Massively parallel evaluation and computational prediction of the activities and specificities of 17 small Cas9s.

Recently, various small Cas9 orthologs and variants have been reported for use in in vivo delivery applications. Although small Cas9s are particularly suited for this purpose, selecting the most optimal small Cas9 for use at a specific target sequence continues to be challenging. Here, to this end, we have systematically compared the activities of 17 small Cas9s for thousands of target sequences. For each small Cas9, we have characterized the protospacer adjacent motif and determined optimal single guide RNA expression formats and scaffold sequence. High-throughput comparative analyses revealed distinct high- and low-activity groups of small Cas9s. We also developed DeepSmallCas9, a set of computational models predicting the activities of the small Cas9s at matched and mismatched target sequences. Together, this analysis and these computational models provide a useful guide for researchers to select the most suitable small Cas9 for specific applications.

The Rab GTPase activating protein TBC-2 regulates endosomal localization of DAF-16 FOXO and lifespan.

FOXO transcription factors have been shown to regulate longevity in model organisms and are associated with longevity in humans. To gain insight into how FOXO functions to increase lifespan, we examined the subcellular localization of DAF-16 in C. elegans. We show that DAF-16 is localized to endosomes and that this endosomal localization is increased by the insulin-IGF signaling (IIS) pathway. Endosomal localization of DAF-16 is modulated by endosomal trafficking proteins. Disruption of the Rab GTPase activating protein TBC-2 increases endosomal localization of DAF-16, while inhibition of TBC-2 targets, RAB-5 or RAB-7 GTPases, decreases endosomal localization of DAF-16. Importantly, the amount of DAF-16 that is localized to endosomes has functional consequences as increasing endosomal localization through mutations in tbc-2 reduced the lifespan of long-lived daf-2 IGFR mutants, depleted their fat stores, and DAF-16 target gene expression. Overall, this work identifies endosomal localization as a mechanism regulating DAF-16 FOXO, which is important for its functions in metabolism and aging.

Cancer Prediction With Machine Learning of Thrombi From Thrombectomy in Stroke: Multicenter Development and Validation.

BACKGROUND: We aimed to develop and validate machine learning models to diagnose patients with ischemic stroke with cancer through the analysis of histopathologic images of thrombi obtained during endovascular thrombectomy. METHODS: This was a retrospective study using a prospective multicenter registry which enrolled consecutive patients with acute ischemic stroke from South Korea who underwent endovascular thrombectomy. This study included patients admitted between July 1, 2017 and December 31, 2021 from 6 academic university hospitals. Whole-slide scanning was performed for immunohistochemically stained thrombi. Machine learning models were developed using transfer learning with image slices as input to classify patients into 2 groups: cancer group or other determined cause group. The models were developed and internally validated using thrombi from patients of the primary center, and external validation was conducted in 5 centers. The model was also applied to patients with hidden cancer who were diagnosed with cancer within 1 month of their index stroke. RESULTS: The study included 70 561 images from 182 patients in both internal and external datasets (119 patients in internal and 63 in external). Machine learning models were developed for each immunohistochemical staining using antibodies against platelets, fibrin, and erythrocytes. The platelet model demonstrated consistently high accuracy in classifying patients with cancer, with area under the receiver operating characteristic curve of 0.986 (95% CI, 0.983-0.989) during training, 0.954 (95% CI, 0.937-0.972) during internal validation, and 0.949 (95% CI, 0.891-1.000) during external validation. When applied to patients with occult cancer, the model accurately predicted the presence of cancer with high probabilities ranging from 88.5% to 99.2%. CONCLUSIONS: Machine learning models may be used for prediction of cancer as the underlying cause or detection of occult cancer, using platelet-stained immunohistochemical slide images of thrombi obtained during endovascular thrombectomy.

γ-Ray Irradiation Enables Annealing- and Light-Soaking-Free Solution Processable SnO2 Electron Transport Layer for Inverted Organic Solar Cells.

