Tonic type 2 immunity is a critical tissue checkpoint controlling autoimmunity in the skin.

Immunoregulatory mechanisms established in the lymphoid organs are vital for preventing autoimmunity. However, the presence of similar mechanisms in non-lymphoid tissues remains unclear. Through transcriptomic and lipidomic analyses, we find a negative association between psoriasis and fatty acid metabolism, as well as Th2 signature. Homeostatic expression of liver X receptor (LXR) and peroxisome proliferator-activated receptor gamma (PPARγ) is essential for maintaining fatty acid metabolism and for conferring resistance to psoriasis in mice. Perturbation of signal transducer and activator of transcription 6 (STAT6) diminishes the homeostatic levels of LXR and PPARγ. Furthermore, mice lacking STAT6, interleukin 4 receptor alpha (IL-4Rα), or IL-13, but not IL-4, exhibit increased susceptibility to psoriasis. Under steady state, innate lymphoid cells (ILCs) are the primary producers of IL-13. In human skin, inhibiting tonic type 2 immunity exacerbates psoriasis-like inflammation and IL-17A, while activating LXR or PPARγ inhibits them. Hence, we propose that tonic type 2 immunity, driven by IL-13-producing ILCs, represents a crucial tissue checkpoint that represses autoimmunity and maintains lipid homeostasis in the skin.

Iodine intake from brown seaweed and the related nutritional risk assessment in Koreans.

BACKGROUND/OBJECTIVES: Although iodine is essential for thyroid hormone production and controls many metabolic processes, there are few reports on the iodine intake of the population because of the scarcity of information on the iodine content in food. This study estimated the iodine intake of Koreans from brown seaweed, the major source of iodine in nature. SUBJECTS/METHODS: The dietary intake data from the recent Korea National Health and Nutrition Examination Survey (2016-2021) and the iodine content in brown seaweed were used for the estimation. Nationwide brown seaweed samples were collected and prepared using the representative preparation/cooking methods in the Koreans' diet before iodine analysis by alkaline digestion followed by inductively coupled plasma mass spectrometry. RESULTS: The mean (± SE) iodine intake from sea mustard was 96.01 ± 2.36 µg/day in the Korean population. Although the iodine content in kelp was approximately seven times higher than that in sea mustard, the mean iodine intake from kelp (except broth) was similar to that of sea mustard, 115.58 ± 7.71 µg/day, whereas that from kelp broth was 347.57 ± 10.03 µg/day. The overall mean iodine intake from brown seaweed was 559.16 ± 13.15 µg/day, well over the Recommended Nutrient Intake of iodine for Koreans. Nevertheless, the median intake was zero because only 37.6% of the population consumed brown seaweed on the survey date, suggesting that Koreans do not consume brown seaweed daily. CONCLUSION: The distribution of the usual intake of iodine from brown seaweed in Koreans would be much tighter, resulting in a lower proportion of people exceeding the tolerable upper intake levels and possibly a lower mean intake than this study presented. Further study evaluating the iodine nutriture of Koreans based on the usual intake is warranted. Nevertheless, this study adds to the few reports on the iodine nutriture of Koreans.

Clinical Significance of Residual Ischemia in Acute Myocardial Infarction Complicated by Cardiogenic Shock Undergoing VA-ECMO.

BACKGROUND: Although culprit-only revascularization during the index procedure has been recommended in patients with acute myocardial infarction (AMI) complicated by cardiogenic shock (CS), the reduction of residual ischemia is also emphasized to improve clinical outcomes. However, few data are available about the significance of residual ischemia in patients undergoing mechanical circulatory supports. This study aimed to evaluate the effects of residual ischemia on clinical outcomes in AMI patients undergoing venoarterial-extracorporeal membrane oxygenation (VA-ECMO). METHODS: AMI patients with multivessel disease who underwent VA-ECMO due to refractory CS were pooled from the RESCUE and SMC-ECMO registries. The included patients were classified into three groups according to residual ischemia evaluated using the residual SYNTAX score (rSS): rSS = 0, 0 < rSS ≤ 8, and rSS > 8. The primary outcome was 1-year all-cause death. RESULTS: A total of 408 patients were classified into the rSS = 0 (N = 100, 24.5%), 0 < rSS ≤ 8 (N = 136, 33.3%), and rSS > 8 (N = 172, 42.2%) groups. The cumulative incidence of the primary outcome differed significantly according to rSS (33.9% vs. 55.4% vs. 66.1% for rSS = 0, 0 < rSS ≤ 8, and rSS > 8, respectively, overall P < 0.001). In a multivariable model, rSS was independently associated with the risk of 1-year all-cause death (HRadj 1.03, 95% CI 1.01-1.05, P = 0.003). Conversely, the baseline SYNTAX score was not associated with the risk of the primary outcome. Furthermore, when patients were stratified by rSS, the primary outcome did not differ significantly between the high and low delta SYNTAX score groups. CONCLUSIONS: In AMI patients with refractory CS who underwent VA-ECMO, residual ischemia was associated with an increased risk of 1-year mortality. Future studies are needed to evaluate the efficacy and safety of revascularization strategies to minimize residual ischemia in patients with CS supported with VA ECMO. CLINICAL TRIAL REGISTRATION: REtrospective and Prospective Observational Study to Investigate Clinical oUtcomes and Efficacy of Left Ventricular Assist Device for Korean Patients With Cardiogenic Shock (RESCUE), NCT02985008.

