Inhibition of neutrophil rolling and migration by caADAMTS13 in vitro and in mouse models of thrombosis and inflammation.

Recent investigation of a constitutively active ADAMTS13 variant (caADAMTS13) in murine models of acute ischaemic stroke (AIS) have revealed a potential anti-inflammatory mechanism of action contributing to its protective effect. However, it remains unclear whether these observations are a direct result of VWF proteolysis by caADAMTS13. We have implemented state of the art in vitro assays of neutrophil rolling and transmigration to quantify the impact of caADAMTS13 on these processes. Moreover, we have tested caADAMTS13 in two in vivo assays of neutrophil migration to confirm the impact of the treatment on the neutrophil response to sterile inflammation. Neutrophil rolling, over an interleukin-1ß stimulated hCMEC/D3 monolayer, is directly inhibited by caADAMTS13, reducing the proportion of neutrophils rolling to 9.5 ± 3.8 % compared to 18.0 ± 4.5 % in untreated controls. Similarly, neutrophil transmigration recorded in real-time, was significantly suppressed in the presence of caADAMTS13 which reduced the number of migration events to a level like that in unstimulated controls (18.0 ± 4.5 and 15.8 ± 7.5 cells/mm2/h, respectively). Brain tissue from mice undergoing experimental focal cerebral ischaemia has indicated the inhibition of this process by caADAMTS13. This is supported by caADAMTS13's ability to reduce neutrophil migration into the peritoneal cavity in an ischaemia-independent model of sterile inflammation, with the VWF-dependent mechanism by which this occurs being confirmed using a second experimental stroke model. These findings will be an important consideration in the further development of caADAMTS13 as a potential therapy for AIS and other thromboinflammatory pathologies, including cardiovascular disease.

Addressing ethnic disparities in neurological research in the United Kingdom: An example from the prospective multicentre COVID-19 Clinical Neuroscience Study.

BACKGROUND: Minority ethnic groups have often been underrepresented in research, posing a problem in relation to external validity and extrapolation of findings. Here, we aimed to assess recruitment and retainment strategies in a large observational study assessing neurological complications following SARS-CoV-2 infection. METHODS: Participants were recruited following confirmed infection with SARS-CoV-2 and hospitalisation. Self-reported ethnicity was recorded alongside other demographic data to identify potential barriers to recruitment. RESULTS: 807 participants were recruited to COVID-CNS, and ethnicity data were available for 93.2%. We identified a proportionate representation of self-reported ethnicity categories, and distribution of broad ethnicity categories mirrored individual centres' catchment areas. White ethnicity within individual centres ranged between 44.5% and 89.1%, with highest percentage of participants with non-White ethnicity in London-based centres. Examples are provided how to reach potentially underrepresented minority ethnic groups. CONCLUSIONS: Recruitment barriers in relation to potentially underrepresented ethnic groups may be overcome with strategies identified here.

Rapid Carotid Screening by Duplex: A Prospective Single Centre Assessment.

OBJECTIVE: A novel carotid quick scan (CQS) protocol was developed to rapidly screen for carotid atherosclerosis greater than 50% stenosis in a vascular outpatient setting. This study assessed accuracy and time saved. MATERIAL & METHODS: The CQS was developed by consensus agreement between vascular surgeons and accredited clinical vascular scientists through a modified Delphi technique. The protocol comprised a rapid B-mode then colour flow transverse sweep of the common and internal carotid arteries, with internal carotid artery velocity assessment. One hundred outpatients attending with peripheral artery disease or abdominal aortic aneurysm were recruited. CQS sensitivity, specificity and accuracy was assessed against a conventional full carotid duplex study, performed to UK and ESVS guidelines. RESULTS: Twenty four percent of patients (n = 100) had >50% carotid NASCET stenosis. CQS achieved an excellent accuracy of 96.5% in detecting >50% stenosis when compared to full duplex; Cohen's ƙ = .88, (95%CI .79-.97; P < .001), sensitivity 91.4%, specificity 97.6%, positive predictive value (PPV) 88.9% and negative predictive value (NPV) 98.2%. Median (IQR) time to complete the CQS was 13 sec (±12) per side, compared to 151 sec (±78) per side for the full carotid duplex. In the presence of >50% carotid disease, median CQS time was 25 sec (±31) per side compared to 214 (±104) by full scan. CONCLUSION: CQS as a carotid screening tool is rapid, accurate and acceptable to the population and workforce. It would be simple to roll out in all vascular laboratories to reduce the time and cost burden of excluding significant carotid disease in any group.

