Displaying publications 1 - 20 of 41 in total

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  1. Sprigg N, Flaherty K, Appleton JP, Al-Shahi Salman R, Bereczki D, Beridze M, et al.
    Health Technol Assess, 2019 07;23(35):1-48.
    PMID: 31322116 DOI: 10.3310/hta23350
    BACKGROUND: Tranexamic acid reduces death due to bleeding after trauma and postpartum haemorrhage.

    OBJECTIVE: The aim of the study was to assess if tranexamic acid is safe, reduces haematoma expansion and improves outcomes in adults with spontaneous intracerebral haemorrhage (ICH).

    DESIGN: The TICH-2 (Tranexamic acid for hyperacute primary IntraCerebral Haemorrhage) study was a pragmatic, Phase III, prospective, double-blind, randomised placebo-controlled trial.

    SETTING: Acute stroke services at 124 hospitals in 12 countries (Denmark, Georgia, Hungary, Ireland, Italy, Malaysia, Poland, Spain, Sweden, Switzerland, Turkey and the UK).

    PARTICIPANTS: Adult patients (aged ≥ 18 years) with ICH within 8 hours of onset.

    EXCLUSION CRITERIA: Exclusion criteria were ICH secondary to anticoagulation, thrombolysis, trauma or a known underlying structural abnormality; patients for whom tranexamic acid was thought to be contraindicated; prestroke dependence (i.e. patients with a modified Rankin Scale [mRS] score > 4); life expectancy  4.5 hours after stroke onset. Pragmatic inclusion criteria led to a heterogeneous population of participants, some of whom had very large strokes. Although 12 countries enrolled participants, the majority (82.1%) were from the UK.

    CONCLUSIONS: Tranexamic acid did not affect a patient's functional status at 90 days after ICH, despite there being significant modest reductions in early death (by 7 days), haematoma expansion and SAEs, which is consistent with an antifibrinolytic effect. Tranexamic acid was safe, with no increase in thromboembolic events.

    FUTURE WORK: Future work should focus on enrolling and treating patients early after stroke and identify which participants are most likely to benefit from haemostatic therapy. Large randomised trials are needed.

    TRIAL REGISTRATION: Current Controlled Trials ISRCTN93732214.

    FUNDING: This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 35. See the NIHR Journals Library website for further project information. The project was also funded by the Pragmatic Trials, UK, funding call and the Swiss Heart Foundation in Switzerland.

  2. Law ZK, Desborough M, Roberts I, Al-Shahi Salman R, England TJ, Werring DJ, et al.
    J Am Heart Assoc, 2021 02;10(5):e019130.
    PMID: 33586453 DOI: 10.1161/JAHA.120.019130
    Background Antiplatelet therapy increases the risk of hematoma expansion in intracerebral hemorrhage (ICH) while the effect on functional outcome is uncertain. Methods and Results This is an exploratory analysis of the TICH-2 (Tranexamic Acid in Intracerebral Hemorrhage-2) double-blind, randomized, placebo-controlled trial, which studied the efficacy of tranexamic acid in patients with spontaneous ICH within 8 hours of onset. Multivariable logistic regression and ordinal regression were performed to explore the relationship between pre-ICH antiplatelet therapy, and 24-hour hematoma expansion and day 90 modified Rankin Scale score, as well as the effect of tranexamic acid. Of 2325 patients, 611 (26.3%) had pre-ICH antiplatelet therapy. They were older (mean age, 75.7 versus 66.5 years), more likely to have ischemic heart disease (25.4% versus 2.7%), ischemic stroke (36.2% versus 6.3%), intraventricular hemorrhage (40.2% versus 27.5%), and larger baseline hematoma volume (mean, 28.1 versus 22.6 mL) than the no-antiplatelet group. Pre-ICH antiplatelet therapy was associated with a significantly increased risk of hematoma expansion (adjusted odds ratio [OR], 1.28; 95% CI, 1.01-1.63), a shift toward unfavorable outcome in modified Rankin Scale (adjusted common OR, 1.58; 95% CI, 1.32-1.91) and a higher risk of death at day 90 (adjusted OR, 1.63; 95% CI, 1.25-2.11). Tranexamic acid reduced the risk of hematoma expansion in the overall patients with ICH (adjusted OR, 0.76; 95% CI, 0.62-0.93) and antiplatelet subgroup (adjusted OR, 0.61; 95% CI, 0.41-0.91) with no significant interaction between pre-ICH antiplatelet therapy and tranexamic acid (P interaction=0.248). Conclusions Antiplatelet therapy is independently associated with hematoma expansion and unfavorable functional outcome. Tranexamic acid reduced hematoma expansion regardless of prior antiplatelet therapy use. Registration URL: https://www.isrctn.com; Unique identifier: ISRCTN93732214.
  3. Moullaali TJ, Wang X, Sandset EC, Woodhouse LJ, Law ZK, Arima H, et al.
    J Neurol Neurosurg Psychiatry, 2022 01;93(1):6-13.
    PMID: 34732465 DOI: 10.1136/jnnp-2021-327195
    OBJECTIVE: To summarise evidence of the effects of blood pressure (BP)-lowering interventions after acute spontaneous intracerebral haemorrhage (ICH).

