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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)

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)

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)

Large cell carcinoma (LCC) is a rare and aggressive lung cancer subtype with poor prognosis and no targeted therapies. Tumor-associated fibroblasts (TAFs) derived from LCC tumors exhibit premature senescence, and coculture of pulmonary fibroblasts with LCC cell lines selectively induces fibroblast senescence, which in turn drives LCC cell growth and invasion. Here we identify MMP1 as overexpressed specifically in LCC cell lines, and we show that expression of MMP1 by LCC cells is necessary for induction of fibroblast senescence and consequent tumor promotion in both cell culture and mouse models. We also show that MMP1, in combination with TGF-ß1, is sufficient to induce fibroblast senescence and consequent LCC promotion. Furthermore, we implicate PAR-1 and oxidative stress in MMP1/TGF-ß1-induced TAF senescence. Our results establish an entirely new role for MMP1 in cancer, and support a novel therapeutic strategy in LCC based on targeting senescent TAFs., Peer Reviewed, Postprint (published version)

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)

The present report aims to provide a comprehensive picture of the pandemic situation of COVID-19 in the EU countries, and to be able to foresee the situation in the next coming days. We employ an empirical model, verified with the evolution of the number of confirmed cases in previous countries where the epidemic is close to conclude, including all provinces of China. The model does not pretend to interpret the causes of the evolution of the cases but to permit the evaluation of the quality of control measures made in each state and a short-term prediction of trends. Note, however, that the effects of the measures’ control that start on a given day are not observed until approximately 7-10 days later. The model and predictions are based on two parameters that are daily fitted to available data: a: the velocity at which spreading specific rate slows down; the higher the value, the better the control. K: the final number of expected cumulated cases, which cannot be evaluated at the initial stages because growth is still exponential. We show an individual report with 8 graphs and a table with the short-term predictions for different countries and regions. We are adjusting the model to countries and regions with at least 4 days with more than 100 confirmed cases and a current load over 200 cases. The predicted period of a country depends on the number of datapoints over this 100 cases threshold, and is of 5 days for those that have reported more than 100 cumulated cases for 10 consecutive days or more. For short-term predictions, we assign higher weight to last 3 points in the fittings, so that changes are rapidly captured by the model. The whole methodology employed in the inform is explained in the last pages of this document. In addition to the individual reports, the reader will find an initial dashboard with a brief analysis of the situation in EU-EFTA-UK countries, some summary figures and tables as well as long-term predictions for some of them, when possible. Th, These reports are funded by the European Commission (DG CONNECT, LC-01485746) PJC and MC received funding from “la Caixa” Foundation (ID 100010434), under agreement LCF/PR/GN17/50300003; CP, DL, SA, MC, received funding from Ministerio de Ciencia, Innovación y Universidades and FEDER, with the project PGC2018-095456-B-I00, Postprint (published version)

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)

Background Evidence regarding whether imaging can be used effectively to select patients for endovascular thrombectomy (EVT) is scarce. We aimed to investigate the association between baseline imaging features and safety and efficacy of EVT in acute ischaemic stroke caused by anterior large-vessel occlusion. Methods In this meta-analysis of individual patient-level data, the HERMES collaboration identified in PubMed seven randomised trials in endovascular stroke that compared EVT with standard medical therapy, published between Jan 1, 2010, and Oct 31, 2017. Only trials that required vessel imaging to identify patients with proximal anterior circulation ischaemic stroke and that used predominantly stent retrievers or second-generation neurothrombectomy devices in the EVT group were included. Risk of bias was assessed with the Cochrane handbook methodology. Central investigators, masked to clinical information other than stroke side, categorised baseline imaging features of ischaemic change with the Alberta Stroke Program Early CT Score (ASPECTS) or according to involvement of more than 33% of middle cerebral artery territory, and by thrombus volume, hyperdensity, and collateral status. The primary endpoint was neurological functional disability scored on the modified Rankin Scale (mRS) score at 90 days after randomisation. Safety outcomes included symptomatic intracranial haemorrhage, parenchymal haematoma type 2 within 5 days of randomisation, and mortality within 90 days. For the primary analysis, we used mixed-methods ordinal logistic regression adjusted for age, sex, National Institutes of Health Stroke Scale score at admission, intravenous alteplase, and time from onset to randomisation, and we used interaction terms to test whether imaging categorisation at baseline modifies the association between treatment and outcome. This meta-analysis was prospectively designed by the HERMES executive committee but has not been registered. Findings Among 1764 pooled patie, Peer Reviewed, Postprint (author's final draft)

