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BACKGROUND Postinterventional cerebral hyperdensities are common on non-contrast-enhanced computed tomography (CT) after endovascular thrombectomy in patients with acute ischemic stroke, which may reflect blood-brain barrier damage. The disruption of the blood-brain barrier may lead to malignant brain edema. The relationship between the extent of postinterventional cerebral hyperdensities and malignant brain edema is unclear. METHODS Patients with middle cerebral artery territory infarction and successful recanalization were consecutively enrolled. Postinterventional non-contrast-enhanced CT was performed to evaluate postinterventional cerebral hyperdensities within 24 h after endovascular thrombectomy. On the basis of the areas of the Alberta Stroke Program Early CT Score, we devised the Hyperdensity on CT Score to evaluate the extent of postinterventional cerebral hyperdensities. The primary outcome was malignant brain edema, defined as the development of clinical signs of herniation (including a decrease in consciousness and/or anisocoria), accompanied by imaging evidence of brain swelling. The component of postinterventional cerebral hyperdensities was divided into contrast staining and hemorrhage on the basis of persistency. RESULTS Three hundred sixty patients were included (50.6% male, mean age 67.9 years), of whom 247 (68.6%) developed postinterventional cerebral hyperdensities and 66 (18.3%) developed malignant brain edema. After adjustment for confounders, including the component of postinterventional cerebral hyperdensities, the extent of postinterventional cerebral hyperdensities assessed by the Hyperdensity on CT Score was significantly associated with malignant brain edema (odds ratio 1.46, 95% confidence interval 1.20-1.77, p

Background Amantadine hydrochloride is one of the most frequently prescribed drugs for patients with severe traumatic brain injury in restoring consciousness and accelerating the pace of functional recovery. However, there is a paucity of studies on the effectiveness of amantadine in patients with severe stroke especially large hemisphere infarction (LHI). The present study aimed to investigate whether amantadine treatment is associated with better clinical outcomes in conservatively treated LHI patients. Methods We retrospectively collected conservatively treated LHI patients according to inclusion/exclusion criteria. The patients were divided into two groups based on the treatment regimen, whether they did receive amantadine hydrochloride in addition to standard therapy (ST) or not. The primary outcomes were in-hospital death, 3-month mortality, and unfavorable outcome (defined as modified Rankin Scale score of 4 to 6). All outcomes were compared between the two groups before and after propensity score matching (PSM). Multivariate logistic regression was performed to identify the association between early amantadine hydrochloride treatment and clinical outcomes in LHI patients. Results Thirty-one LHI patients treated with amantadine combined with ST and 127 patients treated with ST were enrolled. Amantadine group had a shorter prehospital delay (median: 2 vs. 10 h), a higher baseline NIHSS score (21.71 ± 4.76 vs. 17.49 ± 5.84), and a higher rate of dominant hemisphere involvement (67.74% vs. 45.67%). After PSM, amantadine treatment significantly reduced the risk of in-hospital death (7.41% vs. 31.11%, p=0.019) and 3-month mortality (25.93% vs. 55.56%, p=0.008). Amantadine treatment yielded a significant decrease in death in-hospital (before PSM: OR 0.143, 95% CI 0.034 to 0.605; after PSM: OR 0.113, 95% CI 0.020 to 0.635) and 3-month mortality (before PSM: OR 0.214, 95% CI 0.077 to 0.598; after PSM: OR 0.176, 95% CI 0.053 to 0.586) in unmatched and matched multivariate analyses. Conclusion The results of our study provide initial evidence that early amantadine treatment was associated with a decrease in death in conservatively treated LHI patients. Considering the limitations of observational study, randomized controlled trials with a large sample size may help provide a clearer picture of the utility of amantadine in LHI patients.

Lacunar stroke (LS) accounts for about one-quarter of all acute ischemic strokes, represents an important marker of cerebral small vessel disease (CSVD), and has prognostic significance in terms of recurrent vascular events and vascular cognitive impairment. Our understanding of the etiology and pathogenesis of LS is largely based on the meticulous postmortem work of C. Miller Fisher in the late 1960s, with scarce subsequent pathological analysis of the “lacunar hypothesis” and no reliable approaches for direct in vivo imaging of the small intracranial vessels. The recent development of high-resolution MRI, which allows both large-vessel wall and perforating arteries to be imaged in one setting, provides the opportunity to advance understandings of the clinical mechanisms, imaging characteristics, and pathogenesis of LS. Given accumulating evidence of endothelial dysfunction and blood-brain-barrier disruption as early features of CSVD-related LS, advanced imaging may allow various underlying pathogenetic mechanisms to be defined and for better targeting of therapeutic approaches in LS. In this review, progress in understanding the pathogenesis of LS is outlined, covering pathology, pathophysiology, and imaging characteristics, with a focus toward future directions in the complex entity of LS.

Impaired consciousness (IC) at stroke onset in large hemispheric infarctions (LHI) patients is common in clinical practice. However, little is known about the incidence and risk factors of IC at stroke onset in LHI. Besides, stroke-related complications and clinical outcomes in relation to the development of IC has not been systematically examined. Data of 256 consecutive patients with LHI were collected. IC at stroke onset was retrospectively collected from the initial emergency department and/or admission records. Of the 256 LHI patients enrolled, 93 (36.3%) had IC at stroke onset. LHI patients with IC at stroke onset were older (median age 66 vs. 61, p = 0.041), had shorter prehospital delay (24 vs. 26 h, p p p p p = 0.019). The IC group had higher rates of in-hospital death (23.66% vs. 11.66%, p = 0.012), 3-month mortality (49.46% vs. 24.87%, p = 0.002), and 3-month unfavorable outcome (64.51% vs. 49.07%, p = 0.017). However, after adjusting for age, baseline NIHSS score and other confounders, IC at stroke onset was not an independent predictor of in-hospital death (adjusted OR 0.56, 95% CI 0.22 to 1.47), 3-month mortality (adjusted OR 0.54, 95% CI 0.25 to 1.14) and 3-month unfavorable outcome (adjusted OR 0.64, 95% CI 0.31 to 1.33) in LHI patients (all p > 0.05). Our results suggested that IC occur in 1 out of every 3 LHI patients at stroke onset and was associated with initial stroke severity and atrial fibrillation. LHI patients with IC at stroke onset more frequently had stroke-related complications, 3-month mortality and unfavorable outcome, whereas IC was not an independent predictor of poor outcomes.

Accurate prediction of malignant brain edema (MBE) after stroke is paramount to facilitate close monitoring and timely surgical intervention. The Enhanced Detection of Edema in Malignant Anterior Circulation Stroke (EDEMA) score was useful to predict potentially lethal malignant edema in Western populations. We aimed to validate and modify it to achieve a better predictive value for MBE in Chinese patients. Of ischemic stroke patients consecutively admitted in the Department of Neurology, West China Hospital between January 2010 and December 2017, we included patients with anterior circulation stroke, early signs of brain edema on computed tomography within 24 h of onset, and admission National Institutes of Health Stroke Scale (NIHSS) score ≥ 8. MBE was defined as the development of signs of herniation (including decrease in consciousness and/or anisocoria), accompanied by midline shift ≥ 5 mm on follow-up imaging. The EDEMA score consisted of five parameters: glucose, stroke history, reperfusion therapy, midline shift, and cistern effacement. We created a modified score by adding admission NIHSS score to the original EDEMA score. The discrimination of the score was assessed by the area under the receiver operating characteristics curve (AUC). Calibration was assessed by Hosmer–Lemeshow test and calibration plot. We compared the discrimination of the original and modified score by AUC, net reclassification improvement (NRI), and integrated discrimination improvement (IDI). Clinical usefulness of the two scores was compared by plotting net benefits at different threshold probabilities in the decision curve analysis. Of the 478 eligible patients (mean age 67.3 years; median NIHSS score 16), 93 (19%) developed MBE. The EDEMA score showed moderate discrimination (AUC 0.72, 95% confidence interval [CI] 0.67–0.76) and good calibration (Hosmer–Lemeshow test, P = 0.77). The modified score showed an improved discriminative ability (AUC 0.80, 95% CI 0.76–0.84, P

With over 2 million new cases annually, stroke is associated with the highest disability-adjusted life-years lost of any disease in China. The burden is expected to increase further as a result of population ageing, an ongoing high prevalence of risk factors (eg, hypertension), and inadequate management. Despite improved access to overall health services, the availability of specialist stroke care is variable across the country, and especially uneven in rural areas. In-hospital outcomes have improved because of a greater availability of reperfusion therapies and supportive care, but adherence to secondary prevention strategies and long-term care are inadequate. Thrombolysis and stroke units are accepted as standards of care across the world, including in China, but bleeding-risk concerns and organisational challenges hamper widespread adoption of this care in China. Despite little supporting evidence, Chinese herbal products and neuroprotective drugs are widely used, and the increased availability of neuroimaging techniques also results in overdiagnosis and overtreatment of so-called silent stroke. Future efforts should focus on providing more balanced availability of specialised stroke services across the country, enhancing evidence-based practice, and encouraging greater translational research to improve outcome of patients with stroke.

