ORCID Profile
0000-0001-6840-0199
Current Organisation
The University of Edinburgh
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Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-07-2020
DOI: 10.1212/WNL.0000000000009924
Abstract: In UK Biobank (UKB), a large population-based prospective study, cases of many diseases are ascertained through linkage to routinely collected, coded national health datasets. We assessed the accuracy of these for identifying incident strokes. In a regional UKB subpopulation (n = 17,249), we identified all participants with ≥1 code signifying a first stroke after recruitment (incident stroke-coded cases) in linked hospital admission, primary care, or death record data. Stroke physicians reviewed their full electronic patient records (EPRs) and generated reference standard diagnoses. We evaluated the number and proportion of cases that were true-positives (i.e., positive predictive value [PPV]) for all codes combined and by code source and type. Of 232 incident stroke-coded cases, 97% had EPR information available. Data sources were 30% hospital admission only, 39% primary care only, 28% hospital and primary care, and 3% death records only. While 42% of cases were coded as unspecified stroke type, review of EPRs enabled a pathologic type to be assigned in %. PPVs (95% confidence intervals) were 79% (73%–84%) for any stroke (89% for hospital admission codes, 80% for primary care codes) and 83% (74%–90%) for ischemic stroke. PPVs for small numbers of death record and hemorrhagic stroke codes were low but imprecise. Stroke and ischemic stroke cases in UKB can be ascertained through linked health datasets with sufficient accuracy for many research studies. Further work is needed to understand the accuracy of death record and hemorrhagic stroke codes and to develop scalable approaches for better identifying stroke types.
Publisher: Elsevier BV
Date: 10-2020
Publisher: Elsevier BV
Date: 05-2016
Publisher: Elsevier BV
Date: 11-2013
Publisher: BMJ
Date: 02-03-2013
Abstract: Cerebral amyloid angiopathy (CAA) is common in the ageing brain and is associated with dementia and lobar intracerebral haemorrhage. We systematically reviewed genetic associations with CAA to better understand its pathogenesis. We comprehensively sought and critically appraised published studies of associations between any genetic polymorphism and histopathologically confirmed CAA. We assessed the effects of genotype by calculating study specific and pooled odds ratios (ORs) in meta-analyses, and assessed small study bias. 58 studies (6855 participants) investigated apolipoprotein E (APOE) genotype and sporadic CAA. Meta-analysis of 24 (3520 participants) of these showed an association of APOE ε4 with CAA (ε4 present vs absent, pooled OR 2.7, 95% CI 2.3 to 3.1, p<0.00001), which was dose dependent, robust to potential small study biases and occurred irrespective of dementia status. There was no significant association between APOE ε2 and CAA. Among 24 studies (4703 participants) of other genetic polymorphisms, there was preliminary evidence of an association with CAA of polymorphisms in the transforming growth factor β1 gene (two studies, 449 participants), translocase of outer mitochondrial membrane 40 gene (one study, 723 participants) and the complement component receptor 1 gene (one study, 544 participants). There were insufficient data to draw conclusions from 24 studies (∼200 participants) of APOE and hereditary CAA or familial Alzheimer's disease. There is convincing evidence for a dose dependent association between APOE ε4 and sporadic CAA. Further work is needed to better understand the mechanism of this association and to further investigate other genetic associations with CAA.
