Early diagnosis and complications of Acute Ischemic Stroke

Abstract Stroke is the first cause of death and disability in Portugal, and the second cause of death and third cause of disability worldwide. In patients with stroke, treatment interventions are time-dependent, meaning that shorter time from stroke onset to treatment is associated with better outcomes. Blood-based biomarkers represent a potential alternative to neuroimaging for early and rapid stroke diagnosis. Accurate and timely differentiation between patients with acute ischemic stroke (AIS), intracerebral hemorrhage (ICH) and stroke mimics (SM) could improve prehospital pathways and potentially allow earlier treatment administration. We conducted an exploratory prospective observational study on untargeted blood biomarkers in consecutive patients with suspected stroke, collecting blood samples at hospital admission. Quantitative analysis from mass spectrometry data was performed and biomarker-based prediction models were developed to differentiate AIS from ICH and from ICH and SM. Biomarker-based prediction models including intercellular adhesion molecule-2, plasminogen like-A, complement component 3, syntaxin binding protein-5 and immunoglobulin heavy variable 3-64 showed between 75 to 88% sensitivity at 100% specificity for identifying patients with AIS. In addition to the timing of diagnosis and treatment, early stroke recurrences influence long-term prognosis. Stroke patients ideally are hospitalized in stroke units in order to prevent stroke recurrence and other in-hospital complications. However, the impact of being in a stroke unit at the time of an early recurrent stroke has not previously been studied. In a retrospective analysis, we showed that in patients with an in-stroke unit stroke, the exact time of stroke onset was more frequently known than in other stroke patients, that treatment opportunities were less often missed than in other patients with in-hospital stroke, and that the endovascular treatment rate was higher than in patients with community-onset stroke. Finally, patients with in-stroke unit stroke had better functional outcomes than those with other in-hospital strokes or community-onset strokes. Another complication in patients with AIS is early worsening of arterial patency, either due to stroke recurrence or progressive clot formation. However, no study so far has described the frequency, associated factors and outcome of patients with worsening of arterial patency. We conducted a retrospective study showing that 3% of patients with AIS experienced worsening of arterial patency within the first 24 hours (with or without preceding revascularisation treatment). History of hypertension, initial stroke severity, intracranial and extracranial stenosis, and good collaterals were identified as independent predictors, and worsening of arterial patency was associated with a six-fold higher likelihood of poorer functional outcome. In patients undergoing endovascular treatment (EVT), reocclusion after initial successful recanalization is another possible complication. This phenomenon has only seldom been studied. In our retrospective study, we showed that 6.6% of patients experienced reocclusion after successful EVT. Preadmission statin therapy, intracranial internal carotid artery occlusion, number of passes during EVT, transient reocclusion during EVT, and atherosclerotic stroke etiology were identified as independent predictors, and its occurrence was associated with a five times higher rate of unfavorable functional outcome. Using a combination of translational and clinical research, this PhD thesis attempts to add new data to reduce the global burden of stroke. We explored a new blood-based biomarker strategy for stroke diagnosis, investigated the protective role of stroke units on early stroke recurrence, and studied predictors and outcome of patients with worsening of arterial patency and reocclusion after EVT. The final discussion of this thesis integrates the potential applications of the results and proposes future research questions.Resumo O acidente vascular cerebral (AVC) é primeira causa de morte e incapacidade em Portugal, e segunda causa de morte e a terceira causa de incapacidade em todo o mundo. Em doentes com AVC, as