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Effect of SBI-581 on Rab11 vesicle trafficking

Includes Sup. Figures 1-7, Tables 1-6 and Methods.

Effect of SU11333 on TKS5alpha vesicle trafficking

Invadopodia are actin-based proteolytic membrane protrusions required for invasive behavior and tumor growth. In this study, we used our high-content screening assay to identify kinases whose activity affects invadopodia formation. Among the top hits selected for further analysis was TAO3, an STE20-like kinase of the GCK subfamily. TAO3 was overexpressed in many human cancers and regulated invadopodia formation in melanoma, breast, and bladder cancers. Furthermore, TAO3 catalytic activity facilitated melanoma growth in three-dimensional matrices and in vivo. A novel, potent catalytic inhibitor of TAO3 was developed that inhibited invadopodia formation and function as well as tumor cell extravasation and growth. Treatment with this inhibitor demonstrated that TAO3 activity is required for endosomal trafficking of TKS5α, an obligate invadopodia scaffold protein. A phosphoproteomics screen for TAO3 substrates revealed the dynein subunit protein LIC2 as a relevant substrate. Knockdown of LIC2 or expression of a phosphomimetic form promoted invadopodia formation. Thus, TAO3 is a new therapeutic target with a distinct mechanism of action.Significance:An unbiased screening approach identifies TAO3 as a regulator of invadopodia formation and function, supporting clinical development of this class of target.

Effect of SBI-581 on TKS5alpha vesicle trafficking

Trafficking of TKS5alpha vesicles

This is a case of a 32-year-old primigravid who developed sudden severe headache on the 7th day postpartum associated with focal neurologic deficits and altered sensorium. She had a GCS score of 6, anisocoric pupils and an NIHSS score of 31. Cranial MRI with MRA showed multifocal hyperacute to acute infarcts on the left occipital lobe, left thalamus, and midbrain which was more prominent on the right. Due to clinical deterioration, a repeat Cranial MRI with MRA was done and showed progression of infarcts involving both thalami and right pons with interval appearance of contour irregularities in the proximal anterior cerebral, posterior cerebral, basilar and internal carotid arteries. Serial transcranial Doppler showed significant distal right middle cerebral artery vasospasm. She was managed as a case of reversible cerebral vasoconstriction syndrome, associated with postpartum cerebral angiopathy. Intravenous pulse methylprednisolone was started subsequently IVIG was initiated. Intravenous immunoglobulin was given for 5 days. The patient gradually improved, underwent rehabilitation therapy, and was discharged stable after 6 weeks.

The COVID-19 pandemic has impacted the health system worldwide. Stroke is one of the leading causes of death and disability in the world. Asia has a diverse health system and more than two-thirds of strokes occur in this region. The Asian Stroke Advisory Panel (ASAP) conducted a survey among the member countries to explore the impact of COVID-19 on stroke care. The stroke admission numbers have fallen, as have the number of patients who received thrombolysis and mechanical thrombectomy. The stroke unit and rehabilitation beds have been reallocated for COVID-19 care. ASAP recommends emergency department screening of stroke patients for COVID-19 and protected stroke code to be activated for COVID-19 suspect stroke patients. Noncontrast computed tomography (CT), CT angiography, and CT chest are the imaging modalities of choice. All health care professionals involved in triaging, imaging, and stroke care should wear appropriate personal protective equipment. All eligible stroke patients (COVID suspect/positive/non-COVID) should receive intravenous thrombolysis/mechanical thrombectomy. Mobile stroke units and robots can be used wherever available for evaluation and triaging. All stroke patients should receive standard stroke unit care. Limited rehabilitation should be offered to patients and training of caregivers if needed. Telemedicine/telestroke should be used for rehabilitation and follow-up. The ASAP consensus statement can be adapted to suit local and national health care systems.

Introduction: Intracranial arterial stenosis (ICAS) is common among certain race. It is prevalent in Asians, Hispanics, and African Americans, who constitutes about 2/3 of the world population making it the most common cause of stroke worldwide. Objectives: The objectives are to describe the demographic data and risk factors of patients with ICAS and 1-year outcome. Methods: Patients who had ischemic stroke by cranial computed tomography scan or magnetic resonance imaging, magnetic resonance angiography, computed tomographic angiography, or transcranial Doppler with periodic follow-up for 1 year were consecutively collected. Patients without intracranial stenosis were also collected and served as control. The demographic data, risk factors, modified Rankin Scale, stroke recurrence and mortality between ICAS and large artery atherosclerosis (LAA) patients were compared. The distribution and the degree of steno-occlusive lesions were estimated. Results: A total of 258 cases were consecutively collected. ICAS was demonstrated in 109 patients and 149 were LAA patients. There were 62 (56.88%) males. The age range distribution was as follows: 18 to 45 year olds, 15 (13.76%); 46 to 60 year olds, 28 (25.69%); and 61 year olds and above 66 (60.55%). Risk factors were hypertension 82 (75.23%), diabetes mellitus 46 (42.20%), hyperlipidemia 27 (24.77%), atrial fibrillation 16 (14.68%), history of previous stroke 23 (21.10%), alcohol drinker 28 (25.69%), obesity 8 (7.34%), and family history of cerebrovascular disease 33 (30.28%). ICAS was seen in the middle cerebral artery 46 (46.9%), ICA 21 (21.4%), BA 11 (11.2%), VA 8 (8.16%), PCA 7 (7.14%), and ACA 5 (5.1%). Majority of the patients showed moderate to severe stenosis. Modified Rankin Scale ranged from 0 to 2 in the majority of the patients and showed not much difference compared to LAA patients. The recurrence of stroke and death rate showed no significant difference between the 2 groups. Conclusion: In this study, no difference was seen between ICAS and LAA patients.