    METHODS: A prespecified systematic review of the Cochrane Central Register of Controlled Trials, EMBASE and MEDLINE databases from inception to 23 June 2020 to identify randomised controlled trials that compared active BP-lowering agents versus placebo or intensive versus guideline BP-lowering targets for adults <7 days after ICH onset. The primary outcome was function (distribution of scores on the modified Rankin scale) 90 days after randomisation. Radiological outcomes were absolute (>6 mL) and proportional (>33%) haematoma growth at 24 hours. Meta-analysis used a one-stage approach, adjusted using generalised linear mixed models with prespecified covariables and trial as a random effect.

    RESULTS: Of 7094 studies identified, 50 trials involving 11 494 patients were eligible and 16 (32.0%) shared patient-level data from 6221 (54.1%) patients (mean age 64.2 [SD 12.9], 2266 [36.4%] females) with a median time from symptom onset to randomisation of 3.8 hours (IQR 2.6-5.3). Active/intensive BP-lowering interventions had no effect on the primary outcome compared with placebo/guideline treatment (adjusted OR for unfavourable shift in modified Rankin scale scores: 0.97, 95% CI 0.88 to 1.06; p=0.50), but there was significant heterogeneity by strategy (pinteraction=0.031) and agent (pinteraction<0.0001). Active/intensive BP-lowering interventions clearly reduced absolute (>6 ml, adjusted OR 0.75, 95%CI 0.60 to 0.92; p=0.0077) and relative (≥33%, adjusted OR 0.82, 95%CI 0.68 to 0.99; p=0.034) haematoma growth.

    INTERPRETATION: Overall, a broad range of interventions to lower BP within 7 days of ICH onset had no overall benefit on functional recovery, despite reducing bleeding. The treatment effect appeared to vary according to strategy and agent.

    PROSPERO REGISTRATION NUMBER: CRD42019141136.

  4. Wang X, Yang J, Moullaali TJ, Sandset EC, Woodhouse LJ, Law ZK, et al.
    Stroke, 2024 Feb 27.
    PMID: 38410986 DOI: 10.1161/STROKEAHA.123.044358
    OBJECTIVE: To investigate whether an earlier time to achieving and maintaining systolic blood pressure (SBP) at 120 to 140 mm Hg is associated with favorable outcomes in a cohort of patients with acute intracerebral hemorrhage.

    METHODS: We pooled individual patient data from randomized controlled trials registered in the Blood Pressure in Acute Stroke Collaboration. Time was defined as time form symptom onset plus the time (hour) to first achieve and subsequently maintain SBP at 120 to 140 mm Hg over 24 hours. The primary outcome was functional status measured by the modified Rankin Scale at 90 to 180 days. A generalized linear mixed models was used, with adjustment for covariables and trial as a random effect.

    RESULTS: A total of 5761 patients (mean age, 64.0 [SD, 13.0], 2120 [36.8%] females) were included in analyses. Earlier SBP control was associated with better functional outcomes (modified Rankin Scale score, 3-6; odds ratio, 0.98 [95% CI, 0.97-0.99]) and a significant lower risk of hematoma expansion (0.98, 0.96-1.00). This association was stronger in patients with bigger baseline hematoma volume (>10 mL) compared with those with baseline hematoma volume ≤10 mL (0.006 for interaction). Earlier SBP control was not associated with cardiac or renal adverse events.

    CONCLUSIONS: Our study confirms a clear time relation between early versus later SBP control (120-140 mm Hg) and outcomes in the one-third of patients with intracerebral hemorrhage who attained sustained SBP levels within this range. These data provide further support for the value of early recognition, rapid transport, and prompt initiation of treatment of patients with intracerebral hemorrhage.

  5. Law ZK, Appleton JP, Scutt P, Roberts I, Al-Shahi Salman R, England TJ, et al.
    Stroke, 2022 Apr;53(4):1141-1148.
    PMID: 34847710 DOI: 10.1161/STROKEAHA.121.035191
    BACKGROUND: Seeking consent rapidly in acute stroke trials is crucial as interventions are time sensitive. We explored the association between consent pathways and time to enrollment in the TICH-2 (Tranexamic Acid in Intracerebral Haemorrhage-2) randomized controlled trial.

    METHODS: Consent was provided by patients or by a relative or an independent doctor in incapacitated patients, using a 1-stage (full written consent) or 2-stage (initial brief consent followed by full written consent post-randomization) approach. The computed tomography-to-randomization time according to consent pathways was compared using the Kruskal-Wallis test. Multivariable logistic regression was performed to identify variables associated with onset-to-randomization time of ≤3 hours.

    RESULTS: Of 2325 patients, 817 (35%) gave self-consent using 1-stage (557; 68%) or 2-stage consent (260; 32%). For 1507 (65%), consent was provided by a relative (1 stage, 996 [66%]; 2 stage, 323 [21%]) or a doctor (all 2-stage, 188 [12%]). One patient did not record prerandomization consent, with written consent obtained subsequently. The median (interquartile range) computed tomography-to-randomization time was 55 (38-93) minutes for doctor consent, 55 (37-95) minutes for 2-stage patient, 69 (43-110) minutes for 2-stage relative, 75 (48-124) minutes for 1-stage patient, and 90 (56-155) minutes for 1-stage relative consents (P<0.001). Two-stage consent was associated with onset-to-randomization time of ≤3 hours compared with 1-stage consent (adjusted odds ratio, 1.9 [95% CI, 1.5-2.4]). Doctor consent increased the odds (adjusted odds ratio, 2.3 [1.5-3.5]) while relative consent reduced the odds of randomization ≤3 hours (adjusted odds ratio, 0.10 [0.03-0.34]) compared with patient consent. Only 2 of 771 patients (0.3%) in the 2-stage pathways withdrew consent when full consent was sought later. Two-stage consent process did not result in higher withdrawal rates or loss to follow-up.

