P-Lingua 2.0: New Features and First Applications

P-Lingua is a programming language for membrane computing. It was rst presented in Edinburgh, during the Ninth Workshop on Membrane Computing (WMC9). In this paper, the models, simulators and formats included in P-Lingua in version 2.0 are explained. We focus on the stochastic model, associated simulators and updated features. Finally, we present two new applications based on P-Lingua 2.0: a tool for describing and simulating ecosystems and a framework (currently under development) for P systems design.Ministerio de Educación y Ciencia TIN2006–13425Junta de Andalucía P08-TIC-0420

An Overview of P-Lingua 2.0

P–Lingua is a programming language for membrane computing which aims to be a standard to define P systems. In order to implement this idea, a Java library called pLinguaCore has been developed as a software framework for cell–like P systems. It is able to handle input files (either in XML or in P–Lingua format) defining P systems from a number of different cell–like P system models. Moreover, the library includes several built–in simulators for each supported model. For the sake of software portability, pLinguaCore can export a P system definition to any convenient output format (currently XML and binary formats are available). This software is not a closed product, but it can be extended to accept new input or output formats and also new models or simulators. The term P–Lingua 2.0 refers to the software package consisting of the above mentioned library together with a user interface called pLinguaPlugin (more details can be found at http://www.p-lingua.org). Finally, in order to illustrate the software, this paper includes an application using pLinguaCore for describing and simulating ecosystems by means of P systems.Ministerio de Educación y Ciencia TIN2006-13425Junta de Andalucía TIC04200

P–Lingua 2.0: A software framework for cell–like P systems

P-Lingua is a programming language for membrane computing. It was first presented in Edinburgh, during the Ninth Workshop on Membrane Computing (WMC9). In this paper, the models, simulators and formats included in P-Lingua in version 2.0 are explained. We focus on the stochastic model, associated simulators and updated features. Finally, we present one of the first applications based on P- Lingua: a tool for describing and simulating ecosystems

Barium titanate (BaTiO3) RF characterization for application in electro-optic modulators