Background We aimed to explore the association of serum level of the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) and its related inflammatory biomarkers (hypoxia inducible factor-1α, cathepsin B, caspase-1 and matrix metalloproteinase-9) with malignant brain edema (MBE) in patients with acute ischemic stroke. Methods We prospectively enrolled patients with acute ischemic stroke admitted Results 200 patients (69.3 ± 14.3 years; male 55 %) were included for analysis, of whom 26 patients developed MBE (median time from stroke onset to MBE 32.5 h). Compared with patients without MBE, those with MBE had higher level of serum concentration of NLRP3 (median time from onset to blood collection 3 h, 1.85 ng/ml vs. 1.11 ng/ml, P = 0.026). NLRP3 level was positively correlated with NIHSS on admission (Spearman ρ = 0.18, P = 0.01) and the association between NLRP3 and MBE was attenuated (OR 1.47, 95 % CI 0.88–2.46, P = 0.138) after adjusting for age and NIHSS. There was no significant difference in other biomarkers between MBE and non-MBE groups. Conclusions There was a trend of association between a higher level of serum concentration of NLRP3 and an increased risk of MBE after ischemic stroke, possibly confounded by the severity of stroke, which is worth further validation in large cohort studies.

BackgroundStroke is a major cause of adult disability. The 2012 Cochrane Review of SSRIs for stroke recovery demonstrated positive effects on recovery. We updated this review in 2019 because a large trial of fluoxetine for stroke recovery (Fluoxetine or Control Under Supervision, FOCUS) was published in December 2018. ObjectivesTo determine if SSRIs are more effective than placebo or usual care at improving outcomes in people less than 12 months post‐stroke, and to determine associations with adverse effects. Search methodsWe searched several electronic databases up to July 2018, trials registers and grey literature. Selection criteriaWe selected all randomized controlled trials (RCTs) of any SSRI treatment versus no usual care or placebo recruiting patients who had had a stroke in the previous year. Trials had to collect data on at least one of our primary (disability score or independence) or secondary outcomes (impairments, depression, anxiety, quality of life, fatigue, healthcare cost, death, adverse events and leaving the trial early). Data collection and analysisTwo review authors independently extracted data and assessed risk of bias. We calculated standardised mean differences (SMDs), and risk ratios (RRs) as appropriate. We restricted the primary analysis to studies at low risk of bias. Main resultsWe identified a total of 63 eligible trials recruiting 9168 participants. About half the trials required participants to have depression to enter the trial. The duration, drug, and dose varied between trials. Meta‐analysis of the three trials at low risk of bias found no effect of SSRI on disability score (SMD −0.01; 95% CI −0.09 to 0.06; P = 0.75; 2 studies, 2829 participants) or independence (RR 1.00; 95% CI 0.91 to 1.09; P = 0.99; 3 studies, 3249 participants) (see Figure). We downgraded both these outcomes for imprecision. Figure: Forest plot of the outcome independence; comparing SSRIs with usual care or placebo. CI indicates confidence interval.SSRIs reduced the depression scores but increased gastrointestinal side effects. When all trials were included irrespective of risk of bias, SSRIs reduced disability scores but not dependence. Authors' conclusions and implicationThere is no reliable evidence that SSRIs should be used routinely to promote recovery after stroke.

Background Approximately, half of stroke survivors experience fatigue. Fatigue may persist for many months and interferes with participation in everyday activities and has a negative impact on social and family relationships, return to work, and quality of life. Fatigue is among the top 10 priorities for ‘Life after Stroke’ research for stroke survivors, carers, and clinicians. We previously developed and tested in a small uncontrolled pilot study a manualised, clinical psychologist-delivered, face-to-face intervention, informed by cognitive behavioural therapy (CBT). We then adapted it for delivery by trained therapists via telephone. We now aim to test the feasibility of this approach in a parallel group, randomised controlled feasibility trial (Post Stroke Intervention Trial In Fatigue, POSITIF). Methods/design POSITIF aims to recruit 75 stroke survivors between 3 months and 2 years post-stroke who would like treatment for their fatigue. Eligible consenting stroke survivors will be randomised to either a 7-session manualised telephone-delivered intervention based on CBT principles plus information about fatigue, or information only. The aims of the intervention are to (i) provide an explanation for post-stroke fatigue, in particular that it is potentially reversible (an educational approach), (ii) encourage participants to overcome the fear of taking physical activity and challenge negative thinking (a cognitive approach) and (iii) promote a balance between daily activities, rest and sleep and then gradually increase levels of physical activity (a behavioural approach). Fatigue, mood, quality of life, return to work and putative mediators will be assessed at baseline (just before randomisation), at the end of treatment and 6 months after randomisation. POSITIF will determine the feasibility of recruitment, adherence to the intervention and the resources required to deliver the intervention in a larger trial. Discussion The POSITIF feasibility trial will recruit until 31 January 2020. Data will inform the utility and design of a future adequately powered randomised controlled trial. Trial registration ClinicalTrials.gov, NCT03551327. Registered on 11 June 2018.

Background: Neutrophil to lymphocyte ratio (NLR) on admission was reported to be a predictor of pneumonia after stroke. The aim of this study was to investigate the association between the temporal change of NLR and post-stroke infection and whether infection modified the effect of NLR on the outcome. Methods: We enrolled patients with acute ischemic stroke within 24 h after onset. The blood was collected on admission, day 1, 3, 7 after admission to detect white blood cells (WBC), neutrophils, and lymphocytes. Primary outcomes included pneumonia, urinary tract infection (UTI), other infection, and the secondary outcome was 3-month death. Results: Of 798 stroke patients, 299 (37.66%) developed infection with 240 (30.23%) pneumonia, 78 (9.82%) UTI, and 9 (1.13%) other infection. The median time of infection occurrence was 48 h (interquartile range 27-74 h) after onset. NLR reached to the peak at 36 h. For all outcomes, NLR at 36 h after stroke had the highest predictive value than WBC, neutrophil, lymphocyte. NLR was independently associated with the presence of any infection (odds ratio [OR] 1.11, 95% confidence interval [CI] 1.05-1.17), pneumonia (OR 1.12, 95%CI 1.05-1.19), but not UTI (OR 0.95, 95%CI 0.89-1.01). Adding infection or the interaction term did not substantially change the OR of NLR predicting 3-month death (OR 1.09, 95%CI 1.01, 1.17). Conclusion: Increased NLR around 36 h after stroke was a predictor of infection in patients with acute ischemic stroke. The increased NLR value was associated with a higher risk of 3-month death, which was independent of poststroke infection.

Whether matrix metalloproteinase 9 (MMP-9) concentrations in plasma predict risk of spontaneous haemorrhagic transformation (sHT) in acute ischaemic stroke is unclear. From 1 March 2003 to 27 February 2006, patients with acute ischaemic stroke admitted to West China Hospital within 24 h of onset and healthy controls were enrolled and blood samples obtained. Plasma MMP-9 concentrations were determined using enzyme-linked immunosorbent assay, and sHT was diagnosed based on brain computed tomography or magnetic resonance performed 3-14 d after stroke onset. MMP-9 concentrations were compared for sHT patients, non-sHT patients and healthy controls. The threshold concentration for predicting sHT was determined using receiver operating characteristic analysis and the association between MMP-9 concentration and sHT was tested. One hundred and sixty-eight stroke patients and 40 healthy controls were included. Spontaneous HT occurred in 17.3% (29/168) of stroke patients and median plasma MMP-9 concentration in the sHT subgroup [244.3 ng/mL; interquartile range (IQR), 190.6-431.4] was significantly higher than in the non-sHT subgroup (110.0 ng/mL; IQR, 54.4-172.2) as well as in healthy controls (63.3 ng/mL; IQR 37.9-84.9) (both P 0.001). We identified 181.7 ng/mL as the threshold MMP-9 concentration, for which the positive predictive value was 48% and the negative predictive value was 96%. After controlling for potential confounding factors, MMP-9 concentration181.7 ng/mL was an independent predictor of sHT (odds ratio 18.8, 95% confidence interval 6.0-58.5, P 0.001). Plasma MMP-9 concentration181.7 ng/mL within 24 h after stroke onset independently predicts sHT in patients with ischaemic stroke.