    CONCLUSIONS: The use of initial brief consent was associated with shorter times to enrollment, while maintaining good participant retention. Seeking written consent from relatives was associated with significant delays.

    REGISTRATION: URL: https://www.isrctn.com; Unique identifier: ISRCTN93732214.

  6. Sprigg N, Flaherty K, Appleton JP, Al-Shahi Salman R, Bereczki D, Beridze M, et al.
    Lancet, 2018 May 26;391(10135):2107-2115.
    PMID: 29778325 DOI: 10.1016/S0140-6736(18)31033-X
    BACKGROUND: Tranexamic acid can prevent death due to bleeding after trauma and post-partum haemorrhage. We aimed to assess whether tranexamic acid reduces haematoma expansion and improves outcome in adults with stroke due to intracerebral haemorrhage.

    METHODS: We did an international, randomised placebo-controlled trial in adults with intracerebral haemorrhage from acute stroke units at 124 hospital sites in 12 countries. Participants were randomly assigned (1:1) to receive 1 g intravenous tranexamic acid bolus followed by an 8 h infusion of 1 g tranexamic acid or a matching placebo, within 8 h of symptom onset. Randomisation was done centrally in real time via a secure website, with stratification by country and minimisation on key prognostic factors. Treatment allocation was concealed from patients, outcome assessors, and all other health-care workers involved in the trial. The primary outcome was functional status at day 90, measured by shift in the modified Rankin Scale, using ordinal logistic regression with adjustment for stratification and minimisation criteria. All analyses were done on an intention-to-treat basis. This trial is registered with the ISRCTN registry, number ISRCTN93732214.

    FINDINGS: We recruited 2325 participants between March 1, 2013, and Sept 30, 2017. 1161 patients received tranexamic acid and 1164 received placebo; the treatment groups were well balanced at baseline. The primary outcome was assessed for 2307 (99%) participants. The primary outcome, functional status at day 90, did not differ significantly between the groups (adjusted odds ratio [aOR] 0·88, 95% CI 0·76-1·03, p=0·11). Although there were fewer deaths by day 7 in the tranexamic acid group (101 [9%] deaths in the tranexamic acid group vs 123 [11%] deaths in the placebo group; aOR 0·73, 0·53-0·99, p=0·0406), there was no difference in case fatality at 90 days (250 [22%] vs 249 [21%]; adjusted hazard ratio 0·92, 95% CI 0·77-1·10, p=0·37). Fewer patients had serious adverse events after tranexamic acid than after placebo by days 2 (379 [33%] patients vs 417 [36%] patients), 7 (456 [39%] vs 497 [43%]), and 90 (521 [45%] vs 556 [48%]).

    INTERPRETATION: Functional status 90 days after intracerebral haemorrhage did not differ significantly between patients who received tranexamic acid and those who received placebo, despite a reduction in early deaths and serious adverse events. Larger randomised trials are needed to confirm or refute a clinically significant treatment effect.

    FUNDING: National Institute of Health Research Health Technology Assessment Programme and Swiss Heart Foundation.

  7. Appleton JP, Law ZK, Woodhouse LJ, Al-Shahi Salman R, Beridze M, Christensen H, et al.
    BMJ Neurol Open, 2023;5(1):e000423.
    PMID: 37337529 DOI: 10.1136/bmjno-2023-000423
    BACKGROUND: Tranexamic acid reduced haematoma expansion and early death, but did not improve functional outcome in the tranexamic acid for hyperacute spontaneous intracerebral haemorrhage-2 (TICH-2) trial. In a predefined subgroup, there was a statistically significant interaction between prerandomisation baseline systolic blood pressure (SBP) and the effect of tranexamic acid on functional outcome (p=0.019).

    METHODS: TICH-2 was an international prospective double-blind placebo-controlled randomised trial evaluating intravenous tranexamic acid in patients with acute spontaneous intracerebral haemorrhage (ICH). Prerandomisation baseline SBP was split into predefined ≤170 and >170 mm Hg groups. The primary outcome at day 90 was the modified Rankin Scale (mRS), a measure of dependency, analysed using ordinal logistic regression. Haematoma expansion was defined as an increase in haematoma volume of >33% or >6 mL from baseline to 24 hours. Data are OR or common OR (cOR) with 95% CIs, with significance at p<0.05.

    RESULTS: Of 2325 participants in TICH-2, 1152 had baseline SBP≤170 mm Hg and were older, had larger lobar haematomas and were randomised later than 1173 with baseline SBP>170 mm Hg. Tranexamic acid was associated with a favourable shift in mRS at day 90 in those with baseline SBP≤170 mm Hg (cOR 0.73, 95% CI 0.59 to 0.91, p=0.005), but not in those with baseline SBP>170 mm Hg (cOR 1.05, 95% CI 0.85 to 1.30, p=0.63). In those with baseline SBP≤170 mm Hg, tranexamic acid reduced haematoma expansion (OR 0.62, 95% CI 0.47 to 0.82, p=0.001), but not in those with baseline SBP>170 mm Hg (OR 1.02, 95% CI 0.77 to 1.35, p=0.90).