Publisher: Public Library of Science (PLoS)
Date: 19-07-2020
Publisher: BMJ
Date: 02-2022
DOI: 10.1136/BMJNO-2021-000238
Abstract: Pharmacological activation of the antioxidative transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) improves outcomes in experimental models of intracerebral haemorrhage (ICH). However, the Nrf2 pathway has not been previously studied in humans after ICH. Our study aims to address this gap. We selected cases with fatal ICH from a prospective community-based inception cohort study and age-matched and sex-matched controls who died suddenly of non-neurological disease. We used immunohistochemistry to quantify Nrf2 (% total area stained overall and % of nuclei stained) and CD68 expression in controls and perihaematomal, ipsilateral and contralateral brain tissue from cases. We measured downstream haem oxygenase-1 (HMOX1) and NAD(P)H dehydrogenase quinone 1 [NQO1] expression using RNA in situ hybridisation. 26 ICH cases (median age: 82 (IQR 76–86) 13 (50%) male) and eight controls (median age: 79 (IQR 77–80) 3 (37.5%) male) were included. We found no significant differences in overall % of Nrf2 staining between ICH cases and controls. However, the mean % of nuclei staining for Nrf2 seemed higher in perihaematomal compared with contralateral regions, although this was only statistically significant days after ICH (25% (95% CI 17% to 33%) vs 14% (95% CI 11% to 17%), p=0.029). The percentage of perihaematomal tissue staining for CD68 was higher days after ICH (6.75%, 95% CI 2.78% to 10.73%) compared with contralateral tissue (1.45%, 95% CI 0.93% to 1.96%, p=0.027) and controls (1.08%, 95% CI 0.20% to 1.97%, p=0.0008). RNA in situ hybridisation suggested increased abundance of HMOX1 and NQO1 transcripts in perihaematomal versus distant ipsilateral brain tissue obtained days from onset of ICH. We found evidence of Nrf2 activation in human brain tissue after ICH. Pharmacological augmentation of Nrf2 activation after ICH might be a promising therapeutic approach.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 26-07-2017
DOI: 10.1212/WNL.0000000000004259
Abstract: We evaluated recurrent intracerebral hemorrhage (ICH) risk in ICH survivors, stratified by the presence, distribution, and number of cerebral microbleeds (CMBs) on MRI (i.e., the presumed causal underlying small vessel disease and its severity). This was a meta-analysis of prospective cohorts following ICH, with blood-sensitive brain MRI soon after ICH. We estimated annualized recurrent symptomatic ICH rates for each study and compared pooled odds ratios (ORs) of recurrent ICH by CMB presence/absence and presumed etiology based on CMB distribution (strictly lobar CMBs related to probable or possible cerebral amyloid angiopathy [CAA] vs non-CAA) and burden (1, 2–4, 5–10, and CMBs), using random effects models. We pooled data from 10 studies including 1,306 patients: 325 with CAA-related and 981 CAA-unrelated ICH. The annual recurrent ICH risk was higher in CAA-related ICH vs CAA-unrelated ICH (7.4%, 95% confidence interval [CI] 3.2–12.6 vs 1.1%, 95% CI 0.5–1.7 per year, respectively p = 0.01). In CAA-related ICH, multiple baseline CMBs (versus none) were associated with ICH recurrence during follow-up (range 1–3 years): OR 3.1 (95% CI 1.4–6.8 p = 0.006), 4.3 (95% CI 1.8–10.3 p = 0.001), and 3.4 (95% CI 1.4–8.3 p = 0.007) for 2–4, 5–10, and CMBs, respectively. In CAA-unrelated ICH, only CMBs (versus none) were associated with recurrent ICH (OR 5.6, 95% CI 2.1–15 p = 0.001). The presence of 1 CMB (versus none) was not associated with recurrent ICH in CAA-related or CAA-unrelated cohorts. CMB burden and distribution on MRI identify subgroups of ICH survivors with higher ICH recurrence risk, which may help to predict ICH prognosis with relevance for clinical practice and treatment trials.
Publisher: BMJ
Date: 06-08-2021
Abstract: Inflammatory responses to intracerebral haemorrhage (ICH) are potential therapeutic targets. We aimed to quantify molecular markers of inflammation in human brain tissue after ICH compared with controls using meta-analysis. We searched OVID MEDLINE (1946–) and Embase (1974–) in June 2020 for studies that reported any measure of a molecular marker of inflammation in brain tissue from five or more adults after ICH. We assessed risk of bias using a modified Newcastle-Ottawa Scale (mNOS mNOS score 0–9 9 indicates low bias), extracted aggregate data, and used random effects meta-analysis to pool associations of molecules where more than two independent case–control studies reported the same outcome and Gene Ontology enrichment analysis to identify over-represented biological processes in pooled sets of differentially expressed molecules (International Prospective Register of Systematic Reviews ID: CRD42018110204). Of 7501 studies identified, 44 were included: 6 were case series and 38 were case–control studies (median mNOS score 4, IQR 3–5). We extracted data from 21 491 analyses of 20 951 molecules reported by 38 case–control studies. Only one molecule (interleukin-1β protein) was quantified in three case–control studies (127 ICH cases vs 41 ICH-free controls), which found increased abundance of interleukin-1β protein after ICH (corrected standardised mean difference 1.74, 95% CI 0.28 to 3.21, p=0.036, I 2 =46%). Processes associated with interleukin-1β signalling were enriched in sets of molecules that were more abundant after ICH. Interleukin-1β abundance is increased after ICH, but analyses of other inflammatory molecules after ICH lack replication. Interleukin-1β pathway modulators may optimise inflammatory responses to ICH and merit testing in clinical trials.