The electrode buffer layer is crucial for high-performance and stable OSCs, optimizing charge transport and energy level alignment at the interface between the polymer active layer and electrode. Recently, SnO2 has emerged as a promising material for the cathode buffer layer due to its desirable properties, such as high electron mobility, transparency, and stability. Typically, SnO2 nanoparticle layers require a postannealing treatment above 150°C in an air environment to remove the surfactant ligands and obtain high-quality thin films. However, this poses challenges for flexible electronics as flexible substrates can't tolerate temperatures exceeding 100°C. This study presents solution-processable and annealing-free SnO2 nanoparticles by employing y-ray irradiation to disrupt the bonding between surfactant ligands and SnO2 nanoparticles. The SnO2 layer treated with y-ray irradiation is used as an electron transport layer in OSCs based on PTB7-Th:IEICO-4F. Compared to the conventional SnO2 nanoparticles that required high-temperature annealing, the y-SnO2 nanoparticle-based devices exhibit an 11% comparable efficiency without postannealing at a high temperature. Additionally, y-ray treatment has been observed to eliminate the light-soaking effect of SnO2 . By eliminating the high-temperature postannealing and light-soaking effect, y-SnO2 nanoparticles offer a promising, cost-effective solution for future flexible solar cells fabricated using roll-to-roll mass processing.

In vivo gene editing via homology-independent targeted integration for adrenoleukodystrophy treatment.

Adrenoleukodystrophy (ALD) is caused by various pathogenic mutations in the X-linked ABCD1 gene, which lead to metabolically abnormal accumulations of very long-chain fatty acids in many organs. However, curative treatment of ALD has not yet been achieved. To treat ALD, we applied two different gene-editing strategies, base editing and homology-independent targeted integration (HITI), in ALD patient-derived fibroblasts. Next, we performed in vivo HITI-mediated gene editing using AAV9 vectors delivered via intravenous administration in the ALD model mice. We found that the ABCD1 mRNA level was significantly increased in HITI-treated mice, and the plasma levels of C24:0-LysoPC (lysophosphatidylcholine) and C26:0-LysoPC, sensitive diagnostic markers for ALD, were significantly reduced. These results suggest that HITI-mediated mutant gene rescue could be a promising therapeutic strategy for human ALD treatment.

Intensive vs Conventional Blood Pressure Lowering After Endovascular Thrombectomy in Acute Ischemic Stroke: The OPTIMAL-BP Randomized Clinical Trial.

Importance: Optimal blood pressure (BP) control after successful reperfusion with endovascular thrombectomy (EVT) for patients with acute ischemic stroke is unclear. Objective: To determine whether intensive BP management during the first 24 hours after successful reperfusion leads to better clinical outcomes than conventional BP management in patients who underwent EVT. Design, Setting, and Participants: Multicenter, randomized, open-label trial with a blinded end-point evaluation, conducted across 19 stroke centers in South Korea from June 2020 to November 2022 (final follow-up, March 8, 2023). It included 306 patients with large vessel occlusion acute ischemic stroke treated with EVT and with a modified Thrombolysis in Cerebral Infarction score of 2b or greater (partial or complete reperfusion). Interventions: Participants were randomly assigned to receive intensive BP management (systolic BP target <140 mm Hg; n = 155) or conventional management (systolic BP target 140-180 mm Hg; n = 150) for 24 hours after enrollment. Main Outcomes and Measures: The primary outcome was functional independence at 3 months (modified Rankin Scale score of 0-2). The primary safety outcomes were symptomatic intracerebral hemorrhage within 36 hours and death related to the index stroke within 3 months. Results: The trial was terminated early based on the recommendation of the data and safety monitoring board, which noted safety concerns. Among 306 randomized patients, 305 were confirmed eligible and 302 (99.0%) completed the trial (mean age, 73.0 years; 122 women [40.4%]). The intensive management group had a lower proportion achieving functional independence (39.4%) than the conventional management group (54.4%), with a significant risk difference (-15.1% [95% CI, -26.2% to -3.9%]) and adjusted odds ratio (0.56 [95% CI, 0.33-0.96]; P = .03). Rates of symptomatic intracerebral hemorrhage were 9.0% in the intensive group and 8.1% in the conventional group (risk difference, 1.0% [95% CI, -5.3% to 7.3%]; adjusted odds ratio, 1.10 [95% CI, 0.48-2.53]; P = .82). Death related to the index stroke within 3 months occurred in 7.7% of the intensive group and 5.4% of the conventional group (risk difference, 2.3% [95% CI, -3.3% to 7.9%]; adjusted odds ratio, 1.73 [95% CI, 0.61-4.92]; P = .31). Conclusions and Relevance: Among patients who achieved successful reperfusion with EVT for acute ischemic stroke with large vessel occlusion, intensive BP management for 24 hours led to a lower likelihood of functional independence at 3 months compared with conventional BP management. These results suggest that intensive BP management should be avoided after successful EVT in acute ischemic stroke. Trial Registration: ClinicalTrials.gov Identifier: NCT04205305.