    CONCLUSIONS: Tranexamic acid was associated with improved clinical and radiological outcomes in ICH patients with baseline SBP≤170 mm Hg. Further research is needed to establish whether certain subgroups may benefit from tranexamic acid in acute ICH.

    TRIAL REGISTRATION NUMBER: ISRCTN93732214.

  8. Blair GW, Appleton JP, Flaherty K, Doubal F, Sprigg N, Dooley R, et al.
    EClinicalMedicine, 2019 04 24;11:34-43.
    PMID: 31317131 DOI: 10.1016/j.eclinm.2019.04.001
    Background: Lacunar stroke, a frequent clinical manifestation of small vessel disease (SVD), differs pathologically from other ischaemic stroke subtypes and has no specific long-term secondary prevention. Licenced drugs, isosorbide mononitrate (ISMN) and cilostazol, have relevant actions to prevent SVD progression.

    Methods: We recruited independent patients with clinically confirmed lacunar ischaemic stroke without cognitive impairment to a prospective randomised clinical trial, LACunar Intervention-1 (LACI-1). We randomised patients using a central web-based system, 1:1:1:1 with minimisation, to masked ISMN 25 mg bd, cilostazol 100 mg bd, both ISMN and cilostazol started immediately, or both with start delayed. We escalated doses to target over two weeks, sustained for eight weeks. Primary outcome was the proportion achieving target dose. Secondary outcomes included symptoms, safety (haemorrhage, recurrent vascular events), cognition, haematology, vascular function, and neuroimaging. LACI-1 was powered (80%, alpha 0.05) to detect 35% (90% versus 55%) difference between the proportion reaching target dose on one versus both drugs at 55 patients. Registration ISRCTN12580546.

    Findings: LACI-1 enrolled 57 participants between March 2016 and August 2017: 18 (32%) females, mean age 66 (SD 11, range 40-85) years, onset-randomisation 203 (range 6-920) days. Most achieved full (64%) or over half (87%) dose, with no difference between cilostazol vs ISMN, single vs dual drugs. Headache and palpitations increased initially then declined similarly with dual versus single drugs. There was no between-group difference in BP, pulse-wave velocity, haemoglobin or platelet function, but pulse rate was higher (mean difference, MD, 6.4, 95%CI 1.2-11.7, p = 0.02), platelet count higher (MD 35.7, 95%CI 2.8, 68.7, p = 0.03) and white matter hyperintensities reduced more (Chi-square p = 0.007) with cilostazol versus no cilostazol.

    Interpretation: Cilostazol and ISMN are well tolerated when the dose is escalated, without safety concerns, in patients with lacunar stroke. Larger trials with longer term follow-up are justified.

    Funding: Alzheimer's Society (AS-PG-14-033).

  9. Law ZK, Ali A, Krishnan K, Bischoff A, Appleton JP, Scutt P, et al.
    Stroke, 2020 01;51(1):121-128.
    PMID: 31735141 DOI: 10.1161/STROKEAHA.119.026128
    Background and Purpose- Blend, black hole, island signs, and hypodensities are reported to predict hematoma expansion in acute intracerebral hemorrhage. We explored the value of these noncontrast computed tomography signs in predicting hematoma expansion and functional outcome in our cohort of intracerebral hemorrhage. Methods- The TICH-2 (Tranexamic acid for IntraCerebral Hemorrhage-2) was a prospective randomized controlled trial exploring the efficacy and safety of tranexamic acid in acute intracerebral hemorrhage. Baseline and 24-hour computed tomography scans of trial participants were analyzed. Hematoma expansion was defined as an increase in hematoma volume of >33% or >6 mL on 24-hour computed tomography. Poor functional outcome was defined as modified Rankin Scale of 4 to 6 at day 90. Multivariable logistic regression was performed to identify predictors of hematoma expansion and poor functional outcome. Results- Of 2325 patients recruited, 2077 (89.3%) had valid baseline and 24-hour scans. Five hundred seventy patients (27.4%) had hematoma expansion while 1259 patients (54.6%) had poor functional outcome. The prevalence of noncontrast computed tomography signs was blend sign, 366 (16.1%); black hole sign, 414 (18.2%); island sign, 200 (8.8%); and hypodensities, 701 (30.2%). Blend sign (adjusted odds ratio [aOR] 1.53 [95% CI, 1.16-2.03]; P=0.003), black hole (aOR, 2.03 [1.34-3.08]; P=0.001), and hypodensities (aOR, 2.06 [1.48-2.89]; P<0.001) were independent predictors of hematoma expansion on multivariable analysis with adjustment for covariates. Black hole sign (aOR, 1.52 [1.10-2.11]; P=0.012), hypodensities (aOR, 1.37 [1.05-1.78]; P=0.019), and island sign (aOR, 2.59 [1.21-5.55]; P=0.014) were significant predictors of poor functional outcome. Tranexamic acid reduced the risk of hematoma expansion (aOR, 0.77 [0.63-0.94]; P=0.010), but there was no significant interaction between the presence of noncontrast computed tomography signs and benefit of tranexamic acid on hematoma expansion and functional outcome (P interaction all >0.05). Conclusions- Blend sign, black hole sign, and hypodensities predict hematoma expansion while black hole sign, hypodensities, and island signs predict poor functional outcome. Noncontrast computed tomography signs did not predict a better response to tranexamic acid. Clinical Trial Registration- URL: https://www.isrctn.com. Unique identifier: ISRCTN93732214.
  10. Law ZK, Tan HJ, Chin SP, Wong CY, Wan Yahya WNN, Muda AS, et al.
    Cytotherapy, 2021 Sep;23(9):833-840.
    PMID: 33992536 DOI: 10.1016/j.jcyt.2021.03.005
    BACKGROUND AIMS: Mesenchymal stromal cells (MSCs) are characterized by paracrine and immunomodulatory functions capable of changing the microenvironment of damaged brain tissue toward a more regenerative and less inflammatory milieu. The authors conducted a phase 2, single-center, assessor-blinded randomized controlled trial to investigate the safety and efficacy of intravenous autologous bone marrow-derived MSCs (BMMSCs) in patients with subacute middle cerebral artery (MCA) infarct.

