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Background: Subclinical vascular brain lesions are highly prevalent in elderly patients with stroke. Little is known about predisposing factors and their impact on long-term outcome of patients with stroke at a young age. Methods: We quantified magnetic resonance-defined subclinical vascular brain lesions, including lacunes and white matter hyperintensities, perivascular spaces and cerebral microbleeds, and assessed total small-vessel disease (SVD) score in patients with first-ever acute ischemic stroke aged 18 to 45 years, and followed them up, as part of the multicentre Italian Project on Stroke in Young Adults. The primary end point was a composite of ischemic stroke, transient ischemic attack, myocardial infarction, or other arterial events. We assessed the predictive accuracy of magnetic resonance features and whether the addition of these markers improves outcome prediction over a validated clinical tool, such as the Italian Project on Stroke in Young Adults score. Results: Among 591 patients (males, 53.8%; mean age, 37.5±6.4 years), 117 (19.8%) had subclinical vascular brain lesions. Family history of stroke was associated with lacunes (odds ratio, 2.24 [95% CI, 1.30–3.84]) and total SVD score (odds ratio, 2.06 [95% CI, 1.20–3.53] for score≥1), hypertension with white matter hyperintensities (odds ratio, 2.29 [95% CI, 1.22–4.32]). After a median follow-up of 36.0 months (25th–75th percentile, 38.0), lacunes and total SVD score were associated with primary end point (hazard ratio, 2.13 [95% CI, 1.17–3.90] for lacunes; hazard ratio, 2.17 [95% CI, 1.20–3.90] for total SVD score ≥1), and the secondary end point brain ischemia (hazard ratio, 2.55 [95% CI, 1.36–4.75] for lacunes; hazard ratio, 2.61 [95% CI, 1.42–4.80] for total SVD score ≥1). The predictive performances of the models, including magnetic resonance features were comparable to those of the random model. Adding individual magnetic resonance features to the Italian Project on Stroke in Young Adults score did not improve model prediction. Conclusions: Subclinical vascular brain lesions affect ≈2 in 10 young adults with ischemic stroke. Although lacunes and total SVD score are associated with thrombotic recurrence, they do not improve accuracy of outcome prediction over validated clinical predictors.

ObjectiveTo investigate the age-dependent impact of traditional stroke risk factors on the occurrence of intracerebral haemorrhage (ICH).MethodsWe performed a case–control analysis, comparing consecutive patients with ICH with age-matched and sex-matched stroke-free controls, enrolled in the setting of the Multicenter Study on Cerebral Hemorrhage in Italy (MUCH-Italy) between 2002 and 2014 by multivariable logistic regression model within subgroups stratified by age quartiles (Q1–Q4).ResultsWe analysed 3492 patients and 3492 controls. The impact of untreated hypertension on the risk of ICH was higher in the lower than in the upper age quartile (OR 11.64, 95% CI 7.68 to 17.63 in Q1 vs OR 6.05, 95% CI 3.09 to 11.85 in Q4 with intermediate ORs in Q2 and Q3), while the opposite trend was observed for untreated hypercholesterolaemia (OR 0.63, 95% CI 0.45 to 0.97 in Q1 vs OR 0.36, 95% CI 0.26 to 0.56 in Q4 with intermediate ORs in Q2 and Q3). The effect of untreated diabetes and excessive alcohol intake was detected only in the older age group (OR 3.63, 95% CI 1.22 to 10.73, and OR 1.69, 95% CI 1.13 to 2.51, respectively).ConclusionsOur findings provide evidence of age-dependent differences in the effects of susceptibility factors on the risk of ICH.

Background and purpose Whether the reported association between migraine with aura (MA) and cardioembolic stroke may be explained by a higher rate of atrial fibrillation (AF) or by other potential cardiac sources of cerebral embolism remains to be determined.Methods In the setting of a single centre cohort study of consecutive patients with acute brain ischaemia stratified by migraine status, the association between AF as well as patent foramen ovale (PFO) and migraine was explored.Results In all, 1738 patients (1017 [58.5%] men, mean age 67.9 +/- 14.9 years) qualified for the analysis. Aging was inversely associated with migraine, whilst women had a >3-fold increased disease risk (odds ratio [OR] 3.82, 95% confidence interval [CI] 2.58-5.66). No association between AF and history of migraine or its pathogenic subtypes was detected. Conversely, migraine was associated with PFO, both in the entire cohort (OR 1.84, 95% CI 1.07-3.16) and in patients aged

Background and Purpose: Clinical trials on stroke prevention in patients with atrial fibrillation have consistently shown clinical benefit from either warfarin or non–vitamin K antagonist oral anticoagulants (NOACs). NOAC-treated patients have consistently reported to be at lower risk for intracerebral hemorrhage (ICH) than warfarin-treated patients. The aims of this prospective, multicenter, multinational, unmatched, case-control study were (1) to investigate for risk factors that could predict ICH occurring in patients with atrial fibrillation during NOAC treatment and (2) to evaluate the role of CHA 2 DS 2 -VASc and HAS-BLED scores in the same setting. Methods: Cases were consecutive patients with atrial fibrillation who had ICH during NOAC treatment. Controls were consecutive patients with atrial fibrillation who did not have ICH during NOAC treatment. As within the CHA 2 DS 2 -VASc and HAS-BLED scores there are some risk factors in common, several multivariable logistic regression models were performed to identify independent prespecified predictors for ICH events. Results: Four hundred nineteen cases (mean age, 78.8±8.1 years) and 1526 controls (mean age, 76.0±10.3 years) were included in the study. From the different models performed, independent predictors of ICH were increasing age, concomitant use of antiplatelet agents, active malignancy, high risk of fall, hyperlipidemia, low clearance of creatinine, peripheral artery disease, and white matter changes. Low doses of NOACs (given according to label or not) and congestive heart failure were inversely associated with the risk of ICH. HAS-BLED and CHA 2 DS 2 -VASc scores performed poorly in predicting ICH with areas under the curves of 0.496 (95% CI, 0.468–0.525) and 0.530 (95% CI, 0.500–0.560), respectively. Conclusions: Several risk factors were associated to ICH in patients treated with NOACs for stroke prevention but not HAS-BLED and CHA 2 DS 2 -VASc scores.

