42 research outputs found
Breakdown studies for high-gradient RF warm technology in: CLIC and hadron therapy linacs
La presente tesis se centra en el estudio de las limitaciones, debidas principalmente a fenómenos de breakdowns, en el rendimiento de estructuras aceleradoras de radiofrecuencia (RF) de alto gradiente (HG) y de conductividad normal. La formación de arcos en vacío perturban los campos electromagnéticos de las cavidades, lo cual afecta en la calidad del haz de partículas acelerado. El proyecto de Compact Linear Collider (CLIC) estudia la viabilidad de un colisionador lineal electrón-positrón en la escala de energía centro de masa del TeV, y desarrolla las estructuras aceleradoras de última generación para alcanzar altos gradientes de 100 MV/m con una tasa máxima de fenómenos de breakdowns de 3e(-7) eventos por pulso y por metro de acelerador. CLIC ha establecido un amplio programa experimental para el diseño y el test de estructuras aceleradoras eficientes y compactas, gracias a la construcción de tres bancos de prueba de RF a alta potencia en la banda X (12 GHz), conocidos como Xbox, y un sistema pulsado en corriente continua, conocido como Large Electrode System (LES). El Capítulo 1 introduce los conceptos básicos relacionados con los aceleradores lineales (linacs) y la clasificación de los diferentes diseños de RF de las estructuras. Las ventajas que ofrece la tecnología de alto gradiente han sido presentadas para diferentes aplicaciones, tales como Futuros Colisionadores Lineales, linacs destinados a terapia oncológica con hadrones (hadron therapy), láseres de electrones libres (FEL) y láseres de retrodispersión Compton. El Capítulo 2 hace una descripción bibliográfica de los recientes estudios realizados para entender la fenomenología de los breakdowns y sus consecuencias a la hora de diseñar estructuras aceleradoras. En el Capítulo 3, describimos con detalle los laboratorios de alto gradiente operativos en el CERN para la realización de tests de estructuras y componentes RF que ayudan al avance en el diseño y construcción de futuras estructuras, al mismo tiempo que permiten realizar un estudio exhaustivo de la fenomenología de breakdowns. Los diferentes estudios realizados para esta tesis son presentados en el Capítulo 4, los cuales se han llevado a cabo en las Xbox y el LES. Las técnicas empleadas para la localización de breakdowns en estructuras RF durante la operación de las Xbox se describen con detalle junto a resultados experimentales. También se ha realizado un estudio estadístico de la ocurrencia aleatoria de breakdowns para poder comprender los mecanismos que desencadenan estos fenómenos. Según las observaciones experimentales, se ha presentado la formulación de un modelo que incluye una tasa doble de eventos de breakdowns. En este capítulo incluimos un estudio del condicionamiento RF en estructuras aceleradoras de alto gradiente basado en un análisis comparativo de la evolución temporal de los tests de varios prototipos en el CERN y KEK. Los resultados han dado lugar a una nueva forma de entender el proceso de condicionamiento de estas estructuras que permitiría optimizar el tiempo necesario para alcanzar los gradientes más altos. También se ha realizado un estudio preliminar del posible efecto negativo en el uso de compresores de pulso para el rendimiento de estructuras de alto gradiente, debido al exceso de potencia RF que es enviado antes y después del pulso rectangular comprimido. En este caso, se han comparado los datos experimentales con simulaciones de posibles magnitudes que puedan afectar a los resultados de breakdowns. El Capítulo 5 se centra en la descripción del experimento de beam-loading en CTF3 (CERN), junto a los primeros resultados experimentales obtenidos, el cual trata de estudiar el efecto de la presencia de un haz de electrones en la tasa de ocurrencia de breakdowns en un prototipo acelerador de alto gradiente de CLIC. Finalmente, el Capítulo 6 resume las actividades desarrolladas en el CERN centradas en el diseño de linacs para terapia con hadrones. Este capítulo también describe la infraestructura y los planes de trabajo del nuevo laboratorio IFIC HG-RF que se encuentra en construcción en Valencia para el estudio fenomenológico de breakdowns para aceleradores de alto gradiente en la banda S (3 GHz).The present thesis is focused on the study of the breakdown limitations for the high-gradient (HG) performance of normal-conducting Radio-Frequency (RF) accelerating structures. The formation of vacuum arcs perturbs the electromagnetic fields of the cavities and affects in the quality of the accelerating beam. The Compact Linear Collider (CLIC) project studies the feasibility of a multi-TeV e+e- linear collider and develops the current state-of-the-art HG structures to achieve accelerating gradients of 100 MV/m with a maximum breakdown rate of 3e(-7) breakdowns per pulse per meter. A wide experimental programme is established by CLIC for the design and test of efficient and compact accelerating structures, thanks to the construction of three X-band high-power test stands, also known as Xboxes, and the pulsed-DC Large Electrode system dedicated to breakdowns studies.