    METHODS: Patients aged 30-75 years who had severe ischemic stroke (National Institutes of Health Stroke Scale [NIHSS] score of 10-35) involving the MCA territory were recruited within 2 months of stroke onset. Using permuted block randomization, patients were assigned to receive 2 million BMMSCs per kilogram of body weight (treatment group) or standard medical care (control group). The primary outcomes were the NIHSS, modified Rankin Scale (mRS), Barthel Index (BI) and total infarct volume on brain magnetic resonance imaging (MRI) at 12 months. All outcome assessments were performed by blinded assessors. Per protocol, analyses were performed for between-group comparisons.

    RESULTS: Seventeen patients were recruited. Nine were assigned to the treatment group, and eight were controls. All patients were severely disabled following their MCA infarct (median mRS = 4.0 [4.0-5.0], BI = 5.0 [5.0-25.0], NIHSS = 16.0 [11.5-21.0]). The baseline infarct volume on the MRI was larger in the treatment group (median, 71.7 [30.5-101.7] mL versus 26.7 [12.9-75.3] mL, P = 0.10). There were no between-group differences in median NIHSS score (7.0 versus 6.0, P = 0.96), mRS (2.0 versus 3.0, P = 0.38) or BI (95.0 versus 67.5, P = 0.33) at 12 months. At 12 months, there was significant improvement in absolute change in median infarct volume, but not in total infarct volume, from baseline in the treatment group (P = 0.027). No treatment-related adverse effects occurred in the BMMSC group.

    CONCLUSIONS: Intravenous infusion of BMMSCs in patients with subacute MCA infarct was safe and well tolerated. Although there was no neurological recovery or functional outcome improvement at 12 months, there was improvement in absolute change in median infarct volume in the treatment group. Larger, well-designed studies are warranted to confirm this and the efficacy of BMMSCs in ischemic stroke.

