Clinical Impact of Dyspnea after Ticagrelor Treatment and the Effect of Switching to Clopidogrel in Patients with Myocardial Infarction.

BACKGROUND: Dyspnea is frequent during ticagrelor-based dual antiplatelet therapy (DAPT) for acute myocardial infarction (AMI). However, its clinical characteristics or management strategy remains uncertain. METHODS: The study assessed 2,617 AMI patients from the Ticagrelor versus Clopidogrel in Stabilized Patients with AMI (TALOS-AMI) trial. Dyspnea during 1-month ticagrelor-based DAPT and following DAPT strategies with continued ticagrelor or de-escalation to clopidogrel from 1 to 12 months were evaluated for drug adherence, subsequent dyspnea, major adverse cardiovascular events (MACE), and bleeding events. RESULTS: Dyspnea was reported by 538 patients (20.6%) during 1 month of ticagrelor-based DAPT. Adherence to allocated DAPT over the study period was lower in the continued ticagrelor arm than the de-escalation to clopidogrel, particularly among the dyspneic population (81.1% vs. 91.5%, p < 0.001). Among ticagrelor-treated patients with dyspnea, those switched to clopidogrel at 1 month had a lower frequency of dyspnea at 3 months (34.3% vs. 51.7%, p < 0.001) and 6 months (25.5% vs. 38.4%, p = 0.002) than those continued with ticagrelor. In patients with dyspnea in their 1-month ticagrelor-based DAPT, de-escalation was not associated with increased MACE (1.3% vs. 3.9%, hazard ratio [HR]: 0.31, 95% confidence interval [CI]: 0.08-1.11, p = 0.07) or clinically relevant bleeding (3.2% vs. 6.2%, HR: 0.51, 95% CI: 0.22-1.19, p = 0.12) at 1 year. CONCLUSION: Dyspnea is a common side effect among ticagrelor-based DAPTs in AMI patients. Switching from ticagrelor to clopidogrel after 1 month in AMI patients may provide a reasonable option to alleviate subsequent dyspnea in ticagrelor-relevant dyspneic patients, without increasing the risk of ischemic events (NCT02018055).

Dual Antiplatelet Therapy De-Escalation in Stabilized Myocardial Infarction With High Ischemic Risk: Post Hoc Analysis of the TALOS-AMI Randomized Clinical Trial.

Importance: In patients with acute myocardial infarction (AMI) who have high ischemic risk, data on the efficacy and safety of the de-escalation strategy of switching from ticagrelor to clopidogrel are lacking. Objective: To evaluate the outcomes of the de-escalation strategy compared with dual antiplatelet therapy (DAPT) with ticagrelor in stabilized patients with AMI and high ischemic risk following percutaneous coronary intervention (PCI). Design, Setting, and Participants: This was a post hoc analysis of the Ticagrelor vs Clopidogrel in Stabilized Patients With Acute Myocardial Infarction (TALOS-AMI) trial, an open-label, assessor-blinded, multicenter, randomized clinical trial. Patients with AMI who had no event during 1 month of ticagrelor-based DAPT after PCI were included. High ischemic risk was defined as having a history of diabetes or chronic kidney disease, multivessel PCI, at least 3 lesions treated, total stent length greater than 60 mm, at least 3 stents implanted, left main PCI, or bifurcation PCI with at least 2 stents. Data were collected from February 14, 2014, to January 21, 2021, and analyzed from December 1, 2021, to June 30, 2022. Intervention: Patients were randomly assigned to either de-escalation from ticagrelor to clopidogrel or ticagrelor-based DAPT. Main Outcomes and Measures: Ischemic outcomes (composite of cardiovascular death, myocardial infarction, ischemic stroke, ischemia-driven revascularization, or stent thrombosis) and bleeding outcomes (Bleeding Academic Research Consortium type 2, 3, or 5 bleeding) were evaluated. Results: Of 2697 patients with AMI (mean [SD] age, 60.0 [11.4] years; 454 [16.8%] female), 1371 (50.8%; 684 assigned to de-escalation and 687 assigned to ticagrelor-based DAPT) had high ischemic risk features and a significantly higher risk of ischemic outcomes than those without high ischemic risk (1326 patients [49.2%], including 665 assigned to de-escalation and 661 assigned to ticagrelor-based DAPT) (hazard ratio [HR], 1.74; 95% CI, 1.15-2.63; P = .01). De-escalation to clopidogrel, compared with ticagrelor-based DAPT, showed no significant difference in ischemic risk across the high ischemic risk group (HR, 0.88; 95% CI, 0.54-1.45; P = .62) and the non-high ischemic risk group (HR, 0.65; 95% CI, 0.33-1.28; P = .21), without heterogeneity (P for interaction = .47). The bleeding risk of the de-escalation group was consistent in both the high ischemic risk group (HR, 0.64; 95% CI, 0.37-1.11; P = .11) and the non-high ischemic risk group (HR, 0.42; 95% CI, 0.24-0.75; P = .003), without heterogeneity (P for interaction = .32). Conclusions and Relevance: In stabilized patients with AMI, the ischemic and bleeding outcomes of an unguided de-escalation strategy with clopidogrel compared with a ticagrelor-based DAPT strategy were consistent without significant interaction, regardless of the presence of high ischemic risk.

