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Summary Background Individuals who suffered a neurological adverse event after the Coronavirus disease (COVID-19) vaccine could hesitate and defer reimmunization. Aim We examine the risk of recurrence following reimmunization among patients who developed a neurological event after the first dose of the COVID-19 mRNA vaccine. Design Observational study. Methods Individuals who developed an adjudicated neurological adverse event (based on Brighton Collaboration criteria) within 6 weeks of the first dose of the COVID-19 vaccine requiring hospitalization were enrolled into a multicenter national registry in Singapore. Neurological recurrence, defined by the development of another neurological event within 6 weeks of the second vaccine dose, was reviewed. Clinical characteristics were compared between patients who chose to proceed or withhold further vaccination, and between those who received timely (3–6 weeks) or delayed (>6 weeks) reimmunization. Results From 235 patients (median age, 67 years; 63% men) who developed an adjudicated neurological event after their first dose of mRNA vaccine between 30 December 2020 and 20 April 2021, 181 (77%) chose to undergo reimmunization. Those who decided against reimmunization were older (median age, 74 vs. 66 years) and had greater physical disability following their primary neurological event (46% vs. 20%, P Conclusions A prior neurological event should not necessarily preclude reimmunization and the decision to proceed with reimmunization should consider the overwhelming benefits conferred by vaccination toward ending this pandemic.

BackgroundOutpatient medical follow-up post-stroke is not only crucial for secondary prevention but is also associated with a reduced risk of rehospitalization. However, being voluntary and non-urgent, it is potentially determined by both healthcare needs and the socio-demographic context of stroke survivor-caregiver dyads. Therefore, we aimed to examine the role of caregiver factors in outpatient medical follow-up (primary care (PC) and specialist outpatient care (SOC)) post-stroke.MethodStroke survivors and caregivers from the Singapore Stroke Study, a prospective, yearlong, observational study, contributed to the study sample. Participants were interviewed 3-monthly for data collection. Counts of PC and SOC visits were extracted from the National Claims Database. Poisson modelling was used to explore the association of caregiver (and patient) factors with PC/SOC visits over 0–3 months (early) and 4–12 months (late) post-stroke.ResultsFor the current analysis, 256 stroke survivors and caregivers were included. While caregiver-reported memory problems of a stroke survivor (IRR: 0.954; 95% CI: 0.919, 0.990) and caregiver burden (IRR: 0.976; 95% CI: 0.959, 0.993) were significantly associated with lower early post-stroke PC visits, co-residing caregiver (IRR: 1.576; 95% CI: 1.040, 2.389) and negative care management strategies (IRR: 1.033; 95% CI: 1.005, 1.061) were significantly associated with higher late post-stroke SOC visits.ConclusionWe demonstrated that the association of caregiver factors with outpatient medical follow-up varied by the type of service (i.e., PC versus SOC) and temporally. Our results support family-centred care provision by family physicians viewing caregivers not only as facilitators of care in the community but also as active members of the care team and as clients requiring care and regular assessments.

IntroductionPatients who had a stroke are at increased risk of sepsis, dehydration and fluctuations in blood pressure, which may result in acute kidney injury (AKI). The impact of AKI on long-term stroke survival has not been studied well.ObjectiveWe aimed to identify incidence of AKI during acute stroke, follow-up period and its impact on long-term survival and development of chronic kidney disease (CKD).Design, setting and participantsRetrospective analysis of patients who had a stroke admitted at the rehabilitation facility in Changi General Hospital, Singapore, between June 2008 and May 2017, with median follow-up of 141 (95% CI 120 to 163) months.Outcome measures and results of univariate analysisTotal 681 patients, median age (63.6) years, 173 (28%) died during follow-up. Elevated blood urea (3.02, 95% CI 2.17 to 4.22; p≤0.001) and creatinine (1.96, 95% CI 1.50 to 2.57; p≤0.001) during stroke affected survival adversely.Excluding patients with CKD, we analysed the remaining 617 patients. AKI was noted in 75 (12.15%) patients during the index admission, and it affected survival adversely (2.16, 95% CI 1.49 to 3.13; pConclusionsWe found AKI during stroke admission was associated with increased mortality as compared with those without AKI on univariate analysis. AKI without need of renal replacement therapy was also associated with progression to CKD in this cohort. This suggests that patients with AKI need to have their renal function monitored longitudinally for development of CKD.

Cerebral venous thrombosis (CVT) causes significant disability and mortality. Current guidelines for CVT management support the initial use of unfractionated heparin or low molecular weight heparin followed by longer-term oral vitamin K antagonist (VKA). There has been increasing, albeit limited, evidence for the use of direct oral anticoagulants (DOAC) as an alternative to VKA. We performed a systematic review and meta-analysis of studies that compared the safety and efficacy of DOACs to VKA in treating CVT. A comprehensive literature search was carried out in Medline, Embase and Cochrane Stroke Group Trials Register using a suitable keyword/MeSH term search strategy. All studies published in English comparing outcomes of patients with CVT treated with DOAC or VKA were included. In total, 6 studies (5 observational studies and 1 randomized clinical trial) comprising 412 patients (age range 16–83 years) were analyzed. DOAC was used in 151 patients, while 261 received VKA. The follow-up period was 3–11 months. The efficacy of DOACs was comparable with VKA in terms of partial or full thrombus recanalization (RR 1.02, 95% CI 0.89–1.16) and excellent functional recovery with modified Rankin scale