Chapter 1 introduces the basic concepts related to linear accelerators and the classification of different designs of RF accelerating structures. The advantages that HG technology offers are also described for different applications, such as Future Linear Colliders, hadron therapy linacs, Free Electron Lasers and Compton backscattering light sources. A bibliographic description of the current understanding of breakdown phenomena and their consequences in the designs of HG accelerating structures is made in Chapter 2. In Chapter 3, we describe in detail the existing HG test facilities operated for the sake of advancing in the design and construction of HG accelerators, as well as for the better understanding of the RF breakdown mechanisms. Different breakdown studies are presented in Chapter 4, which have been carried out at the Xboxes and pulsed-DC Large Electrode system. The techniques used for the localization of breakdowns in RF structures at the Xboxes are presented in detail with experimental results. A statistical study of breakdown occurrences is also made to understand the underlying random process of these events and the formulation of a double breakdown rate model is presented in agreement with the observations. The study of the RF conditioning in HG accelerating structures is made based on a comparative analysis of different conditioning histories of prototypes tested at CERN and KEK, which have led to new insights that may allow to efficiently reduce the time to achieve their best performance. A preliminary study is performed in Xbox-2 to analyse the possible negative effect of the use of a pulse compressor on the breakdown performance of HG prototypes, due to the excess of RF power that is driven before and after the compressed rectangular-shaped pulse. Experimental data is compared with simulations of possible candidates that may affect in the breakdown rate results. Chapter 5 is focused on the description and first experimental results of the beam-loading experiment, which aims at studying the effect of the presence of the beam on the breakdown rate in a CLIC HG accelerating structure due to the alteration of the longitudinal gradient profile. Finally, Chapter 6 summarizes the current activities in the development of HG hadron therapy linacs at CERN. This chapter also describes the infrastructure and future plans of the new IFIC HG-RF laboratory that is under construction in Valencia for the study of the phenomenology of breakdowns in S-band HG accelerators
Knife-edge based measurement of the 4D transverse phase space of electron beams with picometer-scale emittance
Precise manipulation of high brightness electron beams requires detailed
knowledge of the particle phase space shape and evolution. As ultrafast
electron pulses become brighter, new operational regimes become accessible with
emittance values in the picometer range, with enormous impact on potential
scientific applications. Here we present a new characterization method for such
beams and demonstrate experimentally its ability to reconstruct the 4D
transverse beam matrix of strongly correlated electron beams with sub-nanometer
emittance and sub-micrometer spot size, produced with the HiRES beamline at
LBNL. Our work extends the reach of ultrafast electron accelerator diagnostics
into picometer-range emittance values, opening the way to complex
nanometer-scale electron beam manipulation techniques
On the calculation of the Kalker's creep coefficients for non-elliptical contact areas
[EN] FastSim is the most widely used tangential contact method due to its accuracy
and computational efficiency. However, its use is limited to elliptic contact areas, as it needs
results from Kalker’s Linear Theory, a Hertzian contact theory, to obtain the so-called elastic
parameters. This makes FastSim unable to face some of the current railway challenges, such as
wear, corrugation, Rolling Contact Fatigue (RCF), wheel flats, etc. Taking this limitation into