Objective To characterize patients with acute ischemic stroke related to SARS-CoV-2 infection and assess the classification performance of clinical and laboratory parameters in predicting in-hospital outcome of these patients. Methods In the setting of the STROKOVID study including patients with acute ischemic stroke consecutively admitted to the ten hub hospitals in Lombardy, Italy, between March 8 and April 30, 2020, we compared clinical features of patients with confirmed infection and non-infected patients by logistic regression models and survival analysis. Then, we trained and tested a random forest (RF) binary classifier for the prediction of in-hospital death among patients with COVID-19. Results Among 1013 patients, 160 (15.8%) had SARS-CoV-2 infection. Male sex (OR 1.53; 95% CI 1.06–2.27) and atrial fibrillation (OR 1.60; 95% CI 1.05–2.43) were independently associated with COVID-19 status. Patients with COVID-19 had increased stroke severity at admission [median NIHSS score, 9 (25th to75th percentile, 13) vs 6 (25th to75th percentile, 9)] and increased risk of in-hospital death (38.1% deaths vs 7.2%; HR 3.30; 95% CI 2.17–5.02). The RF model based on six clinical and laboratory parameters exhibited high cross-validated classification accuracy (0.86) and precision (0.87), good recall (0.72) and F1-score (0.79) in predicting in-hospital death. Conclusions Ischemic strokes in COVID-19 patients have distinctive risk factor profile and etiology, increased clinical severity and higher in-hospital mortality rate compared to non-COVID-19 patients. A simple model based on clinical and routine laboratory parameters may be useful in identifying ischemic stroke patients with SARS-CoV-2 infection who are unlikely to survive the acute phase.

Supplemental material, sj-pdf-1-eso-10.1177_23969873231186863 for Anticoagulation in acute ischemic stroke patients with mechanical heart valves: To bridge or not with heparin. The ESTREM study by Maurizio Paciaroni, Valeria Caso, Michele Romoli, Cecilia Becattini, Alexander Salerno, Costanza Rapillo, Fanny Simonnet, Davide Strambo, Isabella Canavero, Marialuisa Zedde, Rosario Pascarella, Sung-Il Sohn, Simona Sacco, Raffaele Ornello, Kristian Barlinn, Daniela Schoene, Jan Rahmig, Maria Giulia Mosconi, Ilaria Leone De Magistris, Andrea Alberti, Michele Venti, Giorgio Silvestrelli, Alfonso Ciccone, Marina Padroni, Michele Laudisi, Andrea Zini, Luana Gentile, Odysseas Kargiotis, Georgios Tsivgoulis, Rossana Tassi, Francesca Guideri, Maurizio Acampa, Luca Masotti, Elisa Grifoni, Alessandro Rocco, Marina Diomedi, Theodore Karapanayiotides, Stefan T Engelter, Alexandros A Polymeris, Annaelle Zietz, Fabio Bandini, Pietro Caliandro, Giuseppe Reale, Marco Moci, Aurelia Zauli, Manuel Cappellari, Andrea Emiliani, Antonio Gasparro, Valeria Terruso, Marina Mannino, Elisa Giorli, Danilo Toni, Marco Andrighetti, Anne Falcou, Lina Palaiodimou, George Ntaios, Dimitrios Sagris, Efstathia Karagkiozi, Anastasia Adamou, Panagiotis Halvatsiotis, Yuriy Flomin, Umberto Scoditti, Antonio Genovese, Nemanja Popovic, Leonardo Pantoni, Francesco Mele, Nicola Molitierno, Piergiorgio Lochner, Alessandro Pezzini, Massimo Del Sette, Davide Sassos, Sotirios Giannopoulos, Maria Kosmidou, Evangelos Ntais, Enrico Maria Lotti, Vincenzo Mastrangelo, Alberto Chiti, Andrea Naldi, Peter Vanacker, Mario Ferrante, Vera Volodina, Michelangelo Mancuso, Nicola Giannini, Marco Baldini, Kostantinos Vadikolias, Sofia Kitmeridou, Carlo Emanuele Saggese, Tiziana Tassinari, Valentina Saia and Patrik Michel in European Stroke Journal

Supplemental material, sj-docx-3-eso-10.1177_23969873231182207 for Reversible cerebral Vasoconstriction syndrome intERnational CollaborativE (REVERCE) network: Study protocol and rationale of a multicentre research collaboration by Kristin Sophie Lange, So Youn Choi, Yu-Hsiang Ling, Shih-Pin Chen, Jérôme Mawet, Claire Duflos, Mi Ji Lee, Anne Ducros, Shuu-Jiun Wang and Alessandro Pezzini in European Stroke Journal

Supplemental material, sj-docx-1-eso-10.1177_23969873231182207 for Reversible cerebral Vasoconstriction syndrome intERnational CollaborativE (REVERCE) network: Study protocol and rationale of a multicentre research collaboration by Kristin Sophie Lange, So Youn Choi, Yu-Hsiang Ling, Shih-Pin Chen, Jérôme Mawet, Claire Duflos, Mi Ji Lee, Anne Ducros, Shuu-Jiun Wang and Alessandro Pezzini in European Stroke Journal

Supplemental material, sj-docx-5-eso-10.1177_23969873231182207 for Reversible cerebral Vasoconstriction syndrome intERnational CollaborativE (REVERCE) network: Study protocol and rationale of a multicentre research collaboration by Kristin Sophie Lange, So Youn Choi, Yu-Hsiang Ling, Shih-Pin Chen, Jérôme Mawet, Claire Duflos, Mi Ji Lee, Anne Ducros, Shuu-Jiun Wang and Alessandro Pezzini in European Stroke Journal

Supplemental material, sj-docx-2-eso-10.1177_23969873231182207 for Reversible cerebral Vasoconstriction syndrome intERnational CollaborativE (REVERCE) network: Study protocol and rationale of a multicentre research collaboration by Kristin Sophie Lange, So Youn Choi, Yu-Hsiang Ling, Shih-Pin Chen, Jérôme Mawet, Claire Duflos, Mi Ji Lee, Anne Ducros, Shuu-Jiun Wang and Alessandro Pezzini in European Stroke Journal