Publisher: BMJ
Date: 05-11-2011
Abstract: The aim of this study was to determine the strength of the association between intracerebral haemorrhage (ICH) and cerebral amyloid angiopathy (CAA) in a systematic review of published neuropathological studies. In April 2011, Ovid Medline (from 1950) and Embase (from 1980) were searched for neuropathological studies that quantified the prevalence of CAA in patients with ICH and in a control group without ICH. Two authors extracted data from each study and meta-analysed their results using a random effects model. 10 neuropathological cross sectional or case control studies were identified, involving 481 cases with ICH and 3219 controls. There was no association between CAA and ICH in any location (OR 1.21, 95% CI 0.87 to 1.68 10 studies, I(2) 29%), deep ICH (OR 0.81, 95% CI 0.30 to 2.19 five studies, I(2) 58%) or cerebellar ICH (OR 2.05, 95% CI 0.55 to 7.63 four studies, I(2) 0%). CAA was significantly associated with lobar ICH, both overall (OR 2.21, 95% CI 1.09 to 4.45 six studies, I(2) 40%) and in the three studies where average ages for cases and controls were comparable (OR 3.24, 95% CI 1.02 to 10.26). There is an association between CAA and lobar ICH, although the association might be stronger if potential confounding factors, distinctive clinical and imaging features of ICH due to CAA and CAA neuropathological severity are taken into account.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 20-07-2021
DOI: 10.1212/WNL.0000000000012227
Abstract: To test the genetic contribution of rare missense variants in COL4A1 and COL4A2 in which common variants are genetically associated with sporadic intracerebral hemorrhage (ICH), we performed rare variant analysis in multiple sequencing data for the risk for sporadic ICH. We performed sequencing across 559 Kbp at 13q34 including COL4A1 and COL4A2 among 2,133 in iduals (1,055 ICH cases 1,078 controls) in United States–based and 1,381 in iduals (192 ICH cases 1,189 controls) from Scotland-based cohorts, followed by sequence annotation, functional impact prediction, genetic association testing, and in silico thermodynamic modeling. We identified 107 rare nonsynonymous variants in sporadic ICH, of which 2 missense variants, rs138269346 (COL4A1 I110T ) and rs201716258 (COL4A2 H203L ), were predicted to be highly functional and occurred in multiple ICH cases but not in controls from the United States–based cohort. The minor allele of rs201716258 was also present in Scottish patients with ICH, and rs138269346 was observed in 2 ICH-free controls with a history of hypertension and myocardial infarction. Rs138269346 was nominally associated with nonlobar ICH risk ( p = 0.05), but not with lobar ICH ( p = 0.08), while associations between rs201716258 and ICH subtypes were nonsignificant ( p 0.12). Both variants were considered pathogenic based on minor allele frequency ( .00035 in European populations), predicted functional impact (deleterious or probably damaging), and in silico modeling studies (substantially altered physical length and thermal stability of collagen). We identified rare missense variants in COL4A1 / A2 in association with sporadic ICH. Our annotation and simulation studies suggest that these variants are highly functional and may represent targets for translational follow-up.
Publisher: Elsevier BV
Date: 06-2021
Publisher: Cambridge University Press
Date: 26-05-2011
Publisher: Elsevier BV
Date: 10-2021
Publisher: American Medical Association (AMA)
Date: 04-2019
Publisher: Elsevier BV
Date: 03-2018
Publisher: Springer Science and Business Media LLC
Date: 31-01-2013
DOI: 10.1007/S00701-013-1621-4
Abstract: Cerebral cavernous malformation (CCM) management decisions are usually made after CCM diagnosis is suspected or definitively diagnosed on axial imaging by indirectly comparing a surgeon's estimate of operative morbidity and mortality against published estimates of CCM untreated clinical course. We used comprehensive electronic strategies to search OVID Medline and EMBASE for original studies published before 2011 of ≥20 adults with CCM that (a) evaluated diagnostic test accuracy, or (b) compared treatment with microsurgery or stereotactic radiosurgery against conservative management in a concurrent or historical control group and reported clinical outcome(s). We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group's approach to identify level 1 or level 2 studies according to the Oxford Centre for Evidence-Based Medicine's 2011 criteria. We found one eligible diagnostic test accuracy study of 72 patients with brain masses accompanied by vasogenic edema and substantial amounts of blood, which found that hyperintense perilesional signal on T1-weighted magnetic resonance imaging could differentiate CCM from other causes with excellent specificity (98 %) and reasonable sensitivity (62 %). We found five potentially eligible observational studies of adults with a CCM that had already bled, but none met level 2 criteria for a "dramatic" effect (the conventionally calculated probability of the two groups of observations coming from the same population should be less than 0.01 and a rate ratio greater than 10). We found 11 potentially eligible observational studies of adults with CCM and epilepsy, but nine studies did not demonstrate dramatic effects and the remaining two studies showed dramatic effects, but they were at high risk of bias. To address the absence of level 1 or 2 evidence to support CCM treatment decisions, there is a need for large studies of CCM treatment with a concurrent control group, ideally with randomized treatment allocation.