BackgroundInformal caregiving is an integral part of post-stroke recovery with strenuous caregiving demands often resulting in caregiving burden, threatening sustainability of caregiving and potentially impacting stroke survivor’s outcomes. Our study aimed to examine and quantify objective and subjective informal care burden after stroke; and to explore the factors associated with informal care burden in Singapore.MethodsStroke patients and their informal caregivers were recruited from all five tertiary hospitals in Singapore from December 2010 to September 2013. Informal care comprised of assistance provided by informal caregivers with any of the activities of daily living. Informal care burden was measured by patients’ likelihood of requiring informal care, hours of informal care required, and informal caregivers’ Zarit’s Burden Score. We examined informal care burden at 3-months and 12-months post-stroke. Generalized linear regressions were applied with control variables including patients’ and informal caregivers’ demographic characteristics, arrangement of informal care, and patients’ health status including stroke severity (measured using National Institute of Health Stroke Scale), functional status (measured using Modified Rankin Scale), self-reported depression, and common comorbidities.ResultsThree hundred and five patients and 263 patients were examined at 3-months and 12-months. Around 35% were female and 60% were Chinese. Sixty three percent and 49% of the patients required informal care at 3-months and 12-months point, respectively. Among those who required informal care, average hours required per week were 64.3 h at 3-months and 76.6 h at 12-months point. Patients with higher functional dependency were more likely to require informal care at both time points, and required more hours of informal care at 3-months point. Female informal caregivers and those caring for patients with higher functional dependency reported higher Zarit’s Burden. While informal caregivers who worked full-time reported higher burden, those caring for married stroke patients reported lower burden at 3-months point. Informal caregivers who co-cared with foreign domestic workers, i.e.: stay-in migrant female waged domestic workers, reported lower burden.ConclusionsInformal care burden remains high up to 12-months post-stroke. Factors such as functional dependency, stroke severity, informal caregiver gender and co-caring with foreign domestic workers were associated with informal care burden.

AimTo study the association of caregiver factors and stroke patient factors with rehospitalizations over the first 3 months and subsequent 3–12 months post-stroke in Singapore.MethodsPatients with stroke and their caregivers were recruited in the Singapore Stroke Study, a prospective yearlong cohort. While caregiver and patient variables were taken from this study, hospitalization data were extracted from the national claims database. We used Poisson modelling to perform bivariate and multivariable analysis with counts of hospitalization as the outcome.ResultsTwo hundred and fifty-six patient with stroke and caregiver dyads (N = 512) were analysed, with patients having spouse (60%), child (29%), sibling (4%) and other (7%) as their caregivers. Among all participants, 89% of index strokes were ischemic, 57% were mild in severity and more than half (59%) of the patients had moderate or severe disability post-stroke as measured on the Modified Rankin Scale. Having social support in the form of a foreign domestic worker for general help of caregiver reduced the hospitalization rate over 3 months post-stroke by 66% (IRR: 0.342; 95% CI: 0.180, 0.651). Compared to having a spousal caregiver, those with a child caregiver had an almost three times greater rate of hospitalizations over 3–12 months post-stroke (IRR: 2.896; 95% CI: 1.399, 5.992). Higher reported caregiving burden at the 3-month point was associated with the higher subsequent rate of hospitalization.ConclusionRecommendations include the adoption of a dyadic or holistic approach to post-stroke care provision by healthcare practitioners, giving due importance to both patients with stroke and their caregivers, integrating caregivers in the healthcare system to extend the care continuum to include informal care in the community and provision of timely support for caregivers.

Peer reviewed: True, OBJECTIVE: The aim of this systematic review is to evaluate the various modalities available for extended ECG monitoring in the detection of atrial fibrillation (AF) following a cryptogenic stroke. METHODS: MEDLINE (Ovid), EMBASE (Ovid), Cochrane Central Register of Controlled Trials (CENTRAL) were searched from January 2011 to November 2021. All randomised controlled trials and prospective cohort studies including the use of extended ECG monitoring >24 hours with a minimum duration of AF of 30 s in patients with either cryptogenic strokes or transient ischaemic attacks were included. A random-effects model was used to pool effect estimates of AF detection rates from different ECG modalities. RESULTS: 3924 studies were identified, of which 47 were included reporting on a pooled population of 6448 patients with cryptogenic stroke. The pooled AF rate for implantable loop recorders (ILRs) increased from 4.9% (3.0%-7.9%) at 1 month to 38.4% (20.4%-60.2%) at 36 months. Mobile cardiac outpatient telemetry (MCOT) had a significantly higher pooled AF detection rate of 12.8% (8.9%-17.9%) versus 4.9% (3.0%-7.9%) for ILR at 1 month (p

Endovascular treatment (EVT) has strong evidence for its effectiveness in treatment of acute ischemic stroke (AIS); however, up to half of the patients who undergo EVT still do not have good functional outcomes. Various prethrombectomy radiological factors have been shown to be associated with good clinical outcomes and may be the key to better functional outcomes, reduced complications, and reduced mortality. In this paper, we reviewed the current literature on these imaging parameters so they can be employed to better estimate the probability of procedural success, therefore allowing for more effective preprocedural planning of EVT strategies. We reviewed articles in the literature related to imaging factors which have been shown to be associated with EVT success. The factors which are reviewed in this paper included: anatomical factors such as 1) the type of aortic arch and its characteristics, 2) the characteristics of the thrombus such as length, clot burden, permeability, location, 3) the middle cerebral artery features including the tortuosity and underlying intracranial stenosis, 4) perfusion scans estimating the volume of infarct and the penumbra and 5) the effect of collaterals on the procedure. The prognostic effect of each factor on the successful outcome of EVT is described. The identification of preprocedural thrombectomy imaging factors can help to improve the chances of recanalization, functional outcomes, and mortality. It allows the interventionist to make time-sensitive decisions in the treatment of acute ischemic stroke.