account, in the present work, an alternative methodology to Kalker’s Linear Theory is proposed,
which will enable FastSim to deal with non-Hertzian conditions.The authors gratefully acknowledge the financial support of Agencia Estatal de Investigación and European Regional Development Fund (grant PRE2018-084067 and project TRA2017-84701-R).Gómez-Bosch, J.; Giner-Navarro, J.; Carballeira, J. (2022). On the calculation of the Kalker's creep coefficients for non-elliptical contact areas. En Proceedings of the YIC 2021 - VI ECCOMAS Young Investigators Conference. Editorial Universitat Politècnica de València. 288-294. https://doi.org/10.4995/YIC2021.2021.12313OCS28829
A fast version of 'CONTACT' for normal problem calculations
[EN] In its different versions, the CONTACT method developed by Prof. Kalker is the primary reference in wheel-rail contact mechanics. Despite adopting simplifications associated with the elastic behaviour of the solids and being a non-conformal contact theory, CONTACT provides precise solutions for most wheel-rail contact conditions, with lower computational and modelling costs than other numerical methods such as Finite Elements. Nevertheless, the computational cost of CONTACT is still too high for its implementation in dynamic simulation. The present work proposes a fast and accurate wheel-rail contact method for normal problems based on Kalker's CONTACT algorithm. Dissimilarly to CONTACT, the new method formulates the normal traction distribution through a suitable basis, which reduces the dimension of the problem. This method is able to faithfully reproduce the contact patch and the normal traction distribution, even when the yaw angle of the wheelset is non-zero. Results obtained with this method are compared with the ones calculated with CONTACT, and errors about 0.05% are obtained in normal contact forces, with a reduction on the computation cost between 30 and 60 times.Grant PRE2018-084067 funded by MCIN/AEI/10.13039/501100011033 and by the EU program "ESF Investing in your future". Grant PID2020-118013RB-C21 funded by MCIN/AEI/10.13039/501100011033. Grant PROMETEO/2021/046 funded by Generalitat Valenciana.Giner Navarro, J.; Gómez-Bosch, J.; Alonso, A.; Baeza González, LM. (2023). A fast version of 'CONTACT' for normal problem calculations. Wear. 530-531:1-12. https://doi.org/10.1016/j.wear.2023.205074112530-53
Enzyme replacement therapy for the treatment of Hunter disease: A systematic review with narrative synthesis and meta-analysis
Background: In the last 10 years enzyme replacement therapy (ERT) has become an alternative for the treatment of patients with Hunter disease (HD). Nevertheless, the information regarding efficacy and safety is scarce and mainly based on the pivotal trials. This scarcity is especially evident for adults and severe forms of HD.
Methods: A systematic review of publications in the electronic databases PUBMED, EMBASE and Cochrane Central was undertaken. Clinical trials and observational studies were included. The data about efficacy and security were retrieved and analysed with Review Manager version 5.3.
Results: 677 records were found, 559 remaining after the removal of duplicates. By title and abstract review, 427 were excluded. Full reading of the rest was made (122 publications) and 42 were finally included. It was not possible to perform meta-analysis of all the endpoints due to high heterogeneity in the reporting and measuring of variables in each publication. Eight clinical trials were included, 6 with high risk of bias. The quality of the other studies was low in 12%, average in 68% and good in 21%. Main findings were: a reduction in the elimination of glycosaminoglycans (GAG) in urine in all the studies (26/26), decrease in liver and spleen size (18/18), increase of 52.59 m (95% CI, 36, 42-68.76, p < .001) in the 6-min walk test (TM6M), increase in forced vital capacity (FVC) of 9.59% (95% CI 4.77-14.51, p < .001), reduction of the left ventricular mass index of 3.57% (95% CI 1.2-5.93) and reduction in mortality (OR) of 0.44 (0.27-0.71).
