First-in-human, real-time artificial intelligence assisted cerebral aneurysm coiling: a preliminary experience.

BACKGROUND: Neuroendovascular procedures require careful and simultaneous attention to multiple devices on multiple screens. Overlooking unintended device movements can result in complications. Advancements in artificial intelligence (AI) have enabled real-time notifications of device movements during procedures. We report our preliminary experience with real-time AI-assisted cerebral aneurysm coiling in humans. METHODS: A real-time AI-assistance software (Neuro-Vascular Assist, iMed technologies, Tokyo, Japan) was used during coil embolization procedures in nine patients with an unruptured aneurysm. The AI system provided real-time notifications for 'coil marker approaching', 'guidewire movement', and 'device entry' on biplane fluoroscopic images. The efficacy, accuracy, and safety of the notifications were evaluated using video recordings. RESULTS: The AI system functioned properly in all cases. The mean number of notifications for coil marker approaching, guidewire movement, and device entry per procedure was 20.0, 3.0, and 18.3, respectively. The overall precision and recall were 92.7% and 97.2%, respectively. Five of 26 true positive guidewire notifications (19%) resulted in adjustment of the guidewire back toward its original position, indicating the potential effectiveness of the AI system. No adverse events occurred. CONCLUSIONS: The software was sufficiently accurate and safe in this preliminary study, suggesting its potential usefulness. To the best of our knowledge, this is the first reported use of a real-time AI system for assisting cerebral aneurysm coiling in humans. Large scale studies are warranted to validate its effectiveness. Real-time AI assistance has significant potential for future neuroendovascular therapy.

Increased door-to-puncture time during off-duty hours results in poor treatment outcomes for acute ischemic stroke: A subanalysis of the K-NET registry.

BACKGROUND: For patients who undergo endovascular treatment for acute ischemic stroke, the total time for treatment may increase during off-duty hours leading to worse outcomes. The present study compared endovascular treatment outcomes for on-duty and off-duty hours and examined factors that could be responsible for the prolonged treatment of patients in a multicenter registry. METHODS: The study group comprised 1571 patients listed in the multicenter stroke registry (K-NET) who had undergone endovascular treatment between January 2018 and June 2020. The modified Rankin Scale (mRS), evaluated at 90 days after stroke onset, was utilized as the primary outcome. Patients were divided into on-duty and off-duty patients based on admission time. Multivariate logistic regression analysis was used to identify the independent factors that increased the time from admission to puncture during the off-duty period. RESULTS: The mean mRS score at 90 days after stroke onset was 2.9, similar in both on-duty and off-duty patients, with no significant difference (p = 0.77); however, significant differences were observed in time from door-to-puncture (74.7 vs. 88.8, p < 0.01). Additionally, the mRS score at 90 days worsened significantly for door-to-puncture time >60 min in the off-duty period. Multivariate logistic regression analysis revealed that a low National Institute of Health Stroke Scale (NIHSS) score, high pre-mRS score, posterior circulation, and diabetes were independent indicators of door-to-puncture time >60 min during the off-duty period. CONCLUSION: Door-to-puncture time >60 min during off-duty hours was associated with poor outcomes related to low NIHSS, high pre-mRS, posterior circulation, and diabetes.

Combined Endovascular Antegrade and Direct Retrograde Carotid Artery Stenting for Chronic and Long Segment Common Carotid Artery Occlusion: Technical Note and Review of Literature.

Common carotid artery (CCA) occlusion (CCAO) is a rare cause of ischemic stroke and bypass surgery is the common treatment approach. However, safer alternatives should be developed to treat CCAO. A 68-year-old male was diagnosed with left-sided CCAO with decreased left visual acuity due to neck radiation therapy for laryngeal cancer. Recanalization therapy using a pull-through technique was initiated because cerebral blood flow progressively decreased during the follow-up period. First, after a short sheath was inserted into the CCA, the occluded CCA was retrogradely penetrated through the sheath. Second, a micro-guidewire was guided to the aorta from the femoral sheath where it was caught using a snare wire guided from the cervical sheath. Subsequently, the micro-guidewire was gently pulled out from the cervical sheath, penetrated the occluded lesion, and was secured to the femoral and cervical sheaths. Finally, the occluded lesion was dilated using a balloon, and the stent was placed. Five days postprocedure, the patient was discharged uneventfully and exhibited improved left visual acuity. In terms of reliable penetration of obstructive lesions and reduction of embolic and hemorrhagic complications, combined endovascular antegrade and direct retrograde carotid artery stenting is a versatile and minimally invasive treatment option for CCAO.

