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Background: Intensive blood pressure (BP) management within 24 hours after successful reperfusion following endovascular thrombectomy (EVT) is associated with worse functional outcomes than conventional BP management in Asian randomized controlled trials. Given the high prevalence of intracranial atherosclerotic stenosis (ICAS) in Asia, ICAS may influence these outcomes., Aims: We aimed to assess whether ICAS affects the outcomes of intensive BP management after successful EVT., Methods: We conducted a secondary analysis of the Outcome in Patients Treated With Intra-Arterial Thrombectomy-Optimal Blood Pressure Control trial, which enrolled participants from June 2020 to November 2022. Patients with anterior circulation large vessel occlusion (LVO) were stratified into ICAS-related and embolic LVO groups. Clinical outcomes for intensive (target systolic BP<140 mmHg) and conventional BP management (target systolic BP 140-180 mmHg) were analyzed in each group. The primary outcome was a favorable outcome, defined as a modified Rankin Scale score of 0 to 2 at 3 months. Safety outcomes included symptomatic intracerebral hemorrhage within 36 hours and stroke-related death within 3 months., Results: Among 192 patients, 59 were in the ICAS-related LVO group, and 133 were in the embolic LVO group. In the ICAS-related LVO group, the rate of achieving a favorable outcome at 3 months was 37.5% with intensive BP management and 55.6% with conventional management (adjusted OR, 0.49 [95% CI, 0.14-1.75]; P=0.27). In the embolic LVO group, these rates were 29.9% and 42.4%, respectively (adjusted OR, 0.64 [95% CI, 0.28-1.45]; P=0.29). No significant interaction was found (P for interaction=0.68). Additionally, the ICAS-related LVO group receiving intensive BP management had lower rates of successful reperfusion at 24 hours compared to conventional management (67.7% vs 91.7%; P=0.03), while no significant difference was found in the embolic LVO group. A significant interaction effect on successful reperfusion at 24 hours was observed between ICAS-related and embolic LVO groups (P for interaction=0.04). No significant differences in safety outcomes were observed between intensive BP management and conventional management within both ICAS-related LVO and embolic LVO groups., Conclusions: ICAS did not significantly affect outcomes of intensive BP management within 24 hours after successful EVT. After successful reperfusion by EVT, intensive BP management should be avoided regardless of ICAS presence.

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., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Rice is a staple crop in Asia, with more than 400 million tons consumed annually worldwide. The protein content of rice is a major determinant of its unique structural, physical, and nutritional properties. Chemical analysis, a traditional method for measuring rice's protein content, demands considerable manpower, time, and costs, including preprocessing such as removing the rice husk. Therefore, of the technology is needed to rapidly and nondestructively measure the protein content of paddy rice during harvest and storage stages. In this study, the nondestructive technique for predicting the protein content of rice with husks (paddy rice) was developed using near-infrared spectroscopy and deep learning techniques. The protein content prediction model based on partial least square regression, support vector regression, and deep neural network (DNN) were developed using the near-infrared spectrum in the range of 950 to 2200 nm. 1800 spectra of the paddy rice and 1200 spectra from the brown rice were obtained, and these were used for model development and performance evaluation of the developed model. Various spectral preprocessing techniques was applied. The DNN model showed the best results among three types of rice protein content prediction models. The optimal DNN model for paddy rice was the model with first-order derivative preprocessing and the accuracy was a coefficient of determination for prediction, R p 2  = 0.972 and root mean squared error for prediction, RMSEP = 0.048%. The optimal DNN model for brown rice was the model applied first-order derivative preprocessing with R p 2  = 0.987 and RMSEP = 0.033%. These results demonstrate the commercial feasibility of using near-infrared spectroscopy for the non-destructive prediction of protein content in both husked rice seeds and paddy rice., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Yang, Kim, Lee, Kim, Sang, Yang and Mo.)

Hypoxia-inducible factor (HIF)-1α is a crucial transcription factor associated with cancer metabolism and is regarded as a potent anticancer therapeutic strategy within the hypoxic microenvironment of cancer. In this study, stilbenoid derivatives were designed, synthesized, and assessed for their capacity to inhibit HIF-1α-associated cancer metabolism and evaluated for inhibition of cancer cell viability and HIF activation. Through the structure-activity relationship studies, compound 28e was identified as the most potent derivative. Specifically, under the hypoxic condition, 28e reduced the accumulation of HIF-1α protein and the expression of its target genes related to glucose metabolism without affecting the expression of HIF-1α mRNA. Furthermore, 28e inhibited glucose uptake, glycolytic metabolism, and mitochondrial respiration, decreasing cellular ATP production under hypoxic conditions. In addition, 28e displayed significant anti-tumor effects and effectively suppressed the accumulation of HIF-1α protein in tumor tissue in vivo xenograft model. These findings suggest that our stilbenoid derivatives exert their anticancer effects by targeting HIF-1α-centered cancer metabolism under hypoxic conditions., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Senescent cells increase in many tissues with age and induce age-related pathologies, including osteoarthritis (OA). Senescent chondrocytes (SnCs) are found in OA cartilage, and the clearance of those chondrocytes prevents OA progression. However, targeting SnCs is challenging due to the absence of a senescent chondrocyte-specific marker. Therefore, we used flow cytometry to screen and select senescent chondrocyte surface markers and cross-validated with published transcriptomic data. Chondrocytes expressing dipeptidyl peptidase-4 (DPP-4), the selected senescent chondrocyte-specific marker, had multiple senescence phenotypes, such as increased senescence-associated-galactosidase, p16, p21, and senescence-associated secretory phenotype expression, and showed OA chondrocyte phenotypes. To examine the effects of DPP-4 inhibition on DPP-4+ SnCs, sitagliptin, a DPP-4 inhibitor, was treated in vitro. As a result, DPP-4 inhibition selectively eliminates DPP-4+ SnCs without affecting DPP-4- chondrocytes. To assess in vivo therapeutic efficacy of targeting DPP-4+ SnCs, three known senolytics (ABT263, 17DMAG, and metformin) and sitagliptin were comparatively verified in a DMM-induced rat OA model. Sitagliptin treatment specifically and effectively eliminated DPP-4+ SnCs, compared to the other three senolytics. Furthermore, Intra-articular sitagliptin injection to the rat OA model increased collagen type II and proteoglycan expression and physical functions and decreased cartilage destruction, subchondral bone plate thickness and MMP13 expression, leading to the amelioration of OA phenotypes. Collectively, OARSI score was lowest in the sitagliptin treatment group. Taken together, we verified DPP-4 as a surface marker for SnCs and suggested that the selective targeting of DPP-4+ chondrocytes could be a promising strategy to prevent OA progression., (© 2024 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

In contrast to normal cells, cancer cells predominantly utilise glycolysis for ATP generation under aerobic conditions, facilitating proliferation and metastasis. Targeting glycolysis is effective for cancer treatment. Prodigiosin (PDG) is a natural compound with various bioactivities, including anticancer effects. However, the precise action mechanisms and molecular targets of PDG, which has demonstrated efficacy in regulating glucose metabolism in cancer cells, remain elusive. Here, we aimed to investigate the anti-cancer activity of PDG and mechanism in cancer metabolism. PDG regulated cancer metabolism by suppressing intracellular ATP production rate and levels. It inhibited glycolysis and mitochondrial oxidative phosphorylation, impeding ATP production dependent on both glycolysis and mitochondrial respiration. Moreover, it inhibited cellular glucose uptake by directly interacting with glucose transporter 1 without affecting its mRNA or protein levels in HCT116 cells. We provide insights into the anti-cancer effects of PDG mediated via cancer metabolism regulation, suggesting its therapeutic potential for cancer.

