Sensibilidad de microorganismos gramnegativos de infecciones intraabdominales y evolución de los aislados con ß-lactamasas de espectro extendido en el estudio smart en españa (2002-2010)

Introducción. El estudio SMART (Study for Monitoring Antimicrobial Resistance Trends) tiene como objetivo monitorizar la sensibilidad a los antimicrobianos de los microorganismos gramnegativos aislados en la infección intraabdominal, con especial seguimiento de los que producen β-lactamasas de espectro extendido (BLEE). Material y métodos. Se han analizado por microdulución los datos de sensibilidad de 8.869 aislados recogidos en el estudio SMART en España entre 2002 y 2010 en el que han participado 16 centros. Resultados. Escherichia coli fue el patógeno más frecuente (60,9% en la infección intraabdominal adquirida en la comunidad y 49,9% en la nosocomial) seguido de Klebsiella pneumoniae (8,9% vs 9,2%). Pseudomonas aeruginosa fue más habitual en la infección nosocomial (5,6% comunitaria y 8,6% nosocomial). La frecuencia de aislados con BLEE fue: E. coli 8,7%, K. pneumoniae 8,4%, Klebsiella oxytoca 1,4% y Proteus mirabilis 1,6%. En los pacientes de mayor edad aumentó la proporción global de aislados con BLEE (6,8% en pacientes >60 años). Ertapenem y meropenem fueron los antimicrobianos más activos en el conjunto de las enterobacterias (rango de sensibilidad con criterios EUCAST, 89-100%) y también entre los aislados con BLEE (95,5-100%). La actividad de amoxicilina/ácido clavulánico y piperacilina/tazobactam fue considerablemente inferior, en particular en los aislados con BLEE. Ertapenem mantuvo una buena actividad (sensibilidad >95%) en los productores de BLEE resistentes a amoxicilina/ácido clavulánico, piperacilina/tazobactam o fluoroquinolonas. Conclusiones. Los datos de sensibilidad del estudio SMART en España avalan las guías terapéuticas actuales de infección intraabdominal que sitúan al ertapenem como tratamiento empírico de elección, teniendo en cuenta sobre todo la elevada frecuencia de aislados con BLEE en nuestro medio. Introduction. The SMART (Study for Monitoring Antimicrobial Resistance Trends) surveillance study records the antimicrobial susceptibility of Gram-negative bacilli obtain from intraabdominal infections with special focus in isolates with extended spectrum ß-lactamases (ESBLs). Material and Methods. The antimicrobial susceptibility of 8,869 isolates was analyzed by microdilution during the SMART study performed in Spain from 2002 to 2010. Isolates were recovered in 16 centres. Results. Escherichia coli was the most prevalent pathogen (60.9% from intraabdominal infections acquired in the community and 49.9% in those from nosocomial origin) followed by Klebsiella pneumoniae (8.9% vs 9.2%). Pseudomonas aeruginosa was more common in intraabdominal infections from nosocomial origin (5.6% community and 8.6% nosocomial). Frequency of ESBL-producing isolates was: E. coli, 8.7%; K. pneumoniae, 8.4%; Klebsiella oxytoca, 1.4%; and Proteus mirabilis, 1.6%. Overall, ESBL-producing isolates were more frequently isolated from elderly patients (6.8% >60 years). Ertapenem and meropenem were the most active antimicrobials (susceptibility range with EUCAST criteria, 89.0-100%) when considering all Enterobacteriaceae isolates and also against ESBL producers (95.5-100%). Susceptibility of amoxicillin/clavulanic acid and piperacillin/tazobactam was lower, particularly among ESBL-producing isolates. Nevertheless, ertapenem maintained a good activity (susceptibility >95%) in ESBL-producers that were resistant to amoxicillin/clavulanic acid, piperacillin/tazobactam or fluoroquinolones. Conclusions. Antimicrobial susceptibility data from the SMART-Spain study reinforce current therapeutic guidelines of intraabdominal infections that include ertapenem as the empirical choice for treatment. This is also supported by the high frequency of ESBL-producers in our geographic area

Assessment of Platelet REACtivity After Transcatheter Aortic Valve Replacement : The REAC-TAVI Trial