intervenções terapêuticas estão dependentes do tempo, ou seja, menor tempo entre início de sintomas e tratamento associa-se a melhor prognóstico funcional. Os biomarcadores séricos representam uma alternativa à neuroimagem para o rápido diagnóstico de doentes com AVC. Uma precoce e precisa diferenciação de doentes com AVC isquémico, AVC hemorrágico e mimetizadores de AVC poderá contribuir para a melhoria das redes de referenciação pré-hospitalar e potencialmente permitir a instituição precoce de terapêutica dirigida. Conduzimos um estudo exploratório, observacional e prospetivo, de biomarcadores séricos em doentes consecutivos com suspeita de AVC, com colheita de amostras à admissão hospitalar. Foi realizada uma análise quantitativa por espectrometria de massa e foram desenvolvidos modelos de predição baseados em biomarcadores séricos para diferenciar AVC isquémico de AVC hemorrágico, e AVC isquémico de AVC hemorrágico e mimetizadores de AVC. Um modelo de predicação baseado em biomarcadores séricos incluindo a molécula de adesão intercelular tipo 2, plasminogénio tipo-A, componente 3 do complemento, proteína de ligação à sintaxina-5 e variável 3-64 da cadeia pesada de imunoglobulina, demonstrou uma sensibilidade entre 75 a 88% na identificação de doentes com AVC isquémico, com uma especificidade de 100%.Para além do diagnóstico e tratamento precoce, o AVC recorrente intra-hospitalar também tem um importante impacto no prognóstico a longo prazo. Idealmente, os doentes com AVC devem ser internados em unidades de AVC pelo seu impacto na prevenção de recorrência e de outras complicações hospitalares. Contudo, o impacto de estar internado numa unidade AVC aquando de AVC recorrente intra-hospitalar nunca foi investigado. Conduzimos um estudo retrospetivo que demonstrou que doentes com AVC durante internamento em unidade AVC, mais frequentemente apresentaram uma hora de início de sintomas conhecida em comparação com outros doentes com AVC. Apresentaram também menos oportunidades perdidas de tratamento de fase aguda em comparação com outros doentes com AVC intra-hospitalar, e maior frequência de tratamento endovascular em comparação com doentes com AVC na comunidade. Os doentes com AVC durante internamento em unidade AVC apresentaram melhor prognóstico funcional do que outros doentes com AVC intra-hospitalar ou AVC na comunidade. Outra complicação em doentes com AVC isquémico é a deterioração de patência arterial. Esta pode resultar de evento recorrente ou progressão da trombose arterial. No entanto, nenhum estudo descreveu a frequência, fatores associados e prognóstico de doentes com deterioração da patência arterial. Realizámos uma análise retrospetiva na qual se identificou que 3% de doentes com AVC isquémico apresentaram deterioração da patência arterial às 24 horas (com ou sem tratamento de recanalização prévio). Hipertensão arterial prévia, gravidade de AVC à admissão, estenose intra-/extracraniana e bons colaterais foram identificados como preditores, e a presença de deterioração de patência arterial associou-se a uma probabilidade seis vezes superior de pior prognóstico funcional.No subgrupo de doentes com AVC isquémico submetidos a tratamento endovascular (TEV), a reoclusão após recanalização é outra possível complicação. Este fenómeno foi pouco estudado. Realizámos outra análise retrospetiva em que identificamos que 6.6% dos doentes com recanalização após TEV apresentam reoclusão. Tratamento prévio com estatinas, oclusão da artéria carótida intracraniana, número de passagens durante TEV, reoclusão transitória durante TEV, e etiologia aterosclerótica foram identificados como preditores, e a sua ocorrência associada a uma probabilidade cinco vezes superior de mau prognóstico funcional. Ao combinar investigação translacional e clínica, a presente tese de doutoramento procura adicionar informação que seja relevante na redução do impacto global do AVC. Explorámos uma nova estratégia de biomarcadores séricos para o diagnóstico de AVC, investigámos o papel protetor das unidades AVC no AVC recorrente, e estudámos os preditores e prognóstico de doentes com deterioração da patência arterial e reoclusão após TEV. A discussão final desta tese integra as potenciais aplicações dos seus resultados, e propõe novas perguntas de investigação

