Total syntheses of Tetrodotoxin and 9-epiTetrodotoxin.

Tetrodotoxin and congeners are specific voltage-gated sodium channel blockers that exhibit remarkable anesthetic and analgesic effects. Here, we present a scalable asymmetric syntheses of Tetrodotoxin and 9-epiTetrodotoxin from the abundant chemical feedstock furfuryl alcohol. The optically pure cyclohexane skeleton is assembled via a stereoselective Diels-Alder reaction. The dense heteroatom substituents are established sequentially by a series of functional group interconversions on highly oxygenated cyclohexane frameworks, including a chemoselective cyclic anhydride opening, and a decarboxylative hydroxylation. An innovative SmI2-mediated concurrent fragmentation, an oxo-bridge ring opening and ester reduction followed by an Upjohn dihydroxylation deliver the highly oxidized skeleton. Ruthenium-catalyzed oxidative alkyne cleavage and formation of the hemiaminal and orthoester under acidic conditions enable the rapid assembly of Tetrodotoxin, anhydro-Tetrodotoxin, 9-epiTetrodotoxin, and 9-epi lactone-Tetrodotoxin.

Diffusion and structural MRI as potential biomarkers in people with Parkinson's disease and cognitive impairment.

OBJECTIVE: To explore the neuroimage change in Parkinson's disease (PD) patients with cognitive impairments, this study investigated the correlation between plasma biomarkers and morphological brain changes in patients with normal cognition and mild cognitive impairment. The objective was to identify the potential target deposition regions of the plasma biomarkers and to search for the relevant early neuroimaging biomarkers on the basis of different cognitive domains. METHODS: Structural brain MRI and diffusion weighted images were analyzed from 49 eligible PD participants (male/female: 27/22; mean age: 73.4 ± 8.5 years) from a retrospective analysis. Plasma levels of α-synuclein, amyloid beta peptide, and total tau were collected. A comprehensive neuropsychological assessment of the general and specific cognitive domains was performed. Difference between PD patients with normal cognition and impairment was examined. Regression analysis was performed to evaluate the correlation between image-derived index and plasma biomarkers or neuropsychological assessments. RESULTS: Significant correlation was found between plasma Aß-42 level and fractional anisotropy of the middle occipital, angular, and middle temporal gyri of the left brain, as well as plasma T-tau level and the surface area of the isthmus or the average thickness of the posterior part of right cingulate gyrus. Visuospatial and executive function is positively correlated with axial diffusivity in bilateral cingulate gyri. CONCLUSION: In nondemented PD patients, the target regions for plasma deposition might be located in the cingulate, middle occipital, angular, and middle temporal gyri. Changes from multiple brain regions can be correlated to the performance of different cognitive domains. CLINICAL RELEVANCE STATEMENT: Cognitive impairment in Parkinson's disease is primarily linked to biomarkers associated with Alzheimer's disease rather than those related to Parkinson's disease and resembles the frontal variant of Alzheimer's disease, which may guide management strategies for cognitive impairment in Parkinson's disease. KEY POINTS: • Fractional anisotropy, surface area, and thickness in the cingulate, middle occipital, angular, and middle temporal gyri can be significantly correlated with plasma Aß-42 and T-tau level. • Axial diffusivity in the cingulate gyri was correlated with visuospatial and executive function. • The pattern of cognitive impairment in Parkinson's disease can be similar to the frontal variant than typical Alzheimer's disease.

Chemical inhibition of mitochondrial fission via targeting the DRP1-receptor interaction.

Mitochondrial fission is critical for mitochondrial dynamics and homeostasis. The dynamin superfamily GTPase DRP1 is recruited by three functionally redundant receptors, MFF, MiD49, and MiD51, to mitochondria to drive fission. Here, we exploit high-content live-cell imaging to screen for mitochondrial fission inhibitors and have developed a covalent compound, mitochondrial division inhibitor (MIDI). MIDI treatment potently blocks mitochondrial fragmentation induced by mitochondrial toxins and restores mitochondrial morphology in fusion-defective cells carrying pathogenic mitofusin and OPA1 mutations. Mechanistically, MIDI does not affect DRP1 tetramerization nor DRP1 GTPase activity but does block DRP1 recruitment to mitochondria. Subsequent biochemical and cellular characterizations reveal an unexpected mechanism that MIDI targets DRP1 interaction with multiple receptors via covalent interaction with DRP1-C367. Taken together, beyond developing a potent mitochondrial fission inhibitor that profoundly impacts mitochondrial morphogenesis, our study establishes proof of concept for developing protein-protein interaction inhibitors targeting DRP1.

