Interleukin 23 levels are increased in carotid atherosclerosis: possible role for the interleukin 23/interleukin 17 axis.

BACKGROUND AND PURPOSE: Interleukin (IL)-23 is a cytokine in the IL-12 family, mainly produced by antigen-presenting cells with a central role in inflammation. We hypothesize that IL-23 is also important in atherogenesis and investigate this in a population with carotid atherosclerosis. METHODS: Plasma levels of IL-23 were measured in patients with carotid artery stenosis and in healthy controls. The mRNA levels of IL-23 and its receptor, IL-23R, were measured in atherosclerotic plaques, nonatherosclerotic vessels, peripheral blood mononuclear cells, and plasmacytoid dendritic cells. RESULTS: Our findings were as follows: (1) patients with carotid atherosclerosis (n=177) had significantly raised plasma levels of IL-23 when compared with healthy controls (n=24) with particularly high levels in those with the most recent symptoms. (2) mRNA levels of IL-23 and IL-23R were markedly increased in carotid plaques (n=68) when compared with nonatherosclerotic vessels (n=8-10). Immunostaining showed colocalization to plaque macrophages. (3) Patients with carotid atherosclerosis had increased mRNA levels of both IL-23 and IL-23R in plasmacytoid dendritic cells, but not in peripheral blood mononuclear cells. (4) IL-23 increased IL-17 release in monocytes and particularly in peripheral blood mononuclear cells from patients with carotid atherosclerosis, but not in cells from healthy controls. (5) IL-23 gave a prominent tumor necrosis factor release in monocytes from patients with carotid atherosclerosis but not in cells from healthy controls. (6) High plasma levels of IL-23 were associated with increased mortality during follow-up. CONCLUSIONS: We have shown an association between IL-23 and disease progression in patients with carotid atherosclerosis, potentially involving IL-17-related mechanisms.

Transcranial Doppler during the first week after cardiac arrest and association with 6-month outcomes.

Background: Early prediction of outcomes in comatose patients after out-of-hospital cardiac arrest is challenging. Prognostication tools include clinical examination, biomarkers, and neuroradiological and neurophysiological tests. We studied the association between transcranial Doppler (TCD) and the outcome. Methods: This was a pre-defined sub-study of the prospective observational Norwegian Cardiorespiratory Arrest Study. Patients underwent standardized post-resuscitation care, including target temperature management (TTM) to 33°C for 24 h. TCD was performed at days 1, 3, and 5-7. The primary endpoint was cerebral performance category (CPC) at 6 months, dichotomized into good (CPC 1-2) and poor (CPC 3-5) outcomes. We used linear mixed modeling time-series analysis. Results: Of 139 TCD-examined patients, 81 (58%) had good outcomes. Peak systolic velocity in the middle cerebral artery (PSV) was low during TTM (Day 1) and elevated after rewarming (Day 3). Thereafter, it continued to rise in patients with poor, but normalized in patients with good, outcomes. At days 5-7, PSV was 1.0 m/s (95% CI 0.9; 1.0) in patients with good outcomes and 1.3 m/s (95% CI 1.1; 1.4) in patients with poor outcomes (p < 0.001). Conclusion: Elevated PSV at days 5-7 indicated poor outcomes. Our findings suggest that serial TCD examinations during the first week after cardiorespiratory arrest may improve our understanding of serious brain injury.

Late awakening, prognostic factors and long-term outcome in out-of-hospital cardiac arrest - results of the prospective Norwegian Cardio-Respiratory Arrest Study (NORCAST).

