Leonid Churilov

The Florey Institute of Neuroscience and Mental Health, Melbourne, Victoria, Australia

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Publications (194)571.89 Total impact

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    ABSTRACT: High-fidelity intracranial electrode arrays for recording and stimulating brain activity have facilitated major advances in the treatment of neurological conditions over the past decade. Traditional arrays require direct implantation into the brain via open craniotomy, which can lead to inflammatory tissue responses, necessitating development of minimally invasive approaches that avoid brain trauma. Here we demonstrate the feasibility of chronically recording brain activity from within a vein using a passive stent-electrode recording array (stentrode). We achieved implantation into a superficial cortical vein overlying the motor cortex via catheter angiography and demonstrate neural recordings in freely moving sheep for up to 190 d. Spectral content and bandwidth of vascular electrocorticography were comparable to those of recordings from epidural surface arrays. Venous internal lumen patency was maintained for the duration of implantation. Stentrodes may have wide ranging applications as a neural interface for treatment of a range of neurological conditions.
    No preview · Article · Feb 2016 · Nature Biotechnology
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    Toby B Cumming · Leonid Churilov · Emily S Sena
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    ABSTRACT: Background: Meta-analyses are considered the gold standard of evidence-based health care, and are used to guide clinical decisions and health policy. A major limitation of current meta-analysis techniques is their inability to pool ordinal data. Our objectives were to determine the extent of this problem in the context of neurological rating scales and to provide a solution. Methods: Using an existing database of clinical trials of oral neuroprotective therapies, we identified the 6 most commonly used clinical rating scales and recorded how data from these scales were reported and analysed. We then identified systematic reviews of studies that used these scales (via the Cochrane database) and recorded the meta-analytic techniques used. Finally, we identified a statistical technique for calculating a common language effect size measure for ordinal data. Results: We identified 103 studies, with 128 instances of the 6 clinical scales being reported. The majority- 80%-reported means alone for central tendency, with only 13% reporting medians. In analysis, 40% of studies used parametric statistics alone, 34% of studies employed non-parametric analysis, and 26% did not include or specify analysis. Of the 60 systematic reviews identified that included meta-analysis, 88% used mean difference and 22% employed difference in proportions; none included rank-based analysis. We propose the use of a rank-based generalised odds ratio (WMW GenOR) as an assumption-free effect size measure that is easy to compute and can be readily combined in meta-analysis. Conclusion: There is wide scope for improvement in the reporting and analysis of ordinal data in the literature. We hope that adoption of the WMW GenOR will have the dual effect of improving the reporting of data in individual studies while also increasing the inclusivity (and therefore validity) of meta-analyses.
    Preview · Article · Dec 2015 · PLoS ONE
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    ABSTRACT: Purpose: To compare physical activity levels of patients in the first week after myocardial infarction (MI) and stroke. Method: We conducted an observational study using behavioural mapping. MI patients were consecutively recruited from Alfred Hospital, Melbourne. Data for stroke patients (Royal Perth Hospital or Austin Hospital, Melbourne) were retrieved from an existing database. Patients were observed for 1 min every 10 min from 8 am to 5 pm. At each observation, the patient's highest level of physical activity, location and people present were recorded. Details of physiotherapy and occupational therapy sessions were recorded by the therapists. Results: Proportion of the day spent physically inactive was lower in MI (n = 32, median 48%) than stroke (n = 125, median 59%) patients, but this difference was not significant in univariate or multivariate (adjusting for age, walking ability and days post-event) regression. Time spent physically active was higher in MI (median 23%) than stroke (median 10%) patients (p = 0.009), but this difference did not survive multivariate adjustment (p = 0.67). More stroke patients (78%) than MI patients (19%) participated in therapy. Conclusions: This study provides the first objective data on physical activity levels of acute MI patients. While they were more active than acute stroke patients, the difference was largely attributable to walking ability. Implications for rehabilitation In the first week after myocardial infarction, patients spent about half the day physically inactive (even though 81% were able to walk independently). Similar levels of inactivity were seen in a comparable cohort of acute stroke patients, suggesting that environmental factors play an important role. There appears to be wide scope for increasing levels of physical rehabilitation after acute cardiovascular events, though optimal timing and dose remain unclear.