Background and purpose To examine sex differences in disease profiles and short-term outcomes after acute ischemic stroke treated with recombinant tissue plasminogen activator. Methods Eight national and regional stroke registries contributed individual participant data from mainland China, Japan, Philippines, Singapore, South Korea and Taiwan in 2005–2018. The primary outcome was ordinal-modified Rankin scale at 90 days. Key safety outcome was symptomatic intracerebral hemorrhage (sICH). Results Of 4453 patients included in the analyses, 1692 (36.3%) were women who were older, more likely to have a more severe neurological deficit, history of hypertension and atrial fibrillation, and a cardioembolic stroke compared to men. Women were more likely than men to have unfavorable shift of modified Rankin scale (fully adjusted odds ratio) (women vs. men) 1.14, 95% confidence interval 1.02–1.28). There was no significant sex difference for death 1.05 (0.84–1.31) or sICH (1.17, 0.89–1.54). Women were more likely to have unfavorable functional outcome with increasing age (P = 0.022 for interaction). In the age groups 70–80 and ≥80 years, women had a worse functional outcome compared to men (1.22, 1.02–1.47 and 1.43, and 1.06–1.92, respectively). Conclusion In this pooled data from Asian acute stroke registries, women had poorer prognosis than men after receiving recombinant tissue plasminogen activator for acute ischemic stroke, which worsened with age. Women older than 70 appear to have a worse outcome than men which could be explained by greater stroke severity, more AF, and cardioembolic stroke.

Background and Purpose— Although cilostazol has shown less hemorrhagic events than aspirin, only marginal difference was observed in hemorrhagic stroke events among patients at high risk for cerebral hemorrhage. To identify patients who would most benefit from cilostazol, this study analyzed interactions between treatment and subgroups of the PICASSO trial (Prevention of Cardiovascular Events in Asian Ischemic Stroke Patients With High Risk of Cerebral Hemorrhage). Methods— Ischemic stroke patients with a previous intracerebral hemorrhage or multiple microbleeds were randomized to treatment with cilostazol or aspirin and followed up for a mean 1.8 years. Efficacy, defined as the composite of any stroke, myocardial infarction, and vascular death, and safety, defined as the incidence of hemorrhagic stroke, were analyzed in the 2 groups. Interactions between treatment and age, sex, presence of hypertension and diabetes mellitus, index of high-risk cerebral hemorrhage, and white matter lesion burden were analyzed for primary and key secondary outcomes. Changes in vital signs and laboratory results were compared in the 2 groups. Results— Among all 1534 patients enrolled, a significant interaction between treatment group and index of high risk for cerebral hemorrhage on hemorrhagic stroke ( P for interaction, 0.03) was observed. Hemorrhagic stroke was less frequent in the cilostazol than in the aspirin group in patients with multiple microbleeds (1 versus 13 events; hazard ratio, 0.08 [95% CI, 0.01–0.61]; P =0.01). A marginal interaction between treatment group and white matter change on any stroke ( P for interaction, 0.08) was observed. Cilostazol reduced any stroke significantly in patients with mild (5 versus 16 events; hazard ratio, 0.36 [95% CI, 0.13–0.97]; P =0.04)-to-moderate (16 versus 32 events; hazard ratio, 0.50 [95% CI, 0.29–0.92]; P =0.03) white matter changes. Heart rate and HDL (high-density lipoprotein) cholesterol level were significantly higher in the cilostazol group than in the aspirin group at follow-up. Conclusions— Cilostazol may be more beneficial for ischemic stroke patients with multiple cerebral microbleeds and before white matter changes are extensive. Registration— URL: https://www.clinicaltrials.gov . Unique identifier: NCT01013532.

One important factor in reperfusion therapy that may predict a favorable outcome is the early onset of recanalization. Clot dissolution through intravenous thrombolysis alone may not produce significant recanalization and depends on the location of the clot. Proximal occlusion either in the terminal internal carotid artery (ICA) or proximal middle cerebral artery (MCA) has shown to have low rate of recanalization. Following this finding, additional interventions to augment early recanalization have been proposed and performed. Simultaneous ultrasound insonation of the occluded blood vessel and thrombolysis with rTPA have been carried out and have shown to be safe with early onset of recanalization. Sonothrombolysis, the utilization of ultrasound with transcranial Doppler emitting 2-MHz single probe, is done simultaneously while IV recombinant tissue plasminogen activator is being administered. In this chapter, we describe the indications and step-by-step procedure in carrying out sonothrombolysis at the neurocritical care unit.