Environmental Enrichment Enhances Cav 2.1 Channel-Mediated Presynaptic Plasticity in Hypoxic-Ischemic Encephalopathy.

Hypoxic-ischemic encephalopathy (HIE) is a devastating neonatal brain condition caused by lack of oxygen and limited blood flow. Environmental enrichment (EE) is a classic paradigm with a complex stimulation of physical, cognitive, and social components. EE can exert neuroplasticity and neuroprotective effects in immature brains. However, the exact mechanism of EE on the chronic condition of HIE remains unclear. HIE was induced by a permanent ligation of the right carotid artery, followed by an 8% O2 hypoxic condition for 1 h. At 6 weeks of age, HIE mice were randomly assigned to either standard cages or EE cages. In the behavioral assessments, EE mice showed significantly improved motor performances in rotarod tests, ladder walking tests, and hanging wire tests, compared with HIE control mice. EE mice also significantly enhanced cognitive performances in Y-maze tests. Particularly, EE mice showed a significant increase in Cav 2.1 (P/Q type) and presynaptic proteins by molecular assessments, and a significant increase of Cav 2.1 in histological assessments of the cerebral cortex and hippocampus. These results indicate that EE can upregulate the expression of the Cav 2.1 channel and presynaptic proteins related to the synaptic vesicle cycle and neurotransmitter release, which may be responsible for motor and cognitive improvements in HIE.

Unusual cortical symptoms of dural arteriovenous fistula mimicking transient ischemic attack.

The clinical presentation of dural arteriovenous fistula (DAVF) can vary. A 47-year-old man complained of transient difficulty playing badminton and speech disturbance for 10 minutes. His symptoms were suspected to be visuomotor coordination deficit similar to optic ataxia and anomic aphasia. Magnetic resonance imaging and angiography revealed vasogenic edema and perfusion delay in the left temporo-occipital area and an abnormal connection between the left occipital artery and transverse sinus. Transverse sinus DAVF was diagnosed by conventional cerebral angiography. We believe that this is the unique case of DAVF manifested as visuomotor coordination deficit suspected optic ataxia and anomic aphasia.

Initial multicentre experience using the neuroform atlas stent for the treatment of un-ruptured saccular cerebral aneurysms.

Purpose: The Neuroform Atlas is a self-expandable and low-profiled stent that is used for aneurysm neck scaffolding and has been recently approved for clinical practice in Korea. We present our initial experiences of endovascular coiling using the Neuroform Atlas stent.Materials and methods: All cerebral aneurysms treated by stent-assisted coiling with a Neuroform atlas stent in two institutions between February and May 2018 were retrospectively evaluated. Fifty-one patients with 55 un-ruptured saccular cerebral aneurysms (mean size: 4.72 ± 1.81 mm, mean neck diameter: 3.82 ± 1.23 mm, mean dome-to-neck ratio: 1.21) were included in our study (40 females, mean age: 59.29 ± 11.96 years). Patient demographics, aneurysm characteristics, initial angiographic post procedural outcomes, and clinical and angiographic follow-up data were analysed.Results: There was one case of procedural failure due to a downward slip during stent deployment. The technical success rate was 98.2% (54/55). A post-procedure control angiogram showed complete occlusion in 27 (50%), residual neck in 16 (29.6%) and residual sac in 11 (20.4%) aneurysms. There were no procedure-related complications. In one case, a symptomatic thromboembolism with left hand grip weakness (grade IV) was observed two days after the procedure and resolved at discharge. The modified Rankin scale score at discharge was 0 in all patients. Angiographic follow-up data at a mean of 4.8 months were available for 51/54 (94.4%) aneurysms. Among them, 27 aneurysms (52.9%) were stable, 20 aneurysms (39.2%) showed progressive occlusion and 4 aneurysms showed an increased modified Raymond Roy occlusion classification score (only one of these patients was included in the recanalization criteria).Conclusion: Our findings suggest the Neuroform Atlas stent can be useful for the coiling of cerebral aneurysms without significant complications regardless of aneurysm location.

