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This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. © 2024 The Author(s). European Journal of Sport Science published by Wiley‐VCH GmbH on behalf of European College of Sport Science., Professional tennis competition at the highest levels requires high physical, technical, tactical, and mental demands. Player retirement is a scenario that often occurs at the highest echelons of the game. The objective of this study was to descriptively determine which factors influence retirement of matches in tennis. Matches from the Women's Tennis Association (WTA) and Association of Tennis Professionals (ATP) tours played over 44 and 46 years were included in the study, respectively. The results showed an increasing trend in the incidence of retirements in both ATP and WTA events, especially in recent years. Factors associated with the match characteristics, such as the type of surface, the type of tournament, and the round of the draw, were shown to influence retirement. Variables associated with player characteristics, such as the age difference between players, did not show to influence retirement, whereas the ranking difference did. When comparing ATP and WTA matches, similar results were observed in which surfaces and tournaments had the highest or lowest incidence of retirements. On the other hand, as per the rounds, the results are not conclusive. The findings highlight the growing trend of match retirements in professional tennis and emphasize the relevant influence of match characteristics such as surface type, tournament type, and round of the draw. These insights can guide coaches, players, and tournament organizers in developing strategies to mitigate retirements and inform future research on enhancing player longevity and performance in tennis., This research was funded by the Ministerio de Ciencia e Innovación (Spain) (PID2019- 352104830RB-I00) and the Departament de Recerca i Universitats de la Generalitat de Catalunya (Spain) [2021 SGR 01421 (GRBIO)]., Peer Reviewed, Postprint (published version)

En els darrers anys el camp de l'aprenentatge automàtic ha guanyat molta rellevància i se n'han desenvolupat molts mètodes i aplicacions. En aquest treball presentem alguns mètodes d'aprenentatge automàtic supervisat i les seves adaptacions i adequacions per tractar problemes d'anàlisi de supervivència. En aquest projecte hem analitzat la capacitat predictiva d'aquests models mitjançant diverses mesures de rendiment predictiu, aplicades a conjunts de dades simulades com a conjunts de dades reals. A més, hem comparat el rendiment d'aquests models respecte al model de riscos proporcionals de Cox. Hem considerat diferents escenaris de simulació, variant la mida mostral, el nombre de variables predictores i la proporció de censura, així com la influència de les variables sobre el temps fins a l'esdeveniment i la proporcionalitat de riscos. En general, els resultats obtinguts indiquen que el model de Cox funciona millor en els escenaris plantejats que els mètodes d'aprenentatge automàtic proposats. D'entre aquests darrers, el mètode que proporciona millors resultats és el d'aprenentatge multitasca, seguit per les xarxes neuronals., In recent years, the field of machine learning has become increasingly relevant, leading to the development of numerous methods and applications. In this work, we present several supervised machine learning methods, along with their adaptations to address survival analysis problems. We have analyzed the predictive capacity of these models using various performance metrics on both simulated and real datasets. Furthermore, we compared their performance against the Cox proportional hazards model. Our study involved different simulation scenarios, where we varied the sample size, the number of predictive variables, and the censorship ratio, as well as the influence of these variables on the time until the event and the proportionality of risks. Overall, the results indicate that the Cox model outperforms the proposed machine learning methods in the planned scenarios. Among the machine learning approaches, multitasking emerged as the most effective, followed closely by neural networks.

Data Availability Statement: https://github.com/mariapalau/tennis-retirements. © 2024 Palau et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited., The demands of professional tennis, including physical and psychological aspects, contribute to the frequency of retirements at elite levels of the sport. The aim of this study was to analyze epidemiological patterns and risk factors associated with retirements in previous ATP and WTA Tour tournaments. A retrospective cohort study was conducted. This study focused on previous ATP and WTA Tour tournaments. The ATP database encompassed 584,806 matches, while the WTA database included 267,380 matches. To assess retirements, potential risk factors such as playing surface, tournament category, match round, and player age were analyzed. Incidence rates were calculated for the period between 1978–2019 for men and 1994–2018 for women. The overall incidence rate was 1.56 (95%CI: 1.54, 1.59) and 1.36 (95%CI: 1.33, 1.39) retirements per 1000 games played in male and female competitions, respectively. Retirements increased over the years. Higher incidence rates were observed on hard (1.59 [95%CI: 1.56, 1.63] and 1.39 [95%CI: 1.34, 1.44]) and clay (1.60 [95%CI: 1.57, 1.63] and 1.36 [95%CI: 1.32, 1.41]) compared to grass courts (0.79 [95%CI: 0.65, 0.94] and 1.06 [95%CI: 0.88, 1.27]). Risk factors differed by gender, with tournament category significant in males (IRR: 1.23 [95%CI: 1.19, 1.28] in ITF vs ATP) and match round in females (IRR: 0.92 [95%CI: 0.88, 0.98] in preliminary vs final). This study provides valuable insights for coaches, players, support teams, and epidemiologists regarding retirements and associated risk factors in previous ATP and WTA Tour tournaments, contributing to injury prevention strategies., This research was funded by the Ministerio de Ciencia e Innovación (Spain) (PID2019- 104830RB-I00) and the Departament de Recerca i Universitats de la Generalitat de Catalunya (Spain) [2021 SGR 01421 (GRBIO)]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript., Peer Reviewed, Postprint (published version)