  11. Ramli K, Aminath Gasim I, Ahmad AA, Hassan S, Law ZK, Tan GC, et al.
    Cell Biol Int, 2019 Mar;43(3):233-252.
    PMID: 30362196 DOI: 10.1002/cbin.11067
    In peripheral nerve injuries, Schwann cells (SC) play pivotal roles in regenerating damaged nerve. However, the use of SC in clinical cell-based therapy is hampered due to its limited availability. In this study, we aim to evaluate the effectiveness of using an established induction protocol for human bone marrow derived-MSC (hBM-MSCs) transdifferentiation into a SC lineage. A relatively homogenous culture of hBM-MSCs was first established after serial passaging (P3), with profiles conforming to the minimal criteria set by International Society for Cellular Therapy (ISCT). The cultures (n = 3) were then subjected to a series of induction media containing β-mercaptoethanol, retinoic acid, and growth factors. Quantitative RT-PCR, flow cytometry, and immunocytochemistry analyses were performed to quantify the expression of specific SC markers, that is, S100, GFAP, MPZ and p75 NGFR, in both undifferentiated and transdifferentiated hBM-MSCs. Based on these analyses, all markers were expressed in undifferentiated hBM-MSCs and MPZ expression (mRNA transcripts) was consistently detected before and after transdifferentiation across all samples. There was upregulation at the transcript level of more than twofolds for NGF, MPB, GDNF, p75 NGFR post-transdifferentiation. This study highlights the existence of spontaneous expression of specific SC markers in cultured hBM-MSCs, inter-donor variability and that MSC transdifferentiation is a heterogenous process. These findings strongly oppose the use of a single marker to indicate SC fate. The heterogenous nature of MSC may influence the efficiency of SC transdifferentiation protocols. Therefore, there is an urgent need to re-define the MSC subpopulations and revise the minimal criteria for MSC identification.
  12. Ramli K, Gasim AI, Ahmad AA, Htwe O, Mohamed Haflah NH, Law ZK, et al.
    Tissue Eng Part A, 2019 10;25(19-20):1438-1455.
    PMID: 30848172 DOI: 10.1089/ten.TEA.2018.0279
    We investigated the efficacy of a muscle-stuffed vein (MSV) seeded with neural-transdifferentiated human mesenchymal stem cells as an alternative nerve conduit to repair a 15-mm sciatic nerve defect in athymic rats. Other rats received MSV conduit alone, commercial polyglycolic acid conduit (Neurotube®), reverse autograft, or were left untreated. Motor and sensory functions as well as nerve conductivity were evaluated for 12 weeks, after which the grafts were harvested for histological analyses. All rats in the treatment groups demonstrated a progressive increase in the mean Sciatic Functional Index (motor function) and nerve conduction amplitude (electrophysiological function) and showed positive withdrawal reflex (sensory function) by the 10th week of postimplantation. Autotomy, which is associated with neuropathic pain, was severe in rats treated with conduit without cells; there was mild or no autotomy in the rats of other groups. Histologically, harvested grafts from all except the untreated groups exhibited axonal regeneration with the presence of mature myelinated axons. In conclusion, treatment with MSV conduit is comparable to that of other treatment groups in supporting functional recovery following sciatic nerve injury; and the addition of cells in the conduit alleviates neuropathic pain. Impact Statement It is shown that pretreated muscle-stuffed vein conduit is comparable to that of commercial nerve conduit and autograft in supporting functional recovery following peripheral nerve injury. The addition of neural-differentiated mesenchymal stem cells in the conduit is shown to alleviate neuropathic pain.
  13. Blair GW, Appleton JP, Law ZK, Doubal F, Flaherty K, Dooley R, et al.
    Int J Stroke, 2018 07;13(5):530-538.
    PMID: 28906205 DOI: 10.1177/1747493017731947
    Rationale The pathophysiology of most lacunar stroke, a form of small vessel disease, is thought to differ from large artery atherothrombo- or cardio-embolic stroke. Licensed drugs, isosorbide mononitrate and cilostazol, have promising mechanisms of action to support their testing to prevent stroke recurrence, cognitive impairment, or radiological progression after lacunar stroke. Aim LACI-1 will assess the tolerability, safety, and efficacy, by dose, of isosorbide mononitrate and cilostazol, alone and in combination, in patients with ischemic lacunar stroke. Sample size A sample of 60 provides 80+% power (significance 0.05) to detect a difference of 35% (90% versus 55%) between those reaching target dose on one versus both drugs. Methods and design LACI-1 is a phase IIa partial factorial, dose-escalation, prospective, randomized, open label, blinded endpoint trial. Participants are randomized to isosorbide mononitrate and/or cilostazol for 11 weeks with dose escalation to target as tolerated in two centers (Edinburgh, Nottingham). At three visits, tolerability, safety, blood pressure, pulse wave velocity, and platelet function are assessed, plus magnetic resonance imaging to assess cerebrovascular reactivity in a subgroup. Study outcomes Primary: proportion of patients completing study achieving target maximum dose. Secondary symptoms whilst taking medications; safety (hemorrhage, recurrent vascular events, falls); blood pressure, platelet function, arterial stiffness, and cerebrovascular reactivity. Discussion This study will inform the design of a larger phase III trial of isosorbide mononitrate and cilostazol in lacunar stroke, whilst providing data on the drugs' effects on vascular and platelet function. Trial registration ISRCTN (ISRCTN12580546) and EudraCT (2015-001953-33).
  14. Tan HJ, Goh CH, Khoo CS, Ng CF, Tan JK, Wan Zaidi WA, et al.
    Neurol Clin Neurosci, 2023 Jan;11(1):17-26.
    PMID: 36714457 DOI: 10.1111/ncn3.12677
    BACKGROUND: Neurological involvement associated with SARS-CoV-2 infection has been reported from different regions of the world. However, data from South East Asia are scarce. We described the neurological manifestations and their associated factors among the hospitalized COVID-19 patients from an academic tertiary hospital in Malaysia.

    METHODS: A cross-sectional observational study of hospitalized COVID-19 patients was conducted. The neurological manifestations were divided into the self-reported central nervous system (CNS) symptoms, stroke associated symptoms, symptoms of encephalitis or encephalopathy and specific neurological complications. Multiple logistic regression was performed using demographic and clinical variables to determine the factors associated with outcome.

    RESULTS: Of 156 hospitalized COVID-19 patients with mean age of 55.88 ± 6.11 (SD) years, 23.7% developed neurological complications, which included stroke, encephalitis and encephalopathy. Patients with neurological complications were more likely to have diabetes mellitus (p = 0.033), symptoms of stroke [limb weakness (p 

  15. Seiffge DJ, Polymeris AA, Law ZK, Krishnan K, Zietz A, Thilemann S, et al.
    Ann Neurol, 2022 Dec;92(6):921-930.
    PMID: 36054211 DOI: 10.1002/ana.26481
    OBJECTIVE: We assessed whether hematoma expansion (HE) and favorable outcome differ according to type of intracerebral hemorrhage (ICH).

    METHODS: Among participants with ICH enrolled in the TICH-2 (Tranexamic Acid for Hyperacute Primary Intracerebral Haemorrhage) trial, we assessed baseline scans for hematoma location and presence of cerebral amyloid angiopathy (CAA) using computed tomography (CT, simplified Edinburgh criteria) and magnetic resonance imaging (MRI; Boston criteria) and categorized ICH as lobar CAA, lobar non-CAA, and nonlobar. The main outcomes were HE and favorable functional outcome. We constructed multivariate regression models and assessed treatment effects using interaction terms.