The VPS34 PI3K negatively regulates RAB-5 during endosome maturation.

The GTPase Rab5 and phosphatidylinositol-3 phosphate [PI(3)P] coordinately regulate endosome trafficking. Rab5 recruits Vps34, the class III phosphoinositide 3-kinase (PI3K), to generate PI(3)P and recruit PI(3)P-binding proteins. Loss of Rab5 and loss of Vps34 have opposite effects on endosome size, suggesting that our understanding of how Rab5 and PI(3)P cooperate is incomplete. Here, we report a novel regulatory loop whereby Caenorhabditis elegans VPS-34 inactivates RAB-5 via recruitment of the TBC-2 Rab GTPase-activating protein. We found that loss of VPS-34 caused a phenotype with large late endosomes, as with loss of TBC-2, and that Rab5 activity (mice have two Rab5 isoforms, Rab5a and Rab5b) is increased in Vps34-knockout mouse embryonic fibroblasts (Vps34 is also known as PIK3C3 in mammals). We found that VPS-34 is required for TBC-2 endosome localization and that the pleckstrin homology (PH) domain of TBC-2 bound PI(3)P. Deletion of the PH domain enhanced TBC-2 localization to endosomes in a VPS-34-dependent manner. Thus, PI(3)P binding of the PH domain might be permissive for another PI(3)P-regulated interaction that recruits TBC-2 to endosomes. Therefore, VPS-34 recruits TBC-2 to endosomes to inactivate RAB-5 to ensure the directionality of endosome maturation.

Depth-dependent electronic band structure at the Au/CH3NH3PbI3-xClx junction.

The electronic properties of the interface between Au and organometallic triiodide perovskite (CH3NH3PbI3-xClx) were investigated by ultraviolet photoelectron spectroscopy (UPS) and X-ray photoemission spectroscopy (XPS). CH3NH3PbI3-xClx films were prepared on Au surfaces by spin casting with various concentrations to control the film thickness. Their morphology was examined by atomic force microscopy (AFM). CH3NH3PbI3-xClx films exhibited a maximum valence band edge of 5.91 eV. The energy levels shifted downward by 0.26 eV with a perovskite coverage of 116.3 nm, indicating that band bending occurs at the interface. The observed energy level shift indicates an interface dipole at the Au/CH3NH3PbI3-xClx junction. These findings contribute to the understanding of how perovskite materials function in electronic devices and aid in the design of new perovskite materials.

The aminoglycoside geneticin permits translational readthrough of the CTNS W138X nonsense mutation in fibroblasts from patients with nephropathic cystinosis.

BACKGROUND: Cystinosis is an ultrarare disorder caused by mutations of the cystinosin (CTNS) gene, encoding a cystine-selective efflux channel in the lysosomes of all cells of the body. Oral therapy with cysteamine reduces intralysosomal cystine accumulation and slows organ deterioration but cannot reverse renal Fanconi syndrome nor prevent the eventual need for renal transplantation. A definitive therapeutic remains elusive. About 15% of cystinosis patients worldwide carry one or more nonsense mutations that halt translation of the CTNS protein. Aminoglycosides such as geneticin (G418) can bind to the mammalian ribosome, relax translational fidelity, and permit readthrough of premature termination codons to produce full-length protein. METHODS: To ascertain whether aminoglycosides permit readthrough of the most common CTNS nonsense mutation, W138X, we studied the effect of G418 on patient fibroblasts. RESULTS: G418 treatment induced translational readthrough of CTNSW138X constructs transfected into HEK293 cells and expression of full-length endogenous CTNS protein in homozygous W138X fibroblasts. CONCLUSIONS: Reduction in intracellular cystine indicates that the CTNS protein produced is functional as a cystine transporter. Interestingly, similar effects were seen even in W138X compound heterozygotes. These studies establish proof-of-principle for the potential of aminoglycosides to treat cystinosis and possibly other monogenic diseases caused by nonsense mutations.