Cerebral foreign body granulomas after mechanical thrombectomy: Two case reports and a review of the literature.

OBJECTIVES: A foreign body granuloma after an endovascular intervention is a rare complication. Some cases of foreign body granulomas, especially after coil embolization, have been reported. However, only four cases of foreign body granulomas after mechanical thrombectomy (MT) have previously been reported. The current study reports two cases of post-MT foreign body granulomas, including a biopsy-proven case. MATERIAL AND METHODS: Case 1: A 73-year-old woman presented with complete occlusion of the right middle cerebral artery. Cerebral angiography and MT were successfully performed with improvement in clinical symptoms. Left hemiparesis and a disturbance in attention appeared after discharge and progressed slowly. She was re-admitted to our hospital 120 days after cerebral infarction owing to foreign body granulomas diagnosed on biopsy. Case 2: A 78-year-old man presented with occlusion of the left cervical internal carotid artery and the left middle cerebral artery. Cerebral angiography, percutaneous transluminal angioplasty, and MT were successfully performed. On the 34th day, he experienced progressive consciousness disorder because of foreign body granulomas. Both cases were successfully treated with steroid therapy. RESULTS: MRI after steroid treatment showed the disappearance of most nodular lesions and improvement of the encephalopathy. CONCLUSIONS: The cause of the granuloma may be an allergic reaction to the hydrophilic polymers that peel from endovascular devices. Steroid therapy is an effective treatment; therefore, neurologists should consider this complication when neurological symptoms or signs on image appears or worsens. A reliable diagnosis is important for prompt treatment.

CaM kinase phosphatase (CaMKP/PPM1F/POPX2) is specifically inactivated through gallate-mediated protein carbonylation.

CaMK phosphatase (CaMKP/PPM1F/POPX2) is a Mn2+-dependent, calyculin A/okadaic acid-insensitive Ser/Thr protein phosphatase that belongs to the PPM family. CaMKP is thought to be involved in regulation of not only various protein kinases, such as CaM kinases and p21-activated protein kinase, but also of cellular proteins regulated by phosphorylation. A large-scale screening of a chemical library identified gallic acid and some of its alkyl esters as novel CaMKP inhibitors highly specific to CaMKP. Surprisingly, they caused specific carbonylation of CaMKP, leading to its inactivation. Under the same conditions, no carbonylation nor inactivation was observed when PPM1A, which is affiliated with the same family as CaMKP, and λ-phosphatase were used. The carbonylation reaction was inhibited by SH compounds such as cysteamine in a dose-dependent manner with a concomitant decrease in CaMKP inhibition by ethyl gallate. The pyrogallol structure of gallate was necessary for the gallate-mediated carbonylation of CaMKP. Point mutations of CaMKP leading to impairment of phosphatase activity did not significantly affect the gallate-mediated carbonylation. Ethyl gallate resulted in almost complete inhibition of CaMKP under the conditions where the carbonylation level was nearly identical to that of CaMKP carbonylation via metal-catalyzed oxidation with ascorbic acid/FeSO4, which resulted in only a partial inhibition of CaMKP. The gallate-mediated carbonylation of CaMKP absolutely required divalent cations such as Mn2+, Cu2+, Co2+ and Fe2+, and was markedly enhanced by a phosphopeptide substrate. When MDA-MB-231 cells transiently expressing CaM kinase I, a CaMKP substrate, were treated by ethyl gallate, significant enhancement of phosphorylation of CaM kinase I was observed, suggesting that ethyl gallate can penetrate into cells to inactivate cellular CaMKP. All the presented data strongly support the hypothesis that CaMKP undergoes carbonylation of its specific amino acid residues by incubation with alkyl gallates and the divalent metal cations, leading to inactivation specific to CaMKP.