Seasonal variation and prognosis in patients with acute myocardial infarction complicated by cardiogenic shock.

Background: Little is known about the association between seasonal variation and prognosis in patients with CS caused by AMI. Objectives: We investigated the 12-month clinical outcomes in patients treated with percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI) complicated by cardiogenic shock (CS) according to season. Methods: A total of 695 patients undergoing PCI for AMI complicated by CS was enrolled from 12 centers in South Korea. The study patients were divided into four groups according to season in which the AMI with CS occurred (spring, n = 178 vs. summer, n = 155 vs. autumn, n = 182 vs. winter, n = 180). We compared major adverse cardiovascular events (MACEs; the composite of cardiac death, myocardial infarction, re-hospitalization due to heart failure, and any revascularization) between the four groups. Results: The risk of MACE during the 12 months after CS was similar in the four groups: spring, 68 patients, vs. summer, 69, vs. autumn, 73, vs. winter, 68 (p = 0.587). Multivariate Cox-regression analysis revealed no significant difference in 12-month MACE among groups compared to the spring group after inverse probability of treatment weighting adjustment (summer, HR 1.40, 95 % CI 0.98-1.99, p = 0.062; autumn, HR 1.26, 95 % CI 0.89-1.80, p = 0.193; winter, HR 1.18, 95 % CI 0.83-1.67, p = 0.356). The similarity of MACE between the four groups was consistent across a variety of subgroups. Conclusions: After adjusting for baseline differences, seasonal variation seems not to influence the mid-term risk of 12-month MACE in patients treated with PCI for AMI complicated by CS. Condensed abstract: Data are limited regarding the association between seasonal variation and prognosis in patients with cardiogenic shock (CS) caused by AMI. This study divided patients undergoing PCI for AMI complicated by CS into four groups based on the season of occurrence and found no significant differences in 12-month MACE between the groups after adjusting for bias and confounding factors. Multivariate analysis revealed consistent MACE similarity across subgroups. The study suggests that seasonal variation has no impact on the mid-term risk of 12-month MACE in patients with CS caused by AMI, after adjusting for baseline differences. Trial registration: ClinicalTrials.gov NCT02985008RESCUE (REtrospective and prospective observational Study to investigate Clinical oUtcomes and Efficacy of left ventricular assist device for Korean patients with cardiogenic shock), NCT02985008, Registered December 5, 2016 - retrospectively and prospectively. Irb information: This study was approved by the institutional review board of Samsung Medical Center (Reference number: 2016-03-130).

Coherence mapping to identify the intermediates of multi-channel dissociative ionization.

Identifying the short-lived intermediates and reaction mechanisms of multi-channel radical cation fragmentation processes remains a current and important challenge to understanding and predicting mass spectra. We find that coherent oscillations in the femtosecond time-dependent yields of several product ions following ultrafast strong-field ionization represent spectroscopic signatures that elucidate their mechanism of formation and identify the intermediate(s) they originate from. Experiments on endo-dicyclopentadiene show that vibrational frequencies from various intermediates are mapped onto their resulting products. Aided by ab initio methods, we identify the vibrational modes of both the cleaved and intact molecular ion intermediates. These results confirm stepwise and concerted fragmentation pathways of the dicyclopentadiene ion. This study highlights the power of tracking the femtosecond dynamics of all product ions simultaneously and sheds further light onto one of the fundamental reaction mechanisms in mass spectrometry, the retro-Diels Alder reaction.

Cardiogenic shock complicating acute myocardial infarction and multivessel disease: revascularization strategy according to ischemic territory.