Associations between blood-based biomarkers of Alzheimer's disease with cognition in motoric cognitive risk syndrome: A pilot study using plasma Aß42 and total tau.

Background: Motoric cognitive risk (MCR) syndrome is a conceptual construct that combines slow gait speed with subjective cognitive complaints and has been shown to be associated with an increased risk of developing dementia. However, the relationships between the pathology of Alzheimer's disease (AD) and MCR syndrome remain uncertain. Therefore, the purpose of this study was to determine the levels of plasma AD biomarkers (Aß42 and total tau) and their relationships with cognition in individuals with MCR. Materials and methods: This was a cross-sectional pilot study that enrolled 25 individuals with normal cognition (NC), 27 with MCR, and 16 with AD. Plasma Aß42 and total tau (t-tau) levels were measured using immunomagnetic reduction (IMR) assays. A comprehensive neuropsychological assessment was also performed. Results: The levels of plasma t-tau proteins did not differ significantly between the MCR and AD groups, but that of plasma t-tau was significantly increased in the MCR and AD groups, compared to the NC group. Visuospatial performance was significantly lower in the MCR group than in the NC group. The levels of plasma t-tau correlated significantly with the Montreal Cognitive Assessment (MoCA) and Boston naming test scores in the MCR group. Conclusion: In this pilot study, we found significantly increased plasma t-tau proteins in the MCR and AD groups, compared with the NC group. The plasma t-tau levels were also significantly correlated with the cognitive function of older adults with MCR. These results implied that MCR and AD may share similar pathology. However, these findings need further confirmation in longitudinal studies.

Prediction of Cognitive Degeneration in Parkinson's Disease Patients Using a Machine Learning Method.

This study developed a predictive model for cognitive degeneration in patients with Parkinson's disease (PD) using a machine learning method. The clinical data, plasma biomarkers, and neuropsychological test results of patients with PD were collected and utilized as model predictors. Machine learning methods comprising support vector machines (SVMs) and principal component analysis (PCA) were applied to obtain a cognitive classification model. Using 32 comprehensive predictive parameters, the PCA-SVM classifier reached 92.3% accuracy and 0.929 area under the receiver operating characteristic curve (AUC). Furthermore, the accuracy could be increased to 100% and the AUC to 1.0 in a PCA-SVM model using only 13 carefully chosen features.

Factors Associated with Fear of Falling in Individuals with Different Types of Mild Cognitive Impairment.

Mild cognitive impairment (MCI) is considered an intermediate state between normal aging and early dementia. Fear of falling (FOF) could be considered a risk indicator for falls and quality of life in individuals with MCI. Our objective was to explore factors associated with FOF in those with MCI due to Alzheimer's disease (AD-MCI) and mild cognitive impairment in Parkinson's disease (PD-MCI). Seventy-one participants were separated into two groups, AD-MCI (n = 37) and PD-MCI (n = 34), based on the disease diagnosis. FOF was assessed using the Activities-specific Balance Confidence scale. The neuropsychological assessment and gait assessment were also measured. FOF was significantly correlated with global cognitive function, attention and working memory, executive function, Tinetti assessment scale scores, gait speed, and stride length in the AD-MCI group. Moreover, attention and working memory were the most important factors contributing to FOF. In the PD-MCI group, FOF was significantly correlated with gait speed, and time up and go subtask performance. Furthermore, turn-to-walk was the most important factor contributing to FOF. We noted that FOF in different types of MCI was determined by different factors. Therapies that aim to lower FOF in AD-MCI and PD-MCI populations may address attention and working memory and turn-to-walk, respectively.

Corrigendum: Associations between blood-based biomarkers of Alzheimer's disease with cognition in motoric cognitive risk syndrome: A pilot study using plasma Aß42 and total tau.

[This corrects the article DOI: 10.3389/fnagi.2022.981632.].

Plasma total tau predicts executive dysfunction in Parkinson's disease.