Preconditioning with interleukin-1 alpha is required for the neuroprotective properties of mesenchymal stem cells after ischemic stroke in mice.

Mesenchymal stem cell (MSC) pre-conditioning with interleukin-1 alpha (IL-1ɑ) drives MSCs toward a potent anti-inflammatory phenotype. The aim of this study was to assess the therapeutic potential of intra-arterially administered IL-1ɑ preconditioned MSCs, after experimental cerebral ischaemia in mice. After 3 h from the start of middle cerebral artery occlusion, animals were treated with vehicle, 9.1 × 104 non-conditioned or IL-1ɑ preconditioned MSCs by intra-arterial administration. Animals were allowed to recover for 1.5 h after treatment to measure cerebral blood flow (CBF), and 3 days or 14 days post-stroke to evaluate lesion volume and functional outcomes. At 3-days post-stroke preconditioned MSCs reduced (by 67%) lesion volume and increased CBF (by 32%) compared to vehicle, while non-conditioned MSCs had no effect. A separate cohort of animals recovered to 14 days post-stroke also showed reduced infarct volume (by 51%) at 48 h (assessed by MRI) and better functional recovery at 14 days when treated with preconditioned MSCs when compared to vehicle. Preconditioning MSCs with IL-1α increases their neuroprotective capability and improves functional recovery after delayed intra-arterial administration. With increasing use of thrombectomy, the adjunct use of preconditioned MSCs therefore represents a highly relevant therapy to improve outcomes in ischemic stroke.

Does stroke-associated pneumonia play an important role on risk of in-hospital mortality associated with severe stroke? A four-way decomposition analysis of a national cohort of stroke patients.

BACKGROUND: Severe strokes and stroke-associated pneumonia (SAP) have long been associated with poorer patient health outcomes, for example, in-hospital mortality. However, it is unclear what role SAP plays in the risk of in-hospital mortality associated with a severe stroke at admission. METHODS: Using the Sentinel Stroke National Audit Program data on stroke admissions (2013-2018) in England and Wales, we modeled the "total" effect for severe stroke on risk of in-hospital mortality. Through four-way decomposition methodology, we broke down the "total" observed risk into four components. The direct "severity on outcome only" effect, the pure indirect effect of severity mediated via SAP only, the interaction between severity and SAP when mediation is not present, and when mediation via SAP is present. RESULTS: Of 339,139 stroke patients included, 9.4% had SAP and 15.6% died in hospital. Of SAP patients, 45% died versus 12% of non-SAP patients. The risk ratio for in-hospital mortality associated with severe versus mild/moderate stroke (i.e. total effect) was 4.72 (95% confidence interval: 4.60-4.85). Of this, 43%-increased risk was due to additive SAP interaction, this increased to 50% for "very severe" stroke. The remaining excess relative risk was due to the direct severity on outcome effect only, that is, there was no evidence here for a mediation effect via SAP. CONCLUSION: SAP was associated with a higher mortality in severe stroke patients. Prioritizing SAP prevention in severe stroke patients may improve in-hospital survival. Our results suggest that in severe stroke patients avoiding SAP might result in an up to 43% reduction in mortality.

Molecular biomarkers predicting newly detected atrial fibrillation after ischaemic stroke or TIA: A systematic review.

