Tenecteplase versus alteplase for the management of acute ischaemic stroke in Norway (NOR-TEST 2, part A): a phase 3, randomised, open-label, blinded endpoint, non-inferiority trial.

BACKGROUND: Tenecteplase is a modified tissue plasminogen activator with pharmacological and practical advantages over alteplase-which is currently the only approved thrombolytic drug for ischaemic stroke. The NOR-TEST trial showed that 0·4 mg/kg tenecteplase had an efficacy and safety profile similar to that of a standard dose (0·9 mg/kg) of alteplase, albeit in a patient population with a high prevalence of minor stroke. The aim of NOR-TEST 2 was to establish the non-inferiority of tenecteplase 0·4 mg/kg to alteplase 0·9 mg/kg for patients with moderate or severe ischaemic stroke. METHODS: This phase 3, randomised, open-label, blinded endpoint, non-inferiority trial was performed at 11 hospitals with stroke units in Norway. Patients with suspected acute ischaemic stroke with a National Institutes of Health Stroke Scale score of 6 or more who were eligible for thrombolysis and admitted within 4·5 h of symptom onset were consecutively included. Random assignment, done by a computer with a block size of 4 and with allocations placed into opaque envelopes to be opened consecutively, was 1:1 between intravenous tenecteplase (0·4 mg/kg) or standard dose alteplase (0·9 mg/kg). Doctors and nurses providing acute care were not masked to treatment, but primary outcome assessment at 3 months was masked. The primary outcome was favourable functional outcome defined as a modified Rankin Scale score of 0-1 at 3 months, assessed in the modified intention-to-treat analysis (excluding patients who did not qualify for thrombolysis after randomisation or who withdrew informed consent). The non-inferiority margin was 3%. This trial (NOR-TEST 2) is registered with EudraCT (number 2018-003090-95) and ClinicalTrials.gov (NCT03854500). The trial was stopped early for safety reasons and is designated part A for analysis. Part B is ongoing with a lower dose of tenecteplase (0·25 mg/kg). FINDINGS: Between Oct 28, 2019, and Sept 26, 2021, 216 patients were enrolled. Patient enrolment was stopped after a per-protocol safety review showed an imbalance in the rates of symptomatic intracranial haemorrhage between the treatment groups, which surpassed the prespecified criteria for stopping the trial. Of 204 patients entering the modified intention-to-treat analysis, 100 were randomly allocated tenecteplase and 104 were allocated alteplase. All patients were followed up within 14 days of the end of the 3-months' follow-up period. A favourable functional outcome was reported less frequently in patients receiving tenecteplase (31 [32%] of 96 patients) compared with alteplase (52 [51%] of 101 patients; unadjusted OR 0·45 [95% CI 0·25-0·80]; p=0·0064). Any intracranial haemorrhage was significantly more frequent with tenecteplase (21 [21%] of 100 patients) than with alteplase (seven [7%] of 104 patients; unadjusted OR 3·68 [95% CI 1·49-9·11]; p=0·0031). Mortality at 3 months was also significantly higher with tenecteplase (15 [16%] of 96 patients) than with alteplase (five [5%] of 101 patients; unadjusted OR 3·56 [95% CI 1·24-10·21]; p=0·013). Numerically more cases of symptomatic intracranial haemorrhage were reported with tenecteplase (six [6%] of 100 patients) than with alteplase (one [1%] of 104 patients; unadjusted OR 6·57 [95% CI 0·78-55·62]; p=0·061). INTERPRETATION: In this prematurely terminated study (terminated to fulfil the prespecified safety criteria), tenecteplase at a dose of 0·4 mg/kg yielded worse safety and functional outcomes compared with alteplase. Our study consequently could not show that 0·4 mg/kg tenecteplase is non-inferior to alteplase in moderate and severe ischaemic stroke. Future stroke trials should assess a lower dose of tenecteplase versus alteplase in patients with moderate or severe stroke. FUNDING: The Norwegian National Programme for Clinical Therapy Research.

Transcutaneous Vagal Nerve Stimulation in Treatment-Resistant Depression: A Feasibility Study.