Background/aim The aim of the study was to evaluate the combined treatment with abiraterone acetate and prednisone (AA+P) in patients with castration-resistant prostate cancer (mCPRC), and to identify the survival prognostic factors. Patients and methods Patients diagnosed with mCPRC not previously treated with chemotherapy and administered with AA+P were classified into two groups: those with lower and higher survival rates (at 30 months vs. 60 months). Results A total of 53 patients were studied at the time of mCRPC diagnosis. Patients with the highest survival rate had suffered prostate cancer for >45 months. At the time of initial prostate cancer diagnosis, they belonged to the risk groups 1-4, had pain intensity measured according to the brief pain inventory (BPI) scale of 0-2, were treated with AA+P>16 months, and had the following tumour marker serum levels: LDH baseline ≤163 U/l, alkaline phosphatase at 6 months ≤56 U/l and PSA at 6 months ≤0.95 ng/ml. Conclusion Good response to treatment with AA+P for patients with mCRPC was demonstrated. Factors that contributed to the higher prognostic accuracy were time suffering from prostate cancer, the intensity of the pain measured by the BPI scale, the duration of AA+P treatment, and tumour marker levels.

Transcranial Doppler (TCD) is an important tool in the armamentarium of stroke neurologists. This, bedsides modality, can help in establishing the presence, location, and severity of intracranial arterial occlusion in acute stroke cases. Various hemodynamic consequences of an acute arterial occlusion such as flow diversion and compensatory flow increase in other intracranial arteries can be monitored by TCD with reasonable accuracy. TCD monitoring during intravenous thrombolysis may demonstrate recanalization in real-time In addition, continuous ultrasound exposure during intravenous thrombolysis can enhance the rates of the recanalization of an acutely occluded intracranial artery. Therapeutic ultrasound or sonothrombolysis remains a widely debated application of TCD. We present the available evidence for sonothrombolysis as well as its current status in the hyperacute treatment of acute ischemic stroke.

Objective To investigate the comparative efficacy and safety of the low-dose versus standard-dose alteplase using real-world acute stroke registry data from Asian countries. Methods Individual participant data were obtained from nine acute stroke registries from China, Japan, Philippines, Singapore, South Korea, and Taiwan between 2005 and 2018. Inverse probability of treatment weight was used to remove baseline imbalances between those receiving low-dose versus standard-dose alteplase. The primary outcome was death or disability defined by modified Rankin Scale scores of 2 to 6 at 90 days. Secondary outcomes were symptomatic intracerebral hemorrhage and death. Generalized linear mixed models with the individual registry as a random intercept were performed to determine associations of treatment with low-dose alteplase and outcomes. Results Of the 6250 patients (mean age 66 years, 36% women) included in these analyses, 1610 (24%) were treated with low-dose intravenous alteplase. Clinical outcomes for low-dose alteplase were not significantly different to those for standard-dose alteplase, adjusted odds ratios for death or disability: 1.00 (0.85–1.19) and symptomatic intracerebral hemorrhage 0.87 (0.63–1.19), except for lower death with borderline significance, 0.77 (0.59–1.01). Conclusions The present analyses of real-world Asian acute stroke registry data suggest that low-dose intravenous alteplase has overall comparable efficacy for functional recovery and greater potential safety in terms of reduced mortality, to standard-dose alteplase for the treatment of acute ischemic stroke.

Background: The Chinese Medicine NeuroAiD Efficacy on Stroke recovery – Extension (CHIMES-E) study is among the few acute stroke trials with long-term outcome data. We aimed to evaluate the recovery pattern and the influence of prognostic factors on treatment effect of MLC601 over 2 years. Methods: The CHIMES-E study evaluated the 2 years outcome of subjects aged ≥ 18 years with acute ischemic stroke, National Institutes of Health Stroke Scale (NIHSS) score 6–14, pre-stroke modified Rankin Scale (mRS) score ≤ 1 included in a multicenter, randomized, double-blind, placebo-controlled trial of MLC601 for 3 months. Standard stroke care and rehabilitation were allowed during follow-up with mRS score being assessed in-person at month (M) 3 and by telephone at M1, M6, M12, M18 and M24. Results: Data from 880 subjects were analyzed. There was no difference in baseline characteristics between treatment groups. The proportion of subjects with mRS score 0–1 increased over time in favor of MLC601 most notably from M3 to M6, thereafter remaining stable up to M24, while the proportion deteriorating to mRS score ≥ 2 remained low at all time points. Older age (p < 0.01), female sex (p = 0.06), higher baseline NIHSS score (p < 0.01) and longer onset to treatment time (OTT; p < 0.01) were found to be predictors of poorer outcome at M3. Greater treatment effect, with more subjects improving on MLC601 than placebo, was seen among subjects with 2 or more prognostic factors (OR 1.65 at M3, 1.78 at M6, 1.90 at M12, 1.65 at M18, 1.39 at M24), especially in subjects with more severe stroke or longer OTT. Conclusions: The sustained benefits of MLC601 over 2 years were due to more subjects improving to functional independence at M6 and beyond compared to placebo. Selection of subjects with poorer prognosis, particularly those with more severe NIHSS score and longer OTT delay, as well as a long follow-up period, may improve the power of future trials investigating the treatment effect of neuroprotective or neurorestorative therapies., published_or_final_version

