EUropean prospective cohort study on Enterobacteriaceae showing REsistance to CArbapenems (EURECA): a protocol of a European multicentre observational study

Introduction: The rapid worldwide spread of carbapenem-resistant Enterobacteriaceae (CRE) constitutes a major challenge. The aim of the EUropean prospective cohort study on Enterobacteriaceae showing REsistance to CArbapenems (EURECA), which is part of the Innovative Medicines Initiative Joint Undertaking (IMI JU) funded COMBACTE-CARE project, is to investigate risk factors for and outcome determinants of CRE infections to inform randomised clinical trial designs and to provide a historical cohort that could eventually be used for future comparisons with new drugs targeting CRE. Methods: A multicentre (50 sites), multinational (11 European countries), analytical observational project was designed, comprising 3 studies. The aims of study 1 (a prospective cohort study) include characterising the features, clinical management and outcomes of hospitalised patients with intra-abdominal infection, pneumonia, complicated urinary tract infections and bloodstream infections caused by CRE (202 patients in each group). The main outcomes will be 30-day all-cause mortality and clinical response. Study 2 (a nested case–control study) will identify the risk factors for target infections caused by CRE; 248 selected patients from study 1 will be matched with patients with carbapenem-susceptible Enterobacteriaceae (1:1) and with hospitalised patients (1:3) and will provide a historical cohort of patients with CRE infections. Study 3 (a matched cohort study) will follow patients in study 2 in order to assess mortality, length of stay and hospital costs associated with CRE. All patients will be followed for 30 days. Different, up-to-date statistical methods will be applied to come to unbiased estimates for all 3 studies. Ethics and dissemination: Before-study sites will be initiated, approval will be sought from appropriate regulatory agencies and local Ethics Committees of Research or Institutional Review Boards (IRBs) to conduct the study in accordance with regulatory requirements. This is an observational study and therefore no intervention in the diagnosis, management or treatment of the patients will be required on behalf of the investigation. Any formal presentation or publication of data collected from this study will be considered as a joint publication by the participating physician(s) and will follow the recommendations of the International Committee of Medical Journal Editors (ICMJE) for authorship.Innovative Medicine Initiative (IMI)European Union's Seventh Framework Programme (FP7)Spanish Network for Research in Infectious Diseases [REIPI RD12/0015, RD16/2016

Discurso pronunciado en la información oral de la Comisión especial arancelaria, nombrada por Real Decreto de 10 de noviembre de 1865

En portada: Sesión pública de 21 de mayo de 1866 bajo la presidencia de Romualdo López Ballesteros

All-in-one biofabrication and loading of recombinant vaults in human cells

Altres ajuts: Fundación Mutua Madrileña (FMMA) through project 'Targeted therapy for selective elimination of metastatic stem cells CXCR4+ in endometrial cancer' (AP1666942017)Altres ajuts: Asociación Española Contra el Cancer (AECC) through project 'Development of an antitumor protein delivery system into ovarian cancer cells using the subcellular vault' (IDEAS18038BENI)One of the most promising approaches in the drug delivery field is the use of naturally occurring self-assembling protein nanoparticles, such as virus-like particles, bacterial microcompartments or vault ribonucleoprotein particles as drug delivery systems (DDSs). Among them, eukaryotic vaults show a promising future due to their structural features, in vitro stability and non-immunogenicity. Recombinant vaults are routinely produced in insect cells and purified through several ultracentrifugations, both tedious and time-consuming processes. As an alternative, this work proposes a new approach and protocols for the production of recombinant vaults in human cells by transient gene expression of a His-tagged version of the major vault protein (MVP-H6), the development of new affinity-based purification processes for such recombinant vaults, and the all-in-one biofabrication and encapsulation of a cargo recombinant protein within such vaults by their co-expression in human cells. Protocols proposed here allow the easy and straightforward biofabrication and purification of engineered vaults loaded with virtually any INT-tagged cargo protein, in very short times, paving the way to faster and easier engineering and production of better and more efficient DDS

Perforación de la pared de la vena cava por distintos dispositivos de filtro. Estudio comparativo y comprobación laparoscópica en modelo ovino.

