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In patients with acute myocardial infarction receiving potent antiplatelet therapy, the bleeding risk remains high during the maintenance phase. We sought data on a uniform unguided de-escalation strategy of dual antiplatelet therapy (DAPT) from ticagrelor to clopidogrel after acute myocardial infarction. In this open-label, assessor-masked, multicentre, non-inferiority, randomised trial (TALOS-AMI), patients at 32 institutes in South Korea with acute myocardial infarction receiving aspirin and ticagrelor without major ischaemic or bleeding events during the first month after index percutaneous coronary intervention (PCI) were randomly assigned in a 1:1 ratio to a de-escalation (clopidogrel plus aspirin) or active control (ticagrelor plus aspirin) group. Unguided de-escalation without a loading dose of clopidogrel was adopted when switching from ticagrelor to clopidogrel. The primary endpoint was a composite of cardiovascular death, myocardial infarction, stroke, or bleeding type 2, 3, or 5 according to Bleeding Academic Research Consortium (BARC) criteria from 1 to 12 months. A non-inferiority test was done to assess the safety and efficacy of de-escalation DAPT compared with standard treatment. The hazard ratio (HR) for de-escalation versus active control group in a stratified Cox proportional hazards model was assessed for non-inferiority by means of an HR margin of 1·34, which equates to an absolute difference of 3·0% in the intention-to-treat population and, if significant, a superiority test was done subsequently. To ensure statistical robustness, additional analyses were also done in the per-protocol population. This trial is registered at ClinicalTrials.gov, NCT02018055. From Feb 26, 2014, to Dec 31, 2018, from 2901 patients screened, 2697 patients were randomly assigned: 1349 patients to de-escalation and 1348 to active control groups. At 12 months, the primary endpoints occurred in 59 (4·6%) in the de-escalation group and 104 (8·2%) patients in the active control group (pnon-inferiority<0·001; HR 0·55 [95% CI 0·40–0·76], psuperiority=0·0001). There was no significant difference in composite of cardiovascular death, myocardial infarction, or stroke between de-escalation (2·1%) and the active control group (3·1%; HR 0·69; 95% CI 0·42–1·14, p=0·15). Composite of BARC 2, 3, or 5 bleeding occurred less frequently in the de-escalation group (3·0% vs 5·6%, HR 0·52; 95% CI 0·35–0·77, p=0·0012). In stabilised patients with acute myocardial infarction after index PCI, a uniform unguided de-escalation strategy significantly reduced the risk of net clinical events up to 12 months, mainly by reducing the bleeding events. ChongKunDang Pharm, Medtronic, Abbott, and Boston Scientific.

The potential benefits of P2Y12 inhibitor deescalation for acute myocardial infarction after percutaneous coronary intervention may be influenced by body mass index (BMI). To investigate the association of BMI on deescalation outcomes after 12 months in patients with acute myocardial infarction after percutaneous coronary intervention who were initially treated with aspirin plus ticagrelor for 1 month, and to assess whether BMI-based switching from aspirin plus ticagrelor (active control strategy) to aspirin plus clopidogrel (deescalation strategy) is associated with individualized benefits. This study is a post hoc analysis, based on BMI, of data from the TALOS-AMI (Ticagrelor vs Clopidogrel in Stabilized Patients with Acute Myocardial Infarction) randomized clinical trial. Data were collected from February 14, 2014, to December 31, 2018, with follow-up to January 21, 2021. Analyses were conducted from December 1, 2021, to August 21, 2024. Among 2697 trial participants from 32 centers in South Korea, 2686 participants whose BMI data were available were included. All patients received aspirin plus ticagrelor for 1 month after percutaneous coronary intervention. Stabilized patients were then randomized to either the active control or deescalation strategy for an additional 11 months. The primary end point was a composite of cardiovascular death, myocardial infarction, stroke, and Bleeding Academic Research Consortium bleeding type 2, 3, or 5 at 12 months after percutaneous coronary intervention. The trial compared the active control and deescalation strategies according to BMIs, including an interaction test. Of the 2686 patients included (mean [SD] age, 60.0 [11.4] years; 2234 [83.2%] male), 2344 (1161 in the deescalation group and 1183 in the active control group) had a BMI less than 28, and 342 (184 in the deescalation group and 158 in the active control group) had a BMI of 28 or greater. The deescalation strategy was associated with significantly reduced composite outcomes compared with the active control strategy in the group with a BMI less than 28 (53 [4.6%] vs 98 [8.3%]; adjusted hazard ratio, 0.54; 95% CI, 0.39-0.76; P < .001), primarily due to fewer bleeding complications. There was no association in the group with a BMI of 28 or greater (6 [3.3%] vs 5 [3.2%]; adjusted hazard ratio, 1.07; 95% CI, 0.33-3.50; P = .91). In this post hoc analysis of the TALOS-AMI randomized clinical trial, in stabilized patients with acute myocardial infarction, an unguided deescalation strategy of switching from ticagrelor to clopidogrel after 1 month was associated with better clinical outcomes in those with lower BMIs. ClinicalTrials.gov Identifier: NCT02018055.

