STAT3 phosphorylation at serine 727 activates specific genetic programs and promotes clear cell renal cell carcinoma (ccRCC) aggressiveness.

The signal transducer and activator of transcription 3 (STAT3) is a transcription factor mainly activated by phosphorylation in either tyrosine 705 (Y705) or serine 727 (S727) residues that regulates essential processes such as cell differentiation, apoptosis inhibition, or cell survival. Aberrant activation of STAT3 has been related to development of nearly 50% of human cancers including clear cell renal cell carcinoma (ccRCC). In fact, phosho-S727 (pS727) levels correlate with overall survival of ccRCC patients. With the aim to elucidate the contribution of STAT3 phosphorylation in ccRCC development and progression, we have generated human-derived ccRCC cell lines carrying STAT3 Y705 and S727 phosphomutants. Our data show that the phosphomimetic substitution Ser727Asp facilitates a pro-tumoral phenotype in vitro, in a Y705-phosphorylation-independent manner. Moreover, we describe that STAT3 phosphorylation state determines the expression of different subsets of target genes associated with distinct biological processes, being pS727-dependent genes the most related to cellular hallmarks of cancer. In summary, the present study constitutes the first analysis on the role of overall STAT3 phosphorylation state in ccRCC and demonstrates that pS727 promotes the expression of a specific subset of target genes that might be clinically relevant as novel biomarkers and potential therapeutic targets for ccRCC.

Influence of free fatty acid content and degree of fat saturation in laying hen diets on egg quality, yolk fatty acid profile, and cholesterol content.

The aim of the present study was to evaluate the effect of dietary free fatty acid (FFA) content and the degree of saturation on egg quality, yolk fatty acid (FA) profile, and yolk cholesterol content. For a 15-wk period, a total of 144 laying hens (19-wk-old) were randomly assigned to 8 treatments arranged in a 2 × 4 factorial design, with 2 sources of crude oil (soybean oil and palm oil) and 4 levels of FFA (10, 20, 30, and 45%). The dietary treatments were achieved by progressively substituting the original oils with equivalent amounts of their corresponding acid oils (soybean acid oil and palm fatty acid distillate, respectively). No differences in ADFI or egg mass were found. However, dietary FFA reduced egg production (linear, P < 0.05) and increased the feed conversion ratio (linear, P < 0.05). Higher levels of FFA in soybean diets resulted in higher egg weight with higher albumen and yolk weights (linear, P < 0.01). Palm diets presented higher yolk:albumen ratio than soybean diets (P < 0.001), but the effect of FFA did not follow a linear trend. Hens fed soybean diets laid eggs with higher Haugh units (HU) than palm diets (P < 0.001), although increasing the dietary FFA% reduced the HU values in both (linear, P < 0.001). Palm diets enhanced shell quality with greater resistance to breakage, and higher dry matter and ash content than soybean diets (P < 0.05). No differences in egg chemical composition and yolk cholesterol content were found (P > 0.05). The saturation degree had a significant effect on all the analyzed yolk FA (P < 0.001) except for arachidonic acid (C20:4 n-6), whereas increasing the FFA content did not affect to a great extent. These results show that varying dietary FFA level did not affect egg quality and yolk composition as much as the dietary fat source did, supporting the use of acid oils and fatty acid distillates as fat ingredients for feed.

Establishment of urinary exosome-like vesicles isolation protocol for FHHNC patients and evaluation of different exosomal RNA extraction methods.

BACKGROUND: Molecular and cellular pathophysiological events occurring in the majority of rare kidney diseases remain to be elucidated. Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare autosomal recessive disorder caused by mutations in either CLDN16 or CLDN19 genes. This disease is characterized by massive urinary wasting of magnesium and calcium, osmosis deregulation and polyuria. Patients with p.G20D homozygous mutation in CLDN19 gene exhibit different progression to kidney failure suggesting that beyond the pathogenic mutation itself, other molecular events are favoring disease progression. Due to the fact that biopsy is not clinically indicated in these patients, urinary exosome-like vesicles (uEVs) can be envisioned as a valuable non-invasive source of information of events occurring in the kidney. Exosome research has increased notably to identify novel disease biomarkers but there is no consensus standardized protocols for uEVs isolation in patients with polyuria. For this reason, this work was aimed to evaluate and refine different uEVs isolation methods based on differential centrifugation, the gold standard method. RESULTS: Characterization by NTA, cryo-TEM and immunoblotting techniques identified the most appropriate protocol to obtain the highest yield and purest uEVs enriched fraction possible from urine control samples and FHHNC patients. Moreover, we tested five different RNA extraction methods and evaluated the miRNA expression pattern by qRT-PCR. CONCLUSIONS: In summary, we have standardized the conditions to proceed with the identification of differentially expressed miRNAs in uEVs of FHHNC patients, or other renal diseases characterized by polyuria.

