Variabilidad genética y susceptibilidad al dolor postoperatorio en CMA tras empleo tramado-paracetamol

[ES]El dolor agudo postoperatorio es una de las complicaciones más frecuentes en Cirugía Mayor Ambulatoria, constituyendo un problema de considerable incidencia desde el postoperatorio inmediato hasta la recuperación tardía en el domicilio. Se ha demostrado que el mal control del dolor postoperatorio, incrementa la necesidad de personal sanitario y disminuye el flujo de pacientes, aumentando los costes y disminuyendo la eficacia del sistema. El analgésico ideal para la CMA, debería reunir las siguientes condiciones: cómoda dosificación oral y parenteral; rápida respuesta analgésica; buena tolerancia gastrointestinal; no interacción con fármacos habituales del período postoperatorio; y que permita disminuir la dosis de opioides y con ello sus efectos secundarios. La combinación óptima será aquella que proporcione la mejor relación entre analgesia y efectos secundarios. La combinación paracetamol-AINE presenta un eficacia analgésica superior a la del AINE solo, sin aumentar el número de efectos secundarios. Asimismo cuando se asocia el paracetamol a un opioide mejora a eficacia analgésica y permite reducir la dosis de opioide. Asociaciones de analgésicos no opioides (paracetamol, AINE) y opioides (codeína, tramadol) presentan menor riesgo de efectos indeseables, y combinados con técnicas de anestesia regional tienen gran aceptación en cirugía sin ingreso. La combinación de tramadol y paracetamol en dosis fijas es una alternativa atractiva para el tratamiento del dolor moderado a grave, presentando ventajas como menor incidencia de eventos adversos y mayor comodidad posológica. Su acción es rápida y prolongada, ya que el paracetamol se absorbe antes y provee de analgesia inicial, y el tramadol, con una vida media más prolongada, provee analgesia más duradera. La Farmacogenética es la ciencia que se ocupa del estudio de los factores genéticos que influyen en la variabilidad interindividual en la respuesta farmacológica, tanto en la eficacia como en la tolerancia. Dentro de estas variaciones se incluyen los polimorfismos de un sólo nucleótido (Single Nucleotide Polymorphism o SNP), inserciones o deleciones que pueden incluir el gen completo, y repeticiones. La forma más común de todas es la sustitución de una base o SNP. El tramadol se metaboliza en el hígado, en la fase I dependiente del Citocromo P450 se forma el mono-O-desmetiltramadol (metabolito activo) y en la fase II por desmetilación, glucoronización y sulfatación produciendo metabolitos inactivos. El paracetamol una cuarta parte de la dosis experimenta en el hígado un metabolismo de primer paso. También es metabolizada en el hígado la mayor parte de la dosis terapéutica, produciéndose conjugados glucurónicos y sulfatos, que son posteriormente eliminados en la orina. Entre un 10-15% de la dosis experimenta un metabolismo oxidativo mediante las isoenzimas de citrocromo P450, siendo posteriormente conjugado con cisteína y ácido mercaptúrico

Design Strategy and Considerations to Improve Corona Discharge Breakdown in Groove Gap Waveguides

Paper submitted to the 15th European Conference on Antennas and Propagation (EuCAP), 22-26 March 2021.This paper studies the corona discharge breakdown thresholds in groove gap waveguides, and proposes a design strategy to enhance its peak power handling capability (PPHC). The theoretical analysis is focused on the study of the quasi-TE 10 mode, and on the PPHC at different frequencies and multiple arrangements of the pin dimensions of the bed of nails. Next, the geometrical parameters width, length and separation of such pins are optimized for improving peak power limits. Finally, the simulated results show reasonably good performance with respect to the equivalent rectangular waveguide power limit.This work has been supported by the University of Alicante through the fellowship grant UAFPU2018-054 and by the ”Ministerio de Ciencia e Innovación” through research projects PID2019-103982RB-C41 and PID2019-103982RB-C43