On-Demand Aligned DNA Hydrogel Via Light Scanning.

DNA is an anisotropic, water-attracting, and biocompatible material, an ideal building block for hydrogel. The alignment of the anisotropic DNA chains is essential to maximize hydrogel properties, which has been little explored. Here, we present a method to fabricate the anisotropic DNA hydrogel that allows precise control for the polymerization process of photoreactive cationic monomers. Scanning ultraviolet light enables the uniaxial alignment of DNA chains through the polymerization-induced diffusive mass flow using a concentration gradient. While studying anisotropic mechanical properties and orientation recovery according to the DNA chain alignment direction, we demonstrate the potential of directionally controlled DNA hydrogels as smart materials.

Avidity-based biosensors for ubiquitylated PCNA reveal choreography of DNA damage bypass.

In eukaryotes, the posttranslational modifier ubiquitin is used to regulate the amounts, interactions, or activities of proteins in diverse pathways and signaling networks. Its effects are mediated by monoubiquitin or polyubiquitin chains of varying geometries. We describe the design, validation, and application of a series of avidity-based probes against the ubiquitylated forms of the DNA replication clamp, proliferating cell nuclear antigen (PCNA), in budding yeast. Directed against total ubiquitylated PCNA or specifically K63-polyubiquitylated PCNA, the probes are tunable in their activities and can be used either as biosensors or as inhibitors of the PCNA-dependent DNA damage bypass pathway. Used in live cells, the probes revealed the timing of PCNA ubiquitylation during damage bypass and a particular susceptibility of the ribosomal DNA locus to the activation of the pathway. Our approach is applicable to a wide range of ubiquitin-conjugated proteins, thus representing a generalizable strategy for the design of biosensors for specific (poly)ubiquitylated forms of individual substrates.

Manipulative-based Activity Using Pop Beads for Demonstration of Sanger Sequencing.

Sanger sequencing, also known as dideoxy sequencing, is a widely used method for DNA sequencing, particularly for cloned plasmids and clinical samples. This technique requires a combination of essential biochemistry skills, such as a chain-termination reaction, gel electrophoresis, and fluorescence detection. Unfortunately, there is a lack of activities that replicate the Sanger sequencing process for students to learn and practice these skills. To address this issue, a manipulative-based Sanger sequencing activity was developed that incorporates colorful pop beads to demonstrate a chain-termination reaction, separation of products, and fluorescence detection. The beads represent deoxynucleotides and dideoxynucleotides, allowing for a visual representation of DNA fragment generation. This kinesthetic learning activity offers a high visual impact for students, aiding in their understanding of the Sanger sequencing process, and can also be used to illustrate polymerase chain reaction (PCR)-based techniques.

Planar Spin Glass with Topologically Protected Mazes in the Liquid Crystal Targeting for Reconfigurable Micro Security Media.

