Transcranial Doppler ultrasonography in bacterial meningitis: A systematic review.

PURPOSE: Bacterial meningitis remains a global threat due to its high mortality. It is estimated that >1.2 million cases of bacterial meningitis are reported annually. Intracranial vasculopathy is an important, under-documented complication, easily detected by transcranial Doppler (TCD) ultrasonography. Following the PRISMA Guidelines, we reviewed the utility of TCD in bacterial meningitis. METHODS: This is a systematic review of observational studies on the use of TCD in patients with CSF-proven bacterial meningitis. Characteristic changes in TCD parameters along the course of the disease, correlation of TCD findings with neuroimaging, and functional outcomes were evaluated. RESULTS: Nine studies were included with a total of 492 participants (mean age of 42). The most common TCD finding was intracranial arterial stenosis of the MCA (50%-82%) and ischemia (33%) was the predominant neuroimaging finding. The presence of an abnormal TCD finding increased the risk of poor outcomes as high as 70%. CONCLUSIONS: Patients diagnosed with bacterial meningitis who underwent TCD show alterations in cerebral blood flow, correlating with imaging findings and poor outcomes. It aids in the diagnosis of its sequelae and can predict the prognosis of its outcome. TCD is a cost-effective, reliable modality for diagnosing vasculopathy associated with bacterial meningitis. It may prove useful in our armamentarium of management. Large prospective studies with long-term follow-up data may help establish the use of TCD in bacterial meningitis.

Cilostazol Versus Aspirin in Ischemic Stroke Patients With High-Risk Cerebral Hemorrhage: Subgroup Analysis of the PICASSO Trial.

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.

Effect of Combined Treatment with MLC601 (NeuroAiDTM) and Rehabilitation on Post-Stroke Recovery: The CHIMES and CHIMES-E Studies.

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.

Prognostic Factors and Pattern of Long-Term Recovery with MLC601 (NeuroAiD™) in the Chinese Medicine NeuroAiD Efficacy on Stroke Recovery - Extension Study.

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.

CHInese Medicine NeuroAiD Efficacy on Stroke Recovery - Extension Study (CHIMES-E): A Multicenter Study of Long-Term Efficacy.

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.

Prognostic factors and treatment effect in the CHIMES study.

BACKGROUND: Stroke 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. METHODS: Analyses 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. RESULTS: Data from 1006 subjects were analyzed. The predictive variables for mRS score greater than 1 at month 3 were age older than 60 years (P < .001), baseline National Institutes of Health Stroke Scale score 10-14 (P < .001), stroke onset to initiation of study treatment of more than 48 hours (P < .001), and female sex (P = .026). A higher number of predictors was associated with poorer mRS score at month 3 for both placebo (P < .001) and treatment (P < .001) groups. The odds ratio (OR) for achieving a good outcome increased with the number of predictors and reached statistical significance in favor of MLC601 among patients with 2 to 4 predictors combined (unadjusted OR = 1.44, 95% confidence interval, 1.02-2.03; adjusted OR = 1.60, 95% confidence interval, 1.10-2.34). CONCLUSIONS: Age, sex, baseline National Institutes of Health Stroke Scale score, and time to first dose are predictors of functional outcome in the CHIMES study. Stratification by prognosis showed that patients with 2 or more predictors of poorer outcome have better treatment effect with MLC601 than patients with single or no prognostic factor. These results have implications on designing future stroke trials.

Fast and accurate database searches with MS-GF+Percolator.

One can interpret fragmentation spectra stemming from peptides in mass-spectrometry-based proteomics experiments using so-called database search engines. Frequently, one also runs post-processors such as Percolator to assess the confidence, infer unique peptides, and increase the number of identifications. A recent search engine, MS-GF+, has shown promising results, due to a new and efficient scoring algorithm. However, MS-GF+ provides few statistical estimates about the peptide-spectrum matches, hence limiting the biological interpretation. Here, we enabled Percolator processing for MS-GF+ output and observed an increased number of identified peptides for a wide variety of data sets. In addition, Percolator directly reports p values and false discovery rate estimates, such as q values and posterior error probabilities, for peptide-spectrum matches, peptides, and proteins, functions that are useful for the whole proteomics community.

Hub-and-Spoke Stroke System: Enhancing Acute ischemic Stroke Care in the Philippines.