INTRODUCTION AND OBJECTIVES: The association of revascularization strategy with clinical outcomes according to the ischemic territory of nonculprit lesion has not been documented in patients with acute myocardial infarction complicated by cardiogenic shock (AMI-CS). This study aimed to compare outcomes between culprit-only and immediate multivessel percutaneous coronary intervention (PCI) according to ischemic territory in patients with AMI-CS. METHODS: A total of 536 patients with AMI-CS and multivessel disease from the SMART-RESCUE registry were categorized according to ischemic territory (nonculprit left main/proximal left anterior descending artery [LM/pLAD] vs culprit LM/pLAD vs no LM/pLAD). The primary outcome was a patient-oriented composite endpoint (POCE) consisting of all-cause death, myocardial infarction, rehospitalization due to heart failure, or repeat revascularization at 1 year. RESULTS: Among the total population, 108 patients had nonculprit LM/pLAD, 228 patients had culprit LM/pLAD, and 200 patients had no LM/pLAD, with the risk of POCE being higher in patients with large ischemic territory lesions (53.6% vs 53.4% vs 39.6%; P = .02). Multivessel PCI was associated with a significantly lower risk of POCE compared with culprit-only PCI in patients with nonculprit LM/pLAD (40.7% vs 66.9%; HR, 0.52; 95%CI, 0.29-0.91; P=.02), but not in those with culprit LM/pLAD (P=.46) or no LM/pLAD (P=.47). A significant interaction existed between revascularization strategy and large nonculprit ischemic territory (P=.03). CONCLUSIONS: Large ischemic territory involvement was associated with worse clinical outcomes in patients with AMI-CS and multivessel disease. Immediate multivessel PCI might improve clinical outcomes in patients with a large nonculprit ischemic burden.

A lipid nanoparticle platform incorporating trehalose glycolipid for exceptional mRNA vaccine safety.

The rapid development of messenger RNA (mRNA) vaccines formulated with lipid nanoparticles (LNPs) has contributed to control of the COVID-19 pandemic. However, mRNA vaccines have raised concerns about their potential toxicity and clinical safety, including side effects, such as myocarditis, anaphylaxis, and pericarditis. In this study, we investigated the potential of trehalose glycolipids-containing LNP (LNP S050L) to reduce the risks associated with ionizable lipids. Trehalose glycolipids can form hydrogen bonds with polar biomolecules, allowing the formation of a stable LNP structure by replacing half of the ionizable lipids. The efficacy and safety of LNP S050L were evaluated by encapsulating the mRNA encoding the luciferase reporter gene and measuring gene expression and organ toxicity, respectively. Furthermore, mice immunized with an LNP S050L-formulated mRNA vaccine expressing influenza hemagglutinin exhibited a significant reduction in organ toxicity, including in the heart, spleen, and liver, while sustaining gene expression and immune efficiency, compared to conventional LNPs (Con-LNPs). Our findings suggest that LNP S050L, a trehalose glycolipid-based LNP, could facilitate the development of safe mRNA vaccines with improved clinical safety.

Crucial Role of Metal Coordination Number in Optimizing Electrocatalyst Activity of Holey Large-Area 2D Ru Nanosheets.

Low-dimensional metal nanostructures have attracted considerable research attention, owing to their potential as catalysts. A controlled reductive phase transition of monolayer RuO2 nanosheets could provide an effective way to produce holey large-area 2D Ru nanosheets with tailored defect structures and metal coordination number. The locally optimized holey Ru metal nanosheet, with a metal coordination number of ∼10.2, exhibited excellent electrocatalytic activity for the hydrogen evolution reaction (HER) with a reduced overpotential of 38 mV in a 1 M KOH electrolyte. The creation of a highly anisotropic holey nanosheet morphology with optimization of local structure was quite effective in developing efficient catalyst materials. The universal importance of controlling the coordination number was confirmed through a comparative study of Ru nanoparticles, which showed optimized HER activity with an identical metal coordination number. The coordination number plays a pivotal role in governing electrocatalytic activity, which could be ascribed to the formation of the most active structure for HER at most 2 defects near active sites (2,2'), resulting in the stabilization of a dihydrogen Ru-(H2) intermediate and the increased contribution of Volmer-Tafel mechanism.

Ticagrelor monotherapy for acute coronary syndrome: an individual patient data meta-analysis of TICO and T-PASS trials.