The planar spin glass pattern is widely known for its inherent randomness, resulting from the geometrical frustration. As such, developing physical unclonable functions (PUFs)-which operate with device randomness-with planar spin glass patterns is a promising candidate for an advanced security systems in the upcoming digitalized society. Despite their inherent randomness, traditional magnetic spin glass patterns pose considerable obstacles in detection, making it challenging to achieve authentication in security systems. This necessitates the development of facilely observable mimetic patterns with similar randomness to overcome these challenges. Here, a straightforward approach is introduced using a topologically protected maze pattern in the chiral liquid crystals (LCs). This maze exhibits a comparable level of randomness to magnetic spin glass and can be reliably identified through the combination of optical microscopy with machine learning-based object detection techniques. The "information" embedded in the maze can be reconstructed through thermal phase transitions of the LCs in tens of seconds. Furthermore, incorporating various elements can enhance the optical PUF, resulting in a multi-factor security medium. It is expected that this security medium, based on microscopically controlled and macroscopically uncontrolled topologically protected structures, may be utilized as a next-generation security system.

Review of North Korean Reports on Cardiovascular Disease Research and Management.

PURPOSE: This study aimed to investigate the quality of medical care in North Korea using data from North Korean medical research. MATERIALS AND METHODS: This study included publications containing the keyword "medical" among North Korea's consecutive publications and selected 415 papers related to heart disease, brain disease, and emergency medical care published at The North Korean Data Center of the Ministry of Unification (https://unibook.unikorea.go.kr). Among 40 research articles, we reviewed ten with representative epidemiological data for cardiovascular treatment, and the latest medical materials were selected and analyzed in detail. RESULTS: Few studies reported the experience of large-scale medical facilities or verified professional performance. Proof of the efficacy of the latest drugs was rare, although the treatment results of interventional therapy and conventional heart surgery were reported. Efforts to improve emergency medical care and innovation of treatment materials using new technologies were being actively studied. However, careful interpretation is required due to the lack of objectivity in research data and some deviation in the composition of patients included in the data. CONCLUSION: Research of cardiovascular disease in North Korea is conducted at a very limited scope, although treatment results appear to be recorded. The management of cardiovascular disease and the establishment of an emergency medical system warrant global attention and cooperation for further improvement.

Customizing Radiative Decay Dynamics of Two-Dimensional Excitons via Position- and Polarization-Dependent Vacuum-Field Interference.

Embodying bosonic and interactive characteristics in two-dimensional space, excitons in transition metal dichalcogenides (TMDCs) have garnered considerable attention. The utilization of the strong-correlation effects, long-range transport, and valley-dependent properties requires customizing exciton decay dynamics. Vacuum-field manipulation allows radiative decay engineering without disturbing intrinsic material properties. However, conventional flat mirrors cannot customize the radiative decay landscape in TMDC's plane or support vacuum-field interference with desired spectrum and polarization properties. Here, we present a meta-mirror platform resolving the issues with more optical degrees of freedom. For neutral excitons of the monolayer MoSe2, the optical layout formed by meta-mirrors manipulated the radiative decay rate in space by 2 orders of magnitude and revealed the statistical correlation between emission intensity and spectral line width. Moreover, the anisotropic meta-mirror demonstrated polarization-dependent radiative decay control. Our platform would be promising to tailor two-dimensional distributions of lifetime, density, diffusion, and polarization of TMDC excitons in advanced opto-excitonic applications.

Real-World Comparison of Transcatheter Versus Surgical Aortic Valve Replacement in the Era of Current-Generation Devices.

Few studies have reported comparisons of out-of-hospital clinical outcomes after transcatheter aortic valve replacement (TAVR) and surgical aortic valve replacement (SAVR) in patients with severe aortic stenosis (AS) in the era of current-generation valves that reflect the real-world situation. Data on patients with severe AS aged 65 years or older who underwent TAVR or SAVR between 2015 and 2018 were obtained from the National Health Insurance Service in Korea and clinical event rate was analyzed. The primary endpoint was all-cause death at 1 year. The cohort included a total of 4623 patients over 65 years of age, of whom 1269 (27.4%) were treated with TAVR. After 1:1 propensity score matching, 2120 patients were included in the study. TAVR was associated with reduced 1-year mortality (hazard ratio (HR): 0.55; 95% confidence interval (CI): 0.42−0.70; p < 0.001). There was no difference between the groups in the incidence of ischemic stroke (HR: 0.72, 95% CI: 0.43−1.20; p = 0.21) and intracranial hemorrhage (HR: 1.10; p = 0.74). Permanent pacemaker insertion was observed more frequently in the TAVR cohort (9.4% vs. 2.5%, HR: 3.95, 95% CI: 2.57−6.09; p < 0.001), whereas repeat procedures were rare in both treatments (0.5% vs. 0.3%, p = 0.499). In the nation-wide real-world data analysis, TAVR with current-generation devices showed significantly lower 1-year mortality compared to SAVR in severe AS patients.