Supplemental material, sj-docx-4-eso-10.1177_23969873231182207 for Reversible cerebral Vasoconstriction syndrome intERnational CollaborativE (REVERCE) network: Study protocol and rationale of a multicentre research collaboration by Kristin Sophie Lange, So Youn Choi, Yu-Hsiang Ling, Shih-Pin Chen, Jérôme Mawet, Claire Duflos, Mi Ji Lee, Anne Ducros, Shuu-Jiun Wang and Alessandro Pezzini in European Stroke Journal

Background: The cerebrospinal fluid (CSF) molecular milieu is a marker of diffuse intrathecal inflammation in the meninges that, in turn, targets the grey matter (GM) in multiple sclerosis (MS). Cognitive impairment (CI) is associated with brain damage in MS and is often present early in people with MS (pwMS). Objective: To investigate whether a specific CSF inflammatory profile is associated with different degrees of CI in newly diagnosed pwMS. Methods: Sixty-nine pwMS and 43 healthy controls (HCs) underwent neuropsychological testing. The presence and levels of 57 inflammatory mediators in the CSF were assessed. Results: Apparently cognitively normal (ACN) pwMS had impaired executive functioning compared to HCs but performed better than pwMS with mild and severe CI (mCI and sCI) in all tests. CSF mediators involving innate immunity and immune activation and recruitment, differentiate ACN from pwMS with mCI, while CSF mediators related to B- and T-cell immunity and chemotaxis differentiate both ACN and mCI from those with sCI. CXCL13 was the only molecule that differentiated sCI from mCI pwMS. Conclusion: Specific CSF molecular patterns, reflecting the involvement of both innate and adaptive immune responses, are associated with the severity of CI in newly diagnosed pwMS.

Background: Solid Dispersions (SDs) have been extensively used to increase the dissolution of poorly water-soluble drugs. However, there are few studies exploring SDs properties that must be considered during tablet development, like tabletability. Poorly water-soluble drugs with poor compression properties and high therapeutic doses, like gemfibrozil, are an additional challenge in the production of SDs-based tablets. Objective: This study evaluates the applicability of SDs to improve both tabletability and dissolution rate of gemfibrozil. A SD-based tablet formulation was also proposed. Methods: SDs were prepared by ball milling, using hydroxypropyl methylcellulose (HPMC) as a carrier, according to a 23 factorial design. The formulation variables were gemfibrozil:HPMC ratio, milling speed, and milling time. The response in the factorial analysis was the tensile strength of the compacted SDs. Dissolution rate and solid-state characterization of SDs were also performed. Results: SDs showed simultaneous drug dissolution enhancement and improved tabletability when compared to corresponding physical mixtures and gemfibrozil. The main variable influencing drug dissolution and tabletability was the gemfibrozil:HPMC ratio. Tablets containing gemfibrozil-HPMC-SD (1:0.250 w/w) and croscarmellose sodium showed fast and complete drug release while those containing the same SD and sodium starch glycolate exhibited poor drug release due to their prolonged disintegration time. Conclusion: SDs proved to be effective for simultaneously improving tabletability and dissolution profile of gemfibrozil. Tablets containing gemfibrozil-HPMC-SD and croscarmellose sodium as disintegrating agent showed improved drug release and good mechanical strength, demonstrating the potential of HPMC-based SDs to simultaneously overcome the poor dissolution and tabletability properties of this drug.

Supplemental Digital Content is available in the text., Background and Purpose: Timely reperfusion is an important goal in treatment of eligible patients with acute ischemic stroke. However, during the coronavirus disease 2019 (COVID-19) pandemic, prehospital and in-hospital emergency procedures faced unprecedented challenges, which might have caused a decline in the number of acute reperfusion therapy applied and led to a worsening of key quality measures for this treatment during lockdown. Methods: This prospective multicenter cohort study used data from the TRISP (Thrombolysis in Ischemic Stroke Patients) registry of patients with acute ischemic stroke treated with reperfusion therapies, that is, intravenous thrombolysis or endovascular therapy. We compared prehospital and in-hospital time-based performance measures (stroke-onset-to-admission, admission-to-treatment, admission-to-image, and image-to-treatment time) during the first 6 weeks after announcement of lockdown (lockdown period) with the same period in 2019 (reference period). Secondary outcomes included stroke severity (National Institutes of Health Stroke Scale) after 24 hours and occurrence of symptomatic intracranial hemorrhage (following the ECASS [European-Australasian Acute Stroke Study]-II criteria). Results: Across 20 stroke centers, 540 patients were treated with intravenous thrombolysis/endovascular therapy during lockdown period compared with 578 patients during reference period (−7% [95% CI, 5%–9%]). Performance measures did not change significantly during the lockdown period (2020/2019 minutes median: onset-to-admission 133/145; admission-to-treatment 51/48). Same was true for admission-to-image (20/19) and image-to-treatment (31/30) time in patients with available time of first image (n=871, 77.9%). Median National Institutes of Health Stroke Scale on admission (2020/2019: 11/11) and after 24 hours (2020/2019: 6/5) and percentage of symptomatic intracranial hemorrhage (2020/2019: 6.2/5.7) did not differ significantly between both periods. Conclusions: The COVID-19 pandemic lockdown resulted in a mild decline in the number of patients with stroke treated with acute reperfusion therapies. More importantly, the solid stability of key quality performance measures between the 2020 and 2019 period may indicate resilience of acute stroke care service during the lockdown, at least in well-established European stroke centers.

As the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) epidemic spreads, it is becoming increasingly evident that coronavirus disease 2019 (COVID-19) is not limited to the respiratory system, and that other organs can be affected. In particular, virus-related neurological manifestations are being reported more and more frequently in the scientific literature. In this article, we review the literature on the association between COVID-19 and neurological manifestations, present evidence from preclinical research suggesting that SARS-CoV-2 could be responsible for many of these manifestations, and summarize the biological pathways that could underlie each neurological symptom. Understanding the mechanisms that lead to neurological manifestations in patients with COVID-19 and how these manifestations correlate with clinical outcomes will be instrumental in guiding the optimal use of targeted therapeutic strategies., In this Perspective, Pezzini and Padovani critique the evidence for neurological manifestations of COVID-19, including epidemiological, neuropathological and neuroimaging data, and highlight the need for further work to establish whether SARS-CoV-2 is responsible for these symptoms.