OBJECTIVES To investigate the association of kidney function with the total burden of Cerebral Small Vessel Disease (CSVD) in primary Intracerebral Hemorrhage (pICH). METHODS Cerebral magnetic resonance imagings of consecutively enrolled pICH patients were reviewed to assess for lacunes, White Matter Hyperintensity (WMH), Cerebral Microbleeds (CMBs) and Enlarged Perivascular Spaces (EPVS). Minor refinements to the CSVD score, namely modified CSVD score 1 and 2, were made by incorporating different weightings of CSVD markers. Kidney function was assessed using the estimated Glomerular Filtration Rate (eGFR). We used ordinal regression analysis to assess the association of kidney function with the CSVD score and modified scores. RESULTS In the 108 patients included, the presence of lacunes, CMBs, MWH and basal ganglia EPVS>10 was 27.8%, 67.6%, 47.2% and 35.2%, respectively. In multivariable ordinal regression, a decreasing eGFR value was associated with an increased CSVD score [Odds Ratio (OR) 0.978, 95% Confidence Interval (CI) 0.962 to 0.995, P=0.013], modified CSVD score 1 (OR 0.973, 95% CI 0.957 to 0.990, P=0.002) and 2 (OR 0.969, 95% CI 0.953 to 0.986, P

This study aimed to help clarify the possible relationships of thyroid function with intracranial arterial stenosis or carotid atheromatous plaques in ischemic stroke patients with euthyroidism. We retrospectively reviewed the medical records of a consecutive series of ischemic stroke patients prospectively entered into the Chengdu Stroke Registry between February 2010 and March2012. We performed univariate and multivariate analysis to assess possible relationships of thyroid function with intracranial artery stenosis or carotid atheromatous plaques. Of the 172 patients analyzed (42 women; 61.7 ± 14.0 years old), 62 (32.0%) had carotid atheromatous plaques, and 81 (47.1%) had intracranial artery stenosis. Free thyroxine levels were lower in patients with carotid atheromatous plaques than in patients without plaques (15.80±2.09 vs. 16.92±2.69, P = 0.005). After adjusting for age, gender, hyperlipidemia, and previous smoking, free thyroxine levels were independently associated with carotid atheromatous plaques (OR 0.73, 95% CI 0.54-0.99, P = 0.04). In contrast, thyroid function indicators showed no associations with intracranial arterial stenosis. In conclusion, low free thyroxine levels were independently associated with carotid atheromatous plaques in ischemic stroke patients with euthyroidism, but thyroid function indicators were not associated with intracranial artery stenosis.

Summary Background Stroke is a leading cause of death and disability worldwide. Despite considerable improvements in diagnosis and treatment, little is known about the short-term and long-term prognosis after a first stroke in low-income and middle-income countries, including China. We aimed to assess the short-term and long-term risk of recurrent stroke and mortality after a first stroke for each of the major pathological stroke types. Methods This population-based cohort study included adults aged 35–74 years without disability who were recruited to the China Kadoorie Biobank (CKB). A baseline survey was conducted in ten geographical areas (five urban, five rural) in China, and participants had clinical measurements recorded. Participants were followed up by monitoring death registries and by electronic linkage to health registries and health insurance claims databases, with follow-up until Jan 1, 2017. Participants were excluded from analyses if they had a previous history of stroke, transient ischaemic attack, or ischaemic heart disease at baseline. All incidences of fatal and non-fatal stroke during the study period were recorded by type (ischaemic stroke, intracerebral haemorrhage, subarachnoid haemorrhage, and unspecified type). Primary outcome measures were 28-day mortality, recurrent stroke, major vascular events (recurrent stroke, myocardial infarction, or vascular death), vascular mortality, and all-cause mortality. Findings Of 512 715 individuals in the CKB, 489 586 participants without previous ischaemic heart disease and stroke at recruitment were included, of whom 45 732 (42 073 [92%] confirmed by brain imaging) had a stroke during the study period. The mean age was 59·3 years (SD 9·8) for participants who had a stroke (54% women) and 50·8 years (10·3) for participants with no stroke (60% women). 36 588 (80%) of the incident cases of stroke were ischaemic stroke, 7440 (16%) were intracerebral haemorrhage, 702 (2%) were subarachnoid haemorrhage, and 1002 (2%) were an unspecified stroke type. 28-day mortality was 3% (95% CI 3–4) for ischaemic stroke, 47% (46–48)for intracerebral haemorrhage, 19% (17–22; 52% for rural areas and 32% for urban areas) subarachnoid haemorrhage, and 24% (22–27) for unspecified stroke. Among participants who survived stroke at 28 days, 41% (41–42) had recurrent stroke at 5 years (ischaemic stroke 41% [41–42], intracerebral haemorrhage 44% [42–46], subarachnoid haemorrhage 22% [18–27], unspecified stroke type 40% [35–44]) and mortality at 5 years was 17% ([17–18] ischaemic stroke 16% [15–16], intracerebral haemorrhage 28% [26–29], subarachnoid haemorrhage 16% [12–20], unspecified stroke type 15% [12–19]). After a first ischaemic stroke, 91% of recurrent strokes were also ischaemic stroke; after an intracerebral haemorrhage, 56% of recurrent strokes were intracerebral haemorrhage, and 41% of recurrent strokes were ischaemic stroke. Interpretation After a first stroke, the risk of recurrence or death within 5 years was high among this population of Chinese adults. Urgent improvements to secondary prevention of stroke in China are needed to reduce these risks. Funding Wellcome Trust, Medical Research Council, British Heart Foundation, Cancer Research UK, Kadoorie Charitable Foundation, Chinese Ministry of Science and Technology, National Natural Science Foundation of China. Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.

Background: Whether preoperative midline shift and its growing rate are associated with outcomes of decompressive craniectomy in patients with malignant middle cerebral artery infarction is unknown. Methods: We retrospectively included patients: 1) who underwent decompressive craniectomy for malignant middle cerebral artery infarction in West China Hospital from August 2010 to December 2, 2018) who had at least two brain computed tomography scans before decompressive craniectomy. Midline shift was measured on the first and last preoperative computed tomography scans. Midline shift growing rate was calculated by dividing Δmidline shift value using Δ time. The primary outcome was inadequate decompression of the mass effect. Secondary outcomes were 3 month death and unfavorable outcomes. Results: Sixty-one patients (mean age 53.7 years, 57.4% (35/61) male) were included. Median time from onset to decompressive craniectomy was 51.8 h (interquartile range: 39.7-77.8). Rates of inadequate decompression, 3 month death, 3 month modified Rankin Scale 5-6 and 4-6 were 50.8% (31/61), 50.9% (29/57), 64.9% (37/57) and 84.2% (48/57), respectively. The inadequate decompression group had a higher midline shift growing rate than the adequate decompression group (median: 2.7 mm/8 h vs. 1.4 mm/8 h, P=0.041). No intergroup difference of 3 month outcomes was found in terms of preoperative midline shift growing rate. Conclusion: Higher preoperative midline shift growing rate was associated with inadequate decompression of decompressive craniectomy in patients with malignant middle cerebral artery infarction.

Background: Little is known about long-term trends in outcomes of patients with ischemic stroke in China. We aimed to assess longitudinal trends in these outcomes over the past 15 years in China and explore possible factors behind the trends. Methods and Results: Patients with ischemic stroke admitted to the Department of Neurology at West China Hospital were prospectively and consecutively enrolled in a central registry since 2002, and the present study analyzed data from those admitted to hospital within 7 days of stroke during the period 2002 to 2016. Patients were binned into three 5-year intervals for temporal analysis. Death, disability, and death/disability at 3 and 12 months after stroke were compared among the time intervals across the entire sample and in subsets stratified by age (P P P ≤0.03). Conclusions: Our study from a large medical center in southwest China suggests that since 2002, risks of disability and death/disability at 3 and 12 months after ischemic stroke have declined. This appears to be due, at least in part, to a significant decline in National Institutes of Health Stroke Scale score on admission, which may reflect greater public awareness of stroke detection, willingness to seek medical attention, and ease of access to healthcare infrastructure. The factors behind this apparent improvement require further study.