Chronic kidney disease (CKD) is a significant risk factor for both ischemic and bleeding complications following percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI). Optimizing dual antiplatelet therapy (DAPT) is essential for improving clinical outcomes. To evaluate whether an 11-month, unguided deescalation strategy from ticagrelor to clopidogrel was associated with reduced bleeding without an increase in ischemic events in stabilized patients with CKD after AMI. This was a post hoc secondary analysis of the multicenter, open-label, Ticagrelor vs Clopidogrel in Stabilized Patients With Acute Myocardial Infarction (TALOS-AMI) randomized clinical trial conducted at 32 major cardiac centers in South Korea. Patients with biomarker-positive AMI who tolerated 1 month of ticagrelor-based DAPT after PCI were included in the trial. Patient enrollment occurred from February 2014 to December 2018, with follow-up at 30 days and 3, 6, and 12 months after PCI. The present analysis focused on the subgroup of patients with CKD (estimated glomerular filtration rate [eGFR]<60 mL/min/1.73 m2). Data analyses were performed from July 2023 to October 2024. In the TALOS-AMI trial, patients were randomized 1:1 to continue ticagrelor (active control group) or switch to clopidogrel (deescalation group) for 11 months after PCI. The primary end point was a composite of death from cardiovascular disease, myocardial infarction, stroke, and bleeding (Bleeding Academic Research Consortium [BARC] types 2, 3, or 5). Of 2646 patients included in the trial, 305 had CKD (11.5%; mean [SD] age, 67.2 [11.4] years; 223 males [73.1%]; mean [SD] eGFR, 49.7 [9.5] mL/min/1.73 m2) and 2341 did not have CKD (1975 male [84.4%]; mean [SD] age, 59.0 [11.0] years). Patients with CKD had an increased risk of ischemic events compared with patients without CKD (hazard ratio [HR], 2.47; 95% CI, 1.38-4.42; P = .002), but there was no difference in bleeding risk (HR, 1.36; 95% CI, 0.80-2.31; P = .26). Among patients with CKD, deescalation (n = 160) vs active control (n = 145) was associated with reduced risks of the primary end point (10 patients [6.2%] vs 19 [13.1%]; HR, 0.45 [95% CI, 0.21-0.98]; P = .04) and BARC 2, 3, or 5 bleeding (4 patients [2.5%] vs 12 [8.3%]; HR, 0.29 [95% CI, 0.09-0.89]; P = .03). No increased risk of ischemic events was observed following deescalation (7 patients [4.4%] vs 8 [5.5%]; HR, 0.78 [95% CI, 0.28-2.16]; P = .64). In this secondary analysis of a randomized clinical trial, deescalation from ticagrelor to clopidogrel at 1 month after PCI for AMI was associated with significant reduction in bleeding without increased risk of ischemic events among study-eligible patients with CKD. Further adequately powered studies are needed to validate these findings.

Insomnia and excessive daytime sleepiness (EDS) are the most common complaints in sleep clinics, and the cost of healthcare services associated with them have also increased significantly. Though the brief questionnaires such as the Insomnia Severity Index (ISI) and Epworth Sleepiness Scale (ESS) can be useful to assess insomnia and EDS, there are some limitations to apply for large numbers of patients. As the researches using the Internet of Things technology become more common, the need for the simplification of sleep questionnaires has been also growing. We aimed to simplify ISI and ESS using machine learning algorithms and deep neural networks with attention models. The medical records of 1,241 patients who examined polysomnography for insomnia or EDS were analyzed. All patients are classified into five groups according to the severity of insomnia and EDS. To develop the model, six machine learning algorithms were firstly applied. After going through normalization, the process with the CNN+ Attention model was applied. We classified a group with an accuracy of 93% even with only the results of 6 items (ISI1a, ISI1b, ISI3, ISI5, ESS4, ESS7). We simplified the sleep questionnaires with maintaining high accuracy by using machine learning models.