Characteristics and outcomes of patients admitted to Spanish ICU: A prospective observational study from the ENVIN-HELICS registry (2006-2011) / Características y evolución de los pacientes ingresados en UCI españolas: un estudio observacional prospectivo del registro ENVIN-HELICS (2006-2011)

OBJECTIVE: To describe the case-mix of patients admitted to intensive care units (ICUs) in Spain during the period 2006-2011 and to assess changes in ICU mortality according to severity level. DESIGN: Secondary analysis of data obtained from the ENVN-HELICS registry. Observational prospective study. SETTING: Spanish ICU. Patients: Patients admitted for over 24h. Interventions: None. VARIABLES: Data for each of the participating hospitals and ICUs were recorded, as well as data that allowed to knowing the case-mix and the individual outcome of each patient. The study period was divided into two intervals, from 2006 to 2008 (period 1) and from 2009 to 2011 (period 2). Multilevel and multivariate models were used for the analysis of mortality and were performed in each stratum of severity level. RESULTS: The study population included 142,859 patients admitted to 188 adult ICUs. There was an increase in the mean age of the patients and in the percentage of patients > 79 years (11.2%vs. 12.7%, P < 0.001). Also, the mean APACHE II score increased from 14.35 ± 8.29 to 14.72 ± 8.43 (P < 0.001). The crude overall intra-UCI mortality remained unchanged (11.4%) but adjusted mortality rate in patients with APACHE II score between 11 and 25 decreased modestly in recent years (12.3% vs. 11.6%, odds ratio = 0.931, 95% CI 0.883-0.982; P = 0.008). Conclusion: This study provides observational longitudinal data on case-mix of patients admitted to Spanish ICUs. A slight reduction in ICU mortality rate was observed among patients with intermediate severity level

OBJETIVO: Describir el case-mix de los pacientes admitidos en las unidades de cuidados intensivos (UCI) españolas durante el periodo 2006-2011 y evaluar los cambios en la mortalidad en UCI según el nivel de gravedad. DISEÑO: Estudio prospectivo y observacional. Análisis secundario procedente del registro ENVIN-HELICS. ÁMBITO: ICU españolas. PACIENTES: Pacientes ingresados más de 24h. Intervención: Ninguna. Variables: Se registraron los datos de cada UCI participante, así como aquellos que permiten conocer el case-mix y el estado al alta de cada paciente. El periodo de estudio se dividió en 2 intervalos, de 2006 a 2008 (periodo 1) y de 2009 a 2011 (periodo 2). Para el análisis de la mortalidad y en cada estrato de nivel de gravedad se realizó un estudio multivariante y multinivel. Resultados: La población estudiada incluye 142.859 pacientes ingresados en 188 UCI de adultos. Se apreció un incremento en la media de edad de los pacientes, así como en el porcentaje de los que eran mayores de 79 años (11,2 vs. 12,7%; p < 0,001). La media de APACHE II se incrementó de 14,35 ± 8,29 a 14,72 ± 8,43 (p < 0,001). La mortalidad bruta no varió (11,4%), pero la mortalidad ajustada en pacientes con APACHE II entre 11 y 25 disminuyó modestamente en los últimos años (12,3 vs. 11,6%, odds ratio = 0,931, IC 95% 0,883-0,982; p = 0,008). CONCLUSIONES: Este estudio proporciona datos observacionales del case-mix de los pacientes ingresados en las UCI de España. Se observa una ligera reducción de la mortalidad en los pacientes con un grado intermedio en la escala de gravedad

Immune checkpoint inhibitor-related hypophysitis and endocrine dysfunction: clinical review.

Immune checkpoint inhibitors are a new and effective class of cancer therapy, with ipilimumab being the most established drug in this category. The drugs' mechanism of action includes promoting the effector T cell response to tumours and therefore increased autoimmunity is a predictable side effect. The endocrine effects of these drugs include hypophysitis and thyroid dysfunction, with rare reports of adrenalitis. The overall incidence of hypophysitis with these medications is up to 9%. Primary thyroid dysfunction occurs in up to 15% of patients, with adrenalitis reported in approximately 1%. The mean onset of endocrine side effects is 9 weeks after initiation (range 5-36 weeks). Investigation and/or screening for hypophysitis requires biochemical and radiological assessment. Hypopituitarism is treated with replacement doses of deficient hormones. Since the endocrine effects of immune checkpoint inhibitors are classed as toxic adverse events, most authors recommend both discontinuation of the immune checkpoint inhibiting medication and 'high-dose' glucocorticoid treatment. However, this has been challenged by some authors, particularly if the endocrine effects can be managed (e.g. pituitary hormone deficiency), and the therapy is proving effective as an anticancer agent. This review describes the mechanism of action of immune checkpoint inhibitors and details the key clinical endocrine-related consequences of this novel class of immunotherapies.

Characteristics and outcomes of patients admitted to Spanish ICU: A prospective observational study from the ENVIN-HELICS registry (2006-2011).