Background and Aim A pre-specified country analysis of subjects from the Philippines in the CHInese Medicine NeuroAiD Efficacy on Stroke recovery (CHIMES) Study showed significantly improved functional and neurological outcomes on MLC601 at month (M) 3. We aimed to assess these effects on long-term functional recovery in the Filipino cohort. Methods The CHIMES-E (extension) Study evaluated subjects who completed three months of randomized placebo-controlled treatment in CHIMES up to two years. Blinding of treatment allocation was maintained and all subjects received standard stroke care and rehabilitation. Modified Rankin Score (mRS) and Barthel Index (BI) were assessed in-person at M3 and by telephone at M6, M12, M18, M24. Odds ratios (OR) with corresponding 95% confidence intervals (CI) for functional recovery using ordinal analysis of mRS and for achieving functional independence (mRS 0-1 or BI ≥ 95) at each time point were calculated, adjusting for age, sex, baseline National Institute of Health Stroke Scale (NIHSS), onset-to-treatment time (OTT) and pre-stroke mRS. Results The 378 subjects (MLC601 192, placebo 186) included in CHIMES-E from the Philippines (mean age 60.2 ± 11.1) had more women ( p Conclusion The beneficial effect of MLC601 seen at M3 in the Filipino cohort is durable up to two years after stroke.

Background and Purpose: MLC601 has been shown in preclinical studies to enhance neurorestorative mechanisms after stroke. The aim of this post hoc analysis was to assess whether combining MLC601 and rehabilitation has an effect on improving functional outcomes after stroke. Methods: Data from the CHInese Medicine NeuroAiD Efficacy on Stroke (CHIMES) and CHIMES-Extension (CHIMES-E) studies were analyzed. CHIMES-E was a 24-month follow-up study of subjects included in CHIMES, a multi-centre, double-blind placebo-controlled trial which randomized subjects with acute ischemic stroke, to either MLC601 or placebo for 3 months in addition to standard stroke treatment and rehabilitation. Subjects were stratified according to whether they received or did not receive persistent rehabilitation up to month (M)3 (non- randomized allocation) and by treatment group. The modified Rankin Scale (mRS) and Barthel Index were assessed at month (M) 3, M6, M12, M18, and M24. Results: Of 880 subjects in CHIMES-E, data on rehabilitation at M3 were available in 807 (91.7%, mean age 61.8 ± 11.3 years, 36% female). After adjusting for prognostic factors of poor outcome (age, sex, pre-stroke mRS, baseline National Institute of Health Stroke Scale, and stroke onset-to-study-treatment time), subjects who received persistent rehabilitation showed consistently higher treatment effect in favor of MLC601 for all time points on mRS 0–1 dichotomy analysis (ORs 1.85 at M3, 2.18 at M6, 2.42 at M12, 1.94 at M18, 1.87 at M24), mRS ordinal analysis (ORs 1.37 at M3, 1.40 at M6, 1.53 at M12, 1.50 at M18, 1.38 at M24), and BI ≥95 dichotomy analysis (ORs 1.39 at M3, 1.95 at M6, 1.56 at M12, 1.56 at M18, 1.46 at M24) compared to those who did not receive persistent rehabilitation. Conclusions: More subjects on MLC601 improved to functional independence compared to placebo among subjects receiving persistent rehabilitation up to M3. The larger treatment effect of MLC601 was sustained over 2 years which supports the hypothesis that MLC601 combined with rehabilitation might have beneficial and sustained effects on neuro-repair processes after stroke. There is a need for more data on the effect of combining rehabilitation programs with stroke recovery treatments.

BackgroundStroke trials often analyze patients with heterogeneous prognoses using a single definition of outcome, which may not be applicable to all subgroups. We aimed to evaluate the treatment effects of MCL601 among patients stratified by prognosis in the Chinese Medicine Neuroaid Efficacy on Stroke Recovery (CHIMES) study.MethodsAnalyses were performed using data from the CHIMES study, an international, randomized, placebo-controlled, double-blind trial comparing MLC601 with placebo in patients with ischemic stroke of intermediate severity in the preceding 72 hours. All subjects with baseline data and the modified Rankin Scale (mRS) score at 3 months were included.ResultsData from 1006 subjects were analyzed. The predictive variables for mRS score greater than 1 at month 3 were age older than 60 years (P