Introduction The aim of this study in patients with acute posterior ischaemic stroke (PS) and atrial fibrillation (AF) was to evaluate (1) the risks of recurrent ischaemic event and severe bleeding and (2) these risks in relation with oral anticoagulant therapy (OAT) and its timing. Materials and Methods Patients with PS were prospectively included; the outcome events of these patients were compared with those of patients with anterior stroke (AS) which were taken from previous registries. The primary outcome was the composite of stroke recurrence, transient ischaemic attack, symptomatic systemic embolism, symptomatic cerebral bleeding and major extracranial bleeding occurring within 90 days from acute stroke. Results A total of 2470 patients were available for the analysis: 473 (19.1%) with PS and 1997 (80.9%) with AS. Over 90 days, 213 (8.6%) primary outcome events were recorded: 175 (8.7%) in patients with AS and 38 (8.0%) in those with PS. In patients who initiated OAT within 2 days, the primary outcome occurred in 5 out of 95 patients (5.3%) with PS compared to 21 out of 373 patients (4.3%) with AS (OR 1.07; 95% CI 0.39–2.94). In patients who initiated OAT between days 3 and 7, the primary outcome occurred in 3 out of 103 patients (2.9%) with PS compared to 26 out of 490 patients (5.3%) with AS (OR 0.54; 95% CI 0.16–1.80). Discussion our findings suggest that, when deciding the time to initiate oral anticoagulation, the location of stroke, either anterior or posterior, does not predict the risk of outcome events. Conclusions Patients with PS or AS and AF appear to have similar risks of ischaemic or haemorrhagic events at 90 days with no difference concerning the timing of initiation of OAT.

The SARS-CoV-2 epidemic is pressuring health care systems worldwide. Disease outcomes in certain subgroups of patients are still scarce, and data are needed. Therefore, we describe here the experience of four dialysis centers of the Brescia Renal COVID task force. During March 2020, within an overall population of 643 hemodialysis patients, SARS-CoV-2 RNA positivity was detected in 94 (15%). At disease diagnosis, 37 of the 94 (39%) patients (group 1) were managed on an outpatient basis whereas the remaining 57 (61%) (group 2) required hospitalization. Choices regarding management strategy were made based on disease severity. In group 1, 41% received antivirals and 76% hydroxychloroquine. Eight percent died and 5% developed acute respiratory distress syndrome (ARDS). In group 2, 79% received antivirals and 77% hydroxychloroquine. Forty two percent died and 79% developed ARDS. Overall mortality rate for the entire cohort was 29%. History of ischemic cardiac disease, fever, older age (over age 70) and dyspnea at presentation were associated with the risk of developing ARDS whereas fever, cough and a C-reactive protein higher than 50 mg/l at disease presentation were associated with the risk of death. Thus, in our population of hemodialysis patients with SARS-CoV-2 infection, we documented a wide range of disease severity. The risk of ARDS and death is significant for patients requiring hospital admission at disease diagnosis., Graphical abstract

ObjectiveTo evaluate whether pretreatment with metformin (MET) is associated with less stroke severity and better outcome after IV thrombolysis (IVT), we analyzed a cohort of 1,919 patients with stroke with type 2 diabetes mellitus in a multicenter exploratory analysis.MethodsData from patients with diabetes and ischemic stroke treated with IVT were collected within the European Thrombolysis in Ischemic Stroke Patients (TRISP) collaboration. We applied propensity score matching (PSM) to obtain balanced baseline characteristics of patients treated with and without MET.ResultsOf 1,919 patients with stroke with type 2 diabetes who underwent IVT, 757 (39%) had received MET before stroke (MET+), whereas 1,162 (61%) had not (MET−). MET+ patients were younger with a male preponderance. Hypercholesterolemia and pretreatment with statins, antiplatelets, or antihypertensives were more common in the MET+ group. After PSM, the 2 groups were well balanced with respect to demographic and clinical aspects. Stroke severity on admission (NIH Stroke Scale 10.0 ± 6.7 vs 11.3 ± 6.5), 3-month degree of independence on modified Rankin Scale (2 [interquartile range (IQR) 1.0–4.0] vs 3 [IQR 1.0–4.0]), as well as mortality (12.5% vs 18%) were significantly lower in the MET+ group. The frequency of symptomatic intracerebral hemorrhages did not differ between groups. HbA1c levels were well-balanced between the groups.ConclusionsPatients with stroke and diabetes on treatment with MET receiving IVT had less severe strokes on admission and a better functional outcome at 3 months. This suggests a protective effect of MET resulting in less severe strokes as well as beneficial thrombolysis outcome.

Introduction Alterations in haemoglobin levels are frequent in stroke patients. The prognostic meaning of anaemia and polyglobulia on outcomes in patients treated with intravenous thrombolysis is ambiguous. Patients and methods In this prospective multicentre, intravenous thrombolysis register-based study, we compared haemoglobin levels on hospital admission with three-month poor outcome (modified Rankin Scale 3–6), mortality and symptomatic intracranial haemorrhage (European Cooperative Acute Stroke Study II-criteria (ECASS-II-criteria)). Haemoglobin level was used as continuous and categorical variable distinguishing anaemia (female: 15.5 g/dl; male: >17 g/dl). Anaemia was subdivided into mild and moderate/severe (female/male: Results Among 6866 intravenous thrombolysis-treated stroke patients, 5448 (79.3%) had normal haemoglobin level, 1232 (17.9%) anaemia – of those 903 (13.2%) had mild and 329 (4.8%) moderate/severe anaemia – and 186 (2.7%) polyglobulia. Anaemia was associated with poor outcome (ORadjusted 1.25 (1.05–1.48)) and mortality (ORadjusted 1.58 (1.27–1.95)). In anaemia subgroups, both mild and moderate/severe anaemia independently predicted poor outcome (ORadjusted 1.29 (1.07–1.55) and 1.48 (1.09–2.02)) and mortality (ORadjusted 1.45 (1.15–1.84) and ORadjusted 2.00 (1.46–2.75)). Each haemoglobin level decrease by 1 g/dl independently increased the risk of poor outcome (ORadjusted 1.07 (1.02–1.11)) and mortality (ORadjusted 1.08 (1.02–1.15)). Anaemia was not associated with occurrence of symptomatic intracranial haemorrhage. Polyglobulia did not change any outcome. Discussion The more severe the anaemia, the higher the probability of poor outcome and death. Severe anaemia might be a target for interventions in hyperacute stroke. Conclusion Anaemia on admission, but not polyglobulia, is a strong and independent predictor of poor outcome and mortality in intravenous thrombolysis-treated stroke patients.