BACKGROUND AND AIMS: In patients with acute coronary syndrome (ACS), dual antiplatelet therapy (DAPT) with aspirin and a potent P2Y12 inhibitor is recommended for 12 months after drug-eluting stent (DES) implantation. Monotherapy with a potent P2Y12 inhibitor after short-term DAPT is an attractive option to better balance the risks of ischaemia and bleeding. Therefore, this study evaluated the efficacy and safety of ticagrelor monotherapy after short-term DAPT, especially in patients with ACS. METHODS: Electronic databases were searched from inception to 11 November 2023, and for the primary analysis, individual patient data were pooled from the relevant randomized clinical trials comparing ticagrelor monotherapy after short-term (≤3 months) DAPT with ticagrelor-based 12-month DAPT, exclusively in ACS patients undergoing DES implantation. The co-primary endpoints were ischaemic endpoint (composite of all-cause death, myocardial infarction, or stroke) and bleeding endpoint [Bleeding Academic Research Consortium (BARC) type 3 or 5 bleeding] at 1 year. RESULTS: Individual patient data from two randomized clinical trials including 5906 ACS patients were analysed. At 1 year, the primary ischaemic endpoint did not differ between the ticagrelor monotherapy and ticagrelor-based DAPT groups [1.9% vs. 2.5%; adjusted hazard ratio (HR) 0.79; 95% confidence interval (CI) 0.56-1.13; P = .194]. The incidence of the primary bleeding endpoint was lower in the ticagrelor monotherapy group (2.4% vs. 4.5%; adjusted HR 0.54; 95% CI 0.40-0.72; P < .001). The results were consistent in a secondary aggregate data meta-analysis including the ACS subgroup of additional randomized clinical trials which enrolled patients with ACS as well as chronic coronary syndrome. CONCLUSIONS: In ACS patients undergoing DES implantation, ticagrelor monotherapy after short-term DAPT was associated with less major bleeding without a concomitant increase in ischaemic events compared with ticagrelor-based 12-month DAPT. STUDY REGISTRATION: PROSPERO (ID: CRD42023476470).

The Role of Index of Microcirculatory Resistance in Left Anterior Descending Artery ST Segment Elevation Myocardial Infarction Patients after Primary Percutaneous Coronary Intervention.

Background: Our aim was to assess the relationship of the index of microvascular resistance (IMR) in left anterior descending (LAD) artery involved STEMI patients. Methods: Data of 316 STEMI patients who had undergone primary percutaneous coronary intervention (PCI) were collected from three cardiovascular centers from 2005 to 2015. In total, 246 patients with LAD STEMI were enrolled for IMR evaluation. Patients were divided into two groups respective of the cut-off IMR value of 30. All-cause mortality, left ventricular function, improvement of systolic function, and cardiac biomarkers were analyzed and compared. Results: A total of 246 patients were enrolled. The number of patients in the IMR above 30 group was 93 and below 30 was 153. The mean ages for each group were 57.91 ± 11.99 and 54 ± 10.63, respectively. The peak creatinine kinase (CK) (3936.85 ± 2827.32 IU/L vs. 2218.08 ± 2310.41 IU/L, p < 0.001) and CKmb (336.15 ± 195.08 mg/mL vs. 231.53 ± 179.53 mg/mL, p < 0.001) levels were higher for an IMR above the 30 group. The left ventricular ejection fraction (LVEF) (44.57 ± 6.685% vs. 47.35 ± 8.17%, p = 0.006) and improvement of LVEF (2.81 ± 7.135% vs. 5.88 ± 7.65%, p = 0.004) was lower in the IMR above 30 group. All-cause mortality (7.5% vs. 1.3%, p = 0.012) was higher in the IMR above 30 group, and a Cox regression analysis showed that an IMR above 30 was a poor prognostic factor regarding all-cause mortality (HR: 5.151, 95% CI 1.062-24.987, p = 0.042) even after adjusting for classical clinical risk factors. Conclusions: An elevated IMR value represented larger infarct size, more severe LV dysfunction, and higher mortality in LAD STEMI patients after successful PCI.

Sesquiterpenoids and hexanorcucurbitacin from Aquilaria malaccensis agarwood with anti-inflammatory effects by inhibiting the STAT1/AKT/MAPK/NLRP3 pathway.

Seven unknown compounds 1-7, including four sesquiterpenoids, one azulene-type, one indene-type, and one rare hexanorcucurbitacin, together with eleven knowns ones (8-16), were isolated from the agarwood chips of Aquilaria malaccensis. The structures of the isolated compounds were elucidated by extensive spectroscopic methods such as mass spectrometry, UV, IR, NMR spectroscopy. The precise stereo-chemical configurations of new compounds were determined by calculated ECD spectra data, as well as a single-crystal X-ray diffraction analysis. The isolated compounds 1-7 were evaluated by estimating the levels of nitric oxide (NO), TNF-α, and the expression of enzyme iNOS, and COX-2. Among them, a rare hexanortriterpenoid (7) derived from a cucurbitane-type triterpenoid showed the significantly attenuated neuro-inflammatory effects via the STAT1/AKT/MAPK/NLRP3 signaling pathway on the mechanistic studies.

Characterization of the structure, anti-inflammatory activity and molecular docking of a neutral polysaccharide separated from American ginseng berries.