In-depth Study of the Corona Discharge Breakdown Thresholds in Groove Gap Waveguides and Enhancement Strategies for Inductive Bandpass Filters

This work focuses on the study of the corona discharge breakdown in groove gap waveguides (GGWs) and inductive bandpass filters (BPFs) based on this technology. With the main aim of improving the peak power handling capability (PPHC), the location of the maximum normalized electric field strength (|Ê MAX |) as a function of the geometrical parameters is analyzed. First, the research deals with wave-guiding structures, comparing the distribution of the transverse electric TE10-like mode of a GGW to that of an equivalent rectangular waveguide (RW). Next, a design strategy based on the adjustment of the geometrical dimensions of the bed of nails is proposed, thus achieving a considerable reduction of |Ê MAX |. The second part of this paper aims for vertically polarized GGW BPFs, where the inductive irises become the most critical part of the component. By a simple modification of their dimensions, a second design criterion is suggested for improving the PPHC. Finally, several Ku-band BPFs centered at 14 GHz and 16 GHz have been manufactured and experimentally verified at the European High-Power Radiofrequency Space Laboratory. This measurement campaign shows peak power thresholds up to 1.09 kW and 3.59 kW at 600 mbar for the non- and full-optimized GGW BPFs, respectively, thereby demonstrating a PPHC enhancement up to 5.16 dB in the high-pressure range when both strategies, proposed in this work, are used.The authors would like to thank the European Space Agency (ESA) and Val Space Consortium (VSC) —Laboratories funded by the European Regional Development Fund—A way of making Europe, and the Antennas and Propagation Lab (APL – iTEAM UPV) for their contributions

DNA damage response-related alterations define the genetic background of patients with chronic lymphocytic leukemia and chromosomal gains

[EN]The presence of chromosomal gains other than trisomy 12 suggesting a hyperdiploid karyotype is extremely rare in chronic lymphocytic leukemia (CLL) and is associated with a dismal prognosis. However, the genetic mechanisms and mutational background of these patients have not been fully explored. To improve our understanding of the genetic underpinnings of this subgroup of CLL, seven CLL patients with several chromosomal gains were sequenced using a next-generation sequencing (NGS)-targeted approach. The mutational status of 54 genes was evaluated using a custom-designed gene panel including recurrent mutated genes observed in CLL and widely associated with CLL pathogenesis. A total of 21 mutations were detected; TP53 (42.8%), ATM (28.5%), SF3B1 (28.5%), and BRAF (28.5%) were the most recurrently mutated genes. Of these mutations, 61.9% were detected in genes previously associated with a poor prognosis in CLL. Interestingly, five of the seven patients exhibited alterations in TP53 or ATM (deletion and/or mutation), genes involved in the DNA damage response (DDR), which could be related to a high genetic instability in this subgroup of patients. In conclusion, CLL patients with several chromosomal gains exhibit high genetic instability, with mutations in CLL driver genes and high-risk genetic alterations involving ATM and/or TP53 genes

Increasing Peak Power Handling in Microstrip Bandpass Filters by Using Rounded-End Resonators

© © 2017 IEEE. Personal use of this material is permitted. Permissíon from IEEE must be obtained for all other uses, in any current or future media, including reprinting/republishing this material for advertisíng or promotional purposes, creating new collective works, for resale or redistribution to servers or lists, or reuse of any copyrighted component of this work in other works.[EN] This work describes a new strategy for improving the peak power handling capability (PPHC) of microstrip bandpass filters (BPFs) without any degradation in the electrical performance. For this purpose, a new resonator topology with rounded open-circuit terminations is proposed. Using this strategy, sharp edges are avoided, and a reduction of the maximum peak voltage (V-peak) is obtained, leading to higher peak power thresholds. An in-depth analysis of the variation of V-peak and PPHC as a function of the circle radius is also carried out. As a validation, two microstrip BPFs centered at 1.6 GHz with different end-circle sizes are designed, manufactured, and measured, showing a PPHC enhancement of 2.10 and 1.15 dB, respectively, compared to a standard microstrip BPF.This work was supported in part by the University of Alicante through the Fellowship Grant UAFPU2018-054 and in part by the Ministry of Science and Innovation through the sub-projects C41 and C43 of the Coordinated Project PID2019-103982RB.Morales-Hernández, A.; Sánchez-Soriano, MÁ.; Marini, S.; Boria Esbert, VE.; Guglielmi, M. (2021). Increasing Peak Power Handling in Microstrip Bandpass Filters by Using Rounded-End Resonators. IEEE Microwave and Wireless Components Letters. 31(3):237-240. https://doi.org/10.1109/LMWC.2021.305076523724031