OBJECTIVE: To describe the case-mix of patients admitted to intensive care units (ICUs) in Spain during the period 2006-2011 and to assess changes in ICU mortality according to severity level. DESIGN: Secondary analysis of data obtained from the ENVN-HELICS registry. Observational prospective study. SETTING: Spanish ICU. PATIENTS: Patients admitted for over 24h. INTERVENTIONS: None. VARIABLES: Data for each of the participating hospitals and ICUs were recorded, as well as data that allowed to knowing the case-mix and the individual outcome of each patient. The study period was divided into two intervals, from 2006 to 2008 (period 1) and from 2009 to 2011 (period 2). Multilevel and multivariate models were used for the analysis of mortality and were performed in each stratum of severity level. RESULTS: The study population included 142,859 patients admitted to 188 adult ICUs. There was an increase in the mean age of the patients and in the percentage of patients >79 years (11.2% vs. 12.7%, P<0.001). Also, the mean APACHE II score increased from 14.35±8.29 to 14.72±8.43 (P<0.001). The crude overall intra-UCI mortality remained unchanged (11.4%) but adjusted mortality rate in patients with APACHE II score between 11 and 25 decreased modestly in recent years (12.3% vs. 11.6%, odds ratio=0.931, 95% CI 0.883-0.982; P=0.008). CONCLUSION: This study provides observational longitudinal data on case-mix of patients admitted to Spanish ICUs. A slight reduction in ICU mortality rate was observed among patients with intermediate severity level.

Análisis comparativo de pacientes ingresados en Unidades de Cuidados Intensivos españolas por causa médica y quirúrgica / Comparative analysis of patients admitted to Spanish Intensive Care Units due to medical and surgical disease

OBJETIVO: Describir el case-mix de los pacientes médicos y quirúrgicos ingresados en UCI y comparar ambas poblaciones. DISEÑO: Análisis de datos de pacientes ingresados en UCI entre 2006 y 2011, extraídos del registro ENVIN-HELICS. Estudio observacional, prospectivo, multicéntrico y de participación voluntaria. Ámbito: Ciento ochenta y ocho Unidades de Cuidados Intensivos españolas. PARTICIPANTES: Pacientes ingresados durante más de 24 h. Variables de interés principales: Datos demográficos, causa de ingreso, escalas de gravedad, tiempo de estancia y mortalidad. RESULTADOS: Se analiza a 138.999 pacientes. El motivo de ingreso era médico no coronario en 65.467 (47,1%), coronario en 27.785 (20,0%), postoperatorio de cirugía programada en 28.044 (20,2%) y urgente en 17.613 (12,7%). Los pacientes quirúrgicos urgentes precisan mayor utilización de dispositivos y presentan más infecciones nosocomiales y por patógenos multirresistentes. La mediana de estancia en UCI es más prolongada en estos pacientes (5 días; rango intercuartílico: 2-11), así como la media de APACHE II y SAPS II. La mortalidad global es superior en pacientes médicos no coronarios (16,6%). Categorizando a los pacientes según el valor APACHE II, la mortalidad es mayor para todos los niveles en los pacientes quirúrgicos urgentes que en los programados, dándose la mayor diferencia en aquellos con APACHE II entre 6 y 10: el 3 y el 0,9%, respectivamente; OR: 2,141 (IC del 95%, 1,825-2,513); p < 0,001. CONCLUSIONES: Los pacientes médicos no coronarios presentan mayor mortalidad, pero son los quirúrgicos urgentes los que precisan mayor uso de recursos por paciente. La escala APACHE II infraestima la mortalidad en pacientes quirúrgicos urgentes

OBJECTIVE: To describe the characteristics of the patients case-mix admitted to ICUs due to medical and surgical disease, and to compare both groups. DESIGN: Analysis of data covering the period 2006-2011 in the ENVIN-HELICS registry. An observational, prospective, multicenter and voluntary participation study. Setting: A total of 188 Spanish ICUs. Patients: All patients admitted for more than 24 hours. MAIN VARIABLES: Demographic data, cause of admission, severity scores, length of stay, mortality. RESULTS: A total of 138,999 patients were analyzed. Of these, 65,467 (47.1%) were admitted due to a non-coronary medical cause, 27,785 (20,0%) due to coronary-related illness, 28,044 (20,2%) after elective surgery and 17,613 (12.7%) after urgent surgery. Use of devices, nosocomial infections and isolation of multirresistant organisms were more prevalent in urgent surgery patients. Longer length of stay (median 5 days; interquartile range 2-11) as well as higher severity scale values (APACHE II and SAPS II) corresponded to this same group of patients. Mortality was higher in non-coronay medical patients. On categorizing the patients according to the APACHE II score, mortality was seen to be higher in urgent surgery cases than in elective surgery patients in all groups. The largest difference was observed in the APACHE II score 6-10 group (3% vs. 0.9%) (OR: 2.14, 95% CI 1.825-2.513; p<0.001). CONCLUSIONS: The mortality rate is higher in non-coronary medical patients, though resource use per patient is greater in the urgent surgery cases. The APACHE II scale underestimates mortality in emergency surgery patients

[Comparative analysis of patients admitted to Spanish Intensive Care Units due to medical and surgical disease]. / Análisis comparativo de pacientes ingresados en Unidades de Cuidados Intensivos españolas por causa médica y quirúrgica.