Immunoglobulin G-based monoclonal antibodies (mAbs) have been effective in treating various diseases, but their large molecular size can limit their penetration of tissue and efficacy in multifactorial diseases, necessitating the exploration of alternative forms. In this study, we constructed a phage display library comprising single-domain antibodies (sdAbs; or "VHHs"), known for their small size and remarkable stability, using a total of 1.6 × 10 9 lymphocytes collected from 20 different alpacas, resulting in approximately 7.16 × 10 10 colonies. To assess the quality of the constructed library, next-generation sequencing-based high-throughput profiling was performed, analyzing approximately 5.65 × 10 6 full-length VHH sequences, revealing 92% uniqueness and confirming the library's diverse composition. Systematic characterization of the library revealed multiple sdAbs with high affinity for three therapeutically relevant antigens. In conclusion, our alpaca sdAb phage display library provides a versatile resource for diagnostics and therapeutics. Furthermore, the library's vast natural VHH antibody repertoire offers insights for generating humanized synthetic sdAb libraries, further advancing sdAb-based therapeutics.

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.

With the global pandemic and the continuous mutations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the need for effective and broadly neutralizing treatments has become increasingly urgent. This study introduces a novel strategy that targets two aspects simultaneously, using bifunctional antibodies to inhibit both the attachment of SARS-CoV-2 to host cell membranes and viral fusion. We developed pioneering IgG4-(HR2) 4 bifunctional antibodies by creating immunoglobulin G4-based and phage display-derived human monoclonal antibodies (mAbs) that specifically bind to the SARS-CoV-2 receptor-binding domain, engineered with four heptad repeat 2 (HR2) peptides. Our in vitro experiments demonstrate the superior neutralization efficacy of these engineered antibodies against various SARS-CoV-2 variants, ranging from original SARS-CoV-2 strain to the recently emerged Omicron variants, as well as SARS-CoV, outperforming the parental mAb. Notably, intravenous monotherapy with the bifunctional antibody neutralizes a SARS-CoV-2 variant in a murine model without causing significant toxicity. In summary, this study unveils the significant potential of HR2 peptide-driven bifunctional antibodies as a potent and versatile strategy for mitigating SARS-CoV-2 infections. This approach offers a promising avenue for rapid development and management in the face of the continuously evolving SARS-CoV-2 variants, holding substantial promise for pandemic control., (© 2024 Wiley Periodicals LLC.)

Background: The periprocedural antithrombotic regimen might affect the risk-benefit profile of emergent carotid artery stenting (eCAS) in patients with acute ischemic stroke (AIS) due to tandem lesions, especially after intravenous thrombolysis. We conducted a systematic review and meta-analysis to evaluate the safety and efficacy of antithrombotics following eCAS., Methods: We followed PRISMA guidelines and searched MEDLINE, Embase, and Scopus from January 1, 2004 to November 30, 2022 for studies evaluating eCAS in tandem occlusion. The primary endpoint was 90-day good functional outcome. Secondary outcomes were symptomatic intracerebral hemorrhage, in-stent thrombosis, delayed stent thrombosis, and successful recanalization. Meta-analysis of proportions and meta-analysis of odds ratios were implemented., Results: 34 studies with 1658 patients were included. We found that the use of no antiplatelets (noAPT), single antiplatelet (SAPT), dual antiplatelets (DAPT), or glycoprotein IIb/IIIa inhibitors (GPI) yielded similar rates of good functional outcomes, with a marginal benefit of GPI over SAPT (OR 1.88, 95% CI 1.05 to 3.35, P heterogeneity =0.31). Sensitivity analysis and meta-regression excluded a significant impact of intravenous thrombolysis and Alberta Stroke Program Early CT Score (ASPECTS). We observed no increase in symptomatic intracerebral hemorrhage (sICH) with DAPT or GPI compared with noAPT or SAPT. We also found similar rates of delayed stent thrombosis across groups, with acute in-stent thrombosis showing marginal, non-significant benefits from GPI and DAPT over SAPT and noAPT., Conclusions: In AIS due to tandem occlusion, the periprocedural antithrombotic regimen of eCAS seems to have a marginal effect on good functional outcome. Overall, high intensity antithrombotic therapy may provide a marginal benefit on good functional outcome and carotid stent patency without a significant increase in risk of sICH., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

The widespread use of mobile devices and laptops has replaced traditional paper-based learning and the question of how the brain efficiency of digital tablet-based learning differs from that of paper-based learning remains unclear. The purpose of this study was to investigate the difference in brain efficiency for learning between paper-based and digital tablet-based learning by measuring activity in the prefrontal cortex (PFC) using functional near-infrared spectroscopy. Thirty-two subjects were randomly assigned to the paper-based learning or the digital tablet-based learning group. Subjects in each group performed a memory task that required memorizing a three-minute novel (encoding phase) on a paper or digital tablet, followed by a test in which they answered four multiple-choice questions based on the novel's content. To compare both groups, behavioral performance on the test (retrieval phase) and activity in the PFC were measured. As a result, no significant difference in behavioral performance between both groups was observed ( p > 0.05). However, the paper-based learning group showed significantly lower activity in the PFC in the encoding phase than the digital tablet-based learning group ( p < 0.05) but not in the retrieval phase. The current study demonstrated that brain efficiency in encoding is higher in subjects with paper-based learning than those with digital tablet-based learning. This finding has important implications for education, particularly in terms of the pros and cons of electronic document-based learning.

Background: Keloids are common benign skin lesions originating from a disorganized fibroproliferative collagen response; these lesions often lead to both physical and psychological problems. The optimal treatment for keloids is yet to be standardized. Intralesional injection, which is simple and nontraumatic, is one of the most commonly used treatment modalities for these lesions. In this study, we compared 5 different drugs (intralesional injections) for the treatment of keloids in terms of efficacy., Methods: We systemically searched relevant studies on PubMed, EMBASE, and Cochrane Library. Randomized clinical trials on the safety and efficacy of triamcinolone acetonide (TAC), 5-fluorouracil (5-FU), botulinum toxin A (BTA), verapamil, and bleomycin were included in this study., Results: This network meta-analysis included a total of 1114 patients from 20 randomized controlled trials. Botulinum toxin A alone and TAC plus 5-FU exhibited significantly better efficacy than did 5-FU, TAC, and verapamil. No significant difference in efficacy between BTA alone and TAC combined with 5-FU was observed. No significant differences were noted in the adverse event rate between BTA, TAC plus 5-FU, 5-FU, and TAC. Furthermore, we performed surface under the cumulative ranking curve analyses to predict the rank of each intervention (by efficacy and adverse event rate). The predicted ranking by efficacy was as follows: TAC plus 5-FU, BTA, bleomycin, TAC, 5-FU, and verapamil; the predicted ranking by adverse events was as follows: TAC, 5-FU, TAC plus 5-FU, and BTA. Funnel plot analysis revealed no publication bias., Conclusions: Botulinum toxin A and TAC plus 5-FU appear to have outstanding therapeutic efficacy for keloids. The rate of adverse events was similar among BTA, TAC, 5-FU, and TAC plus 5-FU. Nonetheless, additional reviews of rigorous, large-scale randomized controlled trials are warranted for further validation of our findings., Competing Interests: Conflicts of interest and sources of funding: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

