A predictive clinical-genetic model of tissue plasminogen activator response in acute ischemic stroke

Wide interindividual variability exists in response to tissue plasminogen activator (t-PA) treatment in the acute phase of ischemic stroke. We aimed to find genetic variations associated with hemorrhagic transformation (HT) and mortality rates after t-PA. We then generated a clinical-genetic model for predicting t-PA response

Glycemic variability : prognostic impact on acute ischemic stroke and the impact of corrective treatment for hyperglycemia. The GLIAS-III translational study

Glycemic variability (GV) represents the amplitude of oscillations in glucose levels over time and is associated with higher mortality in critically ill patients. Our aim is to evaluate the impact of GV on acute ischemic stroke (IS) outcomes in humans and explore the impact of two different insulin administration routes on GV in an animal model. This translational study consists of two studies conducted in parallel: The first study is an observational, multicenter, prospective clinical study in which 340 patients with acute IS will be subcutaneously implanted a sensor to continuously monitor blood glucose levels for 96 h. The second study is a basic experimental study using an animal model (rats) with permanent occlusion of the middle cerebral artery and induced hyperglycemia (through an intraperitoneal injection of nicotinamide and streptozotocin). The animal study will include the following 6 groups (10 animals per group): sham; hyperglycemia without IS; IS without hyperglycemia; IS and hyperglycemia without treatment; IS and hyperglycemia and intravenous insulin; and IS and hyperglycemia and subcutaneous insulin. The endpoint for the first study is mortality at 3 months, while the endpoints for the animal model study are GV, functional recovery and biomarkers. The GLIAS-III study will be the first translational approach analyzing the prognostic influence of GV, evaluated by the use of subcutaneous glucose monitors, in acute stroke. Trial registration (NCT04001049

Data_Sheet_1_Stroke-associated pneumonia according to mCDC criteria: impact on prognosis and antibiotic therapy.docx

ObjectiveThe modified Centers for Disease Control and Prevention (mCDC) criteria have been proposed for diagnosing and managing stroke-associated pneumonia (SAP). The objective was to investigate the impact of SAP on stroke outcome depending on whether or not it conforms to mCDC criteria. Our secondary objective was to identify the responsible factors for antibiotic initiation in stroke patients.MethodsWe conducted a prospective, multicenter, observational study of ischemic stroke patients with moderate to severe stroke (NIHSS≥4) admitted within 24 h. For 7 days, mCDC criteria were assessed daily, and infections and antibiotics were recorded. Pneumonias were divided into those fulfilling mCDC criteria (mCDC-SAP) or not (other pneumonias, OPn). The effect of each type of pneumonia on 3-month outcome was evaluated in separated logistic regression models. Factors associated with antibiotic initiation were explored using a random forest analysis.ResultsOf the 342 patients studied, infections were diagnosed in 72 (21.6%), including 39 (11.7%) cases of pneumonia. Of them, 25 (7.5%) fulfilled mCDC criteria. Antibiotics were used in 92% of mCDC-SAP and 64.3% of OPn. In logistic regression analysis, mCDC-SAP, but not OPn, was an independent predictor of poor outcome [OR, 4.939 (1.022–23.868)]. The random forest analysis revealed that fever had the highest importance for antibiotic initiation.InterpretationThe mCDC criteria might be useful for detecting clinically relevant SAP, which is associated with poor outcomes. Isolated signs of infection were more important for antibiotic initiation than compliance with pre-defined criteria. Therefore, adherence to mCDC criteria might result in antibiotic saving without compromising clinical outcome.</p

Data_Sheet_1_Stroke-associated pneumonia according to mCDC criteria: impact on prognosis and antibiotic therapy.docx

ObjectiveThe modified Centers for Disease Control and Prevention (mCDC) criteria have been proposed for diagnosing and managing stroke-associated pneumonia (SAP). The objective was to investigate the impact of SAP on stroke outcome depending on whether or not it conforms to mCDC criteria. Our secondary objective was to identify the responsible factors for antibiotic initiation in stroke patients.MethodsWe conducted a prospective, multicenter, observational study of ischemic stroke patients with moderate to severe stroke (NIHSS≥4) admitted within 24 h. For 7 days, mCDC criteria were assessed daily, and infections and antibiotics were recorded. Pneumonias were divided into those fulfilling mCDC criteria (mCDC-SAP) or not (other pneumonias, OPn). The effect of each type of pneumonia on 3-month outcome was evaluated in separated logistic regression models. Factors associated with antibiotic initiation were explored using a random forest analysis.ResultsFrom 342 patients included, infections were diagnosed in 72 (21.6%), being 39 (11.7%) pneumonias. Of them, 25 (7.5%) fulfilled mCDC criteria. Antibiotics were used in 92% of mCDC-SAP and 64.3% of OPn. In logistic regression analysis, mCDC-SAP, but not OPn, was an independent predictor of poor outcome [OR, 4.939 (1.022–23.868)]. The random forest analysis revealed that fever had the highest importance for antibiotic initiation.InterpretationThe mCDC criteria might be useful for detecting clinically relevant SAP, which is associated with poor outcomes. Isolated signs of infection were more important for antibiotic initiation than compliance with pre-defined criteria. Therefore, adherence to mCDC criteria might result in antibiotic saving without compromising clinical outcome.</p

