Combination of Antibodies and Antibiotics as a Promising Strategy Against Multidrug-Resistant Pathogens of the Respiratory Tract

The emergence of clinical isolates associated to multidrug resistance is a serious threat worldwide in terms of public health since complicates the success of the antibiotic treatment and the resolution of the infectious process. This is of great concern in pathogens affecting the lower respiratory tract as these infections are one of the major causes of mortality in children and adults. In most cases where the respiratory pathogen is associated to multidrug-resistance, antimicrobial concentrations both in serum and at the site of infection may be insufficient and the resolution of the infection depends on the interaction of the invading pathogen with the host immune response. The outcome of these infections largely depends on the susceptibility of the pathogen to the antibiotic treatment, although the humoral and cellular immune responses also play an important role in this process. Hence, prophylactic measures or even immunotherapy are alternatives against these multi-resistant pathogens. In this sense, specific antibodies and antibiotics may act concomitantly against the respiratory pathogen. Alteration of cell surface structures by antimicrobial drugs even at sub-inhibitory concentrations might result in greater exposure of microbial ligands that are normally hidden or hardly exposed. This alteration of the bacterial envelope may stimulate opsonization by natural and/or specific antibodies or even by host defense components, increasing the recognition of the microbial pathogen by circulating phagocytes. In this review we will explain the most relevant studies, where vaccination or the use of monoclonal antibodies in combination with antimicrobial treatment has demonstrated to be an alternative strategy to overcome the impact of multidrug resistance in respiratory pathogens

Clinical Relevance and Molecular Pathogenesis of the Emerging Serotypes 22F and 33F of Streptococcus pneumoniae in Spain

Streptococcus pneumoniae is the main bacterial cause of respiratory infections in children and the elderly worldwide. Serotype replacement is a frequent phenomenon after the introduction of conjugated vaccines, with emerging serotypes 22F and 33F as frequent non-PCV13 serotypes in children and adults in North America and other countries. Characterization of mechanisms involved in evasion of the host immune response by these serotypes is of great importance in public health because they are included in the future conjugated vaccines PCV15 and PCV20. One of the main strategies of S. pneumoniae to persistently colonize and causes infection is biofilm formation. In this study, we have evaluated the influence of capsule polysaccharide in biofilm formation and immune evasion by using clinical isolates from different sources and isogenic strains with capsules from prevalent serotypes. Since the introduction of PCV13 in Spain in the year 2010, isolates of serotypes 22F and 33F are rising among risk populations. The predominant circulating genotypes are ST43322F and ST71733F , being CC433 in 22F and CC717 in 33F the main clonal complexes in Spain. The use of clinical isolates of different origin, demonstrated that pediatric isolates of serotypes 22F and 33F formed better biofilms than adult isolates and this was statistically significant. This phenotype was greater in clinical isolates from blood origin compared to those from cerebrospinal fluid, pleural fluid and otitis. Opsonophagocytosis assays showed that serotype 22F and 33F were recognized by the PSGL-1 receptor on leukocytes, although serotype 22F, was more resistant than serotype 33F to phagocytosis killing and more lethal in a mouse sepsis model. Overall, the emergence of additional PCV15 serotypes, especially 22F, could be associated to an enhanced ability to divert the host immune response that markedly increased in a biofilm state. Our findings demonstrate that pediatric isolates of 22F and 33F, that form better biofilm than isolates from adults, could have an advantage to colonize the nasopharynx of children and therefore, be important in carriage and subsequent dissemination to the elderly. The increased ability of serotype 22F to avoid the host immune response, might explain the emergence of this serotype in the last years.This work was partially supported by a grant from the MSD-USA (MISP Call, Reference: 57320), Ministerio de Economía, Industria y Competitividad (MINECO) (SAF2017-83388-R), and CIBER de Enfermedades Respiratorias (CIBERES) is an initiative of the Instituto de Salud Carlos III

Combination of Cefditoren and N-acetyl-l-Cysteine Shows a Synergistic Effect against Multidrug-Resistant Streptococcus pneumoniae Biofilms