Real-Time Deubiquitination Assays Using a Free Ubiquitin Sensor.

Deubiquitinating enzymes cleave ubiquitin (Ub) from its attachment to another Ub, other proteins, peptides, or non-peptide adducts. In all cases, substrate hydrolysis by DUBs releases free Ub or polyubiquitin (polyUb) chains. Whereas most quantitative DUB assays depend on fluorescently labeled artificial substrates, employing a sensor able to detect Ub release in real time makes it possible to monitor DUB activity using virtually any Ub conjugate as a substrate. The protocols here describe the preparation of Atto532-tUI, a high-affinity sensor for free Ub, and its use in real-time deubiquitination assays.

Spontaneous generation and active manipulation of real-space optical vortices.

Optical vortices are beams of light that carry orbital angular momentum1, which represents an extra degree of freedom that can be generated and manipulated for photonic applications2-8. Unlike vortices in other physical entities, the generation of optical vortices requires structural singularities9-12, but this affects their quasiparticle nature and hampers the possibility of altering their dynamics or making them interacting13-17. Here we report a platform that allows the spontaneous generation and active manipulation of an optical vortex-antivortex pair using an external field. An aluminium/silicon dioxide/nickel/silicon dioxide multilayer structure realizes a gradient-thickness optical cavity, where the magneto-optic effects of the nickel layer affect the transition between a trivial and a non-trivial topological phase. Rather than a structural singularity, the vortex-antivortex pairs present in the light reflected by our device are generated through mathematical singularities in the generalized parameter space of the top and bottom silicon dioxide layers, which can be mapped onto real space and exhibit polarization-dependent and topology-dependent dynamics driven by external magnetic fields. We expect that the field-induced engineering of optical vortices that we report will facilitate the study of topological photonic interactions and inspire further efforts to bestow quasiparticle-like properties to various topological photonic textures such as toroidal vortices, polarization and vortex knots, and optical skyrmions.

Field-induced orientational switching produces vertically aligned Ti3C2Tx MXene nanosheets.

Controlling the orientation of two-dimensional materials is essential to optimize or tune their functional properties. In particular, aligning MXene, a two-dimensional carbide and/or nitride material, has recently received much attention due to its high conductivity and high-density surface functional group properties that can easily vary based on its arranged directions. However, erecting 2D materials vertically can be challenging, given their thinness of few nanometres. Here, vertical alignment of Ti3C2Tx MXene sheets is achieved by applying an in-plane electric field, which is directly observed using polarised optical microscopy and scanning electron microscopy. The electric field-induced vertical alignment parallel to the applied alternating-current field is demonstrated to be reversible in the absence of a field, back to a random orientation distribution. Interdigitated electrodes with uniaxially aligned MXene nanosheets are demonstrated. These can be further modulated to achieve various patterns using diversified electrode substrates. Anisotropic electrical conductivity is also observed in the uniaxially aligned MXene nanosheet film, which is quite different from the randomly oriented ones. The proposed orientation-controlling technique demonstrates potential for many applications including sensors, membranes, polarisers, and general energy applications.

Efficacy and Safety of 3 Versus 6 Months of Dual-Antiplatelet Therapy in Patients Implanted With a Coroflex ISAR Stents: A Prospective, Multicenter, Randomized Clinical Trial.