BACKGROUND: Outcome prediction after out-of-hospital cardiac arrest (OHCA) may lead to withdrawal of life-sustaining therapy if the prognosis is perceived negative. Single use of uncertain prognostic tools may lead to self-fulfilling prophecies and death. We evaluated prognostic tests, blinded to clinicians and without calls for hasty outcome prediction, in a prospective study. METHODS: Comatose, sedated TTM 33-treated OHCA patients of all causes were included. Clinical-neurological/-neurophysiological/-biochemical predictors were registered. Patients were dichotomized into good/poor outcome using cerebral performance category (CPC) six months and > four years post-arrest. Prognostic tools were evaluated using false positive rates (FPR). RESULTS: We included 259 patients; 49 % and 42 % had good outcome (CPC 1-2) after median six months and 5.1 years. Unwitnessed arrest, non-shockable rhythms, and no-bystander-CPR predicted poor outcome with FPR (CI) 0.05 (0.02-0.10), 0.13 (0.08-0.21), and 0.13 (0.07-0.20), respectively. Time to awakening was median 6 (0-25) days in good outcome patients. Among patients alive with sedation withdrawal >72 h, 49 % were unconscious, of whom 32 % still obtained good outcome. Only absence of pupillary light reflexes (PLR) -and N20-responses in somato-sensory evoked potentials (SSEP), as well as increased neuron-specific enolase (NSE) later than 24 h to >80 µg/L, had FPR 0. Malignant EEG (burst suppression/epileptic activity/flat) differentiated poor/good outcome with FPR 0.05 (0.01-0.15). CONCLUSION: Time to awakening was over six days in good outcome patients. Most clinical parameters had too high FPRs for prognostication, except for absent PLR and SSEP-responses >72 h after sedation withdrawal, and increased NSE later than 24 h to >80 µg/L.

Tenecteplase versus alteplase for management of acute ischaemic stroke (NOR-TEST): a phase 3, randomised, open-label, blinded endpoint trial.

BACKGROUND: Tenecteplase is a newer thrombolytic agent with some pharmacological advantages over alteplase. Previous phase 2 trials of tenecteplase in acute ischaemic stroke have shown promising results. We aimed to investigate the safety and efficacy of tenecteplase versus alteplase in patients with acute stroke who were eligible for intravenous thrombolysis. METHODS: This phase 3, randomised, open-label, blinded endpoint, superiority trial was done in 13 stroke units in Norway. We enrolled adults with suspected acute ischaemic stroke who were eligible for thrombolysis and admitted within 4·5 h of symptom onset or within 4·5 h of awakening with symptoms, or who were eligible for bridging therapy before thrombectomy. Patients were randomly assigned (1:1) to receive intravenous tenecteplase 0·4 mg/kg (to a maximum of 40 mg) or alteplase 0·9 mg/kg (to a maximum of 90 mg), via a block randomisation schedule stratified by centre of inclusion. Patients were not informed of treatment allocation; treating physicians were aware of treatment allocation but those assessing the primary and secondary endpoints were not. The primary outcome was excellent functional outcome defined as modified Rankin Scale (mRS) score 0-1 at 3 months. The primary analysis was an unadjusted and non-stratified intention-to-treat analysis with last observation carried forward for imputation of missing data. This study is registered with ClinicalTrials.gov, number NCT01949948. FINDINGS: Between Sept 1, 2012, and Sept 30, 2016, 1107 patients met the inclusion criteria and seven patients were excluded because informed consent was withdrawn or eligibility for thrombolytic treatment was reconsidered. 1100 patients were randomly assigned to the tenecteplase (n=549) or alteplase (n=551) groups. The median age of participants was 77 years (IQR 64-79) and the median National Institutes of Health Stroke Scale score at baseline was 4 points (IQR 2-8). A final diagnosis other than ischaemic stroke or transient ischaemic attack was found in 99 (18%) patients in the tenecteplase group and 91 (17%) patients in the alteplase group. The primary outcome was achieved by 354 (64%) patients in the tenecteplase group and 345 (63%) patients in the alteplase group (odds ratio 1·08, 95% CI 0·84-1·38; p=0·52). By 3 months, 29 (5%) patients had died in the tenecteplase group compared with 26 (5%) in the alteplase group. The frequency of serious adverse events was similar between groups (145 [26%] in the tenecteplase group vs 141 [26%] in the alteplase group; p=0·74). INTERPRETATION: Tenecteplase was not superior to alteplase and showed a similar safety profile. Most patients enrolled in this study had mild stroke. Further trials are needed to establish the safety and efficacy in patients with severe stroke and whether tenecteplase is non-inferior to alteplase. FUNDING: Research Council of Norway.