Ambiguidades nas telas: “American Horror Story - Coven” e as relações entre imagem, mídia e questões sociais

Trabalho de Conclusão de Curso (Graduação)Este trabalho tem como objetivo a análise da terceira temporada da série estadunidense American Horror Story, exibida entre 2013 e 2014 e denominada Coven, buscando compreender e analisar ambiguidades presentes na produção em relação à abordagem dos temas raça e gênero. São analisadas imagens da temporada e de outras produções que abordam os mesmos temas. Busca-se compreender, dessa forma, o posicionamento político da produção quanto a essas questões sociais bem como a pluralidade de sentidos que as mesmas imagens podem apresentar no contato com diferentes espectadores. Também são examinados textos virtuais, no intuito de compreender como essas abordagens ambíguas foram percebidas pelos espectadores da série. Por fim, desenvolve-se brevemente uma hipótese sobre o possível impacto da recepção na construção de futuras temporadas do seriado

Are we missing an opportunity? Prehospital delay in patients with acute ischemic stroke and known atrial fibrillation

Publisher Copyright: © 2024 Sociedade Portuguesa de CardiologiaIntroduction and Objectives: The follow-up of patients with atrial fibrillation (AF) presents an opportunity to alert patients and their families on how to recognize and act in the event of stroke. Our aim was to compare stroke recognition-to-door time and prehospital stroke code activation in patients with known AF (KAF) and AF detected after stroke (AFDAS). Methods: We performed a retrospective cohort study of consecutive patients receiving acute recanalization treatment for acute ischemic stroke between January 2016 and August 2022, with AF as a potential stroke cause. Patients were divided into KAF and AFDAS, and stroke recognition-to-door time and prehospital stroke code activation were compared. In the KAF subgroup, we assessed whether the use of preadmission anticoagulation was associated with the studied prehospital parameters. Results: We included 438 patients, 290 female (66.2%), mean age 79.3±9.4 years. In total, 238 patients had KAF (54.3%) and 200 (45.7%) had AFDAS. Of those with KAF, 114 (48.1%) were pretreated with anticoagulation. Patients with KAF and AFDAS had no differences in stroke recognition-to-door time (74.0 [55.0–101.0] vs. 78.0 [60.0–112.0] min; p=0.097) or prehospital stroke code activation [148 (64.6%) vs. 128 (65.3%); p=0.965]. In the KAF subgroup, preadmission anticoagulation did not influence stroke recognition-to-door time or mode of hospital admission. Conclusion: Stroke recognition-to-door time and prehospital stroke code activation were similar between patients with known or newly diagnosed AF. Preadmission anticoagulation treatment also did not affect the studied parameters. Our findings highlight a missed opportunity to promote stroke knowledge in patients followed due to AF.publishersversionepub_ahead_of_prin

Pickering Emulsions Stabilized by Calcium Carbonate Particles: A New Topical Formulation

© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).Pickering emulsions are systems composed of two immiscible fluids stabilized by solid organic or inorganic particles. Pickering emulsions are particularly useful in cosmetics, where the surfactants are unwanted, as well as in the pharmaceutical field, where transdermal and/or dermal drug delivery is difficult to achieve and controlled drug release is desired. Here, we studied calcium carbonate particles as stabilizers of Pickering emulsions for topical use. An optimized formulation was obtained using a Quality by Design approach. First, a screening experiment was performed to identify the formulation and process critical variables that affect the quality properties of the Pickering emulsion. The optimization of the production was then studied by establishing the design space. The final formulation was hereinafter investigated regarding the pH, rheological properties, and in vitro cytotoxicity assays. The results showed the formulation had a pH compatible with human skin and a shear thinning behavior. Moreover, this formulation showed a strong network structure, with a suitable spreadability on the skin, allowing an easy application. The in vitro assays were performed to assess the potential cytotoxicity of the calcium carbonate-stabilized emulsion and the particles themselves, and the results revealed that the formulation did not significantly affect the cell viability. In conclusion, the use of calcium carbonate particles as a stabilizer ingredient contributed to achieve an eco-friendly Pickering emulsion.This research was funded by Fundação para a Ciência e a Tecnologia, Portugal (UID/DTP/04138/2019, PTDC/MEC-DER/30198/2017, and CEECINST/00145/2018) and by Carbomin.info:eu-repo/semantics/publishedVersio

Proteomics to Identify New Blood Biomarkers for Diagnosing Patients With Acute Stroke