Background: Several molecular biomarkers are available that predict newly detected atrial fibrillation (NDAF). We aimed to identify such biomarkers that predict NDAF after an Ischaemic stroke (IS)/Transient Ischaemic Attack (TIA) and evaluate their performance. Methods: A systematic review was undertaken in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Studies of patients with IS, TIA, or both, who underwent ECG monitoring for ⩾24 h, which reported molecular biomarkers and frequency of NDAF after electronic searches of multiple databases were included. Results: Twenty-one studies (76% IS, 24% IS and TIA) involving 4640 patients were included. Twelve biomarkers were identified, with cardiac biomarkers evaluated in the majority (75%) of patients. Performance measures were inconsistently reported. Among cohorts selecting high-risk individuals (12 studies), the most studied biomarkers were N-Terminal-Pro Brain Natriuretic Peptide (NT-ProBNP, five studies; C-statistics reported by three studies, 0.69-0.88) and Brain Natriuretic Peptide (BNP, two studies; C-statistics reported in two studies, 0.68-0.77). Among unselected cohorts (nine studies), the most studied biomarker was BNP (six studies; C-statistics reported in five studies, 0.75-0.88). Only BNP was externally validated (two studies) but using different thresholds to categorise risk of NDAF. Conclusion: Cardiac biomarkers appear to have modest to good discrimination for predicting NDAF, although most analyses were limited by small, heterogeneous study populations. Their clinical utility should be explored further, and this review supports the need to assess the role of molecular biomarkers in large prospective studies with standardised selection criteria, definition of clinically significant NDAF and laboratory assays.

Systemic innate myeloid responses to acute ischaemic and haemorrhagic stroke.

Acute ischaemic and haemorrhagic stroke account for significant disability and morbidity burdens worldwide. The myeloid arm of the peripheral innate immune system is critical in the immunological response to acute ischaemic and haemorrhagic stroke. Neutrophils, monocytes, and dendritic cells (DC) contribute to the evolution of pathogenic local and systemic inflammation, whilst maintaining a critical role in ongoing immunity protecting against secondary infections. This review aims to summarise the key alterations to myeloid immunity in acute ischaemic stroke, intracerebral haemorrhage (ICH), and subarachnoid haemorrhage (SAH). By integrating clinical and preclinical research, we discover how myeloid immunity is affected across multiple organ systems including the brain, blood, bone marrow, spleen, and lung, and evaluate how these perturbations associate with real-world outcomes including infection. These findings are placed in the context of the rapidly developing field of human immunology, which offers a wealth of opportunity for further research.

Do Stroke Care Processes Modify Clinical Outcomes in Patients with Stroke-Associated Pneumonia? A Registry Cohort Study in England and Wales.

INTRODUCTION: It is not known whether modern stroke unit care reduces the impact of stroke complications, such as stroke-associated pneumonia (SAP), on clinical outcomes. We investigated the relationship between SAP and clinical outcomes, adjusting for the confounding effects of stroke care processes and their timing. METHODS: The Sentinel Stroke National Audit Programme provided patient data for all confirmed strokes between April 2013 and December 2018. SAP was defined as new antibiotic initiation for suspected pneumonia within the first 7 days from stroke admission. We compared outcomes after SAP versus non-SAP in appropriate multilevel mixed models. Each model was adjusted for patient and clinical characteristics, as well as markers of stroke care and their timing within the first 72 h. The appropriate effect estimates and corresponding 95% confidence intervals (CIs) were reported. RESULTS: Of 201,778 patients, SAP was present in 14.2%. After adjustment for timing of acute stroke care processes and clinical characteristics, adverse outcomes remained for SAP versus non-SAP patients. In these adjusted analyses, patients with SAP maintained an increased risk of longer length of in-hospital stay (IRR of 1.27; 95% CI: 1.25, 1.30), increased odds of worse functional outcome at discharge (OR of 2.9; 95% CI: 2.9, 3.0), and increased risk of in-hospital mortality (HR of 1.78; 95% CI: 1.74, 1.82). CONCLUSION: We show for the first time that SAP remains associated with worse clinical outcomes, even after adjusting for processes of acute stroke care and their timing. These findings highlight the importance of continued research efforts aimed at preventing SAP.

Co-designing for behaviour change: The development of a theory-informed oral-care intervention for stroke survivors.