Final, 2023-2024, 2n quadrimestre

Background Therapeutic ceiling of care is the maximum level of care deemed appropiate to offer to a patient based on their clinical profile and therefore their potential to derive benefit, within the context of the availability of resources. To our knowledge, there are no models to predict ceiling of care decisions in COVID-19 patients or other acute illnesses. We aimed to develop and validate a clinical prediction model to predict ceiling of care decisions using information readily available at the point of hospital admission. Methods We studied a cohort of adult COVID-19 patients who were hospitalized in 5 centres of Catalonia between 2020 and 2021. All patients had microbiologically proven SARS-CoV-2 infection at the time of hospitalization. Their therapeutic ceiling of care was assessed at hospital admission. Comorbidities collected at hospital admission, age and sex were considered as potential factors for predicting ceiling of care. A logistic regression model was used to predict the ceiling of care. The final model was validated internally and externally using a cohort obtained from the Leeds Teaching Hospitals NHS Trust. The TRIPOD Checklist for Prediction Model Development and Validation from the EQUATOR Network has been followed to report the model. Results A total of 5813 patients were included in the development cohort, of whom 31.5% were assigned a ceiling of care at the point of hospital admission. A model including age, COVID-19 wave, chronic kidney disease, dementia, dyslipidaemia, heart failure, metastasis, peripheral vascular disease, chronic obstructive pulmonary disease, and stroke or transient ischaemic attack had excellent discrimination and calibration. Subgroup analysis by sex, age group, and relevant comorbidities showed excellent figures for calibration and discrimination. External validation on the Leeds Teaching Hospitals cohort also showed good performance. Conclusions Ceiling of care can be predicted with great accuracy from a patient’s, This study was partially funded by Secretaria d’Universitats i Recerca del Departament d’Empresa i Coneixement de la Generalitat de Catalunya (2020PANDE00148). The funding was used to collect data from the 4th wave in the MetroSud cohort. This work has also been supported by the Ministerio de Ciencia e Innovación (Spain) [PID2019-104830RB-I00/ DOI (AEI): https://doi.org/10.13039/501100011033, and by grant 2021 SGR 01421 (GRBIO) administrated by the Departament de Recerca i Universitats de la Generalitat de Catalunya (Spain)., Peer Reviewed, Postprint (published version)

Background: It has been suggested that a relevant proportion of patients do not respond to nonselective beta-blockers (NSBB)s, which raises questions regarding the need for individualized therapy. The existence of potential heterogeneity in the treatment response can be assessed using the variability ratio (VR) of the outcome measurement (in this case, HVPG) between the treated and placebo groups. We conducted a systematic review and meta-analysis of randomized controlled trials to assess the potential heterogeneity in the portal pressure response to NSBBs. Methods: After a systematic search, we quantified the heterogeneity of treatment response with the VR between the treatment and control groups, with VR > 1 indicating potential heterogeneity. We used a similar approach to compare carvedilol with propranolol and statins with placebo. Results: We identified 18 studies that included 965 patients. A comparison between beta-blockers and placebo showed a pooled VR of 0.99 (95% CI:0.87–1.14), which suggests a homogeneous HVPG response to NSBB at the individual patient level (ie, no evidence to support that some patients responded to beta-blockers and others did not). For the comparison between carvedilol and propranolol, pooled VR was 0.97 (95% CI 0.82–1.14), suggesting that carvedilol achieves a greater average response (rather than an increase in the proportion of responders). There was no evidence of a heterogeneous response to statins. Conclusion: Our analysis did not support the existence of a heterogeneous patient-by-patient response to NSBBs in cirrhosis. These findings challenge the concept of personalized therapy based on portal pressure response and indicate that routine portal pressure measurement may not be necessary to guide NSBB therapy., The authors JC and EC acknowledge the support of the Ministerio de Ciencia e Innovación (Spain) [PID2019- 104830RB-I00/ DOI (AEI): 10.13039/501100011033] and the Generalitat de Catalunya (Spain) (2021SGR01421)., Peer Reviewed, Postprint (published version)

L’arribada de les noves tecnologies ha tingut un gran impacte en el tenis, específicament en l’obtenció i anàlisi de les dades. Les noves eines d’enregistrament del moviment permeten la recopilació precisa de variables fisiològiques determinants les quals s’estudien per avaluar el rendiment i la càrrega física dels jugadors. Generalment es parla de la distància recorreguda (metres), percentatge del temps de joc efectiu, el nombre de partits disputats, el nombre de rally’s, entre d’altres. Amb les dades recopilades s’elaboren mètodes estadístics per identificar patrons sobre el rendiment dels jugadors i aquesta informació ajuda als entrenadors i jugadors a ajustar les estratègies de joc i a elaborar programes d’entrenament específics. L’objectiu d’aquest estudi és aprendre sobre les variables de càrrega física del tennis mitjançant dades reals de partits jugats als tornejos dels Grand Slams, per dues competicions ATP i WTA analitzades de forma independent, utilitzant el mètode de clustering K-means. Les dades s’han obtingut d’un domini públic, GitHub, i consisteixen en conjunts de dades on es registra informació punt per punt dels 4 tornejos de Grand Slam (Open Australia, Roland Garros, Open EEUU i Wimbledon), tant per la competició ATP com WTA, des del 2016 fins el 2021. El resultat de l’estudi actual ha estat classificar els partits i els jugadors segons les característiques que aquests presenten. S’han distingit 4 tipus de partits diferents tant per la competició masculina (ATP) com per la femenina (WTA) i tres tipus de tennistes diferents, per ambdós sexes, cada un amb particularitats específiques que els defineixen.

This bachelor's final project aims to address the challenge of identifying texts generated by artificial intelligence (AI) systems. The project implements several classification models, including Classification Trees, Random Forests, Logistic Models, and Support Vector Machines to identify AI-generated texts. These models are trained on a dataset which consists of 160 texts of human and AI-generated texts, with the goal of accurately distinguishing them. The project also includes the implementation of a Shiny application, providing a user-friendly interface for text identification. Among the models evaluated, the Logistic Model achieves the highest accuracy, with 86%.

Background Somatosensory evoked potentials (SEP) may add substantial prognostic value in patients with acute ischemic stroke (AIS) and contribute to the selection of patients that may benefit from revascularization therapies beyond the accepted therapeutic time windows. We aimed to study the prognostic accuracy of N20 SEP component of the ischemic hemisphere in patients with anterior large vessel occlusion undergoing endovascular thrombectomy (EVT). Methods: Presence and amplitude of the N20 response were recorded before and after EVT. Its adjusted predictive value for functional independence (modified Rankin scale score, =2) at day 7 was analysed by binary logistic regression adjusting by age, mean arterial blood pressure, NIHSS, ASPECTS score and serum glucose. N20 predictive power was compared with that of clinical and imaging models by using Receiving Operating Characteristics Curve (ROC) analysis. Results: 223 consecutive patients were studied (mean age, 70y; median NIHSS, 18). SEP recordings identified presence of N20 in 110 (49.3%), absence in 58 (26%) and not assessable in 55 patients due to radiofrequency interferences in the angiography room. Prior to EVT, N20 predicted functional independence with a sensitivity of 93% (95%CI, 78-98%) and negative predictive value of 93% (80-98%). The adjusted odds ratio for functional independence was 9.9 (95%CI, 3.1-44.6). In ROC analysis, N20 amplitude showed a higher area under the curve than models using pre-hospital or in-hospital variables, including advanced imaging. Sensitivity increased to 100% (95% CI, 0.85-1) at the end of EVT. Conclusions: SEP monitoring is a non-invasive and bedside technique that could help eligibility of AIS patients for EVT and predict functional recovery., Peer Reviewed, Postprint (published version)