Background: The CHInese Medicine NeuroAiD Efficacy on Stroke recovery (CHIMES) study was an international randomized double-blind placebo-controlled trial of MLC601 (NeuroAiD) in subjects with cerebral infarction of intermediate severity within 72 h. CHIMES-E (Extension) aimed at evaluating the effects of the initial 3-month treatment with MLC601 on long-term outcome for up to 2 years. Methods: All subjects randomized in CHIMES were eligible for CHIMES-E. Inclusion criteria for CHIMES were age ≥18, baseline National Institute of Health Stroke Scale of 6-14, and pre-stroke modified Rankin Scale (mRS) ≤1. Initial CHIMES treatment allocation blinding was maintained, although no further study treatment was provided in CHIMES-E. Subjects received standard care and rehabilitation as prescribed by the treating physician. mRS, Barthel Index (BI), and occurrence of medical events were ascertained at months 6, 12, 18, and 24. The primary outcome was mRS at 24 months. Secondary outcomes were mRS and BI at other time points. Results: CHIMES-E included 880 subjects (mean age 61.8 ± 11.3; 36% women). Adjusted OR for mRS ordinal analysis was 1.08 (95% CI 0.85-1.37, p = 0.543) and mRS dichotomy ≤1 was 1.29 (95% CI 0.96-1.74, p = 0.093) at 24 months. However, the treatment effect was significantly in favor of MLC601 for mRS dichotomy ≤1 at 6 months (OR 1.49, 95% CI 1.11-2.01, p = 0.008), 12 months (OR 1.41, 95% CI 1.05-1.90, p = 0.023), and 18 months (OR 1.36, 95% CI 1.01-1.83, p = 0.045), and for BI dichotomy ≥95 at 6 months (OR 1.55, 95% CI 1.14-2.10, p = 0.005) but not at other time points. Subgroup analyses showed no treatment heterogeneity. Rates of death and occurrence of vascular and other medical events were similar between groups. Conclusions: While the benefits of a 3-month treatment with MLC601 did not reach statistical significance for the primary endpoint at 2 years, the odds of functional independence defined as mRS ≤1 was significantly increased at 6 months and persisted up to 18 months after a stroke.

Summary Background The optimal treatment for patients with ischaemic stroke with a high risk of cerebral haemorrhage is unclear. We assessed the efficacy and safety of cilostazol versus aspirin, with and without probucol, in these patients. Methods In this randomised, controlled, 2 × 2 factorial trial, we enrolled patients with ischaemic stroke with a history of or imaging findings of intracerebral haemorrhage or two or more microbleeds from 67 centres in three Asian countries. Patients were randomly assigned (1:1:1:1) to receive oral cilostazol (100 mg twice a day), aspirin (100 mg once a day), cilostazol plus probucol (250 mg twice a day), or aspirin plus probucol with centralised blocks stratified by centre. Cilostazol versus aspirin was investigated double-blinded; probucol treatment was open-label, but the outcome assessor was masked to assignment. The co-primary outcomes were incidence of the composite of stroke, myocardial infarction, or vascular death (efficacy) and incidence of haemorrhagic stroke (safety), which were assessed in intention-to-treat and modified intention-to-treat populations. Efficacy was analysed with a non-inferiority test and a superiority test if non-inferiority was satisfied. Safety was assessed with a superiority test only. This trial is registered with ClinicalTrials.gov, NCT01013532. Findings Between Aug 1, 2009, and Aug 31, 2015, we randomly assigned 1534 patients to one of the four study groups, of whom 1512 were assessed for the co-primary endpoints. During a median follow-up of 1·9 years (IQR 1·0–3·0), the incidence of composite vascular events was 4·27 per 100 person-years in patients who received cilostazol and 5·33 per 100 person-years in patients who received aspirin (HR 0·80, 95% CI 0·57–1·11; non-inferiority p=0·0077; superiority p=0·18). Incidence of cerebral haemorrhage was 0·61 per 100 person-years in patients who received cilostazol and 1·20 per 100 person-years in those who received aspirin (HR 0·51, 97·5% CI 0·20–1·27; superiority p=0·18). The incidence of vascular events was 3·91 per 100 person-years in the probucol group compared with 5·75 per 100 person-years in the non-probucol group (HR 0·69, 95% CI 0·50–0·97; superiority p=0·0316). The incidence of cerebral haemorrhage was 0·72 per 100 person-years in the probucol group and 1·11 per 100 person-years in the non-probucol group (HR 0·65, 97·5% CI 0·27–1·57; p=0·55). Adverse events were similar across the four study groups; the most common events were dizziness, headache, diarrhoea, and constipation. Interpretation In patients with ischaemic stroke at high risk of cerebral haemorrhage, cilostazol was non-inferior to aspirin for the prevention of cardiovascular events, but did not reduce the risk of haemorrhagic stroke. Addition of probucol to aspirin or cilostazol could be beneficial for reducing the incidence of cardiovascular events. Funding Korea Otsuka Pharmaceutical.

