In Vivo Corneal Microstructural Changes in Herpetic Stromal Keratitis: A Spectral-Domain Optical Coherence Tomography Analysis

Purpose: To describe and analyze the microstructural changes in herpetic stromal keratitis (HSK) observed in vivo by spectral-domain ocular coherence tomography (SD-OCT) at different stages of the disease. Methods: A prospective, cross-sectional, observational, and comparative SD-OCT analysis of corneas with active and inactive keratitis was performed, and the pathologic differences between the necrotizing and non-necrotizing forms of the disease were analyzed. Results: Fifty-three corneas belonging to 43 (81.1%) women and 10 (18.8%) men with a mean age of 41.0 years were included for analysis. Twenty-four (45.3%) eyes had active keratitis, and 29 (54.7%) had inactive keratitis; the majority (83.0%) had the non-necrotizing form. Most corneas (79.1%) with active keratitis showed stromal edema and inflammatory infiltrates. Almost half of the active lesions affected the visual axis, were found at mid-stromal depth, and had a medium density. By contrast, corneas with inactive keratitis were characterized by stromal scarring (89.6%), epithelial remodeling (72.4%), and stromal thinning (68.9%). In contrast to non-necrotizing corneas, those with necrotizing HSK showed severe stromal scarring, inflammatory infiltration, and thinning. Additionally, most necrotizing lesions (77.7%) affected the visual axis and had a higher density (P = 0.010). Conclusion: Active HSK is characterized by significant epithelial and stromal thickening and the inactive disease manifests epithelial remodeling at sites of stromal thinning due to scarring. Necrotizing keratitis is characterized by distorted corneal architecture, substantial stromal inflammatory infiltration, and thinning. In vivo SD-OCT analysis permitted a better understanding of the inflammatory and repair mechanisms occurring in this blinding corneal disease

Blood biomarker changes following therapeutic hypothermia in ischemic stroke

Biomarkers; Hypothermia; IschemiaBiomarcadores; Hipotermia; IsquemiaBiomarcadors; Hipotèrmia; IsquèmiaIntroduction Therapeutic hypothermia is a promising candidate for stroke treatment although its efficacy has not yet been demonstrated in patients. Changes in blood molecules could act as surrogate markers to evaluate the efficacy and safety of therapeutic cooling. Methods Blood samples from 54 patients included in the EuroHYP-1 study (27 treated with hypothermia, and 27 controls) were obtained at baseline, 24 ± 2 h, and 72 ± 4 h. The levels of a panel of 27 biomarkers, including matrix metalloproteinases and cardiac and inflammatory markers, were measured. Results Metalloproteinase-3 (MMP-3), fatty-acid-binding protein (FABP), and interleukin-8 (IL-8) increased over time in relation to the hypothermia treatment. Statistically significant correlations between the minimum temperature achieved by each patient in the hypothermia group and the MMP-3 level measured at 72 h, FABP level measured at 24 h, and IL-8 levels measured at 24 and 72 h were found. No differential biomarker levels were observed in patients with poor or favorable outcomes according to modified Rankin Scale scores. Conclusion Although the exact roles of MMP3, FABP, and IL-8 in hypothermia-treated stroke patients are not known, further exploration is needed to confirm their roles in brain ischemia

Condicionantes pronósticos del ictus isquémico: utilidad de los biomarcadores sanguíneos en su predicción