Discussion: The data suggests a clear and consistent effect of ERT in HD reducing the accumulation of GAGs in the body, demonstrated by the reduction of its urinary excretion, as well as by the reduction of its deposits (spleen, liver and heart). Likewise, there is an improvement in physical and respiratory function. In addition, a reduction in mortality has been observed. Lack of studies, small size of the samples, and methodological deficiencies are the main limitations to establish definite conclusions.
Conclusions: The data suggests that ERT is effective and safe in the treatment of HD. There is a need to evaluate patient-centred outcomes and the impact on quality of life
Prognostic Value of D-dimer to Lymphocyte Ratio (DLR) in Hospitalized Coronavirus Disease 2019 (COVID-19) Patients: A Validation Study in a National Cohort
Background: This study aimed to validate the role of the D-dimer to lymphocyte ratio (DLR) for mortality prediction in a large national cohort of hospitalized coronavirus disease 2019 (COVID-19) patients. Methods: A retrospective, multicenter, observational study that included hospitalized patients due to SARS-CoV-2 infection in Spain was conducted from March 2020 to March 2022. All biomarkers and laboratory indices analyzed were measured once at admission. Results: A total of 10,575 COVID-19 patients were included in this study. The mean age of participants was 66.9 (+/- 16) years, and 58.6% (6202 patients) of them were male. The overall mortality rate was 16.3% (n = 1726 patients). Intensive care unit admission was needed in 10.5% (n = 1106 patients), non-invasive mechanical ventilation was required in 8.8% (n = 923 patients), and orotracheal intubation was required in 7.5% (789 patients). DLR presented a c-statistic of 0.69 (95% CI, 0.68-0.71) for in-hospital mortality with an optimal cut-off above 1. Multivariate analysis showed an independent association for in-hospital mortality for DLR > 1 (adjusted OR 2.09, 95% CI 1.09-4.04; p = 0.03); in the same way, survival analysis showed a higher mortality risk for DLR > 1 (HR 2.24; 95% CI 2.03-2.47; p < 0.01). Further, no other laboratory indices showed an independent association for mortality in multivariate analysis. Conclusions: This study confirmed the usefulness of DLR as a prognostic biomarker for mortality associated with SARS-CoV-2 infection, being an accessible, cost-effective, and easy-to-use biomarker in daily clinical practice
Safety and immunogenicity of the protein-based PHH-1V compared to BNT162b2 as a heterologous SARS-CoV-2 booster vaccine in adults vaccinated against COVID-19 : a multicentre, randomised, double-blind, non-inferiority phase IIb trial
A SARS-CoV-2 protein-based heterodimer vaccine, PHH-1V, has been shown to be safe and well-tolerated in healthy young adults in a first-in-human, Phase I/IIa study dose-escalation trial. Here, we report the interim results of the Phase IIb HH-2, where the immunogenicity and safety of a heterologous booster with PHH-1V is assessed versus a homologous booster with BNT162b2 at 14, 28 and 98 days after vaccine administration. The HH-2 study is an ongoing multicentre, randomised, active-controlled, double-blind, non-inferiority Phase IIb trial, where participants 18 years or older who had received two doses of BNT162b2 were randomly assigned in a 2:1 ratio to receive a booster dose of vaccine-either heterologous (PHH-1V group) or homologous (BNT162b2 group)-in 10 centres in Spain. Eligible subjects were allocated to treatment stratified by age group (18-64 versus ≥65 years) with approximately 10% of the sample enrolled in the older age group. The primary endpoints were humoral immunogenicity measured by changes in levels of neutralizing antibodies (PBNA) against the ancestral Wuhan-Hu-1 strain after the PHH-1V or the BNT162b2 boost, and the safety and tolerability of PHH-1V as a boost. The secondary endpoints were to compare