Background The CHIMES Study compared MLC601 with placebo in patients with ischemic stroke of intermediate severity in the preceding 72 h. Sites from the Philippines randomized 504 of 1099 (46%) patients in the study. We aimed to define the patient characteristics and treatment responses in this subgroup to better plan future trials. Methods The CHIMES dataset was used to compare the baseline characteristics, time from stroke onset to study treatment initiation, and treatment responses to MLC601 between patients recruited from Philippines and the rest of the cohort. Treatment effect was analyzed using end-points at month 3 as described in the primary publication, that is, modified Rankin Score, National Institutes of Health Stroke Scale, and Barthel Index. Results The Philippine cohort was younger, had more women, worse baseline National Institutes of Health Stroke Scale, and longer time delay from stroke onset to study treatment compared with the rest of the cohort. Age ( P = 0·003), baseline National Institutes of Health Stroke Scale ( P < 0·001), and stroke onset to study treatment initiation ( P = 0·016) were predictors of modified Rankin Score at three-months. Primary analysis of modified Rankin Score shift was in favor of MLC601 (adjusted odds ratio 1·41, 95% confidence interval 1·01–1·96). Secondary analyses were likewise in favor of MLC601 for modified Rankin Score dichotomy 0–1, improvement in National Institutes of Health Stroke Scale (total and motor scores), and Barthel Index. Conclusions The treatment effects in the Philippine cohort were in favor of MLC601. This may be due to inclusion of more patients with predictors of poorer outcome.

Background and Purpose— Early vascular events are an important cause of morbidity and mortality in the first 3 months after a stroke. We aimed to investigate the effects of MLC601 on the occurrence of early vascular events within 3 months of stroke onset. Methods— Post hoc analysis was performed on data from subjects included in the CHInese Medicine Neuroaid Efficacy on Stroke recovery (CHIMES) study, a randomized, placebo-controlled, double-blinded trial that compared MLC601 with placebo in 1099 subjects with ischemic stroke of intermediate severity in the preceding 72 hours. Early vascular events were defined as a composite of recurrent stroke, acute coronary syndrome, and vascular death occurring within 3 months of stroke onset. Results— The frequency of early vascular events during the 3-month follow-up was significantly less in the MLC601 group than in the placebo group (16 [2.9%] versus 31 events [5.6%]; risk difference=−2.7%; 95% confidence interval, −5.1% to −0.4%; P =0.025) without an increase in nonvascular deaths. Kaplan–Meier survival analysis showed a difference in the risk of vascular outcomes between the 2 groups as early as the first month after stroke (Log-rank P =0.024; hazard ratio, 0.51; 95% confidence interval, 0.28–0.93). Conclusions— Treatment with MLC601 was associated with reduced early vascular events among subjects in the CHIMES study. The mechanisms for this effect require further study. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00554723.

Objectives: To analyze the patterns of movement disorders prospectively using the registry of movement disorders in our institution and to identify some research priorities. Background and purpose: Movement disorders are common reasons for consultation and referrals in our hospital. They are often thought to affect movement only. However, most patients also experience psychiatric, cognitive, and other non-motor symptoms, either from the disease itself, or as a side-effect of medications. No data has been obtained regarding movement disorders in our institution. With the use of our registry, we aim to document findings prospectively, for use as data mining to support a variety of researches in the future, and to guide us as to priorities in services, teaching and research.

Background and Purpose— High plasma total homocysteine (tHcy) has been associated with cognitive impairment but lowering tHcy with B-vitamins has produced equivocal results. We aimed to determine whether B-vitamin supplementation would reduce tHcy and the incidence of new cognitive impairment among individuals with stroke or transient ischemic attack ≥6 months previously. Methods— A total of 8164 patients with stroke or transient ischemic attack were randomly allocated to double-blind treatment with one tablet daily of B-vitamins (folic acid, 2 mg; vitamin B6, 25 mg; vitamin B12, 500 μg) or placebo and followed up for 3.4 years (median) in the VITAmins TO Prevent Stroke (VITATOPS) trial. For this prespecified secondary analysis of VITATOPS, the primary outcome was a new diagnosis of cognitive impairment, defined as a Mini-Mental State Examination (MMSE) score Results— A total of 3089 participants (38%) voluntarily undertook the MMSE >6 months after the qualifying stroke; 2608 participants were cognitively unimpaired (MMSE ≥24), of whom 2214 participants (1110 B-vitamins versus 1104 placebo) had follow-up MMSEs during 2.8 years (median). At final follow-up, allocation to B-vitamins, compared with placebo, was associated with a reduction in mean tHcy (10.2 μmol/L versus 14.2 μmol/L; P P =0.726) and no difference in the incidence of cognitive impairment (5.51% versus 5.47%; risk ratio, 1.01; 95% confidence interval, 0.69–1.48; P =0.976), cognitive decline (9.1% versus 10.3%; risk ratio, 0.89; 0.67–1.18; P =0.414), or cognitive impairment or decline (11.0% versus 11.3%; risk ratio, 0.98; 0.75–1.27; P =0.855). Conclusions— Daily supplementation with folic acid, vitamin B6, and vitamin B12 to a self-selected clinical trial cohort of cognitively unimpaired patients with previous stroke or transient ischemic attack lowered mean tHcy but had no effect on the incidence of cognitive impairment or cognitive decline, as measured by the MMSE, during a median of 2.8 years. Clinical Trial Registration— URL: http://www.controlled-trials.com . Unique identifier: ISRCTN74743444; URL: http://www.clinicaltrials.gov . Unique identifier: NCT00097669.