OBJECTIVE: To describe the characteristics of the patients case-mix admitted to ICUs due to medical and surgical disease, and to compare both groups. DESIGN: Analysis of data covering the period 2006-2011 in the ENVIN-HELICS registry. An observational, prospective, multicenter and voluntary participation study. SETTING: A total of 188 Spanish ICUs. PATIENTS: All patients admitted for more than 24 hours. MAIN VARIABLES: Demographic data, cause of admission, severity scores, length of stay, mortality. RESULTS: A total of 138,999 patients were analyzed. Of these, 65,467 (47.1%) were admitted due to a non-coronary medical cause, 27,785 (20,0%) due to coronary-related illness, 28,044 (20,2%) after elective surgery and 17,613 (12.7%) after urgent surgery. Use of devices, nosocomial infections and isolation of multirresistant organisms were more prevalent in urgent surgery patients. Longer length of stay (median 5 days; interquartile range 2-11) as well as higher severity scale values (APACHE II and SAPS II) corresponded to this same group of patients. Mortality was higher in non-coronay medical patients. On categorizing the patients according to the APACHE II score, mortality was seen to be higher in urgent surgery cases than in elective surgery patients in all groups. The largest difference was observed in the APACHE II score 6-10 group (3% vs. 0.9%) (OR: 2.14, 95% CI 1.825-2.513; p<0.001). CONCLUSIONS: The mortality rate is higher in non-coronary medical patients, though resource use per patient is greater in the urgent surgery cases. The APACHE II scale underestimates mortality in emergency surgery patients.

Estudio epidemiológico de infección por Clostridium difficile en pacientes críticos ingresados en una Unidad de Cuidados Intensivos / Epidemiological study of Clostridium difficile infection in critical patients admitted to the Intensive Care Unit

La epidemiología de las infecciones por Clostridium difficile (ICD) en pacientes críticos es escasa y centrada en estudios limitados en tiempo y/o en brotes epidémicos. OBJETIVO: Describir las características y los factores de riesgo de pacientes críticos ingresados en UCI con ICD, así como los tratamientos utilizados para su control. MATERIAL Y MÉTODO: Análisis retrospectivo de pacientes incluidos en el registro ENVIN-UCI con ICD en el año 2012. Los pacientes se han seguido hasta 72h después de su alta de UCI. Se ha cumplimentado un cuaderno de recogida de datos, en el que se incluyen variables demográficas, factores de riesgo relacionados con Clostridium difficile, tratamiento y evolución. Los aislamientos se han clasificado por su origen en comunitarios, nosocomiales extra-UCI y nosocomiales intra-UCI en función del día de aislamiento. Se presentan las tasas por episodios por 10.000 días de estancia en UCI. Se describe la mortalidad global intra-UCI y hospitalaria. RESULTADOS: Se han detectado 68 episodios de ICD en 33 (19,1%) UCI de las 173 participantes en el registro (2,1 episodios por 10.000 días de estancia-UCI). En 45 (66,2%) casos eran hombres, con edad media de 63,4 (16,4) años, APACHE II al ingreso de 19,9 (7,4) y enfermedad de base médica 44 (64,7%). En 62 (91,2%) ocasiones presentaron más de 3 deposiciones líquidas/día y en 40 (58,8%) se asoció con sepsis severa o shock séptico. En 13 (19,1%) ocasiones fue de origen comunitario, en 13 (19,1%) de origen nosocomial extra-UCI y en 42 (61,8%) de origen intra-UCI. Factores de riesgo: edad > 64 años 39 (57,4%), ingreso previo hospital (3 meses) 32 (45,6%), antimicrobianos (7 días previos) 57 (83,8%), nutrición enteral 23 (33,8%) e inhibidores H2 39 (57,4%). Siguieron tratamiento inicial combinado 18 (26,5%) casos y se ha utilizado metronidazol en 60 (88,2%) y vancomicina en 31 (45,6%) casos. Hubo mortalidad global intra-UCI en 17 (25,0%) casos y hospitalaria de 19 (27,9%). CONCLUSIONES: La tasa de ICD en pacientes ingresados en UCI es baja y afecta a pacientes con elevada gravedad y mortalidad. La presencia de ICD es un marcador de mal pronóstico