The REAC-TAVI (Assessment of platelet REACtivity after Transcatheter Aortic Valve Implantation) trial enrolled patients with aortic stenosis (AS) undergoing transcatheter aortic valve replacement (TAVR) pre-treated with aspirin + clopidogrel, aimed to compare the efficacy of clopidogrel and ticagrelor in suppressing high platelet reactivity (HPR) after TAVI. Current recommendations support short-term use of aspirin + clopidogrel for patients with severe AS undergoing TAVR despite the lack of compelling evidence. This was a prospective, randomized, multicenter investigation. Platelet reactivity was measured at 6 different time points with the VerifyNow assay (Accriva Diagnostics, San Diego, California). HPR was defined as (P2Y reaction units (PRU) ≥208. Patients with HPR before TAVR were randomized to either aspirin + ticagrelor or aspirin + clopidogrel for 3 months. Patients without HPR continued with aspirin + clopidogrel (registry cohort). The primary endpoint was non-HPR status (PRU <208) in ≥70% of patients treated with ticagrelor at 90 days post-TAVR. A total of 68 patients were included. Of these, 48 (71%) had HPR (PRU 273 ± 09) and were randomized to aspirin + ticagrelor (n = 24, PRU 277 ± 08) or continued with aspirin + clopidogrel (n = 24, PRU 269 ± 49). The remaining 20 patients (29%) without HPR (PRU 133 ± 12) were included in the registry. Overall, platelet reactivity across all the study time points after TAVR was lower in patients randomized to ticagrelor compared with those treated with clopidogrel, including those enrolled in the registry (p < 0.001). The primary endpoint was achieved in 100% of patients with ticagrelor compared with 21% with clopidogrel (p < 0.001). Interestingly, 33% of clopidogrel responder patients at baseline developed HPR status during the first month after TAVR. HPR to clopidogrel is present in a considerable number of patients with AS undergoing TAVR. Ticagrelor achieves a better and faster effect, providing sustained suppression of HPR to these patients. (Platelet Reactivity After TAVI: A Multicenter Pilot Study [REAC-TAVI]; NCT02224066

Ligand-Dependent Conformations and Dynamics of the Serotonin 5-HT2A Receptor Determine Its Activation and Membrane-Driven Oligomerization Properties

From computational simulations of a serotonin 2A receptor (5-HT2AR) model complexed with pharmacologically and structurally diverse ligands we identify different conformational states and dynamics adopted by the receptor bound to the full agonist 5-HT, the partial agonist LSD, and the inverse agonist Ketanserin. The results from the unbiased all-atom molecular dynamics (MD) simulations show that the three ligands affect differently the known GPCR activation elements including the toggle switch at W6.48, the changes in the ionic lock between E6.30 and R3.50 of the DRY motif in TM3, and the dynamics of the NPxxY motif in TM7. The computational results uncover a sequence of steps connecting these experimentally-identified elements of GPCR activation. The differences among the properties of the receptor molecule interacting with the ligands correlate with their distinct pharmacological properties. Combining these results with quantitative analysis of membrane deformation obtained with our new method (Mondal et al, Biophysical Journal 2011), we show that distinct conformational rearrangements produced by the three ligands also elicit different responses in the surrounding membrane. The differential reorganization of the receptor environment is reflected in (i)-the involvement of cholesterol in the activation of the 5-HT2AR, and (ii)-different extents and patterns of membrane deformations. These findings are discussed in the context of their likely functional consequences and a predicted mechanism of ligand-specific GPCR oligomerization

Radiogenic backgrounds in the NEXT double beta decay experiment

Natural radioactivity represents one of the main backgrounds in the search for neutrinoless double beta decay. Within the NEXT physics program, the radioactivity- induced backgrounds are measured with the NEXT-White detector. Data from 37.9 days of low-background operations at the Laboratorio Subterráneo de Canfranc with xenon depleted in 136Xe are analyzed to derive a total background rate of (0.84±0.02) mHz above 1000 keV. The comparison of data samples with and without the use of the radon abatement system demonstrates that the contribution of airborne-Rn is negligible. A radiogenic background model is built upon the extensive radiopurity screening campaign conducted by the NEXT collaboration. A spectral fit to this model yields the specific contributions of 60Co, 40K, 214Bi and 208Tl to the total background rate, as well as their location in the detector volumes. The results are used to evaluate the impact of the radiogenic backgrounds in the double beta decay analyses, after the application of topological cuts that reduce the total rate to (0.25±0.01) mHz. Based on the best-fit background model, the NEXT-White median sensitivity to the two-neutrino double beta decay is found to be 3.5s after 1 year of data taking. The background measurement in a Qßß±100 keV energy window validates the best-fit background model also for the neutrinoless double beta decay search with NEXT-100. Only one event is found, while the model expectation is (0.75±0.12) events