La tromboembolia pulmonar (TEP) sigue constituyendo una enfermedad grave. La anticoagulación en sus diversas modalidades y la fibrinólisis constituyen el tratamiento de elección. El uso de filtros de vena cava inferior (FVCI) para la profilaxis y el tratamiento de la TEP es controvertido. No obstante, existen circunstancias en las que la anticoagulación falla o no es suficiente. En nuestro estudio se utilizaron 3 tipos de filtros, 3 filtros Günther Tulip (GT), 3 filtros Celect (C) y 6 filtros prototipo (P). Para ello, se utilizaron 6 ovejas, implantando a cada una de ellas dos filtros de forma alterna. El objetivo principal de este estudio es comparar la penetración accidental en la pared de la vena cava de tres tipos diferentes de filtro, similares de la misma compañía, con distintos elementos de anclaje, mediante cavografía y laparoscopia abdominal en un modelo animal ovino a los 15, 30 y 45 días. Los resultados de la implantación de los filtros fueron satisfactorios, con un 100% de éxito. Hubo que recolocar 3 filtros debido a un mal posicionamiento y así evitar problemas en la retirada. En cuanto a la penetración de las patas en el día 0 fue de un 0% para el filtro GT, un 0% para el C y un 0% para el P. En el día 15 la cavografía nos mostró un 50% de penetración para el GT y C (2 patas penetrando de 4 visualizadas), un 50% para el prototipo (4 patas penetrando de 8 visualizadas). La laparoscopia a los 15 días nos reveló un 0% de penetración para el filtro GT Y C (0 patas penetrando de 2 visualizadas) y un 25% para el prototipo (1 pata penetrando de 4 visualizadas). Se observa que la laparoscopia hace infradiagnóstico de penetración de patas por la limitación inherente que tiene, y que no hay una buena correlación entre los hallazgos cavográficos y laparoscópicos. La retirada a los 15 días se realizó sin ninguna complicación. A los 30 días solo se pudo valorar a una de las dos ovejas obteniendo en la cavografía un 50% de penetración para el C (2 patas penetrando de 4 visualizadas) y Un 0% para el P (0 patas penetrando de 4 visualizadas); en la laparoscopia se vieron dos patas del filtro C de las cuales una penetraba y del P solo se visualizó una pata que sobresalía a través de la VCI. La inspección macroscópica de la zona de la implantación de los filtros presentaba una gran reacción inflamatoria. Posteriormente se estudiará la histología de la vena cava inferior

Short communication: high effectiveness of etravirine in routine clinical practice in treatment-experienced HIV type 1-infected patients

The effectiveness of etravirine has not been thoroughly investigated in routine clinical practice, where adherence rates and the heterogeneous nature of patients differ from the clinical trial setting. We evaluated the effectiveness of rescue regimens containing etravirine and the factors associated with treatment response. Multicenter retrospective cohort of all consecutive patients was recruited in a routine clinical practice setting. Patients were taking rescue regimens containing etravirine plus an optimized background regimen. The primary endpoint was the percentage of patients with HIV-1 RNA <50 copies/ml at week 48. The secondary endpoints were those factors associated with treatment response to etravirine. Endpoints were evaluated using univariate and multivariate analysis. A total of 122 patients were included with a median viral load of 11,938 (1055-55,500) copies/ml at baseline. The most frequent drugs in the backbone were darunavir/ritonavir in 98 (80.3%) patients and raltegravir in 76 (62.3%). In the full dataset analysis, 73% (89/122; 95% CI, 64-81%) of patients responded to treatment at week 48; in the on-treatment analysis, 82% (89/109; 95% CI, 71-87%) responded. The factors associated with treatment failure to etravirine [HR (95% CI)] were baseline CD4(+) T cell count <200 cells/mm(3) [2.45 (1.17-5.16)] and use of raltegravir [0.47 (0.22-0.99)] and darunavir [0.45 (0.21-0.98)] as backbone drugs. Skin rash was the only adverse event directly related to etravirine and led to withdrawal in three patients (2.5%). In routine clinical practice, rescue ETR-containing regimens are well tolerated and achieve rates of virological suppression higher than those observed in its pivotal clinical trials, especially when combined with darunavir and raltegravir