The effects of cholesterol variability on cataracts, dementia, and osteoporosis remain controversial. Using a common data model, we investigated the effects of variations in cholesterol levels on the development of cataracts, dementia, and osteoporosis. Patients who received statin therapy between 2011 and 2020 and those with 3 or more tests for total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG) levels were included. The patients were divided into those with a coefficient of variation (CV) of TC higher than the mean (high-CV group) and those with a lower CV of TC (low-CV group). Moreover, 1:1 propensity score matching was conducted based on demographic variables. Cataract, dementia, or osteoporosis was defined as having a diagnostic, drug, or surgical code based on the cohort definition. Of the 12,882 patients, cataracts, dementia, and osteoporosis were developed in 525 (4.1%), 198 (1.5%), and 438 (3.4%) patients, respectively. The stratified Cox proportional hazards model showed that the incidences of cataracts and osteoporosis were 1.38 and 1.45 times greater in the high-CV group than in the low-CV group, respectively. Our study revealed that TC variability is associated with developing cataracts and osteoporosis., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: We evaluated long-term seizure outcomes of antiseizure medications (ASMs) and risk factors for drug resistance in patients with adult-onset epilepsy associated with cerebral cavernous malformation (CCM)., Materials and Methods: This retrospective observational study included patients newly diagnosed with adult-onset focal epilepsy associated with CCM. Patients received individualized treatments with ASMs. All patients were followed-up for at least 2 years. The main outcome measure was terminal 2 year seizure freedom (2-YSF)., Results: Forty eight subjects (28 men and 20 women) were included. Thirty-one (64.6%) subjects achieved a terminal 2-YSF (range 2.0-17.0 years). After treatment with the first drug regimen, 31 (64.6%) subjects achieved 2-YSF, with 23 remaining seizure-free until final follow-up visit. Of the 23 subjects treated with the second drug regimen and the six treated with the third drug regimen, ten (43.5%) and one (16.7%), respectively, achieved a terminal 2-YSF. Stepwise logistic regression analyses showed that terminal 2-YSF was negatively associated with epileptiform discharge on EEG at the time of diagnosis (odds ratio = 0.214, p = 0.047) and tended to be associated with age ≥ 45 years at seizure onset (odds ratio = 4.260, p = 0.056)., Conclusion: The present study found that 64.6% of CCM patients with adult-onset epilepsy achieved terminal 2-YSF after ASM initiation. Interictal epileptiform discharge on EEG at the time of diagnosis was associated with poor prognosis. Failure to achieve sustained seizure freedom after two ASMs may indicate the need for surgical treatment., Competing Interests: Declaration of Competing Interest None of the authors has any conflicts of interest to disclose., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Introduction: The emergence of new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants has caused unprecedented health and socioeconomic crises, necessitating the immediate development of highly effective neutralizing antibodies. Despite recent advancements in anti-SARS-CoV-2 receptor-binding domain (RBD)-specific monoclonal antibodies (mAbs) derived from convalescent patient samples, their efficacy against emerging variants has been limited. In this study, we present a novel dual-targeting strategy using bispecific antibodies (bsAbs) that specifically recognize both the SARS-CoV-2 RBD and fusion peptide (FP), crucial domains for viral attachment to the host cell membrane and fusion in SARS-CoV-2 infection., Methods: Using phage display technology, we rapidly isolated FP-specific mAbs from an established human recombinant antibody library, identifying K107.1 with a nanomolar affinity for SARS-CoV-2 FP. Furthermore, we generated K203.A, a new bsAb built in immunoglobulin G4-(single-chain variable fragment) 2 forms and demonstrating a high manufacturing yield and nanomolar affinity to both the RBD and FP, by fusing K102.1, our previously reported RBD-specific mAb, with K107.1., Results: Our comprehensive in vitro functional analyses revealed that the K203.A bsAb significantly outperformed the parental RBD-specific mAb in terms of neutralization efficacy against SARS-CoV-2 variants. Furthermore, intravenous monotherapy with K203.A demonstrated potent in vivo neutralizing activity without significant in vivo toxicity in a mouse model infected with a SARS-CoV-2 variant., Conclusion: These findings present a novel bsAb dual-targeting strategy, directed at SARS-CoV-2 RBD and FP, as an effective approach for rapid development and management against continuously evolving SARS-CoV-2 variants., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Kim, Kim, Heo, Lee, Jang, Lee, Park, Cho, Lee, Shin, Yang, Choi, Shim and Lee.)

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.

Introduction: The D-dimer to fibrinogen ratio (DFR) is a good indicator of clot-producing activity in thrombotic disease, but its clinical usefulness in stroke patients with nonvalvular atrial fibrillation (NVAF) has not been studied. We evaluated the association between the DFR and early neurological deterioration (END) in acute ischemic stroke (AIS) patients with NVAF., Methods: We included consecutive AIS patients with NVAF between 2013 and 2015 from the registry of a real-world prospective cohort from 11 large centers in South Korea. END was defined as an increase ≥2 in the total NIHSS score or ≥ 1 in the motor NIHSS score within the first 72 h of admission. The DFR was calculated as follows: DFR = D-dimer (mg/L)/fibrinogen (mg/dL) x 100., Results: A total of 1018 AIS patients with NVAF were evaluated. In multivariable logistic regression analysis, the highest DFR tertile was closely associated with END (adjusted odds ratio [aOR] = 2.14, 95 % confidence interval [CI]: 1.24-3.69). Hypertension (aOR = 1.71, 95 % CI: 1.09-2.70), initial NIHSS score (aOR = 1.05, 95 % CI: 1.02-1.07) and use of anticoagulants (aOR = 0.41, 95 % CI: 0.28-0.60) were also correlated with END. In addition to END, the DFR was correlated with discharge NIHSS and modified Rankin Scale (mRS) scores and the 3-month mRS score., Conclusions: High DFR values were associated with END in AIS patients with NVAF. As the DFR is an indicator directly related to the main pathological mechanism of NVAF patients (fibrinolysis and coagulation), it may be useful in predicting their prognosis., Competing Interests: Declaration of competing interest None., (Copyright © 2023. Published by Elsevier Ltd.)

Background and Purpose: The congestive heart failure, hypertension, age, diabetes, previous stroke/transient ischemic attack (CHA 2 DS 2 -VASc) and hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol (HAS-BLED) scores have been validated in estimating the risks of ischemic stroke and major bleeding, respectively, in patients with atrial fibrillation (AF). This study investigated stroke-specific predictors of major bleeding in patients with stroke and AF who were taking oral anticoagulants (OACs)., Methods: Subjects were selected from patients enrolled in the Korean ATrial fibrillaTion EvaluatioN regisTry in Ischemic strOke patieNts (K-ATTENTION) nationwide multicenter registry between 2013 and 2015. Patients were excluded if they were not taking OACs, had no brain imaging data, or had intracranial bleeding directly related to the index stroke. Major bleeding was defined according to International Society of Thrombosis and Haemostasis criteria. Cox regression analyses were performed to assess the associations between clinical variables and major bleeding and Kaplan-Meier estimates were performed to analyze event-free survival., Results: Of a total of 3,213 patients, 1,414 subjects (mean age of 72.6 years, 52.5% males) were enrolled in this study. Major bleeding was reported in 34 patients during the median follow-up period of 1.73 years. Multivariable analysis demonstrated that initial National Institutes of Health Stroke Scale scores (hazard ratio [HR] 1.07, p =0.006), hypertension (HR 3.18, p =0.030), persistent AF type (HR 2.51, p =0.016), and initial hemoglobin level (HR 0.74, p =0.001) were independently associated with major bleeding risk. Except for hypertension, these associations remained significant after adjusting for the HAS-BLED score. Intracranial atherosclerosis presented a trend of association without statistical significance (HR 2.21, p =0.050)., Conclusions: This study found that major bleeding risk was independently associated with stroke-specific factors in anticoagulated patients with stroke and AF. This has the clinical implication that baseline characteristics of patients with stroke and AF should be considered in secondary prevention, which would bring the net clinical benefit of balancing recurrent stroke prevention with minimal bleeding complications., Competing Interests: Woo-Keun Seo received honoraria for lectures from Sanofi-Aventis, Otsuka Korea, Dong-A Pharmaceutical Co, Ltd; study grants from Daiichi Sankyo Korea Co, Ltd; a consulting fee from OBELAB, Inc; and a stock option from JLK Inspection. The other authors report no conflicts., (Copyright © 2023 Korean Neurological Association.)

Tumor hypoxia promotes malignant progression and therapeutic resistance in glioblastoma partly by increasing the production of hydrogen peroxide (H 2 O 2 ), a type of reactive oxygen species critical for cell metabolic responses due to its additional role as a second messenger. However, the catabolic pathways that prevent H 2 O 2 overload and subsequent tumor cell damage in hypoxic glioblastoma remain unclear. Herein, we present a hypoxia-coordinated H 2 O 2 regulatory mechanism whereby excess H 2 O 2 in glioblastoma induced by hypoxia is diminished by glutathione peroxidase 1 (GPx1), an antioxidant enzyme detoxifying H 2 O 2 , via the binding of hypoxia-inducible factor-1α (HIF-1α) to GPx1 promoter. Depletion of GPx1 results in H 2 O 2 overload and apoptosis in glioblastoma cells, as well as growth inhibition in glioblastoma xenografts. Moreover, tumor hypoxia increases exosomal GPx1 expression, which assists glioblastoma and endothelial cells in countering H 2 O 2 or radiation-induced apoptosis in vitro and in vivo. Clinical data explorations further demonstrate that GPx1 expression was positively correlated with tumor grade and expression of HIF-1α, HIF-1α target genes, and exosomal marker genes; by contrast, it was inversely correlated with the overall survival outcome in human glioblastoma specimens. Our analyses validate that the redox balance of H 2 O 2 within hypoxic glioblastoma is clinically relevant and could be maintained by HIF-1α-promoted or exosome-related GPx1., Competing Interests: Declaration of competing interest The authors have declared no potential conflict of interest., (Copyright © 2023. Published by Elsevier B.V.)