Background: Modelling the course of a disease regarding severe events and identifying prognostic factors is of great clinical relevance. Multistate models (MSM) can be used to describe diseases or processes that change over time using different states and the transitions between them. Specifically, they are useful to analyse a disease with an increasing degree of severity, that may precede death. The complexity of these models changes depending on the number of states and transitions taken into account. Due to that, a web tool has been developed making it easier to work with those models. Results: MSMpred is a web tool created with the shiny R package that has two main features: 1) to allow fitting an MSM from specific data; 2) to predict the clinical evolution for a given subject. To fit the model, the data to be analysed must be uploaded in a prespecified format. Then, the user has to define the states and transitions as well as the covariates (e.g., age or gender) involved in each transition. From this information, the app returns histograms or barplots, as appropriate, to represent the distributions of the selected covariates and boxplots to show the patient’s length of stay (for uncensored data) in each state. To make predictions, the values of selected covariates from a new subject at baseline has to be provided. From these inputs, the app provides some indicators of the subject’s evolution, such as the probability of 30-day death or the most likely state at a fixed time. Furthermore, visual representations (e.g., the stacked transition probabilities plot) are given to make predictions more understandable. Conclusions: MSMpred is an intuitive and visual app that eases the work of biostatisticians and facilitates to the medical personnel the interpretation of MSMs., This research was funded by the Ministerio de Ciencia e Innovación (Spain) [PID2019-104830RB-I00/ DOI (AEI): 10.13039/501100011033] and by Generalitat de Catalunya (2020PANDE00148)., Peer Reviewed, Postprint (published version)

© The Author(s) 2022, The sports statistics community is rapidly evolving. R is an open-source software in constant development that has gained a lot of popularity within statistical communities and sports analytics. This work presents a systematic review of the available R CRAN sport packages following PRISMA guidelines. We consider all packages active as of 18 February 2021. A total of 81 sport R packages created since 2006 were detected. Of these, 35.9% were authored by an American national, 69.1% include a dataset, 43.2% provide vignettes, and 65.4% have been updated at least once. The sport with the highest representation is basketball (n¿=¿14, 17.3%), followed by soccer (n¿=¿12, 14.8%) and packages related to physical activity (n¿=¿11, 13.6%). There are no sports packages directed solely for the female gender, while 59.3% of packages are focused on professional athletes. Fifty packages (61.7%) are related to the sports performance analysis category, and web scraping (n¿=¿43, 53.1%) was the main functionality in the collected packages. The creation of new R packages in the area of sports could help solve questions and tasks that still remain a challenge in this field, while continuing to help to improve the level of statistical education and computational thinking skills., The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was funded by the Ministerio de Ciencia e Innovación (Spain) (PID2019-104830RB-I00) and the Departament d’Economia i Coneixement de la Generalitat de Catalunya (Spain) (2017 SGR 622 (GRBIO))., Peer Reviewed, Postprint (author's final draft)

This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes., Introduction: PROMISE trial has shown high predictive accuracy of the N20 somatosensory evoked potential (SEP) response on functional recovery in patients with AIS undergoing endovascular thrombectomy (EVT). This secondary study aims to describe the association between the N20 response and imaging biomarkers of ischemic penumbra, infarct volume and collateral flow., Jordi Cortés received financial support for the research from the Ministerio de Ciencia e Innovación (Spain) [PID2019‐104830RB‐I00/ DOI (AEI): 10.13039/501100011033]., Postprint (published version)

Measurement of external load in players provides objective information to optimise the weekly balance between training and recovery to improve performance and prevent injuries. Our aim was to evaluate the incidence of sports-related muscle injuries of the lower limb in relation to external load, measured by global positioning system (GPS), in football players. A descriptive study was carried out. Data were collected from 71 professional male football players (30 professionals and 41 youth players) from an elite football club competing in the Spanish and European League in the 2017–2018 season. As external load variables, we measured High Metabolic Load Distance (HMLD), High Speed Running (HSR), Player Load (PL), and Total Distance (TD) through GPS. Injury rate (IR) was calculated both in relation to such GPS load metrics and to load exposure time. We considered categories (youth and professional), playing positions (centre back, full back, midfielder, and forward), and training day with respect to match-day (-4MD, -3MD, -2MD, -1MD, MD, +1MD, +2MD). The GPS load metrics HMLD, HSR, PL, and TD showed very similar patterns across categories and positions, but varied according to training session or MD. The highest loads were observed on MD and three days prior to the match (-3MD). Similarly, the overall IR, both calculated per load exposure time and per GPS load metrics, was highest on MD and -3MD. Again, no differences were observed between youth and professional players. Midfielders demonstrated the highest IR in all metrics, followed by the forwards. In conclusion, this study suggests that external load and incidence of muscle injuries are directly proportional. Therefore, the measurement of more external load variables other than load exposure time, such as the GPS metrics HMLD, HSR, PL, and TD may help to describe the pattern and magnitude of injuries. Future studies based on ours may help to further improve the understanding of the incidence of muscle injuries on, JC and MC acknowledge the financial support from Ministerio de Ciencia e Innovación y Ministerio de Universidades (Ref: PID2019-104830RB-I00 / AEI DOI: 10.13039/501100011033)., Peer Reviewed, Postprint (published version)