ZnO:Ga-graded ITO electrodes to control interface between PCBM and ITO in planar perovskite solar cells.

Ga-doped ZnO (GZO)-graded layer, facilitating electron extraction from electron transport layer, was integrated on the surface of transparent indium tin oxide (ITO) cathode by using graded sputtering technique to improve the performance of planar n-i-p perovskite solar cells (PSCs). The thickness of graded GZO layer was controlled to optimize GZO-indium tin oxide (ITO) combined electrode for planar n-i-p PSCs. At optimized graded thickness of 15 nm, the GZO-ITO combined electrode showed an optical transmittance of 95%, a resistivity of 2.3 × 10-4 Ohm cm, a sheet resistance of 15.6 Ohm/square, and work function of 4.23 eV, which is well matched with the 4.0-eV lowest unoccupied molecular orbital of [6,6]-phenyl-C61-butyric acid methyl ester. Owing to enhanced extraction of electron by the graded GZO, the n-i-p PSC with GZO-ITO combined electrode showed higher power conversion efficiency (PCE) of 9.67% than the PCE (5.25%) of PSC with only ITO electrode without GZO-graded layer. In addition, the GZO integrated-ITO electrode acts as transparent electrode and electron extraction layer simultaneously due to graded mixing of the GZO at the surface region of ITO electrode.

In Situ Pluripotency Factor Expression Promotes Functional Recovery From Cerebral Ischemia.

Recovery from ischemic tissue injury can be promoted by cell proliferation and neovascularization. Transient expression of four pluripotency factors (Pou5f1, Sox2, Myc, and Klf4) has been used to convert cell types but never been tested as a means to promote functional recovery from ischemic injury. Here we aimed to determine whether transient in situ pluripotency factor expression can improve neurobehavioral function. Cerebral ischemia was induced by transient bilateral common carotid artery occlusion, after which the four pluripotency factors were expressed through either doxycycline administration into the lateral ventricle in transgenic mice in which the four factors are expressed in a doxycycline-inducible manner. Histologic evaluation showed that this transient expression induced the proliferative generation of astrocytes and/or neural progenitors, but not neurons or glial scar, and increased neovascularization with upregulation of angiogenic factors. Furthermore, in vivo pluripotency factor expression caused neuroprotective effects such as increased numbers of mature neurons and levels of synaptic markers in the striatum. Dysplasia or tumor development was not observed. Importantly, neurobehavioral evaluations such as rotarod and ladder walking tests showed that the expression of the four factors dramatically promoted functional restoration from ischemic injury. These results provide a basis for novel therapeutic modality development for cerebral ischemia.

Wilson's disease with cognitive impairment and without extrapyramidal signs: improvement of neuropsychological performance and reduction of MRI abnormalities with trientine treatment.

Extrapyramidal signs are neurological dysfunction commonly associated with Wilson's disease (WD). In addition, cognitive dysfunction has been reported in the early stages of WD. In this report, we describe a 49-year-old woman presenting with memory impairments and without Parkinsonian or extrapyramidal signs. She was diagnosed with WD based on the presence of Kayser-Fleischer rings around the irises of her eyes and two ATP7B gene mutations, R778L at exon 8 and A874V at exdyon 11. Serial magnetic resonance imaging analysis and neuropsychological tests showed improvements following treatment with trientine.

Astroglial Activation by an Enriched Environment after Transplantation of Mesenchymal Stem Cells Enhances Angiogenesis after Hypoxic-Ischemic Brain Injury.