Background and Aims The Hub-and-Spoke stroke system seeks to enhance the efficiency of stroke care by establishing a cohesive network between healthcare facilities providing quality stroke care to patients. This study endeavors to evaluate the effectiveness and characterize the outcomes of acute ischemic stroke patients treated within the Hub-and-Spoke hospital system over 2 years. The assessment focused on thrombolysis rates, mortality, and disability at 3-month follow-up. Methods We conducted a retrospective single-center review to assess the service delivery and outcomes of acute ischemic stroke patients within the hub-and-spoke framework which was implemented in Q3 2021. The hub-and-spoke model aimed to provide appropriate neurological care for stroke patients, growing from four to eight spoke hospitals in two years. Results The study consisted of 132 stroke patients transferred to the hub hospital and 42 (31.8%) of them had acute ischemic stroke. Among these 42 ischemic stroke patients, 76% of them were candidates for thrombolysis with a mean NIHSS of 12 (6-22). Among the subset of 32 patients eligible for intervention within the specified time window, a total of 23 individuals, constituting 72% received r-TPA. Regarding patients administered r-TPA, 91.2% demonstrated favorable functional outcomes with an mRS score of 0-1, while 8.7% exhibited a score of 2-3. Among those not given r-TPA, the mean NIHSS was 17 (ranging from 2 to 32). Their functional outcomes after 3 months revealed 52.5% with an mRS score of 0-1, 16% with a score of 2-3, 21.2% with a score of 4-5, and 10.5% with an mRS score of 6. Conclusion Hub and spoke networks represent a crucial advancement in stroke treatment particularly for facilities lacking the capacity to manage strokes effectively. By leveraging added expertise and reducing the time from onset to diagnosis to treatment, these networks have significantly enhanced patient care. This enhancement is particularly evident in the increased rate of thrombolysis, resulting in reduced morbidity and prevention of mortality.

A systematic-search-and-review of registered pharmacological therapies investigated to improve neuro-recovery after a stroke.

Background: Stroke burden is largely due to long-term impairments requiring prolonged care with loss of productivity. We aimed to identify and assess studies of different registered pharmacological therapies as treatments to improve post-stroke impairments and/or disabilities. Methods: We performed a systematic-search-and-review of treatments that have been investigated as recovery-enhancing or recovery-promoting therapies in adult patients with stroke. The treatment must have received registration or market authorization in any country regardless of primary indication. Outcomes included in the review were neurological impairments and functional/disability assessments. "The best available studies" based on study design, study size, and/or date of publication were selected and graded for level of evidence (LOE) by consensus. Results: Our systematic search yielded 7,801 citations, and we reviewed 665 full-text papers. Fifty-eight publications were selected as "the best studies" across 25 pharmacological classes: 31 on ischemic stroke, 21 on ischemic or hemorrhagic stroke, 4 on intracerebral hemorrhage, and 2 on subarachnoid hemorrhage (SAH). Twenty-six were systematic reviews/meta-analyses, 29 were randomized clinical trials (RCTs), and three were cohort studies. Only nimodipine for SAH had LOE A of benefit (systematic review and network meta-analysis). Many studies, some of which showed treatment effects, were assessed as LOE C-LD, mainly due to small sample sizes or poor quality. Seven interventions had LOE B-R (systematic review/meta-analysis or RCT) of treatment effects. Conclusion: Only one commercially available treatment has LOE A for routine use in stroke. Further studies of putative neuroprotective drugs as adjunctive treatment to revascularization procedures and more confirmatory trials on recovery-promoting therapies will enhance the certainty of their benefit. The decision on their use must be guided by the clinical profile, neurological impairments, and target outcomes based on the available evidence. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=376973, PROSPERO, CRD42022376973.

Effect of B vitamins and lowering homocysteine on cognitive impairment in patients with previous stroke or transient ischemic attack: a prespecified secondary analysis of a randomized, placebo-controlled trial and meta-analysis.

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<24 on ≥2 follow-up visits. Secondary outcomes were cognitive decline, and the mean tHcy and MMSE at final follow-up. 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<0.001) but no change from baseline in the mean MMSE score (-0.22 points versus -0.25 points; difference, 0.03; 95% confidence interval, -0.13 to 0.19; 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.

Chinese medicine neuroaid efficacy on stroke recovery: a double-blind, placebo-controlled, randomized study.

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.

Predictive factors for clinical outcomes in Filipino patients with watershed infarction: A single center study.

Background and purpose: Watershed infarcts denote ischemic lesions involving the distal territories of two major arteries. For years, hypotheses on its pathophysiological mechanisms have been proposed. Yet, the cause is still widely debated. This study aimed to determine the mechanism of watershed strokes and compare their clinical outcomes to acute ischemic stroke from other causes and predict the factors affecting clinical outcomes in patients with watershed infarcts. Methods: This single-center, comparative, six-years retrospective cohort study included patients with a diagnosis of Acute Ischemic Stroke. Patients were classified under watershed group or acute ischemic stroke based on their neuroimaging findings. Stroke mechanisms were determined between groups as well as the factors associated with clinical outcomes in watershed strokes. Results: Among the 424 patients included in the study, large artery atherosclerosis was seen in greater frequency in patients with watershed infarcts regardless of the type (EWIs: n = 68, 73% vs IWIs: n = 89, 75%). No differences observed in the clinical outcomes between groups. Multiple variable analysis showed that age, female sex, high NIHSS score and presence of underlying malignancy were associated with clinical outcomes. Conclusion: Clinical outcomes between watershed infarcts and acute ischemic strokes were similar. Hemodynamic compromise in the setting of severe stenosis is the underlying mechanism for both types of watershed strokes thus, the goal of treatment is to maintain adequate perfusion. High baseline NIHSS score, increased age, female gender and underlying malignancy were all poor predictors of clinical outcomes in patients with watershed strokes.