Several in vivo studies have found that transplanting mesenchymal stem cells (MSCs) into degenerative intervertebral discs (IVDs) leads to regeneration of disc cells. Since the exact underlying mechanisms are not understood, we investigated the mechanisms of action of MSCs in regeneration of degenerative IVDs via paracrine actions. Human MSCs and degenerative disc cells from the same donor vertebrae were directly or indirectly cocultured. The multidifferentiation potential, cell proliferation, collagen synthesis, and mRNA expression levels were assessed. The proliferation rates of MSCs and degenerative disc cells were higher in the coculture system than in the monolayer cultures or in the conditioned medium of each cell type. During coculturing with nucleus pulposus (NP) cells, mRNA expression of the extracellular matrix (ECM) components aggrecan, versican (VCAN), SOX9, and type II and type VI collagen was significantly increased in MSCs, whereas mRNA expression for type V collagen was increased in MSCs cocultured with annulus fibrosus (AF) cells. In addition, the accumulation of total ECM collagen was greater in cocultured degenerative disc cells than in monocultured cells. During coculturing, MSCs downregulated the expression levels of various proinflammatory cytokine genes in degenerative NP [interleukin-1α (IL-1α), IL-1β, IL-6, and tumor necrosis factor-α (TNF-α)] and AF cells (IL-1α and IL-6), which are involved in the degradation of ECM molecules. In association with the trophic effect of MSCs on degenerative disc cells, upregulation of growth factor mRNA expression was shown in MSCs cocultured with degenerative NP cells [epidermal growth factor (EGF), insulin-like growth factor-1 (IGF-1), osteogenic protein-1 (OP-1), growth and differentiation factor-7 (GDF-7), and transforming growth factor-β (TGF-β)] or degenerative AF cells (IGF-1, OP-1, and GDF-7). In terms of MSC-based clinical approaches to IVD regeneration, implanting MSCs into a degenerative IVD may both stimulate MSC differentiation into an NP- or AF-like phenotype and stimulate the biological activation of degenerative disc cells for self-repair.

Background/Objectives: Banhasasim-tang (BHSST) is a traditional herbal formula commonly used to treat gastrointestinal (GI) disorders and has been considered a potential therapeutic option for irritable bowel syndrome (IBS). This study aimed to explore the molecular targets and underlying mechanisms of BHSST in IBS using a combination of network pharmacology, molecular docking, molecular dynamics simulations, and in vivo validation. Methods: Active compounds in BHSST were screened based on drug-likeness and oral bioavailability. Potential targets were predicted using ChEMBL, and IBS-related targets were obtained from GeneCards and DisGeNET. A compound–target–disease network was constructed and analyzed via Gene Ontology and KEGG pathway enrichment. Compound–target interactions were further assessed using molecular docking and molecular dynamics simulations. The in vivo effects of eudesm-4(14)-en-11-ol, elemol, and BHSST were evaluated in a zymosan-induced IBS mouse model. Results: Twelve BHSST-related targets were associated with IBS, with enrichment analysis identifying TNF signaling and apoptosis as key pathways. In silico simulations suggested stable binding of eudesm-4(14)-en-11-ol to TNF-α and kanzonol T to PIK3CD, whereas elemol showed weak interaction with PRKCD. In vivo, eudesm-4(14)-en-11-ol improved colon length, weight, stool consistency, TNF-α levels, and pain-related behaviors—effects comparable to those of BHSST. Elemol, however, showed no therapeutic benefit. Conclusions: These findings provide preliminary mechanistic insight into the anti-inflammatory potential of BHSST in IBS. The integrated in silico and in vivo approaches support the contribution of specific components, such as eudesm-4(14)-en-11-ol, to its observed effects, warranting further investigation.

Cannabidiol (CBD), a nonpsychoactive compound from Cannabis , has various bioactive functions in humans and animals. Evidence suggests that CBD promotes muscle injury recovery in athletes, but whether and how CBD improves endurance performance remains unclear. Here we investigated the effects of CBD treatment on exercise performance in mice and assessed whether this effect involves the gut microbiome. CBD administration significantly increased treadmill running performance in mice, accompanied by an increase in oxidative myofiber composition. CBD also increased mitochondrial biogenesis and the expression of associated genes such as PGC-1α, phosphorylated CREB and AMPK in muscle tissue. Interestingly, CBD altered the composition of the gut microbiome, and antibiotic treatment reduced the muscle endurance-enhancing effects of CBD and mitochondrial biogenesis. We isolated Bifidobacterium animalis , a microbe increased by CBD administration, and named it KBP-1. Treatment with B. animalis KBP-1 in mice resulted in improved running performance. Whole-genome analysis revealed that B. animalis KBP-1 presented high expression of genes involved in branched-chain amino acid biosynthesis, expression of branched-chain amino acid release pumps and metabolism of lactic acid. In summary, our study identified CBD and B. animalis KBP-1 as potential endurance exercise-promoting agents. CBD enhances endurance performance through gut microbiome changes This study explores how cannabidiol (CBD), a compound from the Cannabis sativa plant, affects exercise performance and muscle function. The researchers wanted to see if CBD could improve endurance by changing gut bacteria. They found that CBD improved endurance and increased the presence of certain gut bacteria, including Bifidobacterium animalis , that may help muscles use energy more efficiently. The study involved treating mice with either CBD or B. animalis for 4 weeks and measuring their running ability on a treadmill. The researchers examined changes in muscle fibers and gut bacteria composition. They discovered that CBD and B. animalis increased oxidative muscle fibers, which benefit endurance performance. The results suggest that CBD enhances exercise performance by promoting beneficial gut bacteria and improving muscle energy use. The researchers conclude that both CBD and B. animalis could be used to boost endurance.