The NEXT White (NEW) detector

Conceived to host 5 kg of xenon at a pressure of 15 bar in the fiducial volume, the NEXT-White apparatus is currently the largest high pressure xenon gas TPC using electroluminescent amplification in the world. It is also a 1:2 scale model of the NEXT-100 detector for Xe-136 beta beta 0 nu decay searches, scheduled to start operations in 2019. Both detectors measure the energy of the event using a plane of photomultipliers located behind a transparent cathode. They can also reconstruct the trajectories of charged tracks in the dense gas of the TPC with the help of a plane of silicon photomultipliers located behind the anode. A sophisticated gas system, common to both detectors, allows the high gas purity needed to guarantee a long electron lifetime. NEXT-White has been operating since October 2016 at the Laboratorio Subterraneo de Canfranc (LSC), in Spain. This paper describes the detector and associated infrastructures, as well as the main aspects of its initial operation

Uncovering the multifaceted roles played by neutrophils in allogeneic hematopoietic stem cell transplantation

Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a life-saving procedure used for the treatment of selected hematological malignancies, inborn errors of metabolism, and bone marrow failures. The role of neutrophils in alloHSCT has been traditionally evaluated only in the context of their ability to act as a first line of defense against infection. However, recent evidence has highlighted neutrophils as key effectors of innate and adaptive immune responses through a wide array of newly discovered functions. Accordingly, neutrophils are emerging as highly versatile cells that are able to acquire different, often opposite, functional capacities depending on the microenvironment and their differentiation status. Herein, we review the current knowledge on the multiple functions that neutrophils exhibit through the different stages of alloHSCT, from the hematopoietic stem cell (HSC) mobilization in the donor to the immunological reconstitution that occurs in the recipient following HSC infusion. We also discuss the influence exerted on neutrophils by the immunosuppressive drugs delivered in the course of alloHSCT as part of graft-versus-host disease (GVHD) prophylaxis. Finally, the potential involvement of neutrophils in alloHSCT-related complications, such as transplant-associated thrombotic microangiopathy (TA-TMA), acute and chronic GVHD, and cytomegalovirus (CMV) reactivation, is also discussed. Based on the data reviewed herein, the role played by neutrophils in alloHSCT is far greater than a simple antimicrobial role. However, much remains to be investigated in terms of the potential functions that neutrophils might exert during a highly complex procedure such as alloHSCT

The Bifidobacterium dentium Bd1 Genome Sequence Reflects Its Genetic Adaptation to the Human Oral Cavity

Bifidobacteria, one of the relatively dominant components of the human intestinal microbiota, are considered one of the key groups of beneficial intestinal bacteria (probiotic bacteria). However, in addition to health-promoting taxa, the genus Bifidobacterium also includes Bifidobacterium dentium, an opportunistic cariogenic pathogen. The genetic basis for the ability of B. dentium to survive in the oral cavity and contribute to caries development is not understood. The genome of B. dentium Bd1, a strain isolated from dental caries, was sequenced to completion to uncover a single circular 2,636,368 base pair chromosome with 2,143 predicted open reading frames. Annotation of the genome sequence revealed multiple ways in which B. dentium has adapted to the oral environment through specialized nutrient acquisition, defences against antimicrobials, and gene products that increase fitness and competitiveness within the oral niche. B. dentium Bd1 was shown to metabolize a wide variety of carbohydrates, consistent with genome-based predictions, while colonization and persistence factors implicated in tissue adhesion, acid tolerance, and the metabolism of human saliva-derived compounds were also identified. Global transcriptome analysis demonstrated that many of the genes encoding these predicted traits are highly expressed under relevant physiological conditions. This is the first report to identify, through various genomic approaches, specific genetic adaptations of a Bifidobacterium taxon, Bifidobacterium dentium Bd1, to a lifestyle as a cariogenic microorganism in the oral cavity. In silico analysis and comparative genomic hybridization experiments clearly reveal a high level of genome conservation among various B. dentium strains. The data indicate that the genome of this opportunistic cariogen has evolved through a very limited number of horizontal gene acquisition events, highlighting the narrow boundaries that separate commensals from opportunistic pathogens