In this paper, the circle segments (CS) technique is proposed as a data visualization tool for selecting and analysing the effects of the input features towards the target outputs in constructing neural network models. Specifically, the multi-layer perceptron (MLP) network is employed to tackle function approximation and pattern classification tasks, and CS is used to provide visualization of the correlations between the input features and the target outputs in these tasks. The effectiveness of the proposed approach is evaluated using two benchmark data sets, one for function approximation and another for pattern classification. Performance comparison with the response surface methodology (in function approximation) and with principal component analysis (in pattern classification) is conducted. The results indicate the usefulness of CS in examining the correlations between the input-output data samples, with improved performances. In addition, a real medical diagnosis task is used to evaluate the applicability of the approach. The outcomes, again, demonstrate improvements in accuracy, sensitivity, and specificity with the use of CS for feature selection, even with more than 50% of the input features eliminated.

Background International Consensus Criteria (ICC) consider right-to-left shunt (RLS) present when Transcranial Doppler (TCD) detects even one microbubble (microB). Spencer Logarithmic Scale (SLS) offers more grades of RLS with detection of >30 microB corresponding to a large shunt. We compared the yield of ICC and SLS in detection and quantification of a large RLS. Subjects and methods We prospectively evaluated paradoxical embolism in consecutive patients with ischemic strokes or transient ischemic attack (TIA) using injections of 9 cc saline agitated with 1 cc of air. Results were classified according to ICC [negative (no microB), grade I (1-20 microB), grade II (>20 microB or "shower" appearance of microB), and grade III ("curtain" appearance of microB)] and SLS criteria [negative (no microB), grade I (1-10 microB), grade II (11-30 microB), grade III (31100 microB), grade IV (101300 microB), grade V (>300 microB)]. The RLS size was defined as large (>4 mm) using diameter measurement of the septal defects on transesophageal echocardiography (TEE). Results TCD comparison to TEE showed 24 true positive, 48 true negative, 4 false positive, and 2 false negative cases (sensitivity 92.3%, specificity 92.3%, positive predictive value (PPV) 85.7%, negative predictive value (NPV) 96%, and accuracy 92.3%) for any RLS presence. Both ICC and SLS were 100% sensitive for detection of large RLS. ICC and SLS criteria yielded a false positive rate of 24.4% and 7.7%, respectively when compared to TEE. Conclusions Although both grading scales provide agreement as to any shunt presence, using the Spencer Scale grade III or higher can decrease by one-half the number of false positive TCD diagnoses to predict large RLS on TEE.

Background and Purpose: It was the aim of this study to systematically review available literature on the accuracy of transcranial Doppler (TCD) compared with angiography for the diagnosis of ≧50% middle cerebral artery stenosis in patients with transient ischemic attack or ischemic stroke. Methods: We performed a systematic review that included original articles published on TCD accuracy from 1982 until the end of December 2005 using angiography as the gold standard. The following measures of diagnostic accuracy were obtained from each primary study: sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV). Weighted mean averages were then calculated from individual results for different velocity cutoffs. Results: Six papers met our selection criteria. Using laboratory-specific variable mean flow velocity cutoffs, self-reported best accuracy results yield a mean weighted average sensitivity of 92%, specificity of 92%, PPV of 88% and NPV of 98% for 80 cm/s cutoff. For 100 cm/s cutoff, the sensitivities were 100%, specificity 97%, PPV 88% and NPV 100%. Conclusions: Although limited to few reports, this analysis demonstrates fair TCD performance against angiography. Since increasing velocity cutoffs do not yield decreasing sensitivity and increasing specificity, further studies are required to determine optimal velocity values and possibly other criteria such as velocity ratios to develop a screening test with balanced performance parameters.

Background of the study: In patients with stroke, the most common Sleep Disorder are sleep apnea, insomia (30%), and excessive daytime sleepiness. Ischemic stroke patients had 76.8% sleep disorder and hemorrhagic stroke patients had 82.5% sleep disorder. There were several postulated mechanisms on the pathophysiologic effects of sleep disorders on stroke which includes: acute hemodynamic changes during episodes of apnea, decreased cerebral blood flow, and paradoxical embolization, hypercoagulability, hypoxia-related cerebral ischemia, and atherosclerosis. With these several mechanisms, post stroke recovery among patients with post stroke sleep disorder can be altered. Methodology: A cross sectional study was conducted in Jose Reyes Memorial Medical Center from July 2013 to June 2014. All Medical records and neuroimaging of post stroke patients (≥ 6 months) were reviewed. Those patients with cognitive dysfunction, unable to give consent or unable to understand the study protocol and whose neuroimaging cannot be retrieved were excluded in the study. The interviewer assisted Epworth Sleepiness Scale (ESS) was used in this study to determine daytime sleep propensity. Results: A total of 130 subjects were included. There were 82 (63%) male and 48(37%) female. The mean age is 58. The variables shown to be significantly associated with ESS were duration of stroke, number of risk factor and type of stroke. The more recent the stroke (specifically shorter than 2.7 years which is the mean), the higher the ESS score. A patient with two risk factors was 4.6x more likely to have an ESS of 10-14 compared to one who has only 1 risk factor. Those who had intracranial bleeding were 2.5 times more likely to have an ESS of 10-14. Conclusion: Among post stroke patients, the more recent the stroke, the more risk factors present, and those who had intracerebral hemorrhage have higher propensity for daytime sleepiness.