Current heart failure (HF) guidelines recommend a multidisciplinary approach, discharge education, and self-management for HF. However, the recommendations are challenging to implement in real-world clinical settings. We developed a mobile health (mHealth) platform for HF self-care to evaluate whether a smartphone app-based intervention with Bluetooth-connected monitoring devices and a feedback system can help improve HF symptoms. In this prospective, randomized, multicenter study, we enrolled patients 20 years of age and older, hospitalized for acute HF, and who could use a smartphone from 7 tertiary hospitals in South Korea. In the intervention group (n=39), the apps were automatically paired with Bluetooth-connected monitoring devices. The patients could enter information on vital signs, HF symptoms, diet, medications, and exercise regimen into the app daily and receive feedback or alerts on their input. In the control group (n=38), patients could only enter their blood pressure, heart rate, and weight using conventional, non-Bluetooth devices and could not receive any feedback or alerts from the app. The primary end point was the change in dyspnea symptom scores from baseline to 4 weeks, assessed using a questionnaire. At 4 weeks, the change in dyspnea symptom score from baseline was significantly greater in the intervention group than in the control group (mean -1.3, SD 2.1 vs mean -0.3, SD 2.3; P=.048). A significant reduction was found in body water composition from baseline to the final measurement in the intervention group (baseline level mean 7.4, SD 2.5 vs final level mean 6.6, SD 2.5; P=.003). App adherence, which was assessed based on log-in or the percentage of days when symptoms were first observed, was higher in the intervention group than in the control group. Composite end points, including death, rehospitalization, and urgent HF visits, were not significantly different between the 2 groups. The mobile-based health platform with Bluetooth-connected monitoring devices and a feedback system demonstrated improvement in dyspnea symptoms in patients with HF. This study provides evidence and rationale for implementing mobile app-based self-care strategies and feedback for patients with HF. ClinicalTrials.gov NCT05668000; https://clinicaltrials.gov/study/NCT05668000.

To elucidate the complex interplay of undifferentiated cancer cells in malignancy, we focus on the crucial mechanisms that maintain the undifferentiated state of cancer stem-like cells, which drive tumor growth and therapy resistance. Here, we identify a protein called dehydrogenase/reductase 13 (DHRS13) that is abundant in undifferentiated glioblastoma cells. DHRS13 is primarily located in the mitochondria and functions as a retinaldehyde reductase, converting all- trans -retinaldehyde to all- trans -retinol with high affinity for NADPH. Mechanistically, DHRS13 prevents glioma stem-like cells from differentiating by blocking retinoic acid signaling, thereby maintaining their undifferentiated state. Remarkably, the depletion of DHRS13 results in mitochondrial reactive oxygen species-driven mitophagy and cell death. Consequently, loss of DHRS13 leads to a significant decrease in tumor initiation and progression. These findings hold promise for the development of strategies that target undifferentiated cancer cells, potentially leading to improved treatment outcomes. Cancer stem-like cells contribute to tumor growth and therapy resistance in glioblastoma. Here, authors identify that DHRS13 inhibition promotes differentiation of glioma stem-like cells by activating retinoic acid signaling and induces cell death through mitochondrial reactive oxygen species-driven mitophagy.

Skutch hypothesized that nest predators visually assess parental activities to locate a prey nest, whereas parents modify fitness-related traits to reduce the probability of nest predation. We examined how cavity condition and parental activity interact with avian nest predators to shape the nest success of two coexisting parid species, marsh tits Poecile palustris and oriental tits Parus minor, breeding in nest-boxes during the incubation period. Nest-boxes were manipulated to create a prolonged risk of nest predation (entrance diameter 2.6 cm control vs 5.5 cm treatment) soon after clutch completion. To measure changes in parental behavior, we also simultaneously simulated a pulsed risk of nest predation, using sound playbacks of a coexisting control bird and an avian nest predator. We found that the parent tits merely responded the pulsed risk, presumably due to an environment with high avian nest predator encounters, compared to the prolonged risk. Instead, both species spent more time on vigilance at the nest, only under prolonged risk conditions. The activity of corvids near the nest-box was higher in the marsh tit than that in oriental tits. This activity was also higher in the treatment nest box than that in the control nest-box. Nest predation during the incubation period was higher in marsh tits than in oriental tits, presumably due to higher and more plastic vigilance in oriental tits, compared to marsh tits. Our results highlight that the differences in cavity condition and parental activities at the nests of two coexisting non-excavators may contribute to differential nest predation by attracting avian nest predators.