    No preview · Article · Dec 2015 · Disability and Rehabilitation
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    ABSTRACT: Objective: To report the number of participants needed to recruit per baby born to trial staff during AVERT, a large international trial on acute stroke, and to describe trial management consequences. Design: Retrospective observational analysis. Setting: 56 acute stroke hospitals in eight countries. Participants: 1074 trial physiotherapists, nurses, and other clinicians. Outcome measures: Number of babies born during trial recruitment per trial participant recruited. Results: With 198 site recruitment years and 2104 patients recruited during AVERT, 120 babies were born to trial staff. Births led to an estimated 10% loss in time to achieve recruitment. Parental leave was linked to six trial site closures. The number of participants needed to recruit per baby born was 17.5 (95% confidence interval 14.7 to 21.0); additional trial costs associated with each birth were estimated at 5736 Australian dollars on average. Conclusion: The staff absences registered in AVERT owing to parental leave led to delayed trial recruitment and increased costs, and should be considered by trial investigators when planning research and estimating budgets. However, the celebration of new life became a highlight of the annual AVERT collaborators' meetings and helped maintain a cohesive collaborative group. Trial registration: Australian New Zealand Clinical Trials Registry no 12606000185561. Disclaimer: Participation in a rehabilitation trial does not guarantee successful reproductive activity.
    Full-text · Article · Dec 2015 · BMJ (online)
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    ABSTRACT: Background: Aggression is common in patients with autism spectrum disorders (ASD) along with the core symptoms of impairments in social communication and repetitive behavior. Risperidone, an atypical antipsychotic, is widely used to treat aggression in ASD. In order to understand the neurobiological underpinnings of these challenging behaviors, a thorough characterisation of behavioral endophenotypes in animal models is required. Methods: We investigated aggression in mice containing the ASD-associated R451C (arginine to cysteine residue 451 substitution) mutation in neuroligin-3 (NL3). Furthermore, we sought to verify social interaction impairments and assess olfaction, anxiety, and repetitive and restrictive behavior in NL3(R451C) mutant mice. Results: We show a pronounced elevation in aggressive behavior in NL3(R451C) mutant mice. Treatment with risperidone reduced this aggression to wild-type (WT) levels. Juvenile and adult social interactions were also investigated, and subtle differences in initiation of interaction were seen in juvenile NL3(R451C) mice. No genotype differences in olfactory discrimination or anxiety were observed indicating that aggression was not dependent on altered olfaction, stress response, or social preference. We also describe repetitive behavior in NL3(R451C) mice as assessed by a clinically relevant object exploration task. Conclusions: The presence of aberrant aggression and other behavioral phenotypes in NL3(R451C) mice consistent with clinical traits strengthen face validity of this model of ASD. Furthermore, we demonstrate predictive validity in this model through the reversal of the aggressive phenotype with risperidone. This is the first demonstration that risperidone can ameliorate aggression in an animal model of ASD and will inform mechanistic and therapeutic research into the neurobiology underlying abnormal behaviors in ASD.
    Full-text · Article · Dec 2015 · Molecular Autism
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    ABSTRACT: Background The risks of intracranial haemorrhage (ICH) post intra-arterial therapy (IAT) for stroke are not well understood. We aimed to study the influence of recanalization status post IAT for anterior circulation stroke and posterior circulation stroke on ICH development. Methods Retrospective analysis of 193 patients in a prospectively collected database of IAT stroke patients was performed. Successful recanalization was defined as a Thrombolysis in Cerebral Infarction Score of 2b or 3 and symptomatic ICH (SICH) as parenchymal hematoma type 2 (PH2) with neurological deterioration. The association between the recanalization status and ICH/SICH was investigated using logistic regression models adjusted for