Composite endpoints are widely used as primary endpoints in clinical trials. Designing trials with time-to-event endpoints can be particularly challenging because the proportional hazard assumption usually does not hold when using a composite endpoint, even when the premise remains true for their components. Consequently, the conventional formulae for sample size calculation do not longer apply. We present the R package CompAREdesign by means of which the key elements of trial designs, such as the sample size and effect sizes, can be computed based on the information on the composite endpoint components. CompAREdesign provides the functions to assess the sensitivity and robustness of design calculations to variations in initial values and assumptions. Furthermore, we describe other features of the package, such as functions for the design of trials with binary composite endpoints, and functions to simulate trials with composite endpoints under a wide range of scenarios., This work was supported by the Ministerio de Economía y Competitividad (Spain) under Grant PID2019- 104830RB-I00 and the Departament d’Empresa i Coneixement de la Generalitat de Catalunya (Spain) under Grant 2017 SGR 622 (GRBIO). Marta Bofill Roig is a member of the EU Patient Centric Clinical Trial Platforms (EU-PEARL). This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation program and EFPIA and Children’s Tumor Foundation, Global Alliance for TB Drug Development nonprofit organization, Springworks Therapeutics Inc. This publication reflects the authors’ views. Neither IMI nor the European Union, EFPIA, nor any Associated Partners are responsible for any use that may be made of the information contained herein., Peer Reviewed, Postprint (author's final draft)

A shiny app is presented with two main goals: 1) to fit a MSM from specific data in a friendly way (programming skills are not required); 2) to predict the clinical evolution for a given patient based on the previous MSM. For illustrative purposes, we show how the app works using data from a multicohort study of more than 5,000 hospitalized adult COVID-19 patients from 8 Catalan hospitals during the first five waves of the pandemic. Different models have been fitted for the first Catalan pandemic wave, including as states the main outcomes (discharge and death) together with objective interventions during hospitalization such as non-invasive or invasive mechanical ventilation. The application and the underlying model are intended to be very useful for clinicians and to enhance the approach in modelling the course of other diseases with different stages of severity.

L’estadística en les ciències de l’esport ha despertat un gran interès als darrers anys. Per fer front a qüestions en aquest àmbit es demanen cada vegada més científics de dades. Aquests perfils passen sovint molt de temps analitzant les dades sense tenir habilitats de pensament estadístic i computacional que poden ser rellevants en la fase de disseny d’un estudi. La metodologia PPDAC (Problem – Plan – Data – Analysis – Conclusion) creada al 1999 és una estructura cíclica que ajuda a resoldre problemes i prendre decisions a nivell quantitatiu en qualsevol àmbit de la ciència. El present treball presenta un nou instrument dividit en les cinc parts del PPDAC amb 60 preguntes construïdes a partir d’articles científics d’educació estadística. Per comprovar les possibilitats d’aquest instrument s’exposen dos exemples amb dades reals del camp de l’esport que puguin servir de model a investigadors per conèixer quines preguntes poden ser d’utilitat en el disseny, anàlisi i comunicació d’un estudi científic.

Explicació divulgativa de conceptes epidemiològics com a prevalença, incidència, sensibilitat, especificitat, entre altres a través d'exemples contextualitzats en la Pandèmia per COVID-19. El coneixement d'aquests conceptes ajuda a tenir una visió més informada de les notícies referents a la propagació d'una epidèmia o relatius a l'eficàcia d'una prova diagnòstica., Explicación divulgativa de conceptos epidemiológicos como prevalencia, incidencia, sensibilidad, especificidad, entre otros a través de ejemplos contextualizados en la Pandèmia por COVID-19. El conocimiento de dichos conceptos ayuda a tener una visión más informada de las noticias referentes a la propagación de una epidemia o relativos a la eficacia de una prueba diagnóstica.

Peer Reviewed, Postprint (author's final draft)

Background: The incubation period of an infectious disease is defined as the elapsed time between the exposure to the pathogen and the onset of symptoms. Although both the mRNA-based and the adenoviral vector-based vaccines have shown to be effective, there have been raising concerns regarding possible decreases in vaccine effectiveness for new variants and variations in the incubation period. Methods: We conducted a unicentric observational study at the Hospital Universitari de Bellvitge, Barcelona, using a structured telephone survey performed by trained interviewers to estimate the incubation period of the SARS-CoV-2 Delta variant in a cohort of Spanish hospitalized patients. The distribution of the incubation period was estimated using the generalized odds-rate class of regression models. Results: From 406 surveyed patients, 242 provided adequate information to be included in the analysis. The median incubation period was 2.8 days (95%CI: 2.5–3.1) and no differences between vaccinated and unvaccinated patients were found. Sex and age are neither shown not to be significantly related to the COVID-19 incubation time. Conclusions: Knowing the incubation period is crucial for controlling the spread of an infectious disease: decisions on the duration of the quarantine or on the periods of active monitoring of people who have been at high risk of exposure depend on the length of the incubation period. Furthermore, its probability distribution is a key element for predicting the prevalence and the incidence of the disease., This research was funded by the Ministerio de Ciencia e Innovación (Spain) [PID2019-104830RB-I00/ DOI (AEI): https://doi.org/10.13039/5011000110 33], by the Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR) de la Generalitat de Catalunya (2020PANDE00148), by grant [2017SGR622] (GRBIO) administrated by the Departament d’Economia i Coneixement de la Gener‑ alitat de Catalunya (Spain), and by the National Research Foundation of Korea (2021R1G1A1009269)., Peer Reviewed, Postprint (published version)

BACKGROUND: We studied the evolution over time of diffusion weighted imaging (DWI) lesion volume and the factors involved on early and late infarct growth (EIG and LIG) in stroke patients undergoing endovascular treatment (EVT) according to the final revascularization grade. METHODS: This is a prospective cohort of patients with anterior large artery occlusion undergoing EVT arriving at 1 comprehensive stroke center. Magnetic resonance imaging was performed on arrival (pre-EVT), <2 hours after EVT (post-EVT), and on day 5. DWI lesions and perfusion maps were evaluated. Arterial revascularization was assessed according to the modified Thrombolysis in Cerebral Infarction (mTICI) grades. We recorded National Institutes of Health Stroke Scale at arrival and at day 7. EIG was defined as (DWI volume post-EVT–DWI volume pre-EVT), and LIG was defined as (DWI volume at 5d–DWI volume post-EVT). Factors involved in EIG and LIG were tested via multivariable lineal models. RESULTS: We included 98 patients (mean age 70, median National Institutes of Health Stroke Scale score 17, final mTICI=2b 86%). Median EIG and LIG were 48 and 63.3 mL in patients with final mTICI<2b, and 3.6 and 3.9 cc in patients with final mTICI=2b. Both EIG and LIG were associated with higher National Institutes of Health Stroke Scale at day 7 (¿=0.667; P<0.01 and ¿=0.614; P<0.01, respectively). In patients with final mTICI=2b, each 10% increase in the volume of DWI pre-EVT and each extra pass leaded to growths of 9% (95% CI, 7%–10%) and 14% (95% CI, 2%–28%) in the DWI volume post-EVT, respectively. Furthermore, each 10% increase in the volume of DWI post-EVT, each extra pass, and each 10 mL increase in TMax6s post-EVT were associated with growths of 8% (95% CI, 6%–9%), 9% (95% CI, 0%–19%), and 12% (95% CI, 5%–20%) in the volume of DWI post-EVT, respectively. CONCLUSIONS: Infarct grows during and after EVT, especially in nonrecanalizers but also to a lesser extent in recanalizers. In recanalizers, number of, Postprint (author's final draft)