This article discusses how research to understand the oral care needs and experiences of stroke survivors was translated into a prototypical intervention. It addresses the challenge of how to develop service improvements in healthcare settings that are both person-centred, through the use of co-design, and also based on theory and evidence. A sequence of co-design workshops with stroke survivors, family carers, and with health and social care professionals, ran in parallel with an analysis of behavioural factors. This determined key actions which could improve mouthcare for this community and identified opportunities to integrate recognized behaviour-change techniques into the intervention. In this way, behaviour change theory, evidence from qualitative research, and experience-based co-design were effectively combined. The intervention proposed is predominantly a patient-facing resource, intended to support stroke survivors and their carers with mouth care, as they transition from hospital care to living at home. This addresses a gap in existing provision, as other published oral-care protocols for stroke are clinician-facing and concerned primarily with acute care (in the first days after a stroke). Although it draws on the experiences of a single design project, this study articulates a 'working relationship' between design practice methods and the application of behaviour change theory.

Association of COVID-19 With Major Arterial and Venous Thrombotic Diseases: A Population-Wide Cohort Study of 48 Million Adults in England and Wales.

BACKGROUND: Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces a prothrombotic state, but long-term effects of COVID-19 on incidence of vascular diseases are unclear. METHODS: We studied vascular diseases after COVID-19 diagnosis in population-wide anonymized linked English and Welsh electronic health records from January 1 to December 7, 2020. We estimated adjusted hazard ratios comparing the incidence of arterial thromboses and venous thromboembolic events (VTEs) after diagnosis of COVID-19 with the incidence in people without a COVID-19 diagnosis. We conducted subgroup analyses by COVID-19 severity, demographic characteristics, and previous history. RESULTS: Among 48 million adults, 125 985 were hospitalized and 1 319 789 were not hospitalized within 28 days of COVID-19 diagnosis. In England, there were 260 279 first arterial thromboses and 59 421 first VTEs during 41.6 million person-years of follow-up. Adjusted hazard ratios for first arterial thrombosis after COVID-19 diagnosis compared with no COVID-19 diagnosis declined from 21.7 (95% CI, 21.0-22.4) in week 1 after COVID-19 diagnosis to 1.34 (95% CI, 1.21-1.48) during weeks 27 to 49. Adjusted hazard ratios for first VTE after COVID-19 diagnosis declined from 33.2 (95% CI, 31.3-35.2) in week 1 to 1.80 (95% CI, 1.50-2.17) during weeks 27 to 49. Adjusted hazard ratios were higher, for longer after diagnosis, after hospitalized versus nonhospitalized COVID-19, among Black or Asian versus White people, and among people without versus with a previous event. The estimated whole-population increases in risk of arterial thromboses and VTEs 49 weeks after COVID-19 diagnosis were 0.5% and 0.25%, respectively, corresponding to 7200 and 3500 additional events, respectively, after 1.4 million COVID-19 diagnoses. CONCLUSIONS: High relative incidence of vascular events soon after COVID-19 diagnosis declines more rapidly for arterial thromboses than VTEs. However, incidence remains elevated up to 49 weeks after COVID-19 diagnosis. These results support policies to prevent severe COVID-19 by means of COVID-19 vaccines, early review after discharge, risk factor control, and use of secondary preventive agents in high-risk patients.

uSing rolE-substitutioN In care homes to improve ORal health (SENIOR): a study protocol.

