Secondary injury and inflammation after intracerebral haemorrhage: a systematic review and meta-analysis of molecular markers in patient brain tissue

BACKGROUND: 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. METHODS: 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). RESULTS: 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. CONCLUSION: 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

Risks of recurrent stroke and all serious vascular events after spontaneous intracerebral haemorrhage: pooled analyses of two population-based studies

BACKGROUND: Patients with stroke due to spontaneous (non-traumatic) intracerebral haemorrhage (ICH) are at risk of recurrent ICH, ischaemic stroke, and other serious vascular events. We aimed to analyse these risks in population-based studies and compare them with the risks in RESTART, which assessed antiplatelet therapy after ICH. METHODS: We pooled individual patient data from two prospective, population-based inception cohort studies of all patients with an incident firs-in-a-lifetime ICH in Oxfordshire, England (Oxford Vascular Study; April 1, 2002, to Sept 28, 2018) and Lothian, Scotland, UK (Lothian Audit of the Treatment of Cerebral Haemorrhage; June 1, 2010, to May 31, 2013). We quantified the absolute and relative risks of recurrent ICH, ischaemic stroke, or any serious vascular event (non-fatal stroke, non-fatal myocardial infarction, or vascular death), stratified by ICH location (lobar vs non-lobar) and comorbid atrial fibrillation (AF). We compared pooled event rates with those after allocation to avoid antiplatelet therapy in RESTART. FINDINGS: Among 674 patients (mean age 74·7 years [SD 12·6], 320 [47%] men) with 1553 person-years of follow-up, 46 recurrent ICHs (event rate 3·2 per 100 patient-years, 95% CI 2·0-5·1) and 25 ischaemic strokes (1·7 per 100 patient-years, 0·8-3·3) were reported. Patients with lobar ICH (n=317) had higher risk of recurrent ICH (5·1 per 100 patient-years, 95% CI 3·6-7·2) than patients with non-lobar ICH (n=355; 1·8 per 100 patient-years, 1·0-3·3; hazard ratio [HR] 3·2, 95% CI 1·6-6·3; p=0·0010), but there was no evidence of a difference in the risk of ischaemic stroke (1·8 per 100 patient-years, 1·0-3·2, vs 1·6 per 100 patient-years, 0·6-4·4; HR 1·1, 95% CI 0·5-2·8). Conversely, there was no evidence of a difference in recurrent ICH rate in patients with AF (n=147; 3·3 per 100 patient-years, 95% CI 1·0-10·7) compared with those without (n=526; 3·2 per 100 patient-years, 2·2-4·7; HR 0·9, 95% CI 0·4-2·1), but the risk of ischaemic stroke was higher with AF (6·3 per 100 patient-years, 3·7-10·9, vs 0·7 per 100 patient-years, 0·1-5·6; HR 8·2, 3·3-20·3; p<0·0001), resulting in patients with AF having a higher risk of all serious vascular events than patients without AF (15·5 per 100 patient-years, 10·0-24·1, vs 6·8 per 100 patient-years, 3·6-12·5; HR 1·78, 95% CI 1·16-2·74; p=0·0090). Only for patients with lobar ICH without comorbid AF was the risk of recurrent ICH greater than the risk of ischaemic stroke (5·2 per 100 patient-years, 95% CI 3·6-7·5, vs 0·9 per 100 patient-years, 0·2-4·8; p=0·00034). Comparing data from the pooled population-based studies with that from patients allocated to not receive antiplatelet therapy in RESTART, there was no evidence of a difference in the rate of recurrent ICH (3·5 per 100 patient-years, 95% CI 1·9-6·0, vs 4·4 per 100 patient-years, 2·6-6·1) or ischaemic stroke (3·4 per 100 patient-years, 1·9-5·9, vs 5·3 per 100 patient-years, 3·3-7·2). INTERPRETATION: The risks of recurrent ICH, ischaemic stroke, and all serious vascular events after ICH differ by ICH location and comorbid AF. These data enable risk stratification of patients in clinical practice and ongoing randomised trials. FUNDING: UK Medical Research Council, Stroke Association, British Heart Foundation, Wellcome Trust, and the National Institute for Health Research Oxford Biomedical Research Centre

