Aneurysmal subarachnoid hemorrhage is a devastating condition causing significant morbidity and mortality. While outcomes from subarachnoid hemorrhage have improved in recent years, there continues to be significant interest in identifying therapeutic targets for this disease. In particular, there has been a shift in emphasis toward secondary brain injury that develops in the first 72 hours after subarachnoid hemorrhage. This time period of interest is referred to as the early brain injury period and comprises processes including microcirculatory dysfunction, blood-brain-barrier breakdown, neuroinflammation, cerebral edema, oxidative cascades, and neuronal death. Advances in our understanding of the mechanisms defining the early brain injury period have been accompanied by improved imaging and nonimaging biomarkers for identifying early brain injury, leading to the recognition of an elevated clinical incidence of early brain injury compared with prior estimates. With the frequency, impact, and mechanisms of early brain injury better defined, there is a need to review the literature in this area to guide preclinical and clinical study.

Neuropilins are multifunctional receptors that play important roles in immune regulation. Neuropilin-2 (NRP2) is expressed in the lungs, but whether it regulates airway immune responses is unknown. Here, we report that Nrp2 is weakly expressed by alveolar macrophages (AMs) in the steady state but is dramatically upregulated following in vivo lipopolysaccharide (LPS) inhalation. Ex vivo treatment of human AMs with LPS also increased NRP2 mRNA expression and cell-surface display of NRP2 protein. LPS-induced Nrp2 expression in AMs was dependent upon the myeloid differentiation primary response 88 signaling pathway and the transcription factor NF-κB. In addition to upregulating display of NRP2 on the cell membrane, inhaled LPS also triggered AMs to release soluble NRP2 into the airways. Finally, myeloid-specific ablation of NRP2 resulted in increased expression of the chemokine (C-C motif) ligand 2 ( Ccl2) in the lungs and prolonged leukocyte infiltration in the airways following LPS inhalation. These findings suggest that NRP2 expression by AMs regulates LPS-induced inflammatory cell recruitment to the airways and reveal a novel role for NRP2 during innate immune responses in the lungs.

BackgroundFlow diversion of intracranial aneurysms with the Pipeline Embolization Device (PED) is commonly performed, but the value of long-term angiographic follow-up has not been rigorously evaluated. Here we examine the prevalence of actionable findings of aneurysm recurrence and development of in-stent stenosis in a cohort of patients that underwent long-term angiographic follow-up at multiple time points.MethodsAngiographic data from eligible patients were retrospectively assessed for aneurysm occlusion, in-stent stenosis, and aneurysm regrowth or recurrence. Patients were included in this study if they underwent angiographic imaging at 6 months post-treatment and at least one later time point.Results100% (132/132) of aneurysms occluded at 6 months remained occluded at final follow-up. 85.7% (6/7), 56.3% (27/48), and 25% (6/24) of aneurysms with entry remnant, subtotal filling, and total filling, respectively, at 6 months were completely occluded at final follow-up. 98.7% (147/149) of PED constructs that demonstrated no stenosis at 6 months demonstrated no stenosis at final angiography, while 44.4% (8/18) of PED constructs demonstrating in-stent stenosis at 6 months had resolution of stenosis on final angiography.ConclusionsAmong patients who undergo treatment of intracranial aneurysms with PED, the value of long-term angiography in patients demonstrating complete aneurysm occlusion and no in-stent stenosis on 6 month post-treatment angiography is low.

OBJECTIVE The Pipeline embolization device (PED) is widely used for the treatment of intracranial aneurysms, including in off-label applications. In this work, the authors compared the real-world efficacy and safety of PED use in on-label and off-label aneurysm treatments. METHODS Clinical and angiographic data of patients who underwent PED placement at a high-volume academic medical center were retrospectively obtained. Treatments were classified as on-label if they fell within the applications approved by the United States Food and Drug Administration as of 2021. Recorded outcomes included aneurysm occlusion, procedural complications, ischemic events, in-stent stenosis, intracranial hemorrhage, postprocedural functional status, and death. RESULTS In total, 416 aneurysms in 330 patients were treated with PED, comprising 256 aneurysms that received on-label treatments and 160 that received off-label treatments. The overall rate of complete aneurysm occlusion was 76.4% for on-label aneurysms and 75.6% for off-label aneurysms (p = 0.898). The risk of ischemic stroke in patients who underwent off-label treatments was 15.2%, which was higher than the 4.2% rate in patients who underwent on-label treatment (p = 0.003). All other clinical complications, procedural complications, and long-term functional status were comparable between the on-label and off-label groups. CONCLUSIONS In real-world practice, off-label use of PED is common and can achieve similar efficacy as on-label use. However, in aggregate, off-label use was found to carry an increased rate of ischemic complications. With judicious attention to safety and individual patient characteristics, these results highlight the scale and general feasibility of off-label PED use by experts.

OBJECTIVE Brain arteriovenous malformations (AVMs) carry a risk of rupture and subsequent morbidity or mortality unless fully treated. AVMs in pediatric patients are known to occasionally recur after obliteration. The objective of this study was to characterize the risk of AVM recurrence following angiographically confirmed obliteration in children. METHODS Consecutive pediatric AVMs treated at a single center were identified from a prospective database. Patients with angiographically confirmed AVM obliteration following treatment were included in this study. Associations between AVM recurrence and patient or procedural factors were characterized using the two-tailed Fisher exact test or Mann-Whitney U-test. A literature search was conducted using PubMed, Scopus, Embase, and the Clarivate Web of Science with defined search criteria, and eligible studies were included alongside this study cohort in a meta-analysis. Rates of AVM recurrence following obliteration were pooled across studies with a random-effects model and reported with 95% confidence intervals (CIs). RESULTS Recurrence after angiographic confirmation of AVM obliteration was observed in 10.4% (7/67) of pediatric AVMs treated at the authors’ center. Patients with recurrent AVMs were significantly younger than those without recurrence (p = 0.002). In the meta-analysis, which included 1134 patients across 24 studies, the rate of recurrence was 4.8% (95% CI 3.0%–6.7%). The rate of AVM recurrence following radiosurgery was 0.7% (95% CI 0%–1.6%), which was significantly lower than the 8.5% rate (95% CI 5.0%–12.0%) following microsurgery. CONCLUSIONS Recurrence of obliterated brain AVMs is common in children. Recurrence is more common in young children and following microsurgery.