Publisher: Springer Science and Business Media LLC
Date: 11-2013
Publisher: Public Library of Science (PLoS)
Date: 27-10-2017
Publisher: Elsevier BV
Date: 08-2022
Publisher: SAGE Publications
Date: 18-02-2023
DOI: 10.1177/23969873231157884
Abstract: Perihaematomal oedema (PHO) formation has gained increasing interest as a therapeutic target after spontaneous intracerebral haemorrhage (ICH). Whether PHO contributes to poor outcome is unclear. We aimed to determine the association between PHO and outcome in patients with spontaneous ICH. We searched five databases up to 17 November 2021 for studies of ⩾10 adults with ICH reporting the presence of PHO and outcome. We assessed risk of bias, extracted aggregate data and used random effects meta-analysis to pool studies that reported odds ratios (OR) with 95% confidence intervals (CI). Primary outcome was poor functional outcome defined as modified Rankin Scale score of 3–6 at 3 months. Additionally, we assessed PHO growth and poor outcome at any time of follow-up. We prospectively registered the protocol in PROSPERO (CRD42020157088). We identified 12,968 articles, of which we included 27 studies ( n = 9534). Eighteen studies reported an association between larger PHO volume and poor outcome, six a neutral result and three an inverse relationship. Larger absolute PHO volume was associated with poor functional outcome at 3 months (OR per mL increase of absolute PHO 1.03, 95% CI 1.00–1.06, I 2 44%, four studies). Additionally, PHO growth was associated with poor outcome (OR 1.04, 95% CI 1.02–1.06, I 2 0%, seven studies). In patients with spontaneous ICH, larger PHO volume is associated with poor functional outcome at 3 months. These findings support the development and investigation of new therapeutic interventions targeting PHO formation to evaluate if reduction of PHO improves outcome after ICH.
Publisher: Wiley
Date: 20-11-2020
DOI: 10.1002/ANA.25949
Abstract: A study was undertaken to assess whether cerebral small vessel disease (SVD) computed tomographic (CT) biomarkers are associated with long‐term outcome after intracerebral hemorrhage. We performed a prospective, community‐based cohort study of adults diagnosed with spontaneous intracerebral hemorrhage between June 1, 2010 and May 31, 2013. A neuroradiologist rated the diagnostic brain CT for acute intracerebral hemorrhage features and SVD biomarkers. We used severity of white matter lucencies and cerebral atrophy, and the number of lacunes to calculate the CT SVD score. We assessed the association between CT SVD biomarkers and either death, or death or dependence (modified Rankin Scale scores = 4–6) 1 year after first‐ever intracerebral hemorrhage using logistic regression, adjusting for known predictors of outcome. Within 1 year of intracerebral hemorrhage, 224 (56%) of 402 patients died. In separate models, 1‐year death was associated with severe atrophy (adjusted odds ratio [aOR] = 2.54, 95% confidence interval [CI] = 1.44–4.49, p = 0.001) but not lacunes or severe white matter lucencies, and CT SVD sum score ≥ 1 (aOR = 2.50, 95% CI = 1.40–4.45, p = 0.002). Two hundred seventy‐seven (73%) of 378 patients with modified Rankin Scale data were dead or dependent at 1 year. In separate models, 1‐year death or dependence was associated with severe atrophy (aOR = 3.67, 95% CI = 1.71–7.89, p = 0.001) and severe white matter lucencies (aOR = 2.18, 95% CI = 1.06–4.51, p = 0.035) but not lacunes, and CT SVD sum score ≥ 1 (aOR = 2.81, 95% CI = 1.45–5.46, p = 0.002). SVD biomarkers on the diagnostic brain CT are associated with 1‐year death and dependence after intracerebral hemorrhage, independent of known predictors of outcome. ANN NEUROL 2021 :266–279