Objective To determine whether fluoxetine, at any dose, given within the first year after stroke to patients who did not have to have mood disorders at randomization reduced disability, dependency, neurological deficits and fatigue; improved motor function, mood, and cognition at the end of treatment and follow-up, with the same number or fewer adverse effects. Methods Searches (from 2012) in July 2018 included databases, trials registers, reference lists, and contact with experts. Co-primary outcomes were dependence and disability. Dichotomous data were synthesized using risk ratios (RR) and continuous data using standardized mean differences (SMD). Quality was appraised using Cochrane risk of bias methods. Sensitivity analyses explored influence of study quality. Results The searches identified 3414 references of which 499 full texts were assessed for eligibility. Six new completed RCTs (n = 3710) were eligible, and were added to the seven trials identified in a 2012 Cochrane review (total: 13 trials, n = 4145). There was no difference in the proportion independent (3 trials, n = 3249, 36.6% fluoxetine vs. 36.7% control; RR 1.00, 95% confidence interval 0.91 to 1.09, p = 0.99, I2 = 78%) nor in disability (7 trials n = 3404, SMD 0.05, −0.02 to 0.12 p = 0.15, I2 = 81%) at end of treatment. Fluoxetine was associated with better neurological scores and less depression. Among the four (n = 3283) high-quality RCTs, the only difference between groups was lower depression scores with fluoxetine. Conclusion This class I evidence demonstrates that fluoxetine does not reduce disability and dependency after stroke but improves depression.

Recent subcortical infarction (RSI) in the lenticulostriate artery (LSA) territory with a non-stenotic middle cerebral artery is a heterogeneous entity. We aimed to investigate the role of LSA combined with neuroimaging markers of cerebral small vessel disease (CSVD) in differentiating the pathogenic subtypes of RSI by whole-brain vessel-wall magnetic resonance imaging (WB-VWI). Fifty-two RSI patients without relevant middle cerebral artery (MCA) stenosis on magnetic resonance angiography were prospectively enrolled. RSI was dichotomized as branch atheromatous disease (BAD; a culprit plaque located adjacent to the LSA origin) (n = 34) and CSVD-related lacunar infarction (CSVD-related LI; without plaque or plaque located distal to the LSA origin) (n = 18). Logistic regression analysis showed lacunes (odds ratio [OR] 9.68, 95% confidence interval [CI] 1.71–54.72; P = 0.010) and smaller number of LSA branches (OR 0.59, 95% CI 0.36–0.96; P = 0.034) were associated with of BAD, whereas severe deep white matter hyperintensities (DWMH) (OR 0.11, 95% CI 0.02–0.71; P = 0.021) was associated with CSVD-related LI. In conclusion, the LSA branches combined with lacunes and severe DWMH may delineate subtypes of SSI. The WB-VWI technique could be a credible tool for delineating the heterogeneous entity of SSI in the LSA territory.

Background and Objective Elevated alkaline phosphatase (ALP) is considered as a marker of liver function in clinical practice. Furthermore, it has been identified that liver function can contribute to hemorrhagic transformation (HT). However, whether ALP levels play a role in HT after stroke remains an open question, especially in cardioembolic stroke patients. Methods We prospectively and consecutively enrolled ischemic stroke patients with atrial fibrillation and/or rheumatic heart disease. Baseline data including ALP levels within 48 hours after admission were collected. ALP levels were divided into tertiles. The presence of HT, hemorrhagic infarction (HI), parenchymal hematoma (PH), and symptomatic HT was evaluated according to brain magnetic resonance imaging and European-Australasian Acute Stroke Study III definitions. We used logistic regression to examine the associations between ALP levels and risk of HT, HI, PH, and symptomatic HT. Results Of the 130 patients (56 male; mean age: 63 years) included finally, 50 (38.5%) developed HT and 13 (10.0%) developed symptomatic HT. ALP levels were not associated with risk of HT, HI, and PH. However, compared with the first ALP tertile, patients in the third tertile were 8.96 times more likely to have symptomatic HT (95% confidence interval: 1.33-60.21; P = .02) after adjusting for age, gender, alanine aminotransferase levels, aspartate aminotransferase levels, antiplatelet therapy, anticoagulation therapy, and thrombolysis therapy. Conclusion Elevated ALP levels may help identify high-risk symptomatic HT in ischemic stroke patients with atrial fibrillation and/or rheumatic heart disease. However, further studies with larger cohorts are needed to identify our results.

Elevated alkaline phosphatase (ALP) levels are associated with cerebral small vascular diseases, such as silent brain infarction and cerebral white matter hyperintensity (cWMH), but few prospective data are available for cerebral microbleeds (CMBs). The aim of the study was to investigate associations between serum ALP levels and CMBs in acute ischemic stroke patients with atrial fibrillation and/or rheumatic heart disease. This prospective study involved consecutively recruited acute ischemic stroke patients with atrial fibrillation and/or rheumatic heart disease treated at two large tertiary care hospitals in southwestern China. We used logistic regression to examine the relationships between ALP levels and CMBs. Of 128 patients (56 males; mean age, 68 years) included, 71 (55.5%) patients had CMBs. Compared with the first tertile of ALP concentration, participants in the third tertile were 3.59 times more likely to have multi-CMBs (≥2) [95% confidence interval (CI): 1.21-10.71; P = 0.02] after adjusting for age, gender, smoking habits, drinking habits, ALT (alanine transaminase) levels, AST (aspartate transaminase) levels, renal impairment and cWMH.

BACKGROUND: Whether red blood cell distribution width (RDW) is associated with the prognosis of acute ischemic stroke is inconclusive according to recent studies. We performed a cohort study and meta-analysis to explore the association between RDW and functional outcome. METHODS: Patients with ischemic stroke admitted to the Department of Neurology within 24 hours of stroke onset between January 1, 2015 to December 31, 2018 were enrolled. Blood was sampled within 24 hours after admission. We searched PubMed, Embase, Web of Science databases up to Nov 2019 to identify studies investigating the association between RDW values and prognosis following stroke. Outcomes included 3-month death and poor functional outcome [defined by modified Rankin Scale (mRS) score ≥3]. RESULTS: We included 1,558 patients in cohort study. RDW was independently associated with 3-month death [odds ratio (OR), 1.19; 95% confidence interval (CI), 1.03, 1.37], but not associated with 3-month poor outcome (OR 1.05, 95% CI, 0.95, 1.16), after adjustment for confounders. A dose-dependent relationship between RDW levels and 3-month death was revealed in the restricted cubic spline plot. Seven observational studies with 4,407 patients were identified for systematic review. When combining our study and previous studies, the association was significant for RDW predicting death (5 studies with 3,366 patients, OR 1.25, 95% CI, 1.15, 1.35), as well as for poor outcome (4 studies with 3,483 patients, OR 1.23, 95% CI, 1.05, 1.44). CONCLUSIONS: RDW was an independent predictor of 3-month functional outcome, and a trend of dose-dependent relationship between RDW and 3-month death was detected.