Stroke is the Philippines' second leading cause of death. It has a prevalence of 0·9%; ischemic stroke comprises 70% while hemorrhagic stroke comprises 30%. Age-adjusted hypertension prevalence is 20·6%, diabetes 6·0%, dyslipidemia 72·0%, smoking 31%, and obesity 4·9%. The neurologist-to-patient ratio is 1:330·000, with 67% of neurologists practicing in urban centers. Health care is largely private and the cost is borne out-of-pocket by patients and their families. Challenges include delivering adequate support to the rural communities and to the underprivileged sectors.

Background and Purpose— Previous clinical studies suggested benefit for poststroke recovery when MLC601 was administered between 2 weeks and 6 months of stroke onset. The Chinese Medicine Neuroaid Efficacy on Stroke recovery (CHIMES) study tested the hypothesis that MLC601 is superior to placebo in acute, moderately severe ischemic stroke within a 72-hour time window. Methods— This multicenter, double-blind, placebo-controlled trial randomized 1100 patients with a National Institutes of Health Stroke Scale score 6 to 14, within 72 hours of onset, to trial medications for 3 months. The primary outcome was a shift in the modified Rankin Scale. Secondary outcomes were modified Rankin Scale dichotomy, National Institutes of Health Stroke Scale improvement, difference in National Institutes of Health Stroke Scale total and motor scores, Barthel index, and mini-mental state examination. Planned subgroup analyses were performed according to age, sex, time to first dose, baseline National Institutes of Health Stroke Scale, presence of cortical signs, and antiplatelet use. Results— The modified Rankin Scale shift analysis–adjusted odds ratio was 1.09 (95% confidence interval, 0.86–1.32). Statistical difference was not detected between the treatment groups for any of the secondary outcomes. Subgroup analyses showed no statistical heterogeneity for the primary outcome; however, a trend toward benefit in the subgroup receiving treatment beyond 48 hours from stroke onset was noted. Serious and nonserious adverse events rates were similar between the 2 groups. Conclusions— MLC601 is statistically no better than placebo in improving outcomes at 3 months when used among patients with acute ischemic stroke of intermediate severity. Longer treatment duration and follow-up of participants with treatment initiated after 48 hours may be considered in future studies. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00554723.

Background: Stroke carries a poor long-term prognosis for death and disability. There are few acute treatments that reduce death and disability after stroke. The ongoing international, multicenter, randomized, placebo-controlled, double-blind CHIMES trial is currently testing the hypothesis that a 3-month course of the traditional Chinese medicine MLC601 (NeuroAiD) is superior to placebo in reducing neurological deficit and improving functional outcome after acute ischemic stroke in patients receiving standard stroke care. This extension study tests the hypothesis that at 2 years, an initial 3-month administration of NeuroAiD is superior to placebo in reducing neurological deficit and improving functional outcome in patients with cerebral infarction of an intermediate range of severity. Methods: Study subjects will be those who are already participants in CHIMES - aged above 21 years, had signs and symptoms of acute stroke, 6 ≤ NIHSS ≤ 14, neuroimaging consistent with ischemic stroke, and received study medication within 72 h of stroke onset. A subject will not be eligible for inclusion in CHIMES-E if they have withdrawn consent from all participation and follow-up for CHIMES. Subjects will be contacted at 6, 12, 18 and 24 months after CHIMES enrolment. After verbal consent is obtained, subjects will be assessed for functional state by the modified Rankin scale (mRS) and Barthel Index (BI), and a history of recurrent vascular events as well as medical events. The primary outcome measure will be the mRS at month 24. Secondary outcome measures will be mRS and BI at 6, 12 and 18 months, and BI at 24 months. Analysis will be based on the intention-to-treat principle. If the number of patients lost to follow-up is substantial, a sensitivity analysis based on the last observation carried forward method will be carried out, to compare the results with those from the main analysis without imputation. Based on a cumulative odds ratio of 1.5 for the NeuroAiD group, a two-sided test of 5% type I error and an expected 30% dropout rate after 2 years of follow-up for the 1,100 patients recruited into CHIMES, the 770 subjects with mRS data expected to be available at year 2 yields an 89% power to detect a difference in efficacy between NeuroAiD and placebo. Conclusions: This study will provide evidence for the longer-term efficacy of an initial course of a neurorestorative therapy after acute ischemic stroke of intermediate severity.