changes in levels of neutralizing antibodies against different variants of SARS-CoV-2 and the T-cell responses towards the SARS-CoV-2 spike glycoprotein peptides. The exploratory endpoint was to assess the number of subjects with SARS-CoV-2 infections ≥14 days after PHH-1V booster. This study is ongoing and is registered with , . From 15 November 2021, 782 adults were randomly assigned to PHH-1V (n = 522) or BNT162b2 (n = 260) boost vaccine groups. The geometric mean titre (GMT) ratio of neutralizing antibodies on days 14, 28 and 98, shown as BNT162b2 active control versus PHH-1V, was, respectively, 1.68 (p < 0.0001), 1.31 (p = 0.0007) and 0.86 (p = 0.40) for the ancestral Wuhan-Hu-1 strain; 0.62 (p < 0.0001), 0.65 (p < 0.0001) and 0.56 (p = 0.003) for the Beta variant; 1.01 (p = 0.92), 0.88 (p = 0.11) and 0.52 (p = 0.0003) for the Delta variant; and 0.59 (p ≤ 0.0001), 0.66 (p < 0.0001) and 0.57 (p = 0.0028) for the Omicron BA.1 variant. Additionally, PHH-1V as a booster dose induced a significant increase of CD4 + and CD8 + T-cells expressing IFN-γ on day 14. There were 458 participants who experienced at least one adverse event (89.3%) in the PHH-1V and 238 (94.4%) in the BNT162b2 group. The most frequent adverse events were injection site pain (79.7% and 89.3%), fatigue (27.5% and 42.1%) and headache (31.2 and 40.1%) for the PHH-1V and the BNT162b2 groups, respectively. A total of 52 COVID-19 cases occurred from day 14 post-vaccination (10.14%) for the PHH-1V group and 30 (11.90%) for the BNT162b2 group (p = 0.45), and none of the subjects developed severe COVID-19. Our interim results from the Phase IIb HH-2 trial show that PHH-1V as a heterologous booster vaccine, when compared to BNT162b2, although it does not reach a non-inferior neutralizing antibody response against the Wuhan-Hu-1 strain at days 14 and 28 after vaccination, it does so at day 98. PHH-1V as a heterologous booster elicits a superior neutralizing antibody response against the previous circulating Beta and the currently circulating Omicron BA.1 SARS-CoV-2 variants in all time points assessed, and for the Delta variant on day 98 as well. Moreover, the PHH-1V boost also induces a strong and balanced T-cell response. Concerning the safety profile, subjects in the PHH-1V group report significantly fewer adverse events than those in the BNT162b2 group, most of mild intensity, and both vaccine groups present comparable COVID-19 breakthrough cases, none of them severe. HIPRA SCIENTIFIC, S.L.U
Effectiveness of Fosfomycin for the Treatment of Multidrug-Resistant Escherichia coli Bacteremic Urinary Tract Infections
IMPORTANCE The consumption of broad-spectrum drugs has increased as a consequence of the spread of multidrug-resistant (MDR) Escherichia coli. Finding alternatives for these infections is critical, for which some neglected drugs may be an option. OBJECTIVE To determine whether fosfomycin is noninferior to ceftriaxone or meropenem in the targeted treatment of bacteremic urinary tract infections (bUTIs) due to MDR E coli. DESIGN, SETTING, AND PARTICIPANTS This multicenter, randomized, pragmatic, open clinical trial was conducted at 22 Spanish hospitals from June 2014 to December 2018. Eligible participants were adult patients with bacteremic urinary tract infections due to MDR E coli; 161 of 1578 screened patients were randomized and followed up for 60 days. Data were analyzed in May 2021. INTERVENTIONS Patients were randomized 1 to 1 to receive intravenous fosfomycin disodium at 4 g every 6 hours (70 participants) or a comparator (ceftriaxone or meropenem if resistant; 73 participants) with the option to switch to oral fosfomycin trometamol for the fosfomycin group or an active oral drug or pa renteral ertapenem for the comparator group after 4 days. MAIN OUTCOMES AND MEASURES The primary outcome was clinical and microbiological cure (CMC) 5 to 7 days after finalization of treatment; a