AIM: American ginseng berries, grown in the aerial parts and harvested in August, are a potentially valuable material. The aim of the study was to analyze the specific polysaccharides in American ginseng berries, and to demonstrate the anti-inflammation effect through in vitro and in vivo experiments and molecular docking. METHODS: After deproteinization and dialysis, the extracted crude polysaccharide was separated and purified. The structure of the specific isolated polysaccharide was investigated by Fourier Transform infrared spectroscopy (FT-IR), GC-MS and nuclear magnetic resonance (NMR), and anti-inflammatory activity was evaluated using in vitro and in vivo models (Raw 264.7 cells and zebrafish). Molecular docking was used to analyze the binding capacity and interaction with cyclooxygenase-2 (COX-2). RESULTS: A novel neutral polysaccharide fraction (AGBP-A) was isolated from American ginseng berries. The structural analysis demonstrated that AGBP-A had a weight-average molecular weight (Mw) of 122,988 Da with a dispersity index (Mw/Mn) value of 1.59 and was composed of arabinose and galactose with a core structure containing →6)-Gal-(1→ residues as the backbone and a branching substitution at the C3 position. The side-chains comprised of α-L-Ara-(1→, α-L-Ara-(1→, →5)-α-L-Ara-(1→, ß-D-Gal-(1→. The results showed that it significantly decreased pro-inflammatory cytokines in the cell model. In a zebrafish model, AGBP-A reduced the massive recruitment of neutrophils to the caudal lateral line neuromast, suggesting the relief of inflammation. Molecular docking was used to analyze the combined capacity and interaction with COX-2. CONCLUSION: Our study indicated the potential efficacy of AGBP-A as a safe and valid natural anti-inflammatory component.

Efficacy and safety of durable versus biodegradable polymer drug-eluting stents in patients with acute myocardial infarction complicated by cardiogenic shock.

The clinical impact of different polymer technologies in newer-generation drug-eluting stents (DESs) for patients with acute myocardial infarction (AMI) complicated by cardiogenic shock (CS) remains poorly understood. We investigated the efficacy and safety of durable polymer DESs (DP-DESs) compared with biodegradable polymer DESs (BP-DESs). A total of 620 patients who underwent percutaneous coronary intervention with newer-generation DESs for AMI complicated by CS was divided into two groups based on polymer technology: the DP-DES group (n = 374) and the BP-DES group (n = 246). The primary outcome was target vessel failure (TVF) during a 12-month follow-up, defined as a composite of cardiac death, myocardial infarction, or target vessel revascularization. Both the DP-DES and BP-DES groups exhibited low stent thrombosis rates (1.3% vs. 1.6%, p = 0.660). The risk of TVF did not significantly differ between the two groups (34.2% vs. 28.5%, hazard ratio [HR] 0.94, 95% confidence interval [CI] 0.69-1.29, p = 0.721). This finding remained consistent after adjustment with inverse probability of treatment weighting (28.1% vs. 25.1%, HR 0.98, 95% CI 0.77-1.27, p = 0.899). In AMI patients complicated by CS, the risk of a composite of cardiac death, myocardial infarction, or target vessel revascularization was not significantly different between those treated with DP-DESs and those treated with BP-DESs.Trial registration: RESCUE registry, https://clinicaltrials.gov/ct2/show/NCT02985008 , NCT02985008.

P2Y12 Inhibitor Monotherapy vs Dual Antiplatelet Therapy After Deployment of a Drug-Eluting Stent: The SHARE Randomized Clinical Trial.

