Supervivencia de circuitos de técnicas de depuración extrarrenal continua en pacientes críticos con o sin anticoagulación convencional: estudio observacional prospectivo

Fundamento. El objetivo del presente estudio es describir la eficacia, seguridad y viabilidad, en pacientes críticos con técnica de depuración extrarrenal continua (TDEC) y diferente riesgo de hemorragia, de un sistema de anticoagulación convencional con perfusión continua de heparina no fraccionada (HNF) frente a no anticoagular usando lavados son suero fisiológico. Material y métodos. Se trata de un estudio observacional prospectivo realizado en la Unidad de Cuidados Intensivos (UCI) desde octubre de 2013 hasta abril de 2016. Se incluyeron 61 pacientes que presentaron insuficiencia renal aguda (IRA) con requerimientos de TDEC y un total de 122 circuitos. Tanto los pacientes como los circuitos fueron divididos para su análisis en dos grupos: anticoagulados (AC) y no anticoagulados (No AC). La variable principal fue la supervivencia de los circuitos. Además se recogieron diferentes parámetros analíticos al comienzo del tratamiento y en el momento de coagulación del circuito. Resultados. La distribución de pacientes anticoagulados y no anticoagulados fue similar. No se han encontrado diferencias significativas en la supervivencia de los circuitos entre ambos grupos (30,5 horas AC vs 34,9 horas No AC). Los pacientes con mayor morbilidad (trombopenia severa, coagulopatía, etc.) pertenecían al grupo que no recibió anticoagulación, sino lavados con suero fisiológico. Conclusiones. En pacientes críticos con alto riesgo de sangrado las TDEC son viables sin anticoagulación más el empleo de lavados periódicos con suero fisiológico se comporta como una medida viable, segura y eficaz obteniendo una supervivencia de los circuitos similar a la de pacientes anticoagulados con HNF, evitando los riesgos y costes asociados a la anticoagulación.Background. The aim of this study was to describe the efficacy, security and viability of an anticoagulation system with continuous infusion of unfractionated heparin (UFH) versus one without any type of anticoagulant using 0.9% physiological saline washings, in critically ill patients with continuous renal replacement therapy (CRRT) and different risks of bleeding. Methods. From October 2013 to April 2015 we conducted an observational prospective study in the intensive care unit (ICU). Sixty-one patients with acute kidney injury (AKI) and requiring CRRT were included, with 122 filters. Patients and filters were divided in two groups: anticoagulated (AC) and not anticoagulated (No AC). The main outcome measure was filter life span. Different analytical parameters were also collected at the beginning of treatment and at the moment of circuit coagulation Results. The number of patients was similar in both groups. We did not find statistically significant differences between the two groups in filter life span (30.5 hours AC vs 34.9 hours No AC). Patients with increased morbidity (severe thrombocytopenia, coagulopathy, etc.) were included in the group that did not received anticoagulation but saline flushes. Conclusions. CRRT without anticoagulation with saline flushes is a viable, safe and effective strategy in critically ill patients with high risk of bleeding. This approach achieves a circuit life span similar to that observed in anticoagulated patients with UFH; avoiding the risks and costs associated with anticoagulation

Prognostic models for mortality after cardiac surgery in patients with infective endocarditis: a systematic review and aggregation of prediction models.

