Overall, considering each specimen as an hexahedrium, 240 surgical margins were analyzed. 15 out of 120 margins analyzed in the navigation group (12.5 %) were positive while 30 out of 120 margins analyzed in control group (25 %) were affected (p 0.013). Concerning margin location, the ION group showed less involvement of the upper surface of specimen than in control group (p 0.048)., Conclusion: Navigation Assisted Surgery seems to improve the rate of free surgical margins in patients with locally advanced midface malignancies, specially concerning involvement of the superior margin. Further studies are recommended to corroborate these results and its potential influence in survival rates., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The diagnostic evaluation of coronary artery disease is undergoing a dramatic transformation with a new focus on atherosclerotic plaque. This review details the evidence needed for effective risk stratification and targeted preventive care based on recent advances in automated measurement of atherosclerosis from coronary computed tomography angiography (CTA). To date, research findings support that automated stenosis measurement is reasonably accurate, but evidence on variability by location, artery size, or image quality is unknown. The evidence for quantification of atherosclerotic plaque is unfolding, with strong concordance reported between coronary CTA and intravascular ultrasound measurement of total plaque volume (r >0.90). Statistical variance is higher for smaller plaque volumes. Limited data are available on how technical or patient-specific factors result in measurement variability by compositional subgroups. Coronary artery dimensions vary by age, sex, heart size, coronary dominance, and race and ethnicity. Accordingly, quantification programs excluding smaller arteries affect accuracy for women, patients with diabetes, and other patient subsets. Evidence is unfolding that quantification of atherosclerotic plaque is useful to enhance risk prediction, yet more evidence is required to define high-risk patients across varied populations and to determine whether such information is incremental to risk factors or currently used coronary computed tomography techniques (eg, coronary artery calcium scoring or visual assessment of plaque burden or stenosis). In summary, there is promise for the utility of coronary CTA quantification of atherosclerosis, especially if it can lead to targeted and more intensive cardiovascular prevention, notably for those patients with nonobstructive coronary artery disease and high-risk plaque features. The new quantification techniques available to imagers must not only provide sufficient added value to improve patient care, but also add minimal and reasonable cost to alleviate the financial burden on our patients and the health care system., Competing Interests: Funding Support and Author Disclosures Dr Blankstein has served as a consultant for Caristo Inc, Elucid Inc, HeartFlow Inc, and Nanox AI. Dr Leipsic has served as a consultant for and has stock options in HeartFlow and Circle CV Imaging. Dr Shaw has received speaker honoraria from HeartFlow and Elucid Imaging. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Syntenin-1 is a multidomain protein containing a central tandem of two PDZ domains flanked by two unnamed domains. Previous structural and biophysical studies show that the two PDZ domains are functional both isolated and in tandem, occurring a gain in their respective binding affinities when joined through its natural short linker. To get insight into the molecular and energetic reasons of such a gain, here, the first thermodynamic characterization of the conformational equilibrium of Syntenin-1 is presented, with special focus on its PDZ domains. These studies include the thermal unfolding of the whole protein, the PDZ-tandem construct and the two isolated PDZ domains using circular dichroism, differential scanning fluorimetry and differential scanning calorimetry. The isolated PDZ domains show low stability (ΔG < 10 kJ·mol -1 ) and poor cooperativity compared to the PDZ-tandem, which shows higher stability (20-30 kJ·mol -1 ) and a fully cooperative behaviour, with energetics similar to that previously described for archetypical PDZ domains. The high-resolution structures suggest that this remarkable increase in cooperativity is associated to strong, water-mediated, interactions at the interface between the PDZ domains, associated to nine conserved hydration regions. The low T m value (45 °C), the anomalously high unfolding enthalpy (>400 kJ·mol -1 ), and native heat capacity values (above 40 kJ·K -1 ·mol -1 ), indicate that these interfacial buried waters play a relevant role in Syntenin-1 folding energetics., Competing Interests: Declaration of competing interest The authors declare that they do not have conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: To assess the effect of hydroxychloroquine (HCQ) and Tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) as pre-exposure prophylaxis on COVID-19 risk., Methods: EPICOS is a double-blind, placebo-controlled randomized trial conducted in Spain, Bolivia, and Venezuela. Healthcare workers with negative SARS-CoV-2 IgM/IgG test were randomly assigned to the following: daily TDF/FTC plus HCQ for 12 weeks, TDF/FTC