Importance: P2Y12 inhibitor monotherapy after dual antiplatelet therapy (DAPT; a P2Y12 inhibitor plus aspirin) for a brief duration has recently emerged as an attractive alternative for patients undergoing percutaneous coronary intervention (PCI) with a drug-eluting stent. Objective: To investigate whether P2Y12 inhibitor monotherapy after 3 months of DAPT was noninferior to 12 months of DAPT following PCI with a drug-eluting stent. Design, Setting, and Participants: The Short-Term Dual Antiplatelet Therapy After Deployment of Bioabsorbable Polymer Everolimus-Eluting Stent (SHARE) open-label, noninferiority randomized clinical trial was conducted from December 15, 2017, through December 14, 2020. Final 1-year clinical follow-up was completed in January 2022. This study was a multicenter trial that was conducted at 20 hospitals in South Korea. Patients who underwent successful PCI with bioabsorbable polymer everolimus-eluting stents were enrolled. Interventions: Patients were randomly assigned to receive P2Y12 inhibitor monotherapy after 3 months of DAPT (n = 694) or 12 months of DAPT (n = 693). Main Outcomes and Measures: The primary outcome was a net adverse clinical event, a composite of major bleeding (based on Bleeding Academic Research Consortium type 3 or type 5 bleeding) and major adverse cardiac and cerebrovascular events (cardiac death, myocardial infarction, stent thrombosis, stroke, or ischemia-driven target lesion revascularization) between 3 and 12 months after the index PCI. The major secondary outcomes were major adverse cardiac and cerebrovascular events and major bleeding. The noninferiority margin was 3.0%. Results: Of the total 1452 eligible patients, 65 patients were excluded before the 3-month follow-up, and 1387 patients (mean [SD] age, 63.0 [10.7] years; 1055 men [76.1%]) were assigned to P2Y12 inhibitor monotherapy (n = 694) or DAPT (n = 693). Between 3 and 12 months of follow-up, the primary outcome (using Kaplan-Meier estimates) occurred in 9 patients (1.7%) in the P2Y12 inhibitor monotherapy group and in 16 patients (2.6%) in the DAPT group (absolute difference, -0.93 [1-sided 95% CI, -2.64 to 0.77] percentage points; P < .001 for noninferiority). For the major secondary outcomes (using Kaplan-Meier estimates), major adverse cardiac and cerebrovascular events occurred in 8 patients (1.5%) in the P2Y12 inhibitor monotherapy group and in 12 patients (2.0%) in the DAPT group (absolute difference, -0.49 [95% CI, -2.07 to 1.09] percentage points; P = .54). Major bleeding occurred in 1 patient (0.2%) in the P2Y12 inhibitor monotherapy group and in 5 patients (0.8%) in the DAPT group (absolute difference, -0.60 [95% CI, -1.33 to 0.12] percentage points; P = .10). Conclusions and Relevance: In patients with coronary artery disease undergoing PCI with the latest generation of drug-eluting stents, P2Y12 inhibitor monotherapy after 3-month DAPT was not inferior to 12-month DAPT for net adverse clinical events. Considering the study population and lower-than-expected event rates, further research is required in other populations. Trial Registration: ClinicalTrials.gov Identifier: NCT03447379.

Prediction of In-Hospital Mortality for Ischemic Cardiogenic Shock Requiring Venoarterial Extracorporeal Membrane Oxygenation.

BACKGROUND: Clinical outcome of ischemic cardiogenic shock (CS) requiring extracorporeal membrane oxygenation is highly variable, necessitating appropriate assessment of prognosis. However, a systemic predictive model estimating the mortality of refractory ischemic CS is lacking. The PRECISE (Prediction of In-Hospital Mortality for Patients With Refractory Ischemic Cardiogenic Shock Requiring Veno-Arterial Extracorporeal Membrane Oxygenation Support) score was developed to predict the prognosis of refractory ischemic CS due to acute myocardial infarction. METHODS AND RESULTS: Data were obtained from the multicenter CS registry RESCUE (Retrospective and Prospective Observational Study to Investigate Clinical Outcomes and Efficacy of Left Ventricular Assist Device for Korean Patients With Cardiogenic Shock) that consists of 322 patients with acute myocardial infarction complicated by refractory ischemic CS requiring extracorporeal membrane oxygenation support. Fifteen parameters were selected to assess in-hospital mortality. The developed model was validated internally and externally using an independent external cohort (n=138). Among 322 patients, 138 (42.9%) survived postdischarge. Fifteen predictors were included for model development: age, diastolic blood pressure, hypertension, chronic kidney disease, peak lactic acid, serum creatinine, lowest left ventricular ejection fraction, vasoactive inotropic score, shock to extracorporeal membrane oxygenation insertion time, extracorporeal cardiopulmonary resuscitation, use of intra-aortic balloon pump, continuous renal replacement therapy, mechanical ventilator, successful coronary revascularization, and staged percutaneous coronary intervention. The PRECISE score yielded a high area under the receiver-operating characteristic curve (0.894 [95% CI, 0.860-0.927]). External validation and calibration resulted in competent sensitivity (area under the receiver-operating characteristic curve, 0.895 [95% CI, 0.853-0.930]). CONCLUSIONS: The PRECISE score demonstrated high predictive performance and directly translates into the expected in-hospital mortality rate. The PRECISE score may be used to support clinical decision-making in ischemic CS (www.theprecisescore.com). REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02985008.

Unraveling the role of the mitochondrial one-carbon pathway in undifferentiated thyroid cancer by multi-omics analyses.