Peak Power Handling Capability in Groove Gap Waveguide Filters Based on Horizontally Polarized Resonators and Enhancement Solutions

This letter studies the peak power handling capability (PPHC) in groove gap waveguide filters based on horizontally polarized resonators. Moreover, a modification of the resonant cavity is proposed, where the central pins of the original structure are replaced by a rounded metal block. As a result of this change, the TE₁₀₁-like mode can still be excited, but the maximum electric field strength is shifted to the center of the cavity, which leads to a higher PPHC. The main advantages of the original structure are maintained, and greater robustness in the manufacturing process is achieved. Next, some guidelines for the design of the coupling windows and the dimensions of the blocks are shown to minimize the electric field strength and, consequently, maximize the PPHC. Finally, two third-order bandpass filters (with pins and with blocks) centered at 16 GHz have been manufactured and tested in a measurement campaign, where a PPHC enhancement of 8.7 dB at high pressures is achieved for the novel solution presented in this work.This work was supported in part by the University of Alicante through the Fellowship Grant UAFPU2018-054 and in part by MCIN/AEI/10.13039/501100011033 through the Sub-Projects C41 and C43 of the Coordinated Project under Grant PID2019-103982RB

Estrategia de Diseño para Aumentar la Capacidad en Potencia en Guias de Onda Groove-Gap

[EN] This work describes a new design strategy for improving the power handling capability (PHC) of groove gap waveguides (GGW). First, a theoretical analysis is carried out to study the distribution of the quasi-TE10 mode and the variation of the PHC for different configurations and frequencies. Then, in order to minimize the strength of the maximum electric field above the pins, three of the main geometrical dimensions of the nails are optimized. Finally, the numerical results show that by using this strategy, the corona discharge power thresholds can be enhanced without degrading the electrical response.Este trabajo ha sido financiado por la Universidad de Alicante mediante la beca de investigación UAFPU2018-054, y por el Ministerio de Ciencia e Innovación a través de los proyectos de investigación PID2019-103982RB-C41 y PID2019-103982RB-C43.Morales-Hernández, A.; Ferrando-Rocher, M.; Sánchez-Soriano, MÁ.; Marini, S.; Boria Esbert, VE. (2021). Estrategia de Diseño para Aumentar la Capacidad en Potencia en Guias de Onda Groove-Gap. Íñigo Cuiñas Gómez. 1-4. http://hdl.handle.net/10251/1910731

Enhancement of corona discharge thresholds in microstrip bandpass filters by using cover-ended resonators

This paper studies the corona discharge power thresholds in microstrip bandpass filters (BPFs) and, in particular, is focused on a solution based on λ/2 cover-ended resonators to enhance their peak power handling capability (PPHC). First, a parametric analysis is carried out to evaluate the variation of the maximum electric field and the unloaded quality factor (Qu) as a function of the cover’s geometrical dimensions (i.e. height, length, and width). Next, several microstrip BPFs centered at 1.6 GHz are designed, and their behaviors under moderate-to-high applied RF power signals are simulated to corroborate the previous study. A suitable number and size of covers are selected to enhance PPHC without barely degrading the filters’ electrical performance and, consequently, without hardly increasing the insertion losses. Finally, two third-order filters with covers and without covers (benchmark prototype) are manufactured, by way of illustration, and they are tested in the European High-Power RF Space Laboratory to validate the good performance of the proposed solution, where a PPHC enhancement of 3.1 dB at high pressures is achieved as compared to the benchmark prototype.This work has been supported by the University of Alicante through the fellowship grant UAFPU2018-054 and by the “Ministerio de Ciencia e Innovación” through the sub-projects C41 and C43 of the coordinated project PID2019-103982RB. The authors would like to thank Val Space Consortium for its contribution – Laboratories funded by the European Development Fund – A way of making Europe