Funding Information: UCIBIO-UID/Multi/04378/2019 also supported by FCT (CEEC Funding Information: This work was financed by Fundação para a Ciência e a Tecnologia (FCT) with PTDC/MEC-NEU/28750/2017 grant, LA/P/0140/2020 funding,iNOVA4Health—UIDB/04462/2020, and UCIBIO-UID/Multi/04378/2019 units. A.S.C. is supported by FCT. R.M. is also supported by FCT (CEEC position, 2019–2025 investigator). Funding Information: This work was financed by Fundação para a Ciência e a Tecnologia (FCT) with PTDC/MEC-NEU/28750/2017 grant, LA/P/0140/2020 funding, Publisher Copyright: © 2023 The Authors.BACKGROUND: Blood biomarkers are a potential tool for early stroke diagnosis. We aimed to perform a pilot and exploratory study on untargeted blood biomarkers in patients with suspected stroke by using mass spectrometry analysis. METHODS AND RESULTS: This was a prospective observational study of consecutive patients with suspected stroke admitted within 6 hours of last being seen well. Blood samples were collected at admission. Patients were divided into 3 groups: ischemic stroke (IS), intracerebral hemorrhage (ICH), and stroke mimics. Quantitative analysis from mass spectrometry data was performed using a supervised approach. Biomarker-based prediction models were developed to differentiate IS from ICH and ICH+stroke mimics. Models were built aiming to minimize misidentification of patients with ICH as having IS. We included 90 patients, one-third within each subgroup. The median age was 71 years (interquartile range, 57–81 years), and 49 participants (54.4%) were women. In quantitative analysis, C3 (complement component 3), ICAM-2 (intercellular adhesion molecule 2), PLGLA (plasminogen like A), STXBP5 (syntaxin-binding protein 5), and IGHV3-64 (immunoglobulin heavy variable 3-64) were the 5 most significantly dysregulated proteins for both comparisons. Biomarker-based models showed 88% sensitivity and 89% negative predictive value for differentiating IS from ICH, and 75% sensitivity and 95% negative predictive value for differentiating IS from ICH+stroke mimics. ICAM-2, STXBP5, PLGLA, C3, and IGHV3-64 displayed the highest importance score in our models, being the most informative for identifying patients with stroke. CONCLUSIONS: In this proof-of-concept and exploratory study, our biomarker-based prediction models, including ICAM-2, STXBP5, PLGLA, C3, and IGHV3-64, showed 75% to 88% sensitivity for identifying patients with IS, while aiming to minimize misclassification of ICH. Although our methodology provided an internal validation, these results still need validation in other cohorts and with different measurement techniques.publishersversionpublishe

Potential impact on stroke

Funding Information: The funding agency that supported the work \u201CFunda\u00E7\u00E3o para a Ci\u00EAncia e Tecnologia\u201D (FCT) with four projects: Applied Molecular Biosciences Unit-UCIBIO (UID/Multi/04378/2019), iNOVA4Health - Programme in Translational Medicine (UID/Multi/04462/2013), LA/P/0140/2020 of the Associate Laboratory Institute for Health and Bioeconomy and PTDC/MEC-NEU/28750/2017 and the PhD scholarship for NLS (PD/BD/127819/2016). Publisher Copyright: © 2024 The AuthorsRemote ischemic conditioning (RIC) is a procedure consisting of short cycles of ischemia applied in a limb that activates endogenous protection in distant organs, such as the brain. Despite the promising outcomes of RIC, the biochemical factors governing inter-organ communication remain largely unexplored, particularly in humans. A pilot study on 20 healthy humans was performed to identify potential circulating biochemical factors involved in RIC signalling. Blood was collected before and immediately, 4 and 22 h after the end of RIC. To characterize the responses triggered by RIC, a combination of biochemical and proteomic analysis, along with functional in vitro tests in human cells, were performed. RIC did not alter the levels of nitric oxide, bilirubin and cell-free mitochondrial DNA. In contrast, carboxyhaemoglobin levels increased following RIC at all time points and young subset, suggesting endogenous production of carbon monoxide that is a cytoprotective gasotransmitter. Additionally, the levels of glutathione and cysteinylglycine bound to proteins also increased after RIC, while glutathione catabolism decreased. Plasma proteomic analysis identified overall 828 proteins. Several steps of statistical analysis (Student's t-test, repeated measures ANOVA, with Holm corrected pairwise p-values <0.05 threshold and fold change higher or lower than 100 %) leaded to the identification of 9 proteins with altered circulating levels in response to RIC at 4h and 22h. All 9 proteins are from extracellular space or exosomes, being involved in inflammation, angiogenesis or metabolism control. In addition, RIC-conditioned plasma from young subjects protected microglial cell culture against inflammatory stimuli, indicating an anti-inflammatory effect of RIC. Nevertheless, other functional tests in neurons or endothelial cells had no effect. Overall, we present some evidence for RIC-induced anti-inflammatory and antioxidant responses in healthy human subjects, in particular in young subjects. This study is a first step towards the disclosure of signalling factors involved in RIC-mediated inter-organ communication.publishersversionpublishe