    RESULTS: A total of 2,298 out of 2,325 participants were included with available CT (98.8%; median age = 71 years, interquartile range = 60-80 years; 1,014 female). Additional MRI was available in 219 patients (9.5%). Overall, 1,637 participants (71.2%) had nonlobar ICH; the remaining 661 participants (28.8%) had lobar ICH, of whom 202 patients had lobar CAA-ICH (8.8%, 173 participants according to Edinburgh and 29 participants according to Boston criteria) and 459 did not (lobar non-CAA, 20.0%). For HE, we found a significant interaction of lobar CAA ICH with time from onset to randomization (increasing risk with time, pinteraction  

  16. Pszczolkowski S, Sprigg N, Woodhouse LJ, Gallagher R, Swienton D, Law ZK, et al.
    JAMA Neurol, 2022 May 01;79(5):468-477.
    PMID: 35311937 DOI: 10.1001/jamaneurol.2022.0217
    IMPORTANCE: Hyperintense foci on diffusion-weighted imaging (DWI) that are spatially remote from the acute hematoma occur in 20% of people with acute spontaneous intracerebral hemorrhage (ICH). Tranexamic acid, a hemostatic agent that is under investigation for treating acute ICH, might increase DWI hyperintense lesions (DWIHLs).

    OBJECTIVE: To establish whether tranexamic acid compared with placebo increased the prevalence or number of remote cerebral DWIHLs within 2 weeks of ICH onset.

    DESIGN, SETTING, AND PARTICIPANTS: This prospective nested magnetic resonance imaging (MRI) substudy of a randomized clinical trial (RCT) recruited participants from the multicenter, double-blind, placebo-controlled, phase 3 RCT (Tranexamic Acid for Hyperacute Primary Intracerebral Hemorrhage [TICH-2]) from July 1, 2015, to September 30, 2017, and conducted follow-up to 90 days after participants were randomized to either the tranexamic acid or placebo group. Participants had acute spontaneous ICH and included TICH-2 participants who provided consent to undergo additional MRI scans for the MRI substudy and those who had clinical MRI data that were compatible with the brain MRI protocol of the substudy. Data analyses were performed on an intention-to-treat basis on January 20, 2020.

    INTERVENTIONS: The tranexamic acid group received 1 g in 100-mL intravenous bolus loading dose, followed by 1 g in 250-mL infusion within 8 hours of ICH onset. The placebo group received 0.9% saline within 8 hours of ICH onset. Brain MRI scans, including DWI, were performed within 2 weeks.

    MAIN OUTCOMES AND MEASURES: Prevalence and number of remote DWIHLs were compared between the treatment groups using binary logistic regression adjusted for baseline covariates.

    RESULTS: A total of 219 participants (mean [SD] age, 65.1 [13.8] years; 126 men [57.5%]) who had brain MRI data were included. Of these participants, 96 (43.8%) were randomized to receive tranexamic acid and 123 (56.2%) were randomized to receive placebo. No baseline differences in demographic characteristics and clinical or imaging features were found between the groups. There was no increase for the tranexamic acid group compared with the placebo group in DWIHL prevalence (20 of 96 [20.8%] vs 28 of 123 [22.8%]; odds ratio [OR], 0.71; 95% CI, 0.33-1.53; P = .39) or mean (SD) number of DWIHLs (1.75 [1.45] vs 1.81 [1.71]; mean difference [MD], -0.08; 95% CI, -0.36 to 0.20; P = .59). In an exploratory analysis, participants who were randomized within 3 hours of ICH onset or those with chronic infarcts appeared less likely to have DWIHLs if they received tranexamic acid. Participants with probable cerebral amyloid angiopathy appeared more likely to have DWIHLs if they received tranexamic acid.

    CONCLUSIONS AND RELEVANCE: This substudy of an RCT found no evidence of increased prevalence or number of remote DWIHLs after tranexamic acid treatment in acute ICH. These findings provide reassurance for ongoing and future trials that tranexamic acid for acute ICH is unlikely to induce cerebral ischemic events.

    TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN93732214.

  17. Moullaali TJ, Wang X, Woodhouse LJ, Law ZK, Delcourt C, Sprigg N, et al.
    BMJ Open, 2019 Jul 16;9(7):e030121.
    PMID: 31315876 DOI: 10.1136/bmjopen-2019-030121
    INTRODUCTION: Conflicting results from multiple randomised trials indicate that the methods and effects of blood pressure (BP) reduction after acute intracerebral haemorrhage (ICH) are complex. The Blood pressure in Acute Stroke Collaboration is an international collaboration, which aims to determine the optimal management of BP after acute stroke including ICH.

    METHODS AND ANALYSIS: A systematic review will be undertaken according to the Preferred Reporting Items for Systematic review and Meta-Analysis of Individual Participant Data (IPD) guideline. A search of Cochrane Central Register of Controlled Trials, EMBASE and MEDLINE from inception will be conducted to identify randomised controlled trials of BP management in adults with acute spontaneous (non-traumatic) ICH enrolled within the first 7 days of symptom onset. Authors of studies that meet the inclusion criteria will be invited to share their IPD. The primary outcome will be functional outcome according to the modified Rankin Scale. Safety outcomes will be early neurological deterioration, symptomatic hypotension and serious adverse events. Secondary outcomes will include death and neuroradiological and haemodynamic variables. Meta-analyses of pooled IPD using the intention-to-treat dataset of included trials, including subgroup analyses to assess modification of the effects of BP lowering by time to treatment, treatment strategy and patient's demographic, clinical and prestroke neuroradiological characteristics.

    ETHICS AND DISSEMINATION: No new patient data will be collected nor is there any deviation from the original purposes of each study where ethical approvals were granted; therefore, further ethical approval is not required. Results will be reported in international peer-reviewed journals.

    PROSPERO REGISTRATION NUMBER: CRD42019141136.

