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.

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.

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.

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.

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.

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.

External Validation of Five Scores to Predict Stroke-Associated Pneumonia and the Role of Selected Blood Biomarkers.

BACKGROUND AND PURPOSE: Several clinical scoring systems as well as biomarkers have been proposed to predict stroke-associated pneumonia (SAP). We aimed to externally and competitively validate SAP scores and hypothesized that 5 selected biomarkers would improve performance of these scores. METHODS: We pooled the clinical data of 2 acute stroke studies with identical data assessment: STRAWINSKI and PREDICT. Biomarkers (ultrasensitive procalcitonin; mid-regional proadrenomedullin; mid-regional proatrionatriuretic peptide; ultrasensitive copeptin; C-terminal proendothelin) were measured from hospital admission serum samples. A literature search was performed to identify SAP prediction scores. We then calculated multivariate regression models with the individual scores and the biomarkers. Areas under receiver operating characteristic curves were used to compare discrimination of these scores and models. RESULTS: The combined cohort consisted of 683 cases, of which 573 had available backup samples to perform the biomarker analysis. Literature search identified 9 SAP prediction scores. Our data set enabled us to calculate 5 of these scores. The scores had area under receiver operating characteristic curve of 0.543 to 0.651 for physician determined SAP, 0.574 to 0.685 for probable and 0.689 to 0.811 for definite SAP according to Pneumonia in Stroke Consensus group criteria. Multivariate models of the scores with biomarkers improved virtually all predictions, but mostly in the range of an area under receiver operating characteristic curve delta of 0.05. CONCLUSIONS: All SAP prediction scores identified patients who would develop SAP with fair to strong capabilities, with better discrimination when stricter criteria for SAP diagnosis were applied. The selected biomarkers provided only limited added predictive value, currently not warranting addition of these markers to prediction models. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01264549 and NCT01079728.

Characteristics and outcomes of COVID-19 associated stroke: a UK multicentre case-control study.

OBJECTIVE: We set out to determine which characteristics and outcomes of stroke are associated with COVID-19. METHODS: This case-control study included patients admitted with stroke to 13 hospitals in England and Scotland between 9 March and 5 July 2020. We collected data on 86 strokes (81 ischaemic strokes and 5 intracerebral haemorrhages) in patients with evidence of COVID-19 at the time of stroke onset (cases). They were compared with 1384 strokes (1193 ischaemic strokes and 191 intracerebral haemorrhages) in patients admitted during the same time period who never had evidence of COVID-19 (controls). In addition, the whole group of stroke admissions, including another 37 patients who appeared to have developed COVID-19 after their stroke, were included in two logistic regression analyses examining which features were independently associated with COVID-19 status and with inpatient mortality. RESULTS: Cases with ischaemic stroke were more likely than ischaemic controls to occur in Asians (18.8% vs 6.7%, p<0.0002), were more likely to involve multiple large vessel occlusions (17.9% vs 8.1%, p<0.03), were more severe (median National Institutes of Health Stroke Scale score 8 vs 5, p<0.002), were associated with higher D-dimer levels (p<0.01) and were associated with more severe disability on discharge (median modified Rankin Scale score 4 vs 3, p<0.0001) and inpatient death (19.8% vs 6.9%, p<0.0001). Recurrence of stroke during the patient's admission was rare in cases and controls (2.3% vs 1.0%, NS). CONCLUSIONS: Our data suggest that COVID-19 may be an important modifier of the onset, characteristics and outcome of acute ischaemic stroke.

The Effects of Midline Cerebellar rTMS on Human Pharyngeal Cortical Activity in the Intact Swallowing Motor System.