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2019
DOI: 10.1161/STROKEAHA.118.023746
Abstract: The frequency and prognostic implications of incident cerebral microbleeds (CMB), defined as development of one or more new CMB, after intracerebral hemorrhage (ICH) is unclear. Therefore, we performed a systematic review and meta-analysis to investigate the frequency and prognostic implications of incident CMB after ICH. We searched Ovid Medline and Embase in May 2018 for longitudinal studies of adults who underwent brain magnetic resonance imaging at 2 or more times after ICH. We calculated the pooled proportion of adults with incident CMB and sought associations between incident CMB and clinical outcomes (death, recurrent ICH, or new ischemic stroke). We planned subgroup analyses to investigate clinical variables associated with incident CMB. We identified 2354 publications, of which we included 4 cohort studies involving 349 patients. The pooled proportion of adults with at least one new CMB during a mean 27 months follow-up (SD 20 months) was ≈40% (95% CI, 30%–50%). In one study, as the number of incident CMB increased (0 versus 1–3 new CMB versus ≥4 new CMB) the risk of recurrent symptomatic lobar ICH increased (hazard ratio 3.0 95% CI, 1.2–7.3). No study reported on outcomes of incident ischemic stroke or death. Incident CMB occurs in ≈40% of adults after ICH. The association of incident CMB with recurrent lobar ICH needs confirmation and their association with death and ischemic stroke investigation.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2013
DOI: 10.1161/STROKEAHA.113.001493
Abstract: Acute treatments specifically for intracerebral hemorrhage (ICH) are being sought in randomized controlled trials. The treatment effect sizes in ongoing and future trials are likely to be small, necessitating large s le sizes. We searched online trial registries for randomized controlled trials investigating an acute treatment for ICH. For the trials whose eligibility criteria could be assessed in a prospective, community-based ICH cohort study (2010–2011), we quantified the proportions of patients who were eligible and investigated influences on these proportions. We applied the eligibility criteria of 17 trials to 166 adults with ICH, of whom between 0.6% (95% confidence interval, 0.1–3.3) to 40% (95% confidence interval, 33–48) were eligible for each trial. Fewer patients were eligible for trials restricted to patients randomized within 12 hours of ICH onset (versus trials with a longer time window P =0.03) and trials restricting eligibility according to premorbid disability (versus trials without this restriction P =0.046). Each additional eligibility criterion reduced the portion of eligible patients by 1.3% (95% confidence interval, 0.4–2.2 adjusted R 2 =0.47 P =0.004). Less than half of patients with ICH were eligible for current randomized controlled trials. Future trials could maximize enrollment by minimizing the number of eligibility criteria, maximizing the time window for recruiting patients after ICH onset, permitting premorbid disability, and using a simulator to assess the impact of other eligibility critiera ( www.dcn.ed.ac.uk/ICHsimulator/ ).