BACKGROUND: Major depression (MD) contributes significantly to the global burden of disease with up to one-third of patients being treatment resistant. Therefore, the development of new treatment options for treatment-resistant depression (TRD) is needed. Vagus nerve stimulation (VNS) has shown mood improvements in patients with TRD. However, due to high costs related to the implantation and the invasive nature of VNS, an application with transcutaneous VNS (t-VNS) has been developed stimulating a vagal nerve branch in the earlobe (Arnold's nerve). A few studies with t-VNS in MD have shown a possible antidepressant effect, but feasibility is poorly described and patients with TRD have not been investigated. OBJECTIVES: As the full antidepressant effect of t-VNS takes months we wanted to assess feasibility and side effects of daily treatments. MATERIALS AND METHODS: Single-arm feasibility trial assessing compliance, usability, side effects, cognitive speed, and depression in a four-week period with a recommended t-VNS stimulation duration of four hours per day in patients with TRD. The primary outcome was compliance with 80% of the recommended daily treatment time. RESULTS: Compliance threshold was reached for 80.0% of the 20 included participants. Usability was acceptable. Side effects were few, mild or moderate, mostly as local effects at the contact point in the ear. The device was difficult to use for some participants. A statistically significant reduction in depression severity and an increase in cognitive speed were seen with unchanged suicidal ideation and sleep. CONCLUSIONS: We would recommend larger long-term randomized studies of t-VNS to access any antidepressant effect in TRD. The design of the device might be improved for higher usability.

Mitochondrial C5aR1 activity in macrophages controls IL-1ß production underlying sterile inflammation.

While serum-circulating complement destroys invading pathogens, intracellularly active complement, termed the "complosome," functions as a vital orchestrator of cell-metabolic events underlying T cell effector responses. Whether intracellular complement is also nonredundant for the activity of myeloid immune cells is currently unknown. Here, we show that monocytes and macrophages constitutively express complement component (C) 5 and generate autocrine C5a via formation of an intracellular C5 convertase. Cholesterol crystal sensing by macrophages induced C5aR1 signaling on mitochondrial membranes, which shifted ATP production via reverse electron chain flux toward reactive oxygen species generation and anaerobic glycolysis to favor IL-1ß production, both at the transcriptional level and processing of pro­IL-1ß. Consequently, atherosclerosis-prone mice lacking macrophage-specific C5ar1 had ameliorated cardiovascular disease on a high-cholesterol diet. Conversely, inflammatory gene signatures and IL-1ß produced by cells in unstable atherosclerotic plaques of patients were normalized by a specific cell-permeable C5aR1 antagonist. Deficiency of the macrophage cell-autonomous C5 system also protected mice from crystal nephropathy mediated by folic acid. These data demonstrate the unexpected intracellular formation of a C5 convertase and identify C5aR1 as a direct modulator of mitochondrial function and inflammatory output from myeloid cells. Together, these findings suggest that the complosome is a contributor to the biologic processes underlying sterile inflammation and indicate that targeting this system could be beneficial in macrophage-dependent diseases, such as atherosclerosis.

Fibrocartilaginous embolism as a cause of anterior spinal artery syndrome? / Fibrocartilaginøs emboli som årsak til arteria spinalis anterior-syndrom?

BACKGROUND: Fibrocartilaginous embolism (FCE) is a rare cause of spinal cord infarction. Most spinal cord infarctions are due to aortic pathologies and aortic surgeries. One theory is that material from the intervertebral discs follows a retrograde route to the anterior spinal artery. Fibrocartilaginous embolism and spinal cord infarction have also been described in veterinary literature. Spinal cord MRI diffusion-weighted imaging is of great help in finding the right diagnosis. CASE PRESENTATION: A young man was admitted to hospital after he woke up due to a sudden pain between his shoulders. He developed paresis in both his arms and legs within three hours. A neurological examination uncovered urinary retention, sensory deficits and paresis. The clinical picture was consistent with an infarction in the anterior spinal arterial distribution area. MRI of the patient's spine revealed an infarction in the anterior medulla. INTERPRETATION: Fibrocartilaginous embolism is probably more common than previously presumed.

Semiautomated Magnetic Resonance Imaging Assessment of Carotid Plaque Lipid Content.