We sought to compare the effects of 10 Hz cerebellar vermis (vs. unilateral hemispheric and sham) repetitive transcranial magnetic stimulation (rTMS) on cortical neuroelectrical activity and thereafter 10 Hz cerebellar vermis (vs. sham) rTMS on swallowing behaviour. Healthy participants (n = 25) were randomly allocated to receive vermis, unilateral hemisphere or sham 10 Hz cerebellar rTMS. Recordings were made using pharyngeal electromyography and manometry catheters, obtaining motor-evoked potentials (MEPs) and pressure recordings. The amplitudes of MEPs elicited using single-pulse TMS delivered to the pharyngeal areas of the motor cortex bilaterally were measured pre- and post-cerebellar stimulation. As in previous studies, abductor policis brevis (APB) MEPs were measured to assess post-rTMS modulation specificity. Swallowing was assessed using a swallowing accuracy task. Measurements were made at baseline and 15-min intervals for an hour post-intervention. Measurements involved TMS being used to elicit 10 MEPs bilaterally over the pharyngeal areas of the motor cortex, over the APB cortical representation adjacent to the pharyngeal area with the lowest resting motor threshold and 5 MEPs bilaterally over pharyngeal areas of the cerebellar hemispheres. Swallowing accuracy was assessed by giving participants 10 attempts to swallow and hit a digital target. Cerebellar vermis rTMS caused significant suppression of cortical pharyngeal MEP amplitudes compared with unilateral rTMS and sham (P = 0.0005, 0.002). APB and cerebellar MEP amplitudes were unaffected as were pharyngeal and APB MEP latencies. Following cerebellar vermis rTMS there was a significant reduction in swallowing accuracy compared with sham (P = 0.001). Our findings demonstrate cerebellar vermis rTMS exerts a suppressive effect on pharyngeal motor cortical activity and swallowing behaviour.

Use of Pulmonary Computed Tomography for Evaluating Suspected Stroke-Associated Pneumonia.

OBJECTIVES: Accurate and timely diagnosis of pneumonia complicating stroke remains challenging and the diagnostic accuracy of chest X-ray (CXR) in the setting of stroke-associated pneumonia (SAP) is uncertain. The overall objective of this study was to evaluate the use of pulmonary computed tomography (CT) in diagnosis of suspected SAP. MATERIALS AND METHODS: Patients with acute ischemic stroke (IS) or intracerebral hemorrhage (ICH) were recruited within 24h of clinically suspected SAP and underwent non-contrast pulmonary CT within 48h of antibiotic initiation. CXR and pulmonary CT were reported by two radiologists. Pulmonary CT was used as the reference standard for final diagnosis of SAP. Sensitivity, specificity, positive and negative predictive values (PPV and NPV), and diagnostic odds ratio (OR) for CXR were calculated. RESULTS: 40 patients (36 IS, 4 ICH) with a median age of 78y (range 44y-90y) and a median National Institute of Health Stroke Scale score of 13 (range 3-31) were included. All patients had at least one CXR and 35/40 patients (88%) underwent pulmonary CT. Changes consistent with pneumonia were present in 15/40 CXRs (38%) and 12/35 pulmonary CTs (34%). 9/35 pulmonary CTs (26%) were reported normal. CXR had a sensitivity of 58.3%, specificity of 73.9%, PPV of 53.8 %, NPV of 77.2 %, diagnostic OR of 3.7 (95% CI 0.7 - 22) and an accuracy of 68.5% (95% CI 50.7% -83.1%). DISCUSSION: CXR has limited diagnostic accuracy in SAP. The majority of patients started on antibiotics had no evidence of pneumonia on pulmonary CT with potential implications for antibiotic stewardship. CONCLUSIONS: Pulmonary CT could be applied as a reference standard for evaluation of clinical and biomarker diagnostic SAP algorithms in multi-center studies.

Infection as a Stroke Risk Factor and Determinant of Outcome After Stroke.

Understanding the relationship between infection and stroke has taken on new urgency in the era of the coronavirus disease 2019 (COVID-19) pandemic. This association is not a new concept, as several infections have long been recognized to contribute to stroke risk. The association of infection and stroke is also bidirectional. Although infection can lead to stroke, stroke also induces immune suppression which increases risk of infection. Apart from their short-term effects, emerging evidence suggests that poststroke immune changes may also adversely affect long-term cognitive outcomes in patients with stroke, increasing the risk of poststroke neurodegeneration and dementia. Infections at the time of stroke may also increase immune dysregulation after the stroke, further exacerbating the risk of cognitive decline. This review will cover the role of acute infections, including respiratory infections such as COVID-19, as a trigger for stroke; the role of infectious burden, or the cumulative number of infections throughout life, as a contributor to long-term risk of atherosclerotic disease and stroke; immune dysregulation after stroke and its effect on the risk of stroke-associated infection; and the impact of infection at the time of a stroke on the immune reaction to brain injury and subsequent long-term cognitive and functional outcomes. Finally, we will present a model to conceptualize the many relationships among chronic and acute infections and their short- and long-term neurological consequences. This model will suggest several directions for future research.