Publisher: BMJ
Date: 25-10-2013
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2015
DOI: 10.1161/STROKEAHA.114.007953
Abstract: The characteristics of intracerebral hemorrhage (ICH) may vary by ICH location because of differences in the distribution of underlying cerebral small vessel diseases. Therefore, we investigated the incidence, characteristics, and outcome of lobar and nonlobar ICH. In a population-based, prospective inception cohort study of ICH, we used multiple overlapping sources of case ascertainment and follow-up to identify and validate ICH diagnoses in 2010 to 2011 in an adult population of 695 335. There were 128 participants with first-ever primary ICH. The overall incidence of lobar ICH was similar to nonlobar ICH (9.8 [95% confidence interval, 7.7–12.4] versus 8.6 [95% confidence interval, 6.7–11.1] per 100 000 adults/y). At baseline, adults with lobar ICH were more likely to have preceding dementia (21% versus 5% P =0.01), lower Glasgow Coma Scale scores (median, 13 versus 14 P =0.03), larger ICHs (median, 38 versus 11 mL P .001), subarachnoid extension (57% versus 5% P .001), and subdural extension (15% versus 3% P =0.02) than those with nonlobar ICH. One-year case fatality was lower after lobar ICH than after nonlobar ICH (adjusted odds ratio for death at 1 year: lobar versus nonlobar ICH 0.21 95% confidence interval, 0.07–0.63 P =0.006, after adjustment for known predictors of outcome). There were 4 recurrent ICHs, which occurred exclusively in survivors of lobar ICH (annual risk of recurrent ICH after lobar ICH, 11.8% 95% confidence interval, 4.6%–28.5% versus 0% after nonlobar ICH log-rank P =0.04). The baseline characteristics and outcome of lobar ICH differ from other locations.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2014
DOI: 10.1161/STROKEAHA.114.006202
Abstract: Whether intracerebral hemorrhage (ICH) survivors should restart antithrombotic drugs is unknown. We analyzed the frequency of restarting antithrombotic drugs in ICH survivors who had taken prophylactic antithrombotic drugs in atrial fibrillation or after thromboembolic disease in 5 cohorts and explored factors associated with doing so. We compared the characteristics and proportions of patients taking antithrombotic drugs at ICH onset and discharge in 4 hospital-based cohorts (Lille, France, n=542 Utrecht, The Netherlands, n=389 multicenter Clinical Relevance of Microbleeds in Stroke-2 (CROMIS-2) ICH, United Kingdom, n=667 and Amsterdam, The Netherlands, n=403) and 1 community-based study (Lothian, Scotland, n=137), using bivariate analyses. We sought characteristics associated with restarting using bivariate and multivariable logistic regression analyses. A total of 942 (44%) patients with ICH took antithrombotic drugs at hospital admission (no difference between cohorts). Antithrombotic drugs were restarted in 96 (20%) of the 469 survivors who had taken antithrombotic drugs for secondary prevention or atrial fibrillation, but this proportion differed when stratified by the cohort of origin (Lille, 18% Utrecht, 45% Lothian, 15% CROMIS-2 ICH, 11% Amsterdam, 20% P .001) and by type of antithrombotic drug pre-ICH (14% in patients with previous antiplatelet drugs versus 26% in patients with previous vitamin K antagonists and 41% in patients with both drugs P .001). We did not find other consistent, independent associations with restarting antithrombotic drugs. The variation in clinical practice and lack of consistent associations with restarting antithrombotic drugs after ICH reflect current knowledge and support the need for randomized controlled trials to resolve this dilemma.
Publisher: F1000 Research Ltd
Date: 12-06-2023
DOI: 10.12688/WELLCOMEOPENRES.19187.1
Abstract: Background : Currently, there are no specific medical treatments for intracerebral haemorrhage (ICH), but the inflammatory response may provide a potential route to treatment. Given the known effects of acute brain injury on peripheral immunity, we hypothesised that inflammatory biomarkers in peripheral blood may be associated with clinical outcome following ICH, as well as perihaematomal oedema (PHO), which is an imaging marker of the neuroinflammatory response. Methods : We searched OVID Medline and EMBASE on 07 April 2021 for studies of humans with ICH measuring an inflammatory biomarker in peripheral blood and PHO or clinical outcome. Risk of bias was assessed using a scale comprising features of the Newcastle-Ottawa Assessment Scale, STROBE-ME and REMARK guidelines. We used random effects meta-analysis to pool standardised mean differences (SMD) if ≥1 study quantified the association between identical biomarkers and measures of PHO or functional outcome. Results : Of 8,615 publications, 16 examined associations between 21 inflammatory biomarkers and PHO (n=1,299 participants), and 93 studies examined associations between ≥1 biomarker and clinical outcome (n=17,702 participants). Overall, 20 studies of nine biomarkers (n=3,199) met criteria for meta-analysis of associations between inflammatory biomarkers and clinical outcome. Death or dependency (modified Rankin Scale (mRS) 3–6) 90 days after ICH was associated with higher levels of C-reactive protein (CRP) (SMD 0.80 95%CI [0.44, 1.17] p .0001), fibrinogen (SMD 0.32 95%CI [0.04, 0.61] p=0.025), white blood cell (WBC) count (SMD 0.27 95%CI [0.11, 0.44] p=0.001) and high mobility group box protein 1 (HMGB1) (SMD 1.67 95%CI [0.05, 3.30] p=0.04). Conclusions : Higher circulating levels of WBC, CRP, fibrinogen and HMGB1 are associated with poorer outcomes after ICH. This study highlights the clinical importance of the inflammatory response to ICH and identifies additional research needs in determining if these associations are mediated via PHO and are potential therapeutic targets. Registration: PROSPERO ( CRD42019132628 28/05/2019).