The role of the serine/glycine metabolic pathway (SGP) has recently been demonstrated in tumors; however, the pathological relevance of the SGP in thyroid cancer remains unexplored. Here, we perform metabolomic profiling of 17 tumor-normal pairs; bulk transcriptomics of 263 normal thyroid, 348 papillary, and 21 undifferentiated thyroid cancer samples; and single-cell transcriptomes from 15 cases, showing the impact of mitochondrial one-carbon metabolism in thyroid tumors. High expression of serine hydroxymethyltransferase-2 (SHMT2) and methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is associated with low thyroid differentiation scores and poor clinical features. A subpopulation of tumor cells with high mitochondrial one-carbon pathway activity is observed in the single-cell dataset. SHMT2 inhibition significantly compromises mitochondrial respiration and decreases cell proliferation and tumor size in vitro and in vivo. Collectively, our results highlight the importance of the mitochondrial one-carbon pathway in undifferentiated thyroid cancer and suggest that SHMT2 is a potent therapeutic target.

Ceramide promotes lytic reactivation of Epstein-Barr virus in gastric carcinoma.

Epstein-Barr virus (EBV) has a lifelong latency period after initial infection. Rarely, however, when the EBV immediate early gene BZLF1 is expressed by a specific stimulus, the virus switches to the lytic cycle to produce progeny viruses. We found that EBV infection reduced levels of various ceramide species in gastric cancer cells. As ceramide is a bioactive lipid implicated in the infection of various viruses, we assessed the effect of ceramide on the EBV lytic cycle. Treatment with C6-ceramide (C6-Cer) induced an increase in the endogenous ceramide pool and increased production of the viral product as well as BZLF1 expression. Treatment with the ceramidase inhibitor ceranib-2 induced EBV lytic replication with an increase in the endogenous ceramide pool. The glucosylceramide synthase inhibitor Genz-123346 inhibited C6-Cer-induced lytic replication. C6-Cer induced extracellular signal-regulated kinase 1/2 (ERK1/2) and CREB phosphorylation, c-JUN expression, and accumulation of the autophagosome marker LC3B. Treatment with MEK1/2 inhibitor U0126, siERK1&2, or siCREB suppressed C6-Cer-induced EBV lytic replication and autophagy initiation. In contrast, siJUN transfection had no impact on BZLF1 expression. The use of 3-methyladenine (3-MA), an inhibitor targeting class III phosphoinositide 3-kinases (PI3Ks) to inhibit autophagy initiation, resulted in reduced beclin-1 expression, along with suppressed C6-Cer-induced BZLF1 expression and LC3B accumulation. Chloroquine, an inhibitor of autophagosome-lysosome fusion, increased BZLF1 protein intensity and LC3B accumulation. However, siLC3B transfection had minimal effect on BZLF1 expression. The results suggest the significance of ceramide-related sphingolipid metabolism in controlling EBV latency, highlighting the potential use of drugs targeting sphingolipid metabolism for treating EBV-positive gastric cancer.IMPORTANCEEpstein-Barr virus remains dormant in the host cell but occasionally switches to the lytic cycle when stimulated. However, the exact molecular mechanism of this lytic induction is not well understood. In this study, we demonstrate that Epstein-Barr virus infection leads to a reduction in ceramide levels. Additionally, the restoration of ceramide levels triggers lytic replication of Epstein-Barr virus with increase in phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and CREB. Our study suggests that the Epstein-Barr virus can inhibit lytic replication and remain latent through reduction of host cell ceramide levels. This study reports the regulation of lytic replication by ceramide in Epstein-Barr virus-positive gastric cancer.

Suppressing Redox Reactions at the Perovskite-Nickel Oxide Interface with Zinc Nitride to Improve the Performance of Perovskite Solar Cells.

For p-i-n perovskite solar cells (PSCs), nickel oxide (NiOx) hole transport layers (HTLs) are the preferred interfacial layer due to their low cost, high mobility, high transmittance, and stability. However, the redox reaction between the Ni≥3+ and hydroxyl groups in the NiOx and perovskite layer leads to oxidized CH3NH3 + and reacts with PbI in the perovskite, resulting in a large number of non-radiative recombination sites. Among various transition metals, an ultra-thin zinc nitride (Zn3N2) layer on the NiOx surface is chosen to prevent these redox reactions and interfacial issues using a simple solution process at low temperatures. The redox reaction and non-radiative recombination at the interface of the perovskite and NiOx reduce chemically by using interface modifier Zn3N2 to reduce hydroxyl group and defects on the surface of NiOx. A thin layer of Zn3N2 at the NiOx/perovskite interface results in a high Ni3+/Ni2+ ratio and a significant work function (WF), which inhibits the redox reaction and provides a highly aligned energy level with perovskite crystal and rigorous trap-passivation ability. Consequently, Zn3N2-modified NiOx-based PSCs achieve a champion PCE of 21.61%, over the NiOx-based PSCs. After Zn3N2 modification, the PSC can improve stability under several conditions.