Premi Extraordinari de Doctorat concedit pels programes de doctorat de la UAB per curs acadèmic 2017-2018El ictus es una de las principales causas de mortalidad y discapacidad en nuestro medio. El pronóstico del ictus depende en gran parte de factores basales no modificables como la edad o la gravedad inicial del mismo, pero también de circunstancias que ocurren durante la historia natural del mismo y conllevan un mal desenlace. En la presente tesis doctoral nos focalizamos en éstas últimas, las complicaciones del ictus. Así, nuestros objetivos en el presente trabajo son, en primer lugar, establecer cuáles de las complicaciones del ictus presentan un mayor impacto sobre el pronóstico del mismo en nuestro medio. En segundo lugar, evaluar en qué indicaciones el uso de biomarcadores sanguíneos constituye una necesidad asistencial. En tercer lugar, evaluar la asociación de los biomarcadores sanguíneos al pronóstico del ictus y las complicaciones del mismo en la literatura y, finalmente testar el valor predictivo de biomarcadores candidatos para las indicaciones identificadas en los puntos anteriores. Para esto hemos realizado un análisis del registro de ictus de la Sociedad Española de Neurología (RENISEN), en el que identificamos que el edema cerebral con hipertensión intracraneal y las infecciones respiratorias son las complicaciones con un mayor impacto sobre la mortalidad del ictus, encontrándose en un segundo escalón las complicaciones cardiológicas. Un interesante hallazgo de este análisis es que el impacto de esas complicaciones depende de la gravedad del ictus. Por otra parte, hemos realizado una encuesta a neurólogos vasculares europeos en los que vemos que la indicación más demandada para el uso de biomarcadores en el ictus es el manejo de las terapias de reperfusión. A través de revisiones sistemáticas y metaanálisis, hemos detectado que el uso de biomarcadores para el manejo de las complicaciones del ictus ha sido poco estudiado. De entre los marcadores metaanalizados, la proteína C-reactiva constituye un candidato para el manejo de las infecciones asociadas al ictus. Respecto a los estudios experimentales, hemos identificado dos candidatos nuevos para guiar las terapias de reperfusión, la proteasa activadora del factor VII (FSAP) y la proteasa de clivaje del factor de Von Willebrand (ADAMTS13), relacionadas con la recanalización arterial, y hemos descrito la utilidad de la medición de troponina I ultrasensible en la fase aguda del ictus, identificando a los pacientes con mayor riesgo de desarrollar complicaciones cardiológicas. Si nuestros resultados se confirmasen en estudios prospectivos, podríamos llegar a implementar el uso de biomarcadores sanguíneos en pacientes con ictus isquémico para el manejo de las complicaciones del mismo.Stroke represents one of the main causes of mortality and disability. Stroke outcome depends mainly on baseline, non-modifiable factors, such as age or stroke severity, but also on several conditions that may occur across the natural history of stroke and leads to a poor outcome. In the present doctoral thesis we focus on these conditions, namely post-stroke complications. Therefore, our objectives in the present project are: first, to assess which post-stroke complications have the highest impact on stroke prognosis; second, to evaluate in which indications the use of blood biomarkers is more demanded by physicians; third, to evaluate across the literature whether the association between blood biomarkers and stroke outcome and complications has been assessed; and fourth, to test the predictive value of some candidates for the previously identified indications. To assess these objectives, we performed a comprehensive analysis of the stroke registry of the Spanish Neurological Society (RENISEN), finding that brain edema with increased intracranial pressure and respiratory tract infections were the complications with the highest impact on in-hospital mortality, followed by cardiologic complications in a second step. An interesting finding of the analysis is that the impact of these complications depends on stroke severity. Moreover, we performed a survey across European stroke neurologists, finding that the indication in which the use of biomarkers is more requested is the management of reperfusion therapies. By applying systematic reviews and meta-analysis, we have found that the use of biomarkers for the management of post-stroke complications has been poorly studied. From the meta-analyzed biomarkers, C-reactive protein appears as a surrogate biomarker for the management of post-stroke infections. Regarding experimental studies, factor seven activating protease (FSAP) and ADAMTS13 (A Disintegrin And Metalloproteinase with a ThromboSpondin type 1 motif, member 13), both associated with arterial recanalization, have emerged as candidates to guide reperfusion therapies. Moreover, we have described a role for high-sensitive troponin-I determination in acute stroke, in identifying those patients at the highest risk of suffering cardiologic complications. If our results are confirmed in future prospective studies evaluating the prognostic implications of the use of these biomarkers, such biomarkers could be translated into clinical practice for the management of post-stroke complications

Predictive model for atrial fibrillation in hypertensive diabetic patients

Diabetes; Hpertension; Prediction modelsDiabetes; Hipertensión; Modelos de predicciónDiabetis; Hipertensió; Models de prediccióBackground Several scores to identify patients at high risk of suffering atrial fibrillation have been developed. Their applicability in hypertensive diabetic patients, however, remains uncertain. Our aim is to develop and validate a diagnostic predictive model to calculate the risk of developing atrial fibrillation at five years in a hypertensive diabetic population. Methods The derivation cohort consisted of patients with both hypertension and diabetes attended in any of the 52 primary healthcare centres of Barcelona; the validation cohort came from the 11 primary healthcare centres of Terres de l’Ebre (Catalonia South) from January 2013 to December 2017. Multivariable Cox regression identified clinical risk factors associated with the development of atrial fibrillation. The overall performance, discrimination and calibration of the model were carried out. Results The derivation data set comprised 54 575 patients. The atrial fibrillation rate incidence was 15.3 per 1000 person/year. A 5-year predictive model included age, male gender, overweight, heart failure, valvular heart disease, peripheral vascular disease, chronic kidney disease, number of antihypertensive drugs, systolic and diastolic blood pressure, heart rate, thromboembolism, stroke and previous history of myocardial infarction. The discrimination of the model was good (c-index = 0.692; 95% confidence interval, 0.684-0.700), and calibration was adequate. In the validation cohort, the discrimination was lower (c-index = 0.670). Conclusions The model accurately predicts future atrial fibrillation in a population with both diabetes and hypertension. Early detection allows the prevention of possible complications arising from this disease

