Impact of statin use and lipid profile on symptomatic intracerebral haemorrhage, outcome and mortality after intravenous thrombolysis in acute stroke

Background: It is unclear if a certain lipid profile and/or statin use contribute to symptomatic intracerebral haemorrhage (sICH), poor outcome or mortality after intravenous thrombolysis for ischaemic stroke. The aim of the current study was to assess the impact of statin use and lipid profile on sICH, outcome and mortality following thrombolysis in acute stroke. Methods: From 2001 to 2010, all patients admitted to our hospital and undergoing intravenous thrombolysis for acute ischaemic stroke were included into an open, prospective database. Initial stroke severity was assessed using the National Institute of Health Stroke Scale. Demographics, vascular risk factors, admission blood pressure, glucose levels, previous medication including statin use, lipid profiles including low-density lipoprotein (LDL), high-density lipoprotein (HDL) and triglyceride levels were recorded. Outcome measures included sICH according to the European Cooperative Acute Stroke Study II criteria, modified Rankin scale and mortality at 3 months. Results: 1,066 patients were included in the analysis; 5.3% (57 patients) had sICH. Mortality at 3 months was 17.6% (188 patients). A favourable outcome (modified Rankin scale 0-1) at 3 months was attained by 35.6% (379 patients). Prior statin use was not associated with increased odds for sICH (OR 1.05, 95% CI 0.55–2.04, p = 0.864), mortality (OR 1.32, 95% CI 0.90–1.93, p = 0.152) or favourable outcome (OR 0.89, 95% CI 0.65–1.24, p = 0.507). Similar results were found for the different lipid variables: high LDL (OR 0.96, 95% CI 0.36–2.60, p = 0.942), high triglyceride (OR 1.74, 95% CI 0.84–3.56, p = 0.132) and low HDL (OR 1.78, 95% CI 0.68–4.65, p = 0.279) were not associated with increased odds for sICH. Likewise, neither mortality nor functional outcome at 3 months was significantly associated with any of the lipid variables in the univariable analysis following Bonferroni adjustment for multiple comparisons. The same results were found in the multivariable analysis adjusting for imbalances in baseline characteristics. Conclusions: In contrast to previous studies, we found that in stroke patients receiving thrombolysis therapy, neither the lipid profile nor prior statin use were associated with increased odds for sICH, functional outcome or mortality at 3 months

The Relationship Between Attitudes Toward Inclusion, Beliefs About Teaching and Learning, and Subsequent Automatic Evaluations Amongst Student Teachers

Teachers' attitudes toward inclusion are frequently cited as being an important predictor of how successfully a given inclusive school system is implemented. At the same time, beliefs about the nature of teaching and learning are discussed as a possible predictor of attitudes toward inclusion. However, more recent research emphasizes the need of considering implicit processes, such as automatic evaluations, when describing attitudes and beliefs. Previous evidence on the association of attitudes toward inclusion and beliefs about teaching and learning is solely based on explicit reports. Therefore, this study aims to examine the relationship between attitudes toward inclusion, beliefs about teaching and learning, and the subsequent automatic evaluations of pre-service teachers (N = 197). The results revealed differences between pre-service teachers' explicit attitudes/beliefs and their subsequent automatic evaluations. Differences in the relationship between attitudes toward inclusion and beliefs about teaching and learning occur when teachers focus either on explicit measures or automatic evaluations. These differences might be due to different facets of the same attitude object being represented. Relying solely on either explicit measures or automatic evaluations at the exclusion of the other might lead to erroneous assumptions about the relation of attitudes toward inclusion and beliefs about teaching and learning

Interleukin-37 Inhibits Colon Carcinogensis During Chronic Colitis

Inflammatory bowel disease increases the risk of developing colon cancer. Interleukin (IL-) 37 is a fundamental inhibitor of innate immunity by reducing systemic and local inflammation. IL-37 protein is expressed in healthy and diseased bowel and liver tissue. Here, we tested whether transgenic expression of human IL-37 protects IL-10 deficient (IL-10KO) mice from chronic colitis. IL-37tg mice were crossbred with IL-10KO mice. Homozygous IL-10KO/IL-37tg and IL10KO drank 2% dextran sulfate sodium (DSS) in water for 5 days to induce mild colitis. Colon carcinogenesis was triggered by intragastric administration of celecoxib. Endpoints were clinical parameters of colitis, cytokine responses in LPS-stimulated whole blood and explanted colon specimen and qPCR analysis of colon biopsies. Colon inflammation and number of adenoma—carcinoma were analyzed by histology. During the DSS-induction phase IL-10KO and IL-10KO/IL-37tg mice had a similar weight loss due to mild acute colitis. From day 115 there was a significantly improved weight gain in IL-10KO/IL37-tg mice, though colon length was similar. After ex vivo LPS stimulation whole blood of IL-10KO/IL-37tg compared to IL-10KO mice released less IL-6, IL-17, IFNγ, and TNFα and ex vivo colon cultures showed reduced IL-6 production both indicative of reduced inflammatory conditions under the influence of IL-37. Six out of 10 IL-10KO mice developed colon adenoma and carcinoma. Only one adenoma but no carcinoma was detected in colons of IL-10KO/IL-37tg mice. In conclusion, IL-37 transgene expression protects IL-10KO mice from colon carcinogenesis. It remains unclear whether IL-37 has direct tumor suppressing properties