Background: The 2012 Cochrane Review of Selective Serotonin Reuptake Inhibitors of randomised controlled trials (RCTs) in stroke demonstrated that fluoxetine might reduce disability even in patients who did not have to have mood disorders to be randomised. This hypothesis was tested in the FOCUS trial in 3127 patients with stroke, and so, to set the trial's results in context, we updated our searches to identify and include new RCTs of fluoxetine. Methods: Data sources included several databases, trials registers, reference lists of included studies, and contact with experts. Searches (from 2012) were performed in July 2018. We excluded RCTs which required patients to have mood disorder at randomisation. Co-primary outcomes were dependence and disability. Quality was appraised using Cochrane risk of bias methods. Dichotomous data were synthesised using risk ratios (RR) and continuous data using standardised mean differences (SMD). Sensitivity analyses explored the effect of study quality. Results: From the searches, 3412 references were identified, 426 duplicates removed, 2986 references screened, and 491 full texts assessed for eligibility. Six new completed RCTs (n=3710) were eligible making a total of 13 trials (n=4145). There was no difference in the proportion independent at end of treatment (3 trials, n=3249, 36·6% in fluoxetine vs 36·7% control; RR 1·00, 95% confidence interval 0·91 to 1.09, p=0·99, I2 78%) and no difference in disability (7 trials n=3404, SMD 0·05, -0·02 to 0·12 p=0·15, I2=81%). Fluoxetine was associated with better neurological scores, less depression but more seizures. When only the four (n=3283) high quality RCTs were included, the only statistically significant difference between groups was a small reduction in depression scores with fluoxetine. Conclusion: Fluoxetine does not reduce disability and dependency after stroke. It improves depression scores but probably increases seizures. Ongoing RCTs will determine whether its effects in stroke vary depending on ethnicity, background treatment and other factors. Funding Statement: Maree L. Hackett held a National Health and Medical Research Council Career Development Fellowship, Level 2 (APP1141328 2018-2021). This review was not funded. Declaration of Interests: Dr. Barugh has nothing to disclose. Dr. Soleimani has nothing to disclose. Dr. Rudberg has nothing to disclose. Dr. Lundstrom has nothing to disclose. Dr. Legg has nothing to disclose. Dr. Hankey reports grants from the National Health and Medical Research Council of Australia, outside the submitted work. Dr. Hackett reports grants from National Health and Medical Research Council, outside the submitted work. Dr. Hsieh has nothing to disclose. Dr. Mead reports grants from University of Edinburgh, during the conduct of the study. Dr. Kutlubaev has nothing to disclose. Dr. Dennis reports and I was co-chief investigator of the FOCUS trial which was included in the review, and received a grant from NIHR to run the trial. Dr. Tilney has nothing to disclose. Dr. Wu has nothing to disclose.

Fatigue is ubiquitous but it is more common and more severe in patients with acute and chronic conditions, including stroke. The reported proportion of people with fatigue after stroke ranges from 23% to 75%.1 The variation in proportion between studies reflects the heterogeneity in the studied populations, time since stroke, and assessment methods for fatigue. Fatigue is common immediately after stroke, and it tends to persist in most but not all patients. It contributes to lower quality of life and a higher risk of death.2,3 How to manage and prevent fatigue is ranked by stroke survivors and health professionals among the top 10 research priorities relating to life after stroke.4 However, there is no effective treatment, which is partly because of our lack of knowledge of its mechanisms. Fatigue after stroke may share some common underlying mechanisms with other conditions. For example, Zedlitz and colleagues found that the psychosocial profiles of stroke patients with fatigue were similar to those reported in patients with cancer, multiple sclerosis, and chronic fatigue syndrome.5 Several fatigue models have been developed for patients with other conditions; a myriad of biological,6,7 psychosocial,8,9 and behavioral factors,9 as well as other symptoms, such as pain and sleep problems,10 are involved. In this review, we explored whether these factors contribute to fatigue after stroke. We systematically reviewed studies of post-stroke fatigue (PSF) and discussed the definition of PSF, its natural history, and its associations. By drawing on literature of fatigue in other conditions alongside evidence from stroke studies, we propose a conceptual model of PSF. This model is potentially useful in understanding the mechanisms of PSF and informing the development of its treatment. In stroke studies, PSF is usually defined by cut-off scores on fatigue …

To compare the burden of non-symptomatic cerebral ischemia (NSCI) detected on magnetic resonance imaging (MRI) and computed tomography (CT), and assess the association of MRI-NSCI with clinical outcomes among patients with first-ever intracerebral hemorrhage (ICH).Two thousand three hundred and five consecutive ICH patients admitted to our institution from May 2012 to October 2015 were retrospectively reviewed. Data on clinical characteristics and MRI/CT scans were collected during hospitalization. Information on clinical outcomes at three-month were also obtained.Three hundred and seventy-seven patients performed MRIs and 1966 had CTs during hospitalization. NSCI was detected in 152 (40.3%) patients with MRIs and in 638 (32.5%) with CTs. Comparing with CT, NSCI detected by MRI was more common (40.3% vs. 32.5%; P = 0.011), more likely to be multiple loci (93.4% vs. 79.6%; P0.001) and bilateral hemispheres (84.9% vs. 73.2%; P = 0.003). Furthermore, the presence of NSCI, multiple NSCI, bilateral NSCI and bilateral hematoma combined with bilateral NSCI were associated with poor outcomes (P0.001, P0.001, P0.001, P = 0.041, respectively) in univariate analysis. In multivariable logistic regression, bilateral hematoma combined with bilateral NSCI was still associated with poor outcomes (OR 3.983, 95% CI 1.172-13.539; P = 0.027).Compared with CT, NSCI on MRI tends to be multiple loci and located in bilateral hemispheres. The results of NSCI in ICH may be underestimated based on CT. In addition, the increased poor outcomes at three-month suggest that NSCI may play an important role in reducing clinical outcomes.

Background and Purpose.Anxiety affects 25% of stroke survivors. There are no effective treatments. Poststroke depression, prestroke anxiety and depression, locus of control, coping, confidence, fatigue, and sleep are factors that may be associated with poststroke anxiety and can potentially be targeted by therapy. We systematically reviewed the literature and performed a meta-analysis to identify associations with these factors.Methods. We searched electronic databases from January 2014 to July 2015 to complement a literature search performed from inception to May 2014. Study quality was assessed using an internationally endorsed checklist. We used odds ratios (ORs) to estimate the strength of associations and random-effects modelling to calculate summary effect sizes.Results.There were 24 studies recruiting 15448 patients. Quality of reporting was satisfactory. 13 studies with 2408 patients reported associations between poststroke anxiety and poststroke depression (OR=4.66, 95% confidence interval: 2.23, 9.74). One study reported association with prestroke anxiety, three with prestroke depression, one with fatigue, and two with sleep. No studies reported on locus of control, coping, or confidence.Conclusion.Poststroke anxiety was associated with depression but there are limited data on other modifiable associations. Further research is needed to identify potential targets for treatment.

Background and Purpose— Fatigue is common after stroke but has no effective treatments. Psychological interventions improve fatigue in other conditions by targeting psychological factors such as mood. If psychological factors correlate with fatigue in stroke, this would justify the development of similar interventions for poststroke fatigue (PSF). We used systematic review and meta-analysis to determine psychological associations of PSF. Methods— We systematically searched for studies that reported psychological associations of PSF. We used odds ratios (ORs) to estimate the strength of associations and random-effects modeling to calculate summary estimates of ORs. We used stratified meta-analysis to investigate the impact of study design and conducted sensitivity analyses limited to studies that excluded patients with clinical depression and to studies that used depression scales without fatigue items. Results— Thirty-five studies (n=9268) reported the association between PSF and ≥1 psychological factor. For PSF and depressive symptoms, we identified 19 studies (n=6712; pooled OR=4.14; 95% confidence interval, 2.73–6.27); this association existed in patients without clinical depression (pooled OR=1.39; 95% confidence interval, 1.27–1.53) and in studies using depression scales without fatigue items (pooled OR=5.41; 95% confidence interval, 1.54–18.93). For PSF and anxiety, we identified 4 studies (n=3884; pooled OR=2.34; 95% confidence interval, 0.98–5.58). Two studies (n=123) found an association with poor coping styles and 1 study (n=167) with loss of control. Six studies (n=1978) reported other emotional or behavioral associations. Conclusions— PSF is associated with depressive symptoms, anxiety, poor coping, loss of control, emotional, and behavioral symptoms. These factors are potential targets for treatment of PSF.