Long-term consequences of cervical artery dissection (CeAD), a major cause of ischemic stroke in young people, have been poorly investigated. The Italian Project on Stroke at Young Age - Cervical Artery Dissection (IPSYS CeAD) project is a multicenter, hospital-based, consecutively recruiting, observational, cohort study aimed to address clinically important questions about long-term outcome of CeAD patients, which are not covered by other large-scale registries. Patients with radiologically diagnosed CeAD were consecutively included in the registry. Baseline demographic and clinical variables, as well as information on risk factors, were systematically collected for each eligible patient. Follow-up evaluations were conducted between 3 and 6 months after the initial event (t1) and then annually (t2 at 1 year, t3 at 2 years , and so on), in order to assess outcome events (long-term recurrent CeAD, any fatal/nonfatal ischemic stroke, transient ischemic attack (TIA), or other arterial thrombotic event, and death from any cause). Between 2000 and 2019, data from 1530 patients (age at diagnosis, 47.2 ± 11.5 years; women, 660 [43.1%]) have been collected at 39 Italian neurological centers. Dissection involved a single vessel in 1308 (85.5%) cases and caused brain ischemia in 1303 (85.1%) (190 TIA/1113 ischemic stroke). Longitudinal data are available for 1414 (92.4%) patients (median follow-up time in patients who did not experience recurrent events, 36.0 months [25th to 75th percentile, 63.0]). The collaborative IPSYS CeAD effort will provide novel information on the long-term outcome of CeAD patients. This could allow for tailored treatment approaches based on patients' individual characteristics.

Background and Purpose— We investigated whether subarachnoid extension (SAHE) of intracerebral hemorrhage (ICH) is associated with hematoma expansion (HE). Methods— Retrospective analysis of patients with primary spontaneous ICH admitted at 3 academic hospitals in Italy. The study population was divided into a development and a replication cohort. SAHE was rated on baseline noncontrast computed tomography by investigators blinded to clinical data. The main outcome of interest was HE, defined as ICH growth >33% mL and/or >6 mL. Predictors of HE were explored with multivariable logistic regression stratified by ICH location (lobar versus nonlobar). Results— A total of 360 and 192 patients were included in the development and replication cohort, respectively. SAHE was identified with good interrater reliability ( K =0.82), and its frequency was 27.8% in the development and 24.5% in the replication cohort. In univariate analysis, HE was more common in patients with SAHE (52.0% versus 27.3%; P P =0.001) whereas there was no association with HE in nonlobar ICH (odds ratio, 0.55 [95% CI, 0.17–1.84]; P =0.334). The increased risk of HE in lobar ICH with SAHE was confirmed in the replication cohort (odds ratio, 3.46 [95% CI, 1.07–11.20]; P =0.038). Conclusions— SAHE predicts HE in lobar ICH. This may improve the stratification of HE risk in clinical practice or future trials targeting HE. Further research is needed to confirm our findings and characterize the underlying biological mechanisms.

Chronic liver disease is an important cause of morbidity and mortality among people living with human immunodeficiency virus (HIV) and is frequently related to non-alcoholic fatty liver disease (NAFLD). The objective is to estimate the prevalence and risk factors of hepatic steatosis among consecutive patients with stable HIV infection on antiretroviral therapy (ART). Also, the use of transient elastography (TE) as a mean to identify a subgroup at risk for non-alcoholic steatohepatitis (NASH) and/or liver fibrosis. HIV infected patients were enrolled between August2016 and February2017. Inclusion criteria: ≥18 years with undetectable HIV viral load. Exclusion criteria: pregnancy; alcohol intake ≥20 g/day and co-infection B or C viruses. Patients underwent ultrasound (US) to diagnose liver steatosis. Significant fibrosis (≥F2) was estimated if at least one of the following were present: APRI > 1.0, FIB4 > 3 and/or liver stiffness ≥7.1kPa. Subjects with TE ≥ 7.1kPa were proposed a liver biopsy and NAFLD Scoring System (NAS) ≥ 3 was considered as diagnosis of NASH. A total of 98 patients were included. Liver steatosis was diagnosed in 31 patients (31.6%) and was independently associated with male gender, BMI, ALT and total bilirubin levels. The prevalence of significant fibrosis assessed by TE, APRI and FIB4 was 26.9%, 6.4% and 3.2%, respectively. Seven patients had a TE result ≥7.1kPa. NASH was found in 5 (83.3%). Among HIV infected patients undergoing ART, almost one third have NAFLD. Neither TE, APRI or FIB4 were able to act as surrogates for significant liver fibrosis. Nevertheless, TE ≥ 7.1kPa was able to accurately select a subgroup of patients at risk for NASH.

Background The diagnostic accuracy of reflectance confocal microscopy (RCM) of cutaneous malignant melanoma (MM) seems promising. However, clinical scenarios in which RCM is most useful are still to be established. Objectives To assess the diagnostic accuracy of RCM for MM diagnosis according to study design, lesion type and diagnostic modality. Secondary outcomes include a comparison with dermoscopy. Methods A systematic literature search was conducted on PubMed, Embase, Scopus and Cochrane Public Library Databases for English articles published prior to January 2019. Statistical analyses were conducted with Meta-Disc v. 1.4, STATA 14.0 software and the QUADAS-2 tool. Results A total of 32 studies (7352 lesions) were included in the meta-analysis. Pooled sensitivity and specificity resulted 92% (95% CI: 0.91-0.93) and 70% (95% CI: 0.69-0.71), respectively. According to study design, diagnostic sensitivity was high for all study types, confirming a lower specificity for prospective interventional studies. Diagnostic accuracy remained high for all lesion types, with the highest specificity obtained for consecutive lesions of 77% (95% CI: 0.75-0.78) vs. 65% (95% CI: 0.63-0.66) for lesions highly suspicious for MM. RCM diagnostic accuracy was superior to dermoscopy, most notably in terms of specificity of 56% (95% CI: 0.52-0.60) vs. 38% (95% CI: 0.34-0.42), respectively. Studies were generally assessed across all domains as low or unclear risk of bias with a mainly low concern regarding applicability of evidence. Publication bias was asymmetrical (11.2 ± 4.0; 95% CI 2.97-19.43; P Conclusions Independent of study design, RCM has a high diagnostic power for MM detection, and unnecessary excisions are reduced compared to dermoscopy. This reduction is most evident in non-decisional RCM scenarios and for lesions analysed at RCM consecutively compared to those selected highly suspicious for MM. However, the scarcity, heterogeneity and bias associated with the data in literature should be considered when interpreting present conclusions.