The objective of this end-to-degree project is to find the factors related to the growth of cerebral infarction after mechanical thrombectomy in patients who have suffered a stroke. Different types of statistical modelling (general linear models, generalized linear models and mixed models) are used to evaluate the association between those factors and the infarct growth. The sample of the study is composed of 98 stroke patients undergone mechanical thrombectomy. Measurements of infarct volumes are taken from the neuroimages obtained in Magnetic Resonance Imaging (MRI) scans, which are performed in three different time points: pre-procedure on arrival at the hospital, immediately after the procedure and after five days.

Background: Sample size calculation is a key point in the design of a randomized controlled trial. With time-to-event outcomes, it’s often based on the logrank test. We provide a sample size calculation method for a composite endpoint (CE) based on the geometric average hazard ratio (gAHR) in case the proportional hazards assumption can be assumed to hold for the components, but not for the CE. Methods: The required number of events, sample size and power formulae are based on the non-centrality parameter of the logrank test under the alternative hypothesis which is a function of the gAHR. We use the web platform, CompARE, for the sample size computations. A simulation study evaluates the empirical power of the logrank test for the CE based on the sample size in terms of the gAHR. We consider different values of the component hazard ratios, the probabilities of observing the events in the control group and the degrees of association between the components. We illustrate the sample size computations using two published randomized controlled trials. Their primary CEs are, respectively, progression-free survival (time to progression of disease or death) and the composite of bacteriologically confirmed treatment failure or Staphylococcus aureus related death by 12 weeks. Results: For a target power of 0.80, the simulation study provided mean (± SE) empirical powers equal to 0.799 (±0.004) and 0.798 (±0.004) in the exponential and non-exponential settings, respectively. The power was attained in more than 95% of the simulated scenarios and was always above 0.78, regardless of compliance with the proportional-hazard assumption. Conclusions: The geometric average hazard ratio as an effect measure for a composite endpoint has a meaningful interpretation in the case of non-proportional hazards. Furthermore it is the natural effect measure when using the logrank test to compare the hazard rates of two groups and should be used instead of the standard hazard ratio., G. G´omez and J. Cort´es were partially supported by the Ministerio de Econom´ıa y Competitividad (Spain) [MTM2015-64465-C2-1-R (MINECO/FEDER)], the Ministerio de Ciencia, innovaci´on y Universidades [PID2019-104830RB-I00] and the Departament d’Economia i Coneixement de la Generalitat de Catalunya (Spain)[2017 SGR 622 (GRBIO)]. Ronald B. Geskus was supported by the Wellcome Trust (grant number 106680/Z/14/Z)., Peer Reviewed, Postprint (author's final draft)

Objective: To evaluate the association between prematurity (by the gestational week [gw]) and ADHD during childhood. Method: Observational, matched cohort study using data from children born in a tertiary-level hospital (Hospital Universitari Vall d'Hebron, Catalonia, Spain) during 1995-2007 and data from the Information System for the Development of Research in Primary Health Care (SIDIAP database, Catalonia, Spain). Results: Prevalence of ADHD increases as gestational age decreases, 12.7% for those born =28 gw, compared to 3.2% for those born after the 37 gw. The risk of developing ADHD in the non-premature children tends to increase as the gw decreases (35-36 gw, hazard ratio [HR] = 1.70, 95% confidence interval [CI] [1.19, 2.44]; 33-34 gw, HR = 3.38, 95% CI [2.08, 5.50]; 29-32 gw, HR = 2.37, 95% CI [1.54, 3.63]; and =28 gw, HR = 5.57, 95% CI [2.49, 12.46]) Conclusion: Being born preterm is associated with a risk of developing ADHD, also in late preterm children (35-36 gw). Attention when taking care of these infants regarding their mental health must be made., Peer Reviewed, Postprint (author's final draft)

A role of iron as a target to prevent stroke-induced neurodegeneration has been recently revisited due to new evidence showing that ferroptosis inhibitors are protective in experimental ischemic stroke and might be therapeutic in other neurodegenerative brain pathologies. Ferroptosis is a new form of programmed cell death attributed to an overwhelming lipidic peroxidation due to excessive free iron and reactive oxygen species (ROS). This study aims to evaluate the safety and tolerability and to explore the therapeutic efficacy of the iron chelator and antioxidant deferoxamine mesylate (DFO) in ischemic stroke patients. Administration of placebo or a single DFO bolus followed by a 72 h continuous infusion of three escalating doses was initiated during the tPA infusion, and the impact on blood transferrin iron was determined. Primary endpoint was safety and tolerability, and secondary endpoint was good clinical outcome (clinicalTrials.gov NCT00777140). DFO was found safe as adverse effects were not different between placebo and DFO arms. DFO (40–60 mg/Kg/day) reduced the iron saturation of blood transferrin. A trend to efficacy was observed in patients with moderate-severe ischemic stroke (NIHSS > 7) treated with DFO 40–60 mg/Kg/day. A good outcome was observed at day 90 in 31% of placebo vs. 50–58% of the 40–60 mg/Kg/day DFO-treated patients., Peer Reviewed, Postprint (published version)