Data on the epidemiology of infections caused by Clostridium difficile (CDI) in critically ill patients are scarce and center on studies with a limited time framework and/or epidemic outbreaks. OBJECTIVE: To describe the characteristics and risk factors of critically ill patients admitted to the ICU with CDI, as well as the treatments used for the control of such infections. MATERIAL AND METHODS: A retrospective study was made of patients included in the ENVIN-ICU registry with CDI in 2012. Patients were followed up to 72h after discharge from the ICU. A case report form was used to record the following data: demographic variables, risk factors related to CDI, treatment and outcome. Infections were classified as community-acquired, nosocomial out-ICU and nosocomial in-ICU, according to the day on which Clostridium difficile isolates were obtained. Infection rates as episodes per 10,000 days of ICU stay are presented. The global in-ICU and hospital mortality rates were calculated. RESULTS: Sixty-eight episodes of CDI in 33 out of a total of 173 ICUs participating in the registry were recorded (19.1%) (2.1 episodes per 10,000 days of ICU stay). Forty-five patients were men (66.2%), with a mean (SD) age of 63.4 (16.4) years, a mean APACHE II score on ICU admission of 19.9 (7.4), and an underlying medical condition in 44 (64.7%). Sixty-two patients (91.2%) presented more than 3 liquid depositions/day, 40 (58.8%) in association with severe sepsis or septic shock. Community-acquired infection occurred in 13 patients (19.1%), nosocomial out-ICU infection in 13 (19.1%), and in-ICU infection in 42 (61.8%). Risk factors included age > 64 years in 39 cases (57.4%), previous hospital admission (3 months) in 32 (45.6%), use of antimicrobials (previous 7 days) in 57 (83.8%), enteral nutrition in 23 (33.8%), and the use of H2 inhibitors in 39 (57.4%). Initial combined treatment was administered to 18 patients (26.5%). Metronidazole was used in 60 (88.2%) and vancomycin in 31 (45.6%). The in-ICU mortality rate was 25.0% (n=17), with a hospital mortality 27.9% (n=19). CONCLUSIONS: The rate of ICD in ICU patients is low, the infection affects severely ill patients, and is associated with high mortality. The presence of CDI is a marker of poor prognosis

Quality indicators on the use of antimicrobials in critically ill patients

Quality indicators have been applied to many areas of health care in recent years, including intensive care. However, they have not been specifically developed and validated for antimicrobial use in critically ill patients. Antimicrobials play a key role in intensive care units not only in the prognosis of each individual patient, but also in the development of resistance and changes in the flora in this setting. Evaluating the use of these agents is complex in the intensive care unit, however, because the indications vary greatly and antimicrobial treatment is often changed during admission. We designed and developed specific quality indicators regarding the use of antimicrobials in critically ill patients admitted to the intensive care unit. These indicators are proposed as a tool for application in intensive care units to detect problems in the use of antimicrobials. Future trials are needed, however, to validate these indicators in a large population over time

Los indicadores de calidad se han aplicado a muchas áreas de la atención sanitaria en los últimos años, incluyendo el área de cuidados intensivos. Sin embargo, no se han desarrollado y validado indicadores específicos para el uso de antimicrobianos en pacientes críticos. Los antimicrobianos desempeñan un papel clave en las unidades de cuidados intensivos no sólo en el pronóstico de cada paciente individual, sino también en el desarrollo de resistencias y los cambios en la flora bacteriana. La evaluación del uso de estos fármacos es compleja en las unidades de cuidados intensivos debido a la variedad de indicaciones y a los cambios en el tratamiento antimicrobiano durante el ingreso. Hemos diseñado y desarrollado un conjunto de indicadores de calidad específicos en relación con el uso de antimicrobianos en pacientes críticos ingresados en las unidades de cuidados intensivos. Estos indicadores se proponen como una herramienta para su aplicación en las unidades de cuidados intensivos para detectar problemas en el uso de antimicrobianos. Serán necesarios posteriormente, ensayos para validar estos indicadores en una población grande y a lo largo del tiempo

Quality indicators on the use of antimicrobials in critically ill patients.

Quality indicators have been applied to many areas of health care in recent years, including intensive care. However, they have not been specifically developed and validated for antimicrobial use in critically ill patients. Antimicrobials play a key role in intensive care units not only in the prognosis of each individual patient, but also in the development of resistance and changes in the flora in this setting. Evaluating the use of these agents is complex in the intensive care unit, however, because the indications vary greatly and antimicrobial treatment is often changed during admission. We designed and developed specific quality indicators regarding the use of antimicrobials in critically ill patients admitted to the intensive care unit. These indicators are proposed as a tool for application in intensive care units to detect problems in the use of antimicrobials. Future trials are needed, however, to validate these indicators in a large population over time.

Guidelines for the prevention of ventilator-associated pneumonia and their implementation. The Spanish ‘‘Zero-VAP’’ bundle

BACKGROUND: ''Zero-VAP'' is a proposal for the implementation of a simultaneous multimodal intervention in Spanish intensive care units (ICU) consisting of a bundle of ventilator-associated pneumonia (VAP) prevention measures. Methods/DESIGN: An initiative of the Spanish Societies of Intensive Care Medicine and of Intensive Care Nurses, the project is supported by the Spanish Ministry of Health, and participation is voluntary. In addition to guidelines for VAP prevention, the ''Zero-VAP'' Project incorporates an integral patient safety program and continuous online validation of the application of the bundle. For the latter, VAP episodes and participation indices are entered into the web-based Spanish ICU Infection Surveillance Program ''ENVIN-HELICS'' database, which provides continuous information about local, regional and national VAP incidence rates. Implementation of the guidelines aims at the reduction of VAP to less than 9 episodes per 1000 days of mechanical ventilation. A total of 35 preventive measures were initially selected. A task force of experts used the Grading of Recommendations, Assessment, Development and Evaluation Working Group methodology to generate a list of 7 basic "mandatory" recommendations (education and training in airway management, strict hand hygiene for airway management, cuff pressure control, oral hygiene with chlorhexidine, semi-recumbent positioning, promoting measures that safely avoid or reduce time on ventilator, and discouraging scheduled changes of ventilator circuits, humidifiers and endotracheal tubes) and 3 additional "highly recommended" measures (selective decontamination of the digestive tract, aspiration of subglottic secretions, and a short course of IV antibiotic). Discussion: We present the Spanish VAP prevention guidelines and describe the methodology used for the selection and implementation of the recommendations and the organizational structure of the project. Compared to conventional guideline documents, the associated safety assurance program, the online data recording and compliance control systems, as well as the existence of a pre-defined objective are the distinct features of "Zero VAP"