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Physical activity (PhA) prior to stroke has been associated with good outcomes after the ischemic insult, but there is scarce data on the involved molecular mechanisms. Methods: We studied consecutive acute ischemic stroke patients admitted to a single tertiary stroke center. Pre-stroke PhA was evaluated with the International Physical Activity Questionnaire (METS-minute/week). We studied several circulating angiogenic and neurogenic factors at different time-points: Vascular Endothelial Growth Factor (VEGF), Granulocyte Colony-Stimulating Factor (G-CSF) and Brain-Derived Neurotrophic Factor (BDNF) at admission, day 7, and at 3 months. We considered good functional outcome at 3 months (mRS = 2) as primary endpoint, and final infarct volume as secondary outcome. Results: We studied 83 patients with at least two time-point serum determinations (mean age 69.6 years, median NIHSS 17 at admission). Patients more physically active before stroke had a significantly higher increment of serum Vascular Endothelial Growth Factor (VEGF) at 7th day when compared to less active patients. This increment was an independent predictor of good functional outcome at 3 months and was associated with smaller infarct volume in multivariate analyses adjusted for relevant covariates. We did not find independent associations of G-CSF or BDNF levels neither with level of pre-stroke PhA nor with stroke outcomes. Conclusions: Although there are probably more molecular mechanisms by which physical activity exerts its beneficial effects in stroke outcomes, our observation regarding the potential role of VEGF is plausible and in line with previous experimental studies. Further research in this field is needed., Peer Reviewed, Postprint (author's final draft)

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Background and Purpose A progressive decline in the odds of favorable outcome as time to reperfusion increases is well known. However, the impact of specific workflow intervals is not clear.; Methods We studied the mechanical thrombectomy group (n=103) of the prospective, randomized REVASCAT (Randomized Trial of Revascularization With Solitaire FR Device Versus Best Medical Therapy in the Treatment of Acute Stroke due to Anterior Circulation Large Vessel Occlusion Presenting Within Eight Hours of Symptom Onset) trial. We defined 3 workflow metrics: time from symptom onset to reperfusion (OTR), time from symptom onset to computed tomography, and time from computed tomography (CT) to reperfusion. Clinical characteristics, core laboratory-evaluated Alberta Stroke Program Early CT Scores (ASPECTS) and 90-day outcome data were analyzed. The effect of time on favorable outcome (modified Rankin scale, 0-2) was described via adjusted odds ratios (ORs) for every 30-minute delay.; Results Median admission National Institutes of Health Stroke Scale was 17.0 (14.0-20.0), reperfusion rate was 66%, and rate of favorable outcome was 43.7%. Mean (SD) workflow times were as follows: OTR: 342 (107) minute, onset to CT: 204 (93) minute, and CT to reperfusion: 138 (56) minute. Longer OTR time was associated with a reduced likelihood of good outcome (OR for 30-minute delay, 0.74; 95% confidence interval [CI], 0.59-0.93). The onset to CT time did not show a significant association with clinical outcome (OR, 0.87; 95% CI, 0.67-1.12), whereas the CT to reperfusion interval showed a negative association with favorable outcome (OR, 0.72; 95% CI, 0.54-0.95). A similar subgroup analysis according to admission ASPECTS showed this relationship for OTR time in ASPECTS<8 patients (OR, 0.56; 95% CI, 0.35-0.9) but not in ASPECTS8 (OR, 0.99; 95% CI, 0.68-1.44).; Conclusions Time to reperfusion is negatively associated with favorable outcome, being CT to reperfusion, as opposed to onset to CT, the mai, Peer Reviewed, Postprint (author's final draft)

Background and Purpose-Recent trials have shown the superiority of endovascular thrombectomy (EVT) over medical therapy alone in certain stroke patients with proximal arterial occlusion. Using data from the Randomized Trial of Revascularization With Solitaire FR Device Versus Best Medical Therapy in the Treatment of Acute Stroke due to Anterior Circulation Large Vessel Occlusion Presenting Within 8-Hours of Symptom Onset (REVASCAT) and a parallel reperfusion treatment registry, we sought to assess the utilization of EVT in a defined patient population, comparing the outcomes of patients treated in and outside the REVASCAT trial. Methods-SONIIA [Sistema Online d'Informacio de l'Ictus Agut], a population-based, government-mandated, prospective registry of reperfusion therapies for stroke encompassing the entire population of Catalonia, was used as data source. The registry documents 5 key inclusion criteria of the REVASCAT trial: age, stroke severity, time to treatment, baseline functional status, and occlusion site. We compared procedural, safety, and functional outcomes in patients treated inside and outside the trial. Results-From November 2012 to December 2014, out of 17596 ischemic stroke patients in Catalonia (population 7.5 million), 2576 patients received reperfusion therapies (17/100000 inhabitants-year), mainly intravenous thrombolysis only (2036). From the remaining 540 treated with EVT, 103 patients (out of 206 randomized) were treated within REVASCAT and 437 outside the trial. Of these, 399 did not fulfill some of the study criteria, and 38 were trial candidates (8 treated at REVASCAT centers and 30 at 2 non-REVASCAT centers). The majority of procedural, safety, and functional outcomes were similar in patients treated with EVT within and outside REVASCAT. Conclusions-REVASCAT enrolled nearly all eligible patients representing one third of all patients treated with EVT. Patients treated with EVT within and outside REVASCAT had similar outcomes, reinforcing, Peer Reviewed, Postprint (author's final draft)