Background: Mesenchymal stem cells (MSCs) are a promising cell source for cartilage regeneration. However, the function of MSC can vary according to cell culture conditions, donor age, and heterogeneity of the MSC population, resulting in unregulated MSC quality control. To overcome these limitations, we previously developed a fluorescent real-time thiol tracer (FreSHtracer) that monitors cellular levels of glutathione (GSH), which are known to be closely associated with stem cell function. In this study, we investigated whether using FreSHtracer could selectively separate high-functioning MSCs based on GSH levels and evaluated the chondrogenic potential of MSCs with high GSH levels to repair cartilage defects in vivo., Methods: Flow cytometry was conducted on FreSHtracer-loaded MSCs to select cells according to their GSH levels. To determine the function of FreSHtracer-isolated MSCs, mRNA expression, migration, and CFU assays were conducted. The MSCs underwent chondrogenic differentiation, followed by analysis of chondrogenic-related gene expression. For in vivo assessment, MSCs with different cellular GSH levels or cell culture densities were injected in a rabbit chondral defect model, followed by histological analysis of cartilage-regenerated defect sites., Results: FreSHtracer successfully isolated MSCs according to GSH levels. MSCs with high cellular GSH levels showed enhanced MSC function, including stem cell marker mRNA expression, migration, CFU, and oxidant resistance. Regardless of the stem cell tissue source, FreSHtracer selectively isolated MSCs with high GSH levels and high functionality. The in vitro chondrogenic potential was the highest in pellets generated by MSCs with high GSH levels, with increased ECM formation and chondrogenic marker expression. Furthermore, the MSCs' function was dependent on cell culture conditions, with relatively higher cell culture densities resulting in higher GSH levels. In vivo, improved cartilage repair was achieved by articular injection of MSCs with high levels of cellular GSH and MSCs cultured under high-density conditions, as confirmed by Collagen type 2 IHC, Safranin-O staining and O'Driscoll scores showing that more hyaline cartilage was formed on the defects., Conclusion: FreSHtracer selectively isolates highly functional MSCs that have enhanced in vitro chondrogenesis and in vivo hyaline cartilage regeneration, which can ultimately overcome the current limitations of MSC therapy., (© 2023. The Author(s).)

MDH1 and MDH2 enzymes play an important role in the survival of lung cancer. In this study, a novel series of dual MDH1/2 inhibitors for lung cancer was rationally designed and synthesized, and their SAR was carefully investigated. Among the tested compounds, compound 50 containing a piperidine ring displayed an improved growth inhibition of A549 and H460 lung cancer cell lines compared with LW1497 . Compound 50 reduced the total ATP content in A549 cells in a dose-dependent manner; it also significantly suppressed the accumulation of hypoxia-inducible factor 1-alpha (HIF-1α) and the expression of HIF-1α target genes such as GLUT1 and pyruvate dehydrogenase kinase 1 ( PDK1) in a dose-dependent manner. Furthermore, compound 50 inhibited HIF-1α-regulated CD73 expression under hypoxia in A549 lung cancer cells. Collectively, these results indicate that compound 50 may pave the way for the development of next-generation dual MDH1/2 inhibitors to target lung cancer.

Rapid emergence of new variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has prompted an urgent need for the development of broadly applicable and potently neutralizing antibody platform against the SARS-CoV-2, which can be used for combatting the coronavirus disease 2019 (COVID-19). In this study, based on a noncompeting pair of phage display-derived human monoclonal antibodies (mAbs) specific to the receptor-binding domain (RBD) of SARS-CoV-2 isolated from human synthetic antibody library, we generated K202.B, a novel engineered bispecific antibody with an immunoglobulin G4-single-chain variable fragment design, with sub- or low nanomolar antigen-binding avidity. Compared with the parental mAbs or mAb cocktail, the K202.B antibody showed superior neutralizing potential against a variety of SARS-CoV-2 variants in vitro. Furthermore, structural analysis of bispecific antibody-antigen complexes using cryo-electron microscopy revealed the mode of action of K202.B complexed with a fully open three-RBD-up conformation of SARS-CoV-2 trimeric spike proteins by simultaneously interconnecting two independent epitopes of the SARS-CoV-2 RBD via inter-protomer interactions. Intravenous monotherapy using K202.B exhibited potent neutralizing activity in SARS-CoV-2 wild-type- and B.1.617.2 variant-infected mouse models, without significant toxicity in vivo. The results indicate that this novel approach of development of immunoglobulin G4-based bispecific antibody from an established human recombinant antibody library is likely to be an effective strategy for the rapid development of bispecific antibodies, and timely management against fast-evolving SARS-CoV-2 variants., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Antibody phage display is a key technology for the discovery and development of target-specific monoclonal antibodies (mAbs) for use in research, diagnostics, and therapy. The construction of a high-quality antibody library, with larger and more diverse antibody repertoires, is essential for the successful development of phage display-derived mAbs. In this study, a large human combinatorial single-chain variable fragment library (1.5 × 10 11 colonies) was constructed from Epstein-Barr virus-infected human peripheral blood mononuclear cells stimulated with a combination of two of the activators of human B cells, the Toll-like receptor 7/8 agonist R848 and interleukin-2. Next-generation sequencing analysis with approximately 1.9 × 10 6 and 2.7 × 10 6 full-length sequences of heavy chain variable (VH) and κ light chain variable (Vκ) domains, respectively, revealed that the library consists of unique VH (approximately 94%) and Vκ (approximately 91%) sequences with greater diversity than germline sequences. Lastly, multiple unique mAbs with high affinity and broad cross-species reactivity could be isolated from the library against two therapeutically relevant target antigens, validating the library quality. These findings suggest that the novel antibody library we have developed may be useful for the rapid development of target-specific phage display-derived recombinant human mAbs for use in therapeutic and diagnostic applications.

This study was conducted to increase the productivity of biomass that contains high astaxanthin content by developing a mutant Haematococcus pluvialis strain with strong environmental tolerance. H. pluvialis has a low cell-growth rate and is vulnerable to stressors such as salinity or light intensity, which may hinder large-scale commercial cultivation. A mutant M5 strain selected through 5000-Gy gamma irradiation showed improved biomass and astaxanthin production under high-salinity and high-light intensity conditions. With enhanced SOD activity and overexpressed astaxanthin biosynthesis genes (lyc, crtR-b, bkt2), M5 demonstrated an increase in biomass and astaxanthin productivity by 86.70 % and 66.15 %, respectively compared to those of untreated cells. Also, the omega-3 content of M5 increased by 149.44 % under 40 mM CaCl 2 compared to the untreated cells. Finally, even when subjected to high-intensity light irradiation for the whole life cycle, the biomass and astaxanthin concentration increased by 84.99 % and 241 %, respectively, compared to the wild-type cells., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Little is known regarding the effects of continuous positive airway pressure (CPAP) on sleep misperception in obstructive sleep apnea (OSA)., Methods: Sleep state perception was measured by subtracting the objective total sleep time from the subjective sleep duration. Sleep underestimation and overestimation were defined as ± 60 minutes sleep perception. Insomnia and depressive symptoms were assessed using questionnaires. Finally, nonparametric statistical analyses were performed., Results: Of the 339 patients with OSA included in the study, 90 (26.5%) and 45 (13.3%) showed sleep underestimation and overestimation, respectively. Overall, a significant underestimation of sleep was noted during CPAP titration comparing to a diagnostic PSG ( P < 0.001). OSA patients with insomnia or depressive symptoms did not show any changes in sleep perception between diagnostic and CPAP titration studies, whereas those without insomnia or depressed mood showed significantly underestimated sleep duration during CPAP titration. Patients with OSA and either underestimated or overestimated misperception showed perceptual improvements during CPAP titration regardless of the presence of insomnia or depressive symptoms. However, of 204 patients with normal sleep perception, 138 (67.6%) and 10 (4.9%) had underestimation and overestimation of sleep during CPAP titration., Conclusion: CPAP titration may improve sleep perception with moderate to severe OSA who have sleep misperception. However, CPAP titration may result in sleep misperception especially underestimation of sleep in those who have normal sleep perception., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2023 The Korean Academy of Medical Sciences.)