baseline characteristics selected by univariate analyses. Results One hundred and thirty-six patients had successful recanalization post procedure, 41 patients developed ICH and 10 patients SICH. There was a statistically significant baseline imbalance between the groups with and without successful recanalization on gender, baseline National Institute of Health Stroke Scale (NIHSS) score, the use of intravenous tPA and intra-arterial urokinase (p <0.05). Logistic regression analysis adjusted for the above variables and the time to digital subtraction angiography demonstrated a statistically significant association between successful recanalization and ICH (odds ratio 0.42; 95 % CI 0.19, 0.95; p = 0.04). Conclusion Successful recanalization post endovascular therapy is statistically significantly and negatively associated with ICH.
    Preview · Article · Dec 2015 · BMC Neurology
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    ABSTRACT: Background and Purpose Cardiovascular risk factors significantly increase the risk of developing Alzheimer disease. A possible mechanism may be via ischemic infarction-driving amyloid deposition. We conducted a study to determine the presence of -amyloid in infarct, peri-infarct, and hemispheric areas after stroke. We hypothesized that an infarct would trigger -amyloid deposition, with deposition over time. Methods Patients were recruited within 40 days of acute ischemic stroke and imaged with computed tomographic or magnetic resonance imaging and Pittsburgh compound B (11C-PiB) positron emission tomographic scans. Follow-up positron emission tomographic scanning was performed in a subgroup 18 months after the stroke event. Standardized uptake value ratios for regions of interest were analyzed after coregistration. Results Forty-seven patients were imaged with C-11-PiB positron emission tomography. There was an increase in C-11-PiB accumulation in the stroke area compared with a reference region in the contralesional hemisphere, which was not statistically significant (median difference in standardized uptake value ratio, 0.07 [95% confidence interval, -0.06 to 0.123]; P=0.452). There was no significant increase in the accumulation of C-11-PiB in the peri-infarct region or in the ipsilesional hemisphere (median difference in standardized uptake value ratio, 0.04 [95% confidence interval, -0.02 to 0.10]; P=0.095). We repeated C-11-PiB positron emission tomography in 21 patients and found a significant reduction in accumulation of C-11-PiB between regions of interest (median difference in standardized uptake value ratio, -0.08 [95% confidence interval, -0.23 to -0.03]; P=0.04). Conclusions There was no significant increase in C-11-PiB accumulation in or around the infarct. There was no increase in ipsilesional hemispheric C-11-PiB accumulation over time. We found no evidence that infarction leads to sustained or increased -amyloid deposition 18 months after stroke.
    Full-text · Article · Nov 2015 · Stroke
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    ABSTRACT: The reliability of experimental findings depends on the rigour of experimental design. Here we show limited reporting of measures to reduce the risk of bias in a random sample of life sciences publications, significantly lower reporting of randomisation in work published in journals of high impact, and very limited reporting of measures to reduce the risk of bias in publications from leading United Kingdom institutions. Ascertainment of differences between institutions might serve both as a measure of research quality and as a tool for institutional efforts to improve research quality.
    Full-text · Article · Nov 2015 · PLoS Biology
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    ABSTRACT: Objective To use admission inpatient glycated hemoglobin (HbA1c) testing to help investigate the prevalence of unrecognized diabetes, the cumulative prevalence of unrecognized and known diabetes, and the prevalence of poor glycemic control in both. Moreover, we aimed to determine the 6-month outcomes for these patients. Finally, we aimed to assess the independent association of diabetes with these outcomes. Research, design, and methods Prospective observational cohort study conducted in a tertiary hospital in Melbourne, Australia. Patients A cohort of 5082 inpatients ≥54 years admitted between July 2013 and January 2014 underwent HbA1c measurement. A previous diagnosis of diabetes was obtained from the hospital medical record. Patient follow-up was extended to 6 months. Results The prevalence of diabetes (known and unrecognized) was 34%. In particular, we identified that unrecognized but HbA1c-confirmed diabetes in 271 (5%, 95% CI 4.7% to 6.0%) patients, previously known diabetes in 1452 (29%, 95% CI 27.3% to 29.8%) patients; no diabetes in 3359 (66%, 95% CI 64.8–67.4%) patients. Overall 17% (95% CI 15.3% to 18.9%) of patients with an HbA1c of >6.5% had an HbA1c ≥8.5%. After adjusting