The effects of unilateral and bilateral cerebellar rTMS on human pharyngeal motor cortical activity and swallowing behavior.

The cerebellum is recognised to bilaterally modulate sensorimotor function and has recently been shown to play a role in swallowing. Unilateral cerebellar repetitive trans-cranial magnetic stimulation (rTMS) excites corticobulbar motor pathways to the pharynx but the effects of bilateral versus unilateral cerebellar rTMS on these pathways are unknown. In this three-part cross-over study, healthy participants (n = 13) were randomly allocated to receive unilateral or bilateral 10 Hz cerebellar rTMS. Participants were intubated with pharyngeal electromyography and/or manometry catheters for motor evoked potentials (MEPs) and pressure recordings. In part 1 of the study, single pulse TMS was used to measure baseline motor cortical pharyngeal MEP (PMEP) and hemispheric cerebellar MEP (CMEP) amplitudes, before cerebellar rTMS was administered. Repeat measures of PMEP amplitude were performed at 15-min intervals for an hour post unilateral and bilateral rTMS. Thereafter, in two further studies, a cortical 'virtual lesion' (V/L) was applied prior to cerebellar rTMS with pre and post PMEPs (part 2) and measurements of swallowing accuracy (part 3) using a behavioural task. Compared to baseline, unilateral and bilateral cerebellar rTMS provoked increases in pharyngeal cortical excitation (P = 0.028, 0.0005, respectively). Bilateral rTMS was significantly more effective than unilateral in causing cortical excitation (P = 0.0005) and in reversing the suppressive neurological (P = 0.0005) and behavioural (P = 0.0005) effects of a cortical V/L. Our findings suggest bilateral cerebellar rTMS has greater facilitatory effects on corticobulbar motor pathways to the pharynx than unilateral stimulation with the potential to be a more effective clinical therapy if its effects are reproduced in populations with neurogenic dysphagia.

A qualitative exploration of oral health care among stroke survivors living in the community.

BACKGROUND: Dental disease is highly prevalent in people with stroke. Stroke survivors regard oral hygiene as an important, yet neglected, area. The aim was to explore experiences of and barriers to oral care, particularly in relation to oral hygiene practice and dental attendance, among stroke survivors in the community. METHODS: This was a qualitative study incorporating a critical realist approach. Interviews were conducted with community-dwelling stroke survivors requiring assistance with activities of daily living, and focus groups were held with health and care professionals. Interviews and focus groups were recorded and transcribed verbatim. Thematic analysis was conducted. RESULTS: Twenty-three stroke survivors were interviewed, and 19 professionals took part in 3 focus groups. Professionals included nurses, speech and language therapists, occupational therapists, dieticians, professional carers and dental staff. Interviews revealed difficulties in carrying out oral hygiene self-care due to fatigue, forgetfulness and limb function and dexterity problems. Routine was considered important for oral hygiene self-care and was disrupted by hospitalization resulting from stroke. Professionals highlighted gaps in staff training and confidence in supporting patients with oral care. Access to dental services appeared particularly problematic for those who were not registered with a dentist pre-stroke. CONCLUSION: Oral hygiene routines may be disrupted by stroke, and resulting disabilities may make regular oral self-care more difficult. This study has identified specific barriers to oral hygiene self-care and dental service access. Findings from this study are feeding into the development of an intervention to support stroke survivors with oral care.

Factors Associated with Risk of Stroke-Associated Pneumonia in Patients with Dysphagia: A Systematic Review.