BACKGROUND: Dental service provision in the care home sector is poor, with little emphasis on prevention. Emerging evidence suggests that the use of Dental Care Professionals (dental therapists and dental nurses) as an alternative to dentists has the potential to improve preventive advice, the provision of care and access to services within care homes. However, robust empirical evidence from definitive trials on how to successfully implement and sustain these interventions within care homes is currently lacking. The aim of the study is to determine whether Dental Care Professionals could reduce plaque levels of dentate older adults (65 + years) residing in care homes. METHODS: This protocol describes a two-arm cluster-randomised controlled trial that will be undertaken in care homes across Wales, Northern Ireland and England. In the intervention arm, the dental therapists will visit the care homes every 6 months to assess and then treat eligible residents, where necessary. All treatment will be conducted within their Scope of Practice. Dental nurses will visit the care homes every month for the first 3 months and then three-monthly afterwards to promulgate advice to improve the day-to-day prevention offered to residents by carers. The control arm will be 'treatment as usual'. Eligible care homes (n = 40) will be randomised based on a 1:1 ratio (20 intervention and 20 control), with an average of seven residents recruited in each home resulting in an estimated sample of 280. Assessments will be undertaken at baseline, 6 months and 12 months and will include a dental examination and quality of life questionnaires. Care home staff will collect weekly information on the residents' oral health (e.g. episodes of pain and unscheduled care). The primary outcome will be a binary classification of the mean reduction in Silness-Löe Plaque Index at 6 months. A parallel process evaluation will be undertaken to explore the intervention's acceptability and how it could be embedded in standard practice (described in a separate paper), whilst a cost-effectiveness analysis will examine the potential long-term costs and benefits of the intervention. DISCUSSION: This trial will provide evidence on how to successfully implement and sustain a Dental Care Professional-led intervention within care homes to promote access and prevention. TRIAL REGISTRATION: ISRCTN16332897 . Registered on 3 December 2021.

The role of CYP2C19 genotyping to guide antiplatelet therapy following ischemic stroke or transient ischemic attack.

INTRODUCTION: Clopidogrel is an antiplatelet agent recommended for secondary prevention of ischemic stroke (IS) and transient ischemic attack (TIA). Conversion of clopidogrel to its active metabolite by hepatic cytochrome P450-2C19 (CYP2C19) is essential for the inhibition of the P2Y12 receptor and subsequent platelet aggregation to prevent thrombotic events. CYP2C19 is highly polymorphic, with over 30 loss of function (LoF) alleles. This review considers whether there is sufficient data to support genotype guided antiplatelet therapy after stroke. AREAS COVERED: A systematic literature review retrieved articles, which describe the interaction between CYP2C19 genotype and clinical outcomes following IS or TIA when treated with clopidogrel. The review documents efforts to identify optimal antiplatelet regimens and explores the value genotype guided antiplatelet therapy. The work outlines the contemporary understanding of clopidogrel metabolism and appraises evidence linking CYP2C19 LoF variants with attenuated platelet inhibition and poorer outcomes. EXPERT OPINION: There is good evidence that CYP2C19 LoF allele carriers of Han-Chinese ancestry have increased risk for further vascular events following TIA or IS when treated with clopidogrel. The evidence base is less certain in other populations. The expansion of pharmacogenetics into routine clinical practice will facilitate further research and help tailor other aspects of secondary prevention.

Treatment with IgM-enriched intravenous immunoglobulins enhances clearance of stroke-associated bacterial lung infection.

Post-stroke infection is a common complication of stroke that is associated with poor outcome. We previously reported that stroke induces an ablation of multiple sub-populations of B cells and reduces levels of immunoglobulin M (IgM) antibody, which coincides with the development of spontaneous bacterial pneumonia. The loss of IgM after stroke could be an important determinant of infection susceptibility and highlights this pathway as a target for intervention. We treated mice with a replacement dose of IgM-enriched intravenous immunoglobulin (IgM-IVIg) prior to and 24 h after middle cerebral artery occlusion (MCAO) and allowed them to recover for 2- or 5-day post-surgery. Treatment with IgM-IVIg enhanced bacterial clearance from the lung after MCAO and improved lung pathology but did not impact brain infarct volume. IgM-IVIg treatment induced immunomodulatory effects systemically, including rescue of splenic plasma B cell numbers and endogenous mouse IgM and IgA circulating immunoglobulin concentrations that were reduced by MCAO. Treatment attenuated MCAO-induced elevation of selected pro-inflammatory cytokines in the lung. IgM-IVIg treatment did not increase the number of lung mononuclear phagocytes or directly modulate macrophage phagocytic capacity but enhanced phagocytosis of Staphylococcus aureus bioparticles in vitro. Low-dose IgM-IVIg contributes to increased clearance of spontaneous lung bacteria after MCAO likely via increasing availability of antibody in the lung to enhance opsonophagocytic activity. Immunomodulatory effects of IgM-IVIg treatment may also contribute to reduced levels of damage in the lung after MCAO. IgM-IVIg shows promise as an antibacterial and immunomodulatory agent to use in the treatment of post-stroke infection.