Mutation status and immunoglobulin gene rearrangements in patients from northwest and central region of Spain with chronic lymphocytic leukemia

This is an open access article distributed under the Creative Commons Attribution License.-- et al.The aim of this study was to investigate the frequency and mutation status of the immunoglobulin heavy variable chain (IGHV) in a cohort of 224 patients from northwest and central region of Spain diagnosed with chronic lymphocytic leukemia (CLL), and to correlate it with cytogenetic abnormalities, overall survival (OS) and time to first treatment (TTFT). 125 patients had mutated IGHV, while 99 had unmutated IGHV. The most frequently used IGHV family was IGHV3, followed by IGHV1 and IGHV4. The regions IGHV3-30, IGHV1-69, IGHV3-23, and IGHV4-34 were the most commonly used. Only 3.1% of the patients belonged to the subfamily IGHV3-21 and we failed to demonstrate a worse clinical outcome in this subgroup. The IGHV4 family appeared more frequently with mutated pattern, similar to IGHV3-23 and IGHV3-74. By contrast, IGHV1-69 was expressed at a higher frequency in unmutated CLL patients. All the cases from IGHV3-11 and almost all from IGHV5-51 subfamily belonged to the group of unmutated CLL.The study was partially supported by grants from the Spanish Fondo de Investigaciones Sanitarias 02/1041, FIS 09/01382, FIS 09/01543, and PI12/00281; RD12/0036/0069 from Red Tematica de Investigación Cooperativa en Cáncer (RTICC), Instituto de Salud Carlos III (ISCIII), Spanish Ministry of Economy and Competitiveness & European Regional Development Fund (ERDF) “Una manera de hacer Europa”; and Caja de Burgos-Banca Cívica. A. Rodrígues was fully supported by an Ayuda Predoctoral FIS de Formación en Investigacion by the Spanish Fondo de Investigaciones Sanitarias. M. Hernandez-Sanchez was partially supported by a grant from the “Fundacion Española de Hematología y Hemoterapia.” Partially supported by grants from “Proyectos de Investigacion Biomédica del SACYL” 106/A/06.Peer Reviewe

CRISPR/Cas9-generated models uncover therapeutic vulnerabilities of del(11q) CLL cells to dual BCR and PARP inhibition

[EN]The deletion of 11q (del(11q)) invariably comprises ATM gene in chronic lymphocytic leukemia (CLL). Concomitant mutations in this gene in the remaining allele have been identified in 1/3 of CLL cases harboring del(11q), being the biallelic loss of ATM associated with adverse prognosis. Although the introduction of targeted BCR inhibition has significantly favored the outcomes of del(11q) patients, responses of patients harboring ATM functional loss through biallelic inactivation are unexplored, and the development of resistances to targeted therapies have been increasingly reported, urging the need to explore novel therapeutic approaches. Here, we generated isogenic CLL cell lines harboring del(11q) and ATM mutations through CRISPR/Cas9-based gene-editing. With these models, we uncovered a novel therapeutic vulnerability of del(11q)/ATM-mutated cells to dual BCR and PARP inhibition. Ex vivo studies in the presence of stromal stimulation on 38 CLL primary samples confirmed a synergistic action of the combination of olaparib and ibrutinib in del(11q)/ATM-mutated CLL patients. In addition, we showed that ibrutinib produced a homologous recombination repair impairment through RAD51 dysregulation, finding a synergistic link of both drugs in the DNA damage repair pathway. Our data provide a preclinical rationale for the use of this combination in CLL patients with this high-risk cytogenetic abnormality