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has resulted in an ongoing global pandemic crisis, caused by the life-threatening illness coronavirus disease 2019 (COVID-19). Thus, the rapid development of monoclonal antibodies (mAbs) to cope with COVID-19 is urgently necessary. In this study, we used phage display to develop four human mAbs specific to the receptor-binding domain (RBD) of SARS-CoV-2. Our intensive in vitro functional analyses demonstrated that K102.1, an anti-SARS-CoV-2 RBD-specific mAb, exerted potent neutralizing activity against pseudoviral and live viral infection and the interaction between SARS-CoV-2 RBD and human angiotensin-converting enzyme 2. Monotherapy with K102.1 also revealed the therapeutic potential against SARS-CoV-2 infection in vivo. Further, this study developed a sandwich enzyme-linked immunosorbent assay with a non-competing mAb pair, K102.1 and K102.2, that accurately detected the RBDs of SARS-CoV-2 wild-type and variants with high sensitivity in the picomolar range. These findings suggest that the phage-display-based mAb selection from an established antibody library may be an effective strategy for the rapid development of mAbs against the constantly evolving SARS-CoV-2.

Owing to their unique properties and biological activities, ionic liquids (ILs) have attracted research interest in pharmaceutics and medicine. Hypoxia-inducible factor (HIF)- 1α is an attractive cancer drug target involved in cancer malignancy in the hypoxic tumor microenvironment. Herein, we report the inhibitory activity of ILs on the HIF-1α pathway and their mechanism of action. Substitution of a dimethylamino group on pyridinium reduced hypoxia-induced HIF-1α activation. It selectively inhibited the viability of the human colon cancer cell line HCT116, compared to that of the normal fibroblast cell line WI-38. These activities were enhanced by increasing the alkyl chain length in the pyridinium. Under hypoxic conditions, dimethylaminopyridinium reduced the accumulation of HIF-1α and its target genes without affecting the HIF1A mRNA level in cancer cells. It suppressed the oxygen consumption rate and ATP production by directly inhibiting electron transfer chain complex I, which led to enhanced intracellular oxygen content and oxygen-dependent degradation of HIF-1α under hypoxia. These results indicate that dimethylaminopyridinium suppresses the mitochondria and HIF-1α-dependent glucose metabolic pathway in hypoxic cancer cells. This study provides insights into the anticancer activity of pyridinium-based ILs through the regulation of cancer metabolism, making them promising candidates for cancer treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Declaration of competing interest The authors report no declarations of interest., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Little is known regarding the prevalence of sleep state misperception and the factors related to this in patients with obstructive sleep apnea (OSA)., Methods: This retrospective study included patients with OSA defined by an apnea-hypopnea index (AHI) of ≥ 5 and used the Insomnia Severity Index (ISI), the Epworth sleepiness scale, the Patient Health Questionnaire-9, and the Generalized Anxiety Disorder-7. Underestimation and overestimation of sleep state perception were defined as < 80% and > 120%, respectively, of the ratio between subjective and objective total sleep time. An ISI score > 14 indicated clinically significant insomnia and an AHI ≥ 30 indicated severe OSA. A multinomial logistic regression was conducted with the category of sleep state perception as an outcome variable., Results: Of the 707 patients with OSA, underestimation and overestimation of sleep state perception were noted in 22.5% and 10.6% of subjects, respectively. The median absolute differences (and percentages of the ratio) between subjective and objective total sleep time were 116 min (66.9%) and 87 min (127.3%) in the underestimated and overestimated perception groups, respectively. In the adjusted model, the underestimated group was more likely to have an ISI score > 14 (OR = 1.812, P = .006). The overestimated group was more likely to be older (OR = 1.025, P = .025) and has severe OSA (OR = 1.729, P = .035)., Conclusions: There are two patterns of sleep state misperception in patients with OSA: underestimation associated with comorbid insomnia symptoms and overestimation associated with severe OSA. These findings enhance understanding of the pathophysiology of sleep state misperception in patients with OSA., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Hydrogen as a clean fuel is receiving attention because it generates only water and a small amount of nitrogen oxide upon combustion. Biohydrogen production using microalgae is considered to be a highly promising carbon-neutral technology because it can secure renewable energy while efficiently reducing CO 2 emissions. However, previous studies have mainly focused on improving the biological performance of microalgae; these approaches have struggled to achieve breakthroughs in commercialization because they do not heavily consider the complexity of the entire production process with microalgae, including large-scale cultivation, biomass harvest, and biomass storage. This work presents an in-depth analysis of the state-of-the-art technologies focused on large-scale cultivation systems with efficient downstream processes. Considering the individual processes of biohydrogen production, strategies are discussed to minimize carbon emissions and improve productivity simultaneously. A comprehensive understanding of microalgae-derived biohydrogen production suggests future directions for realizing environmental and economic sustainability., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

In this study, the effects of microalgae-based biomineralization in a semi-continuous process (M-BSP) on biomass productivity and CO 2 fixation rate were investigated. M-BSP significantly improved biomass production and CO 2 fixation rate at the second stage of induction by sustaining relatively high photosynthetic rate without exposure to toxic substances (e.g., chlorellin) from aging cells using the microalgae Chlorella HS2. In conventional systems, cells do not receive irradiated light evenly, and many cells age and burst because of the long culture period. In contrast, in the M-BSP, the photosynthesis efficiency increases and biomass production is not inhibited because most of the cells can be harvested during shorter culture period. The accumulated biomass production and CO 2 fixation rate of the HS2 cells cultured under M-BSP increased by 4.67- (25 ± 1.09 g/L) and 10.9-fold (30.29 ± 1.79 g/L day -1 ), respectively, compared to those cultured without the CaCl 2 treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Patients with extensive cutaneous damage resulting from poor wound healing often have other comorbidities such as diabetes that may lead to impaired skin functions and scar formation. Many recent studies have shown that the application of electrical stimulation (ES) to cutaneous lesions significantly improves skin regeneration via activation of AKT intracellular signaling cascades and secretion of regeneration-related growth factors. In this study, we fabricated varying concentrations of gelatin-methacrylate (GelMa) hydrogels with poly(3,4-ethylenedioxythiophene) (PEDOT): polystyrene sulfonate (PSS), which is a conductive material commonly used in tissue engineering due to its efficiency among conductive thermo-elastic materials. The results showed successful modification of PEDOT:PSS with GelMa while retaining the original structural characteristics of the GelMa hydrogels. In addition, the incorporation of PEDOT:PSS increased the interactions between both the materials, thus leading to enhanced mechanical strength, improved swelling ratio, and decreased hydrophilicity of the scaffolds. Our GelMa/PEDOT:PSS scaffolds were designed to have micro-grooves on the surfaces of the scaffolds for the purpose of directional guiding. In addition, our scaffolds were shown to have excellent electrical conductivity, thus leading to enhanced cellular proliferation and directional migration and orientation of human dermal fibroblasts. In vivo studies revealed that the GelMa/PEDOT:PSS scaffolds with electrical stimulation were able to induce full skin thickness regeneration, as seen from the various stainings. These results indicate the potential of GelMa/PEDOT:PSS as an electro-conductive biomaterial for future skin regeneration applications., Competing Interests: Declaration of competing interest All authors declare no conflict of interest in regard to this publication., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Nelonemdaz is a multitarget neuroprotectant that selectively blocks N-methyl-D-aspartate receptors and scavenges free radicals, as proven in preclinical ischemia-reperfusion studies. We aimed to evaluate the safety and efficacy of nelonemdaz in patients with acute ischemic stroke receiving endovascular reperfusion therapy., Methods: This phase II randomized trial involved participants with large-artery occlusion in the anterior circulation at baseline who received endovascular reperfusion therapy <8 hours from symptom onset at 7 referral stroke centers in South Korea between October 29, 2016, and June 1, 2020. Two hundred thirteen patients were screened and 209 patients were randomly assigned at a 1:1:1 ratio using a computer-generated randomization system. Patients were divided into 3 groups based on the medication received-placebo, low-dose (2750 mg) nelonemdaz, and high-dose (5250 mg) nelonemdaz. The primary outcome was the proportion of patients with modified Rankin Scale scores of 0-2 at 12 weeks., Results: Two hundred eight patients were assigned to the placebo (n=70), low-dose (n=71), and high-dose (n=67) groups. The groups had similar baseline characteristics. The primary outcome was achieved in 183 patients, and it did not differ among the groups (33/61 [54.1%], 40/65 [61.5%], and 36/57 [63.2%] patients; P =0.5578). The common odds ratio (90% CI) indicating a favorable shift in the modified Rankin Scale scores at 12 weeks was 1.55 (0.92-2.60) between the placebo and low-dose groups and 1.61 (0.94-2.76) between the placebo and high-dose groups. No serious adverse events were reported., Conclusions: The study arms showed no significant difference in the proportion of patients achieving modified Rankin Scale scores of 0-2 at 12 weeks. Nevertheless, nelonemdaz-treated patients showed a favorable tendency toward achieving these scores at 12 weeks, without serious adverse effects. Thus, a large-scale phase III trial is warranted., Registration: URL: https://clinicaltrials.gov; Unique identifier: NCT02831088.