Background and purpose The relationship between neutrophil to lymphocyte ratio (NLR) and prognosis after acute ischemic stroke (AIS) remains controversial. The aim of this cohort study and systematic review was to ascertain the association of admission NLR with major clinical poor outcomes after AIS. Methods We analyzed data from Chengdu stroke registry and performed a systematic review for previous literature. The outcomes were hemorrhagic transformation (HT), parenchymal hematoma (PH), symptomatic intracranial hemorrhage (sICH), 3-month death or disability (modified Rankin Scale≥3), and 3-month death. Odds ratios (ORs) and 95% confidence intervals (CIs) of NLR as a continuous and categorical variable and poor outcomes were pooled separately. We also calculated the predictive accuracy of admission NLR in different outcomes. Results We included 808 patients from registry database and 9563 patients from previous studies. Our registry data showed that NLR ≥5 was associated with HT (OR 2.03, 95%CI 1.19–3.46), PH (OR 2.54, 95%CI 1.20–5.35) and 3-month death (OR 5.55, 95%CI 1.41–21.89); meta-analysis with our data and other observational studies indicated that higher NLR was associated with HT (OR 1.99, 95% CI 1.45–2.73), sICH (OR 2.22, 95% CI 1.60–3.09), 3-month death or disability (OR 1.68, 95% CI 1.18–2.38), and 3-month death (OR 2.79, 95% CI 1.57, 4.94). NLR had the highest predictive accuracy for 3-month death. Conclusions Higher NLR is positively associated with the risk of HT and 3-month death after stroke. Considering the limited predictive ability of a single biomarker, more studies should validate the role of NLR in prognostic models.

Objective: Neurological and medical complications are major causes of morbidity and mortality after ischemic stroke. This study aimed to identify the incidence of stroke-related complications following large hemisphere infarction (LHI) and to explore their influence on unfavorable outcome in LHI patients. Methods: We prospectively enrolled consecutive patients with LHI. The unfavorable outcome was defined as an modified Rankin Scale (mRS) score of 4–6 at 3 months. Multivariate logistic regression analysis was employed to identify the stroke-related complications associated with unfavorable outcome. Results: Of the 256 cases with LHI included, 41 (16.0%) died during hospitalization, 94 (36.7%) died and 140 (55.3%) patients had unfavorable outcome at 3 months. A total of 194 (75.8%) had at least one complication. The three most common medical complications were pneumonia (53.5%), electrolyte disorder (30.9%), and urinary incontinence (18.4%), and the three most common neurological complications were malignant brain edema (31.2%), hemorrhagic transformation (27.7%), and poststroke seizures (7.0%). Overall, LHI patients with unfavorable outcome had more frequent stroke-related complications (91.4% versus 55.8%, p Conclusions: More than three-quarters of LHI patients have at least one stroke-related complication. LHI patients with the unfavorable outcome had stroke-related complications more frequently, whereas only malignant brain edema and pneumonia are independently associated with 3-month unfavorable outcome.

Edaravone has been used in patients with acute ischemic stroke in Japan for over 10 years but does not have marketing authorization in Europe or America. Either patients in Europe and America are not receiving an effective treatment, or those in Asia are being given a treatment which is not effective. Finding out which of these is true will require further clinical trials, and a better understanding of its efficacy in animal models may help inform the design of those trials so that it might be tested under conditions where there is the greatest prospect of success. We systematically reviewed the efficacy of edaravone in animal models of focal ischemia and summarized data using weighted mean difference DerSimonian and Laird random-effects modeling. We used stratified meta-analysis and metaregression to assess the influence of study design and methodological quality. We identified 49 experiments describing outcome in 814 animals; 30 experiments (519 animals) reported functional and 35 experiments (503 animals) reported structural outcome. Edaravone improved functional and structural outcome by 30.3% (95% confidence interval 23.4–37.2%) and 25.5% (95% confidence interval, 21.1–29.9%), respectively. For functional outcome, there was an inverse relationship between study quality and effect size ( P < 0.0017). Effect sizes were larger in studies where randomization or blinded assessment was not reported. There was no evidence of publication bias. Edaravone is a promising treatment for stroke. However, because of the methodological weakness in current animal studies, no sufficient preclinical evidence is available to optimize the study design of clinical trials. Higher quality animal studies are expected to inform further clinical study.

Background The prognostic significance of intraventricular hemorrhage (IVH) in patients with vascular structural abnormality-related intracerebral hemorrhage (VSARICH) is poorly understood. Method We prospectively included consecutive patients diagnosed with VSARICH. Imaging of initial brain computed tomography (CT) scans within 48 hours of symptom onset was analyzed. The presence and severity of IVH were recorded. Severity of IVH was measured using the modified Graeb (mGraeb) score. Baseline characteristics and 3-month outcomes were compared between the IVH and non-IVH groups. Multivariate logistic regression was used to examine the independent association between IVH and 3-month outcomes. Results A total of 132 VSARICH patients were included for analysis, and 71 (53.8%) of them had IVH on initial CT imaging. IVH patients had a median mGraeb score of 15 (6-21), and compared to non-IVH patients, they had shorter delay to first CT scan and higher stroke severity on admission (all P ≤ .005). At 3 months, IVH patients had higher death rates (30.3% versus 7.0%; P = .001) and poor outcome rates (48.5% versus 21.1%; P = .002) than non-IVH patients. After multivariate analysis, IVH severity was associated with 3-month death (Model 1 OR 1.112, 95% CI [1.027-1.204], P = .009; Model 2 OR 1.110, 95% CI [1.027-1.200], P = .009) and poor outcome (Model 2 OR 1.053, 95% CI [1.001-1.108], P = .047), although no independent association between IVH presence and outcomes was observed. Conclusion IVH severity measured by mGraeb score independently predicts death and poor functional outcome in patients with VSARICH.

Results from previous studies on the association between methylenetetrahydrofolate reductase (MTHFR) polymorphisms C677T and A1298C and lung cancer have been conflicting. The aim of this meta-analysis was to clarify the effect of MTHFR polymorphisms on the risk of lung cancer. An electronic search of PubMed, EMBASE, the Cochrane library, and the China Knowledge Resource Integrated Database for papers on C677T and A1298C and susceptibility to lung cancer was performed. The STATA software (Version 13.0) was used for statistical analysis. Statistical heterogeneity, tests of publication bias, and a sensitivity analysis were performed. Twenty-six studies on C677T (12,324 cases and 12,532 controls) and thirteen studies on A1298C (6773 cases and 8207 controls) were included in the meta-analysis. The MTHFR C677T polymorphism showed significant pooled ORs for the homozygote comparison (TT versus CC: OR = 1.518, 95%CI = 1.220-1.890), heterozygote comparison (CT versus CC: OR = 1.053, 95%CI = 0.940-1.179), dominant model (CT + TT versus CC: OR = 1.143, 95%CI = 1.013-1.291), recessive model (TT versus CT + CC: OR = 1.435, 95%CI = 1.190-1.730), and additive model (T versus C: OR = 1.176, 95%CI = 1.066-1.298). In summary, our meta-analysis showed that the MTHFR C677T polymorphism is associated with a significant increase in lung cancer risk in Asian and overall populations, but not in Caucasian populations. However, no significant association between the MTHFR A1298C polymorphism and lung cancer risk was found in either the Caucasian or Asian group with any genetic models.

Published studies on the association between the C677T and A1298C polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) gene and male infertility risk are controversial. To obtain a more precise evaluation, we performed a meta-analysis based on published case-control studies. We conducted an electronic search of PubMed, EMBASE, the Cochrane Library, the Web of Science, and the China Knowledge Resource Integrated Database for papers on MTHFR gene C677T and A1298C polymorphisms and male infertility risk. Pooled odds ratios (ORs) with 95% confidence intervals (95%CIs) were used to assess the strength of association in homozygote, heterozygote, dominant, recessive, and additive models. Statistical heterogeneity, test of publication bias, and sensitivity analysis were carried out using the STATA software (Version 13.0). Overall, 21 studies of C677T (4505 cases and 4024 controls) and 13 studies of A1298C (2785 cases and 3094 controls) were included in this meta-analysis. For C677T, the homozygote comparison results were OR = 1.629, 95%CI (1.215- 2.184), and the recessive model results were OR = 1.462 (1.155- 1.850). For A1298C, the homozygote comparison results were OR = 1.289 (1.029-1.616), and the recessive model results were OR = 1.288 (1.034-1.604). In conclusion, the current meta-analysis showed that the MTHFR C677T polymorphism was associated with a significantly increased male infertility risk in the Asian and overall populations, but not in the Caucasian population, and there was a significant association between the A1298C polymorphism and male infertility risk in the Asian, Caucasian, and overall groups.