Modulation of Liver Inflammation and Fibrosis by Interleukin-37

Background and Aims: Chronic inflammation induces liver fibrosis, cirrhosis and potentially liver cancer. Kupffer cells modulate hepatic stellate cells by secreting immunologically active proteins as TGF-beta. TGF-beta promotes liver fibrosis via the activation of Sma- and Mad-related protein 3. IL-37 broadly suppresses innate and adaptive immune responses. Intracellular IL-37 interacts with Smad3. We hypothesize that IL-37 downregulates the activation of hepatic Kupffer and stellate cells and interferes with the TGF-beta signaling cascade to modulate liver fibrogenesis. Methods: The role of IL-37 on liver inflammation and fibrogenesis was assessed in three mouse models as well as isolated Kupffer- and stellate cells. Serum IL-37 was tested by ELISA in a clinical cohort and correlated with liver disease severity. Results: Transgene expression of IL-37 in mice extends survival, reduces hepatic damage, expression of early markers of fibrosis and histologically assessed liver fibrosis after bile duct ligation. IL-37tg mice were protected against CCl4-induced liver inflammation. Colitis-associated liver inflammation and fibrosis was less severe in IL-10 knockout IL-37tg mice. Spontaneous and LPS/TGF-beta-induced cytokine release and profibrogenic gene expression was lower in HSC and KC isolated from IL-37tg mice and IL-37 overexpressing, IL-1 beta stimulated human LX-2 stellate cells. However, administration of recombinant human IL-37 did not modulate fibrosis pathways after BDL in mice, LX2 cells or murine HSCs. In a large clinical cohort, we observed a positive correlation of serum IL-37 levels with disease severity in liver cirrhosis. Conclusions: Predominantly intracellular IL-37 downregulates liver inflammation and fibrosis. The correlation of serum IL-37 with disease severity in cirrhosis suggests its potential as a novel target modulating the course of liver fibrosis

Association of cholesterol levels with hemorrhagic transformation and cerebral edema after reperfusion therapies

[Background] The association between cholesterol levels and cerebral edema (CED) or hemorrhagic transformation (HT) as an expressions of blood-brain barrier (BBB) dysfunction after ischemic stroke is not well established. The aim of this study is to determine the association of total cholesterol (TC) levels with the incidence of HT and CED after reperfusion therapies.[Methods] We analyzed SITS Thrombolysis and Thrombectomy Registry data from January 2011 to December 2017. We identified patients with data on TC levels at baseline. TC values were categorized in three groups (reference group ⩾200 mg/dl). The two primary outcomes were any parenchymal hemorrhage (PH) and moderate to severe CED on follow up imaging. Secondary outcomes included death and functional independence (mRS 0–2) at 3 months. Multivariable logistic regression analysis adjusted for baseline factors including statin pretreatment was used to assess the association between TC levels and outcomes.[Results] Of 35,314 patients with available information on TC levels at baseline, 3372 (9.5%) presented with TC levels ⩽130 mg/dl, 8203 (23.2%) with TC 130–200 mg/dl and 23,739 (67.3%) with TC ⩾ 200 mg/dl. In the adjusted analyses, TC level as continuous variable was inversely associated with moderate to severe CED (OR 0.99, 95% CI 0.99–1.00, p = 0.025) and as categorical variable lower TC levels were associated with a higher risk of moderate to severe CED (aOR 1.24, 95% CI 1.10–1.40, p = 0.003). TC levels were not associated with any PH, functional independence, and mortality at 3 months.[Conclusions] Our findings indicate an independent association between low levels of TC and higher odds of moderate/severe CED. Further studies are needed to confirm these findings.The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The SITS registry is financed directly and indirectly by grants from Karolinska Institutet, Stockholm County Council, the Swedish Heart-Lung Foundation, as well as from an unrestricted sponsorship from Boehringer-Ingelheim. SITS has previously received grants from the European Union Framework 7, the European Union Public Health Authority, and conducted studies supported by EVER Pharma and Ferrer Internacional, as well as in collaboration with Karolinska Institutet, supported by Stryker, Covidien, and Phenox. SITS is currently conducting studies supported by Boehringer-Ingelheim and Biogen. N Ahmed is supported by Stockholm County Council and Swedish Heart-lung Foundation. Irene Escudero-Martínez has received a grant from “Fundación Progreso y Salud, Junta de Andalucía” (grant EF-0437-2018).Peer reviewe

Recanalization Therapies for Large Vessel Occlusion Due to Cervical Artery Dissection: A Cohort Study of the EVA-TRISP Collaboration