The Timing of Stroke Care Processes and Development of Stroke Associated Pneumonia: A National Registry Cohort Study.

Introduction: Timely stroke care can result in significant improvements in stroke recovery. However, little is known about how stroke care processes relate to complications such as the development of stroke associated pneumonia (SAP). Here we investigated associations between stroke care processes, their timing and development of SAP. Methods: We obtained patient-level data from the Sentinel Stroke National Audit Programme for all confirmed strokes between 1st April 2013 and 31st December 2018. SAP was identified if new antibiotic initiation for pneumonia occurred within the first 7 days of admission. Time to key stroke care processes in the pre-hospital, hyperacute and acute phase were investigated. A mixed effects logistic regression model estimated the association between SAP [Odds ratios (OR) with 95% CI] and each process of care after controlling for pre-determined confounders such as age, stroke severity and comorbidities. Results: SAP was identified in 8.5% of 413,133 patients in 169 stroke units. A long time to arrival at a stroke unit after symptom onset or time last seen well [OR (95% CI) = 1.29 (1.23-1.35)], from admission to assessment by a stroke specialist [1.10 (1.06-1.14)] and from admission to assessment by a physiotherapist [1.16 (1.12-1.21)] were all independently associated with SAP. Short door to needle times were associated with lower odds of SAP [0.90 (0.83-0.97)]. Conclusion: Times from stroke onset and admission to certain key stroke care processes were associated with SAP. Understanding how timing of these care processes relate to SAP may enable development of preventive interventions to reduce antibiotic use and improve clinical outcomes.

Do Concentration or Activity of Selenoproteins Change in Acute Stroke Patients? A Systematic Review and Meta-Analyses.

INTRODUCTION: Stroke is characterized by deleterious oxidative stress. Selenoprotein enzymes are essential endogenous antioxidants, and detailed insight into their role after stroke could define new therapeutic treatments. This systematic review aimed to elucidate how blood selenoprotein concentration and activity change in the acute phase of stroke. METHODS: We searched PubMed, EMBASE, and Medline databases for studies measuring serial blood selenoprotein concentration or activity in acute stroke patients or in stroke patients compared to non-stroke controls. Meta-analyses of studies stratified by the type of stroke, blood compartment, and type of selenoprotein measurement were conducted. RESULTS: Eighteen studies and data from 941 stroke patients and 708 non-stroke controls were included in this review. Glutathione peroxidase (GPx) was the only identified selenoprotein, and its activity was most frequently measured. Results from 12 studies and 693 patients showed that compared to non-stroke controls in acute ischaemic stroke patients, the GPx activity increased in haemolysate (standardized mean difference [SMD]: 0.27, 95% CI: 0.07-0.47) but decreased in plasma (mean difference [MD]: -1.08 U/L, 95% CI: -1.94 to -0.22) and serum (SMD: -0.54, 95% CI: -0.91 to -0.17). From 4 identified studies in 106 acute haemorrhagic stroke patients, the GPx activity decreased in haemolysate (SMD: -0.40, 95% CI: -0.68 to -0.13) and remained unchanged in plasma (MD: -0.10 U/L, 95% CI: -0.81 to 0.61) and serum (MD: -5.00 U/mL, 95% CI: -36.17 to 26.17) compared to non-stroke controls. Results from studies assessing the GPx activity in the haemolysate compartment were inconsistent and characterized by high heterogeneity. CONCLUSIONS: Our results suggest a reduction of the blood GPx activity in acute ischaemic stroke patients, a lack of evidence regarding a role for GPx in haemorrhagic stroke patients, and insufficient evidence for other selenoproteins.

Are Differences in Dysphagia Assessment, Oral Care Provision, or Nasogastric Tube Insertion Associated with Stroke-Associated Pneumonia? A Nationwide Survey Linked to National Stroke Registry Data.