[EN] Barium titanate (BaTiO3 or BTO) is currently one of the most promising ferroelectric materials for enabling Pockels modulation that is compatible with silicon photonic circuits. The relative permittivity of BTO has been characterized in thin films deposited on a silicon-on-insulator (SOI) substrate. High values between 800 and 1600 have been estimated at 20 GHz. Furthermore, no substantial difference has been obtained by using BTO grown by molecular beam epitaxy and sputtering. The obtained permittivity has been used to properly design the RF electrodes for high-speed modulation in hybrid BTO/Si devices. Electrodes have been fabricated and the possibility of achieving modulation bandwidths up to 40 GHz has been demonstrated. The bandwidth is limited by the microwave propagation losses and, in this case, different losses have been measured depending on the BTO growth process.Financial support from European Commission under project FP7-ICT-2013-11-619456 SITOGA, and from TEC2016-76849-C2-2-R and NANOMET Conselleria de Educació, Cultura i Esport -PROMETEOII/2014 034 are acknowledged. Álvaro Rosa also acknowledges the Spanish Ministry of Economy and Competitiveness for funding his grant.Rosa Escutia, Á.; Tulli, D.; Castera-Molada, P.; Gutiérrez Campo, AM.; Griol Barres, A.; Baquero Escudero, M.; Vilquin, B.... (2017). Barium titanate (BaTiO3) RF characterization for application in electro-optic modulators. Optical Materials Express. 7(12):4328-4336. https://doi.org/10.1364/OME.7.004328S43284336712Hennings, D. (1987). Barium titanate based ceramic materials for dielectric use. International Journal of High Technology Ceramics, 3(2), 91-111. doi:10.1016/0267-3762(87)90031-2Sengupta, L., & Sengupta, S. (1997). Novel ferroelectric materials for phased array antennas. IEEE Transactions on Ultrasonics, Ferroelectrics and Frequency Control, 44(4), 792-797. doi:10.1109/58.655193De Flaviis, F., Alexopoulos, N. G., & Stafsudd, O. M. (1997). Planar microwave integrated phase-shifter design with high purity ferroelectric material. IEEE Transactions on Microwave Theory and Techniques, 45(6), 963-969. doi:10.1109/22.588610Zgonik, M., Bernasconi, P., Duelli, M., Schlesser, R., Günter, P., Garrett, M. H., … Wu, X. (1994). Dielectric, elastic, piezoelectric, electro-optic, and elasto-optic tensors ofBaTiO3crystals. Physical Review B, 50(9), 5941-5949. doi:10.1103/physrevb.50.5941Reed, G. T., Mashanovich, G., Gardes, F. Y., & Thomson, D. J. (2010). Silicon optical modulators. Nature Photonics, 4(8), 518-526. doi:10.1038/nphoton.2010.179Petraru, A., Schubert, J., Schmid, M., & Buchal, C. (2002). Ferroelectric BaTiO3 thin-film optical waveguide modulators. Applied Physics Letters, 81(8), 1375-1377. doi:10.1063/1.1498151Tang, P., Towner, D. J., Hamano, T., Meier, A. L., & Wessels, B. W. (2004). Electrooptic modulation up to 40 GHz in a barium titanate thin film waveguide modulator. Optics Express, 12(24), 5962. doi:10.1364/opex.12.005962Tang, P., Meier, A. L., Towner, D. J., & Wessels, B. W. (2005). BaTiO_3 thin-film waveguide modulator with a low voltage–length product at near-infrared wavelengths of 098 and 155 µm. Optics Letters, 30(3), 254. doi:10.1364/ol.30.000254Dicken, M. J., Sweatlock, L. A., Pacifici, D., Lezec, H. J., Bhattacharya, K., & Atwater, H. A. (2008). Electrooptic Modulation in Thin Film Barium Titanate Plasmonic Interferometers. Nano Letters, 8(11), 4048-4052. doi:10.1021/nl802981qGirouard, P., Liu, Z., Chen, P., Jeong, Y. K., Tu, Y., Ho, S.-T., & Wessels, B. W. (2016). Enhancement of the pockels effect in photonic crystal modulators through slow light. Optics Letters, 41(23), 5531. doi:10.1364/ol.41.005531Abel, S., Stöferle, T., Marchiori, C., Rossel, C., Rossell, M. D., Erni, R., … Fompeyrine, J. (2013). A strong electro-optically active lead-free ferroelectric integrated on silicon. Nature Communications, 4(1). doi:10.1038/ncomms2695Xiong, C., Pernice, W. H. P., Ngai, J. H., Reiner, J. W., Kumah, D., Walker, F. J., … Tang, H. X. (2014). Active Silicon Integrated Nanophotonics: Ferroelectric BaTiO3 Devices. Nano Letters, 14(3), 1419-1425. doi:10.1021/nl404513pAbel, S., Stoferle, T., Marchiori, C., Caimi, D., Czornomaz, L., Stuckelberger, M., … Fompeyrine, J. (2016). A Hybrid Barium Titanate–Silicon Photonics Platform for Ultraefficient Electro-Optic Tuning. Journal of Lightwave Technology, 34(8), 1688-1693. doi:10.1109/jlt.2015.2510282Eltes, F., Caimi, D., Fallegger, F., Sousa, M., O’Connor, E., Rossell, M. D., … Abel, S. (2016). Low-Loss BaTiO3–Si Waveguides for Nonlinear Integrated Photonics. ACS Photonics, 3(9), 1698-1703. doi:10.1021/acsphotonics.6b00350Hsu, M.-H. M., Marinelli, A., Merckling, C., Pantouvaki, M., Van Campenhout, J., Absil, P., & Van Thourhout, D. (2017). Orientation-dependent electro-optical response of BaTiO_3 on SrTiO_3-buffered Si(001) studied via spectroscopic ellipsometry. Optical Materials Express, 7(6), 2030. doi:10.1364/ome.7.002030Rabiei, P., Ma, J., Khan, S., Chiles, J., & Fathpour, S. (2013). Heterogeneous lithium niobate photonics on silicon substrates. Optics Express, 21(21), 25573. doi:10.1364/oe.21.025573Pernice, W. H. P., Xiong, C., Walker, F. J., & Tang, H. X. (2014). Design of a Silicon Integrated Electro-Optic Modulator Using Ferroelectric BaTiO3 Films. IEEE Photonics Technology Letters, 26(13), 1344-1347. doi:10.1109/lpt.2014.2322501Hu, X., Cueff, S., Romeo, P. R., & Orobtchouk, R. (2015). Modeling the anisotropic electro-optic interaction in hybrid silicon-ferroelectric optical modulator. Optics Express, 23(2), 1699. doi:10.1364/oe.23.001699Castera, P., Tulli, D., Gutierrez, A. M., & Sanchis, P. (2015). Influence of BaTiO_3 ferroelectric orientation for electro-optic modulation on silicon. Optics Express, 23(12), 15332. doi:10.1364/oe.23.015332Castera, P., Gutierrez, A. M., Tulli, D., Cueff, S., Orobtchouk, R., Rojo Romeo, P., … Sanchis, P. (2016). Electro-Optical Modulation Based on Pockels Effect in BaTiO3With a Multi-Domain Structure. IEEE Photonics Technology Letters, 28(9), 990-993. doi:10.1109/lpt.2016.2522509Salama, C. A. T., & Siciunas, E. (1972). Characteristics of rf Sputtered Barium Titanate Films on Silicon. Journal of Vacuum Science and Technology, 9(1), 91-96. doi:10.1116/1.1316695Hayashi, T., Oji, N., & Maiwa, H. (1994). Film Thickness Dependence of Dielectric Properties ofBaTiO3Thin Films Prepared by Sol-Gel Method. Japanese Journal of Applied Physics, 33(Part 1, No. 9B), 5277-5280. doi:10.1143/jjap.33.5277Hamano, T., Towner, D. J., & Wessels, B. W. (2003). Relative dielectric constant of epitaxial BaTiO3 thin films in the GHz frequency range. Applied Physics Letters, 83(25), 5274-5276. doi:10.1063/1.1635967McKee, R. A., Walker, F. J., Conner, J. R., Specht, E. D., & Zelmon, D. E. (1991). Molecular beam epitaxy growth of epitaxial barium silicide, barium oxide, and barium titanate on silicon. Applied Physics Letters, 59(7), 782-784. doi:10.1063/1.105341Janezic, M. D., & Jargon, J. A. (1999). Complex permittivity determination from propagation constant measurements. IEEE Microwave and Guided Wave Letters, 9(2), 76-78. doi:10.1109/75.755052Engen, G. F., & Hoer, C. A. (1979). Thru-Reflect-Line: An Improved Technique for Calibrating the Dual Six-Port Automatic Network Analyzer. IEEE Transactions on Microwave Theory and Techniques, 27(12), 987-993. doi:10.1109/tmtt.1979.1129778Alferness, R. C. (1982). Waveguide Electrooptic Modulators. IEEE Transactions on Microwave Theory and Techniques, 30(8), 1121-1137. doi:10.1109/tmtt.1982.1131213Chung, H., Chang, W. S. C., & Adler, E. L. (1991). Modeling and optimization of traveling-wave LiNbO/sub 3/ interferometric modulators. IEEE Journal of Quantum Electronics, 27(3), 608-617. doi:10.1109/3.8137