Background and Purpose: This study aimed to investigate the effect of endovascular treatment (EVT, with or without intravenous thrombolysis [IVT]) versus IVT alone on outcomes in patients with acute ischemic stroke (AIS) and intracranial large vessel occlusion (LVO) attributable to cervical artery dissection (CeAD). Methods: This multinational cohort study was conducted based on prospectively collected data from the EVA-TRISP (EndoVAscular treatment and ThRombolysis for Ischemic Stroke Patients) collaboration. Consecutive patients (2015–2019) with AIS-LVO attributable to CeAD treated with EVT and/or IVT were included. Primary outcome measures were (1) favorable 3-month outcome (modified Rankin Scale score 0–2) and (2) complete recanalization (thrombolysis in cerebral infarction scale 2b/3). Odds ratios with 95% confidence intervals (OR [95% CI]) from logistic regression models were calculated (unadjusted, adjusted). Secondary analyses were performed in the patients with LVO in the anterior circulation (LVOant) including propensity score matching. Results: Among 290 patients, 222 (76.6%) had EVT and 68 (23.4%) IVT alone. EVT-treated patients had more severe strokes (National Institutes of Health Stroke Scale score, median [interquartile range]: 14 [10–19] vs. 4 [2–7], Padjusted 0.56 [0.24–1.32]). EVT was associated with higher rates of recanalization (80.5% vs. 40.7%; ORadjusted 8.85 [4.28–18.29]) compared to IVT. All secondary analyses showed higher recanalization rates in the EVT-group, which however never translated into better functional outcome rates compared to the IVT-group. Conclusion: We observed no signal of superiority of EVT over IVT regarding functional outcome in CeAD-patients with AIS and LVO despite higher rates of complete recanalization with EVT. Whether pathophysiological CeAD-characteristics or their younger age might explain this observation deserves further research

Thrombolysis in stroke patients with elevated inflammatory markers.

OBJECTIVE To investigate the prognostic value of white blood cell count (WBC) on functional outcome, mortality and bleeding risk in stroke patients treated with intravenous thrombolysis (IVT). METHODS In this prospective multicenter study from the TRISP registry, we assessed the association between WBC on admission and 3-month poor outcome (modified Rankin Scale 3-6), mortality and occurrence of symptomatic intracranial hemorrhage (sICH; ECASS-II-criteria) in IVT-treated stroke patients. WBC was used as continuous and categorical variable distinguishing leukocytosis (WBC > 10 × 109/l) and leukopenia (WBC  10 mg/l) on outcomes. RESULTS Of 10,813 IVT-treated patients, 2527 had leukocytosis, 112 leukopenia and 8174 normal WBC. Increasing WBC (by 1 × 109/l) predicted poor outcome (ORadjusted 1.04[1.02-1.06]) but not mortality and sICH. Leukocytosis was independently associated with poor outcome (ORadjusted 1.48[1.29-1.69]) and mortality (ORadjusted 1.60[1.35-1.89]) but not with sICH (ORadjusted 1.17[0.94-1.45]). Leukopenia did not predict any outcome. In a subgroup, combined leukocytosis and elevated CRP had the strongest association with poor outcome (ORadjusted 2.26[1.76-2.91]) and mortality (ORadjusted 2.43[1.86-3.16]) when compared to combined normal WBC and CRP. CONCLUSION In IVT-treated patients, leukocytosis independently predicted poor functional outcome and death. Bleeding complications after IVT were not independently associated with leukocytosis

EndoVAscular treatment and ThRombolysis for Ischemic Stroke Patients (EVA-TRISP) registry: basis and methodology of a pan-European prospective ischaemic stroke revascularisation treatment registry.

PURPOSE The Thrombolysis in Ischemic Stroke Patients (TRISP) collaboration was a concerted effort initiated in 2010 with the purpose to address relevant research questions about the effectiveness and safety of intravenous thrombolysis (IVT). The collaboration also aims to prospectively collect data on patients undergoing endovascular treatment (EVT) and hence the name of the collaboration was changed from TRISP to EVA-TRISP. The methodology of the former TRISP registry for patients treated with IVT has already been published. This paper focuses on describing the EVT part of the registry. PARTICIPANTS All centres committed to collecting predefined variables on consecutive patients prospectively. We aim for accuracy and completeness of the data and to adapt local databases to investigate novel research questions. Herein, we introduce the methodology of a recently constructed academic investigator-initiated open collaboration EVT registry built as an extension of an existing IVT registry in patients with acute ischaemic stroke (AIS). FINDINGS TO DATE Currently, the EVA-TRISP network includes 20 stroke centres with considerable expertise in EVT and maintenance of high-quality hospital-based registries. Following several successful randomised controlled trials (RCTs), many important clinical questions remain unanswered in the (EVT) field and some of them will unlikely be investigated in future RCTs. Prospective registries with high-quality data on EVT-treated patients may help answering some of these unanswered issues, especially on safety and efficacy of EVT in specific patient subgroups. FUTURE PLANS This collaborative effort aims at addressing clinically important questions on safety and efficacy of EVT in conditions not covered by RCTs. The TRISP registry generated substantial novel data supporting stroke physicians in their daily decision making considering IVT candidate patients. While providing observational data on EVT in daily clinical practice, our future findings may likewise be hypothesis generating for future research as well as for quality improvement (on EVT). The collaboration welcomes participation of further centres willing to fulfill the commitment and the outlined requirements