Biomarkers predictive value for early diagnosis of stroke- associated pneumonia

Stroke-associated pneumonia; SAP; Diagnostic accuracy; BiomarkersNeumonía asociada al accidente cerebrovascular; NAA; Precisión diagnóstica; BiomarcadoresPneumònia associada a l'accident cerebrovascular; Precisió diagnòstica; BiomarcadorsTo confirm the diagnostic accuracy of candidate biomarkers in stroke‐associated pneumonia (SAP), we prospectively enrolled ischemic stroke patients with NIHSS ≥ 10 on admission from March‐2016 to August‐2017. Blood samples were collected at baseline, 24 and 48 h after stroke onset. Biomarkers (MR‐proADM, suPAR, SAA) were determined by immunoassays. Regarding biomarkers, MR‐proADM at 24 h (P = 0.04) and both suPAR and SAA at 48 h (P = 0.036 and P = 0.057) were associated with pneumonia. The combination of SAA > 25.15 mg/dL and suPAR> 3.14 ng/mL at 48 h had 80% sensitivity and 95.8% specificity when both biomarkers were above the cut‐off. The evaluated biomarkers represent promising tools to be evaluated in future large, prospective studies on SAP. An accurate SAP diagnosis by thorax CT might help to reduce variability in such studies.This project was partially funded by the ISCIII project PI14/00971. The ITRIBiS project (Improving Translational Research Potential at the Institute of Biomedicine of Seville) has the registration number REGPOT-2013-1. Cooperative Cerebrovascular Disease Research Network (INVICTUS+) (RD16/0019/ 0015). AB is supported by a Juan Rodes research contract (JR16/0008) from Instituto de Salud Carlos III

Blood Biomarkers to Predict Long-Term Mortality after Ischemic Stroke

Biomarcador; Endostatina; Accident cerebrovascular isquèmicBiomarcador; Endostatina; Accidente cerebrovascular isquémicoBiomarker; Endostatin; Ischemic strokeStroke is a major cause of disability and death globally, and prediction of mortality represents a crucial challenge. We aimed to identify blood biomarkers measured during acute ischemic stroke that could predict long-term mortality. Nine hundred and forty-one ischemic stroke patients were prospectively recruited in the Stroke-Chip study. Post-stroke mortality was evaluated during a median 4.8-year follow-up. A 14-biomarker panel was analyzed by immunoassays in blood samples obtained at hospital admission. Biomarkers were normalized and standardized using Z-scores. Multiple Cox regression models were used to identify clinical variables and biomarkers independently associated with long-term mortality and mortality due to stroke. In the multivariate analysis, the independent predictors of long-term mortality were age, female sex, hypertension, glycemia, and baseline National Institutes of Health Stroke Scale (NIHSS) score. Independent blood biomarkers predictive of long-term mortality were endostatin > quartile 2, tumor necrosis factor receptor-1 (TNF-R1) > quartile 2, and interleukin (IL)-6 > quartile 2. The risk of mortality when these three biomarkers were combined increased up to 69%. The addition of the biomarkers to clinical predictors improved the discrimination (integrative discriminative improvement (IDI) 0.022 (0.007–0.048), p quartile 3 was an independent predictor of mortality due to stroke. Altogether, endostatin, TNF-R1, and IL-6 circulating levels may aid in long-term mortality prediction after stroke.This work has been funded by Instituto de Salud Carlos III (PI18/00804) and by La Fundació La Marató (Reg. 84/240 proj. 201702). Neurovascular Research Laboratory takes part in the Spanish stroke research network INVICTUS+ (RD16/0019/0021). L.R. is supported by a pre-doctoral fellowship from the Instituto de Salud Carlos III (IFI17/00012)

Blood Biomarker Panels for the Early Prediction of Stroke‐Associated Complications