Biofilm formation by Streptococcus pneumoniae is associated with colonization of the upper respiratory tract, including the carrier state, and with chronic respiratory infections in patients suffering from chronic obstructive pulmonary disease (COPD). The use of antibiotics alone to treat recalcitrant infections caused by biofilms is insufficient in many cases, requiring novel strategies based on a combination of antibiotics with other agents, including antibodies, enzybiotics, and antioxidants. In this work, we demonstrate that the third-generation oral cephalosporin cefditoren (CDN) and the antioxidant N-acetyl-l-cysteine (NAC) are synergistic against pneumococcal biofilms. Additionally, the combination of CDN and NAC resulted in the inhibition of bacterial growth (planktonic and biofilm cells) and destruction of the biofilm biomass. This marked antimicrobial effect was also observed in terms of viability in both inhibition (prevention) and disaggregation (treatment) assays. Moreover, the use of CDN and NAC reduced bacterial adhesion to human lung epithelial cells, confirming that this strategy of combining these two compounds is effective against resistant pneumococcal strains colonizing the lung epithelium. Finally, administration of CDN and NAC in mice suffering acute pneumococcal pneumonia caused by a multidrug-resistant strain was effective in clearing the bacteria from the respiratory tract in comparison to treatment with either compound alone. Overall, these results demonstrate that the combination of oral cephalosporins and antioxidants, such as CDN and NAC, respectively, is a promising strategy against respiratory biofilms caused by S. pneumoniae. IMPORTANCE Streptococcus pneumoniae is one of the deadliest bacterial pathogens, accounting for up to 2 million deaths annually prior to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Vaccines have decreased the burden of diseases produced by S. pneumoniae, but the rise of antibiotic-resistant strains and nonvaccine serotypes is worrisome. Pneumococcal biofilms are associated with chronic respiratory infections, and treatment is challenging, making the search for new antibiofilm therapies a priority as biofilms become resistant to traditional antibiotics. In this work, we used the combination of an antibiotic (CDN) and an antioxidant (NAC) to treat the pneumococcal biofilms of relevant clinical isolates. We demonstrated a synergy between CDN and NAC that inhibited and treated pneumococcal biofilms, impaired pneumococcal adherence to the lung epithelium, and treated pneumonia in a mouse pneumonia model. We propose the widely used cephalosporin CDN and the repurposed drug NAC as a new antibiofilm therapy against S. pneumoniae biofilms, including those formed by antibiotic-resistant clinical isolates.This work was supported by Ministerio de Ciencia e Innovación (MICINN) (grant PID2020-119298RB-I00) and by Meiji Pharma Spain (grant MVP 119/20). J.Y. has received grants from MSD-USA (MISP Call) and Pfizer that are not related to this work. J.Y. has participated in advisory boards organized by MSD and Pfizer. M.G. and P.C. are members of the Scientific Department of Meiji Pharma Spain. The other authors declare no competing interests.S

Electrochemical analysis of the first Polish coins using voltammetry of immobilized particles

[EN] A series of 20 denarii from Boleslaus the Brave (992-1025) and Mieszko II Lambert (1025-1034), corresponding to the beginning of the Polish state were studied using the voltammetry of immobilized particles (VIMP) methodology. VIMP experiments, applied to nanosamples of the corrosion layers of the coins in contact with aqueous acetate buffer, provided well-defined responses mainly corresponding to the corrosion products of copper and lead. Such voltammetric responses, combined with X-ray fluorescence (XRF) spectroscopy experiments performed on the same set of coins, and complemented by focusing ion beam-field emission scanning electron microscope (FIB-FESEM) on silver coins from the 19th century, supported the hypothesis that two different metal sources were used in the former historical period and suggested that the coins were produced in three different mints. (C) 2016 Elsevier B.V. All rights reserve.Financial support from the MINECO Projects CTQ2014-53736-C3-1-P and CTQ2014-53736-C3-2-P which are supported with ERDF funds is gratefully acknowledged. The authors are very grateful to the Polish Ministry of Science and Higher Education for partly financing the work presented in this paper through a grant within the framework of the National Program for the Development of the Humanities (Decision No. 0100/NPRH3/H12/82/2014) and also wish to thank Dr. Jose Luis Moya Lopez and Mr. Manuel Planes Insausti (Microscopy Service of the Universitat Politecnica de Valencia) for technical support.Doménech Carbó, A.; Del Hoyo Meléndez, JM.; Domenech Carbo, MT.; Piquero-Cilla, J. (2017). Electrochemical analysis of the first Polish coins using voltammetry of immobilized particles. Microchemical Journal. 130:47-55. https://doi.org/10.1016/j.microc.2016.07.020S475513