BACKGROUND: The composition of a carotid plaque is important for plaque vulnerability and stroke risk. The main aim of this study was to assess the potential of semiautomated segmentation of carotid plaque magnetic resonance imaging (MRI) in the assessment of the size of the lipid-rich necrotic core (LRNC). METHODS: Thirty-four consecutive patients with carotid stenosis of 70% or higher, who were scheduled for carotid endarterectomy, underwent a clinical neurological examination, Color duplex ultrasound, 3-T MRI with an 8-channel carotid coil, and blood tests. All examinations were performed less than 24 hours prior to surgery and plaques were assessed histologically immediately following endarterectomy. Plaques were defined as symptomatic when associated with ipsilateral cerebral ischemic symptoms within 30 days prior to inclusion. The level of agreement between the size of the LRNC and calcification on MRI to the histological estimation of the same tissue components, plaque echolucency on ultrasound, and symptoms was assessed. RESULTS: The size of the LRNC on MRI was significantly correlated to the percentage amount of lipid per plaque on histological assessment (P = .010, r = .5), and to echogenicity on ultrasound with echolucent plaques having larger LRNC than echogenic plaques (P = .001, r = -.7). CONCLUSIONS: In this study, we found that semiautomated MRI assessments of the percentage LRNC in carotid plaques were significantly correlated to the percentage LRNC per plaque on histological assessment, and to echogenicity on ultrasound with echolucent plaques having larger LRNC than echogenic plaques.

Carotid Atherosclerosis in Adult Patients with Persistently Active Juvenile Idiopathic Arthritis Compared with Healthy Controls.

OBJECTIVE: Juvenile idiopathic arthritis (JIA) is the most common inflammatory rheumatic disease in childhood. It is regarded as a systemic inflammatory disease with possible increased risk of cardiovascular disease (CVD). The aim of this study was to assess carotid intima-media thickness (IMT) and carotid stenosis as surrogate measures for CVD in adults with longterm active JIA and healthy age- and sex-matched controls. METHODS: Seventy-five patients with JIA (age 28-45 yrs) with persistently active disease at least 15 years after disease onset were reexamined after a median of 29 years and compared with 75 matched controls. Patients and controls were examined by color duplex ultrasound of the carotid arteries to compare carotid IMT and carotid stenosis in the 2 groups. RESULTS: Patients with JIA did not have increased carotid IMT values compared with the controls (mean ± SD: 0.56 mm ± 0.09 vs 0.58 mm ± 0.07, p = 0.289). Patients with a higher disease activity indicated by the Juvenile Arthritis Disease Activity Score value above the median value had increased carotid IMT compared with the patients with a lower value, but not statistically different compared with controls. No carotid stenoses were detected in patients or controls. CONCLUSION: We found similar carotid IMT values in adult patients with JIA and controls.

Carotid plaque inflammation assessed with (18)F-FDG PET/CT is higher in symptomatic compared with asymptomatic patients.

BACKGROUND: Carotid artery plaque inflammation is thought to be an important marker of plaque vulnerability and increased stroke risk. AIM: The main aim of this study was to assess the level of agreement between 2-deoxy-2-[(18)F] fluoro-D-glucose (18F-FDG) uptake on PET (positron emission tomography) scan in carotid plaques, with cerebrovascular symptoms, carotid plaque ultrasound echogenicity and histological assessments of plaque inflammation. METHODS: Thirty-six patients with ≥70% carotid stenosis scheduled for carotid endarterectomy underwent a Colour Duplex ultrasound, (18)F-FDG PET/CT and blood tests less than 24 h prior to surgery. Plaques were defined as symptomatic when associated with ipsilateral cerebral ischemic symptoms within 30 days prior to inclusion. Plaques were assessed histologically following endarterectomy. The level of agreement between (18)F-FDG uptake (mean SUVmax and SUVmax ), and target-to-background ratio, symptoms, plaque echolucency, and histological evidence of inflammation was assessed. RESULTS: The amount of (18)F-FDG uptake in plaques and the amount of inflammation on histological assessment were significantly correlated (r = 0·521, P = 0·003). (18)F-FDG uptake was significantly higher in symptomatic plaques with median SUVmax 1·75 (1·26-2·04) in symptomatic, and 1·43 (1·15-2·28) in asymptomatic patients (P = 0·03). (18)F-FDG uptake was also positively correlated with echolucency on Doppler ultrasound (P = 0·03). CONCLUSION: (18)F-FDG uptake on PET/CT correlated with histological assessments of inflammation and was higher in patients with symptomatic compared with asymptomatic carotid artery plaques. These results support the use of (18)F-FDG PET/CT in the detection inflammation in carotid atherosclerosis, which may be of help in the detection of vulnerable plaques.

The assessment of carotid atherosclerosis using a new multipurpose ultrasound probe.