INTRODUCTION: Stroke-associated pneumonia (SAP) is a common complication associated with poor outcomes. Early dysphagia screening and specialist assessment is associated with a reduced risk of SAP. Evidence about oral care and nasogastric tube (NGT) placement is equivocal. This study aimed to expose variations in dysphagia management practices and explore their associations with SAP. PARTICIPANTS AND METHODS: Speech pathologists from 166 stroke units in England and Wales were surveyed about dysphagia assessment and management, oral care, and NGT placement. Survey data were then linked to the Sentinel Stroke National Audit Programme (SSNAP), the national register of stroke. Univariable and multivariable linear regression models were fitted to estimate the association between dysphagia management practices and SAP incidence. RESULTS: 113 hospitals completed the survey (68%). Variation was evident in dysphagia screening protocols (DSPs), oral care, and NGT practice while specialist swallow assessment data patterns were more consistent. Multivariable analysis showed no evidence of an association in incidence of SAP when using a water-only hospital DSP compared to a multiconsistency DSP (B -0.688, 95% CI: -2.912 to 1.536), when using written swallow assessment guidelines compared to not using written guidelines (B 0.671, 95% CI: -1.567 to 2.908), when teams inserted NGTs overnight compared to teams which did not (B -0.505, 95% CI: -2.759 to 1.749), and when teams had a written oral care protocol compared to those which did not (B -1.339, 95% CI: -3.551 to 0.873). DISCUSSION AND CONCLUSION: Variation exists in dysphagia screening and management, but there was no evidence of an association between clinical practice patterns and incidence of SAP. Further research with larger sample sizes is needed to examine association with SAP.

Robust thrombolytic and anti-inflammatory action of a constitutively active ADAMTS13 variant in murine stroke models.

Advances in our understanding of ADAMTS13 structure, and the conformation changes required for full activity, have rejuvenated the possibility of its use as a thrombolytic therapy. We have tested a novel Ala1144Val ADAMTS13 variant (constitutively active [ca] ADAMTS13) that exhibits constitutive activity, characterized using in vitro assays of ADAMTS13 activity, and greatly enhanced thrombolytic activity in 2 murine models of ischemic stroke, the distal FeCl3 middle cerebral artery occlusion (MCAo) model and transient middle cerebral artery occlusion (tMCAO) with systemic inflammation and ischemia/reperfusion injury. The primary measure of efficacy in both models was restoration of regional cerebral blood flow (rCBF) to the MCA territory, which was determined using laser speckle contrast imaging. The caADAMTS13 variant exhibited a constitutively active conformation and a fivefold enhanced activity against fluorescence resonance energy transfer substrate von Willebrand factor 73 (FRETS-VWF73) compared with wild-type (wt) ADAMTS13. Moreover, caADAMTS13 inhibited VWF-mediated platelet capture at subphysiological concentrations and enhanced t-PA/plasmin lysis of fibrin(ogen), neither of which were observed with wtADAMTS13. Significant restoration of rCBF and reduced lesion volume was observed in animals treated with caADAMTS13. When administered 1 hour after FeCl3 MCAo, the caADAMTS13 variant significantly reduced residual VWF and fibrin deposits in the MCA, platelet aggregate formation, and neutrophil recruitment. When administered 4 hours after reperfusion in the tMCAo model, the caADAMTS13 variant induced a significant dissolution of platelet aggregates and a reduction in the resulting tissue hypoperfusion. The caADAMTS13 variant represents a potentially viable therapeutic option for the treatment of acute ischemic stroke, among other thrombotic indications, due to its enhanced in vitro and in vivo activities that result from its constitutively active conformation.

Use of risk scores for predicting new atrial fibrillation after ischemic stroke or transient ischemic attack-A systematic review.