plus HCQ placebo, HCQ plus TDF/FTC placebo, and TDF/FTC placebo plus HCQ placebo. Randomization was performed in groups of four. Primary outcome was laboratory-confirmed, symptomatic COVID-19. We also studied any (symptomatic or asymptomatic) COVID-19. We compared group-specific 14-week risks via differences and ratios with 95% CIs., Results: Of 1002 individuals screened, 926 (92.4%) were eligible and there were 14 cases of symptomatic COVID-19: 220 were assigned to the TDF/FTC plus HCQ group (3 cases), 231 to the TDF/FTC placebo plus HCQ group (3 cases), 233 to the TDF/FTC plus HCQ placebo group (3 cases), and 223 to the double placebo group (5 cases). Compared with the double placebo group, 14-week risk ratios (95% CI) of symptomatic COVID-19 were 0.39 (0.00-1.98) for TDF + HCQ, 0.34 (0.00-2.06) for TDF, and 0.49 (0.00-2.29) for HCQ. Corresponding risk ratios of any COVID-19 were 0.51 (0.21-1.00) for TDF + HCQ, 0.81 (0.44-1.49) for TDF, and 0.73 (0.41-1.38) for HCQ. Adverse events were generally mild., Discussion: The target sample size was not met. Our findings are compatible with both benefit and harm of pre-exposure prophylaxis with TDF/FTC and HCQ, alone or in combination, compared with placebo., (Copyright © 2022 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Abstract: The antimicrobial activity of a commercial Lippia citriodora extract (LCE) at 2,500 μg mL-1 (maximum sensory acceptable level) and vanillin (MIC and 2 MIC) alone and in combination were analyzed in four strains of Escherichia coli (two nonverotoxigenic and two verotoxigenic) in cation-adjusted Mueller-Hinton medium and in Piel de Sapo melon juice (MJ) stored under refrigeration (4°C) for 7 days. The bacterial counts of the four strains together in untreated samples were higher (≈4 log CFU/mL) in cation-adjusted Mueller-Hinton medium than in stored MJ. LCE showed higher antimicrobial activity in MJ than in standard culture broth, but vanillin showed a higher effect in broth. The verotoxigenic strain E. coli O146:H stx2 was the most sensitive to LCE in refrigerated MJ. Combinations of vanillin (at MIC and 2 MIC) with LCE were very effective in reducing E. coli counts either in broth or in refrigerated MJ to undetectable levels. Bactericidal effects were observed for the combinations in all strains in broth and in MJ. Also, these combinations showed an antimicrobial synergistic effect after day 3 of storage in MJ in three of the bacterial strains tested. These results indicate that the combination of LCE (at maximum sensory acceptable levels) and vanillin (at low concentrations) could be considered as a promising natural antimicrobial agent to inhibit verotoxigenic E. coli growth in refrigerated MJ and improve its quality., (Copyright ©, International Association for Food Protection.)

Acute myeloid leukemia (AML) treatment landscape had evolved over the last decades with better understanding of the disease genomics and the use of the targeted therapy, despite this treatment evolution, 7 + 3 remains the mainstay treatment for most AML cases. Many attempts had been made to improve the treatment outcome with 7 + 3 like manipulating the doses or the duration, but with no significant change in the outcome. In 2017 FDA approved CPX-351,a liposomal formulation of cytarabine and daunorubicin at a fixed 5:1 molar ratio, for the treatment of adults with newly diagnosed AML with myelodysplasia-related changes and therapy-related AML (t-AML). Since the approval, many trials were conducted or still ongoing in assessing the role of CPX-351 in treating different patient populations, AML subcategories or when combined with different agents. In this review, we will summarize the current role of CPX-351 in treating this largely heterogeneous disease., (Copyright © 2022. Published by Elsevier Inc.)

The aim of this study is to compare the accuracy of maxilla positioning in orthognathic surgery with the use of custom-made devices (cutting guides and patient-fitted osteosynthesis plates) comparing to CAD/CAM splints. A prospective randomized study was performed. Patients with dentofacial deformities undergoing orthognathic surgery were compared, using customized guides (experimental group) vs. CAD/CAM surgical splints (control group) for the repositioning of the upper maxilla. Preoperative and postoperative CT scans were used to compare positioning and fixation of the maxilla in the three planes of space. A total of 30 patients were included in the study (15 patients in each study group). The mean error obtained with customized guides was 0.8 mm (range 0.1-1.9) in the anterior-posterior axis, 0.4 mm (range 0-1.4) in the vertical axis and 0.2 mm (range 0-1.1) in the horizontal axis. There were statistically significant differences in the anterior-posterior and vertical axes in favour of the customized implants, whereas there were no differences in the horizontal plane. Furthermore, there was a mean reduction of the operative time of 36.5 min in the experimental group. Within the limitations of the study it seems that patient specific surgical guides should be preferred when accuracy of repositioning of the maxilla and saving operative time are the priority., Competing Interests: Declaration of competing interest None., (Copyright © 2022 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.)