BACKGROUND AND PURPOSE: Multipurpose ultrasound probes combined with ultra-mobile ultrasound instrumentation have the potential to increase the availability and use of ultrasound examinations in the assessment of atherosclerotic burden and cardiac disease. The aim of this study was to compare the agreement of a newly developed multipurpose probe to a standard linear carotid probe in detection of atherosclerosis of the precerebral arteries. METHODS: We examined 103 patients with a multipurpose probe (General Electric, G9L MPP-9 MHz) and a standard linear probe (General Electric, Vivid 7-M12L-14 MHz). Measurements included intima-media thickness (IMT) in the common carotid arteries (CCA), carotid bifurcations (BIF), internal carotid arteries (ICA), and detection of carotid plaques and stenoses. RESULTS: We found a significant level of agreement between the two probes for all IMT measurements with intraclass correlation coefficients (ICC) of: left CCA .91, left BIF .68, left ICA .75, right CCA .84, right BIF .74, and right ICA .59. Agreement with regard to carotid plaque and stenosis detection had kappa values of .94 and .93. CONCLUSION: The multipurpose probe showed agreement with a standard linear probe in detecting atherosclerosis of the carotid arteries and has therefore the potential for use in both cardiac and precerebral ultrasound examinations.

Increased subclinical atherosclerosis in patients with chronic plaque psoriasis.

BACKGROUND: Psoriasis is an immune-mediated inflammatory skin condition of unknown aetiology which usually requires life-long treatment. It is regarded a systemic inflammatory disease with a possible increased risk of cardiovascular disease. The aim of this study was to assess carotid intima-media thickness (IMT), plaque prevalence and carotid stenosis as surrogate measures for cardiovascular disease in psoriasis patients and healthy controls. METHODS: Sixty-two patients with psoriasis and thirty-one healthy controls were included in the study. All were examined by Colour duplex ultrasound of the carotid arteries to compare carotid IMT values, carotid plaques and carotid stenosis in the two groups. Adjustments were made for traditional cardiovascular risk factors. RESULTS: Patients with psoriasis had increased carotid IMT values compared to the controls: mean ± SD 0.71 ± 0.17 mm vs. 0.59 ± 0.08 mm; p = 0.001. When adjusted for known atherosclerotic risk factors this difference remained significant (p = 0.04). Carotid plaques were also more common (p = 0.03) in patients with psoriasis 13 (21%) compared to controls 1 (3%). There was no difference with regard to the number of carotid stenoses in patients and controls. CONCLUSION: The results of this study support previous evidence which suggests that psoriasis is associated with an increased risk for atherosclerosis and subsequent cardiovascular disease.

Carotid artery intima-media thickness is closely related to impaired left ventricular function in patients with coronary artery disease: a single-centre, blinded, non-randomized study.

BACKGROUND: Atherosclerosis is the underlying cause of the majority of myocardial infarctions and ischemic strokes. Carotid intima-media thickness (IMT) is a surrogate measure of atherosclerotic cardiovascular disease. Left ventricular (LV) function can be accurately assessed by 2D speckle-tracking strain echocardiography (2D-STE). The aim of this study was to assess the relationship between carotid IMT and LV dysfunction assessed by strain echocardiography in patients with coronary artery disease (CAD). METHODS: Thirty-one patients with symptoms of CAD were examined with coronary angiography, cardiac echocardiography and carotid ultrasound. Layer-specific longitudinal strains were assessed from endo-, mid- and epicardium by 2D-STE. LV global longitudinal strain (LVGLS) was averaged from 16 longitudinal LV segments in all 3 layers. LVGLS results were compared with coronary angiography findings in a receiver operating curve (ROC) to determine the cut-off for normal and pathological strain values. The calculated optimal strain value was compared to maximal carotid IMT measurements. RESULTS: The ROC analysis for strain versus coronary angiography was: area under curve (AUC)=0.91 (95% CI 0.80 - 1.0), cut-off value for endocardial LVGLS: -16.7%. Further analyses showed that increased carotid IMT correlated with low absolute strain values (p=0.006) also when adjusted for hypertension, smoking, hyperlipidemia, diabetes and BMI (p=0.02). CONCLUSIONS: In this study increased carotid IMT values were associated with decreased LV function assessed by strain measurements. These findings support the use of carotid IMT measurements to predict the risk of coronary heart disease.