Background: Acute ischemic stroke (AIS) is a life-threatening complication of coronavirus disease 2019 (COVID-19) infection. Increasing reports suggest an association between COVID-19 and AIS, although the underlying mechanism remains uncertain. Objectives: We performed a systematic review to characterize the clinical characteristics, neuroimaging findings, and outcomes of AIS in COVID-19 patients. Methods: A literature search was performed in PubMed and Embase using a suitable keyword search strategy from 1st December 2019 to 29th May 2020. All studies reporting AIS occurrence in COVID-19 patients were included. Results: A total of 39 studies comprising 135 patients were studied. The pooled incidence of AIS in COVID-19 patients from observational studies was 1.2% (54/4466) with a mean age of 63.4 ± 13.1 years. The mean duration of AIS from COVID-19 symptoms onset was 10 ± 8 days, and the mean NIHSS score was 19 ± 8. Laboratory investigations revealed an elevated mean D-dimer (9.2 ± 14.8 mg/L) and fibrinogen (5.8 ± 2.0 g/L). Antiphospholipid antibodies were detected in a significant number of cases. The majority of AIS neuroimaging patterns observed was large vessel thrombosis, embolism or stenosis (62.1%, 64/103), followed by multiple vascular territory (26.2%, 27/103). A high mortality rate was reported (38.0%, 49/129). Conclusion: We report the pooled incidence of AIS in COVID-19 patients to be 1.2%, with a high mortality rate. Elevated D-dimer, fibrinogen and the presence of antiphospholipid antibodies appear to be prominent in COVID-19 patients with concomitant AIS, but further mechanistic studies are required to elucidate their role in pathogenesis.

Introduction: Endovascular thrombectomy(EVT) is considered standard of care for anterior circulation acute ischemic stroke(AIS) with large vessel occlusion(LVO). Young AIS-LVO patients have distinctly different underlying stroke mechanisms and etiologies. Methods: In this multicenter cohort study conducted from August 2014 to January 2020, we investigated the safety and effectiveness of EVT in young AIS-LVO patients aged≤50 years and evaluated associations between demographics, stroke etiology, neuroimaging factors and clinical outcomes, including functional outcomes, in-hospital mortality and symptomatic intracranial haemorrhage(sICH) in univariable and multivariable regression models. Results: 275 AIS-LVO patients from 10 tertiary centers in Germany, Sweden, Singapore and Taiwan were included. The more common TOAST subtypes included cardioembolism (82/275, 29.8%) and stroke of undetermined etiology (85/275, 30.9%). Arterial dissection was the most prevalent stroke etiology (42/195, 21.5%) and had the highest rate of good functional outcomes (29/42, 69.0%). Successful reperfusion was achieved in 85.1% (234/275). Excellent and good functional outcomes were achieved in 48.0% (132/275) and 66.0% (182/275) respectively. sICH occurred in 6.5% (18/275). National Institute of Health Stroke Scale (NIHSS) at presentation was inversely related with good functional outcomes (aOR0.92, 95% CI 0.88- 0.96 per point increase, p Conclusion: While differences in functional outcomes exist across varying stroke aetiologies, high rates of successful reperfusion and good outcomes are generally achieved in young AIS-LVO patients undergoing EVT.

Endovascular thrombectomy (EVT) is the standard of care for anterior circulation acute ischemic stroke (AIS) with large vessel occlusion (LVO). Young patients with AIS-LVO have distinctly different underlying stroke mechanisms and etiologies. Much is unknown about the safety and efficacy of EVT in this population of young AIS-LVO patients. All consecutive AIS-LVO patients aged 50 years and below were included in this multicenter cohort study. The primary outcome measured was functional recovery at 90 days, with modified Rankin Scale of 0-2 deemed as good functional outcome. A total of 275 AIS-LVO patients that underwent EVT from 10 tertiary centers in Germany, Sweden, Singapore, and Taiwan were included. Successful reperfusion was achieved in 85.1% (234/275). Good functional outcomes were achieved in 66.0% (182/275). Arterial dissection was the most prevalent stroke etiology (42/195, 21.5%). National Institutes of Health Stroke Scale (NIHSS) score at presentation was inversely related to good functional outcomes (aOR: 0.92, 95% CI: 0.88-0.96 per point increase, p

This paper examines how co-presence is enacted in technology-mediated medical practices, particularly under time pressure. Extant literature highlights time (e.g. immediacy and duration of interactions) as a critical condition for copresence, but there has been little attention to the variation of copresence over time. In this paper, we investigate this variation through an ethnographic study in three emergency departments that are linked via a telemedicine system called Telestroke, which is used to diagnose and treat stroke patients at a distance. We draw on the sensemaking literature to uncover how copresence is enacted across different phases of technology-mediated medical practice. Our findings reveal four mechanisms that shape the variation of copresence across time, namely extracting cues, retrospection, perspective-taking, and selective attention."