  18. Law ZK, England TJ, Mistri AK, Woodhouse LJ, Cala L, Dineen R, et al.
    Eur Stroke J, 2020 Jun;5(2):123-129.
    PMID: 32637645 DOI: 10.1177/2396987320901391
    Introduction: Seizures are common after intracerebral haemorrhage. Tranexamic acid increases the risk of seizures in non-intracerebral haemorrhage population but its effect on post-intracerebral haemorrhage seizures is unknown. We explored the risk factors and outcomes of seizures after intracerebral haemorrhage and if tranexamic acid increased the risk of seizures in the Tranexamic acid for IntraCerebral Haemorrhage-2 trial.

    Patients and methods: Seizures were reported prospectively up to day 90. Cox regression analyses were used to determine the predictors of seizures within 90 days and early seizures (≤7 days). We explored the effect of early seizures on day 90 outcomes.

    Results: Of 2325 patients recruited, 193 (8.3%) had seizures including 163 (84.5%) early seizures and 30 (15.5%) late seizures (>7 days). Younger age (adjusted hazard ratio (aHR) 0.98 per year increase, 95% confidence interval (CI) 0.97-0.99; p = 0.008), lobar haematoma (aHR 5.84, 95%CI 3.58-9.52; p 

  19. Dineen RA, Pszczolkowski S, Flaherty K, Law ZK, Morgan PS, Roberts I, et al.
    BMJ Open, 2018 02 03;8(2):e019930.
    PMID: 29431141 DOI: 10.1136/bmjopen-2017-019930
    OBJECTIVES: To test whether administration of the antifibrinolytic drug tranexamic acid (TXA) in patients with spontaneous intracerebral haemorrhage (SICH) leads to increased prevalence of diffusion-weighted MRI-defined hyperintense ischaemic lesions (primary hypothesis) or reduced perihaematomal oedema volume, perihaematomal diffusion restriction and residual MRI-defined SICH-related tissue damage (secondary hypotheses).

    DESIGN: MRI substudy nested within the double-blind randomised controlled Tranexamic Acid for Hyperacute Primary Intracerebral Haemorrhage (TICH)-2 trial (ISRCTN93732214).

    SETTING: International multicentre hospital-based study.

    PARTICIPANTS: Eligible adults consented and randomised in the TICH-2 trial who were also able to undergo MRI scanning. To address the primary hypothesis, a sample size of n=280 will allow detection of a 10% relative increase in prevalence of diffusion-weighted imaging (DWI) hyperintense lesions in the TXA group with 5% significance, 80% power and 5% imaging data rejection.

    INTERVENTIONS: TICH-2 MRI substudy participants will undergo MRI scanning using a standardised protocol at day ~5 and day ~90 after randomisation. Clinical assessments, randomisation to TXA or placebo and participant follow-up will be performed as per the TICH-2 trial protocol.

    CONCLUSION: The TICH-2 MRI substudy will test whether TXA increases the incidence of new DWI-defined ischaemic lesions or reduces perihaematomal oedema or final ICH lesion volume in the context of SICH.

    ETHICS AND DISSEMINATION: The TICH-2 trial obtained ethical approval from East Midlands - Nottingham 2 Research Ethics Committee (12/EM/0369) and an amendment to allow the TICH-2 MRI sub study was approved in April 2015 (amendment number SA02/15). All findings will be published in peer-reviewed journals. The primary outcome results will also be presented at a relevant scientific meeting.

    TRIAL REGISTRATION NUMBER: ISRCTN93732214; Pre-results.

  20. Bala U, Leong MP, Lim CL, Shahar HK, Othman F, Lai MI, et al.
    PLoS One, 2018;13(5):e0197711.
    PMID: 29795634 DOI: 10.1371/journal.pone.0197711
    BACKGROUND: Down syndrome (DS) is a genetic disorder caused by presence of extra copy of human chromosome 21. It is characterised by several clinical phenotypes. Motor dysfunction due to hypotonia is commonly seen in individuals with DS and its etiology is yet unknown. Ts1Cje, which has a partial trisomy (Mmu16) homologous to Hsa21, is well reported to exhibit various typical neuropathological features seen in individuals with DS. This study investigated the role of skeletal muscles and peripheral nerve defects in contributing to muscle weakness in Ts1Cje mice.

    RESULTS: Assessment of the motor performance showed that, the forelimb grip strength was significantly (P<0.0001) greater in the WT mice compared to Ts1Cje mice regardless of gender. The average survival time of the WT mice during the hanging wire test was significantly (P<0.0001) greater compared to the Ts1Cje mice. Also, the WT mice performed significantly (P<0.05) better than the Ts1Cje mice in the latency to maintain a coordinated motor movement against the rotating rod. Adult Ts1Cje mice exhibited significantly (P<0.001) lower nerve conduction velocity compared with their aged matched WT mice. Further analysis showed a significantly (P<0.001) higher population of type I fibres in WT compared to Ts1Cje mice. Also, there was significantly (P<0.01) higher population of COX deficient fibres in Ts1Cje mice. Expression of Myf5 was significantly (P<0.05) reduced in triceps of Ts1Cje mice while MyoD expression was significantly (P<0.05) increased in quadriceps of Ts1Cje mice.

    CONCLUSION: Ts1Cje mice exhibited weaker muscle strength. The lower population of the type I fibres and higher population of COX deficient fibres in Ts1Cje mice may contribute to the muscle weakness seen in this mouse model for DS.

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