Corrigendum: Tandem occlusions involving the internal carotid and anterior cerebral arteries-A rare form of stroke: results from the multicenter EVATRISP collaboration study.

[This corrects the article DOI: 10.3389/fneur.2022.1024891.]

Nationwide access to endovascular treatment for acute ischemic stroke in portugal

Publisher Copyright: Copyright Ordem dos M dicos 2021.Introduction: Since the publication of endovascular treatment trials and European Stroke Guidelines, Portugal has re-organized stroke healthcare. The nine centers performing endovascular treatment are not equally distributed within the country, which may lead to differential access to endovascular treatment. Our main aim was to perform a descriptive analysis of the main treatment metrics regarding endovascular treatment in mainland Portugal and its administrative districts. Material and Methods: A retrospective national multicentric cohort study was conducted, including all ischemic stroke patients treated with endovascular treatment in mainland Portugal over two years (July 2015 to June 2017). All endovascular treatment centers contributed to an anonymized database. Demographic, stroke-related and procedure-related variables were collected. Crude endovascular treatment rates were calculated per 100 000 inhabitants for mainland Portugal, and each district and endovascular treatment standardized ratios (indirect age-sex standardization) were also calculated. Patient time metrics were computed as the median time between stroke onset, first-door, and puncture. Results: A total of 1625 endovascular treatment procedures were registered. The endovascular treatment rate was 8.27/100 000 inhabitants/year. We found regional heterogeneity in endovascular treatment rates (1.58 to 16.53/100 000/year), with higher rates in districts closer to endovascular treatment centers. When analyzed by district, the median time from stroke onset to puncture ranged from 212 to 432 minutes, reflecting regional heterogeneity. Discussion: Overall endovascular treatment rates and procedural times in Portugal are comparable to other international registries. We found geographic heterogeneity, with lower endovascular treatment rates and longer onset-to-puncture time in southern and inner regions. Conclusion: The overall national rate of EVT in the first two years after the organization of EVT-capable centers is one of the highest among European countries, however, significant regional disparities were documented. Moreover, stroke-onset-to-first-door times and in-hospital procedural times in the EVT centers were comparable to those reported in the randomized controlled trials performed in high-volume tertiary hospitalspublishersversionpublishe

Acesso a Tratamento Endovascular para Acidente Vascular Cerebral Isquémico em Portugal