Acute ischemic stroke (AIS) is a life-threatening complication of coronavirus disease 2019 (COVID-19) infection. Increasing reports suggest an association between COVID-19 and AIS, although the underlying mechanism remains uncertain. We performed a systematic review to characterize the clinical characteristics, neuroimaging findings, and outcomes of AIS in COVID-19 patients. A literature search was performed in PubMed and Embase using a suitable keyword search strategy from 1st December 2019 to 29th May 2020. All studies reporting AIS occurrence in COVID-19 patients were included. A total of 39 studies comprising 135 patients were studied. The pooled incidence of AIS in COVID-19 patients from observational studies was 1.2% (54/4466) with a mean age of 63.4 ± 13.1 years. The mean duration of AIS from COVID-19 symptoms onset was 10 ± 8 days, and the mean NIHSS score was 19 ± 8. Laboratory investigations revealed an elevated mean d-dimer (9.2 ± 14.8 mg/L) and fibrinogen (5.8 ± 2.0 g/L). Antiphospholipid antibodies were detected in a significant number of cases. The majority of AIS neuroimaging patterns observed was large vessel thrombosis, embolism or stenosis (62.1%, 64/103), followed by multiple vascular territory (26.2%, 27/103). A high mortality rate was reported (38.0%, 49/129). We report the pooled incidence of AIS in COVID-19 patients to be 1.2%, with a high mortality rate. Elevated d-dimer, fibrinogen and the presence of antiphospholipid antibodies appear to be prominent in COVID-19 patients with concomitant AIS, but further mechanistic studies are required to elucidate their role in pathogenesis. Electronic supplementary material The online version of this article (10.1007/s11239-020-02228-y) contains supplementary material, which is available to authorized users.

Background Acute ischemic stroke is a time-sensitive emergency where accurate diagnosis is required promptly. Due to time pressures, stroke mimics, whom present with similar signs and symptoms as acute ischemic stroke, pose a diagnostic challenge to the emergency physician. With limited access to investigative tools, clinical prediction tools, based only on clinical features, may be useful to identify stroke mimics. We aim to externally validate the performance of 4 stroke mimic prediction scales and aim to derive a novel decision tree, to improve identification of stroke mimics. Methods We performed a retrospective cross-sectional study at a primary stroke centre, served by a telestroke hub. We included consecutive patients whom were administered intravenous thrombolysis for suspected acute ischemic stroke from January 2015 to October 2017. Four stroke mimic prediction tools (FABS, simplified FABS, Telestroke Mimic Score and Khan Score) were rated simultaneously, using only clinical information prior to administration of thrombolysis. The final diagnosis was ascertained by an independent stroke neurologist. Area under receiver operating curve (AUROC) analysis was performed. A classification tree analysis was also conducted using variables which were found to be significant in the univariate analysis. Results Telestroke Mimic Score had the highest discrimination for stroke mimics among the 4 scores tested (AUROC = 0.75, 95% CI = 0.63–0.87), although it was not statistically significantly better. Telestroke Mimic Score had the highest sensitivity (91.3%), while Khan score had the highest specificity (88.2%). All 4 scores had high positive predictive value (88.1–97.5%) and low negative predictive values (4.7–32.3%). A novel decision tree, using only age, presence of migraine and psychiatric history, had a higher prediction performance (AUROC = 0.80). Conclusion Four tested stroke mimic prediction scales performed similarly well to identify stroke mimics in the emergency setting. A novel decision tree may improve the identification of stroke mimics.

Cerebral venous thrombosis (CVT) causes significant disability and mortality. Current guidelines for CVT management support the initial use of unfractionated heparin or low molecular weight heparin followed by longer-term oral vitamin K antagonist (VKA). There has been increasing, albeit limited, evidence for the use of direct oral anticoagulants (DOAC) as an alternative to VKA. We performed a systematic review and meta-analysis of studies that compared the safety and efficacy of DOACs to VKA in treating CVT. A comprehensive literature search was carried out in Medline, Embase and Cochrane Stroke Group Trials Register using a suitable keyword/MeSH term search strategy. All studies published in English comparing outcomes of patients with CVT treated with DOAC or VKA were included. In total, 6 studies (5 observational studies and 1 randomized clinical trial) comprising 412 patients (age range 16-83 years) were analyzed. DOAC was used in 151 patients, while 261 received VKA. The follow-up period was 3-11 months. The efficacy of DOACs was comparable with VKA in terms of partial or full thrombus recanalization (RR 1.02, 95% CI 0.89-1.16) and excellent functional recovery with modified Rankin scale 2 (RR 1.02, 95% CI 0.93-1.13). Patients treated with DOAC developed lower major bleeding events when compared to VKA, although this did not reach statistical significance (RR 0.44, 95% CI 0.12-1.59). We provide preliminary evidence to support DOAC as effective and safe alternatives to VKA in CVT treatment. We await the results of upcoming randomized trials to further support our results and validate the use of DOAC.