Real-world experience with bezlotoxumab for prevention of recurrence of Clostridioides difficile infection

Bezlotoxumab is marketed for the prevention of recurrent Clostridioides difficile infection (rCDI). Its high cost could be determining its prescription to a different population than that represented in clinical trials. The objective of the study was to verify the effectiveness and safety of bezlotoxumab in preventing rCDI and to investigate factors related to bezlotoxumab failure in the real world. A retrospective, multicentre cohort study of patients treated with bezlotoxumab in Spain was conducted. We compared the characteristics of cohort patients with those of patients treated with bezlotoxumab in the pivotal MODIFY trials. We assessed recurrence rates 12 weeks after completion of treatment against C. difficile, and we analysed the factors associated with bezlotoxumab failure. Ninety-one patients were included in the study. The cohort presented with more risk factors for rCDI than the patients included in the MODIFY trials. Thirteen (14.2%) developed rCDI at 12 weeks of follow-up, and rCDI rates were numerically higher in patients with two or more previous episodes (25%) than in those who had fewer than two previous episodes of C. difficile infection (CDI) (10.4%); p = 0.09. There were no adverse effects attributable to bezlotoxumab. Despite being used in a more compromised population than that represented in clinical trials, we confirm the effectiveness of bezlotoxumab for the prevention of rCDI

Complement component 3 as biomarker of disease activity and cardiometabolic risk factor in rheumatoid arthritis and spondyloarthritis.