Dysphagia is associated with increased risk of stroke-associated pneumonia (SAP). However, it is unclear what other factors contribute to that risk or which measures may reduce it. This systematic review aimed to provide evidence on interventions and care processes associated with SAP in patients with dysphagia. Studies were screened for inclusion if they included dysphagia only patients, dysphagia and non-dysphagia patients or unselected patients that included dysphagic patients and evaluated factors associated with a recorded frequency of SAP. Electronic databases were searched from inception to February 2017. Eligible studies were critically appraised. Heterogeneity was evaluated using I2. The primary outcome was SAP. Eleven studies were included. Sample sizes ranged from 60 to 1088 patients. There was heterogeneity in study design. Measures of immunodepression are associated with SAP in dysphagic patients. There is insufficient evidence to justify screening for aerobic Gram-negative bacteria. Prophylactic antibiotics did not prevent SAP and proton pump inhibitors may increase risk. Treatment with metoclopramide may reduce SAP risk. Evidence that nasogastric tube (NGT) placement increases risk of SAP is equivocal. A multidisciplinary team approach and instrumental assessment of swallowing may reduce risk of pneumonia. Patients with impaired mobility were associated with increased risk. Findings should be interpreted with caution given the number of studies, heterogeneity and descriptive analyses. Several medical interventions and care processes, which may reduce risk of SAP in patients with dysphagia, have been identified. Further research is needed to evaluate the role of these interventions and care processes in clinical practice.

An Exploration of the Application of Noninvasive Cerebellar Stimulation in the Neuro-rehabilitation of Dysphagia after Stroke (EXCITES) Protocol.

BACKGROUND: Poststroke dysphagia is common, associated with a poor outcome and has no definitive treatments. Repetitive transcranial magnetic stimulation (rTMS) targeting the cerebellum is a noninvasive technique requiring minimal physical or cognitive input from the patient, and has been shown to induce positive swallow-related brain changes in physiological studies as measured by increased cortical excitability. AIM: To explore in patients with acute/sub-acute poststroke dysphagia: (1) the feasibility and immediate effect; and (2) the optimal dose for long-term benefit, of cerebellar rTMS in patients with dysphagia in acute/sub-acute stroke. METHODS: Two double-blind sham-controlled randomized phase II trials. Participants will be recruited from stroke units in Nottingham and Greater Manchester. Dysphagia will be confirmed via baseline videofluoroscopy (VFS). Participants will be blinded to treatment and receive cerebellar rTMS or sham stimulation: (1) single treatment of (10Hz, 250 pulse) in 24 participants; (2) daily for 3 days, twice-daily for 5 days, or twice-daily sham treatment for 5 days, in 48 participants. RESULTS: The severity of dysphagia will be assessed with VFS, using the penetration aspiration scale (PAS) at: (1) 1-hour, (2) 2-weeks, post-treatment. Additional comparative measures will be taken from: (1) pharyngeal motor evoked potential (MEP) amplitudes, (2) the functional oral intake score and dysphagia severity rating scale. CONCLUSIONS: If these studies demonstrate feasibility and identify optimal dosing, further trials to assess the safety and efficacy of cerebellar rTMS as a treatment for poststroke dysphagia will be warranted.

Environmental Factors and Hyperacute Stroke Care Activity During the COVID-19 Pandemic: An Interrupted Time-Series Analysis.

BACKGROUND AND AIMS: Concerns have arisen regarding patient access and delivery of acute stroke care during the COVID-19 pandemic. We investigated key population level events on activity of the three hyperacute stroke units (HASUs) within Greater Manchester and East Cheshire (GM & EC), whilst adjusting for environmental factors. METHODS: Weekly stroke admission & discharge counts in the three HASUs were collected locally from Emergency Department (ED) data and Sentinel Stroke National Audit Programme core dataset prior to, and during the emergence of the COVID-19 pandemic (Jan 2020 to May 2020). Whilst adjusting for local traffic-related air pollution and ambient measurement, an interrupted time-series analysis using a segmented generalised linear model investigated key population level events on the rate of stroke team ED assessments, admissions for stroke, referrals for transient ischaemic attack (TIA), and stroke discharges. RESULTS: The median total number of ED stroke assessments, admissions, TIA referrals, and discharges across the three HASU sites prior to the first UK COVID-19 death were 150, 114, 69, and 76 per week. The stable weekly trend in ED assessments and stroke admissions decreased by approximately 16% (and 21% for TIAs) between first UK hospital COVID-19 death (5th March) and the implementation of the Act-FAST campaign (6th April) where a modest 4% and 5% increase per week was observed. TIA referrals increased post Government intervention (23rd March), without fully returning to the numbers observed in January and February. Trends in discharges from stroke units appeared unaffected within the study period reported here. CONCLUSION: Despite adjustment for environmental factors stroke activity was temporarily modified by the COVID-19 pandemic. Underlying motivations within the population are still not clear. This raises concerns that patients may have avoided urgent health care risking poorer short and long-term health outcomes.