Background: Carotid and femoral plaque burden is a recognized biomarker of cardiovascular disease risk. A new electronic-sweep 3-dimensional (3D)-matrix transducer method can improve the functionality and image quality of vascular ultrasound atherosclerosis imaging., Objectives: This study aimed to validate this method for plaque volume measurement in early and intermediate-advanced plaques in the carotid and femoral territories., Methods: Plaque volumes were measured ex vivo in pig carotid and femoral artery specimens by 3-dimensional vascular ultrasound (3DVUS) using a 3D-matrix (electronic-sweep) transducer and its associated 3D plaque quantification software, and were compared with gold-standard histology. To test the clinical feasibility and accuracy of the 3D-matrix transducer, an experiment was conducted in intermediate-high risk individuals with carotid and femoral atherosclerosis. The results were compared with those obtained using the previously validated mechanical-sweep 3D transducer and established 2-dimensional (2D)-based plaque quantification software., Results: In the ex vivo study, the authors assessed 19 atherosclerotic plaques (plaque volume, 0.76 µL-56.30 μL), finding strong agreement between measurements with the 3D-matrix transducer and the histological gold-standard (intraclass correlation coefficient [ICC]: 0.992; [95% CI: 0.978-0.997]). In the clinical analysis of 20 patients (mean age 74.6 ± 4.45 years; 40% men), the authors found 64 (36 carotid and 28 femoral) of 80 scanned territories with atherosclerosis (measured atherosclerotic volume, 10 μL-859 μL). There was strong agreement between measurements made from electronic-sweep and mechanical-sweep 3DVUS transducers (ICC: 0.997 [95% CI: 0.995-0.998]). Agreement was also high between plaque volumes estimated by the 2D and 3D plaque quantification software applications (ICC: 0.999 [95% CI: 0.998-0.999]). Analysis time was significantly shorter with the 3D plaque quantification software than with the 2D multislice approach with a mean time reduction of 46%., Conclusions: 3DVUS using new matrix transducer technology, together with improved 3D plaque quantification software, simplifies the accurate volume measurement of early (small) and intermediate-advanced plaques located in carotid and femoral arteries., Competing Interests: Funding Support and Author Disclosures This study was partially funded by grants from the Ministerio de Economia, Industria y Competividad (MEIC) with cofunding from the European Regional Development Fund (ERDF) (SAF2016-75580-R to Dr Bentzon) and (BES-2016-076633 to Dr Nogales). Research funding was also received from the Instituto de Salud Carlos III Spain (PIE16/00021 to Drs Bueno and Fuster). The CNIC is supported by the Ministerio de Ciencia, Innovacion y Universidades (MICINN) and the Pro CNIC Foundation and is a Severo Ochoa Center of Excellence (CEX2020-001041-S). This study forms part of a Master Research Agreement between the CNIC and Philips Healthcare. Drs Sánchez-González, Entrekin, and Collet-Billon are employees of Philips Healthcare. All other authors have reported that they have no relationships to disclose related to the contents of this paper., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Spondyloarthritis (SpA) is one of the most common extraintestinal manifestations of inflammatory bowel disease (IBD). Diagnostic delay must be avoided., Aims: We assessed the validity of SpA screening criteria (any of the following characteristics: chronic low back pain with onset before 45 years of age; inflammatory lower back pain or alternating buttock pain; arthritis; heel enthesitis; dacylitis; HLA-B27 positivity; sacroiliitis on imaging)., Methods: This was a multicenter cross-sectional observational study in IBD patients aged ≥18 years. After evaluating the SpA screening criteria, the gastroenterologists referred the participants to the rheumatologists, who determined whether the patient fulfilled the screening criteria and carried out the necessary tests for SpA diagnosis., Results: 35 (11.7%) out of 300 patients were diagnosed with SpA. The combination with the best balance between sensitivity and specificity (91.4% and 72.1%, respectively, when applied by the rheumatologists; 80% and 78.9%, when applied by the gastroenterologists) for SpA screening, was fulfillment of any of the following: chronic low back pain with onset before age 45 years, inflammatory low back pain or alternating buttock pain, arthritis, or dactylitis., Conclusion: This is one of the first studies to validate SpA screening criteria in IBD patients in routine clinical practice., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest related to this work., (Copyright © 2021. Published by Elsevier Ltd.)