Background: Randomized controlled trials (RCTs) are the most important evidence to guide clinical practice in the treatment of acute stroke. This study aims to evaluate the changes of quantity and methodological quality of acute stroke RCTs in Mainland China published in recent 15 years. Method: We included un-confounded RCTs on acute stroke from eight databases published in Chinese or English from 1996 to 2010. General characteristics, design methodology, and outcome measures of studies were assessed. Results: Totally, 9061 RCTs were identified. The number of acute stroke RCTs had increased by years, the total of trials published in 2010 was 20 times of that published in 1996. Three thousand four hundred eighty-eight trials (38.5%) used western drugs in the treatment, 3026 (33.4%) trials used traditional Chinese medicine (TCM), and 1933 (22.0%) trials used physical therapy. Ischemic stroke was the most common research subject among all trials (65.1%, 5,989). There were 541 (6.0%) RCTs using adequate randomization methods, 34 (0.4%) RCTs using adequate allocation concealment, and 195 (2.2%) using adequate blinding methods. Thirty-three (0.4%) RCTs adopted both adequate randomization methods and allocation concealment. Only 23 (0.3%) trials used all three methods of adequate randomization methods, allocation concealment, and blinding. During the 15 years, only the number of trials using adequate randomized methods and reporting adverse events had significantly increased (both P < 0.001). As for these RCTs, only the number of trials using adequate blinding method in pharmaceutical intervention was statistical differences compared with that of nondrug intervention trials (P = 0.043). Outcomes were assessed blindly in 72 trials. Death was reported by 14.2% of trials, impairment by 85.1%, disability by 22.5%, and handicap or quality of life by 0.4%. 99.7% trials reported positive results. Larger trials were more likely to use adequate randomized methods, allocation concealment and blinding methods, as well as to measure disability. Only 14 large-sample high-quality RCTs were found. Conclusion: During 15 years, the number of acute stroke RCTs has increased dramatically, but the quality of trials improves slowly. Most acute stroke trials used inadequate outcome measures in terms of their content, reliability, validity, blinding assessment.

IntroductionSevere ischaemic stroke is a devastating condition with high mortality and morbidity; however, there is insufficient evidence on its management. The aim of this study is to investigate causes, risk factors, clinical course, management and outcomes of severe ischaemic stroke in a real-world setting in tertiary hospitals in China.Methods and analysisThis is a prospective, multicentre, registry-based observational study. We will recruit 2500 patients with acute ischaemic stroke from nine tertiary hospitals in Western China. Patients with acute ischaemic stroke admitted to the Department of Neurology within 30 days of stroke onset will be included. Patients will be visited within 24 hours after admission, on day 3, day 7 and at discharge, to collect data on their clinical state, blood biomarkers and brain imaging. Severe stroke is defined as severe neurological deficits (National Institute of Health Stroke Scale (NIHSS) ≥15 or in coma) on admission or clinical worsening (NIHSS increased by ≥4 scores) during hospitalisation. Patients will be followed up by structured telephone interviews at 3 months and 1 year after stroke onset. In-hospital outcomes include symptomatic haemorrhagic transformation and brain oedema by day 7 of admission, and survival status (death or survival) by discharge; follow-up outcomes will include survival status and functional outcome (assessed by modified Rankin Scale) at 3 months and 1 year. The current study will improve our knowledge about the development of severe ischaemic stroke at acute phase and factors influencing its outcomes, which will eventually facilitate optimisation of individualised interventions for its prevention and treatment.Ethics and disseminationEthics approval is obtained from The Biomedical Research Ethics Committee of West China Hospital, Sichuan University (Reference No. 2017(130)). We will present our findings at the national and international conferences and peer-reviewed journals in stroke and neurology.Trial registration numberNCT03222024; Pre-results.

SummaryObjectivesWe aimed to investigate trends in the prevalence of multidrug-resistant tuberculosis (MDR-TB) among Chinese people from first report to 2006, and to detect the high prevalence regions in order to guide control efforts.Materials and methodsThe CBM, VIP, CNKI, and MEDLINE databases were searched through both keywords and subject headings. The literature was screened, and two investigators assessed the quality and extracted the data. Trends in MDR-TB prevalence in three groups – primary, acquired, and combined MDR-TB – were examined separately, using the Cochran–Armitage trend test. Differences were tested with the Kruskal–Wallis test. High prevalence provinces were explored through comparison of the 95% confidence interval (95% CI) with the national average level.ResultsOverall 169 studies were included, with 165 in Chinese and four in English. One hundred and sixteen studies concerned primary MDR-TB, 103 acquired MDR-TB, and 130 combined MDR-TB, with total positive Mycobacterium tuberculosis (MTB) isolates of 110 076, 25 187, and 150 233, respectively. The prevalences of MDR-TB in the three groups in 2005 were 2.64-, 6.20-, and 3.84-times that of 1985, respectively, all showing an upward trend (p

Background and Aim Post-stroke fatigue is a common and distressing problem but little is known about its biological mechanisms. This cohort study was to investigate associations between C-reactive protein (CRP) and fatigue after stroke. Methods Patients were assessed at one, six and 12 months after their stroke onset, with the Fatigue Assessment Scale, a case definition of post-stroke fatigue, Hospital Anxiety and Depression Scale, and daily step counts. Blood samples were collected at each assessment and the CRP level was determined by a standard CRP immunoassay. Cross-sectional associations between CRP and fatigue at each time point were determined by Pearson correlation coefficient and independent-samples t-test. Whether CRP levels at one month predict fatigue scores at six and 12 months was explored by multiple linear regression, with anxiety, depression, and daily step counts as covariates. Results Sixty-five patients (mean age 67 years, 65% men) were included: 61 at one month, 49 at six months, and 41 at 12 months. CRP levels and fatigue scores were not associated at one month (p = 0.88) or 12 months (p = 0.56), but weakly associated at six months (r = 0.27, p = 0.04); however, this association was no longer significant (p = 0.14) after controlling for the effects of covariates. The CRP level was not associated with the fulfilment of case definition of post-stroke fatigue at any time points (all p > 0.05). The CRP level at one month was not a significant predictor for fatigue levels at either six months (p = 0.93) or 12 months (p = 0.78). Conclusions There is insufficient evidence for the association between CRP and PSF in stroke patients. Future studies with larger sample sizes and controlling for potential confounders are needed to investigate whether this association exists.

Background Few strategies are effective for the treatment of acute ischaemic stroke. Buflomedil is a vasoactive agent that has been used for peripheral arterial diseases. Research studies have suggested that buflomedil may have beneficial effects in people with cerebral vascular diseases, including acute ischaemic stroke, however it has not been approved for treating stroke in clinical practice. Objectives To assess the efficacy and safety of buflomedil for the treatment of acute ischaemic stroke. Search methods We searched the Cochrane Stroke Group Trials Register (September 2014), the Cochrane Central Register of Controlled Trials (CENTRAL) (2014, Issue 4), MEDLINE (1950 to February 2014), EMBASE (1980 to February 2014), ProQuest Dissertations and Theses Database (July 2014), Web of Science (including Conference Proceedings Citation Index Science (CPCI-S)) (July 2014), and four Chinese databases (February 2014). We also searched five ongoing trials registers and reference lists of the included trials. Selection criteria We included randomised controlled trials (RCTs) that investigated the efficacy of buflomedil in people with acute ischaemic stroke. The primary outcome of this review was long-term death or disability/dependence. Other outcomes included short-term death, short-term disability, neurological deficits, and adverse events. We included trials comparing buflomedil versus a placebo control, trials comparing buflomedil plus usual medical care versus usual medical care alone, or those comparing buflomedil plus another intervention versus that intervention alone. We excluded trials comparing buflomedil alone with other potentially active intervention(s). Data collection and analysis Two review authors independently scrutinised citations, selected studies, extracted data and assessed risk of bias in the included trials. We reported risk ratios (RRs) for dichotomous data and standardised mean differences (SMDs) for continuous data. We performed meta-analysis, using a random-effects model, for death and improvement of neurological deficits. Data for disability/dependence and adverse events were not suitable for meta-analysis thus we reported these narratively. We performed subgroup analyses for time of recruitment since stroke, delivery route, daily dose, and treatment duration. Main results We included 26 trials (2756 participants), all conducted in China. All participants were inpatients within the first few days after stroke onset (mean age 58 to 75 years and male proportion 45% to 80%). Most trials delivered buflomedil intravenously, with a daily dose of 200 mg for 14 days. The study quality was generally poor and many trials were poorly reported.Only one trial reported long-term death and disability, where stroke survivors in the buflomedil group had a lower risk of suffering 'death or disability' than those in the control group (200 participants, RR 0.71, 95% confidence interval (CI) 0.53 to 0.94). All 26 trials assessed outcomes by the end of treatment (eight trials with 1056 participants reported death, one trial with 85 participants reported disability, and 26 trials with 2756 participants reported neurological deficits), but there was no robust evidence for any of these short-term outcomes. Seventeen trials (1899 participants) investigated the presence of adverse events during the treatment, of which six trials (853 participants) reported "no significant adverse event in any participants" and the other 11 trials (1046 participants) reported a total of 38 adverse events in the buflomedil group and two events in the control group. In general, for each of these outcomes the quality of evidence was low according to the GRADE principles. Authors' conclusions There is insufficient evidence on the efficacy or safety of buflomedil to support its use for the treatment of acute ischaemic stroke. Given these uncertainties, the data support the rationale for an adequately powered RCT of buflomedil in people with acute ischaemic stroke.