noninferiority margin of 7% was considered. RESULTS Among 143 patients in the modified intention-to-treat population (median [IQR] age, 72 [62-81] years; 73 [51.0%] women), 48 of 70 patients (68.6%) treated with fosfomycin and 57 of 73 patients (78.1%) treated with comparators reached CMC (risk difference, -9.4 percentage points; 1-sided 95% CI, -21.5 to infinity percentage points; P = .10). While clinical or microbiological failure occurred among 10 patients (14.3%) treated with fosfomycin and 14 patients (19.7%) treated with comparators (risk difference, -5.4 percentage points; 1-sided 95% CI. -infinity to 4.9; percentage points; P = .19), an increased rate of adverse event-related discontinuations occurred with fosfomycin vs comparators (6 discontinuations [8.5%] vs 0 discontinuations; P = .006). In an exploratory analysis among a subset of 38 patients who underwent rectal colonization studies, patients treated with fosfomycin acquired a new ceftriaxone-resistant or meropenem-resistant gram-negative bacteria at a decreased rate compared with patients treated with comparators (0 of 21 patients vs 4 of 17 patients [23.5%]; 1-sided P = .01). CONCLUSIONS AND RELEVANCE This study found that fosfomycin did not demonstrate noninferiority to comparators as targeted treatment of bUTI from MDR E coli; this was due to an increased rate of adverse event-related discontinuations. This finding suggests that fosfomycin may be considered for selected patients with these infections
CARB-ES-19 Multicenter Study of Carbapenemase-Producing Klebsiella pneumoniae and Escherichia coli From All Spanish Provinces Reveals Interregional Spread of High-Risk Clones Such as ST307/OXA-48 and ST512/KPC-3
ObjectivesCARB-ES-19 is a comprehensive, multicenter, nationwide study integrating whole-genome sequencing (WGS) in the surveillance of carbapenemase-producing K. pneumoniae (CP-Kpn) and E. coli (CP-Eco) to determine their incidence, geographical distribution, phylogeny, and resistance mechanisms in Spain.MethodsIn total, 71 hospitals, representing all 50 Spanish provinces, collected the first 10 isolates per hospital (February to May 2019); CPE isolates were first identified according to EUCAST (meropenem MIC > 0.12 mg/L with immunochromatography, colorimetric tests, carbapenem inactivation, or carbapenem hydrolysis with MALDI-TOF). Prevalence and incidence were calculated according to population denominators. Antibiotic susceptibility testing was performed using the microdilution method (EUCAST). All 403 isolates collected were sequenced for high-resolution single-nucleotide polymorphism (SNP) typing, core genome multilocus sequence typing (cgMLST), and resistome analysis.ResultsIn total, 377 (93.5%) CP-Kpn and 26 (6.5%) CP-Eco isolates were collected from 62 (87.3%) hospitals in 46 (92%) provinces. CP-Kpn was more prevalent in the blood (5.8%, 50/853) than in the urine (1.4%, 201/14,464). The cumulative incidence for both CP-Kpn and CP-Eco was 0.05 per 100 admitted patients. The main carbapenemase genes identified in CP-Kpn were blaOXA–48 (263/377), blaKPC–3 (62/377), blaVIM–1 (28/377), and blaNDM–1 (12/377). All isolates were susceptible to at least two antibiotics. Interregional dissemination of eight high-risk CP-Kpn clones was detected, mainly ST307/OXA-48 (16.4%), ST11/OXA-48 (16.4%), and ST512-ST258/KPC (13.8%). ST512/KPC and ST15/OXA-48 were the most frequent bacteremia-causative clones. The average number of acquired resistance genes was higher in CP-Kpn (7.9) than in CP-Eco (5.5).ConclusionThis study serves as a first step toward WGS integration in the surveillance of carbapenemase-producing Enterobacterales in Spain. We detected important epidemiological changes, including increased CP-Kpn and CP-Eco prevalence and incidence compared to previous studies, wide interregional dissemination, and increased dissemination of high-risk clones, such as ST307/OXA-48 and ST512/KPC-3