OBJECTIVES: Cognitive impairment is an important non-motor aspect of Parkinson's disease (PD). Amyloid-ß and tau pathologies are well-established in Alzheimer's disease and commonly coexist with synucleinopathy in PD. However, the levels of these biomarkers in the plasma of patients with PD and their relationship with specific cognition domains remain to be clarified. The current study compared the motor severity and neuropsychological assessment of general and specific cognition, with plasma levels of α-synuclein (α-syn), amyloid-ß 42 (Aß42), and total tau (t-tau) in PD subjects. METHODS: Plasma levels of α-syn, Aß42, and t-tau were measured in 55 participants with PD through immunomagnetic reduction assay. The evaluation of motor severity and comprehensive neuropsychological assessment was performed in all participants. RESULTS: The level of plasma α-syn was negatively correlated with the scores of Unified Parkinson's Disease Rating Scale part III [r = (-.352), p = .008]. The level of plasma t-tau was negatively correlated with the scores of digits recall forwards and digits recall backwards [r = (-.446), p = .001; r = (-.417), p = .002, respectively]. No correlations were found between the levels of α-syn and Aß42 and any neuropsychological tests. CONCLUSIONS: This study concluded a lower level of plasma α-syn was correlated with motor dysfunction in PD patients, and a higher level of plasma t-tau was correlated with lower cognitive performance, especially for attention and executive function. These results propose the possibility of using plasma biomarkers to predict specific cognitive performance in PD subjects.

Do cognitive performance and physical function differ between individuals with motoric cognitive risk syndrome and those with mild cognitive impairment?

BACKGROUND: Motoric cognitive risk syndrome (MCR) is defined by slow gait speed combined with subjective cognitive complaint. MCR is a predementia syndrome, similar to mild cognitive impairment (MCI). However, there is currently no study comparing the differences in cognitive performance and physical function between these two types of cognitive impairment. Thus, the aim of this study is to compare cognitive performance and physical function in individuals with MCR versus MCI. METHODS: A total of 77 participants, free of dementia, were recruited from the neurological outpatient clinic of a medical center in Taiwan. Participants were separated into 2 groups, MCR (n = 33) and MCI (n = 44) groups, based on definition criteria from previous studies. The priority was to assign a diagnosis of MCR first, followed by MCI. Hence, "pure" MCI had no overlap with MCR syndrome. Cognitive performance, including executive function, attention, working memory, episode memory, visuospatial function, and language, were measured. Physical functions such as activities in daily living, the Tinetti Assessment Scale, and the Timed Up and Go test were also measured. RESULTS: Executive function, attention, working memory, episodic memory and language were all significantly lower in the MCR group than the MCI group. Abilities related to physical function, including those measured by the Tinetti Assessment Scale and the Timed Up and Go test, were significantly lower in the MCR group than the MCI group. CONCLUSIONS: We noted that cognitive performance and physical function were lower in MCR individuals than MCI but without MCR syndrome. However, the conclusions were based on the enrollment procedure of participants prioritizes the MCR syndrome. Because of the overlap of MCR and MCI, future studies should use different enrollment strategies to further clarify the status of these two populations.

Predicting Cognitive Decline in Parkinson's Disease with Mild Cognitive Impairment: A One-Year Observational Study.

We conducted an observational study to investigate clinical predictors of cognitive decline in patients with mild cognitive impairment (MCI), with a focus on patients with Parkinson's disease (PD) and Alzheimer's disease (AD). The study was performed with detailed neuropsychological testing, a portable device for gait analysis, and a comprehensive geriatric assessment for patients with MCI. Cognitive decline was defined as subjective cognitive impairment with an objective decline in the Mini-Mental State Examination (MMSE) ≥2 points at the one-year follow-up. Participants (n = 74) had a median age of 70 (interquartile range 60-79) years, and 45.9% of them were women. At the end of the study, 17.6% of the patients with MCI had a cognitive decline. Although no differences were observed between groups at the baseline cognitive study, patients with PD-MCI demonstrated more cognitive decline than patients with AD-MCI (28.6% vs. 7.7% p = 0.03). Patients with PD-MCI had more physical disabilities, including scores of instrumental activities of daily living (IADL), Tinetti balance, and gait scores, and some Timed Up and Go components. Initial Clinical Dementia Rating-Sum of Boxes score was a better predictor of future cognitive decline than MMSE in PD-MCI. For predicting the occurrence of cognitive decline in PD-MCI, the prediction accuracy increased from the reduced model (AUC = 0.822, p < 0.001) to the full model (a total of five independent variables, AUC = 0.974, p < 0.001). Given the potentially modifiable predictor, our findings also highlight the importance of identifying sleep quality and the ability to perform IADL.