ANTECEDENTES: «Neumonía Zero» es una propuesta de aplicación de una intervención multimodal simultánea en las unidades de cuidados intensivos españolas que consiste en un paquete de medidas preventivas de la neumonía asociada a la ventilación mecánica (NAVM).Métodos/DISEÑO: Se trata de una iniciativa de las sociedades españolas de Medicina Intensiva y Enfermería Intensiva. El proyecto cuenta con el apoyo del Ministerio de Sanidad y la participación es voluntaria. Además de las directrices para la prevención de la NAVM, el proyecto« Neumonía Zero» incluye un programa integral de seguridad del paciente y una validación continua« online» de la aplicación de las medidas. Para ello se introducen los episodios de NAVM y los índices de participación en la base de datos en red del programa« ENVIN-HELICS» de vigilancia de las infecciones en las unidades de cuidados intensivos españolas, que ofrece información continua acerca de las tasas de incidencia de NAVM a nivel local, autonómico y nacional. La aplicación de «Neumonía Zero»preten de reducir las NAVM a menos de 9 episodios por cada 1.000 días de ventilación mecánica. Inicialmente, se seleccionaron 35 medidas de prevención. Un grupo de expertos utilizó la metodología del Grading of Recommendations, Assessment, Developmentand Evaluation Working Group para crear una lista de 7 recomendaciones básicas «obligatorias»(formación y entrenamiento en el manejo de la vía aérea, higiene estricta de manos en el manejo de la vía aérea, control de la presión del neumotaponamiento, higiene bucal con clorhexidina, posición semiincorporada, fomento de medidas que de forma segura eviten o reduzcan la duración de la ventilación mecánica, y desaconsejar los cambios programados de tubuladuras, humidificadores y tubos endotraqueales) y 3 medidas adicionales «muy recomendables» (descontaminación selectiva del tubo digestivo, aspiración de las secreciones subglóticas y un breve curso de antibióticos intravenosos). Debate: Presentamos las directrices españolas para la prevención de la NAVM y describimos la metodología utilizada para seleccionar y aplicar las recomendaciones y la estructura organizativa del proyecto. En comparación con recomendaciones convencionales, el programa de seguridad asociado, el registro de datos «online» y los sistemas de control del cumplimiento, además de la existencia de un objetivo predefinido, son características distintivas de «Neumonía Zero»

Guidelines for the prevention of ventilator-associated pneumonia and their implementation. The Spanish "Zero-VAP" bundle

"BACKGROUND: ""Zero-VAP"" is a proposal for the implementation of a simultaneous multimodal intervention in Spanish intensive care units (ICU) consisting of a bundle of ventilator-associated pneumonia (VAP) prevention measures. METHODS/DESIGN: An initiative of the Spanish Societies of Intensive Care Medicine and of Intensive Care Nurses, the project is supported by the Spanish Ministry of Health, and participation is voluntary. In addition to guidelines for VAP prevention, the ""Zero-VAP"" Project incorporates an integral patient safety program and continuous online validation of the application of the bundle. For the latter, VAP episodes and participation indices are entered into the web-based Spanish ICU Infection Surveillance Program ""ENVIN-HELICS"" database, which provides continuous information about local, regional and national VAP incidence rates. Implementation of the guidelines aims at the reduction of VAP to less than 9 episodes per 1000 days of mechanical ventilation. A total of 35 preventive measures were initially selected. A task force of experts used the Grading of Recommendations, Assessment, Development and Evaluation Working Group methodology to generate a list of 7 basic ""mandatory"" recommendations (education and training in airway management, strict hand hygiene for airway management, cuff pressure control, oral hygiene with chlorhexidine, semi-recumbent positioning, promoting measures that safely avoid or reduce time on ventilator, and discouraging scheduled changes of ventilator circuits, humidifiers and endotracheal tubes) and 3 additional ""highly recommended"" measures (selective decontamination of the digestive tract, aspiration of subglottic secretions, and a short course of iv antibiotic). DISCUSSION: We present the Spanish VAP prevention guidelines and describe the methodology used for the selection and implementation of the recommendations and the organizational structure of the project. Compared to conventional guideline documents, the associated safety assurance program, the online data recording and compliance control systems, as well as the existence of a pre-defined objective are the distinct features of ""Zero VAP"""

Guidelines for the prevention of ventilator-associated pneumonia and their implementation. The Spanish "Zero-VAP" bundle.