Transcranial Doppler ultrasonography in tuberculous meningitis: A systematic review.

BACKGROUND AND PURPOSE: Tuberculous (TB) meningitis is a common type of central nervous system infection, and may cause multifocal cerebral infarctions due to the involvement of cerebral vasculature. This systematic review aims to review and synthesize the utility of transcranial Doppler (TCD) in TB meningitis. METHODS: This is a systematic review of observational studies on the use of TCD in patients diagnosed to have TB meningitis. Study outcomes included changes in TCD parameters during stages of TB meningitis, frequency of neurologic complications (such as hydrocephalus, vasculopathy, and cerebral infarction), correlation of TCD findings with neuroimaging, and functional outcomes. RESULTS: Five studies were included with a total of 141 participants, with ages from 4 months to 75 years. The most common neurologic complication was hydrocephalus (87.1%), cerebral infarction (29.2%), and arterial stenosis (26.3%). There was increased mean flow velocity (MFV) most commonly in the middle cerebral artery in the early stage of TB meningitis, and decreased MFV in the advanced disease stage. TCD findings of stenosis were well correlated with CT or MR angiogram. Among patients with hydrocephalus, pulsatility indices were significantly decreased after ventriculoperitoneal shunting. CONCLUSIONS: A considerable proportion of patients with TB meningitis develop cerebral hemodynamic disturbances which lead to cerebral ischemia and affect clinical outcomes. TCD is a reliable tool for the diagnosis of vasculopathy and increased intracranial pressure and can thus help monitor disease progression and treatment response. Future studies with larger populations and longer follow-ups are recommended to determine the association of TCD findings with functional outcomes.

Treatment with B vitamins and incidence of cancer in patients with previous stroke or transient ischemic attack: results of a randomized placebo-controlled trial.

BACKGROUND AND PURPOSE: To determine the effect of B vitamin treatment on the incidence of cancer among patients with stroke or transient ischemic attack. METHODS: A total of 8164 patients with recent stroke or transient ischemic attack were randomly allocated to double-blind treatment with 1 tablet daily of placebo or B vitamins (2 mg folic acid, 25 mg vitamin B(6), 500 µg vitamin B(12)) and followed for a median of 3.4 years for any cancer as an adverse event. RESULTS: There was no significant difference in the incidence of any cancer among participants assigned B vitamins compared with placebo (4.04% versus 4.59%; risk ratio, 0.86; 95% CI, 0.70-1.07) and no difference in cancer mortality (2.35% versus 2.09%; risk ratio, 1.09; 0.81-1.46). Among 1899 patients with diabetes, the incidence of cancer was higher among participants assigned B vitamins compared with placebo (5.35% versus 3.28%; adjusted risk ratio, 2.21; 1.31-3.73), whereas among 6168 patients without diabetes, the incidence of cancer was lower among participants assigned B vitamins compared with placebo (3.66% versus 5.03%; adjusted risk ratio, 0.67; 0.51-0.87; P for interaction=0.0001). CONCLUSIONS: Daily administration of folic acid, vitamin B(6), and vitamin B(12) to 8164 patients with recent stroke or transient ischemic attack for a median of 3.4 years had no significant effect, compared with placebo, on cancer incidence or mortality. However, a post hoc subgroup analysis raises the hypothesis that folic acid treatment may increase the incidence of cancer among diabetics and reduce the incidence of cancer among nondiabetics with a history of stroke or transient ischemic attack.

A Case of Reversible Cerebral Vasoconstriction Syndrome: Postpartum Cerebral Angiopathy in a 32-Year-Old Primigravid Treated with Intravenous Immunoglobulin.

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.

Serine-Threonine Kinase TAO3-Mediated Trafficking of Endosomes Containing the Invadopodia Scaffold TKS5α Promotes Cancer Invasion and Tumor Growth.

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.

Worse prognosis in women, compared with men, after thrombolysis: An individual patient data pooling study of Asian acute stroke registries.

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.

Low-dose versus standard-dose alteplase in acute ischemic stroke in Asian stroke registries: an individual patient data pooling study.

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.

Erratum: Stroke Epidemiology in South, East, and South-East Asia: A Review.

[This corrects the article on p. 286 in vol. 19.].

Prevention of cardiovascular events in Asian patients with ischaemic stroke at high risk of cerebral haemorrhage (PICASSO): a multicentre, randomised controlled trial.

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.