Purpose: B-Mode ultrasound imaging is commonly used for detection and measurement of atherosclerotic carotid plaques, which are an important cause of ischemic stroke. However, accurate interpretation of ultrasound can be difficult and subjective. Artificial Intelligence (AI) models can assist in image interpretation, reducing subjectivity, and speeding up the process of detection and measurement of carotid plaques. We evaluated the accuracy of a deep learning model for automatic detection of carotid plaques in b-mode ultrasound compared against expert interpretation of the images. Methods: We propose an automated method using convolutional neural networks to detect atherosclerotic plaques and measure intima-media thickness (IMT) in B-Mode carotid images. In contrast to most of the existing methods, our goal was to not only measure IMT in healthy subjects (max IMT below 1.2 mm) but also to provide accurate detection of plaques and other vessel wall pathology. Given the B-mode longitudinal image as the input, the neural network first finds a region of interest (ROI) surrounding the artery and then segments both near wall and far wall of the artery. The network was trained and tested on two separate datasets obtained retrospectively from 3 stroke centers and 4 different ultrasound machine manufacturers. The training dataset was comprised of 1021 images. Results: The performance of the method was assessed on an independent dataset not used for model development to prevent bias, consisting of 205 images, where 54% (111 out of 205) of the images had pathology. The ground truth was determined by an expert reader interpreting images, and Pearson coefficient (IMT correlation) and Bland-Altman analysis were used to assess the performance of the method. The obtained correlation coefficient was 0.93 and r-squared was 0.87, showing a strong correlation. There was no significant over or under estimation of IMT (bias = -0.002 mm, lower limit of agreement (LOA) = -0.246 mm, upper LOA = 0.242 mm). Conclusion: The results show that the proposed deep learning method can be used for accurate analysis and interpretation of carotid ultrasound scans in a clinical setting and potentially reduce the reporting time while increasing objectivity of the reports.

Purpose: Modelling blood flow in cerebral arteries presents an opportunity to go beyond current luminal stenosis. These models could improve stroke prognostication by adding hemodynamic biomarkers such as translesional shear stress and pressure gradient. Such models, however, are rarely validated against real clinical data. We evaluated the accuracy of a computational fluid dynamics (CFD) model which uses allometric scaling laws against population-based Phase Contrast MRI (PC-MRI) measurements of blood flow in the brain. Methods: 3D models of the anterior circulation of 23 healthy subjects were reconstructed based on their MRA Time of Flight (TOF) images and CFD was used for modelling the blood flow. Lumped parameter Windkessel models were used as boundary conditions and allometric scaling laws were used to divide the flow and tune these boundary conditions, i.e. the resistance at each boundary was automatically adjusted based on the dimensions and branching of upstream vasculature. The results were compared against 4 PC-MRI studies from literature, covering a combined number of 417 healthy subjects. Results: The flow rate across 3 major intracranial arteries (ICA, MCA, and ACA) was obtained from the CFD simulations and was in good agreement with population-based PC-MRI studies. The agreement was 82.6% for the ICA, 85.9% for the MCA, and 80.4% for the ACA when comparing the average flow rate. The inter-patient variability of the flow rate (i.e. standard deviation) obtained from CFD simulations matched closely with the variation range measured in the literature. Allometric scaling enabled the model to accurately divide the flow at bifurcations (MCA/ICA flow ratio was 58.6% for the model vs 56.3% in the literature). We observed an average of 8 mmHg in pressure drop along the anterior circulation of healthy subjects (from ICA to MCA-M1 and ACA-A1), which agrees with the physiological range reported in the literature. Conclusion: This study shows the potential of accurately modelling blood flow based only on static images and demonstrates the validity of using allometric scaling in intracranial CFD simulations. The current modelling approach can potentially assist in stroke prognostication by obtaining hemodynamic risk factors from standard MRA TOF or CTA.

The accurate segmentation of medical images has important consequences in clinical applications. Noisy and artefact-heavy images can result in erroneous image segmentation and often require expert understanding of the target anatomy by clinicians to interpret and compensate for missing and obfuscated data. This is especially true in ultrasound imaging where shadowing and speckle artefacts are common. We propose a novel approach to handle such artefacts using a conditional Generative Adversarial Network called Anatomical GAN (AGAN) that can correct anatomically-invalid pixel-wise segmentation and impose shape priors in carotid artery ultrasound images by learning the underlying structure of the arteries. These anatomically accurate outputs can then be used in the clinical work flow by clinicians or be further processed by other automated methods for assistance in clinical decision making. AGAN can be chained with any pixel-wise segmentation method and is generalisable for both anatomy and artefacts. Experimental results on a longitudinal ultrasound carotid artery dataset show that AGAN can correct anatomically-invalid segmentation masks obtained with different pixel-wise segmentation methods when other state-of-the-art methods fail.

Reports of cerebral venous thrombosis (CVT) after messenger RNA (mRNA)-based SARS-CoV-2 vaccination has caused safety concerns, but CVT is also known to occur after SARS-CoV-2 infection. Comparing the relative incidence of CVT after infection vs vaccination may provide a better perspective of this complication.To compare the incidence rates and clinical characteristics of CVT following either SARS-CoV-2 infection or mRNA-based SARS-CoV-2 vaccines.Between January 23, 2020, and August 3, 2021, this observational cohort study was conducted at all public acute hospitals in Singapore, where patients hospitalized with CVT within 6 weeks of SARS-CoV-2 infection or after mRNA-based SARS-CoV-2 vaccination (BNT162b2 [Pfizer-BioNTech] or mRNA-1273 [Moderna]) were identified. Diagnosis of SARS-CoV-2 infection was based on quantitative reverse transcription-polymerase chain reaction or positive serology. National SARS-CoV-2 infection data were obtained from the National Centre for Infectious Disease, Singapore, and vaccination data were obtained from the National Immunisation Registry, Singapore.SARS-CoV-2 infection or mRNA-based SARS-CoV-2 vaccines.Clinical characteristics, crude incidence rate (IR), and incidence rate ratio (IRR) of CVT after SARS-CoV-2 infection and after mRNA SARS-CoV-2 vaccination.Among 62 447 individuals diagnosed with SARS-CoV-2 infections included in this study, 58 989 (94.5%) were male; the median (range) age was 34 (0-102) years; 6 CVT cases were identified (all were male; median [range] age was 33.5 [27-40] years). Among 3 006 662 individuals who received at least 1 dose of mRNA-based SARS-CoV-2 vaccine, 1 626 623 (54.1%) were male; the median (range) age was 50 (12-121) years; 9 CVT cases were identified (7 male individuals [77.8%]; median [range] age: 60 [46-76] years). The crude IR of CVT after SARS-CoV-2 infections was 83.3 per 100 000 person-years (95% CI, 30.6-181.2 per 100 000 person-years) and 2.59 per 100 000 person-years (95% CI, 1.19-4.92 per 100 000 person-years) after mRNA-based SARS-CoV-2 vaccination. Six (66.7%) received BNT162b2 (Pfizer-BioNTech) vaccine and 3 (33.3%) received mRNA-1273 (Moderna) vaccine. The crude IRR of CVT hospitalizations with SARS-CoV-2 infection compared with those who received mRNA SARS-CoV-2 vaccination was 32.1 (95% CI, 9.40-101; P .001).The incidence rate of CVT after SARS-CoV-2 infection was significantly higher compared with after mRNA-based SARS-CoV-2 vaccination. CVT remained rare after mRNA-based SARS-CoV-2 vaccines, reinforcing its safety.