Biomarkers; Stroke; Stroke‐associated infectionBiomarcadors; Ictus; Infecció associada a un ictusBiomarcadores; Ictus; Infección asociada a un ictusBackground Acute decompensated heart failure (ADHF) and respiratory tract infections (RTIs) are potentially life‐threatening complications in patients experiencing stroke during hospitalization. We aimed to test whether blood biomarker panels might predict these complications early after admission. Methods and Results Nine hundred thirty‐eight patients experiencing ischemic stroke were prospectively recruited in the Stroke‐Chip study. Post‐stroke complications during hospitalization were retrospectively evaluated. Blood samples were drawn within 6 hours after stroke onset, and 14 biomarkers were analyzed by immunoassays. Biomarker values were normalized using log‐transformation and Z score. PanelomiX algorithm was used to select panels with the best accuracy for predicting ADHF and RTI. Logistic regression models were constructed with the clinical variables and the biomarker panels. The additional predictive value of the panels compared with the clinical model alone was evaluated by receiver operating characteristic curves. An internal validation through a 10‐fold cross‐validation with 3 repeats was performed. ADHF and RTI occurred in 19 (2%) and 86 (9.1%) cases, respectively. Three‐biomarker panels were developed as predictors: vascular adhesion protein‐1 >5.67, NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide) >4.98 and d‐dimer >5.38 (sensitivity, 89.5%; specificity, 71.7%) for ADHF; and interleukin‐6 >3.97, von Willebrand factor >3.67, and d‐dimer >4.58 (sensitivity, 82.6%; specificity, 59.8%) for RTI. Both panels independently predicted stroke complications (panel for ADHF: odds ratio [OR] [95% CI], 10.1 [3–52.2]; panel for RTI: OR, 3.73 [1.95–7.14]) after adjustment by clinical confounders. The addition of the panel to clinical predictors significantly improved areas under the curve of the receiver operating characteristic curves in both cases. Conclusions Blood biomarkers could be useful for the early prediction of ADHF and RTI. Future studies should assess the usefulness of these panels in front of patients experiencing stroke with respiratory symptoms such as dyspnea.This project received funding from Instituto de Salud Carlos III (ISCIII) [DTS14/00004, PI17/02130], co‐financed by the European Regional Development Fund (FEDER), and from Fundació La Marató de TV3 [201706] and the European Union's Horizon 2020 research and innovation program [754517]. Neurovascular Research Laboratory takes part into the Spanish stroke research network INVICTUS+ (RD16/0019/0021). The funders had no role in the study design and conduction

Blood-biomarkers and devices for atrial fibrillation screening: Lessons learned from the AFRICAT (Atrial Fibrillation Research In CATalonia) study

Biomarkers; Electrocardiography; Blood plasmaBiomarcadores; Electrocardiografía; Plasma sanguíneoBiomarcadors; Electrocardiografia; Plasma sanguiniBackground and objective AFRICAT is a prospective cohort study intending to develop an atrial fibrillation (AF) screening program through the combination of blood markers, rhythm detection devices, and long-term monitoring in our community. In particular, we aimed to validate the use of NT-proBNP, and identify new blood biomarkers associated with AF. Also, we aimed to compare AF detection using various wearables and long-term Holter monitoring. Methods 359 subjects aged 65–75 years with hypertension and diabetes were included in two phases: Phase I (n = 100) and Phase II (n = 259). AF diagnosis was performed by baseline 12-lead ECG, 4 weeks of Holter monitoring (NuuboTM), and/or medical history. An aptamer array including 1310 proteins was measured in the blood of 26 patients. Candidates were selected according to p-value, logFC and biological function to be tested in verification and validation phases. Several screening devices were tested and compared: AliveCor, Watch BP, MyDiagnostick and Fibricheck. Results AF was present in 34 subjects (9.47%). The aptamer array revealed 41 proteins with differential expression in AF individuals. TIMP-2 and ST-2 were the most promising candidates in the verification analysis, but none of them was further validated. NT-proBNP (log-transformed) (OR = 1.934; p<0.001) was the only independent biomarker to detect AF in the whole cohort. Compared to an ECG, WatchBP had the highest sensitivity (84.6%) and AUC (0.895 [0.780–1]), while MyDiagnostick showed the highest specificity (97.10%). Conclusion The inclusion and monitoring of a cohort of primary care patients for AF detection, together with the testing of biomarkers and screening devices provided useful lessons about AF screening in our community. An AF screening strategy using rhythm detection devices and short monitoring periods among high-risk patients with high NT-proBNP levels could be feasible.This work was supported by Fundació Marató de TV3 in the research call “La Marató 2014: malalties del cor” [grant number: 201528-30-31-3]. EP received a predoctoral grant from Vall d’Hebron Institute of Research. Neurovascular Research Laboratory also takes part in the Span-ish stroke research network INVICTUS+ [RD16/0019]. This project is supported by AFFECT-EU, receiving funding from the European Union’s Horizon 2020 research and innovation pro-gramme under grant agreement N°847770. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Colaboración universidad/empresa para la promoción de las titulaciones de grado en química y grado en ingeniería química

Memoria ID-0018. Ayudas de la Universidad de Salamanca para la innovación docente, curso 2013-2014