Transplantation of mesenchymal stem cells (MSCs) has paracrine effects; however, the effects are known to be largely limited. Here we investigated the combination effects of cell transplantation and enriched environment (EE) in a model of hypoxic-ischemic brain injury. Brain damage was induced in seven-day-old mice by unilateral carotid artery ligation and exposure to hypoxia (8% O2 for 90 min). At six weeks of age, the mice were randomly assigned to four groups: phosphate-buffered saline (PBS)-control (CON), PBS-EE, MSC-CON, and MSC-EE. Rotarod and grip strength tests were performed to evaluate neurobehavioral functions. Histologic evaluations were also performed to confirm the extent of astrocyte activation and endogenous angiogenesis. An array-based multiplex ELISA and Western blot were used to identify growth factors in vivo and in vitro. Two weeks after treatment, levels of astrocyte density and angiogenic factors were increased in MSC-EE mice, but glial scarring was not increased. Eight weeks after treatment, angiogenesis was increased, and behavioral outcomes were synergistically improved in the MSC-EE group. Astrocytes co-cultured with MSCs expressed higher levels of angiogenic factors than astrocytes cultured alone. The mechanisms of this synergistic effect included enhanced repair processes, such as increased endogenous angiogenesis and upregulation of angiogenic factors released from activated astrocytes.

In Vivo Reprogramming Using Yamanaka Factors in the CNS: A Scoping Review.

Central nervous system diseases, particularly neurodegenerative disorders, pose significant challenges in medicine. These conditions, characterized by progressive neuronal loss, have remained largely incurable, exacting a heavy toll on individuals and society. In recent years, in vivo reprogramming using Yamanaka factors has emerged as a promising approach for central nervous system regeneration. This technique involves introducing transcription factors, such as Oct4, Sox2, Klf4, and c-Myc, into adult cells to induce their conversion into neurons. This review summarizes the current state of in vivo reprogramming research in the central nervous system, focusing on the use of Yamanaka factors. In vivo reprogramming using Yamanaka factors has shown promising results in several animal models of central nervous system diseases. Studies have demonstrated that this approach can promote the generation of new neurons, improve functional outcomes, and reduce scar formation. However, there are still several challenges that need to be addressed before this approach can be translated into clinical practice. These challenges include optimizing the efficiency of reprogramming, understanding the cell of origin for each transcription factor, and developing methods for reprogramming in non-subventricular zone areas. Further research is needed to overcome the remaining challenges, but this approach has the potential to revolutionize the way we treat central nervous system disorders.

Deep learning models to predict the editing efficiencies and outcomes of diverse base editors.

Applications of base editing are frequently restricted by the requirement for a protospacer adjacent motif (PAM), and selecting the optimal base editor (BE) and single-guide RNA pair (sgRNA) for a given target can be difficult. To select for BEs and sgRNAs without extensive experimental work, we systematically compared the editing windows, outcomes and preferred motifs for seven BEs, including two cytosine BEs, two adenine BEs and three C•G to G•C BEs at thousands of target sequences. We also evaluated nine Cas9 variants that recognize different PAM sequences and developed a deep learning model, DeepCas9variants, for predicting which variants function most efficiently at sites with a given target sequence. We then develop a computational model, DeepBE, that predicts editing efficiencies and outcomes of 63 BEs that were generated by incorporating nine Cas9 variants as nickase domains into the seven BE variants. The predicted median efficiencies of BEs with DeepBE-based design were 2.9- to 20-fold higher than those of rationally designed SpCas9-containing BEs.

Functional Outcomes Associated With Blood Pressure Decrease After Endovascular Thrombectomy.