Background There are several prognostic models to estimate the risk of mortality after surgery for active infective endocarditis (IE). However, these models incorporate different predictors and their performance is uncertain. Objective We systematically reviewed and critically appraised all available prediction models of postoperative mortality in patients undergoing surgery for IE, and aggregated them into a meta-model. Data sources We searched Medline and EMBASE databases from inception to June 2020. Study eligibility criteria We included studies that developed or updated a prognostic model of postoperative mortality in patient with IE. Methods We assessed the risk of bias of the models using PROBAST (Prediction model Risk Of Bias ASsessment Tool) and we aggregated them into an aggregate meta-model based on stacked regressions and optimized it for a nationwide registry of IE patients. The meta-model performance was assessed using bootstrap validation methods and adjusted for optimism. Results We identified 11 prognostic models for postoperative mortality. Eight models had a high risk of bias. The meta-model included weighted predictors from the remaining three models (EndoSCORE, specific ES-I and specific ES-II), which were not rated as high risk of bias and provided full model equations. Additionally, two variables (age and infectious agent) that had been modelled differently across studies, were estimated based on the nationwide registry. The performance of the meta-model was better than the original three models, with the corresponding performance measures: C-statistics 0.79 (95% CI 0.76–0.82), calibration slope 0.98 (95% CI 0.86–1.13) and calibration-in-the-large –0.05 (95% CI –0.20 to 0.11). Conclusions The meta-model outperformed published models and showed a robust predictive capacity for predicting the individualized risk of postoperative mortality in patients with IE. Protocol registration PROSPERO (registration number CRD42020192602).pre-print270 K

Neutrophil infiltration regulates clock-gene expression to organize daily hepatic metabolism.

Liver metabolism follows diurnal fluctuations through the modulation of molecular clock genes. Disruption of this molecular clock can result in metabolic disease but its potential regulation by immune cells remains unexplored. Here, we demonstrated that in steady state, neutrophils infiltrated the mouse liver following a circadian pattern and regulated hepatocyte clock-genes by neutrophil elastase (NE) secretion. NE signals through c-Jun NH2-terminal kinase (JNK) inhibiting fibroblast growth factor 21 (FGF21) and activating Bmal1 expression in the hepatocyte. Interestingly, mice with neutropenia, defective neutrophil infiltration or lacking elastase were protected against steatosis correlating with lower JNK activation, reduced Bmal1 and increased FGF21 expression, together with decreased lipogenesis in the liver. Lastly, using a cohort of human samples we found a direct correlation between JNK activation, NE levels and Bmal1 expression in the liver. This study demonstrates that neutrophils contribute to the maintenance of daily hepatic homeostasis through the regulation of the NE/JNK/Bmal1 axis.BGT and MC were fellows of the FPI: Severo Ochoa CNIC program (SVP-2013–067639) and (BES-2017–079711) respectively. IN was funded by EFSD/Lilly grants (2017 and 2019), the CNIC IPP FP7 Marie Curie Programme (PCOFUND-2012–600396), EFSD Rising Star award (2019), JDC-2018-Incorporación (MIN/JDC1802). T-L was a Juan de la Cierva fellow (JCI2011–11623). C.F has a Sara Borrell contract (CD19/00078). RJD is an Investigator of the Howard Hughes Medical Institute. This work was funded by the following grants to GS: funding from the European Union’s Seventh Framework Programme (FP7/2007-2013) under grant agreement n˚ ERC 260464, EFSD/Lilly European Diabetes Research Programme Dr Sabio, 2017 Leonardo Grant for Researchers and Cultural Creators, BBVA Foundation (Investigadores-BBVA-2017) IN[17] _BBM_BAS_0066, MINECO-FEDER SAF2016-79126-R and PID2019-104399RB-I00 , EUIN201785875, Comunidad de Madrid IMMUNOTHERCAN-CM S2010/BMD-2326 and B2017/BMD-3733 and Fundación AECC AECC PROYE19047SABI and AECC: INVES20026LEIV to ML. MM was funded by ISCIII and FEDER PI16/01548 and Junta de Castilla y León GRS 1362/A/16 and INT/M/17/17 and JL-T by Junta de Castilla y León GRS 1356/A/16 and GRS 1587/A/17. The study was additionally funded by MEIC grants to ML (MINECO-FEDER-SAF2015-74112-JIN) AT-L (MINECO-FEDERSAF2014-61233-JIN), RJD: Grant DK R01 DK107220 from the National Institutes of Health. AH: (SAF2015-65607-R). The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia, Innovación y Universidades (MCNU) and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015–0505).S

PATJ Low Frequency Variants Are Associated with Worse Ischemic Stroke Functional Outcome: A Genome-Wide Meta-Analysis