Background and aimPost-stroke fatigue (PSF) is common and distressing, but there is insufficient evidence to recommend any effective treatment for it. Psychological interventions are effective in treating fatigue in other conditions. This paper describes the development and evaluation of the feasibility of a psychological intervention for PSF.MethodsBased on psychological correlates of PSF and evidence-based psychological interventions for fatigue in other medical conditions, we developed a manualised psychological intervention for PSF, with input from stroke clinicians, psychological therapists, and stroke survivors. The intervention was delivered by a clinical psychologist to 12 participants with PSF to test its acceptability and feasibility. According to the feedback from participants and therapists, the intervention was refined for future use.ResultsThe intervention consisted of six individual, face-to-face treatment sessions, and one follow-up, telephone-delivered booster session. It included psycho-education and discussion of strategies to promote physical and social activities and to challenge unhelpful thoughts. Four participants dropped out and the remaining eight participants completed the intervention. These eight participants also completed all assessments and feedback and reported fatigue levels as lower at the end of the study than at the baseline. All participants reported favourable opinions on the intervention and suggested that the last two treatment sessions be combined and the booster session be delivered in person as opposed to telephone.ConclusionsThis psychological intervention was acceptable to stroke patients and was feasible in the local health service. These findings suggest that a randomised controlled trial to test efficacy is warranted.

To investigate the correlations of atheromatous plaques in the aortic arch or supra-aortic arteries with intracranial arterial stenosis and carotid plaques in stroke patients, and to determine whether taking these plaques into account will reduce the proportion of patients in the undetermined etiology group.We prospectively enrolled 308 ischemic stroke patients, whose clinical characteristics and A-S-C-O classifications were compared with analyses of intracranial arteries, carotid arteries, aortic arch, and supra-aortic arteries.125(40.6%) patients had plaques in the aortic arch or supra-aortic arteries, of which 106 (84.8%) had complex plaques. No correlations were observed between these plaques and carotid plaques ( p = 0.283) or intracranial arterial stenosis ( p = 0.097). After detecting the mobile thrombi in the aortic arch and supra-aortic arteries, the proportion of patients in the atherothrombosis group was increased from 33.8% to 55.5% ( p = 0.00), whereas the proportion of patients in stroke of undetermined etiology group was decreased from 19.2% to 11.0% ( p = 0.00).Examining only the carotid and intracranial arteries may not provide adequate information about large arteries in stroke patients. Therefore, it would be better to include a search for relevant plaques in the aortic arch or supra-aortic arteries in modern stroke workup, for it may lead to more accurate stroke subtype classification and guide secondary prevention.

Background Fatigue is a common and distressing symptom after stroke. Stroke survivors and health professionals need to know whether fatigue is likely to improve, or get worse over time; and whether there is a temporal association with depression or anxiety, which might provide a target for treatment, Aims and objectives To systematically review all longitudinal observational studies which have assessed fatigue on at least two separate time points after stroke onset to determine its frequency, natural history and temporal relationship with anxiety and/or depression. Method We systematically searched MEDLINE, EMBASE, CINAHL and PsychInfo using the keywords “fatigue” and “stroke” and their associated terms or synonyms. Data were extracted regarding time points after stroke where fatigue was assessed, frequency of fatigue at each time point and any reported associations with anxiety and/or depression. Results 101 full texts were retrieved after scrutinising the titles and abstracts. Nine fulfilled our inclusion criteria. Fatigue was assessed at a variety of time points after stroke (from admission—to 36 months). The frequency of fatigue ranged from 35%–92% at the first time point. Frequency of fatigue declined across time points in seven of the studies (n = 764) and increased in two studies (n = 195). Three papers found significant associations between fatigue and mood at the same time point. The single study investigating temporal associations between fatigue and mood disorders reported that depression predicted subsequent fatigue. Conclusions Fatigue is present soon after stroke onset and remains common in the longer term. There is little evidence regarding the temporal relationship between fatigue and mood: this is an area where further research is needed.

Objective To evaluate the effectiveness and safety of heat-killed M.vaccae added to chemotherapy of never-treated tuberculosis (TB) patients. Methods The databases of Medline, Embase, Biosis, Cochrane Central Register of Controlled Trials, SCI, CBM, VIP and CNKI were searched. Randomized controlled trials (RCT) and Controlled clinical trials (CCT) comparing M.vaccae with or without a placebo-control injection as adjuvant therapy in the chemotherapy of never-treated TB patients were included. Two reviewers independently performed data extraction and quality assessment. Data were analyzed using RevMan 5.0 software by The Cochrane Collaboration. Results Fifty four studies were included. At the end of the follow-up period, Pooled RR (Risk Ratio) and its 95% CI of sputum smear conversion rate were 1.07 (1.04, 1.10) in TB patients without complications, 1.17 (0.92, 1.49) in TB patients with diabetes mellitus, 1.02 (0.94, 1.10) in TB patients with hepatitis B, and 1.46 (0.21, 10.06) in TB patients with pneumosilicosis. In elderly TB patients the RR was 1.22 (1.13, 1.32). Analysis of each time point during the follow-up period showed that M.vaccae could help to improve the removal of acid-fast bacilli from the sputum, and promote improvement of radiological focal lesions and cavity closure. Compared with the control group, the differences in levels of immunological indicators of Th1 such as IL-2 and TNF-α were not statistical significant (P = 0.65 and 0.31 respectively), and neither was that of IL-6 produced by Th2 (P = 0.52). An effect of M.vaccae of prevention of liver damage was found in TB patients with hepatitis B (RR 0.20 and 95% CI (0.12, 0.33). No systemic adverse events were reported. Conclusion Added to chemotherapy, M.vaccae is helpful in the treatment of never-treated TB patients in terms of improving both sputum conversion and X-ray appearances.

BackgroundAlteplase improves functional outcomes of patients with acute ischaemic stroke, but its effects on symptomatic infarct swelling, an adverse complication of stroke and the influence of CT hyperdense artery sign (HAS) are unclear. This substudy of the Third International Stroke Trial aimed to investigate the association between HAS and symptomatic infarct swelling and effect of intravenous alteplase on this association.MethodsWe included stroke patients whose prerandomisation scan was non-contrast CT. Raters, masked to clinical information, assessed baseline (prerandomisation) and follow-up (24–48 hours postrandomisation) CT scans for HAS, defined as an intracranial artery appearing denser than contralateral arteries. Symptomatic infarct swelling was defined as clinically significant neurological deterioration ≤7 days after stroke with radiological evidence of midline shift, effacement of basal cisterns or uncal herniation.ResultsAmong 2961 patients, HAS presence at baseline was associated with higher risk of symptomatic infarct swelling (OR 2.21; 95% CI 1.42 to 3.44). Alteplase increased the risk of swelling (OR 1.69; 95% CI 1.11 to 2.57), with no difference between patients with and those without baseline HAS (p=0.49). In patients with baseline HAS, alteplase reduced the proportion with HAS at follow-up (OR 0.67; 95% CI 0.50 to 0.91), where HAS disappearance was associated with reduced risk of swelling (OR 0.25, 95% CI 0.14 to 0.47).ConclusionAlthough alteplase was associated with increased risk of symptomatic infarct swelling in patients with or without baseline HAS, it was also associated with accelerated clearance of HAS, which in return reduced swelling, providing further mechanistic insights to underpin the benefits of alteplase.