Automatic Semantic Segmentation of the Lumbar Spine: Clinical Applicability in a Multi-parametric and Multi-centre Study on Magnetic Resonance Images

One of the major difficulties in medical image segmentation is the high variability of these images, which is caused by their origin (multi-centre), the acquisition protocols (multi-parametric), as well as the variability of human anatomy, the severity of the illness, the effect of age and gender, among others. The problem addressed in this work is the automatic semantic segmentation of lumbar spine Magnetic Resonance images using convolutional neural networks. The purpose is to assign a class label to each pixel of an image. Classes were defined by radiologists and correspond to different structural elements like vertebrae, intervertebral discs, nerves, blood vessels, and other tissues. The proposed network topologies are variants of the U-Net architecture. Several complementary blocks were used to define the variants: Three types of convolutional blocks, spatial attention models, deep supervision and multilevel feature extractor. This document describes the topologies and analyses the results of the neural network designs that obtained the most accurate segmentations. Several of the proposed designs outperform the standard U-Net used as baseline, especially when used in ensembles where the output of multiple neural networks is combined according to different strategies.Comment: 19 pages, 9 Figures, 8 Tables; Supplementary Material: 6 pages, 8 Table

Looking for old grapevine varieties

This work was supported by the MINECO project CGL2015-70843-R co-funded with FEDER Funds. The authors would like to thanks several cellars ("Rafael Cambra", "Vins del Comtat" and "El Pinaret") and particulars (D. Garcia, T. Doménech, J. Soler and J. Carlos Pavía) for helping us in the localization of old vineyards. We thank the IMIDRA and The Domain de Vassal Collection that provided two accessions each used as controls in our work.Jiménez, C.; Peiró Barber, RM.; Yuste Del Carmen, A.; García, J.; Martínez-Gil, F.; Gisbert Domenech, MC. (2019). Looking for old grapevine varieties. VITIS. 58(2):59-60. https://doi.org/10.5073/vitis.2019.58.59-60S596058

Design considerations of a randomized clinical trial on a cognitive behavioural intervention using communication and information technologies for managing chronic low back pain

Background: Psychological treatments have been successful in treating chronic low back pain (CLBP). However, the effect sizes are still modest and there is room for improvement. A way to progress is by enhancing treatment adherence and self-management using information and communication technologies (ICTs). Therefore, the objective of this study was to design a trial investigating the short- and long-term efficacy of cognitive behavioural treatment (CBT) for CLBP using or not ICTs. A secondary objective of this trial will be to evaluate the influence of relevant variables on treatment response. Possible barriers in the implementation of CBT with and without ICT will also be investigated. Methods: A randomised controlled trial with 180 CLBP patients recruited from specialised care will be conducted. Participants will be randomly assigned to three conditions: Control group (CG), CBT, and CBT supported by ICTs (CBT + ICT). Participants belonging to the three conditions will receive a conventional rehabilitation program (back school). The CBT group program will last six sessions. The CBT + ICT group will use the internet and SMS to practice the therapeutic strategies between sessions and in the follow-ups at their homes. Primary outcome variables will be self-reported disability and pain intensity. Assessment will be carried out by blinded assessors in five moments: pretreatment, post-treatment and 3-, 6-, and 12-month follow-ups. The influence of catastrophizing, fear-avoidance beliefs, anxiety and depression in response to treatment in the primary outcomes will also be analysed. Discussion: This study will show data of the possible benefits of using ICTs in the improvement of CBT for treating CLBP