Background: There has been no comparison of the determinants of admission route between acute ischemic stroke (AIS) and acute myocardial infarction (AMI). We examined whether factors associated with direct versus transferred-in admission to regional cardiocerebrovascular centers (RCVCs) differed between AIS and AMI., Methods: Using a nationwide RCVC registry, we identified consecutive patients presenting with AMI and AIS between July 2016 and December 2018. We explored factors associated with direct admission to RCVCs in patients with AIS and AMI and examined whether those associations differed between AIS and AMI, including interaction terms between each factor and disease type in multivariable models. To explore the influence of emergency medical service (EMS) paramedics on hospital selection, stratified analyses according to use of EMS were also performed., Results: Among the 17,897 and 8,927 AIS and AMI patients, 66.6% and 48.2% were directly admitted to RCVCs, respectively. Multivariable analysis showed that previous coronary heart disease, prehospital awareness, higher education level, and EMS use increased the odds of direct admission to RCVCs, but the odds ratio (OR) was different between AIS and AMI (for the first 3 factors, AMI > AIS; for EMS use, AMI < AIS). EMS use was the single most important factor for both AIS and AMI (OR, 4.72 vs. 3.90). Hypertension and hyperlipidemia increased, while living alone decreased the odds of direct admission only in AMI; additionally, age (65-74 years), previous stroke, and presentation during non-working hours increased the odds only in AIS. EMS use weakened the associations between direct admission and most factors in both AIS and AMI., Conclusions: Various patient factors were differentially associated with direct admission to RCVCs between AIS and AMI. Public education for symptom awareness and use of EMS is essential in optimizing the transportation and hospitalization of patients with AMI and AIS., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2022 The Korean Academy of Medical Sciences.)

Background: The underlying etiology of intracranial non-occlusive intraluminal thrombus (iNOT) remains unknown. This study aimed to investigate whether the presence of iNOT can indicate the underlying etiology of large vessel occlusion (LVO) in patients undergoing endovascular therapy (EVT)., Methods: Among patients who underwent EVT at three comprehensive stroke centers, we included those with intracranial LVO in the anterior circulation. The presence of iNOT was determined by pretreatment DSA. We investigated the association between iNOT and intracranial atherosclerotic stenosis (ICAS) related LVO., Results: Of 546 patients, 44 (8.1%) had iNOT. Patients with iNOT were younger, had less hypertension, atrial fibrillation, and a history of antiplatelet use. In addition, the involvement of the M1 segment of the middle cerebral artery (MCA) was more frequent. However, they had a lower National Institutes of Health Stroke Scale (NIHSS) score on admission and longer onset to recanalization time compared with patients with no iNOT. In a logistic regression model adjusting for age, sex, atrial fibrillation, smoking, prior antiplatelet and anticoagulant use, intravenous tissue plasminogen activator, NIHSS on admission, number of technical trials, intraprocedural re-occlusion, and the location of LVO (p<0.10 in the univariate analysis), the presence of iNOT was significantly associated with ICAS related LVO (adjusted OR 3.04; 95% CI 1.33 to 6.90; p=0.007)., Conclusions: The presence of iNOT may reflect an underlying ICAS related LVO in patients undergoing EVT., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: This study assessed whether patients with epilepsy have a higher level of impulsivity than healthy controls, and compared impulsivity among patients with different subtypes of epilepsy., Methods: The multicenter study included 108 subjects with epilepsy and 56 healthy volunteers. Subjects were evaluated by the Barratt Impulsiveness Scale-11 (BIS-11) and Patient Health Questionnaire-9, with BIS-11 scores analyzed as both dichotomized and continuous variables. High impulsivity was defined as a total BIS-11 score ≥ 67., Results: Of the 108 subjects with epilepsy, 36 had idiopathic generalized epilepsy (IGE), 47 had temporal lobe epilepsy (TLE), and 25 had frontal lobe epilepsy (FLE). A significantly higher percentage of subjects with epilepsy (22.2%) than controls (1.8%) had BIS-11 scores ≥ 67 (p = 0.001), although mean BIS-11 scores were similar in subjects with epilepsy (59.5 ± 10.0) and controls (58.8 ± 4.6). Higher percentages of subjects with IGE and FLE had BIS-11 scores ≥ 67 than subjects with TLE and controls. Mean total BIS-11 scores did not differ between controls and subjects with IGE and FLE, but were lower in subjects with TLE than in controls. Differences in impulsivity among controls and subjects with epilepsy subtypes varied depending on BIS-11 subscale., Conclusions: Patients with epilepsy, particularly IGE and FLE, were more likely to have high impulsivity scores, defined by a certain cutoff on the BIS-11, than controls and subjects with TLE. However, mean impulsivity scores did not differ among controls and subjects with IGE and FLE. Dichotomizing BIS-11 scores may be necessary to avoid false negative results in subjects with epilepsy., Competing Interests: Conflicts of interest The authors declare no conflicts of interest in relation to this study., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Local tirofiban infusion has been reported as a rescue strategy for intracranial atherosclerotic stenosis (ICAS)-related stroke. However, the long-term outcomes of local tirofiban infusion during endovascular reperfusion therapy (ERT) for ICAS-related stroke are still uncertain. This study aimed to investigate the long-term outcomes of local tirofiban infusion during ERT. We retrospectively analyzed acute patients with ICAS-related stroke who were treated with local tirofiban as a rescue strategy during ERT. The primary outcomes were ischemic stroke, transient ischemic stroke (TIA), and stroke-related death within 30 days. Secondary outcomes included ischemic stroke and TIA beyond 30 days and up to 2 years after ERT in the corresponding treated vessel, symptomatic brain hemorrhage, any stroke, and non-stroke-related death. During a median follow-up of 24.0 months, 12 patients developed an ischemic stroke and TIA (4 within 30 days and 8 afterward). The 1-year risk of stroke and TIA was 9.2% (95% confidence interval, 8.0-18.6%). This study demonstrates that 1-year outcomes of local tirofiban infusion were comparable to the results of intracranial stenting in patients with symptomatic ICAS. Local tirofiban infusion for ICAS-related stroke may be a feasible rescue strategy that can have a bridging role until the maximum effect of antiplatelet agents is achieved.