GRECOS project (Genotyping Recurrence Risk of Stroke). The use of genetics to predict the vascular recurrence after stroke

Altres ajuts: This study was funded by Marato TV3, by the Spanish stroke research network (INVICTUS-PLUS) and by Generacion project (PI15/01978) Instituto de Salud Carlos III. Dr Fernández-Cadenas is supported by the Miguel Servet program (CP12/03298), Instituto de Salud Carlos III. Several groups participate in the International Stroke Genetics Consortium and the Spanish Stroke Genetics Consortium. The Hospital del Mar is supported by Spain's Ministry of Health (III FEDER, RD12/0042/0020). Study recruitment and collection of data sets for the VISP trial were supported by a grant (R01 NS34447; PI James Toole) from the National Institute of Neurological Disorders and Stroke (NINDS). Genome-wide association studies genotyping (U01 HG004438l; PI David Valle), funded by the National Human Genome Research Institute and the Genomics and Randomized Trials (GARNET) Network (U01HG00516-03; co-PI Michèle M. Sale and Bradford B. Worrall), and genetic data cleaning was provided by the GARNET Coordinating Center (U01HG005157; PI Bruce S. Weir)Background and Purpose-Vascular recurrence occurs in 11% of patients during the first year after ischemic stroke (IS) or transient ischemic attack (TIA). Clinical scores do not predict the whole vascular recurrence risk, therefore we aimed to find genetic variants associated with recurrence that might improve the clinical predictive mode is in IS. Methods-We analyzed 256 polymorphisms from 115 candidate genes in three patient cohorts comprising 4,482 IS or TIA patients. The discovery cohort was prospectively recruited and included 1,494 patients, 6.2% of them developed a new IS during the first year of follow-up. Replication analysis was performed in 2,988 patients using SNPlex or HumanOmni1-Quad technology. We generated a predictive model using Cox regression (GRECOS score), and generated risk groups using a classification tree method. Results-The analyses revealed that rs1800801 in the MGP gene (HR: 1.33, p= 9×10−03), a gene related to artery calcification, was associated with new IS during the first year of follow-up. This polymorphism was replicated in a Spanish cohort (n=1.305), however it was not significantly associated in a North American cohort (n=1.683). The GRECOS score predicted new IS (p=3.2×10−09) and could classify patients, from low risk of stroke recurrence (1.9%) to high risk (12.6%). Moreover, the addition of genetic risk factors to the GRECOS score improves the prediction compared to previous SPI-II score (p=0.03). Conclusions-The use of genetics could be useful to estimate vascular recurrence risk after IS. Genetic variability in the MGP gene was associated with vascular recurrence in the Spanish population

GRECOS project (Genotyping Recurrence Risk of Stroke). The use of genetics to predict the vascular recurrence after stroke

Altres ajuts: This study was funded by Marato TV3, by the Spanish stroke research network (INVICTUS-PLUS) and by Generacion project (PI15/01978) Instituto de Salud Carlos III. Dr Fernández-Cadenas is supported by the Miguel Servet program (CP12/03298), Instituto de Salud Carlos III. Several groups participate in the International Stroke Genetics Consortium and the Spanish Stroke Genetics Consortium. The Hospital del Mar is supported by Spain's Ministry of Health (III FEDER, RD12/0042/0020). Study recruitment and collection of data sets for the VISP trial were supported by a grant (R01 NS34447; PI James Toole) from the National Institute of Neurological Disorders and Stroke (NINDS). Genome-wide association studies genotyping (U01 HG004438l; PI David Valle), funded by the National Human Genome Research Institute and the Genomics and Randomized Trials (GARNET) Network (U01HG00516-03; co-PI Michèle M. Sale and Bradford B. Worrall), and genetic data cleaning was provided by the GARNET Coordinating Center (U01HG005157; PI Bruce S. Weir)Background and Purpose-Vascular recurrence occurs in 11% of patients during the first year after ischemic stroke (IS) or transient ischemic attack (TIA). Clinical scores do not predict the whole vascular recurrence risk, therefore we aimed to find genetic variants associated with recurrence that might improve the clinical predictive mode is in IS. Methods-We analyzed 256 polymorphisms from 115 candidate genes in three patient cohorts comprising 4,482 IS or TIA patients. The discovery cohort was prospectively recruited and included 1,494 patients, 6.2% of them developed a new IS during the first year of follow-up. Replication analysis was performed in 2,988 patients using SNPlex or HumanOmni1-Quad technology. We generated a predictive model using Cox regression (GRECOS score), and generated risk groups using a classification tree method. Results-The analyses revealed that rs1800801 in the MGP gene (HR: 1.33, p= 9×10−03), a gene related to artery calcification, was associated with new IS during the first year of follow-up. This polymorphism was replicated in a Spanish cohort (n=1.305), however it was not significantly associated in a North American cohort (n=1.683). The GRECOS score predicted new IS (p=3.2×10−09) and could classify patients, from low risk of stroke recurrence (1.9%) to high risk (12.6%). Moreover, the addition of genetic risk factors to the GRECOS score improves the prediction compared to previous SPI-II score (p=0.03). Conclusions-The use of genetics could be useful to estimate vascular recurrence risk after IS. Genetic variability in the MGP gene was associated with vascular recurrence in the Spanish population