Funder: Europeo de Desarrollo Regional de la Unión EuropeaFunder: Rheumatic Diseases NetworkOBJECTIVE: To analyze the relationship between complement component 3 (C3) and the prevalence of cardiometabolic risk factors and disease activity in the rheumatic diseases having the highest rates of cardiovascular morbidity and mortality: rheumatoid arthritis (RA), psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA). METHODS: This is a cross-sectional study including 200 RA, 80 PsA, 150 axSpA patients and 100 healthy donors. The prevalence of cardiometabolic risk factors [obesity, insulin resistance, type 2 diabetes mellitus, hyperlipidemia, apolipoprotein B/apolipoprotein A (apoB/apoA) and atherogenic risks and hypertension] was analyzed. Serum complement C3 levels, inflammatory markers and disease activity were evaluated. Cluster analysis was performed to identify different phenotypes. Receiver operating characteristic (ROC) curve analysis to assess the accuracy of complement C3 as biomarker of insulin resistance and disease activity was carried out. RESULTS: Levels of complement C3, significantly elevated in RA, axSpA and PsA patients, were associated with the prevalence of cardiometabolic risk factors. Hard clustering analysis identified two distinctive phenotypes of patients depending on the complement C3 levels and insulin sensitivity state. Patients from cluster 1, characterized by high levels of complement C3 displayed increased prevalence of cardiometabolic risk factors and high disease activity. ROC curve analysis showed that non-obesity related complement C3 levels allowed to identify insulin resistant patients. CONCLUSIONS: Complement C3 is associated with the concomitant increased prevalence of cardiometabolic risk factors in rheumatoid arthritis and spondyloarthritis. Thus, complement C3 should be considered a useful marker of insulin resistance and disease activity in these rheumatic disorders

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

Treatment with tocilizumab or corticosteroids for COVID-19 patients with hyperinflammatory state: a multicentre cohort study (SAM-COVID-19)

Objectives: The objective of this study was to estimate the association between tocilizumab or corticosteroids and the risk of intubation or death in patients with coronavirus disease 19 (COVID-19) with a hyperinflammatory state according to clinical and laboratory parameters. Methods: A cohort study was performed in 60 Spanish hospitals including 778 patients with COVID-19 and clinical and laboratory data indicative of a hyperinflammatory state. Treatment was mainly with tocilizumab, an intermediate-high dose of corticosteroids (IHDC), a pulse dose of corticosteroids (PDC), combination therapy, or no treatment. Primary outcome was intubation or death; follow-up was 21 days. Propensity score-adjusted estimations using Cox regression (logistic regression if needed) were calculated. Propensity scores were used as confounders, matching variables and for the inverse probability of treatment weights (IPTWs). Results: In all, 88, 117, 78 and 151 patients treated with tocilizumab, IHDC, PDC, and combination therapy, respectively, were compared with 344 untreated patients. The primary endpoint occurred in 10 (11.4%), 27 (23.1%), 12 (15.4%), 40 (25.6%) and 69 (21.1%), respectively. The IPTW-based hazard ratios (odds ratio for combination therapy) for the primary endpoint were 0.32 (95%CI 0.22-0.47; p < 0.001) for tocilizumab, 0.82 (0.71-1.30; p 0.82) for IHDC, 0.61 (0.43-0.86; p 0.006) for PDC, and 1.17 (0.86-1.58; p 0.30) for combination therapy. Other applications of the propensity score provided similar results, but were not significant for PDC. Tocilizumab was also associated with lower hazard of death alone in IPTW analysis (0.07; 0.02-0.17; p < 0.001). Conclusions: Tocilizumab might be useful in COVID-19 patients with a hyperinflammatory state and should be prioritized for randomized trials in this situatio

Complement component C4 structural variation and quantitative traits contribute to sex-biased vulnerability in systemic sclerosis

Altres ajuts: Fondo Europeo de Desarrollo Regional (FEDER), "A way of making Europe".Copy number (CN) polymorphisms of complement C4 play distinct roles in many conditions, including immune-mediated diseases. We investigated the association of C4 CN with systemic sclerosis (SSc) risk. Imputed total C4, C4A, C4B, and HERV-K CN were analyzed in 26,633 individuals and validated in an independent cohort. Our results showed that higher C4 CN confers protection to SSc, and deviations from CN parity of C4A and C4B augmented risk. The protection contributed per copy of C4A and C4B differed by sex. Stronger protection was afforded by C4A in men and by C4B in women. C4 CN correlated well with its gene expression and serum protein levels, and less C4 was detected for both in SSc patients. Conditioned analysis suggests that C4 genetics strongly contributes to the SSc association within the major histocompatibility complex locus and highlights classical alleles and amino acid variants of HLA-DRB1 and HLA-DPB1 as C4-independent signals

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality