Hepatic encephalopathy-associated cerebral vasculopathy in acute-on-chronic liver failure: Alterations on endothelial factor release and influence on cerebrovascular function

The acute-on-chronic liver failure (ACLF) is a syndrome characterized by liver decompensation, hepatic encephalopathy (HE) and high mortality. We aimed to determine the mechanisms implicated in the development of HE-associated cerebral vasculopathy in a microsurgical liver cholestasis (MHC) model of ACLF. Microsurgical liver cholestasis was induced by ligating and extracting the common bile duct and four bile ducts. Sham-operated and MHC rats were maintained for eight postoperative weeks Bradykinin-induced vasodilation was greater in middle cerebral arteries from MHC rats. Both Nω-Nitro-L-arginine methyl ester and indomethacin diminished bradykinin-induced vasodilation largely in arteries from MHC rats. Nitrite and prostaglandin (PG) F releases were increased, whereas thromboxane (TX) B was not modified in arteries from MHC. Expressions of endothelial nitric oxide synthase (eNOS), inducible NOS, and cyclooxygenase (COX) 2 were augmented, and neuronal NOS (nNOS), COX-1, PGI synthase, and TXA S were unmodified. Phosphorylation was augmented for eNOS and unmodified for nNOS. Altogether, these endothelial alterations might collaborate to increase brain blood flow in HE. 1α 2 2 2This research was funded by the Ministerio de Economía y Competitividad (SAF2016-80305-P), CiberCV (Grant number: CB16/11/00286), the European Regional Development Grant (FEDER) (Comunidad de Madrid, grant number B2017/BMD- 3676), and R C D projects for young researchers, Universidad Autónoma de Madrid-Comunidad de Madrid (SI1-PJI-2019- 00321). RR-D received a fellowship from Juan de la Cierva Program (IJCI-2017-31399)

MIC of amoxicillin/clavulanate according to CLSI and EUCAST: discrepancies and clinical impact in patients with bloodstream infections due to Enterobacteriaceae

[Objectives] To compare results of amoxicillin/clavulanate susceptibility testing using CLSI and EUCAST methodologies and to evaluate their impact on outcome in patients with bacteraemia caused by Enterobacteriaceae.[Patients and methods] A prospective observational cohort study was conducted in 13 Spanish hospitals. Patients with bacteraemia due to Enterobacteriaceae who received empirical intravenous amoxicillin/clavulanate treatment for at least 48 h were included. MICs were determined following CLSI and EUCAST recommendations. Outcome variables were: failure at the end of treatment with amoxicillin/clavulanate (FEAMC); failure at day 21; and 30 day mortality. Classification and regression tree (CART) analysis and logistic regression were performed.[Results] Overall, 264 episodes were included; the urinary tract was the most common source (64.7%) and Escherichia coli the most frequent pathogen (76.5%). Fifty-two isolates (19.7%) showed resistance according to CLSI and 141 (53.4%) according to EUCAST. The kappa index for the concordance between the results of both committees was only 0.24. EUCAST-derived, but not CLSI-derived, MICs were associated with failure when considered as continuous variables. CART analysis suggested a ‘resistance’ breakpoint of > 8/4 mg/L for CLSI-derived MICs; it predicted FEAMC in adjusted analysis (OR = 1.96; 95% CI: 0.98–3.90). Isolates with EUCAST-derived MICs >16/2 mg/L independently predicted FEAMC (OR = 2.10; 95% CI: 1.05–4.21) and failure at day 21 (OR= 3.01; 95% CI: 0.93–9.67). MICs >32/2 mg/L were only predictive of failure among patients with bacteraemia from urinary or biliary tract sources.[Conclusions] CLSI and EUCAST methodologies showed low agreement for determining the MIC of amoxicillin/clavulanate. EUCAST-derived MICs seemed more predictive of failure than CLSI-derived ones. EUCAST-derived MICs >16/2 mg/L were independently associated with therapeutic failure.The study was funded by the Instituto de Salud Carlos III, Ministry of Economy and Competitiveness, Spain (Fondo de investigación en salud; PI10/02021) co-financed by European Development Regional Fund ‘A way to achieve Europe’ ERDF, Spanish Network for Research in Infectious Diseases (REIPI RD12/0015).Peer reviewe

Seven-versus 14-day course of antibiotics for the treatment of bloodstream infections by Enterobacterales: a randomized, controlled trial

[Objective] To prove that 7-day courses of antibiotics for bloodstream infections caused by members of the Enterobacterales (eBSIs) allow a reduction in patients' exposure to antibiotics while achieving clinical outcomes similar to those of 14-day schemes.[Methods] A randomized trial was performed. Adult patients developing eBSI with appropriate source control were assigned to 7 or 14 days of treatment, and followed 28 days after treatment cessation; treatments could be resumed whenever necessary. The primary endpoint was days of treatment at the end of follow-up. Clinical outcomes included clinical cure, relapse of eBSI and relapse of fever. A superiority margin of 3 days was set for the primary endpoint, and a non-inferiority margin of 10% was set for clinical outcomes. Efficacy and safety were assessed together with a DOOR/RADAR (desirability of outcome ranking and response adjusted for duration of antibiotic risk) analysis.[Results] 248 patients were assigned to 7 (n = 119) or 14 (n = 129) days of treatment. In the intention-to-treat analysis, median days of treatment at the end of follow-up were 7 and 14 days (difference 7, 95%CI 7–7). The non-inferiority margin was also met for clinical outcomes, except for relapse of fever (–0.2%, 95%CI –10.4 to 10.1). The DOOR/RADAR showed that 7-day schemes had a 77.7% probability of achieving better results than 14-day treatments.[Conclusions] 7-day schemes allowed a reduction in antibiotic exposure of patients with eBSI while achieving outcomes similar to those of 14-day schemes. The possibility of relapsing fever in a limited number of patients, without relevance to final outcomes, may not be excluded, but was overcome by the benefits of shortening treatments.This work received technical support from the Spanish Network of Research in Infectious Diseases (REIPI) and the Spanish Clinical Research Network (SCReN) of the Instituto de Salud Carlos III, Ministerio de Economía y Competitividad, Spanish Government (PT13/0002/0010).Peer reviewe

Genetic landscape of 6089 inherited retinal dystrophies affected cases in Spain and their therapeutic and extended epidemiological implications

Inherited retinal diseases (IRDs), defined by dysfunction or progressive loss of photoreceptors, are disorders characterized by elevated heterogeneity, both at the clinical and genetic levels. Our main goal was to address the genetic landscape of IRD in the largest cohort of Spanish patients reported to date. A retrospective hospital-based cross-sectional study was carried out on 6089 IRD affected individuals (from 4403 unrelated families), referred for genetic testing from all the Spanish autonomous communities. Clinical, demographic and familiar data were collected from each patient, including family pedigree, age of appearance of visual symptoms, presence of any systemic findings and geographical origin. Genetic studies were performed to the 3951 families with available DNA using different molecular techniques. Overall, 53.2% (2100/3951) of the studied families were genetically characterized, and 1549 different likely causative variants in 142 genes were identified. The most common phenotype encountered is retinitis pigmentosa (RP) (55.6% of families, 2447/4403). The most recurrently mutated genes were PRPH2, ABCA4 and RS1 in autosomal dominant (AD), autosomal recessive (AR) and X-linked (XL) NON-RP cases, respectively; RHO, USH2A and RPGR in AD, AR and XL for non-syndromic RP; and USH2A and MYO7A in syndromic IRD. Pathogenic variants c.3386G > T (p.Arg1129Leu) in ABCA4 and c.2276G > T (p.Cys759Phe) in USH2A were the most frequent variants identified. Our study provides the general landscape for IRD in Spain, reporting the largest cohort ever presented. Our results have important implications for genetic diagnosis, counselling and new therapeutic strategies to both the Spanish population and other related populations.This work was supported by the Instituto de Salud Carlos III (ISCIII) of the Spanish Ministry of Health (FIS; PI16/00425 and PI19/00321), Centro de Investigación Biomédica en Red Enfermedades Raras (CIBERER, 06/07/0036), IIS-FJD BioBank (PT13/0010/0012), Comunidad de Madrid (CAM, RAREGenomics Project, B2017/BMD-3721), European Regional Development Fund (FEDER), the Organización Nacional de Ciegos Españoles (ONCE), Fundación Ramón Areces, Fundación Conchita Rábago and the University Chair UAM-IIS-FJD of Genomic Medicine. Irene Perea-Romero is supported by a PhD fellowship from the predoctoral Program from ISCIII (FI17/00192). Ionut F. Iancu is supported by a grant from the Comunidad de Madrid (CAM, PEJ-2017-AI/BMD7256). Marta del Pozo-Valero is supported by a PhD grant from the Fundación Conchita Rábago. Berta Almoguera is supported by a Juan Rodes program from ISCIII (JR17/00020). Pablo Minguez is supported by a Miguel Servet program from ISCIII (CP16/00116). Marta Corton is supported by a Miguel Servet program from ISCIII (CPII17/00006). The funders played no role in study design, data collection, data analysis, manuscript preparation and/or publication decisions