Stomata are a pivotal adaptation of land plants and control gas exchange. While most plants present solitary stomata, some plant species experiencing chronic water deficiency display clustered stomata on their epidermis; for instance, limestone-grown begonias. Moreover, the membrane receptor TOO MANY MOUTHS (TMM) plays a major role in spacing stomata on the epidermis in Arabidopsis , but the function of its Begonia orthologs is unknown. We used two Asian begonias, Begonia formosana (single stomata) and B. hernandioides (clustered stomata), to explore the physiological function of stomatal clustering. We also introduced the Begonia TMM s into Arabidopsis tmm mutants to study the function of Begonia TMMs. B. hernandioides showed higher water use efficiency under high light intensity, smaller stomata, and faster pore opening than B. formosana . The short distance between stomata in a cluster may facilitate cell-to-cell interactions to achieve synchronicity in stomatal movement. Begonia TMMs function similarly to Arabidopsis TMM to inhibit stomatal formation, although complementation by TMM from the clustered species was only partial. Stomatal clustering in begonias may represent a developmental strategy to build small and closer stomata to achieve fast responses to light which provides tight support between stomatal development and environmental adaption., Competing Interests: The authors declare no competing interests., (© 2022 The Authors. Plant‐Environment Interactions published by New Phytologist Foundation and John Wiley & Sons Ltd.)

Background: Little is known about the changes in hemodynamic parameters during arteriovenous (AV) access maturation using duplex ultrasound according to radiocephalic fistula (RCF), brachiocephalic fistula (BCF), and AV graft (AVG) in incident hemodialysis (HD) patient. The objective of this study was to evaluate changes and differences in brachial artery flow rate (BAFR) and related parameters affecting maturation by duplex ultrasound in incident HD patients according to access type., Methods: This study was an observational study conducted from March 2019 to October 2020. During the study period, 109 incident patients underwent new AV access creation, of which 100 were included in the study. The duplex ultrasound was performed on the day prior to access creation, further, day 1, 2 weeks, and 4 weeks later after access creation in incident HD patients., Results: Among all the patients, 38 (38%) received BCF, while 26 (26%) underwent RCF. Of the patients with AVG, 18 (50%) had a forearm loop AVG. The overall mean age was 62.2 ± 13.8 years (range, 32-89). The BAFR increased about 6.9 times in the RCF, 17.4 times in the BCF, and 19.5 times in the AVG at day 1. The median BAFR measured on day 1 was 580.4 mL/min for RC, 1029.0 mL/min for BC, and 1133.0 mL/min for AVG. Relative to the values measured in week 4, the BAFR on day 1 was 69.5% in RCF, 90.6% in BCF, and 93.9% in AVG. The acceleration decreased most significantly on day 1( p  < 0.05). The acceleration time increased significantly on day 1 ( p  < 0.05) and beyond during maturation in the RCF and BCF. The BAFR of the RCF had a significantly negative correlation with the pulsatility index. The BAFR of the BCF showed a significantly positive correlation with the systolic and diastolic blood pressure but negatively correlated with pulse rate. The BAFR of the AVG showed a significant positive correlation with the diameter of the outflow vein., Conclusions: There were differences in the clinical and duplex parameters during maturation according to access type. The most dramatic changes of duplex parameters were on the day after AV access creation regardless of AV access types. Though RCF had a lower BAFR rate compared to BCF and AVG, it already had a sufficient BAFR required for adequate HD treatment the day after creation. The BAFR of BCF was not different from that of AVG.

Small-cell lung cancer (SCLC) is the most aggressive form of lung cancer and the leading cause of global cancer-related mortality. Despite the earlier identification of membrane-proximal cleavage of cell adhesion molecule 1 (CADM1) in cancers, the role of the membrane-bound fragment of CAMD1 (MF-CADM1) is yet to be clearly identified. In this study, we first isolated MF-CADM1-specific fully human single-chain variable fragments (scFvs) from the human synthetic scFv antibody library using the phage display technology. Following the selected scFv conversion to human immunoglobulin G1 (IgG1) scFv-Fc antibodies (K103.1-4), multiple characterization studies, including antibody cross-species reactivity, purity, production yield, and binding affinity, were verified. Finally, via intensive in vitro efficacy and toxicity evaluation studies, we identified K103.3 as a lead antibody that potently promotes the death of human SCLC cell lines, including NCI-H69, NCI-H146, and NCI-H187, by activated Jurkat T cells without severe endothelial toxicity. Taken together, these findings suggest that antibody-based targeting of MF-CADM1 may be an effective strategy to potentiate T cell-mediated SCLC death, and MF-CADM1 may be a novel potential therapeutic target in SCLC for antibody therapy.

The ischemic stroke animal model evaluates the efficacy of reperfusion and neuroprotective strategies for ischemic injuries. Various conventional methods have been reported to induce the ischemic models; however, controlling specific neurological deficits, mortality rates, and the extent of the infarction is difficult as the size of the affected region is not precisely controlled. In this paper, we report a single laser-based localized target ischemic stroke model development method by simultaneous vessel monitoring and photothrombosis induction using photoacoustic microscopy (PAM), which has minimized the infarct size at precise location with high reproducibility. The proposed method has significantly reduced the infarcted region by illuminating the precise localization. The reproducibility and validity of suggested method have been demonstrated through repeated experiments and histological analyses. These results demonstrate that our method can provide the ischemic stroke model closest to the clinical pathology for brain ischemia research from inducement, occurrence mechanisms to the recovery process., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Cancer is the second leading cause of death worldwide after cardiovascular diseases. Harnessing the power of immune cells is a promising strategy to improve the antitumor effect of cancer immunotherapy. Recent progress in recombinant DNA technology and antibody engineering has ushered in a new era of bispecific antibody (bsAb)-based immune-cell engagers (ICEs), including T- and natural-killer-cell engagers. Since the first approval of blinatumomab by the United States Food and Drug Administration (US FDA), various bsAb-based ICEs have been developed for the effective treatment of patients with cancer. Simultaneously, several potential therapeutic targets of bsAb-based ICEs have been identified in various cancers. Therefore, this review focused on not only highlighting the action mechanism, design and structure, and status of bsAb-based ICEs in clinical development and their approval by the US FDA for human malignancy treatment, but also on summarizing the currently known and emerging therapeutic targets in cancer. This review provides insights into practical considerations for developing next-generation ICEs.

Background: Regional eloquence of brainstem structures may contribute to neurological status in basilar artery occlusion (BAO) stroke. The corticospinal tract (CST) which is vulnerable to BAO is important for motor activity. This study investigated the impact of CST salvage on outcomes and its associated factors in patients with BAO treated with thrombectomy., Methods: We retrospectively investigated 88 patients with BAO admitted ≤24 h after onset and presented with motor deficits and who underwent thrombectomy. Patients with a pre-stroke modified Rankin Scale (mRS) score of 4-5 who did not undergo baseline brain computed tomography angiography were excluded. CST salvage was evaluated using follow-up imaging (magnetic resonance imaging [MRI] or computed tomography when MRI was not available) after thrombectomy. A good outcome was defined as a 3-month mRS score of ≤2 or 3 if a patient's pre-stroke mRS score was 3. The associations between CST salvage and outcomes and clinical parameters were analyzed using logistic regression analyses., Results: Thirty-nine (44.3%) patients had CST salvage and the same number of patients had good outcomes. CST salvage was independently associated with a good outcome [adjusted odds ratio (aOR): 18.52, 95% confidence interval (CI): 4.31-79.67, p < 0.001]. After adjusting for confounders, atrial fibrillation (aOR: 3.92, 95% CI: 1.18-13.00, p = 0.026), location of occlusion (mid-BAO; aOR: 0.21, 95% CI: 0.06-0.72, p = 0.013), length of occlusion (involved segment of BAO <2; aOR: 4.77, 95% CI: 1.30-17.59, p = 0.019), and onset-to-puncture-time ≤180 min (aOR: 4.84, 95% CI: 1.13-20.75, p = 0.034) were significantly associated with CST salvage., Conclusion: CST salvage was associated with good functional outcomes in patients with BAO treated with thrombectomy. The presence of atrial fibrillation, location and length of BAO may predict CST salvage after thrombectomy, and rapid treatment with thrombectomy may protect this eloquent tract in these patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Gwak, Choi, Kim, Kang, Son and Hwang.)