Sicily, during the 9th-12thcentury AD, thrived politically, economically, and culturally under Islamic political rule and the capital of Palermo stood as a cultural and political centre in the Mediterranean Islamic world. However, to what extent the lifeways of the people that experienced these regimes were impacted during this time is not well understood, particularly those from lesser studied rural contexts. This paper presents the first organic residue analysis of 134 cooking pots and other domestic containers dating to the 9th-12thcentury in order to gain new insights into the culinary practices during this significant period. Ceramics from three sites in the urban capital of Palermo and from the rural town of Casale San Pietro were analysed and compared. The multi-faceted organic residue analysis identified a range of commodities including animal products, vegetables, beeswax, pine and fruit products in the ceramics, with a complex mixing of resources observed in many cases, across all four sites and ceramic forms. Alongside the identification of commodities and how they were combined, new light has been shed on the patterning of resource use between these sites. The identification of dairy products in calcite wares from the rural site of Casale San Pietro and the absence of dairy in ceramics from the urban centre of Palermo presents interesting questions regarding the role of rural sites in food consumption and production in Islamic Sicily. This is the first time organic residue analysis of ceramics has been used to explore foodways in a medieval multi-faith society and offers new pathways to the understanding of pottery use and resources that were prepared, consumed and combined, reflecting cuisine in different socio-economic environments within the pluralistic population of medieval Sicily.

Objective The aim of this study is to evaluate the differences in clinical presentations and the impact of healthcare organization on outcomes of neurological COVID-19 patients admitted during the first and second pandemic waves. Methods In this single-center cohort study, we included all patients with SARS-CoV-2 infection admitted to a Neuro-COVID Unit. Demographic, clinical, and laboratory data were compared between patients admitted during the first and second waves of the COVID-19 pandemic. Results Two hundred twenty-three patients were included, of whom 112 and 111 were hospitalized during the first and second pandemic waves, respectively. Patients admitted during the second wave were younger and exhibited pulmonary COVID-19 severity, resulting in less oxygen support (n = 41, 36.9% vs n = 79, 70.5%, p p = 0.004). The different healthcare strategies and early steroid treatment emerged as significant predictors of mortality independently from age, pre-morbid conditions and COVID-19 severity in Cox regression analyses. Conclusions Differences in healthcare strategies during the second phase of the COVID-19 pandemic probably explain the differences in clinical outcomes independently of disease severity, underlying the importance of standardized early management of neurological patients with SARS-CoV-2 infection.

Objective: To investigate the safety and effectiveness of direct oral anticoagulants (DOAC) versus vitamin K antagonists (VKA) after recent stroke in patients with atrial fibrillation (AF) aged ≥85 years. Methods: Individual patient data analysis from seven prospective stroke cohorts. We compared DOAC versus VKA treatment among patients with AF and recent stroke (≥85y = 0.65, 95%-CI [0.52, 0.81]) and < 85 years (HR = 0.79, 95%-CI [0.66, 0.95]) in simple (p interaction = 0.129), adjusted (p interaction = 0.094) or weighted (p interaction = 0.512) models. Analyses on recurrent stroke, ICH and death separately were consistent with the primary analysis, as were sensitivity analyses using age dichotomized at 90 years and as a continuous variable. DOAC had a similar net clinical benefit in patients aged ≥85 (+1.73 to +2.66) and < 85 years (+1.90 to +3.36 events/100 patient-years for ICH-weights 1.5 to 3.1). Interpretation: The favorable profile of DOAC over VKA in patients with AF and recent stroke was maintained in the oldest old. ANN NEUROL 2021.

Background/objectives Non-invasive skin imaging features of main skin inflammatory and autoimmune diseases have been reported, although a comprehensive review of their correlation with histopathologic features is currently lacking. Therefore, the aim of this paper was to review the correlation of dermoscopic, reflectance confocal microscopy (RCM) and optical coherence tomography (OCT) criteria of main inflammatory and autoimmune skin diseases with their corresponding histopathologic criteria correlation. Methods Studies on human subjects affected by main inflammatory and autoimmune diseases, defining the correlation of dermoscopic, RCM or OCT with histopathologic criteria, were included in the review. Five groups of diseases were identified and described: psoriasiform, spongiotic and interface dermatitis, bullous diseases and scleroderma. Results Psoriasiform dermatitis was typified by white scales, corresponding to hyperkeratosis, and vessels, observed with RCM and OCT. Spongiosis, corresponding to dark areas within the epidermis with RCM and OCT, was the main feature of spongiotic dermatitis. Interface dermatitis was characterised by dermoepidermal junction obscuration. Blisters, typical of bullous diseases, were visualised as dark areas with RCM and OCT while scleroderma lesions were characterised by dermoscopic fibrotic beams, related to dermal thickness variations, with specific OCT and histopathologic correlations. Conclusions Although the role of RCM and OCT has yet to be defined in clinical practice, non-invasive skin imaging shows promising results on inflammatory and autoimmune skin diseases, due to the correlation with histopathologic features.

The authors will present a comprehensive account of the neurological aspects of SARS-CoV-2 infection. The aim is to provide a practical clinical book which will serve as a guide for clinicians from all specialties involved in the management of COVID-19 patients. The authors share the extensive clinical experience gained in major hospitals in Lombardy, the first European region to face the COVID-19 emergency in 2020. All are recognized international experts in their respective fields and have been involved in the management of COVID-19 cases from the very beginning of the Italian SARS-CoV-2 outbreak. The text begins with a description of pathobiological and pathophysiological aspects related to the involvement of the nervous system, moving on to the discussion of the neurological complications observed in COVID-19 patients; these range from central to peripheral symptoms, and can occur in the acute or post-acute phases of the disease. Further topics are: neuropathology, seizures and EEG, neuroimaging, delirium, encephalomyelitis, stroke, psychopathology and psychiatry, neuropsychology and cognitive impairment, neuromuscu-lar disorders, and the impact of COVID-19 on other pre-existing neurological disorders. In addi-tion, the book will discuss the new developments in teleneurology approaches, which have been a direct response to the ongoing pandemic. Finally, the possible neurological complications of the COVID-19 vaccines and the neurological complications in children will be considered.Each chapter will present a critical review of the existing literature concerning the specific subject matter, followed by practical clinical recommendations, as well as personal considerations based on the experience gained by each author during the course of the COVID-19 pandemic.Neurology of COVID-19 will be an original and innovative reference book for clinicians of all the specialties involved in the management of patients with SARS-CoV-2 infection. ________________________________________________ List of chapters ________________________________________________