RATIONALE: Ischemic stroke is among the leading causes of adult disability. Part of the variability in functional outcome after stroke has been attributed to genetic factors but no locus has been consistently associated with stroke outcome. OBJECTIVE: Our aim was to identify genetic loci influencing the recovery process using accurate phenotyping to produce the largest GWAS (genome-wide association study) in ischemic stroke recovery to date. METHODS AND RESULTS: A 12-cohort, 2-phase (discovery-replication and joint) meta-analysis of GWAS included anterior-territory and previously independent ischemic stroke cases. Functional outcome was recorded using 3-month modified Rankin Scale. Analyses were adjusted for confounders such as discharge National Institutes of Health Stroke Scale. A gene-based burden test was performed. The discovery phase (n=1225) was followed by open (n=2482) and stringent joint-analyses (n=1791). Those cohorts with modified Rankin Scale recorded at time points other than 3-month or incomplete data on previous functional status were excluded in the stringent analyses. Novel variants in PATJ (Pals1-associated tight junction) gene were associated with worse functional outcome at 3-month after stroke. The top variant was rs76221407 (G allele, β=0.40, P=1.70×10-9). CONCLUSIONS: Our results identify a set of common variants in PATJ gene associated with 3-month functional outcome at genome-wide significance level. Future studies should examine the role of PATJ in stroke recovery and consider stringent phenotyping to enrich the information captured to unveil additional stroke outcome loci

Supervivencia de circuitos de técnicas de depuración extrarrenal continua en pacientes críticos con o sin anticoagulación convencional: estudio observacional prospectivo

Fundamento. El objetivo del presente estudio es describir la eficacia, seguridad y viabilidad, en pacientes críticos con técnica de depuración extrarrenal continua (TDEC) y diferente riesgo de hemorragia, de un sistema de anticoagulación convencional con perfusión continua de heparina no fraccionada (HNF) frente a no anticoagular usando lavados son suero fisiológico. Material y métodos. Se trata de un estudio observacional prospectivo realizado en la Unidad de Cuidados Intensivos (UCI) desde octubre de 2013 hasta abril de 2016. Se incluyeron 61 pacientes que presentaron insuficiencia renal aguda (IRA) con requerimientos de TDEC y un total de 122 circuitos. Tanto los pacientes como los circuitos fueron divididos para su análisis en dos grupos: anticoagulados (AC) y no anticoagulados (No AC). La variable principal fue la supervivencia de los circuitos. Además se recogieron diferentes parámetros analíticos al comienzo del tratamiento y en el momento de coagulación del circuito. Resultados. La distribución de pacientes anticoagulados y no anticoagulados fue similar. No se han encontrado diferencias significativas en la supervivencia de los circuitos entre ambos grupos (30,5 horas AC vs 34,9 horas No AC). Los pacientes con mayor morbilidad (trombopenia severa, coagulopatía, etc.) pertenecían al grupo que no recibió anticoagulación, sino lavados con suero fisiológico. Conclusiones. En pacientes críticos con alto riesgo de sangrado las TDEC son viables sin anticoagulación más el empleo de lavados periódicos con suero fisiológico se comporta como una medida viable, segura y eficaz obteniendo una supervivencia de los circuitos similar a la de pacientes anticoagulados con HNF, evitando los riesgos y costes asociados a la anticoagulación.Background. The aim of this study was to describe the efficacy, security and viability of an anticoagulation system with continuous infusion of unfractionated heparin (UFH) versus one without any type of anticoagulant using 0.9% physiological saline washings, in critically ill patients with continuous renal replacement therapy (CRRT) and different risks of bleeding. Methods. From October 2013 to April 2015 we conducted an observational prospective study in the intensive care unit (ICU). Sixty-one patients with acute kidney injury (AKI) and requiring CRRT were included, with 122 filters. Patients and filters were divided in two groups: anticoagulated (AC) and not anticoagulated (No AC). The main outcome measure was filter life span. Different analytical parameters were also collected at the beginning of treatment and at the moment of circuit coagulation Results. The number of patients was similar in both groups. We did not find statistically significant differences between the two groups in filter life span (30.5 hours AC vs 34.9 hours No AC). Patients with increased morbidity (severe thrombocytopenia, coagulopathy, etc.) were included in the group that did not received anticoagulation but saline flushes. Conclusions. CRRT without anticoagulation with saline flushes is a viable, safe and effective strategy in critically ill patients with high risk of bleeding. This approach achieves a circuit life span similar to that observed in anticoagulated patients with UFH; avoiding the risks and costs associated with anticoagulation