Importance: The associations between blood pressure (BP) decreases induced by medication and functional outcomes in patients with successful endovascular thrombectomy remain uncertain. Objective: To evaluate whether BP reductions induced by intravenous BP medications are associated with poor functional outcomes at 3 months. Design, Setting, and Participants: This cohort study was a post hoc analysis of the Outcome in Patients Treated With Intra-Arterial Thrombectomy-Optimal Blood Pressure Control trial, a comparison of intensive and conventional BP management during the 24 hours after successful recanalization from June 18, 2020, to November 28, 2022. This study included 302 patients who underwent endovascular thrombectomy, achieved successful recanalization, and exhibited elevated BP within 2 hours of successful recanalization at 19 stroke centers in South Korea. Exposure: A BP decrease was defined as at least 1 event of systolic BP less than 100 mm Hg. Patients were divided into medication-induced BP decrease (MIBD), spontaneous BP decrease (SpBD), and no BP decrease (NoBD) groups. Main Outcomes and Measures: The primary outcome was a modified Rankin scale score of 0 to 2 at 3 months, indicating functional independence. Primary safety outcomes were symptomatic intracerebral hemorrhage within 36 hours and mortality due to index stroke within 3 months. Results: Of the 302 patients (median [IQR] age, 75 [66-82] years; 180 [59.6%] men), 47 (15.6%)were in the MIBD group, 39 (12.9%) were in the SpBD group, and 216 (71.5%) were in the NoBD group. After adjustment for confounders, the MIBD group exhibited a significantly smaller proportion of patients with functional independence at 3 months compared with the NoBD group (adjusted odds ratio [AOR], 0.45; 95% CI, 0.20-0.98). There was no significant difference in functional independence between the SpBD and NoBD groups (AOR, 1.41; 95% CI, 0.58-3.49). Compared with the NoBD group, the MIBD group demonstrated higher odds of mortality within 3 months (AOR, 5.15; 95% CI, 1.42-19.4). The incidence of symptomatic intracerebral hemorrhage was not significantly different among the groups (MIBD vs NoBD: AOR, 1.89; 95% CI, 0.54-5.88; SpBD vs NoBD: AOR, 2.75; 95% CI, 0.76-9.46). Conclusions and Relevance: In this cohort study of patients with successful endovascular thrombectomy after stroke, MIBD within 24 hours after successful recanalization was associated with poor outcomes at 3 months. These findings suggested lowering systolic BP to below 100 mm Hg using BP medication might be harmful.

Impact of intensive blood pressure lowering after multiple-attempt endovascular thrombectomy: A secondary analysis of the OPTIMAL-BP trial.

BACKGROUND: Multiple attempts of thrombectomy have been linked to a higher risk of intracerebral hemorrhage and worsened functional outcomes, potentially influenced by blood pressure (BP) management strategies. Nonetheless, the impact of intensive BP management following successful recanalization through multiple attempts remains uncertain. AIMS: This study aimed to investigate whether conventional and intensive BP managements differentially affect outcomes according to multiple-attempt recanalization (MAR) and first-attempt recanalization (FAR) groups. METHODS: In this secondary analysis of the OPTIMAL-BP trial, which was a comparison of intensive (systolic BP target: <140 mm Hg) and conventional (systolic BP target = 140-180 mm Hg) BP managements during the 24 h after successful recanalization, we included intention-to-treat population of the trial. Patients were divided into the MAR and the FAR groups. We examined a potential interaction between the number of thrombectomy attempts (MAR and FAR groups) and the effect of BP managements on clinical and safety outcomes. The primary outcome was functional independence at 3 months. Safety outcomes were symptomatic intracerebral hemorrhage within 36 h and mortality within 3 months. RESULTS: Of the 305 patients (median = 75 years), 102 (33.4%) were in the MAR group and 203 (66.6%) were in the FAR group. The intensive BP management was significantly associated with a lower rate of functional independence in the MAR group (intensive, 32.7% vs conventional, 54.9%, adjusted odds ratio (OR) = 0.33, 95% confidence interval (CI) = 0.12-0.90, p = 0.03). In the FAR group, the proportion of patients with functional independence was not significantly different between the BP managements (intensive, 42.5% vs conventional, 54.2%, adjusted OR = 0.73, 95% CI = 0.38-1.40). Incidences of symptomatic intracerebral hemorrhage and mortality rates were not significantly different according to the BP managements in both MAR and FAR groups. CONCLUSIONS: Among stroke patients who received multiple attempts of thrombectomy, intensive BP management for 24 h resulted in a reduced chance of functional independence at 3 months and did not reduce symptomatic intracerebral hemorrhage following successful reperfusion.