La millora i el manteniment continu de la qualitat de l’atenció als malalts amb ictus agut requereix una avaluació periòdica de la pràctica clínica. Els Audits de l’Ictus són l’instrument avaluatiu del PDMVC. La millora dels seus resultats pretén garantir la millora dels resultats dels pacients., S’han auditat 4.008 casos ingressats per ictus agut entre 2018 i 2019. El període d’estudi s’ha ampliat a 6 mesos, en períodes de 1 mes i mig al llarg de 12 mesos, similars per a tots els centres. L’obtenció prospectiva de dades s’ha realitzat majoritàriament per infermeres de cada hospital. La mediana del temps entre l’inici dels símptomes i l’arribada a urgències va ser de 2,1 hores. El 72% dels casos van arribar a l’hospital dins les primeres quatre hores i mitja. Respecte al 4t Audit: * Augmenten els ingressos en Unitat d’ictus agut (44,2% a 61,3%), les activacions del Codi Ictus (42,9 a 61,4; realitzades pel SEM de 43,4 a 67,8%) i els tractaments de reperfusió (16% a 30% dels ictus isquèmics) * Augmenta el nombre de pacients en els que es diagnostica durant l’ingrés una fibril·lació auricular no coneguda prèviament (7% a 18,8%). * Hi ha un lleuger augment de les pneumònies(6% a 8%)ibaixa la mor talitat intrahospitalària (12% a 9%). * Sis indicadors de qualitat milloren significativament, tres 3 indicadors es mantenen i 3 indicadors empitjoren. Destaca una important millora en alguns indicadors de qualitat rellevants com són la realització del test de disfàgia, l’avaluació del perfil lipídic, l’educació sanitària als pacients i familiars, el registre de l’etiologia de l’ictus i la utilització d’escales neurològiques. Es necessiten accions de milloradels indicadors següents: pauta d’antitrombòtics abans de 48 hores, mobilització precoç i avaluació de l’estat d’ànim. L’estat d’ànim s’avalua en un baix percentatge i es fa servir una gran variabilitat d’eines de mesura., Preprint

El aprendizaje humano es autónomo debido a que tenemos un sistema de captación de información a través de los sentidos que es combinada usando las neuronas y permite generar conocimiento de nuestro entorno. Las redes neuronales artificiales son algoritmos que pretenden emular este comportamiento dando lugar a un proceso de aprendizaje automático. En este vídeo se explica la mecánica y el funcionamiento de estas redes a la vez que se muestran aplicaciones prácticas en diferentes disciplinas.

The past decade has seen continuous growth in so-called precision medicine, due especially to great advances in the genetics. While applying it presently goes unquestioned in certain fields like oncology, it is more controversia! in other medical specialties that usually practice it. Precision medicine is justified under two assumptions. First, it must be more cost-effective than the universal standard of care, as a world with limited resources requires that an individual treatment's benefits be inversely related to the number of people on whom it is effective. Second, and most importantly, the intervention under study should actually show different responses among patients or subgroups of them, which this work focuses on. Strictly speaking, the fundamental problem of causal inference makes the latter requirement impossible to prove, because a conventional trial observes patient outcome only under a single treatment. However, the variability of a continuous outcome provides important information about the presence (or absence) of a constant treatment effect, of which a direct consequence is that outcome variance remains unchanged under different treatment regimens. Thus, homoscedasticity may be a useful tool for testing the hypothesis of a homogeneous effect. Our work here conducts a methodological review of randomized clinical triaIs (RCT) with two ·treatment arms and a quantitative primary end point. Among other variables, we collected the outcome and baseline variances for each treatment group with two purposes: to quantify the outcome variance ratio between the experimental and reference groups; and to estimate the proportion of studies with variance discrepancies large enough to be attributed to a heterogeneous treatment effect among participants. This variance comparison was carried out between treatment arms (independent by randomization) and overtime, contrasting the end-of-study and baseline outcomes. The Medline database provided us 208 randomized clinical, La medicina de precisión ha experimentado un auge continuo en la última década debido sobre todo a grandes avances en la genética. Aunque su uso es actualmente incuestionable en campos como la oncología, es más controvertido en otras especialidades médicas. La medicina de precisión queda justificada bajo dos supuestos. Por una parte, debe ser más rentable que el tratamiento estándar en el sentido que los beneficios individuales de un tratamiento deben relacionarse inversamente con el número de personas en las que es realmente eficaz. En segundo lugar, y más importante, la intervención debe actuar realmente de forma diferencial entre los pacientes. Formalmente, el problema fundamental de la inferencia causal establece que este último requisito es indemostrable debido a que los ensayos convencionales muestran la respuesta de cada paciente bajo un único tratamiento. Sin embargo, la variabilidad de una respuesta continua proporciona información valiosa sobre la presencia de un efecto constante, siendo una consecuencia directa que la variabilidad permanece inalterable bajo diferentes intervenciones. Por tanto, el estudio de la homoscedasticidad de la respuesta puede ser una herramienta útil para probar la hipótesis de homogeneidad del efecto. Se realizó una revisión metodológica de ensayos clínicos aleatorizados paralelos con una variable respuesta principal cuantitativa. Se recogió información referente a las varianzas de dicha variable respuesta al final y al inicio del estudio para cada grupo de tratamiento con dos propósitos: estimar la razón de varianzas y estimar la proporción de estudios con discrepancias en la varianza lo suficientemente grandes como para ser atribuidas a un efecto heterogéneo. Se compararon las varianzas entre brazos de tratamiento (independiente por la asignación aleatoria) y a lo largo del tiempo, comparando las varianzas de las respuestas al final y al inicio del estudio. Se obtuvieron 208 ensayos clínicos publicados en los años 2004, 2007, 2, Postprint (published version)

En estadística, el análisis de supervivencia estudia el tiempo hasta que ocurre un determinado evento. En este vídeo se explican los pilares básicos de este tipo de análisis, se define el concepto de censura y se ahonda en la interpretación de unos gráficos muy útiles en este contexto, las curvas de Kaplan-Meier, que representan la probabilidad de no padecer el evento en un instante de tiempo determinado.