Viral Kinetics in Semen With Different Antiretroviral Families in Treatment-Naive Human Immunodeficiency Virus-Infected Patients: A Randomized Trial

Background. There are several regimens for starting antiretroviral treatment, but it remains unknown whether either of them is more advantageous regarding the time course and magnitude of human immunodeficiency virus (HIV) RNA decay in semen.Objective. To evaluate the differential effect of different antiretroviral drug families on viral kinetics in seminal plasma (SP) of treatment-naive HIV-infected patients.Methods. Phase II, randomized, open-label study in which participants were randomized 1: 1: 1 to receive tenofovir-disoproxil fumarate (DF) plus emtricitabine, and either cobicistat-boosted elvitegravir (EVG(cobi)), rilpivirine (RPV), or ritonavir-boosted darunavir (DRVrtv). The primary endpoint was the proportion of participants with undetectable HIV-RNA in SP at week 12. HIV type 1 (HIV-1) RNA was measured in paired SP and blood plasma (BP) at baseline and after 1, 2, 4, 6, 8, 12, 18, and 24 weeks. Elvitegravir (EVG), RPV, and darunavir (DRV) concentrations were quantified by the liquid chromatography-tandem mass spectrometry method.Results. In SP, the HIV-RNA decay rate with RPV was as fast as with EVG(cobi); by week 12, all participants in the RPV and the EVG(cobi) groups reached an undetectable viral load but only 58.3% in the DRVrtv arm (P = .003). The highest SP/BP drug concentration ratio was for EVG (0.43), followed-up by RPV (0.19), and DRV (0.10). For both EVG and RPV, the SP concentrations exceeded >2-fold the protein binding-adjusted EC90 for wild-type HIV-1; for DRV, only 33.7% of the SP showed concentrations above the protein binding-adjusted EC90.Conclusions. In SP, both RPV and EVG(cobi), associated to tenofovir-DF and emtricitabine, behave similarly and achieve an undetectable viral load much faster than DRVrtv

Prognostic models for mortality after cardiac surgery in patients with infective endocarditis: a systematic review and aggregation of prediction models

Background: There are several prognostic models to estimate the risk of mortality after surgery for active infective endocarditis (IE). However, these models incorporate different predictors and their performance is uncertain. Objective: We systematically reviewed and critically appraised all available prediction models of postoperative mortality in patients undergoing surgery for IE, and aggregated them into a meta-model. Data sources: We searched Medline and EMBASE databases from inception to June 2020. Study eligibility criteria: We included studies that developed or updated a prognostic model of postoperative mortality in patient with IE. Methods: We assessed the risk of bias of the models using PROBAST (Prediction model Risk Of Bias ASsessment Tool) and we aggregated them into an aggregate meta-model based on stacked regressions and optimized it for a nationwide registry of IE patients. The meta-model performance was assessed using bootstrap validation methods and adjusted for optimism. Results: We identified 11 prognostic models for postoperative mortality. Eight models had a high risk of bias. The meta-model included weighted predictors from the remaining three models (EndoSCORE, specific ES-I and specific ES-II), which were not rated as high risk of bias and provided full model equations. Additionally, two variables (age and infectious agent) that had been modelled differently across studies, were estimated based on the nationwide registry. The performance of the meta-model was better than the original three models, with the corresponding performance measures: C-statistics 0.79 (95% CI 0.76–0.82), calibration slope 0.98 (95% CI 0.86–1.13) and calibration-in-the-large –0.05 (95% CI –0.20 to 0.11). Conclusions: The meta-model outperformed published models and showed a robust predictive capacity for predicting the individualized risk of postoperative mortality in patients with IE