Detectives de alimentos: un trabajo en equipo para la investigación de toxiinfecciones alimentarias

Proyecto de Innovación Docente en el que los estudiantes realizan un trabajo cooperativo mediante el método del puzle para diseñar fichas descriptivas de patógenos de transmisión alimentaria y resolver un caso de toxiinfección alimentari

Actividades alternativas al currículo ordinario

El trabajo no ha sido publicadoDurante el curso 2001-2002, 9 maestros/as del CRA Ribera del Porma se implicaron en este proyecto con 3 objetivos bien claros: 1) iniciar y fomentar en los alumnos la utilización de los medios informáticos, la utilización de Internet, y en general el uso de las nuevas tecnologías, 2)elaborar diferentes materiales didácticos para utilizar y experimentar en posteriores cursos académicos, 3)establecer nuevas vías de relación social a través del uso de las nuevas tecnologías que favorezca la interacción de los alumnos. El plan de trabajo ha constado de 3 fases: fase de preparación, en la que se diseñaron los objetivos y contenidos del trabajo y se planificaron las actividades; fase práctica, en la que se realizaron las actividades; fase final o de evaluación, aquí se han evaluado todos los elementos que intervienen en el proceso de enseñanza-aprendizaje y para ello se han utilizado diferentes medios, aunque ha sido la observación continua y sistemática el más utilizado. La evaluación ha sido muy positiva, respecto al primer objetivo hay que destacar que el grado de consecución está relacionado con la etapa o ciclo a la que pertenecen los alumnos, así los de E. Infantil apagan y encienden el ordenador correctamente, acceden a juegos, dominan el ratón e incluso algunos acceden a alguna página de Internet de juegos; los de Primaria sacan información de Internet, visitan páginas web de otros centros, se ha creado una cuenta de correo y se han comunicado con otros centros a través de ella, trabajan con procesadores de texto , utilizan programas como el paint... ; sobre el segundo objetivo hay q destacar que se han recopilado una serie de páginas web interesantes para trabajar con los niños, así como una serie de CD-R que se han reproducido para las diferentes escuelas; en cuanto al tercer objetivo se han sentado las bases para ampliar el círculo de centros educativos con los que poder intercambiar correos, foros o video conferencias, además los niños han enviado correos electrónicos y postales, algunas en inglés, en Navidad. La interacción entre las escuelas de la zona se ha visto claramente favorecida por este proyecto. Se han utilizado los equipos informáticos del CRA y del resto de escuelas de la zona, aunque en estas últimas se trabajó con dificultad al disponer de pocos equipos..Castilla y LeónES