Percepciones del alumnado en el aprendizaje en competencias. Antes y después del practicum

La decisión del aprendizaje en competencias plantea no sólo cambios importantes en la determinación de los contenidos sino especialmente, y de forma profunda, en la práctica educativa. En tres cursos académicos (2012-1015) se ha incorporado la figura de alumno interno como nexo de unión entre necesidades e intereses de aprendizaje en distintas materias. Se presenta esta experiencia y su implicación en los acuerdos, en la innovación y mejora en resultados de aprendizaje/evaluación y calificación. El objetivo es describir las percepciones del alumnado previa incorporación en el ámbito de la empresa, instituciones sanitarias y centros de bienestar social (prácticas curriculares). Estudio cualitativo utilizando el método de comparación constante para el análisis de contenido de las entrevistas a más del 70% del alumnado de segundo curso de la titulación de grado enfermería. Se podría concluir que en la innovación, mejora de la calidad, búsqueda de nuevas estrategias organizativas para responder a la necesidad de adaptación y cambio, es muy valorada y necesaria la participación del alumnado, para adaptar los contenidos teórico-prácticos a las competencias reales del Practicum y la innovación a la calidad sentida por el alumnado

Targeted Simplification Versus Antipseudomonal Broad-Spectrum Beta-Lactams in Patients With Bloodstream Infections Due to Enterobacteriaceae (SIMPLIFY): A Study Protocol for a Multicentre, Open-Label, Phase III Randomised, Controlled, Non-Inferiority Clinical Trial.

Introduction Within the context of antimicrobial stewardship programmes, de-escalation of antimicrobial therapy is one of the proposed strategies for reducing the unnecessary use of broad-spectrum antibiotics (BSA). The empirical treatment of nosocomial and some healthcare- associated bloodstream infections (BSI) frequently includes a beta-lactam with antipseudomonal activity as monotherapy or in combination with other drugs, so there is a great opportunity to optimise the empirical therapy based on microbiological data. De-escalation is assumed as standard of care for experts in infectious diseases. However, it is less frequent than it would desirable. Methods and analysis The SIMPLIFY trial is a multicentre, open-label, non-inferiority phase III randomised controlled clinical trial, designed as a pragmatic ‘real-practice’ trial. The aim of this trial is to demonstrate the non-inferiority of de-escalation from an empirical beta-lactam with antipseudomonal activity to a targeted narrow-spectrum antimicrobial in patients with BSI due to Enterobacteriaceae. The primary outcome is clinical cure, which will be assessed at the test of cure visit. It will be conducted at 19 Spanish public and university hospitals. Ethics and dissemination Each participating centre has obtained the approval of the ethics review committee, the agreement of the directors of the institutions and authorisation from the Spanish Regulatory Agency (Agencia Española del Medicamento y Productos Sanitarios). Data will be presented at international conferences and published in peer-reviewed journals. [Discussion] Strategies to reduce the use of BSA should be a priority. Most of the studies that support de-escalation are observational, retrospective and heterogeneous. A recent Cochrane review stated that well-designed clinical trials should be conducted to assess the safety and efficacy of de-escalation.Instituto de Salud Carlos III (ISCIII): PI15/00439, integrado en el Plan Nacional de I+D+i 2013-2016 y cofinanciado por la Unión Europea (ERDF/ESF, “Investing in your future”)

Retinal Thickness Changes Over Time in a Murine AD Model APP NL-F/NL-F.