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REVASCAT is a prospective, multicenter, randomized trial seeking to establish whether subjects meeting following main inclusion criteria: age 18-80, baseline National Institutes of Health Stroke Scale = 6, evidence of intracranial internal carotid artery or proximal (M1 segment) middle cerebral artery occlu- sion, Alberta Stroke Program Early Computed Tomography score of > 7 on non-contrast CT or > 6 on diffusion-weighted magnetic resonance imaging , ineligible for or with persistent occlusion after intravenous alteplase and procedure start within 8 hours from symptom onset, have higher rates of favorable outcome when treated with the SolitaireTM FR embolectomy device compared to standard medical therapy alone The primary end-point, based on intention-to-treat cri- teria is the distribution of modified Rankin Scale scores at 90 days. Projected sample size is 690 patients. Estimated common odds ratio is 1•615. Randomization is performed under a mini- mization process using age, baseline NIHSS, therapeutic window, occlusion location and investigational center. The study follows a sequential analysis (triangular model) with the first approach to test efficacy at 174 patients and subsequent analyses (if necessary) at 346, 518, and 690 subjects. Secondary end-points are infarct volume evaluated on CT at 24 h, dra- matic early favorable response, defined as NIHSS of 0–2 or NIHSS improvement = 8 points at 24 h and successful recanali- zation in the Solitaire arm according to the thrombolysis in cerebral infarction (TICI) classification defined as TICI 2b or 3. Safety variables are mortality at 90 days, symptomatic intrac- ranial haemorrhage rates at 24 hours and procedure related complications., Peer Reviewed, Postprint (author's final draft)

Background and Purpose-The standard outcome measure in stroke research is modified Rankin scale (mRS) evaluated by local blinded investigators. We aimed to assess feasibility and reliability of 2 central adjudication methods of mRS in the setting of a randomized endovascular stroke trial. Methods-This is a secondary analysis derived from the Randomized Trial of Revascularization With Solitaire FR Device Versus Best Medical Therapy in the Treatment of Acute Stroke Due to Anterior Circulation Large Vessel Occlusion Presenting Within Eight Hours of Symptom Onset (REVASCAT) trial cohort. Primary outcome was distribution of mRS at 90 days. Local evaluation was done by certified investigators masked to treatment assignment using structured face-to-face interviews. In addition, central assessment was performed by 2 independent raters via structured phone interview (n=120) and via video recordings of the face-to-face interviews with local investigators (n=106). Interrater agreement was evaluated using kappa and discordance statistics. Sensitivity analyses for the primary end point using different adjudication approaches were performed. Correlation between mRS obtained with each modality and 24-hour follow-up infarct volumes was studied. Results-Using local evaluation as the reference, higher agreement rates were noted with central video than with central phone evaluations (k(w) 0.92 [0.88-0.96] versus 0.77 [0.72-0.83]). Discrepancies in mRS scoring between local and central raters (phone- and video-based) were similar in both treatment allocation arms. Sensitivity analyses showed benefit of endovascular treatment irrespective of adjudication method, but higher odds ratios were observed with local evaluations. Final infarct volume was similarly correlated with mRS across all 3 evaluation modalities. Conclusions-Central adjudication of mRS is feasible, reducing interrater variability and avoiding potential problems related to lack of blinding. Our findings may have implicatio, Peer Reviewed, Postprint (author's final draft)

Circadian rhythm interactions of hemostatic factors can modify tissue plasminogen activator (tPA) effects. We assess the relationship of the time frame of intravenous tPA administration with the outcome of patients with acute ischemic stroke (AIS). We studied 135 consecutive patients with AIS and transcranial duplex documented middle cerebral artery (MCA) occlusion treated with intravenous tPA. Complete recanalization was defined as total improvement on thrombolysis in brain ischemia (TIBI) grades 2 h after tPA infusion. Clinical response was evaluated by the modified Rankin scale at 90 days. We determined plasminogen activator inhibitor-1 (PAI-1) levels in 33 patients with available plasma samples before treatment. Our results are follows: 92 (68.1%) patients were treated in the diurnal (9:00–21:00) and 43 (31.8%) in the nocturnal period (21:00–9:00). Complete recanalization was recorded in 52/135 (38.5%) patients. Both the rate of complete recanalization (45.6% vs. 23.2%; p = .01) and good clinical outcome (64.1% vs. 44.2%; p = .02) were significantly higher in the group of diurnal tPA administration compared with those treated in the nocturnal period. The adjusted odds ratio (OR) of diurnal tPA treatment for complete MCA recanalization was 2.37 (95% confidence interval [CI], 1.02–5.52; p = .045). Diurnal tPA infusion significantly improved the overall distribution of scores on the modified Rankin scale, as compared with nocturnal treatment (OR, 2.07; 95% CI, 1.16–4.64 by ordinal regression analysis). Low PAI-1 levels were associated with complete recanalization but did not significantly differ between the two time frames. In conclusion, diurnal administration of tPA is associated with complete MCA recanalization and better functional outcome at 90 days in patients with AIS., Peer Reviewed, Postprint (author's final draft)