Discovery of a molecular glue promoting CDK12-DDB1 interaction to trigger cyclin K degradation.

Molecular-glue degraders mediate interactions between target proteins and components of the ubiquitin-proteasome system to cause selective protein degradation. Here, we report a new molecular glue HQ461 discovered by high-throughput screening. Using loss-of-function and gain-of-function genetic screening in human cancer cells followed by biochemical reconstitution, we show that HQ461 acts by promoting an interaction between CDK12 and DDB1-CUL4-RBX1 E3 ubiquitin ligase, leading to polyubiquitination and degradation of CDK12-interacting protein Cyclin K (CCNK). Degradation of CCNK mediated by HQ461 compromised CDK12 function, leading to reduced phosphorylation of a CDK12 substrate, downregulation of DNA damage response genes, and cell death. Structure-activity relationship analysis of HQ461 revealed the importance of a 5-methylthiazol-2-amine pharmacophore and resulted in an HQ461 derivate with improved potency. Our studies reveal a new molecular glue that recruits its target protein directly to DDB1 to bypass the requirement of a substrate-specific receptor, presenting a new strategy for targeted protein degradation.

Generating Visually Aligned Sound from Videos.

We focus on the task of generating sound from natural videos, and the sound should be both temporally and content-wise aligned with visual signals. This task is extremely challenging because some sounds generated outside a camera can not be inferred from video content. The model may be forced to learn an incorrect mapping between visual content and these irrelevant sounds. To address this challenge, we propose a framework named REGNET. In this framework, we first extract appearance and motion features from video frames to better distinguish the object that emits sound from complex background information. We then introduce an innovative audio forwarding regularizer that directly considers the real sound as input and outputs bottlenecked sound features. Using both visual and bottlenecked sound features for sound prediction during training provides stronger supervision for the sound prediction. The audio forwarding regularizer can control the irrelevant sound component and thus prevent the model from learning an incorrect mapping between video frames and sound emitted by the object that is out of the screen. During testing, the audio forwarding regularizer is removed to ensure that REGNET can produce purely aligned sound only from visual features. Extensive evaluations based on Amazon Mechanical Turk demonstrate that our method significantly improves both temporal and contentwise alignment. Remarkably, our generated sound can fool the human with a 68.12% success rate. Code and pre-trained models are publicly available at https://github.com/PeihaoChen/regnet.

An alkaloid initiates phosphodiesterase 3A-schlafen 12 dependent apoptosis without affecting the phosphodiesterase activity.

The promotion of apoptosis in tumor cells is a popular strategy for developing anti-cancer drugs. Here, we demonstrate that the plant indole alkaloid natural product nauclefine induces apoptosis of diverse cancer cells via a PDE3A-SLFN12 dependent death pathway. Nauclefine binds PDE3A but does not inhibit the PDE3A's phosphodiesterase activity, thus representing a previously unknown type of PDE3A modulator that can initiate apoptosis without affecting PDE3A's canonical function. We demonstrate that PDE3A's H840, Q975, Q1001, and F1004 residues-as well as I105 in SLFN12-are essential for nauclefine-induced PDE3A-SLFN12 interaction and cell death. Extending these molecular insights, we show in vivo that nauclefine inhibits tumor xenograft growth, doing so in a PDE3A- and SLFN12-dependent manner. Thus, beyond demonstrating potent cytotoxic effects of an alkaloid natural product, our study illustrates a potentially side-effect-reducing strategy for targeting PDE3A for anti-cancer therapeutics without affecting its phosphodiesterase activity.

Gait-Based Machine Learning for Classifying Patients with Different Types of Mild Cognitive Impairment.

Mild cognitive impairment (MCI) may be caused by Alzheimer's disease, Parkinson's disease (PD), cerebrovascular accident, nutritional or metabolic disorders, or mental disorders. It is important to determine the cause and treatment of dementia as early as possible because dementia may appear in remission. Decline in MCI cognitive function may affect a patient's walking performance. Therefore, all participants in this study participated in an experiment using a portable gait analysis system to perform walk, time up and go, and jump tests. The collected gait parameters are used in a machine learning classification model based on a support vector machine (SVM) and principal component analysis (PCA). The aim of the study is to predict different types of MCI patients based on gait information. It is shown that the machine learning classification model can predict different types of MCI patients. Specifically, the PCA-SVM model demonstrated better classification performance with 91.67% accuracy and 0.9714 area under the receiver operating characteristic curve (ROC AUC) using the polynomial kernel function in classifying PD-MCI and non-PD-MCI patients.