Condicionantes pronósticos del ictus isquémico: utilidad de los biomarcadores sanguíneos en su predicción

El ictus es una de las principales causas de mortalidad y discapacidad en nuestro medio. El pronóstico del ictus depende en gran parte de factores basales no modificables como la edad o la gravedad inicial del mismo, pero también de circunstancias que ocurren durante la historia natural del mismo y conllevan un mal desenlace. En la presente tesis doctoral nos focalizamos en éstas últimas, las complicaciones del ictus. Así, nuestros objetivos en el presente trabajo son, en primer lugar, establecer cuáles de las complicaciones del ictus presentan un mayor impacto sobre el pronóstico del mismo en nuestro medio. En segundo lugar, evaluar en qué indicaciones el uso de biomarcadores sanguíneos constituye una necesidad asistencial. En tercer lugar, evaluar la asociación de los biomarcadores sanguíneos al pronóstico del ictus y las complicaciones del mismo en la literatura y, finalmente testar el valor predictivo de biomarcadores candidatos para las indicaciones identificadas en los puntos anteriores. Para esto hemos realizado un análisis del registro de ictus de la Sociedad Española de Neurología (RENISEN), en el que identificamos que el edema cerebral con hipertensión intracraneal y las infecciones respiratorias son las complicaciones con un mayor impacto sobre la mortalidad del ictus, encontrándose en un segundo escalón las complicaciones cardiológicas. Un interesante hallazgo de este análisis es que el impacto de esas complicaciones depende de la gravedad del ictus. Por otra parte, hemos realizado una encuesta a neurólogos vasculares europeos en los que vemos que la indicación más demandada para el uso de biomarcadores en el ictus es el manejo de las terapias de reperfusión. A través de revisiones sistemáticas y metaanálisis, hemos detectado que el uso de biomarcadores para el manejo de las complicaciones del ictus ha sido poco estudiado. De entre los marcadores metaanalizados, la proteína C-reactiva constituye un candidato para el manejo de las infecciones asociadas al ictus. Respecto a los estudios experimentales, hemos identificado dos candidatos nuevos para guiar las terapias de reperfusión, la proteasa activadora del factor VII (FSAP) y la proteasa de clivaje del factor de Von Willebrand (ADAMTS13), relacionadas con la recanalización arterial, y hemos descrito la utilidad de la medición de troponina I ultrasensible en la fase aguda del ictus, identificando a los pacientes con mayor riesgo de desarrollar complicaciones cardiológicas. Si nuestros resultados se confirmasen en estudios prospectivos, podríamos llegar a implementar el uso de biomarcadores sanguíneos en pacientes con ictus isquémico para el manejo de las complicaciones del mismo.Stroke represents one of the main causes of mortality and disability. Stroke outcome depends mainly on baseline, non-modifiable factors, such as age or stroke severity, but also on several conditions that may occur across the natural history of stroke and leads to a poor outcome. In the present doctoral thesis we focus on these conditions, namely post-stroke complications. Therefore, our objectives in the present project are: first, to assess which post-stroke complications have the highest impact on stroke prognosis; second, to evaluate in which indications the use of blood biomarkers is more demanded by physicians; third, to evaluate across the literature whether the association between blood biomarkers and stroke outcome and complications has been assessed; and fourth, to test the predictive value of some candidates for the previously identified indications. To assess these objectives, we performed a comprehensive analysis of the stroke registry of the Spanish Neurological Society (RENISEN), finding that brain edema with increased intracranial pressure and respiratory tract infections were the complications with the highest impact on in-hospital mortality, followed by cardiologic complications in a second step. An interesting finding of the analysis is that the impact of these complications depends on stroke severity. Moreover, we performed a survey across European stroke neurologists, finding that the indication in which the use of biomarkers is more requested is the management of reperfusion therapies. By applying systematic reviews and meta-analysis, we have found that the use of biomarkers for the management of post-stroke complications has been poorly studied. From the meta-analyzed biomarkers, C-reactive protein appears as a surrogate biomarker for the management of post-stroke infections. Regarding experimental studies, factor seven activating protease (FSAP) and ADAMTS13 (A Disintegrin And Metalloproteinase with a ThromboSpondin type 1 motif, member 13), both associated with arterial recanalization, have emerged as candidates to guide reperfusion therapies. Moreover, we have described a role for high-sensitive troponin-I determination in acute stroke, in identifying those patients at the highest risk of suffering cardiologic complications. If our results are confirmed in future prospective studies evaluating the prognostic implications of the use of these biomarkers, such biomarkers could be translated into clinical practice for the management of post-stroke complications