The recognition of PPxY viral Late domains by the third WW domain of the human HECT-E3 ubiquitin ligase NEDD4 (NEDD4-WW3) is essential for the budding of many viruses. Blocking these interactions is a promising strategy to develop broad-spectrum antivirals. As all WW domains, NEDD4-WW3 is a challenging therapeutic target due to the low binding affinity of its natural interactions, its high conformational plasticity, and its complex thermodynamic behavior. In this work, we set out to investigate whether high affinity can be achieved for monovalent ligands binding to the isolated NEDD4-WW3 domain. We show that a competitive phage-display set-up allows for the identification of high-affinity peptides showing inhibitory activity of viral budding. A detailed biophysical study combining calorimetry, nuclear magnetic resonance, and molecular dynamic simulations reveals that the improvement in binding affinity does not arise from the establishment of new interactions with the domain, but is associated to conformational restrictions imposed by a novel C-terminal -LFP motif in the ligand, unprecedented in the PPxY interactome. These results, which highlight the complexity of WW domain interactions, provide valuable insight into the key elements for high binding affinity, of interest to guide virtual screening campaigns for the identification of novel therapeutics targeting NEDD4-WW3 interactions., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction and Objectives: Fetal pericardial effusion appears in different pathologies such as hydrops fetalis, heart structural or rhythm alterations, however, it can be observed in isolation but an increase in its incidence has been observed in relation to the presence of severe pathologies., Methods: Analysis of all cases of IFPE detected in Aragon and assessed in a cardiological consultation for prenatal diagnosis of a tertiary hospital collected over ten years, as well as the evolution of the patients to the present., Results: A sample of 38 fetuses was obtained from 37 pregnant women diagnosed with DPFA with spontaneous resolution in 86.8%. Two abortions (voluntary interruptions after prenatal diagnosis of 22q13 deletion and primary infection by cytomegalovirus) and one spontaneous fetal death were recorded. Pathological alterations were observed in 10/38 newborns: two patients with metabolic disease, two patients with chromosomopathies, one patient with pulmonary hypoplasia and unilateral hydronephrosis, one patient with hypertrophic cardiomyopathy, and four patients studied for alterations in psychomotor development and/or congenital ophthalmological or hearing disorders. The overall morbidity rate was 34.2% and death rate 15.7%. The detection of other ultrasound alterations and the alteration in the first trimester screening were significantly associated with the presence of pathology., Conclusions: IFPE has been classically associated with a good prognosis, although it is sometimes related to clinical entities with high morbidity and mortality: more than a third of the patients in our sample are affected. An exhaustive pre and postnatal follow-up of these cases is recommended in order to perform an early intervention., (Copyright © 2022 Asociación Española de Pediatría. Published by Elsevier España, S.L.U. All rights reserved.)

Introduction: Short stature is the most frequent reason for consultation in Pediatric Endocrinology consultations and sometimes requires treatment with growth hormone. The aim of the study was to analyze the response to treatment based on its onset in pubertal or prepubertal stages and to analyze the possible benefit of an early onset., Patients and Methods: Longitudinal, retrospective and observational study in 139 patients treated for idiopathic growth hormone deficiency up to adult height., Main Variables Studied: (a) genetic background: maternal, paternal and genetic height; (b) perinatal history; (c) anthropometry during follow-up and at pubertal onset: weight, height, body mass index; (d) variables during follow-up and at pubertal onset: growth rate, bone age and growth prognosis. Final response variables: adult height, adult height with respect to target height, adult height with respect to initial growth prediction, adult height with respect to initial height at the start of treatment and adult height with respect to height at pubertal onset., Results: Total pubertal gain was 0.84 ± 0.6 SD. 61.9% of the patients started treatment with rhGH in prepuberty. The initiation of treatment in the prepubertal stage and a higher total pubertal gain are correlated with a better final height (P = 0.001 and r = 0.507, P = 0.00, respectively). Furthermore, a longer duration of treatment in pre-puberty is correlated with a better final response (r = 0.328, P = 0.00)., Conclusions: The start of treatment in the prepubertal stage and its longer duration during this period are determining factors to achieve a good long-term response. Total pubertal gain was greater in patients who started treatment in the pubertal stage., (Copyright © 2022 Asociación Española de Pediatría. Published by Elsevier España, S.L.U. All rights reserved.)

Epicardial Adipose Tissue (EAT) is drawing increasing attention. As a quantifiable, modifiable, and potentially new cardiovascular therapeutic target, its accurate measurement is particularly relevant. In Cardiac Magnetic Resonance (CMR) different methods can be used to assess EAT burden. We take advantage of CMR-studies of EMPATROPISM trial to assess EAT through three different methods, evaluate the effect of Empagliflozin and look for significant difference in the ability to detect changes in serial measurements. In some settings such as treatment-induced changes or patient follow-up, multi-slice method of EAT evaluation provides higher accuracy to detect significant differences, otherwise unnoticed by single-slice approaches., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Within the modular protein domains there are five families that recognize proline-rich sequences: SH3, WW, EVH1, GYF and UEV domains. This chapter reviews the main strategies developed for the design of ligands for these families, including peptides, peptidomimetics and drugs. We also describe some studies aimed to understand the molecular reasons responsible for the intrinsic affinity and specificity of these domains., (Copyright © 2022 Elsevier Inc. All rights reserved.)