Background and Purpose: Observational studies have suggested a link between fibromuscular dysplasia and spontaneous cervical artery dissection (sCeAD). However, whether patients with coexistence of the two conditions have distinctive clinical characteristics has not been extensively investigated. Methods: In a cohort of consecutive patients with first-ever sCeAD, enrolled in the setting of the multicenter IPSYS CeAD study (Italian Project on Stroke in Young Adults Cervical Artery Dissection) between January 2000 and June 2019, we compared demographic and clinical characteristics, risk factor profile, vascular pathology, and midterm outcome of patients with coexistent cerebrovascular fibromuscular dysplasia (cFMD; cFMD+) with those of patients without cFMD (cFMD–). Results: A total of 1283 sCeAD patients (mean age, 47.8±11.4 years; women, 545 [42.5%]) qualified for the analysis, of whom 103 (8.0%) were diagnosed with cFMD+. In multivariable analysis, history of migraine (odds ratio, 1.78 [95% CI, 1.13–2.79]), the presence of intracranial aneurysms (odds ratio, 8.71 [95% CI, 4.06–18.68]), and the occurrence of minor traumas before the event (odds ratio, 0.48 [95% CI, 0.26–0.89]) were associated with cFMD. After a median follow-up of 34.0 months (25th to 75th percentile, 60.0), 39 (3.3%) patients had recurrent sCeAD events. cFMD+ and history of migraine predicted independently the risk of recurrent sCeAD (hazard ratio, 3.40 [95% CI, 1.58–7.31] and 2.07 [95% CI, 1.06–4.03], respectively) in multivariable Cox proportional hazards analysis. Conclusions: Risk factor profile of sCeAD patients with cFMD differs from that of patients without cFMD. cFMD and migraine are independent predictors of midterm risk of sCeAD recurrence.

Cervical artery dissection (CeAD) is the most common cause of ischemic stroke in young and middle-aged adults. Over the last decade, a relation between CeAD and fibromuscular dysplasia (FMD), an idiopathic, segmental, non-atherosclerotic and non-inflammatory arterial disease, has been suggested based on a number of epidemiologic observations, while preliminary data support the idea that the two conditions may share common biologic mechanisms. In this article, we review the literature on the relation between CeAD and FMD, focus on the potential pathogenetic mechanisms common to the two conditions, summarize clinical features, management and outcome, and provide support to the hypothesis that the coexistence of the two diseases in one individual might be conceptualized as a distinct non-atherosclerotic non-inflammatory arteriopathy.

Objective Cerebral venous thrombosis (CVT) is an uncommon form of stroke affecting mostly young individuals. Although genetic factors are thought to play a role in this cerebrovascular condition, its genetic etiology is not well understood. Methods A genome-wide association study was performed to identify genetic variants influencing susceptibility to CVT. A 2-stage genome-wide study was undertaken in 882 Europeans diagnosed with CVT and 1,205 ethnicity-matched control subjects divided into discovery and independent replication datasets. Results In the overall case-control cohort, we identified highly significant associations with 37 single nucleotide polymorphisms (SNPs) within the 9q34.2 region. The strongest association was with rs8176645 (combined p = 9.15 x 10(-24); odds ratio [OR] = 2.01, 95% confidence interval [CI] = 1.76-2.31). The discovery set findings were validated across an independent European cohort. Genetic risk score for this 9q34.2 region increases CVT risk by a pooled estimate OR = 2.65 (95% CI = 2.21-3.20, p = 2.00 x 10(-16)). SNPs within this region were in strong linkage disequilibrium (LD) with coding regions of the ABO gene. The ABO blood group was determined using allele combination of SNPs rs8176746 and rs8176645. Blood groups A, B, or AB, were at 2.85 times (95% CI = 2.32-3.52, p = 2.00 x 10(-16)) increased risk of CVT compared with individuals with blood group O. Interpretation We present the first chromosomal region to robustly associate with a genetic susceptibility to CVT. This region more than doubles the likelihood of CVT, a risk greater than any previously identified thrombophilia genetic risk marker. That the identified variant is in strong LD with the coding region of the ABO gene with differences in blood group prevalence provides important new insights into the pathophysiology of CVT. ANN NEUROL 2021

ObjectiveThe systematic review aimed to compare agreement with behavior guidance techniques (BGT) between parents of children with special health care needs (SHCN) and those non-SHCN.MethodsA structured search of Cochrane Library, Latin American and Caribbean Health Sciences, PubMed, PsycInfo, Scopus, Web of Science, ProQuest Dissertations and Theses Database, Opengrey and Google Scholar was taken up to October 2020. Two authors selected studies independently, extracted the data, assessed the studies’ methodological quality using the Joanna Briggs scale and the Recommendations, Assessment, Development and Evaluation (GRADE).ResultsForty-eight studies covering the parents’ agreement with BGT were included and 41 were retained for random-effects proportion meta-analysis. The methodological quality assessment varied from low to high. Among the parents of non-SHCN children, the agreement with BGT varied from 84.1% (95% CI: 75.8-90.9; p2 93.3%) for tell-show-do to 25.7% (95% CI: 17.8-34.4; p2 90.4%) for passive protective stabilization, without hand-over-mouth. Among the parents of children with SHCN, the acceptance of BGT varied from 89.1% (95% CI: 56.1-99.7; p2 95.7%) for tell-show-do to 29.1% (95% CI: 11.8-50.0; p=0.001; I2 84.8%) to general anesthesia.ConclusionThere is very low certainty in evidence that both the parents of children SHCN and non-SHCN were more likely to agree with basic BGT and that they were less likely to agree with the advanced ones.

