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Background In vitro systems of primary cystic fibrosis (CF) airway epithelial cells are an important tool to study molecular and functional features of the native respiratory epithelium. However, undifferentiated CF airway cell cultures grown under submerged conditions do not appropriately represent the physiological situation. A more advanced CF cell culture system based on airway epithelial cells grown at the air-liquid interface (ALI) recapitulates most of the in vivo-like properties but requires the use of invasive sampling methods. In this study, we describe a detailed characterization of fully differentiated primary CF airway epithelial cells obtained by non-invasive nasal brushing of pediatric patients. Methods Differentiated cell cultures were evaluated with immunolabelling of markers for ciliated, mucus-secreting and basal cells, and tight junction and CFTR proteins. Epithelial morphology and ultrastructure was examined by histology and transmission electron microscopy. Ciliary beat frequency was investigated by a video-microscopy approach and trans-epithelial electrical resistance was assessed with an epithelial Volt-Ohm meter system. Finally, epithelial permeability was analysed by using a cell layer integrity test and baseline cytokine levels where measured by an enzyme-linked immunosorbent assay. Results Pediatric CF nasal cultures grown at the ALI showed a differentiation into a pseudostratified epithelium with a mucociliary phenotype. Also, immunofluorescence analysis revealed the presence of ciliated, mucus-secreting and basal cells and tight junctions. CFTR protein expression was observed in CF (F508del/F508del) and healthy cultures and baseline interleukin (IL)-8 and IL-6 release were similar in control and CF ALI cultures. The ciliary beat frequency was 9.67 Hz and the differentiated pediatric CF epithelium was found to be functionally tight. Conclusion In summary, primary pediatric CF nasal epithelial cell cultures grown at the ALI showed full differentiation into ciliated, mucus-producing and basal cells, which adequately reflect the in vivo properties of the human respiratory epithelium.

Abstract Background and aims Incomplete reperfusion following mechanical thrombectomy (MT) occurs in a significant proportion of patients with acute ischemic stroke and is associated with poor clinical outcomes. Intra-arterial tenecteplase (IA-TNK) may enhance reperfusion of residual occlusions that are not amenable to additional mechanical rescue maneuvers. The TECNO trial was designed to evaluate whether IA-TNK improves early and late reperfusion compared with best medical treatment (BMT) alone among patients with incomplete reperfusion. Methods TECNO is an international multicenter clinical trial that will randomize 156 patients with incomplete reperfusion to either IA-TNK or BMT arm (1:1). The two co-primary imaging endpoints were: (1) early reperfusion, defined as improvement in reperfusion on angiography 25 minutes after randomization, and (2) late reperfusion, defined as absence of a perfusion deficit on MR/CT perfusion imaging at 24 h ± 6 h after randomization. The main safety endpoint was symptomatic intracranial haemorrhage assessed in all randomly assigned and consenting participants. Analyses were performed according to the intention-to-treat principle. Results A total of 159 patients were randomized and the primary results of the trial will be presented at ESOC 2026. Conclusions This randomized controlled trial of patients with incomplete reperfusion after MT, will provide evidence on the value of IA TNK as compared to BMT in patients with residual occlusions. Conflict of interest

Abstract Rationale Intra-arterial fibrinolytics may be used for distal remaining vessel occlusions after incomplete mechanical thrombectomy (MT). However, their efficacy in improving reperfusion in this specific clinical scenario is unclear. While better reperfusion may lead to improved clinical outcomes, additional fibrinolytics could also increase the risk of hemorrhagic complications. Aim To assess the safety and reperfusion efficacy of intra-arterial tenecteplase (TNK) compared to no further interventional treatment in patients with incomplete reperfusion and mechanically non-amendable residual occlusions after MT. Methods and design This is an international, multicenter, randomized (1:1) controlled, two-arm, open, assessor-blinded, surrogate endpoint trial. The interventional arm receives 3 mg (not weight-adjusted) intra-arterial TNK, administered as close as possible to the residual occlusion. The control arm receives no further interventional treatment. Sample size TECNO will randomize 156 participants 1:1 to 3 mg intra-arterial tenecteplase or no further interventional treatment. This sample size is based on anticipated absolute improvements in early and late reperfusion with intra-arterial TNK of 25% and 30%, respectively. Outcomes The two co-primary imaging outcomes are early and late reperfusion. Early reperfusion is defined as an extended Thrombolysis in Cerebral Infarction (eTICI) score ⩾ 2a for residual occlusions on angiography 25 min after randomization. Late reperfusion is defined as the absence of a wedge-shaped perfusion delay on delay-sensitive perfusion maps assessed on 24 h ± 6 h perfusion imaging. Standard secondary clinical outcomes will be assessed at 24 h and 90 ± 15 days. Discussion The TECNO trial will provide evidence on the safety and reperfusion efficacy of locally administered intra-arterial TNK in patients with residual occlusions following MT. Graphical Abstract Graphical Abstract