Survival effect after a therapeutic hypothermia protocol implementation

OBJETIVE. To evaluate whether implementation of a therapeutic hypothermia (TH) protocol improved survival and neurologic outcomes in patients successfully resuscitated from cardiac arrest. METHOD AND PATIENTS. A Retrospective Historic Cohort Study realized in a Cardiac Intensive Care Unit from January 2007 to December 2010. An active cooling therapeutic hypothermia protocol, using a cooling surface method with hydrogel patches (Arctic Sun) to achieve a temperature of 33degreeC for 24 h was initiated on July 2009 for unconscious patients resuscitated from cardiac arrest. The device is connected to a temperature control console, measuring core temperature with an urinary catheter. In this study we compare patients who presented after implementation of a therapeutic hypothermia protocol with those who presented before the protocol was implemented. Demographics and outcomes were obtained from an intensive care medical database. RESULTS. A total of 81 consecutive adults, with nontraumatic cardiac arrest, admitted between January 2007 and December 2010 were included, 35 on TH group and 46 on control group. Both groups were similar with no statistic differences on personal previous medical history characteristics or cardiopulmonary resuscitation time. The only differences between groups was a greater number of patients with ventricular fibrillation (VF) as an initial rhythm and ECG changes in the TH group (72, 7%, p = 0.059), which results in a greater coronarography number (65.7%, p<0.001). Mortality at hospital discharge decreased in the therapeutic hypothermia group (p = 0.005, OR 0.154, 95% IC 0.043-0.546). In adjusted analysis, VF as an initial rhythm (p<0.05, OR 0.30, 95% confidence interval 0.096-0.96), short resuscitation time period (p = 0.02, OR 1.085, CI 1.013-1.162) and younger patients (p = 0.018, OR 1.055, CI 1.010-1.102) also result in a better survival. CONCLUSIONS. The implementation of a therapeutic hypothermia (TH) protocol was associated with a signifi

MIC of amoxicillin/clavulanate according to CLSI and EUCAST: Discrepancies and clinical impact in patients with bloodstream infections due to Enterobacteriaceae

Objectives: To compare results of amoxicillin/clavulanate susceptibility testing using CLSI and EUCAST methodologies and to evaluate their impact on outcome in patients with bacteraemia caused by Enterobacteriaceae. Patients and methods: A prospective observational cohort study was conducted in 13 Spanish hospitals. Patients with bacteraemia due to Enterobacteriaceae who received empirical intravenous amoxicillin/clavulanate treatment for at least 48h were included. MICs were determined following CLSI and EUCAST recommendations. Outcome variables were: failure at the end of treatment with amoxicillin/clavulanate (FEAMC); failure at day 21; and 30 day mortality. Classification and regression tree (CART) analysis and logistic regression were performed. Results: Overall, 264 episodes were included; the urinary tract was the most common source (64.7%) and Escherichia coli themost frequent pathogen (76.5%). Fifty-two isolates (19.7%) showed resistance according to CLSI and 141 (53.4%) according to EUCAST. The kappa index for the concordance between the results of both committees was only 0.24. EUCAST-derived, but not CLSI-derived, MICs were associated with failure when considered as continuous variables. CART analysis suggested a 'resistance' breakpoint of > 8/4mg/L for CLSI-derived MICs; it predicted FEAMC in adjusted analysis (OR=1.96; 95% CI: 0.98-3.90). Isolates with EUCAST-derived MICs > 16/2 mg/L independently predicted FEAMC (OR=2.10; 95%CI: 1.05-4.21) and failure at day 21 (OR=3.01; 95%CI: 0.93-9.67).MICs.32/2mg/Lwere only predictive of failure among patientswith bacteraemia from urinary or biliary tract sources. Conclusions: CLSI and EUCAST methodologies showed low agreement for determining the MIC of amoxicillin/clavulanate. EUCAST-derived MICs seemed more predictive of failure than CLSI-derived ones. EUCAST-derived MICs > 16/2 mg/L were independently associated with therapeutic failure