Transpetrosal Approach for a Giant Thrombosed P2 Segment Posterior Cerebral Artery Aneurysm.

OBJECTIVE: Posterior cerebral artery (PCA) aneurysms are extremely rare and can be difficult to treat. We report successful trapping and thrombectomy of a giant thrombosed P2 segment aneurysm via a transpetrosal approach. CASE PRESENTATION: A 62-year-old woman was admitted to our hospital with a progressive left hemiparesis. Magnetic resonance imaging (MRI) showed a 30 mm mass lesion in the right ambient cistern. On vertebral angiography, the right P2 trunk was deviated medially and inferiorly, and the right posterior temporal artery (PTA) was not visualized. We diagnosed a giant thrombosed aneurysm of the right PTA. Surgery was performed via a right posterior transpetrosal approach. The proximal P2 was identified above the oculomotor nerve in the ambient cistern, and a giant PTA aneurysm was found. After coagulating the distal PCA, a temporary clip was applied to the proximal P2, the aneurysm wall was incised, thrombus was removed, and a permanent titanium clip was applied to complete trapping. Postoperative MRI showed disappearance of the aneurysm. The patient's left hemiparesis was resolved 2 months after the operation, and she was discharged home. CONCLUSION: Although trans-sylvian and subtemporal approaches are often performed for P2 aneurysms, they have difficulty identifying the distal PCA and may require excessive brain retraction. The transpetrosal approach can also be effective for giant thrombosed P2 aneurysms.

Regulated IFN signalling preserves the stemness of intestinal stem cells by restricting differentiation into secretory-cell lineages.

Intestinal stem cells (ISCs) are located at the crypt base and fine-tune the balance of their self-renewal and differentiation1,2, but the physiological mechanism involved in regulating that balance remains unknown. Here we describe a transcriptional regulator that preserves the stemness of ISCs by restricting their differentiation into secretory-cell lineages. Interferon regulatory factor 2 (IRF2) negatively regulates interferon signalling3, and mice completely lacking Irf24 or with a selective Irf2 deletion in their intestinal epithelial cells have significantly fewer crypt Lgr5hi ISCs than control mice. Although the integrity of intestinal epithelial cells was unimpaired at steady state in Irf2-deficient mice, regeneration of their intestinal epithelia after 5-fluorouracil-induced damage was severely impaired. Similarly, extended treatment with low-dose poly(I:C) or chronic infection of lymphocytic choriomeningitis virus clone 13 (LCMV C13)5 caused a functional decline of ISCs in wild-type mice. In contrast, massive accumulations of immature Paneth cells were found at the crypt base of Irf2-/- as well as LCMV C13-infected wild-type mice, indicating that excess interferon signalling directs ISCs towards a secretory-cell fate. Collectively, our findings indicate that regulated interferon signalling preserves ISC stemness by restricting secretory-cell differentiation.

CD86-based analysis enables observation of bona fide hematopoietic responses.

Hematopoiesis is a system that provides red blood cells (RBCs), leukocytes, and platelets, which are essential for oxygen transport, biodefense, and hemostasis; its balance thus affects the outcome of various disorders. Here, we report that stem cell antigen-1 (Sca-1), a cell surface marker commonly used for the identification of multipotent hematopoietic progenitors (Lin-Sca-1+c-Kit+ cells; LSKs), is not suitable for the analysis of hematopoietic responses under biological stresses with interferon production. Lin-Sca-1-c-Kit+ cells (LKs), downstream progenitors of LSKs, acquire Sca-1 expression upon inflammation, which makes it impossible to distinguish between LSKs and LKs. As an alternative and stable marker even under such stresses, we identified CD86 by screening 180 surface markers. The analysis of infection/inflammation-triggered hematopoiesis on the basis of CD86 expression newly revealed urgent erythropoiesis producing stress-resistant RBCs and intact reconstitution capacity of LSKs, which could not be detected by conventional Sca-1-based analysis.