A Comparison of Prediction Algorithms for Prefetching in the Current Web

[EN] This paper reviews a representative subset of the prediction algorithms used for Web prefetching classifying them according to the information gathered. Then, the DDG algorithm is described. The main novelty of this algorithm lies in the fact that, unlike previous algorithms, it creates a prediction model according to the structure of the current web. To this end, the algorithm distinguishes between container objects and embedded objects. Its performance is compared against important existing algorithms, and results show that, for the same amount of extra requests to the server, DDG always outperforms those algorithms by reducing the perceived latency up to 70% more without increasing the complexity order.This work has been partially supported by the Spanish Ministry of Science and Innovation under Grant TIN2009-08201, the Generalitat Valenciana under Grant GV/2011/002 and the Universitat Politecnica de Valencia under Grant PAID-06-10/2424.Josep Domenech; Sahuquillo Borrás, J.; Gil Salinas, JA.; Pont Sanjuan, A. (2012). A Comparison of Prediction Algorithms for Prefetching in the Current Web. Journal of Web Engineering. 11(1):64-78. http://hdl.handle.net/10251/44349S647811

A taxonomy of web prediction algorithms

Web prefetching techniques are an attractive solution to reduce the user-perceived latency. These techniques are driven by a prediction engine or algorithm that guesses following actions of web users. A large amount of prediction algorithms has been proposed since the first prefetching approach was published, although it is only over the last two or three years when they have begun to be successfully implemented in commercial products. These algorithms can be implemented in any element of the web architecture and can use a wide variety of information as input. This affects their structure, data system, computational resources and accuracy. The knowledge of the input information and the understanding of how it can be handled to make predictions can help to improve the design of current prediction engines, and consequently prefetching techniques. This paper analyzes fifty of the most relevant algorithms proposed along 15 years of prefetching research and proposes a taxonomy where the algorithms are classified according to the input data they use. For each group, the main advantages and shortcomings are highlighted. © 2012 Elsevier Ltd. All rights reserved.This work has been partially supported by Spanish Ministry of Science and Innovation under Grant TIN2009-08201, Generalitat Valenciana under Grant GV/2011/002 and Universitat Politecnica de Valencia under Grant PAID-06-10/2424.Domenech, J.; De La Ossa Perez, BA.; Sahuquillo Borrás, J.; Gil Salinas, JA.; Pont Sanjuan, A. (2012). A taxonomy of web prediction algorithms. Expert Systems with Applications. 39(9):8496-8502. https://doi.org/10.1016/j.eswa.2012.01.140S8496850239

Nationwide trends of invasive pneumococcal disease in Spain (2009-2019) in children and adults during the pneumococcal conjugate vaccine era.

Introduction of pneumococcal conjugate vaccines (PCVs) has shown a marked reduction in the disease caused by vaccine serotypes in children providing herd protection to the elderly group. However, the emergence of non-vaccine serotypes is of great concern worldwide. This study includes national laboratory data from invasive pneumococcal disease (IPD) cases affecting pediatric and adult population during 2009-2019. The impact of implementing different vaccine strategies for immunocompetent adults comparing Spanish regions using PCV13 vs regions using PPV23 vaccine was also analyzed for 2017-2019. The overall reductions of IPD cases by PCV13 serotypes in children and adults were 88% and 59% respectively during 2009-2019 with a constant increase of serotype 8 in adults since 2015. IPD cases by additional serotypes covered by PPV23 increased from 20% in 2009 to 52% in 2019. In children, serotype 24F was the most frequent in 2019 whereas in adults, serotypes 3 and 8 accounted for 36% of IPD cases. Introduction of PCV13 or PPV23 in the adult calendar of certain Spanish regions reduced up to 25% and 11% respectively the IPD cases by PCV13 serotypes, showing a decrease of serotype 3 when PCV13 was used. Use of PCV13 in children has shown a clear impact in pneumococcal epidemiology reducing the burden of IPD in children but also in adults by herd protection although the increase of serotype 8 in adults is worrisome. Vaccination with PCV13 in immunocompetent adults seems to control IPD cases by PCV13 serotypes including serotype 3.This work was supported by Ministerio de Economía, Industria y Competitividad (MINECO) [grant SAF2017-83388] and internal funding fromS