Publisher: SAGE Publications
Date: 25-11-2020
Abstract: Hospital-based studies have reported variable associations between outcome after spontaneous intracerebral hemorrhage and peri-hematomal edema volume. In a community-based study, we aimed to investigate the existence, strength, direction, and independence of associations between intracerebral hemorrhage and peri-hematomal edema volumes on diagnostic brain CT and one-year functional outcome and long-term survival. We identified all adults, resident in Lothian, diagnosed with first-ever, symptomatic spontaneous intracerebral hemorrhage between June 2010 and May 2013 in a community-based, prospective inception cohort study. We defined regions of interest manually and used a semi-automated approach to measure intracerebral hemorrhage volume, peri-hematomal edema volume, and the sum of these measurements (total lesion volume) on first diagnostic brain CT performed at ≤3 days after symptom onset. The primary outcome was death or dependence (scores 3–6 on the modified Rankin Scale) at one-year after intracerebral hemorrhage. Two hundred ninety-two (85%) of 342 patients (median age 77.5 y, IQR 68–83, 186 (54%) female, median time from onset to CT 6.5 h (IQR 2.9–21.7)) were dead or dependent one year after intracerebral hemorrhage. Peri-hematomal edema and intracerebral hemorrhage volumes were colinear ( R 2 = 0.77). In models using both intracerebral hemorrhage and peri-hematomal edema, 10 mL increments in intracerebral hemorrhage (adjusted odds ratio (aOR) 1.72 (95% CI 1.08–2.87) p = 0.029) but not peri-hematomal edema volume (aOR 0.92 (0.63–1.45) p = 0.69) were independently associated with one-year death or dependence. 10 mL increments in total lesion volume were independently associated with one-year death or dependence (aOR 1.24 (1.11–1.42) p = 0.0004). Total volume of intracerebral hemorrhage and peri-hematomal edema, and intracerebral hemorrhage volume alone on diagnostic brain CT, undertaken at three days or sooner, are independently associated with death or dependence one-year after intracerebral hemorrhage, but peri-hematomal edema volume is not. Anonymized summary data may be requested from the corresponding author.
Publisher: Wiley
Date: 19-10-2016
DOI: 10.1002/ANA.24780
Abstract: In observational epidemiologic studies, higher plasma high‐density lipoprotein cholesterol (HDL‐C) has been associated with increased risk of intracerebral hemorrhage (ICH). DNA sequence variants that decrease cholesteryl ester transfer protein ( CETP ) gene activity increase plasma HDL‐C as such, medicines that inhibit CETP and raise HDL‐C are in clinical development. Here, we test the hypothesis that CETP DNA sequence variants associated with higher HDL‐C also increase risk for ICH. We performed 2 candidate‐gene analyses of CETP . First, we tested in idual CETP variants in a discovery cohort of 1,149 ICH cases and 1,238 controls from 3 studies, followed by replication in 1,625 cases and 1,845 controls from 5 studies. Second, we constructed a genetic risk score comprised of 7 independent variants at the CETP locus and tested this score for association with HDL‐C as well as ICH risk. Twelve variants within CETP demonstrated nominal association with ICH, with the strongest association at the rs173539 locus (odds ratio [OR] = 1.25, standard error [SE] = 0.06, p = 6.0 × 10 −4 ) with no heterogeneity across studies ( I 2 = 0%). This association was replicated in patients of European ancestry ( p = 0.03). A genetic score of CETP variants found to increase HDL‐C by ∼2.85mg/dl in the Global Lipids Genetics Consortium was strongly associated with ICH risk (OR = 1.86, SE = 0.13, p = 1.39 × 10 −6 ). Genetic variants in CETP associated with increased HDL‐C raise the risk of ICH. Given ongoing therapeutic development in CETP inhibition and other HDL‐raising strategies, further exploration of potential adverse cerebrovascular outcomes may be warranted. Ann Neurol 2016 :730–740
Publisher: Elsevier BV
Date: 07-2023
Publisher: Public Library of Science (PLoS)
Date: 24-08-2015
Publisher: Public Library of Science (PLoS)
Date: 10-07-2017
Publisher: Elsevier BV
Date: 2021
DOI: 10.2139/SSRN.3767901
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Neshika Samarasekera.