A thiazole-derived oridonin analogue exhibits antitumor activity by directly and allosterically inhibiting STAT3.

Constitutive activation of signal transducer and activator of transcription 3 (STAT3) occurs in ∼70% of human cancers, and STAT3 is regarded as one of the most promising targets for cancer therapy. However, specific direct STAT3 inhibitors remain to be developed. Oridonin is an ent-kaurane plant-derived diterpenoid with anti-cancer and anti-inflammatory activities. Here, using an array of cell-based and biochemical approaches, including cell proliferation and apoptosis assays, pulldown and reporter gene assays, site-directed mutagenesis, and molecular dynamics analyses, we report that a thiazole-derived oridonin analogue, CYD0618, potently and directly inhibits STAT3. We found that CYD0618 covalently binds to Cys-542 in STAT3 and suppresses its activity through an allosteric effect, effectively reducing STAT3 dimerization and nuclear translocation, as well as decreasing expression of STAT3-targeted oncogenes. Remarkably, CYD0618 not only strongly inhibited growth of multiple cancer cell lines that harbor constitutive STAT3 activation, but it also suppressed in vivo tumor growth via STAT3 inhibition. Taken together, our findings suggest Cys-542 as a druggable site for selectively inhibiting STAT3 and indicate that CYD0618 represents a promising lead compound for developing therapeutic agents against STAT3-driven diseases.

Breaking Winner-Takes-All: Iterative-Winners-Out Networks for Weakly Supervised Temporal Action Localization.

We address the challenging problem of weakly supervised temporal action localization from unconstrained web videos, where only the video-level action labels are available during training. Inspired by the adversarial erasing strategy in weakly supervised semantic segmentation, we propose a novel iterative-winners-out network. Specifically, we make two technical contributions: we propose an iterative training strategy, namely, winners-out, to select the most discriminative action instances in each training iteration and remove them in the next training iteration. This iterative process alleviates the "winner-takes-all" phenomenon that existing approaches tend to choose the video segments that strongly correspond to the video label but neglects other less discriminative video segments. With this strategy, our network is able to localize not only the most discriminative instances but also the less discriminative ones. To better select the target action instances in winners-out, we devise a class-discriminative localization technique. By employing the attention mechanism and the information learned from data, our technique is able to identify the most discriminative action instances effectively. The two key components are integrated into an end-to-end network to localize actions without using the frame-level annotations. Extensive experimental results demonstrate that our method outperforms the state-of-the-art weakly supervised approaches on ActivityNet1.3 and improves mAP from 16.9% to 20.5% on THUMOS14. Notably, even with weak video-level supervision, our method attains comparable accuracy to those employing frame-level supervisions.

Dynamic responses of DOC and DIC transport to different flow regimes in a subtropical small mountainous river.

Transport of riverine dissolved carbon (including DOC and DIC) is a crucial process linking terrestrial and aquatic C reservoirs, but has rarely been examined in subtropical small mountainous rivers (SMRs). This study monitored DOC and DIC concentrations on a biweekly basis during non-event flow periods and at 3 h intervals during two typhoon events in three SMRs in southwestern Taiwan between January 2014 and August 2016. Two models, HBV (the Hydrologiska Byråns Vattenbalansavdelning model) and a three-endmember mixing model, were applied to determine the quantities of DOC and DIC transport from different flow paths. The results show that the annual DOC and DIC fluxes were 2.7-4.8 and 48.4-54.3 t C km-2 yr-1, respectively, which were approx. 2 and 20 times higher than the global mean of 1.4 and 2.6 t C km-2 yr-1, respectively. The DIC / DOC ratio was 14.08, which is much higher than the mean of large rivers worldwide (1.86), and indicates the high rates of chemical weathering in this region. The two typhoons contributed 12%-14% of the annual streamflow in only 3 days (about 1.0% of the annual time), whereas 15.0%-23.5% and 9.2%-12.6% of the annual DOC and DIC flux, respectively, suggested that typhoons play a more important role in DOC transport than DIC transport. The end-member mixing model suggested that DOC and DIC export was mainly from surface runoff and deep groundwater, respectively. The unique patterns seen in Taiwan SMRs characterized by high dissolved carbon flux, high DIC / DOC ratio, and large transport by intense storms should be taken into consideration when estimating global carbon budgets.

