Tenecteplase versus alteplase before mechanical thrombectomy: experience from a US healthcare system undergoing a system-wide transition of primary thrombolytic.

BACKGROUND: Tenecteplase (TNK) is a genetically modified variant of alteplase (TPA) and has been established as a non-inferior alternative to TPA in acute ischemic stroke (AIS). Whether TNK exerts distinct benefits in large vessel occlusion (LVO) AIS is still being investigated. OBJECTIVE: To describe our first-year experience after a healthcare system-wide transition from TPA to TNK as the primary thrombolytic. METHODS: Patients with AIS who received intravenous thrombolytics between January 2020 and August 2022 were retrospectively reviewed. All patients with LVO considered for mechanical thrombectomy (MT) were included in this analysis. Spontaneous recanalization (SR) after TNK/TPA was a composite variable of reperfusion >50% of the target vessel territory on cerebral angiography or rapid, significant neurological recovery averting MT. Propensity score matching (PSM) was performed to compare SR rates between TNK and TPA. RESULTS: A total of 148 patients were identified; 51/148 (34.5%) received TNK and 97/148 (65.5%) TPA. The middle cerebral arteries M1 (60.8%) and M2 (29.7%) were the most frequent occlusion sites. Baseline demographics were comparable between TNK and TPA groups. Spontaneous recanalization was significantly more frequently observed in the TNK than in the TPA groups (unmatched: 23.5% vs 10.3%, P=0.032). PSM substantiated the observed SR rates (20% vs 10%). Symptomatic intracranial hemorrhage, 90-day mortality, and functional outcomes were similar. CONCLUSIONS: The preliminary experience from a real-world setting demonstrates the effectiveness and safety of TNK before MT. The higher spontaneous recanalization rates with TNK are striking. Additional studies are required to investigate whether TNK is superior to TPA in LVO AIS.

A Genome-Wide Association Study of Outcome After Aneurysmal Subarachnoid Haemorrhage: Discovery Analysis.

Candidate gene studies have identified genetic variants associated with clinical outcomes following aneurysmal subarachnoid haemorrhage (aSAH), but no genome-wide association studies have been performed to date. Here we report the results of the discovery phase of a two-stage genome-wide meta-analysis of outcome after aSAH. We identified 157 independent loci harbouring 756 genetic variants associated with outcome after aSAH (p < 1 × 10-4), which require validation. A single variant (rs12949158), in SPNS2, achieved genome-wide significance (p = 4.29 × 10-8) implicating sphingosine-1-phosphate signalling in outcome after aSAH. A large multicentre international effort to recruit samples for validation is required and ongoing. Validation of these findings will provide significant insight into the pathophysiology of outcomes after aSAH with potential implications for treatment.

Genome-Wide Association Study of Clinical Outcome After Aneurysmal Subarachnoid Haemorrhage: Protocol.

Aneurysmal subarachnoid haemorrhage (aSAH) results in persistent clinical deficits which prevent survivors from returning to normal daily functioning. Only a small fraction of the variation in clinical outcome following aSAH is explained by known clinical, demographic and imaging variables; meaning additional unknown factors must play a key role in clinical outcome. There is a growing body of evidence that genetic variation is important in determining outcome following aSAH. Understanding genetic determinants of outcome will help to improve prognostic modelling, stratify patients in clinical trials and target novel strategies to treat this devastating disease. This protocol details a two-stage genome-wide association study to identify susceptibility loci for clinical outcome after aSAH using individual patient-level data from multiple international cohorts. Clinical outcome will be assessed using the modified Rankin Scale or Glasgow Outcome Scale at 1-24 months. The stage 1 discovery will involve meta-analysis of individual-level genotypes from different cohorts, controlling for key covariates. Based on statistical significance, supplemented by biological relevance, top single nucleotide polymorphisms will be selected for replication at stage 2. The study has national and local ethical approval. The results of this study will be rapidly communicated to clinicians, researchers and patients through open-access publication(s), presentation(s) at international conferences and via our patient and public network.

P2Y12 inhibitors in neuroendovascular surgery: An opportunity for precision medicine.

INTRODUCTION: Dual antiplatelet therapy (DAPT), primarily the combination of aspirin with a P2Y12 inhibitor, in patients undergoing intravascular stent or flow diverter placement remains the primary strategy to reduce device-related thromboembolic complications. However, selection, timing, and dosing of DAPT is critical and can be challenging given the existing significant inter- and intraindividual response variations to P2Y12 inhibitors. METHODS: Assessment of indexed, peer-reviewed literature from 2000 to 2020 in interventional cardiology and neuroendovascular therapeutics with critical, peer-reviewed appraisal and extraction of evidence and strategies to utilize DAPT in cardio- and neurovascular patients with endoluminal devices. RESULTS: Both geno- and phenotyping for DAPT are rapidly and conveniently available as point-of-care testing at a favorable cost-benefit ratio. Furthermore, systematic inclusion of a quantifying clinical risk score combined with an operator-linked, technical risk assessment for potential adverse events allows a more precise and individualized approach to new P2Y12 inhibitor therapy. CONCLUSIONS: The latest evidence, primarily obtained from cardiovascular intervention trials, supports that combining patient pharmacogenetics with drug response monitoring, as part of an individually tailored, precision medicine approach, is both predictive and cost-effective in achieving and maintaining individual target platelet inhibition levels. Indirect evidence supports that this gain in optimizing drug responses translates to reducing main adverse events and overall treatment costs in patients undergoing DAPT after intracranial stent or flow diverting treatment.

Human and Murine Tissue-Engineered Colon Exhibit Diverse Neuronal Subtypes and Can Be Populated by Enteric Nervous System Progenitor Cells When Donor Colon Is Aganglionic.

PURPOSE: Tissue-engineered colon (TEC) might potentially replace absent or injured large intestine, but the enteric nervous system (ENS), a key component, has not been investigated. In various enteric neuropathic diseases in which the TEC is derived from aganglionic donor colon, the resulting construct might also be aganglionic, limiting tissue engineering applications in conditions such as Hirschsprung disease (HD). We hypothesized that TEC might contain a diverse population of enteric neuronal subtypes, and that aganglionic TEC can be populated by neurons and glia when supplemented with ENS progenitor cells in the form of neurospheres. MATERIALS AND METHODS: Human and murine organoid units (OU) and multicellular clusters containing epithelium and mesenchyme were isolated from both mouse and human donor tissues, including from normally innervated and aganglionic colon. The OU were seeded onto a biodegradable scaffold and implanted within a host mouse, resulting in the growth of TEC. Aganglionic murine and human OU were supplemented with cultured neurospheres to populate the absent ENS not provided by the OU to rescue the HD phenotype. RESULTS: TEC demonstrated abundant smooth muscle and clusters of neurons and glia beneath the epithelium and deeper within the mesenchyme. Motor and afferent neuronal subtypes were identified in TEC. Aganglionic OU formed TEC with absent neural elements, but neurons and glia were abundant when aganglionic OU were supplemented with ENS progenitor cells. CONCLUSION: Murine and human TEC contain key components of the ENS that were not previously identified, including glia, neurons, and fundamental neuronal subtypes. TEC derived from aganglionic colon can be populated with neurons and glia when supplemented with neurospheres. Combining tissue engineering and cellular replacement therapies represents a new strategy for treating enteric neuropathies, particularly HD.