Background Health-related quality of life (HRQoL) is a key metric to understand the impact of stroke from patients’ perspective. Yet HRQoL is not readily measured in clinical practice. This study aims to investigate the extent to which clinical outcomes during admission predict HRQoL at 3 months and 1 year post-stroke. Methods Stroke patients admitted to five tertiary hospitals in Singapore were assessed with Shah-modified Barthel Index (Shah-mBI), National Institute of Health Stroke Scale (NIHSS), Modified Rankin Scale (mRS), Mini-Mental State Examination (MMSE), and Frontal Assessment Battery (FAB) before discharge, and the EQ-5D questionnaire at 3 months and 12 months post-stroke. Association of clinical measures with the EQ index at both time points was examined using multiple linear regression models. Forward stepwise selection was applied and consistently significant clinical measures were analyzed for their association with individual dimensions of EQ-5D in multiple logistic regressions. Results All five clinical measures at baseline were significant predictors of the EQ index at 3 months and 12 months, except that MMSE was not significantly associated with the EQ index at 12 months. NIHSS (3-month standardized β = − 0.111; 12-month standardized β = − 0.109) and mRS (3-month standardized β = − 0.122; 12-month standardized β = − 0.080) were shown to have a larger effect size than other measures. The contribution of NIHSS and mRS as significant predictors of HRQoL was mostly explained by their association with the mobility, self-care, and usual activities dimensions of EQ-5D. Conclusions HRQoL at 3 months and 12 months post-stroke can be predicted by clinical outcomes in the acute phase. NIHSS and mRS are better predictors than BI, MMSE, and FAB.

Purpose We describe the spectrum of acute neurological disorders among hospitalized patients who recently had COVID-19 mRNA vaccination. Method We performed a prospective study at 7 acute hospitals in Singapore. Hospitalized patients who were referred for neurological complaints and had COVID-19 mRNA vaccines, BNT162b2 and mRNA-1273, in the last 6 weeks were classified into central nervous system (CNS) syndromes, cerebrovascular disorders, peripheral nervous system (PNS) disorders, autonomic nervous system (ANS) disorders and immunization stress-related responses (ISRR). Results From 30 December 2020 to 20 April 2021, 1,398,074 persons (median age 59 years, 54.5% males) received COVID-19 mRNA vaccine (86.7% BNT162b2, 13.3% mRNA-1273); 915,344(65.5%) completed 2 doses. Four hundred and fifty-seven(0.03%) patients were referred for neurological complaints [median age 67(20–97) years, 281(61.5%) males; 95.8% received BNT162b2 and 4.2% mRNA-1273], classified into 73(16.0%) CNS syndromes, 286(62.6%) cerebrovascular disorders, 59(12.9%) PNS disorders, 0 ANS disorders and 39(8.5%) ISRRs. Eleven of 27 patients with cranial mononeuropathy had Bell's palsy. Of 33 patients with seizures, only 4 were unprovoked and occurred within 2 weeks of vaccination. All strokes occurred among individuals with pre-existing cardiovascular risk factors. We recorded 2 cases of cerebral venous thrombosis; none were vaccine-induced thrombotic thrombocytopenia. Five had mild flares of immune-mediated diseases. Conclusion Our observational study does not establish causality of the described disorders to vaccines. Though limited by the lack of baseline incidence data of several conditions, we observed no obvious signal of serious neurological morbidity associated with mRNA vaccination. The benefits of COVID-19 vaccination outweigh concerns over neurological adverse events.