An Observational Cohort Study Investigating Risk of Malnutrition Using the Malnutrition Universal Screening Tool in Patients with Stroke.

BACKGROUND: Malnutrition in patients hospitalized with a stroke have been assessed using different nutritional screening methods but there is a paucity of data linking risk of malnutrition to clinical outcomes using a validated tool. AIMS: To identify the prevalence of malnutrition risk in patients after a stroke and assess the predictive value of the Malnutrition Universal Screening Tool (MUST) on clinical outcomes. PATIENTS AND METHODS: Using data from electronic records and the Sentinel Stroke National Audit Programme (January 2013 and March 2016), patients aged more than 18 years with confirmed stroke admitted to a tertiary care stroke unit were assessed for risk of malnutrition. The association between malnutrition risk and clinical outcomes was investigated and adjusted for confounding variables. RESULTS: Of 1101 patients, 66% were screened at admission. Most patients (n = 571, 78.5%) were identified as being at low risk, 4.1% (n = 30) at medium risk, and 17.4% (n = 126) at high risk of malnutrition. Compared with low risk, patients with medium or high risk of malnutrition were more likely to have a longer hospital stay (IRR 1.30, 95% confidence interval [CI] 1.07, 1.58), and had greater risk of mortality (10.9% versus 3.5%, 95% CI .03, .13). CONCLUSIONS: Prevalence of malnutrition assessed by MUST in patients after a stroke was relatively low, but nearly a third of patients were not screened. Patients classified as being at medium or high risk of malnutrition were more likely to experience negative outcomes. Early identification of this population may improve outcome if appropriate care is provided.

Microbiological Etiologies of Pneumonia Complicating Stroke: A Systematic Review.

BACKGROUND AND PURPOSE: Identifying the causal pathogens of pneumonia complicating stroke is challenging, and antibiotics used are often broad spectrum, without recourse to the microbiological cause. We aimed to review existing literature to identify organisms responsible for pneumonia complicating stroke, before developing a consensus-based approach to antibiotic treatment. METHODS: A systematic literature review of multiple electronic databases using predefined search criteria was undertaken, in accordance with Cochrane and PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidance. Published studies of hospitalized adults with ischemic stroke, intracerebral hemorrhage, or both, which identified microbiological etiologies for pneumonia complicating stroke up to January 1, 2017, were considered. Analysis included summary statistics and random-effects meta-analysis where appropriate. RESULTS: Fifteen studies (40% ischemic stroke, 60% ischemic stroke and intracerebral hemorrhage) involving 7968 patients were included. Reported occurrence of pneumonia varied considerably between studies (2%-63%) with a pooled frequency of 23% (95% confidence interval, 14%-34%; I2=99%). Where reported (60%), the majority of pneumonia occurred within 1 week of stroke (78%). Reported frequency of positive culture data (15%-88%) varied widely. When isolated, aerobic Gram-negative bacilli (38%) and Gram-positive cocci (16%) were most frequently cultured; commonly isolated organisms included Enterobacteriaceae (21.8%: Klebsiella pneumoniae, 12.8% and Escherichia coli, 9%), Staphylococcus aureus (10.1%), Pseudomonas aeruginosa (6%), Acinetobacter baumanii (4.6%), and Streptococcus pneumoniae (3.5%). Sputum was most commonly used to identify pathogens, in isolation (40%) or in conjunction with tracheal aspirate (15%) or blood culture (20%). CONCLUSIONS: Although the analysis was limited by small and heterogeneous study populations, limiting determination of microbiological causality, this review suggests aerobic Gram-negative bacilli and Gram-positive cocci are frequently associated with pneumonia complicating stroke. This supports the need for appropriately designed studies to determine microbial cause and a consensus-based approach in antibiotic usage and further targeted antibiotic treatment trials for enhanced antibiotic stewardship.