© 2020. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0, Objective: We aimed to describe sociodemographic, comorbidities, co-medication and risk of thromboembolic events and bleeding in patients with NVAF initiating oral anticoagulants (OAC) for stroke prevention, and to estimate adherence and persistence to OAC. Setting: Primary Health Care (PHC) in the Catalan Health Institute (ICS), Catalunya, Spain. Participants: All NVAF adult patients initiating OAC for stroke prevention in August 2013-December 2015. Methods: Population-based cohort study. Persistence was measured in patients initiating OAC in August 2013-December 2014. Data source: SIDIAP, which captures electronic health records from PHC in the (ICS), covering approximately 5.8 million people. Results: 51,690 NVAF patients initiated OAC; 47,197 (91.3%) were naive to OAC and 32,404 (62.7%) initiated acenocoumarol. Mean age was 72.8 years (SD 12.3) and 49.4% were women. Platelet-aggregation inhibitors were taken by 9,105 (17.6%) of the patients. Persistence and adherence were estimated up to the end of follow-up. For 22,075 patients, persistence was higher among the non-naive patients [n=258 (61.7%)] than among the naive [n=11,502 (53.1%)]. Adherence was estimated for patients initiating DOAC and it was similar in naive and non-naive patients. Among the naive to DOAC treatment, those starting rivaroxaban showed a highest proportion [(n=360 (80.1%)] of good adherence at implementation (MPR>80%) while patients starting dabigatran were less adherent [n= 203 [47.8%)]. Conclusions: Acenocoumarol was the most frequently prescribed OAC as first therapy in NVAF patients. Non-naive to DOAC showed better persistence than naive. Rivaroxaban showed higher proportion of adherent patients during the implementation phase than apixaban and dabigatran the lowest., Peer Reviewed, Postprint (author's final draft)

This article considers the combination of two binary or two time-to-event endpoints to form the primary composite endpoint for leading a trial. • It discusses the relative efficiency of choosing a composite endpoint over one of its components in terms of: the frequencies of observing each component; the relative treatment effect of the tested therapy; and the association between both components. • We highlight the very important role of the association between components in choosing the most efficient endpoint to use as primary. • For better grounded future trials, we recommend trialists to always reporting the association between components of the composite endpoint • Common fallacies to note when using composite endpoints: i) composite endpoints always imply higher power; ii) treatment effect on the composite endpoint is similar to the average effects of its components; and iii) the probability of observing the primary endpoint increases significantly., Peer Reviewed, Preprint

The incubation period of coronavirus disease 2019 (COVID-19) is not always observed exactly due to uncertain onset times of infection and disease symptoms. In this paper, we demonstrate how to estimate the distribution of incubation and its association with patient demographic factors when the exact dates of infection and symptoms’ onset may not be observed. The findings from analysis of the confirmed COVID-19 cases indicate that age could be associated with the incubation period, and an age-specific quarantine policy might be more efficient than a unified one in confining COVID-19., This research was funded by the Ministerio de Ciencia e Innovación (Spain) (PID2019-104830RB-I00),the Ministerio de Economía y Competitividad (Spain) (MTM2015-64465-C2-1-R (MINECO/FEDER)), and theDepartament d’Economia i Coneixement de la Generalitat de Catalunya (Spain) (2017 SGR 622 (GRBIO))., Peer Reviewed, Postprint (author's final draft)

L'adherència al tractament és una mesura àmpliament utilitzada en farmacoepidemiologia, una estimacióprecisad aquestaésunanecessitatessencialperalaseguretatdelpacient,aixícomper a l estalvi de costos d assistència sanitària. Diferents enfocaments ja han abordat aquest problema, prenent certes limitacions, com ser només vàlids per a medicaments específics o resumir el compliment del pacient en un únic valor. La present memòria presenta una nova metodologia per a estimar la probabilitat de presa de la medicació a partir de dades de dispensació electrònica. A més, es duu a terme una anàlisi exploratòria per mitjà de tècniques de clustering, a fi d observar visualment perfils d ús de medicació. Finalment, s aborda una anàlisi inferencial per avaluar si el risc de patir un accident cerebrovascular pot ser augmentat segons els diferents perfils d adherència obtinguts.

Background Agomelatine is a melatonin receptor agonist and serotonin 5-HT2C receptor antagonist indicated for depression in adults. Hepatotoxic reactions like acute liver injury (ALI) are an identified risk in the European risk management plan for agomelatine. Hepatotoxic reactions have been reported for other antidepressants, but population studies quantifying these risks are scarce. Antidepressants are widely prescribed, and users often have risk factors for ALI (e.g. metabolic syndrome). Objective The goal was to estimate the risk of ALI associated with agomelatine and other antidepressants (fluoxetine, paroxetine, sertraline, escitalopram, mirtazapine, venlafaxine, duloxetine, and amitriptyline) when compared with citalopram in routine clinical practice. Method A nested case–control study was conducted using data sources in Denmark, Germany, Spain, and Sweden (study period 2009–2014). Three ALI endpoints were defined using International Classification of Diseases (ICD) codes: primary (specific codes) and secondary (all codes) endpoints used only hospital discharge codes; the tertiary endpoint included both inpatient and outpatient settings (all codes). Validation of endpoints was implemented. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for current use were estimated for each data source and combined. Results We evaluated 3,238,495 new antidepressant and 74,440 agomelatine users. For the primary endpoint, the OR for agomelatine versus citalopram was 0.48 (CI 0.13–1.71). Results were also¿<¿1 when no exclusion criteria were applied (OR 0.37; CI 0.19–0.74), when all exclusion criteria except alcohol and drug abuse were applied (OR 0.47; CI 0.20–1.07), and for the secondary (OR 0.40; CI 0.05–3.11) and tertiary (OR 0.79; CI 0.50–1.25) endpoints. Regarding other antidepressants versus citalopram, most OR point estimates were also below one, although with varying widths of the 95% CIs. The result of the tertiary endpoint and the sensitivity analyses o, Peer Reviewed, Postprint (published version)