for age, gender, Charlson Index score, estimated glomerular filtration rate, and hemoglobin levels, with admission unit treated as a random effect, patients with previously known diabetes had lower 6-month mortality (OR 0.69, 95% CI 0.56 to 0.87, p=0.001). However, there were no significant differences in proportions of intensive care unit admission, mechanical ventilation or readmission within 6 months between the 3 groups. Conclusions Approximately one-third of all inpatients ≥54 years of age admitted to hospital have diabetes of which about 1 in 6 was previously unrecognized. Moreover, poor glycemic control was common. Proportions of intensive care unit admission, mechanical ventilation, or readmission were similar between the groups. Finally, diabetes was independently associated with lower 6-month mortality.
    Full-text · Article · Sep 2015
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    ABSTRACT: Introduction: Cerebral atrophy after stroke is associated with poor functional outcome. The prediction and prevention of post-stroke brain atrophy could therefore represent a target for neurorestorative therapies. We investigated the associations between peri-infarct metabolite concentrations measured by quantitative MRS and brain volume change in the infarct hemisphere after stroke. Methods: Twenty patients with ischemic stroke were enrolled. Patients underwent 3T-MRI within 1 week of onset, and at 1 and 3 months. At the baseline scan, an MRS voxel was placed manually in the peri-infarct area and another in the corresponding contralateral region. Volumetric analysis of T1 images was performed using two automated processing packages. Changes in gray and white matter volume were assessed as percentage change between 1 and 3 months. Results: Mean concentrations (institutional units) of N-acetylaspartic acid (NAA) (6.1 vs 7.0, p = 0.039), total creatine (Cr+PCr) (5.4 vs 5.8, p = 0.043), and inositol (4.5 vs 5.0, p = 0.014), were significantly lower in the peri-infarct region compared with the contralateral hemisphere. There was a significant correlation between baseline peri-infarct NAA and white matter volume change in the infarct hemisphere between 1 and 3 months, with lower NAA being associated with subsequent white matter atrophy (Spearman's rho = 0.66, p = 0.010). The baseline concentration of Cr+PCr was also significantly correlated with white matter atrophy in the infarct hemisphere (Spearman's rho = 0.59, p = 0.027). Both of these associations were significant after adjustment for the false discovery rate and were validated using the secondary volumetric method. Conclusion: MRS may be useful in the prediction of white matter atrophy post-stroke and in the testing of novel neurorestorative therapies.
    No preview · Article · Sep 2015 · Neuroradiology
  • M Lin · M Todaro · J Chan · L Churilov · W S Zhu · S Ramdave · P J Mitchell · R J Dowling · P Kwan · B Yan
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    ABSTRACT: Differing responses to clopidogrel following endovascular treatment of cerebrovascular diseases may increase the risk of vascular complications. CYP2C19 gene polymorphisms influence clopidogrel activity. We aimed to study the clinical impact of CYP2C19 gene polymorphisms in patients undergoing endovascular treatment. This was a prospective, longitudinal, observational study. Information on demographics and cerebrovascular status was collected as baseline. Clopidogrel response was tested by the VerifyNow P2Y12 assay. CYP2C19 genotyping was undertaken by polymerase chain reaction-restriction fragment length polymorphism. Three-month follow-up data included vascular complications, mortality, and modified Rankin Scale score. Associations were investigated among CYP2C19 genotypes, clopidogrel responsiveness, and clinical outcomes. One hundred and eight participants were included. Median age was 56 years (interquartile range, 48.8-65.0 years), and 35 (32.4%) were male. Forty-four participants were classified into group 1 (homozygous CYP2C19*1/*1); 31, into group 2 (25 with CYP2C19*1/*2, two with CYP2C19*1/*3, three with CYP2C19*3/*3, one with CYP2C19*2/*3); 28, into group 3 (24 with CYP2C19*1/*17, four with CYP2C19*17/*17); and 5, into group 4 (CYP2C19*2/*17). A significantly higher proportion of participants in group 3 experienced ischemic events (9 of 28, 32.1%) compared with group 1 (5 of 44, 11.4%; P = .04; odds ratio, 3.7; 95% confidence interval, 1.1-12.6). There was no significant difference in clopidogrel response among the 4 genotype groups. Individuals with CYP2C19*17 may have increased risk of ischemic events following endovascular treatment, independent of clopidogrel responsiveness. Larger studies are required to confirm the influence of CYP2C19*17 on clinical outcomes and to understand the mechanisms for increased ischemic events. © 2016 American Society of Neuroradiology.
    No preview · Article · Sep 2015 · American Journal of Neuroradiology