Objective At present, the absence of a pharmacological neuroprotectant represents an important unmet clinical need in the treatment of ischemic and traumatic brain injury. Recent evidence suggests that administration of apolipoprotein E mimetic therapies represent a viable therapeutic strategy in this setting. We investigate the neuroprotective and anti-inflammatory properties of the apolipoprotein E mimetic pentapeptide, CN-105, in a microglial cell line and murine model of ischemic stroke. Methods Ten to 13-week-old male C57/BL6 mice underwent transient middle cerebral artery occlusion and were randomly selected to receive CN-105 (0.1 mg/kg) in 100 μL volume or vehicle via tail vein injection at various time points. Survival, motor-sensory functional outcomes using rotarod test and 4-limb wire hanging test, infarct volume assessment using 2,3,5-Triphenyltetrazolium chloride staining method, and microglial activation in the contralateral hippocampus using F4/80 immunostaining were assessed at various time points. In vitro assessment of tumor necrosis factor-alpha secretion in a microglial cell line was performed, and phosphoproteomic analysis conducted to explore early mechanistic pathways of CN-105 in ischemic stroke. Results Mice receiving CN-105 demonstrated improved survival, improved functional outcomes, reduced infarct volume, and reduced microglial activation. CN-105 also suppressed inflammatory cytokines secretion in microglial cells in vitro. Phosphoproteomic signals suggest that CN-105 reduces proinflammatory pathways and lower oxidative stress. Interpretation CN-105 improves functional and histological outcomes in a murine model of ischemic stroke via modulation of neuroinflammatory pathways. Recent clinical trial of this compound has demonstrated favorable pharmacokinetic and safety profile, suggesting that CN-105 represents an attractive candidate for clinical translation.

Reperfusion therapy is currently the gold standard treatment for acute ischemic stroke. However, reperfusion injuries such as oedema and haemorrhagic transformation largely limit the use of this potent treatment to a narrow time window. Recently, transient receptor potential melastatin 4 (TRPM4) channel has emerged as a potential target for vascular protection in stroke management. Non-specificity and side effects are major concerns for current TRPM4 blockers. The present study was undertaken to develop a novel TRPM4 blocker for stroke management. We report the generation of a TRPM4-specific antibody M4P which binds to a region close to the channel pore. M4P could inhibit TRPM4 current and downregulate TRPM4 surface expression, therefore prevent hypoxia-induced cell swelling. In the rat model of 3-h stroke reperfusion, application of M4P at 2 h after occlusion ameliorated reperfusion injury by improving blood–brain barrier integrity, and enhanced functional recovery. Our results demonstrate that TRPM4 blockade could attenuate reperfusion injury in stroke recanalization. When applied together with reperfusion treatments, TRPM4 blocking antibody has the potential to extend the therapeutic time window for acute ischemic stroke. Electronic supplementary material The online version of this article (10.1007/s00424-019-02326-8) contains supplementary material, which is available to authorized users.

Aim: Intraplaque hemorrhage increases the risk of stroke in patients with carotid artery atherosclerosis. Magnetic resonance imaging (MRI) is more accurate in detecting intraplaque hemorrhage, but ultrasound is cheaper and widely available. Nonetheless, detecting intraplaque hemorrhage in ultrasound is difficult even for expert clinicians. We evaluate the ability of an automated software that uses machine learning (See-Mode Technologies, Singapore) to improve intraplaque hemorrhage detection in b-mode ultrasound. Methods: 100 longitudinal b-mode ultrasound images of carotid artery were retrospectively analyzed using an automated vascular analysis software according to a blinded protocol. Two neurosonologists assessed the corresponding MRI images of the patients and confirmed the presence of intraplaque hemorrhage in 50 of these ultrasound images based on MRI. Using this dataset, a 2-class support vector machine classifier was trained to detect intraplaque hemorrhage in ultrasound images. Intensity and texture features were used for classification of ultrasound images and the performance of the classifier was assessed against intraplaque hemorrhage identified in MRI. 5-fold cross validation was then used to assess the accuracy of the classifier. Results: The software detected intraplaque hemorrhage in b-mode ultrasound images with high accuracy. The classification accuracy on the 100 ultrasound images was 80% for the software, while it was on average 62% for two neurosonologists (61% and 63%) assessing the ultrasound images blinded to the MRI labels. The classifier has a sensitivity of 82% and specificity of 78% in detecting intraplaque hemorrhage in b-mode ultrasound when compared against MRI. Conclusion: Interpretation of ultrasound images for intraplaque hemorrhage can be difficult for both experts and machine learning methods. Our proposed method benefits from learning from MRI in the training phase and applies it on ultrasound during the test phase. The machine learning method is implemented in an automated software and accurately detect intraplaque hemorrhage in ultrasound images, which can be used to increase confidence in management of patients with carotid artery atherosclerosis.

Aim: Duplex ultrasound is used for non-invasive assessment of internal carotid artery (ICA) disease and stenosis grading based on The North American Symptomatic Carotid Endarterectomy Trial (NASCET) criteria. Computational fluid dynamics (CFD) can be used to model blood flow based on static scans (like CT or MR angiograms), but such models are rarely validated in real clinical settings. We evaluated the accuracy of an automated vascular analysis software that simulates blood flow given a CT or MR angiogram (See-Mode Technologies, Singapore) against NASCET grading done by duplex ultrasound. Methods: 20 carotid arteries from patients with ICA disease were retrospectively analyzed using an automated vascular analysis software according to a blinded protocol. Three-dimensional models of the carotid arteries were reconstructed from MR or CT angiogram DICOM images, and CFD was used for patient-specific modelling of blood flow in the vasculature. Blood flow velocities, specifically ICA peak systolic velocity (PSV) and PSV ratio between the ICA and the common carotid artery (CCA) were obtained from the software and used for stenosis grading based on the NASCET criteria. Bland-Altman analysis was used to assess the agreement between the software and duplex ultrasound. Results: The blood flow simulations were in excellent agreement with duplex ultrasound for both metrics, i.e. ICA PSV (r 2 = 0.936, P < 0.001) and ICA/CCA PSV ratio (r 2 = 0.932, P < 0.001). There was no significant over or under estimation of ICA PSV, but there was a slight over estimation of the ICA/CCA PSV ratio with the software (ICA PSV: bias = 5 cm/s, lower limit of agreement (LOA) = -43 cm/s, upper LOA = 52 cm/s; ICA/CCA PSV ratio: bias = 0.16, lower LOA = -0.54, upper LOA = 0.86). All carotid arteries were correctly classified with the software compared against the NASCET grading done with duplex ultrasound. Conclusion: While CFD is commonly used for modelling blood flow, its accuracy is rarely assessed in real clinical settings. This is the first validated comparison of carotid artery stenosis grading using blood flow simulations against duplex ultrasound. When the data was categorized according to NASCET criteria, all cases were correctly classified with the software compared against duplex ultrasound.