INHIBITING CSF1R ALLEVIATES CEREBROVASCULAR WHITE MATTER DISEASE AND COGNITIVE IMPAIRMENT

White matter abnormalities, related to poor cerebral perfusion, are a core feature of small vessel cerebrovascular disease, and critical determinants of vascular cognitive impairment and dementia. Despite this importance there is a lack of treatment options. Proliferation of microglia producing an expanded, reactive population and associated neuroinflammatory alterations have been implicated in the onset and progression of cerebrovascular white matter disease, in patients and in animal models, suggesting that targeting microglial proliferation may exert protection. Colony-stimulating factor-1 receptor (CSF1R) is a key regulator of microglial proliferation. We found that the expression of CSF1R/Csf1r and other markers indicative of increased microglial abundance are significantly elevated in damaged white matter in human cerebrovascular disease and in a clinically relevant mouse model of chronic cerebral hypoperfusion and vascular cognitive impairment. Using the mouse model, we investigated long-term pharmacological CSF1R inhibition, via GW2580, and demonstrated that the expansion of microglial numbers in chronic hypoperfused white matter is prevented. Transcriptomic analysis of hypoperfused white matter tissue showed enrichment of microglial and inflammatory gene sets, including phagocytic genes that were the predominant expression modules modified by CSF1R inhibition. Further, CSF1R inhibition attenuated hypoperfusion-induced white matter pathology and rescued spatial learning impairments and to a lesser extent cognitive flexibility. Overall, this work suggests that inhibition of CSF1R and microglial proliferation mediates protection against chronic cerebrovascular white matter pathology and cognitive deficits. Our study nominates CSF1R as a target for the treatment of vascular cognitive disorders with broader implications for treatment of other chronic white matter diseases.<br/

Accuracy of identifying incident stroke cases from linked healthcare data in UK Biobank

Objective 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. Methods 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. Results 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 >99%. 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. Conclusions 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

Rare missense functional variants at COL4A1 and COL4A2 in sporadic intracerebral Hhmorrhage

Objective: 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. Methods: We performed sequencing across 559Kbp at 13q34 including COL4A1 and COL4A2 among 2,133 individuals (1,055 ICH cases; 1,078 controls) in US-based and 1,492 individuals (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. Results: We identified 107 rare nonsynonymous variants in sporadic ICH, of which two missense variants, rs138269346 (COL4A1I110T) and rs201716258 (COL4A2H203L), were predicted to be highly functional and occurred in multiple ICH cases but not in controls from the US-based cohort. The minor allele of rs201716258 was also present in Scottish ICH patients, and rs138269346 was observed in two ICH-free controls with a history of hypertension and myocardial infarction. Rs138269346 was nominally associated with non-lobar ICH risk (P=0.05), but not with lobar ICH (P=0.08), while associations between rs201716258 and ICH subtypes were non-significant (P&gt;0.12). Both variants were considered pathogenic based on minor allele frequency (&lt;0.00035 in EUR), predicted functional impact (deleterious or probably damaging), and in silico modeling studies (substantially altered physical length and thermal stability of collagen). Conclusions: 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

The Boston criteria version 2.0 for cerebral amyloid angiopathy:a multicentre, retrospective, MRI–neuropathology diagnostic accuracy study