Background Unlike patients with stroke caused by other mechanisms, the effect of elevated plasma total homocysteine (tHcy) on the prognosis of patients with both ischemic stroke and atrial fibrillation (AF) is unknown. This study aimed to evaluate the association between tHcy level and the functional outcome of patients with AF-related stroke. Methods and Results We included consecutive patients with AF-related stroke between 2013 and 2015 from the registry of a real-world prospective cohort from 11 large centers in South Korea. A 3-month modified Rankin Scale score ≥3 was considered an unfavorable outcome. Since tHcy is strongly affected by renal function, we performed a subgroup analysis according to the presence of renal dysfunction. A total of 910 patients with AF-related stroke were evaluated (mean age, 73 years; male sex, 56.0%). The mean tHcy level was 11.98±8.81 μmol/L. In multivariable analysis, the tHcy level (adjusted odds ratio, 1.04; 95% CI, 1.01-1.07, per 1 μmol/L) remained significantly associated with unfavorable outcomes. In the subgroup analysis based on renal function, tHcy values above the cutoff point (≥14.60 μmol/L) showed a close association with the unfavorable outcome only in the normal renal function group (adjusted odds ratio, 3.10; 95% CI, 1.60-6.01). In patients with renal dysfunction, tHcy was not significantly associated with the prognosis of AF-related stroke. Conclusions A higher plasma tHcy level was associated with unfavorable outcomes in patients with AF-related stroke. This positive association may vary according to renal function but needs to be verified in further studies.

Background and Purpose: To identify sex differences in daytime sleepiness associated with apnea severity and periodic limb movements during sleep (PLMS) in subjects with obstructive sleep apnea (OSA)., Methods: This study used the Epworth Sleepiness Scale (ESS), Beck Depression Inventory (BDI), and Sleep Hygiene Index (SHI) in logistic regression analyses with interaction terms. Severe OSA, excessive daytime sleepiness (EDS), and PLMS were defined as an apnea-hypopnea index of ≥30, an ESS score of ≥11, and a periodic limb movements index of >15, respectively., Results: The 1,624 subjects with OSA (males, 79.1%) comprised 45.3%, 38.2%, and 16.4% with severe OSA, EDS, and PLMS, respectively. Multiple logistic regression without interaction terms showed that sex, severe OSA, and PLMS were not significantly associated with EDS. However, significant interactions were noted between sex and severe OSA and PLMS in EDS in both crude and adjusted models (all p values<0.05). In the adjusted model, severe OSA was associated with EDS in males ( p =0.009) but not in females. PLMS were more likely to be associated with EDS in females ( p =0.013), whereas PLMS were less likely to be associated with EDS in males ( p =0.041). The models were adjusted by the BDI score, SHI, and presence of medical comorbidities., Conclusions: There are significant sex differences in subjective daytime sleepiness in subjects with severe OSA and PLMS. Severe OSA and PLMS may influence daytime sleepiness more in males and females, respectively., Competing Interests: The authors have no potential conflicts of interest to disclose., (Copyright © 2022 Korean Neurological Association.)

Purpose: We evaluated the relative contributions of emotional instability, impulsivity, and aggression to the presence of suicide risk in people with epilepsy after adjusting for depressive symptoms., Methods: This was a cross-sectional study that used the short form of the Affective Lability Scale (ALS-18), the Barratt Impulsiveness Scale Version 11 (BIS-11), the Brief Aggression Questionnaire (BAQ), and the Patient Health Questionnaire-9 (PHQ-9). Suicidality was assessed using the Mini International Neuropsychiatric Interview (MINI), and the presence of suicide risk was defined as a MINI suicidality score ≥1. Stepwise logistic regression and mediation analyses using a two-stage regression method were performed., Results: Of the 171 subjects (63.2% men) included, suicide risk was present in 38 subjects (22.2%). The stepwise logistic regression analysis identified four variables that were independently associated with suicide risk: higher PHQ-9 score, higher BAQ score, longer duration of epilepsy, and unemployment. The univariate analysis showed that ALS-18 and BIS-11 scores were significantly associated with suicide risk; however, they were backward eliminated from the logistic model according to the criterion of p > 0.1. The mediating effects of ALS-18 and BIS-11 scores on suicide risk via PHQ-9 scores (but not BAQ scores) were significant, with the proportion mediated 61.5% and 54.0% of the total effect, respectively., Conclusions: Alongside depressive symptoms, aggression may be a more useful concept than emotional instability and impulsivity for identifying suicidal risk in people with epilepsy., Competing Interests: Conflicts of interest The authors declare no conflicts of interest in relation to this study., (Copyright © 2022 Elsevier Inc. All rights reserved.)

In ischemic stroke patients undergoing endovascular treatment (EVT), we aimed to test the hypothesis that cerebral microbleeds (CMBs) are associated with clinical outcomes, while estimating the mediating effects of hemorrhagic transformation (HT), small-vessel disease burden (white matter hyperintensities, WMH), and procedural success. From a multicenter EVT registry, patients who underwent pretreatment MR imaging were analyzed. They were trichotomized according to presence of CMBs (none vs. 1-4 vs. ≥ 5). The association between CMB burden and 3-month mRS was evaluated using multivariable ordinal logistic regression, and mediation analyses were conducted to estimate percent mediation. Of 577 patients, CMBs were present in 91 (15.8%); 67 (11.6%) had 1-4 CMBs, and 24 (4.2%) had ≥ 5. Increases in CMBs were associated with hemorrhagic complications (β = 0.27 [0.06-0.047], p = 0.010) in multivariable analysis. The CMB effect on outcome was partially mediated by post-procedural HT degree (percent mediation, 14% [0-42]), WMH (23% [7-57]) and lower rates of successful reperfusion (6% [0-25]). In conclusion, the influence of CMBs on clinical outcomes is mediated by small-vessel disease burden, post-procedural HT, and lower reperfusion rates, listed in order of percent mediation size., (© 2022. The Author(s).)

Background and Purpose: The outcome of endovascular treatment in stroke patients with a large ischemic core is not always satisfactory. We evaluated whether the severity of baseline diffusion-weighted imaging abnormalities, as assessed by different apparent diffusion coefficient (ADC) thresholds, correlates with the clinical outcome in these patients after successful endovascular treatment., Methods: In 82 consecutive patients with a large vessel occlusion in the anterior circulation admitted ≤24 hours after onset, a baseline diffusion lesion volume (ADC ≤620×10 -6 mm 2 /s [ADC 620 ]) ≥50 mL and successful recanalization by endovascular treatment were retrospectively investigated. Lesion volumes of 3 ADC thresholds (ADC 620 , ADC ≤520×10 -6 mm 2 /s [ADC 520 ], and ADC ≤540×10 -6 mm 2 /s [ADC 540 ]) were measured using an automated Olea software program. The performance of the ADC 520 /ADC 620 and ADC 540 /ADC 620 ratios in predicting the functional outcome was assessed by receiver operating characteristic curve analysis. The ADC ratio with optimal threshold showing better receiver operating characteristic performance was dichotomized at its median value into low versus high subgroup and its association with the outcome subsequently evaluated in a multivariable logistic regression model., Results: The median baseline diffusion lesion volume was 80.8 mL (interquartile range, 64.4-105.4). A good functional outcome (modified Rankin Scale score, ≤2) was achieved in 35 patients (42.7%). The optimal threshold for predicting the functional outcome was identified as ADC 540 /ADC 620 (area under the curve, 0.833) and dichotomized at 0.674. After adjusting for age, baseline National Institutes of Health Stroke Scale score, intravenous tissue-type plasminogen activator, baseline diffusion lesion volume, and onset-to-recanalization time, a low ADC 540 /ADC 620 was independently associated with a good functional outcome (adjusted odds ratio, 10.72 [95% CI, 3.06-37.50]; P <0.001)., Conclusions: A low ADC 540 /ADC 620 , which may reflect less severe ischemic stress inside a diffusion lesion, may help to identify patients who would benefit from endovascular treatment despite having a large ischemic core.