Prospective study on embolization of intracranial aneurysms with the pipeline device (PREMIER study): 3-year results with the application of a flow diverter specific occlusion classification

BACKGROUND: The pipeline embolization device (PED; Medtronic) has presented as a safe and efficacious treatment for small- and medium-sized intracranial aneurysms. Independently adjudicated long-term results of the device in treating these lesions are still indeterminate. We present 3-year results, with additional application of a flow diverter specific occlusion scale. METHODS: PREMIER (prospective study on embolization of intracranial aneurysms with pipeline embolization device) is a prospective, single-arm trial. Inclusion criteria were patients with unruptured wide-necked intracranial aneurysms \u3c /=12 mm. Primary effectiveness (complete aneurysm occlusion) and safety (major neurologic event) endpoints were independently monitored and adjudicated. RESULTS: As per the protocol, of 141 patients treated with a PED, 25 (17.7%) required angiographic follow-up after the first year due to incomplete aneurysm occlusion. According to the Core Radiology Laboratory review, three (12%) of these patients progressed to complete occlusion, with an overall rate of complete aneurysm occlusion at 3 years of 83.3% (115/138). Further angiographic evaluation using the modified Cekirge-Saatci classification demonstrated that complete occlusion, neck residual, or aneurysm size reduction occurred in 97.1%. The overall combined safety endpoint at 3 years was 2.8% (4/141), with only one non-debilitating major event occurring after the first year. There was one case of aneurysm recurrence but no cases of delayed rupture in this series. CONCLUSIONS: The PED device presents as a safe and effective modality in treating small- and medium-sized intracranial aneurysms. The application of a flow diverter specific occlusion classification attested the long-term durability with higher rate of successful aneurysm occlusion and no documented aneurysm rupture. TRIAL REGISTRATION: NCT02186561

Safety and efficacy of balloon-mounted stent in the treatment of symptomatic intracranial atherosclerotic disease: a multicenter experience

Background Randomized clinical trials have failed to prove that the safety and efficacy of endovascular treatment for symptomatic intracranial atherosclerotic disease (ICAD) is better than that of medical management. A recent study using a self-expandable stent showed acceptable lower rates of periprocedural complications. Objective To study the safety and efficacy of a balloon-mounted stent (BMS) in the treatment of symptomatic ICAD. Methods Prospectively maintained databases from 15 neuroendovascular centers between 2010 and 2020 were reviewed. Patients were included if they had severe symptomatic intracranial stenosis in the target artery, medical management had failed, and they underwent intracranial stenting with BMS after 24 hours of the qualifying event. The primary outcome was the occurrence of stroke and mortality within 72 hours after the procedure. Secondary outcomes were the occurrence of stroke, transient ischemic attacks (TIAs), and mortality on long-term follow-up. Results A total of 232 patients were eligible for the analysis (mean age 62.8 years, 34.1% female). The intracranial stenotic lesions were located in the anterior circulation in 135 (58.2%) cases. Recurrent stroke was the qualifying event in 165 (71.1%) while recurrent TIA was identified in 67 (28.9%) cases. The median (IQR) time from the qualifying event to stenting was 5 (2–20.75) days. Strokes were reported in 13 (5.6%) patients within 72 hours of the procedure; 9 (3.9%) ischemic and 4 (1.7%) hemorrhagic, and mortality in 2 (0.9%) cases. Among 189 patients with median follow-up time 6 (3–14.5) months, 12 (6.3%) had TIA and 7 (3.7%) had strokes. Three patients (1.6%) died from causes not related to stroke. Conclusion Our study has shown that BMS may be a safe and effective treatment for medically refractory symptomatic ICAD. Additional prospective randomized clinical trials are warranted

Neuroendovascular clinical trials disruptions due to COVID-19. Potential future challenges and opportunities

Objective: To assess the impact of COVID-19 on neurovascular research and deal with the challenges imposed by the pandemic. Methods: A survey-based study focused on randomized controlled trials (RCTs) and single-arm studies for acute ischemic stroke and cerebral aneurysms was developed by a group of senior neurointerventionalists and sent to sites identified through the clinical trials website (https:// clinicaltrials. gov/), study sponsors, and physician investigators. Results: The survey was sent to 101 institutions, with 65 responding (64%). Stroke RCTs were being conducted at 40 (62%) sites, aneurysm RCTs at 22 (34%) sites, stroke single-arm studies at 37 (57%) sites, and aneurysm single-arm studies at 43 (66%) sites. Following COVID-19, enrollment was suspended at 51 (78%) sites—completely at 21 (32%) and partially at 30 (46%) sites. Missed trial-related clinics and imaging follow-ups and protocol deviations were reported by 27 (42%), 24 (37%), and 27 (42%) sites, respectively. Negative reimbursements were reported at 17 (26%) sites. The majority of sites, 49 (75%), had put new trials on hold. Of the coordinators, 41 (63%) worked from home and 20 (31%) reported a personal financial impact. Remote consent was possible for some studies at 34 (52%) sites and for all studies at 5 (8%) sites. At sites with suspended trials (n=51), endovascular treatment without enrollment occurred at 31 (61%) sites for stroke and 23 (45%) sites for aneurysms. A total of 277 patients with acute ischemic stroke and 184 with cerebral aneurysms were treated without consideration for trial enrollment. Conclusion: Widespread disruption of neuroendovascular trials occurred because of COVID-19. As sites resume clinical research, steps to mitigate similar challenges in the future should be considered

The origin of large molecules in primordial autocatalytic reaction networks

Large molecules such as proteins and nucleic acids are crucial for life, yet their primordial origin remains a major puzzle. The production of large molecules, as we know it today, requires good catalysts, and the only good catalysts we know that can accomplish this task consist of large molecules. Thus the origin of large molecules is a chicken and egg problem in chemistry. Here we present a mechanism, based on autocatalytic sets (ACSs), that is a possible solution to this problem. We discuss a mathematical model describing the population dynamics of molecules in a stylized but prebiotically plausible chemistry. Large molecules can be produced in this chemistry by the coalescing of smaller ones, with the smallest molecules, the `food set', being buffered. Some of the reactions can be catalyzed by molecules within the chemistry with varying catalytic strengths. Normally the concentrations of large molecules in such a scenario are very small, diminishing exponentially with their size. ACSs, if present in the catalytic network, can focus the resources of the system into a sparse set of molecules. ACSs can produce a bistability in the population dynamics and, in particular, steady states wherein the ACS molecules dominate the population. However to reach these steady states from initial conditions that contain only the food set typically requires very large catalytic strengths, growing exponentially with the size of the catalyst molecule. We present a solution to this problem by studying `nested ACSs', a structure in which a small ACS is connected to a larger one and reinforces it. We show that when the network contains a cascade of nested ACSs with the catalytic strengths of molecules increasing gradually with their size (e.g., as a power law), a sparse subset of molecules including some very large molecules can come to dominate the system.Comment: 49 pages, 17 figures including supporting informatio