Characterization of radioresistant epithelial stem cell heterogeneity in the damaged mouse intestine.

The small intestine has a robust regenerative capacity, and various cell types serve as "cells-of-origin" in the epithelial regeneration process after injury. However, how much each population contributes to regeneration remains unclear. Using lineage tracing, we found that Lgr5-expressing cell derivatives contained radioresistant intestinal stem cells (ISCs) crucial for epithelial regeneration in the damaged intestine after irradiation. Single-cell qRT-PCR analysis showed that surviving Lgr5-expressing cell derivatives in the damaged intestine are remarkably heterogeneous, and that the expression levels of a YAP-target gene Sca1 were inversely correlated with their "stemness", suggesting that the YAP/Wnt signal balance in surviving crypt epithelial cells determines the cellular contribution to epithelial regeneration. Single-cell RNA sequencing of Sca1-Lgr5-derivatives revealed that expression of a tetraspanin family member CD81 correlated well with the expression of ISC- and proliferation-related genes. Consistent with these findings, organoid-forming ability was confined to the CD81hiSca1- fraction within the damaged crypt epithelial cells. Characterization of radioresistant epithelial stem cell heterogeneity in the damaged intestine may contribute to therapeutic strategies for gastrointestinal diseases.

Aberrant Amygdala-Dependent Cued Fear Memory in Na+/Ca2+ Exchanger 1 Heterozygous Mice.

Na+/Ca2+ exchangers (NCXs) are mainly expressed in the plasma membrane and exchange one Ca2+ for three Na+, depending on the electrochemical gradients across the plasma membrane. NCXs have three isoforms, NCX1-3, encoded by distinct genes in mammals. Here, we report that heterozygous mice lacking NCX1 (NCX1+/-) exhibit impaired amygdala-dependent cued fear memory. NCX1+/- mice showed significant impairment in fear-related behaviors measured with the elevated-plus maze, light-dark, open-field, and marble-burying tasks. In addition, NCX1+/- mice showed abnormality in cued fear memory but not in contextual fear memory in a fear-conditioning task. In immunohistochemical analyses, NCX1+/- mice had significantly increased number of c-Fos-positive cells in the lateral amygdala (LA) but not in the central amygdala following fear-related tone stimuli. c-Fos expression peaked at 1 h. In concordance with the aberrant fear-related behaviors in NCX1+/- mice, enhanced long-term potentiation was also observed in the LA of these mice. Furthermore, enhancement of CaMKII or CaMKIV activity in the LA was observed in NCX1+/- mice by immunoblot analyses. In contrast, CaMKII+/- but not CaMKIV-/- mice insufficiently exhibited tone-induced cued fear memory and there was no increase in the number of c-Fos-positive cells in the LA. Altogether, the increased CaMKII activity and consequent c-Fos expression likely account for the dysregulation of amygdala-dependent cued fear memory in NCX1+/- mice.

Assessment of robotic patient simulators for training in manual physical therapy examination techniques.

Robots that simulate patients suffering from joint resistance caused by biomechanical and neural impairments are used to aid the training of physical therapists in manual examination techniques. However, there are few methods for assessing such robots. This article proposes two types of assessment measures based on typical judgments of clinicians. One of the measures involves the evaluation of how well the simulator presents different severities of a specified disease. Experienced clinicians were requested to rate the simulated symptoms in terms of severity, and the consistency of their ratings was used as a performance measure. The other measure involves the evaluation of how well the simulator presents different types of symptoms. In this case, the clinicians were requested to classify the simulated resistances in terms of symptom type, and the average ratios of their answers were used as performance measures. For both types of assessment measures, a higher index implied higher agreement among the experienced clinicians that subjectively assessed the symptoms based on typical symptom features. We applied these two assessment methods to a patient knee robot and achieved positive appraisals. The assessment measures have potential for use in comparing several patient simulators for training physical therapists, rather than as absolute indices for developing a standard.