BACKGROUND: "Zero-VAP" is a proposal for the implementation of a simultaneous multimodal intervention in Spanish intensive care units (ICU) consisting of a bundle of ventilator-associated pneumonia (VAP) prevention measures. METHODS/DESIGN: An initiative of the Spanish Societies of Intensive Care Medicine and of Intensive Care Nurses, the project is supported by the Spanish Ministry of Health, and participation is voluntary. In addition to guidelines for VAP prevention, the "Zero-VAP" Project incorporates an integral patient safety program and continuous online validation of the application of the bundle. For the latter, VAP episodes and participation indices are entered into the web-based Spanish ICU Infection Surveillance Program "ENVIN-HELICS" database, which provides continuous information about local, regional and national VAP incidence rates. Implementation of the guidelines aims at the reduction of VAP to less than 9 episodes per 1000 days of mechanical ventilation. A total of 35 preventive measures were initially selected. A task force of experts used the Grading of Recommendations, Assessment, Development and Evaluation Working Group methodology to generate a list of 7 basic "mandatory" recommendations (education and training in airway management, strict hand hygiene for airway management, cuff pressure control, oral hygiene with chlorhexidine, semi-recumbent positioning, promoting measures that safely avoid or reduce time on ventilator, and discouraging scheduled changes of ventilator circuits, humidifiers and endotracheal tubes) and 3 additional "highly recommended" measures (selective decontamination of the digestive tract, aspiration of subglottic secretions, and a short course of iv antibiotic). DISCUSSION: We present the Spanish VAP prevention guidelines and describe the methodology used for the selection and implementation of the recommendations and the organizational structure of the project. Compared to conventional guideline documents, the associated safety assurance program, the online data recording and compliance control systems, as well as the existence of a pre-defined objective are the distinct features of "Zero VAP".

Epidemiological study of Clostridium difficile infection in critical patients admitted to the Intensive Care Unit.

UNLABELLED: Data on the epidemiology of infections caused by Clostridium difficile (CDI) in critically ill patients are scarce and center on studies with a limited time framework and/or epidemic outbreaks. OBJECTIVE: To describe the characteristics and risk factors of critically ill patients admitted to the ICU with CDI, as well as the treatments used for the control of such infections. MATERIAL AND METHODS: A retrospective study was made of patients included in the ENVIN-ICU registry with CDI in 2012. Patients were followed up to 72 h after discharge from the ICU. A case report form was used to record the following data: demographic variables, risk factors related to CDI, treatment and outcome. Infections were classified as community-acquired, nosocomial out-ICU and nosocomial in-ICU, according to the day on which Clostridium difficile isolates were obtained. Infection rates as episodes per 10,000 days of ICU stay are presented. The global in-ICU and hospital mortality rates were calculated. RESULTS: Sixty-eight episodes of CDI in 33 out of a total of 173 ICUs participating in the registry were recorded (19.1%) (2.1 episodes per 10,000 days of ICU stay). Forty-five patients were men (66.2%), with a mean (SD) age of 63.4 (16.4) years, a mean APACHE II score on ICU admission of 19.9 (7.4), and an underlying medical condition in 44 (64.7%). Sixty-two patients (91.2%) presented more than 3 liquid depositions/day, 40 (58.8%) in association with severe sepsis or septic shock. Community-acquired infection occurred in 13 patients (19.1%), nosocomial out-ICU infection in 13 (19.1%), and in-ICU infection in 42 (61.8%). Risk factors included age>64 years in 39 cases (57.4%), previous hospital admission (3 months) in 32 (45.6%), use of antimicrobials (previous 7 days) in 57 (83.8%), enteral nutrition in 23 (33.8%), and the use of H2 inhibitors in 39 (57.4%). Initial combined treatment was administered to 18 patients (26.5%). Metronidazole was used in 60 (88.2%) and vancomycin in 31 (45.6%). The in-ICU mortality rate was 25.0% (n=17), with a hospital mortality 27.9% (n=19). CONCLUSIONS: The rate of ICD in ICU patients is low, the infection affects severely ill patients, and is associated with high mortality. The presence of CDI is a marker of poor prognosis.

Leaf water dynamics of Arabidopsis thaliana monitored in-vivo using terahertz time-domain spectroscopy.

The declining water availability for agriculture is becoming problematic for many countries. Therefore the study of plants under water restriction is acquiring extraordinary importance. Botanists currently follow the dehydration of plants comparing the fresh and dry weight of excised organs, or measuring their osmotic or water potentials; these are destructive methods inappropriate for in-vivo determination of plants' hydration dynamics. Water is opaque in the terahertz band, while dehydrated biological tissues are partially transparent. We used terahertz spectroscopy to study the water dynamics of Arabidopsis thaliana by comparing the dehydration kinetics of leaves from plants under well-irrigated and water deficit conditions. We also present measurements of the effect of dark-light cycles and abscisic acid on its water dynamics. The measurements we present provide a new perspective on the water dynamics of plants under different external stimuli and confirm that terahertz can be an excellent non-contact probe of in-vivo tissue hydration.

Invasive device-related infections after heart surgery.