BACKGROUND: The optimal duration of dual-antiplatelet therapy (DAPT) after implantation of a drug-eluting stent (DES), especially recently developed polymer-free DESs, is unknown. This study examined the efficacy and safety of 3- versus 6-month DAPT in patients implanted with Coroflex ISAR polymer-free DESs. METHODS: Between May 2015 and August 2020, 488 patients who underwent Coroflex ISAR stent implantation were enrolled in the study and randomly assigned to the 3-month (n=244) or 6-month (n=244) DAPT group. RESULTS: At 1 year, the primary endpoint (composite of cardiovascular death, myocardial infarction, target vessel revascularization, and Bleeding Academic Research Consortium [BARC] type 2-5 bleeding) occurred in 9 (3.7%) patients in the 3-month DAPT group and in 7 (2.9%) patients in the 6-month DAPT group (hazard ratio 1.31; P=.60). There was no difference between the 3- and 6-month DAPT groups in either BARC type 2-5 bleeding (1.6% vs 0.8%; hazard ratio 2.00; P=.42) or any bleeding (2.9% vs 3.3%; hazard ratio 0.87; P=.80). CONCLUSION: Compared with 6 months of DAPT, 3 months of DAPT did not increase the risk of primary endpoint 1 year after Coroflex ISAR stent implantation, although it should be noted that the trial has limited power to see differences due to low event rate and low recruitment rate.

Fabrication of Arrays of Topological Solitons in Patterned Chiral Liquid Crystals for Real-Time Observation of Morphogenesis.

Topological solitons have knotted continuous field configurations embedded in a uniform background, and occur in cosmology, biology, and electromagnetism. However, real-time observation of their morphogenesis and dynamics is still challenging because their size and timescale are enormously large or tiny. Liquid crystal (LC) structures are promising candidates for a model-system to study the morphogenesis of topological solitons, enabling direct visualization due to the proper size and timescale. Here, a new way is found to rationalize the real-time observation of the generation and transformation of topological solitons using cholesteric LCs confined in patterned substrates. The experimental demonstration shows the topologically protected structures arise via the transformation of topological defects. Numerical modeling based on minimization of free energy closely reconstructs the experimental findings. The fundamental insights obtained from the direct observations pose new theoretical challenges in understanding the morphogenesis of different types of topological solitons within a broad range of scales.

Light-Driven Fabrication of a Chiral Photonic Lattice of the Helical Nanofilament Liquid Crystal Phase.

A photonic lattice is an efficient platform for optically exploring quantum phenomena. However, its fabrication requires high costs and complex procedures when conventional materials, such as silicon or metals, are used. Here, we demonstrate a simple and cost-effective fabrication method for a reconfigurable chiral photonic lattice of the helical nanofilament (HNF) liquid crystal (LC) phase and diffraction grating showing wavelength-dependent diffraction with a rotated polarization state. Furthermore, the UV-exposed areas of the HNF film having chiral characteristics act as optical building blocks that induce resonant intensity modulation in the reflectance and transmittance modes and the optical rotation of the linear polarization. Our photonic lattice of the HNF can be an efficient platform for a chirality-embedded photonic lattice at a low cost.

Unveiling the Genesis and Effectiveness of Negative Fading in Nanostructured Iron Oxide Anode Materials for Lithium-Ion Batteries.

Iron oxide anode materials for rechargeable lithium-ion batteries have garnered extensive attention because of their inexpensiveness, safety, and high theoretical capacity. Nanostructured iron oxide anodes often undergo negative fading, that is, unconventional capacity increase, which results in a capacity increasing upon cycling. However, the detailed mechanism of negative fading still remains unclear, and there is no consensus on the provenance. Herein, we comprehensively investigate the negative fading of iron oxide anodes with a highly ordered mesoporous structure by utilizing advanced synchrotron-based analysis. Electrochemical and structural analyses identified that the negative fading originates from an optimization of the electrolyte-derived surface layer, and the thus formed layer significantly contributes to the structural stability of the nanostructured electrode materials, as well as their cycle stability. This work provides an insight into understanding the origin of negative fading and its influence on nanostructured anode materials.

Unguided de-escalation from ticagrelor to clopidogrel in stabilised patients with acute myocardial infarction undergoing percutaneous coronary intervention (TALOS-AMI): an investigator-initiated, open-label, multicentre, non-inferiority, randomised trial.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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). INTERPRETATION: 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. FUNDING: ChongKunDang Pharm, Medtronic, Abbott, and Boston Scientific.