Rationale: Decompressive craniectomy (DC) is beneficial in people with malignant middle cerebral artery infarction. Whether DC improves outcome in spontaneous intracerebral haemorrhage (ICH) is unknown. Aim: To determine whether DC without haematoma evacuation plus best medical treatment (BMT) in people with ICH decreases the risk of death or dependence at 6 months compared to BMT alone. Methods and design: SWITCH is an international, multicentre, randomised (1:1), two-arm, open-label, assessor-blinded trial. Key inclusion criteria are age ⩽75 years, stroke due to basal ganglia or thalamic ICH that may extend into cerebral lobes, ventricles or subarachnoid space, Glasgow coma scale of 8–13, NIHSS score of 10–30 and ICH volume of 30–100 mL. Randomisation must be performed <66 h after onset and DC <6 h after randomisation. Both groups will receive BMT. Participants randomised to the treatment group will receive DC of at least 12 cm in diameter according to institutional standards. Sample size: A sample of 300 participants randomised 1:1 to DC plus BMT versus BMT alone provides over 85% power at a two-sided alpha-level of 0.05 to detect a relative risk reduction of 33% using a chi-squared test. Outcomes: The primary outcome is the composite of death or dependence, defined as modified Rankin scale score 5–6 at 6 months. Secondary outcomes include death, functional status, quality of life and complications at 180 days and 12 months. Discussion: SWITCH will inform physicians about the outcomes of DC plus BMT in people with spontaneous deep ICH, compared to BMT alone. Trial registration: ClinicalTrials.gov Identifier: NCT02258919 Graphical abstract

Rationale: Direct oral anticoagulants (DOAC) are highly effective in preventing ischaemic strokes in people with atrial fibrillation (AF). However, it is unclear how soon they should be started after acute ischaemic stroke (AIS). Early initiation may reduce early risk of recurrence but might increase the risk of haemorrhagic complications. Aim: To estimate the safety and efficacy of early initiation of DOACs compared to late guideline-based initiation in people with AIS related to AF. Methods and design: An international, multicentre, randomised (1:1) controlled, two-arm, open, assessor-blinded trial is being conducted. Early treatment is defined as DOAC initiation within 48 h of a minor or moderate stroke, or at day 6–7 following major stroke. Late treatment is defined as DOAC initiation after day 3–4 following minor stroke, after day 6–7 following moderate stroke and after day 12–14 following major stroke. Severity of stroke is defined according to imaging assessment of infarct size. Sample size: ELAN will randomise 2000 participants 1:1 to early versus late initiation of DOACs. This assumes a risk difference of 0.5% favouring the early arm, allowing an upper limit of the 95% confidence interval up to 1.5% based on the Miettinen & Nurminen formula. Outcomes: The primary outcome is a composite of symptomatic intracranial haemorrhage, major extracranial bleeding, recurrent ischaemic stroke, systemic embolism or vascular death at 30 ± 3 days after randomisation. Secondary outcomes include the individual components of the primary outcome at 30 ± 3 and 90 ± 7 days and functional status at 90 ± 7 days. Discussion: ELAN will estimate whether there is a clinically important difference in safety and efficacy outcomes following early anticoagulation with a DOAC compared to late guideline-based treatment in neuroimaging-selected people with an AIS due to AF.

Background and aim Explicit diagnostic criteria for transient ischemic attack (TIA) (EDCT) have been recently proposed based on the assumption, that a migraine aura-like symptom is not typical for a TIA. However, migraine-like symptoms have been unexpectedly frequent in patients with confirmed ischemic stroke. This cross-sectional study aimed to field-test the EDCT to distinguish transient neurological symptoms caused by cerebral infarction from those caused by migraine aura. Methods The sensitivity, specificity, positive and negative predictive values of the EDCT score were calculated in samples of patients with (i) transient symptoms caused by cerebral infarction confirmed by imaging and (ii) patients with migraine with aura diagnosed according to the International Classification of Headache Disorders 3rd edition. Sensitivity, specificity, positive and negative predictive values of the original and modified EDCT were calculated, as well as area under the curve adjusted for age and sex using the logistic regression method. Results The study population included 59 patients with cerebral infarction and 324 patients with migraine with aura. The median age of the stroke group was 72 (IQR 61–81) and of the migraine group 39 (IQR 29–53). There were 36 (61%) men in the stroke group and 221 (68%) women in the migraine group. For the detection of TIA with imaging-proven cerebral infarction, the original EDCT had a sensitivity of 90% (95%CI 79–96), a specificity 77% (95%CI 72–82), a positive predictive value of 42% (95%CI 33–51), and the negative predictive value 98% (95% CI 95–99). For the modified EDCT, the sensitivity was 81% (95%CI 69–90), the specificity 97% (95%CI 94–98), the positive predictive value 81% (95%CI 69–90), and the negative predictive value 97% (95%CI 94–98). Conclusions The original and modified EDCT criteria miss up to 1 of 10 and 1 of 5 patients, respectively, with transient symptoms due to cerebral infarction. However, the modified EDCT criteria are more specific but less sensitive in detection of ischemic events. The optimal combination of clinical markers to reliably distinguish TIA from migraine aura remains to be found.