SCIL-STROKE (Subcutaneous Interleukin-1 Receptor Antagonist in Ischemic Stroke): A Randomized Controlled Phase 2 Trial.

BACKGROUND AND PURPOSE: The proinflammatory cytokine IL-1 (interleukin-1) has a deleterious role in cerebral ischemia, which is attenuated by IL-1 receptor antagonist (IL-1Ra). IL-1 induces peripheral inflammatory mediators, such as interleukin-6, which are associated with worse prognosis after ischemic stroke. We investigated whether subcutaneous IL-1Ra reduces the peripheral inflammatory response in acute ischemic stroke. METHODS: SCIL-STROKE (Subcutaneous Interleukin-1 Receptor Antagonist in Ischemic Stroke) was a single-center, double-blind, randomized, placebo-controlled phase 2 trial of subcutaneous IL-1Ra (100 mg administered twice daily for 3 days) in patients presenting within 5 hours of ischemic stroke onset. Randomization was stratified for baseline National Institutes of Health Stroke Scale score and thrombolysis. Measurement of plasma interleukin-6 and other peripheral inflammatory markers was undertaken at 5 time points. The primary outcome was difference in concentration of log(interleukin-6) as area under the curve to day 3. Secondary outcomes included exploratory effect of IL-1Ra on 3-month outcome with the modified Rankin Scale. RESULTS: We recruited 80 patients (mean age, 72 years; median National Institutes of Health Stroke Scale, 12) of whom 73% received intravenous thrombolysis with alteplase. IL-1Ra significantly reduced plasma interleukin-6 (P<0.001) and plasma C-reactive protein (P<0.001). IL-1Ra was well tolerated with no safety concerns. Allocation to IL-1Ra was not associated with a favorable outcome on modified Rankin Scale: odds ratio (95% confidence interval)=0.67 (0.29-1.52), P=0.34. Exploratory mediation analysis suggested that IL-1Ra improved clinical outcome by reducing inflammation, but there was a statistically significant, alternative mechanism countering this benefit. CONCLUSIONS: IL-1Ra reduced plasma inflammatory markers which are known to be associated with worse clinical outcome in ischemic stroke. Subcutaneous IL-1Ra is safe and well tolerated. Further experimental studies are required to investigate efficacy and possible interactions of IL-1Ra with thrombolysis. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: ISRCTN74236229.

Impact of Dysphagia Assessment and Management on Risk of Stroke-Associated Pneumonia: A Systematic Review.

BACKGROUND: Patients with dysphagia are at an increased risk of stroke-associated pneumonia. There is wide variation in the way patients are screened and assessed during the acute phase. The aim of this review was to identify the methods of assessment and management in acute stroke that influence the risk of stroke-associated pneumonia. Studies of stroke patients that reported dysphagia screening, assessment or management and occurrence of pneumonia during acute phase stroke were screened for inclusion after electronic searches of multiple databases from inception to November 2016. The primary outcome was association with stroke-associated pneumonia. SUMMARY: Twelve studies of 87,824 patients were included. The type of dysphagia screening protocol varied widely across and within studies. There was limited information on what comprised a specialist swallow assessment and alternative feeding was the only management strategy, which was reported for association with stroke-associated pneumonia. Use of a formal screening protocol and early dysphagia screening (EDS) and assessment by a speech and language pathologist (SLP) were associated with a reduced risk of stroke-associated pneumonia. There was marked heterogeneity between the included studies, which precluded meta-analysis. Key Messages: There is variation in the assessment and management of dysphagia in acute stroke. There is increasing evidence that EDS and specialist swallow assessment by an SLP may reduce the odds of stroke-associated pneumonia. There is the potential for other factors to influence the incidence of stroke-associated pneumonia during the acute phase.