Introduction: Since the publication of endovascular treatment trials and European Stroke Guidelines, Portugal has re-organized stroke healthcare. The nine centers performing endovascular treatment are not equally distributed within the country, which may lead to differential access to endovascular treatment. Our main aim was to perform a descriptive analysis of the main treatment metrics regarding endovascular treatment in mainland Portugal and its administrative districts. Material and Methods: A retrospective national multicentric cohort study was conducted, including all ischemic stroke patients treated with endovascular treatment in mainland Portugal over two years (July 2015 to June 2017). All endovascular treatment centers contributed to an anonymized database. Demographic, stroke-related and procedure-related variables were collected. Crude endovascular treatment rates were calculated per 100 000 inhabitants for mainland Portugal, and each district and endovascular treatment standardized ratios (indirect age-sex standardization) were also calculated. Patient time metrics were computed as the median time between stroke onset, first-door, and puncture. Results: A total of 1625 endovascular treatment procedures were registered. The endovascular treatment rate was 8.27/100 000 inhabitants/year. We found regional heterogeneity in endovascular treatment rates (1.58 to 16.53/100 000/year), with higher rates in districts closer to endovascular treatment centers. When analyzed by district, the median time from stroke onset to puncture ranged from 212 to 432 minutes, reflecting regional heterogeneity. Conclusion: The overall national rate of EVT in the first two years after the organization of EVT-capable centers is one of the highest among European countries, however, significant regional disparities were documented. Moreover, stroke-onset-to-first-door times and in-hospital procedural times in the EVT centers were comparable to those reported in the randomized controlled trials performed in high-volume tertiary hospitals.Introdução: A aprovação do tratamento endovascular para o acidente vascular cerebral isquémico obrigou à reorganização dos cuidados de saúde em Portugal. Os nove centros que realizam tratamento endovascular não estão distribuídos equitativamente pelo território, o que poderá causar acesso diferencial a tratamento. O principal objetivo deste estudo é realizar uma análise descritiva da frequência e métricas temporais do tratamento endovascular em Portugal continental e seus distritos. Material e Métodos: Estudo de coorte nacional multicêntrico, incluindo todos os doentes com acidente vascular cerebral isquémico submetidos a tratamento endovascular em Portugal continental durante um período de dois anos (julho 2015 a junho 2017). Foram colhidos dados demográficos, relacionados com o acidente vascular cerebral e variáveis do procedimento. Taxas de tratamento endovascular brutas e ajustadas (ajuste indireto a idade e sexo) foram calculadas por 100 000 habitantes/ano para Portugal continental e cada distrito. Métricas de procedimento como tempo entre instalação, primeira porta e punção foram também analisadas. Resultados: Foram registados 1625 tratamentos endovasculares, indicando uma taxa bruta nacional de tratamento endovascular de 8,27/100 000 habitantes/ano. As taxas de tratamento endovascular entre distritos variaram entre 1,58 e 16,53/100 000/ano, com taxas mais elevadas nos distritos próximos a hospitais com tratamento endovascular. O tempo entre sintomas e punção femural entre distritos variou entre 212 e 432 minutos. Conclusão: Portugal continental apresenta uma taxa nacional de tratamento endovascular elevada, apresentando, contudo, assimetrias regionais no acesso. As métricas temporais foram comparáveis com as observadas nos ensaios clínicos piloto

Endovascular Therapy in the Extended Time Window for Large Vessel Occlusion in Patients With Pre-Stroke Disability.

BACKGROUND AND PURPOSE We compared the outcomes of endovascular therapy (EVT) in an extended time window in patients with large-vessel occlusion (LVO) between patients with and without pre-stroke disability. METHODS In this prespecified analysis of the multinational CT for Late Endovascular Reperfusion study (66 participating sites, 10 countries between 2014 and 2022), we analyzed data from patients with acute ischemic stroke with a pre-stroke modified Rankin Scale (mRS) score of 0-4 and LVO who underwent EVT 6-24 hours from the time last seen well. The primary outcome was the composite of functional independence (FI; mRS score 0-2) or return to the pre-stroke mRS score (return of Rankin, RoR) at 90 days. Outcomes were compared between patients with pre-stroke disability (pre-stroke mRS score 2-4) and those without (mRS score 0-1). RESULTS A total of 2,231 patients (median age, 72 years; median National Institutes of Health Stroke Scale score, 16) were included in the present analysis. Of these, 564 (25%) had pre-stroke disability. The primary outcome (FI or RoR) was observed in 30.7% of patients with pre-stroke disability (FI, 16.5%; RoR, 30.7%) compared to 44.1% of patients without (FI, 44.1%; RoR, 13.0%) (P<0.001). In multivariable logistic regression analysis with inverse probability of treatment weighting, pre-stroke disability was not associated with significantly lower odds of achieving FI or RoR (adjusted odds ratio 0.73, 95% confidence interval 0.43-1.25). Symptomatic intracranial hemorrhage occurred in 6.3% of both groups (P=0.995). CONCLUSION A considerable proportion of patients with late-presenting LVO and pre-stroke disability regained pre-stroke mRS scores after EVT. EVT may be appropriate for patients with pre-stroke disability presenting in the extended time window