OBJECTIVE: To analyze postoperative infections in critically ill patients undergoing heart surgery. SETTING: Intensive care units (ICUs). DESIGN: An observational, prospective, multicenter study was carried out. PATIENTS: Patients in the postoperative period of heart surgery admitted to the ICU and included in the ENVIN-HELICS registry between 2005 and 2011. MAIN OUTCOME VARIABLES: Mechanical ventilation associated pneumonia (MVP), urinary catheter-related infection (UCI), primary bacteremia (PB), PB related to vascular catheters (PB-VC) and secondary bacteremia. RESULTS: Of a total of 97,692 patients included in the study, 9089 (9.3%) had undergone heart surgery. In 440 patients (4.8%), one or more infections were recorded. Infection rates were 9.94 episodes of MVP per 1000 days of mechanical ventilation, 3.4 episodes of UCI per 1000 days of urinary catheterization, 3.10 episodes of BP-VC per 1000 days of central venous catheter, and 1.84 episodes of secondary bacteremia per 1000 days of ICU stay. Statistically significant risk factors for infection were ICU stay (odds ratio [OR] 1.18, 95%CI 1.16-1.20), APACHE II upon admission to the ICU (OR 1.05, 95%CI 1.03-1.07), emergency surgery (OR 1.67, 95%CI 1.13-2.47), previous antibiotic treatment (OR 1.38, 95%CI 1.04-1.83), and previous colonization by Pseudomonas aeruginosa (OR 18.25, 95%CI 3.74-89.06) or extended spectrum beta-lactamase producing enterobacteria (OR 16.97, 95%CI 5.4-53.2). The overall ICU mortality rate was 4.1% (32.2% in patients who developed one or more infections and 2.9% in uninfected patients) (P < .001). CONCLUSIONS: Of the patients included in the ENVIN-HELICS registry, 9.3% were postoperative heart surgery patients. The overall mortality was low but increased significantly in patients who developed one or more infection episodes.

Urethral catheter-related urinary infection in critical patients admitted to the ICU. Descriptive data of the ENVIN-UCI study.

OBJECTIVE: To describe trends in national catheter-related urinary tract infection (CRUTI) rates, as well as etiologies and multiresistance markers. DESIGN: An observational, prospective, multicenter voluntary participation study was conducted from 1 April to 30 June in the period between 2005 and 2010. SETTING: Intensive Care Units (ICUs) that participated in the ENVIN-ICU registry during the study period. PATIENTS: We included all patients admitted to the participating ICUs and patients with urinary catheter placement for more than 24 hours (78,863 patients). INTERVENTION: Patient monitoring was continued until discharge from the ICU or up to 60 days. VARIABLES OF INTEREST: CRUTIs were defined according to the CDC system, and frequency is expressed as incidence density (ID) in relation to the number of urinary catheter-patients days. RESULTS: A total of 2329 patients (2.95%) developed one or more CRUTI. The ID decreased from 6.69 to 4.18 episodes per 1000 days of urinary catheter between 2005 and 2010 (p<0.001). In relation to the underlying etiology, gramnegative bacilli predominated (55.6 to 61.6%), followed by fungi (18.7 to 25.2%) and grampositive cocci (17.1 to 25.9%). In 2010, ciprofloxacin-resistant E. coli strains (37.1%) increased, as well as imipenem-resistant (36.4%) and ciprofloxacin-resistant (37.1%) strains of P. aeruginosa. CONCLUSIONS: A decrease was observed in CRUTI rates, maintaining the same etiological distribution and showing increased resistances in gramnegative pathogens, especially E. coli and P. aeruginosa.

Impact of the emergence of non-vaccine pneumococcal serotypes on the clinical presentation and outcome of adults with invasive pneumococcal pneumonia.

The introduction of the 7-valent pneumococcal conjugate vaccine in children has led to a change in the pattern of pneumococcal serotypes causing pneumococcal disease. The aim of this study was to compare the clinical presentation and outcome of invasive pneumococcal pneumonia (IPP) in adults between the pre and post-vaccine era. We have conducted an observational study of all adults hospitalized with IPP, from 1996 to 2001 (pre-vaccine period), and from 2005 to 2009 (post-vaccine period). Incidence, serotype distribution and clinical data were compared between both periods. A total of 653 episodes of IPP were diagnosed. The overall incidence of IPP increased from 14.2 to 17.9 cases per 100 000 population-year (p 0.003). In the post-vaccine period IPP caused by vaccine serotypes decreased (-36%; 95% CI, -52 to -15) while IPP caused by non-vaccine serotypes increased (71%; 95% CI, 41-106). IPP in the post-vaccine period was associated with higher rates of septic shock (19.1% vs. 31.1%, p <0.001). Among patients aged 50-65 years there was a trend towards a greater proportion of case-fatalities (11.6-23.5%, p 0.087). Independent risk factors for septic shock were IPP caused by serotype 3 (OR 2.38; 95% CI, 1.16-4.87) and serotype 19A (OR 6.47, 95% CI, 1.55-27). Serotype 1 was associated with a lower risk of death (OR 0.1; 95% CI, 0.01-0.78). In conclusion, the incidence of IPP in the post-vaccine period has increased in our setting, it is caused mainly by non-vaccine serotypes and it is associated with higher rates of septic shock.