To describe the spectrum of COVID-19 neurology in Singapore.We prospectively studied all microbiologically-confirmed COVID-19 patients in Singapore, who were referred for any neurological complaint within three months of COVID-19 onset. Neurological diagnoses and relationship to COVID-19 was made by consensus guided by contemporaneous literature, refined using recent case definitions.47,572 patients (median age 34 years, 98% males) were diagnosed with COVID-19 in Singapore between 19 March to 19 July 2020. We identified 90 patients (median age 38, 98.9% males) with neurological disorders; 39 with varying certainty of relationship to COVID-19 categorised as: i) Central nervous system syndromes-4 acute disseminated encephalomyelitis (ADEM) and encephalitis, ii) Cerebrovascular disorders-19 acute ischaemic stroke and transient ischaemic attack (AIS/TIA), 4 cerebral venous thrombosis (CVT), 2 intracerebral haemorrhage, iii) Peripheral nervous system-7 mono/polyneuropathies, and a novel group, iv) Autonomic nervous system-4 limited dysautonomic syndromes. Fifty-one other patients had pre/co-existent neurological conditions unrelated to COVID-19. Encephalitis/ADEM is delayed, occurring in critical COVID-19, while CVT and dysautonomia occurred relatively early, and largely in mild infections. AIS/TIA was variable in onset, occurring in patients with differing COVID-19 severity; remarkably 63.2% were asymptomatic. CVT was more frequent than expected and occurred in mild/asymptomatic patients. There were no neurological complications in all 81 paediatric COVID-19 cases.COVID-19 neurology has a wide spectrum of dysimmune-thrombotic disorders. We encountered relatively few neurological complications, probably because our outbreak involved largely young men with mild/asymptomatic COVID-19. It is also widely perceived that the pandemic did not unduly affect the Singapore healthcare system.

Spontaneous intracranial hemorrhage (ICH) remains a devastating stroke subtype, affecting as many as 80,000 people annually in the United States and associated with extremely high mortality. In the absence of any pharmacological interventions demonstrated to improve outcome, care for patients with ICH remains largely supportive. Thus, despite advances in the understanding of ICH and brain injury, there remains an unmet need for interventions that improve neurologic recovery and outcomes. Recent research suggesting inflammation and APOE genotype play a role in modifying neurologic outcome after brain injury has led to the development of an APOE-derived peptide agent (CN-105). Preclinical studies have demonstrated that CN-105 effectively downregulates the inflammatory response in acute brain injury, including ICH. Following Investigational New Drug (IND) enabling studies in murine models, this first-in-human single escalating dose and multiple dose placebo-controlled clinical trial was performed to define the safety and pharmacokinetics (PK) of CN-105. A total of 48 subjects (12 control, 36 active) were randomized in this study; all subjects completed the study. No significant safety issues were identified with both dosing regimens, and PK analysis revealed linearity without significant drug accumulation. The median half-life in the terminal elimination phase of CN-105 following a single or repeated dosing regimen did not change (approximately 3.6 hours). With the PK and preliminary safety of CN-105 established, the drug is now poised to begin first-in-disease phase 2 clinical trials in patients with ICH who urgently need new therapeutic options.

Background There has been increasing reports associating the coronavirus disease 2019 (COVID-19) with thromboembolic phenomenon including ischemic strokes and venous thromboembolism. Cerebral venous thrombosis (CVT) is a rare neurovascular emergency that has been observed in some COVID-19 patients, yet much remains to be learnt of its underlying pathophysiology. Objective We present a case series of local patients with concomitant COVID-19 infection and CVT; and aim to perform a systematic review of known cases in the current literature. Methods We describe two patients with concomitant COVID-19 infection and CVT from a nationwide registry in Singapore. We then conducted a literature search in PubMed and Embase using a suitable keyword search strategy from 1st December 2019 to 11th June 2020. All studies reporting CVT in COVID-19 patients were included. Results Nine studies and 14 COVID-19 patients with CVT were studied. The median age was 43 years (IQR=36-58) and majority had no significant past medical conditions (60.0%). The time taken from onset of COVID-19 symptoms to CVT diagnosis was a median of 7 days (IQR=6-14). CVT was commonly seen in the transverse (75.0%) and sigmoid sinus (50.0%); 33.3% had involvement of the deep venous sinus system. A significant proportion of patients had raised D-dimer (75.0%) and CRP levels (50.0%). Two patients reported presence of antiphospholipid antibodies. Most patients received anticoagulation (91.7%) while overall mortality rate was 45.5%. Conclusions The high mortality rate of CVT in COVID-19 infection warrants a high index of suspicion from physicians, and early treatment with anticoagulation should be initiated.