Quality of Life in Patients with Dementia with Lewy Bodies.

Dementia with Lewy bodies (DLB) is a complex, multisymptom disorder. When making decisions regarding the treatment of DLB, the patient's quality of life (QoL) should always be the main consideration. To our knowledge, this is the first review article focusing on the QoL in DLB patients. We searched the PubMed database using the keywords "quality of life" and "dementia with Lewy bodies." Previously, no specific instrument had been developed for assessing the QoL in DLB patients. Patients with DLB have a decreased QoL compared to patients with Alzheimer's disease, which is reportedly caused by several factors including level of independence in instrumental activities of daily living, whether the patient is living with the caregiver, apathy, delusion, and dysautonomia. The direct effect of visual hallucination, sleep, and movement disorders on the QoL in DLB patients has not been previously studied. The role of cognitive function on the QoL is still controversial. In a randomized controlled study, memantine may improve the QoL in PDD or DLB patients. We concluded that it is important to develop a specific instrument to assess the QoL in DLB patients. Furthermore, there is an urgent need for large clinical trials to identify factors associated with the QoL and how they can be managed.

Risk Factors for the Progression of Mild Cognitive Impairment in Different Types of Neurodegenerative Disorders.

OBJECTIVE: Mild cognitive impairment (MCI) is a transitional state between normal aging and early dementia. It has a heterogeneous etiology and clinical course. This study aimed to examine the factors associated with the progression of MCI in different types of dementia disorders. METHOD: A retrospective, longitudinal, observational study of outpatients with MCI was conducted at a medical center in northern Taiwan. Patient medical records were reviewed, and risk factors were analyzed by multivariate analysis. RESULTS: Among 279 patients with MCI, 163 (58.4%), 68 (24.4%), and 48 (17.2%) were diagnosed with Alzheimer's disease, vascular cognitive impairment, and Lewy body diseases, respectively. During the observation period, 37.2% of patients progressed to dementia. Older age and a higher Clinical Dementia Rating Scale-Sum of Boxes were associated with the risk of progression. Hyperlipidemia was associated with a decreased risk. Converters were more likely to receive an antidementia prescription. CONCLUSION: Our study suggests the importance of comprehensive clinical profiling, risk factor assessment, and detailed drug history evaluations in improving our understanding and management of dementia subtypes.

Gender Gap and Risk Factors for Poor Stroke Outcomes: A Single Hospital-Based Prospective Cohort Study.

BACKGROUND: This study intended to investigate whether etiological stroke subtypes and their corresponding major risk factors have differential effects on outcomes between genders. PATIENTS AND METHODS: We enrolled 403 consecutive patients with first-ever acute ischemic stroke (170 women, 233 men), from a referral hospital in Taiwan over a 2-year period. Gender differences in demographics, vascular risk factors, access to health care, etiological stroke subtypes, stroke severity, and outcomes were examined. The primary outcome variable of the study was any unfavorable outcome due to acute ischemic stroke, defined as a modified Rankin Scale score of 3 or higher at 90 days after stroke. Multivariable logistic regression models were used to identify predictors of poor outcomes. RESULTS: There were no gender disparities in baseline severity, stroke subtypes, access to health care, and medical comorbidities. Although women had poorer outcomes, female gender was not a predictor of unfavorable outcomes. Important predictors included age of 75years or older (odds ratio [OR] = 2.67; 95% confidence interval [CI], 1.46-4.90), National Institutes of Health Stroke Scale greater than or equal to 8 (OR = 8.38; 95% CI, 4.61-15.2), lack of cohabitation (OR = 2.13; 95% CI, 1.26-3.61), subtypes of cardioembolism (OR = 2.76; 95% CI, 1.29-5.93), and large-artery atherosclerosis (OR = 2.93; 95% CI, 1.47-5.85). In subgroup analyses, the gender-specific independent predictors were cardioembolism (OR = 7.42; 95% CI, 2.21-24.9) or atrial fibrillation (OR = 3.57; 95% CI, 1.31-9.74) in women, and large-artery atherosclerosis (OR = 3.35; 95% CI, 1.30-8.64) or symptomatic large-artery stenosis (OR = 3.42; 95% CI, 1.69-6.96) in men. The differential effects of these predictors according to gender were revealed by interaction tests. CONCLUSION: Atrial fibrillation and symptomatic large-artery stenosis are predictors of poor stroke outcomes in women and men, respectively.