This is the peer reviewed version of the following article: Forns, J. [et al.]. Validity of ICD-9 and ICD-10 codes used to identify acute liver injury: a study in three European data sources. "Pharmacoepidemiology and drug safety", 6 Juny 2019, vol. 28, núm. 7, p. 965-975, which has been published in final form at 10.1002/pds.4803. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.", Purpose Validating cases of acute liver injury (ALI) in health care data sources is challenging. Previous validation studies reported low positive predictive values (PPVs). Methods Case validation was undertaken in a study conducted from 2009 to 2014 assessing the risk of ALI in antidepressants users in databases in Spain (EpiChron and SIDIAP) and the Danish National Health Registers. Three ALI definitions were evaluated: primary (specific hospital discharge codes), secondary (specific and nonspecific hospital discharge codes), and tertiary (specific and nonspecific hospital and outpatient codes). The validation included review of patient profiles (EpiChron and SIDIAP) and of clinical data from medical records (EpiChron and Denmark). ALI cases were confirmed when liver enzyme values met a definition by an international working group. Results Overall PPVs (95% CIs) for the study ALI definitions were, for the primary ALI definition, 84% (60%-97%) (EpiChron), 60% (26%-88%) (SIDIAP), and 74% (60%-85%) (Denmark); for the secondary ALI definition, 65% (45%-81%) (EpiChron), 40% (19%-64%) (SIDIAP), and 70% (64%-77%) (Denmark); and for the tertiary ALI definition, 25% (18%-34%) (EpiChron), 8% (7%-9%) (SIDIAP), and 47% (42%-52%) (Denmark). The overall PPVs were higher for specific than for nonspecific codes and for hospital discharge than for outpatient codes. The nonspecific code “unspecified jaundice” had high PPVs in Denmark. Conclusions PPVs obtained apply to patients using antidepressants without preexisting liver disease or ALI risk factors. To maximize validity, studies on ALI should prioritize hospital specific discharge codes and should include hospital codes for unspecified jaundice. Case validation is required when ALI outpatient cases are considered., Peer Reviewed, Postprint (author's final draft)

Background The use of direct oral anticoagulants (DOAC) for stroke prevention in non-valvular atrial fibrillation (NVAF) has not been previously assessed in our setting. We aimed to describe sociodemographic, comorbidities, co-medication and risk of thromboembolic events and bleeding in patients with NVAF initiating oral anticoagulants (OAC) for stroke prevention, and to estimate adherence and persistence to OAC. Methods Population-based cohort study including all NVAF adult patients initiating OAC for stroke prevention in August 2013-December 2015. Persistence was measured in patients initiating OAC in August 2013-December 2014. Data source is SIDIAP, which captures electronic health records from Primary Health Care in the Catalan Health Institute, covering approximately 5.8 million people. Results 51,690 NVAF patients initiated OAC; 47,197 (91.3%) were naive to OAC and 32,404 initiated acenocoumarol (62.7%). Mean age was 72.8 years (SD 12.3) and 49.4% were women. Platelet-aggregation inhibitors were taken by 9,105 (17.6%) of the patients. For 22,075 patients, persistence was higher among the non-naive patients [n=258 (61.7%)] than among the naive [n=11,502 (53.1%)]. Adherence was estimated for patients initiating DOAC and was similar in naive and non-naive patients. Among the naive to DOAC treatment, those starting rivaroxaban showed a highest proportion [(n=360 (80.1%)] of good adherence at implementation (MPR>80%) while patients starting dabigatran were less adherent [n= 203 47.8%)]. Conclusions Acenocoumarol was the most frequently prescribed OAC as first therapy in NVAF patients. Non-naive to DOAC showed better persistence than naive. Rivaroxaban showed higher proportion of adherent patients during the implementation phase than apixaban and dabigatran the lowest., Preprint

The hazard ratio is routinely used as a summary measure to assess the treatment effect in clinical trials with time-to-event endpoints. It is frequently assumed as constant over time although this assumption often does not hold. When the hazard ratio deviates considerably from being constant, the average of its plausible values is not a valid measure of the treatment effect, can be clinically misleading and common sample size formulas are not appropriate. In this paper, we study the hazard ratio along time of a two-component composite endpoint under the assumption that the hazard ratio for each component is constant. This work considers two measures for quantifying the non-proportionality of the hazard ratio: the difference D between the maximum and minimum values of hazard ratio over time and the relative measure R representing the ratio between the sample sizes for the minimum detectable and the average effects. We illustrate D and R by means of the ZODIAC trial where the primary endpoint was progression-free survival. We have run a simulation study deriving scenarios for different values of the hazard ratios, different event rates and different degrees of association between the components. We illustrate situations that yield non-constant hazard ratios for the composite endpoints and consider the likely impact on sample size. Results show that the distance between the two component hazard ratios plays an important role, especially when they are close to 1. Furthermore, even when the treatment effects for each component are similar, if the two-component hazards are markedly different, hazard ratio of the composite is often non-constant., Peer Reviewed, Preprint

From 2005 to 2010, we conducted 2 randomized studies on a journal (Medicina Clínica), where we took manuscripts received for publication and randomly assigned them to either the standard editorial process or to additional processes. Both studies were based on the use of methodological reviewers and reporting guidelines (RG). Those interventions slightly improved the items reported on the Manuscript Quality Assessment Instrument (MQAI), which assesses the quality of the research report. However, masked evaluators were able to guess the allocated group in 62% (56/90) of the papers, thus presenting a risk of detection bias. In this post-hoc study, we analyse whether those interventions that were originally designed for improving the completeness of manuscript reporting may have had an effect on the number of citations, which is the measured outcome that we used., Peer Reviewed, Postprint (author's final draft)

Rationale: Optimal pre-hospital delivery pathways for acute stroke patients suspected to harbor a large vessel occlusion (LVO) have not been assessed in randomized trials. Aim: To establish whether stroke subjects with RACE scale based suspicion of LVO evaluated by Emergency Medical Services in the field, have higher rates of favorable outcome when transferred directly to an Endovascular Center (EVT-SC), as compared to the standard transfer to the closest Local Stroke Center (Local-SC). Design: Multicenter, superiority, cluster randomized within a cohort trial with blinded endpoint assessment. Procedure: Eligible patients must be 18 or older, have acute stroke symptoms and not have an immediate life threatening condition requiring emergent medical intervention. They must be suspected to have intracranial LVO based on a pre-hospital RACE scale of =5, be located in geographical areas where the default health authority assigned referral stroke center is a non-thrombectomy capable hospital, and estimated arrival at a thrombectomy capable stroke hospital in less than 7 hours from time last seen well. Cluster randomization is performed according to a pre-established temporal sequence (temporal cluster design) with 3 strata: day/night, distance to the EVT-SC and week/week-end day. Study outcome: The primary endpoint is the modified Rankin Scale (mRS) score at 90 days. The primary safety outcome is mortality at 90 days. Analysis: The primary endpoint based on the modified intention-to-treat population is the distribution of modified Rankin Scale scores (mRS) at 90 days analyzed under a sequential triangular design. The maximum sample size is 1754 patients, with two planned interim analyses when 701 (40%) and 1227 patients have completed follow-up. Hypothesized common odds ratio is 1.35., Peer Reviewed, Postprint (author's final draft)