Background: Alzheimer's disease (AD) may present retinal changes before brain pathology, suggesting the retina as an accessible biomarker of AD. The present work is a diachronic study using spectral domain optical coherence tomography (SD-OCT) to determine the total retinal thickness and retinal nerve fiber layer (RNFL) thickness in an APPNL-F/NL-F mouse model of AD at 6, 9, 12, 15, 17, and 20 months old compared to wild type (WT) animals. Methods: Total retinal thickness and RNFL thickness were determined. The mean total retinal thickness was analyzed following the Early Treatment Diabetic Retinopathy Study sectors. RNFL was measured in six sectors of axonal ring scans around the optic nerve. Results: In the APPNL-F/NL-F group compared to WT animals, the total retinal thickness changes observed were the following: (i) At 6-months-old, a significant thinning in the outer temporal sector was observed; (ii) at 15-months-old a significant thinning in the inner temporal and in the inner and outer inferior retinal sectors was noticed; (iii) at 17-months-old, a significant thickening in the inferior and nasal sectors was found in both inner and outer rings; and (iv) at 20-months-old, a significant thinning in the inner ring of nasal, temporal, and inferior retina and in the outer ring of superior and temporal retina was seen. In RNFL thickness, there was significant thinning in the global analysis and in nasal and inner-temporal sectors at 6 months old. Thinning was also found in the supero-temporal and nasal sectors and global value at 20 months old. Conclusions: In the APPNL-F/NL-F AD model, the retinal thickness showed thinning, possibly produced by neurodegeneration alternating with thickening caused by deposits and neuroinflammation in some areas of the retina. These changes over time are similar to those observed in the human retina and could be a biomarker for AD. The APPNL-F/NL-F AD model may help us better understand the different retinal changes during the progression of AD.This research was funded by the Ophthalmological Network OFTARED (RD16/0008/0005) of the Institute of Health of Carlos III of the Spanish Ministry of Science and Innovation; and the Research Network RETIBRAIN (RED2018-102499-T) and Grant PID2019-106581RB-I00 of the Spanish Ministry of Science and Innovation; and Leducq Foundation for Cardiovascular Research TNE-19CVD01. IL-C was currently supported by a Pre-doctoral Fellowship (CT42/18-CT43/18) from the Complutense University of Madrid. JF-A was currently supported by a Pre-doctoral Fellowship (FPU17/01023) from the Spanish Ministry of Science, Innovation, and Universities.S

Molecular typing reveals the co-existence of two transmission cycles of American cutaneous leishmaniasis in the Andean Region of Venezuela with Lutzomyia migonei as the vector.

BACKGROUND The transmission routes for American cutaneous leishmaniasis (ACL) are in flux, so studies examining its transmission in humans, mammalian hosts, and sand fly vectors are urgently needed. OBJECTIVES The aim of this work was understand the epidemiological cycles of Leishmania spp., which causes ACL in the Andean Region of Venezuela, by identifying the Leishmania and the sand fly species involved in human and dog infections. METHODS Thirty-one biopsies from patients in Mérida and Táchira states with suspected ACL were studied by both parasitological tests (cultures and hamster inoculation) and a molecular test [Internal transcribed spacer 1 (ITS1) nested polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP)]. We also conducted a survey to detect Leishmania infection in dogs (Immunifluorescence antibody test and ITS1 nested PCR-RFLP) and sand flies (ITS1 nested PCR-RFLP) from El Carrizal, a highly endemic focus of ACL in Venezuela. FINDINGS Three different Leishmania species were identified in the clinical samples from humans (Leishmania braziliensis, L. guyanensis, and L. mexicana) and dogs (L. guyanensis and L. mexicana). The predominant sand fly species found were those from the Verrucarum group (infected with L. mexicana) and Lutzomyia migonei (infected with L. guyanensis and L. mexicana). MAIN CONCLUSIONS We show that Lu. migonei may be the putative vector in two ACL epidemiological cycles, involving L. guyanensis and L. mexicana. We also report for the first time the presence of L. guyanensis in domestic animals