Introdução – Esta pesquisa teve o objetivo de analisar a aquisição fonológica e sua relação com dados demográficos e a deficiência de ferro em pré-escolares da cidade de Vicente Dutra-RS. Método – Foi realizado estudo transversal, utilizando dados de hemograma (hemoglobina, ferritina e saturação transferrina) e dados sobre a aquisição da linguagem oral e da escrita numa população de 51 crianças (26 meninas, 51%), com 5,3±0,3 anos de idade. Resultados – Não foi encontrada associação da deficiência de ferro com aquisição da linguagem oral e escrita. Contudo, foi observada associação entre as variáveis aquisição fonológica e hipótese de escrita (valor sonoro), p=0,006, e aquisição fonológica e desvios fonéticos (p=0,012). Conclusões – Os dados encontrados nesta pesquisa transversal não sugerem relação entre linguagem e deficiência de ferro; contudo, amostras maiores em estudos longitudinais seriam interessantes para melhor compreensão dos achados Introduction - This research aimed to analyze the phonological acquisition and its relationship with demographic data and iron deficiency in preschool children from Vicente Dutra-RS. Method - It was performed a cross-sectional study, using hemogram data (hemoglobin, ferritin and transferrin saturation), and data on acquisition of oral and written language in a population of 51 children (26 girls, 51%), with 5.3±0.3 years of age. Results - It was not found an association between iron deficiency and acquisition of oral and written language. However, it was observed an association between the variables phonological acquisition and chance of writing (value), p = 0.006, and phonological acquisition and phonetic deviations (p = 0.012). Conclusions - The data found in this cross-sectional research do not suggest a relationship between language and iron deficiency; however, larger samples in longitudinal studies would be interesting for a better understanding of the findings Introducción - Esta investigación tuvo el objetivo de analizar la adquisición fonológica y su relación con datos demográficos y la deficiencia de hierro en preescolares de la ciudad de Vicente Dutra-RS. Método – Se realizó un estudio transversal, utilizando datos de hemograma (hemoglobina, ferritina y saturación transferrina) y datos sobre la adquisición del lenguaje oral y de la escritura en una población de 51 niños (26 niñas, 51%), con 5,3 ± 0, 3 años de edad. Resultados - No se encontró asociación de la deficiencia de hierro con adquisición del lenguaje oral y escrito. Sin embargo, se observó asociación entre las variables de adquisición fonológica y hipótesis de escritura (valor sonoro), p = 0,006, y adquisición fonológica y desvíos fonéticos (p = 0,012). Conclusiones - Los datos encontrados en esta investigación transversal no sugieren una relación entre el lenguaje y la deficiencia de hierro; sin embargo, muestras más grandes en estudios longitudinales serían interesantes para una mejor comprensión de los hallazgos

Photodynamic therapy is a therapeutic resource used to treat different pathologies such as neoplasias and wound healing. It consists of a light coupled to a photosensitizer that is used to react with oxygen and forming reactive oxygen species that reach target cells. This study aimed to evaluate the effect of PDT on the healing of second-degree burns. The study used 45 Wistar Rattus Norvegicus divided into three groups, two with lesions and treatment and one with lesions and without treatment (control group). Group PDT6 was lesioned and treated with 630- nm LED PDT and group PDT9 was lesioned and treated with 945- nm LED PDT. The results suggest collagen deposition and development of cellular structures of normal tissue in the treated groups compared to the control groups. It was concluded that the PDT treatment induced enhanced tissue repair in the treated groups; the best results were observed using the 630- nm LED.

Background and PURPOSE Migraine has been shown to increase cerebral excitability, promote rapid infarct expansion into tissue with perfusion deficits, and result in larger infarcts in animal models of focal cerebral ischemia. Whether these effects occur in humans has never been properly investigated. METHODS In a series of consecutive patients with acute ischemic stroke, enrolled in the setting of the Italian Project on Stroke at Young Age, we assessed acute as well as chronic infarct volumes by volumetric magnetic resonance imaging, and compared these among different subgroups identified by migraine status. RESULTS A cohort of 591 patients (male, 53.8%; mean age, 37.5±6.4 years) qualified for the analysis. Migraineurs had larger acute infarcts than non-migraineurs (median, 5.9 cm3 [interquartile range (IQR), 1.4 to 15.5] vs. 2.6 cm3 [IQR, 0.8 to 10.1], P

Background and Purpose— Despite treatment with oral anticoagulants, patients with nonvalvular atrial fibrillation (AF) may experience ischemic cerebrovascular events. The aims of this case-control study in patients with AF were to identify the pathogenesis of and the risk factors for cerebrovascular ischemic events occurring during non–vitamin K antagonist oral anticoagulants (NOACs) therapy for stroke prevention. Methods— Cases were consecutive patients with AF who had acute cerebrovascular ischemic events during NOAC treatment. Controls were consecutive patients with AF who did not have cerebrovascular events during NOACs treatment. Results— Overall, 713 cases (641 ischemic strokes and 72 transient ischemic attacks; median age, 80.0 years; interquartile range, 12; median National Institutes of Health Stroke Scale on admission, 6.0; interquartile range, 10) and 700 controls (median age, 72.0 years; interquartile range, 8) were included in the study. Recurrent stroke was classified as cardioembolic in 455 cases (63.9%) according to the A-S-C-O-D (A, atherosclerosis; S, small vessel disease; C, cardiac pathology; O, other causes; D, dissection) classification. On multivariable analysis, off-label low dose of NOACs (odds ratio [OR], 3.18; 95% CI, 1.95–5.85), atrial enlargement (OR, 6.64; 95% CI, 4.63–9.52), hyperlipidemia (OR, 2.40; 95% CI, 1.83–3.16), and CHA 2 DS 2 -VASc score (OR, 1.72 for each point increase; 95% CI, 1.58–1.88) were associated with ischemic events. Among the CHA 2 DS 2 -VASc components, age was older and presence of diabetes mellitus, congestive heart failure, and history of stroke or transient ischemic attack more common in patients who had acute cerebrovascular ischemic events. Paroxysmal AF was inversely associated with ischemic events (OR, 0.45; 95% CI, 0.33–0.61). Conclusions— In patients with AF treated with NOACs who had a cerebrovascular event, mostly but not exclusively of cardioembolic pathogenesis, off-label low dose, atrial enlargement, hyperlipidemia, and high CHA 2 DS 2 -VASc score were associated with increased risk of cerebrovascular events.