  • No preview · Article · Sep 2015 · International Journal of Stroke

  • No preview · Article · Sep 2015 · International Journal of Stroke
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    ABSTRACT: Aims: To assess the performance of the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation at baseline and longitudinally in people with type 2 diabetes. Methods: Adults with type 2 diabetes attending Austin Health, Melbourne, with≥3 prospective GFR measurements were included in this retrospective study. Plasma disappearance rate of DTPA (diethylene-triamine-penta-acetic acid) was used to calculate measured GFR (mGFR) and compared to estimated GFR (eGFR). The agreement between mGFR and eGFR was estimated using Intraclass Correlation Coefficient (ICC). Results: 152 patients had a median of 4 (IQR: 3, 5) mGFR measurements over a period of 11years (IQR: 9, 12). The difference between mGFR and eGFR increased proportionally to the magnitude of the GFR, increasing by 0.2ml/min/1.73m(2) for every 1ml/min/1.73m(2) increase in mGFR, indicative of proportional bias. At lower mGFR levels, eGFR overestimated mGFR, and at higher mGFR levels, eGFR underestimated mGFR. There was a significant association between LDL cholesterol, triglycerides, HbA1c, diastolic blood pressure and the difference between mGFR and eGFR. Conclusions: The CKD-EPI formula underestimates mGFR and the rate of decline of mGFR in patients with type 2 diabetes with an mGFR greater than 60ml/min/1.73m(2). The association between LDL cholesterol, triglycerides, HbA1c, diastolic blood pressure and the difference between mGFR and eGFR warrants further study.
    No preview · Article · Sep 2015 · Journal of diabetes and its complications

  • No preview · Article · Sep 2015 · International Journal of Stroke

  • No preview · Article · Sep 2015 · International Journal of Stroke
  • S. Rewell · L. Churilov · K. Sidon · D. Howells

    No preview · Article · Sep 2015 · International Journal of Stroke

  • No preview · Article · Sep 2015 · International Journal of Stroke
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    ABSTRACT: sec> Objective The purpose of this paper is to examine potential threats to generalisability of the results of a multicentre randomised controlled trial using data from A Very Early Rehabilitation Trial (AVERT). Design AVERT is a prospective, parallel group, assessor-blinded randomised clinical trial. This paper presents data assessing the generalisability of AVERT. Setting Acute stroke units at 44 hospitals in 8 countries. Participants The first 20&emsp14;000 patients screened for AVERT, of whom 1158 were recruited and randomised. Model We use the Proximal Similarity Model, which considers the person, place, and setting and practice, as a framework for considering generalisability. As well as comparing the recruited patients with the target population, we also performed an exploratory analysis of the demographic, clinical, site and process factors associated with recruitment. Results The demographics and stroke characteristics of the included patients in the trial were broadly similar to population-based norms, with the exception that AVERT had a greater proportion of men. The most common reason for non-recruitment was late arrival to hospital (ie, >24&emsp14;h). Overall, being older and female reduced the odds of recruitment to the trial. More women than men were excluded for most of the reasons, including refusal. The odds of exclusion due to early deterioration were particularly high for those with severe stroke (OR=10.4, p<0.001, 95% CI 9.27 to 11.65). Conclusions A model which explores person, place, and setting and practice factors can provide important information about the external validity of a trial, and could be applied to other clinical trials. Trial registration number Australian New Zealand Clinical Trials Registry (ACTRN12606000185561) and Clinicaltrials.gov (NCT01846247). </sec
    Full-text · Article · Aug 2015 · BMJ Open
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    ABSTRACT: Background: The hyperdense middle cerebral artery sign [HMCAS]and hyperdense basilar sign [HBAS]are associated with poor outcome with thrombolysis [t-PA). Intra-arterial [IA]therapy is sometimes used in the management of acute anterior circulation strokes in addition to t-PA. The utility of these signs in stratifying outcomes with IA therapy is limited. We compared recanalisation rates with IA therapy in patients with and without the signs.
    Full-text · Article · Jul 2015

Publication Stats

2k Citations
571.89 Total Impact Points

Institutions

  • 2011-2015
    • The Florey Institute of Neuroscience and Mental Health
      • Stroke Division
      Melbourne, Victoria, Australia
  • 2008-2015
    • University of Melbourne
      • • Florey Institute of Neuroscience and Mental Health
      • • Department of Mathematics and Statistics
      Melbourne, Victoria, Australia
  • 2005-2015
    • University of Vic
      Vic, Catalonia, Spain
  • 2013-2014
    • RMIT University
      • School of Mathematical and Geospatial Sciences
      Melbourne, Victoria, Australia
    • Royal Melbourne Hospital
      • Department of Radiology
      Melbourne, Victoria, Australia
  • 2012
    • National Neuroscience Institute
      • Department of Neurology
      Singapore, Singapore
  • 2003-2008
    • Monash University (Australia)
      • • Department of Microbiology
      • • School of Computer Science & Software Engineering
      Melbourne, Victoria, Australia
  • 1970
    • National Stroke Foundation
      Melbourne, Victoria, Australia