BACKGROUND: Newly detected atrial fibrillation (NDAF) following an ischemic stroke or transient ischemic attack is often paroxysmal in nature. While challenging to detect, extended electrocardiographic (ECG) monitoring is often used to identify NDAF which has resource implications. Prognostic risk scores have been derived which may stratify the risk of NDAF and inform patient selection for ECG monitoring approaches after ischemic stroke/transient ischemic attack. AIM: The overall aim was to identify risk scores that were derived and/or validated to predict NDAF after ischemic stroke/transient ischemic attack and evaluate their performance. SUMMARY OF REVIEW: A systematic literature review was undertaken in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement, with application of the Quality Assessment of Diagnostic Accuracy-2 tool. Published studies, which derived and validated clinical risk scores in patients with ischemic stroke/transient ischemic attack, or externally validated an existing score to predict NDAF after ischemic stroke/transient ischemic attack, were considered and independently screened by two reviewers. Twenty-one studies involving 23 separate cohorts were analyzed from which 17 integer-based risk scores were identified. The overall frequency of NDAF was 9.7% (95% confidence intervals 8%-11.5%; I2 = 98%). The performance of the scores varied widely among derivation and validation cohorts (area under the receiver operating characteristic curve (AUC) 0.54-0.94); scores derived from stroke cohorts (12 scores) appeared to perform better (AUC 0.7-0.94) than those derived from non-stroke cohorts (five scores; AUC 0.53-0.79). The scores also varied considerably in their complexity, ascertainment, component variables, participant characteristics, outcome definition, and ease of application limiting their generalizability and utility. CONCLUSION: Overall, the risk scores identified performed variably in their discriminative ability and the utility of these scores to predict NDAF in clinical practice remains uncertain. Further studies are required using larger prospective cohorts and randomized control trials to evaluate the usefulness of such scores for clinical decision making and preventative intervention.

Variation of stroke-associated pneumonia in stroke units across England and Wales: A registry-based cohort study.

BACKGROUND: Pneumonia is common in stroke patients and is associated with worse clinical outcomes. Prevalence of stroke-associated pneumonia varies between studies, and reasons for this variation remain unclear. We aimed to describe the variation of observed stroke-associated pneumonia in England and Wales and explore the influence of patient baseline characteristics on this variation. METHODS: Patient data were obtained from the Sentinel Stroke National Audit Programme for all confirmed strokes between 1 April 2013 and 31 December 2018. Stroke-associated pneumonia was defined by new antibiotic initiation for pneumonia within the first seven days of admission. The probability of stroke-associated pneumonia occurrence within stroke units was estimated and compared using a multilevel mixed model with and without adjustment for patient-level characteristics at admission. RESULTS: Of the 413,133 patients included, median National Institutes of Health Stroke Scale was 4 (IQR: 2-10) and 42.3% were aged over 80 years. Stroke-associated pneumonia was identified in 8.5% of patients. The median within stroke unit stroke-associated pneumonia prevalence was 8.5% (IQR: 6.1-11.5%) with a maximum of 21.4%. The mean and variance of the predicted stroke-associated pneumonia probability across stroke units decreased from 0.08 (0.68) to 0.05 (0.63) when adjusting for patient admission characteristics. This difference in the variance suggests that clinical characteristics account for 5% of the observed variation in stroke-associated pneumonia between units. CONCLUSIONS: Patient-level clinical characteristics contributed minimally to the observed variation of stroke-associated pneumonia between stroke units. Additional explanations for the observed variation in stroke-associated pneumonia need to be explored which could reduce variation in antibiotic use for stroke patients.

Stroke-induced changes to immune function and their relevance to increased risk of severe COVID-19 disease.

As the COVID-19 pandemic moves towards endemic disease, it remains of key importance to identify groups of individuals vulnerable to severe infection and understand the biological factors that mediate this risk. Stroke patients are at increased risk of developing severe COVID-19, likely due to stroke-induced alterations to systemic immune function. Furthermore, immune responses associated with severe COVID-19 in patients without a history of stroke parallel many of the immune alterations induced by stroke, possibly resulting in a compounding effect that contributes to worsened disease severity. In this review, we discuss the changes to systemic immune function that likely contribute to augmented COVID-19 severity in patients with a history of stroke and the effects of COVID-19 on the immune system that may exacerbate these effects.