BACKGROUND: Cerebral amyloid angiopathy (CAA) is an age-related small vessel disease, characterised pathologically by progressive deposition of amyloid β in the cerebrovascular wall. The Boston criteria are used worldwide for the in-vivo diagnosis of CAA but have not been updated since 2010, before the emergence of additional MRI markers. We report an international collaborative study aiming to update and externally validate the Boston diagnostic criteria across the full spectrum of clinical CAA presentations. METHODS: In this multicentre, hospital-based, retrospective, MRI and neuropathology diagnostic accuracy study, we did a retrospective analysis of clinical, radiological, and histopathological data available to sites participating in the International CAA Association to formulate updated Boston criteria and establish their diagnostic accuracy across different populations and clinical presentations. Ten North American and European academic medical centres identified patients aged 50 years and older with potential CAA-related clinical presentations (ie, spontaneous intracerebral haemorrhage, cognitive impairment, or transient focal neurological episodes), available brain MRI, and histopathological assessment for CAA diagnosis. MRI scans were centrally rated at Massachusetts General Hospital (Boston, MA, USA) for haemorrhagic and non-haemorrhagic CAA markers, and brain tissue samples were rated by neuropathologists at the contributing sites. We derived the Boston criteria version 2.0 (v2.0) by selecting MRI features to optimise diagnostic specificity and sensitivity in a prespecified derivation cohort (Boston cases 1994-2012, n=159), then externally validated the criteria in a prespecified temporal validation cohort (Boston cases 2012-18, n=59) and a geographical validation cohort (non-Boston cases 2004-18; n=123), comparing accuracy of the new criteria to the currently used modified Boston criteria with histopathological assessment of CAA as the diagnostic standard. We also assessed performance of the v2.0 criteria in patients across all cohorts who had the diagnostic gold standard of brain autopsy. FINDINGS: The study protocol was finalised on Jan 15, 2017, patient identification was completed on Dec 31, 2018, and imaging analyses were completed on Sept 30, 2019. Of 401 potentially eligible patients presenting to Massachusetts General Hospital, 218 were eligible to be included in the analysis; of 160 patient datasets from other centres, 123 were included. Using the derivation cohort, we derived provisional criteria for probable CAA requiring the presence of at least two strictly lobar haemorrhagic lesions (ie, intracerebral haemorrhages, cerebral microbleeds, or foci of cortical superficial siderosis) or at least one strictly lobar haemorrhagic lesion and at least one white matter characteristic (ie, severe visible perivascular spaces in centrum semiovale or white matter hyperintensities in a multispot pattern). The sensitivity and specificity of these criteria were 74·8% (95% CI 65·4-82·7) and 84·6% (71·9-93·1) in the derivation cohort, 92·5% (79·6-98·4) and 89·5% (66·9-98·7) in the temporal validation cohort, 80·2% (70·8-87·6) and 81·5% (61·9-93·7) in the geographical validation cohort, and 74·5% (65·4-82·4) and 95·0% (83·1-99·4) in all patients who had autopsy as the diagnostic standard. The area under the receiver operating characteristic curve (AUC) was 0·797 (0·732-0·861) in the derivation cohort, 0·910 (0·828-0·992) in the temporal validation cohort, 0·808 (0·724-0·893) in the geographical validation cohort, and 0·848 (0·794-0·901) in patients who had autopsy as the diagnostic standard. The v2.0 Boston criteria for probable CAA had superior accuracy to the current Boston criteria (sensitivity 64·5% [54·9-73·4]; specificity 95·0% [83·1-99·4]; AUC 0·798 [0·741-0854]; p=0·0005 for comparison of AUC) across all individuals who had autopsy as the diagnostic standard. INTERPRETATION: The Boston criteria v2.0 incorporate emerging MRI markers of CAA to enhance sensitivity without compromising their specificity in our cohorts of patients aged 50 years and older presenting with spontaneous intracerebral haemorrhage, cognitive impairment, or transient focal neurological episodes. Future studies will be needed to determine generalisability of the v.2.0 criteria across the full range of patients and clinical presentations. FUNDING: US National Institutes of Health (R01 AG26484)

The Persisting Burden of Intracerebral Haemorrhage: Can Effective Treatments Be Found?

Colin Josephson, Rustam Al-Shahi Salman, and colleagues discuss the effectiveness of treatments for intracerebral haemorrhage

Yrityksen toiminnanohjausjärjestelmä

Tämä opinnäytetyö tehtiin Kouvolassa ja Laukaassa sijaitsevalle Sammet Asennus Oy:lle. Opinnäytetyön tarkoituksena oli päivittää yrityksen laadunhallintastandardi ISO 9001:2015 ja samalla luoda yritykselle yksi toimintajärjestelmä, joka sisältää edellä mainitun standardin lisäksi ISO 14001 ja OHSAS 18001-standardit. Työhön liittyvä tieto on kerätty yrityksen kanssa käydyistä keskusteluista, vanhasta standardista sekä työskentelystä yrityksen projektissa Porvoon jalostamolla puolentoista kuukauden ajan. Muu aineisto on kerätty aiheeseen liittyvästä kirjallisuudesta ja artikkeleista. Työn alussa kerrotaan yleisesti siitä, standardeista ja niihin liittyvien organisaatioiden toiminnasta sekä miten uusi standardi eroaa vanhasta. Opinnäytetyön viimeinen osa käsittelee työn etenemistä sekä yrityksen uuden toimintajärjestelmän suurimmista muutoksen kohteita. Yritys sertifioi järjestelmän syksyllä 2017, ja opinnäytetyön onnistuminen on nähtävissä sertifioinnin jälkeen. Yrityksen kanssa tehdyn salassapitosopimuksen takia työssä ei ole voitu kuvata kaikkia prosesseja tarkasti tai avata yrityksen toimintaa kyseisissä prosesseissaThis thesis was made to Sammet Asennus Oy in Kouvola and Laukaa The purpose of the thesis was to update the company's quality management standard ISO 9001: 2015, and at the same time create an operating system for the company, which includes in addition to the above-mentioned standards ISO 14001 and OHSAS 18001. Job related information have been gathered from the meetings with the company, old standards and working in a company project for a one month and a half. Other materials are collected from the related literature and articles. At the beginning of the work, general information about the standard and the activities of related organizations were discussed, and how the new standard differs from the old one. At the final part, the thesis explains about the progress of the work and the biggest changes occurred in the company's new operating system. The results of the success of the work will be discovered by the company's certification in the autumn of 2017