Integrative Multi-omics Analysis Reveals Different Metabolic Phenotypes Based on Molecular Characteristics in Thyroid Cancer.

PURPOSE: Thyroid cancer metabolic characteristics vary depending on the molecular subtype determined by mutational status. We aimed to investigate the molecular subtype-specific metabolic characteristics of thyroid cancers. EXPERIMENTAL DESIGN: An integrative multi-omics analysis was conducted, incorporating transcriptomics, metabolomics, and proteomics data obtained from human tissues representing distinct molecular characteristics of thyroid cancers: BRAF-like (papillary thyroid cancer with BRAFV600E mutation; PTC-B), RAS-like (follicular thyroid cancer with RAS mutation; FTC-R), and ATC-like (anaplastic thyroid cancer with BRAFV600E or RAS mutation; ATC-B or ATC-R). To validate our findings, we employed tissue microarray of human thyroid cancer tissues and performed in vitro analyses of cancer cell phenotypes and metabolomic assays after inducing genetic knockdown. RESULTS: Metabolic properties differed between differentiated thyroid cancers of PTC-B and FTC-R, but were similar in dedifferentiated thyroid cancers of ATC-B/R, regardless of their mutational status. Tricarboxylic acid (TCA) intermediates and branched-chain amino acids (BCAA) were enriched with the activation of TCA cycle only in FTC-R, whereas one-carbon metabolism and pyrimidine metabolism increased in both PTC-B and FTC-R and to a great extent in ATC-B/R. However, the protein expression levels of the BCAA transporter (SLC7A5) and a key enzyme in one-carbon metabolism (SHMT2) increased in all thyroid cancers and were particularly high in ATC-B/R. Knockdown of SLC7A5 or SHMT2 inhibited the migration and proliferation of thyroid cancer cell lines differently, depending on the mutational status. CONCLUSIONS: These findings define the metabolic properties of each molecular subtype of thyroid cancers and identify metabolic vulnerabilities, providing a rationale for therapies targeting its altered metabolic pathways in advanced thyroid cancer.

Stopping Aspirin Within 1 Month After Stenting for Ticagrelor Monotherapy in Acute Coronary Syndrome: The T-PASS Randomized Noninferiority Trial.

BACKGROUND: Stopping aspirin within 1 month after implantation of a drug-eluting stent for ticagrelor monotherapy has not been exclusively evaluated for patients with acute coronary syndrome. The aim of this study was to investigate whether ticagrelor monotherapy after <1 month of dual antiplatelet therapy (DAPT) is noninferior to 12 months of ticagrelor-based DAPT for adverse cardiovascular and bleeding events in patients with acute coronary syndrome. METHODS: In this randomized, open-label, noninferiority trial, 2850 patients with acute coronary syndrome who underwent drug-eluting stent implantation at 24 centers in South Korea were randomly assigned (1:1) to receive either ticagrelor monotherapy (90 mg twice daily) after <1 month of DAPT (n=1426) or 12 months of ticagrelor-based DAPT (n=1424) between April 24, 2019, and May 31, 2022. The primary end point was the net clinical benefit as a composite of all-cause death, myocardial infarction, definite or probable stent thrombosis, stroke, and major bleeding at 1 year after the index procedure in the intention-to-treat population. Key secondary end points were the individual components of the primary end point. RESULTS: Among 2850 patients who were randomized (mean age, 61 years; 40% ST-segment-elevation myocardial infarction), 2823 (99.0%) completed the trial. Aspirin was discontinued at a median of 16 days (interquartile range, 12-25 days) in the group receiving ticagrelor monotherapy after <1 month of DAPT. The primary end point occurred in 40 patients (2.8%) in the group receiving ticagrelor monotherapy after <1-month DAPT, and in 73 patients (5.2%) in the ticagrelor-based 12-month DAPT group (hazard ratio, 0.54 [95% CI, 0.37-0.80]; P<0.001 for noninferiority; P=0.002 for superiority). This finding was consistent in the per-protocol population as a sensitivity analysis. The occurrence of major bleeding was significantly lower in the ticagrelor monotherapy after <1-month DAPT group compared with the 12-month DAPT group (1.2% versus 3.4%; hazard ratio, 0.35 [95% CI, 0.20-0.61]; P<0.001). CONCLUSIONS: This study provides evidence that stopping aspirin within 1 month for ticagrelor monotherapy is both noninferior and superior to 12-month DAPT for the 1-year composite outcome of death, myocardial infarction, stent thrombosis, stroke, and major bleeding, primarily because of a significant reduction in major bleeding, among patients with acute coronary syndrome receiving drug-eluting stent implantation. Low event rates, which may suggest enrollment of relatively non-high-risk patients, should be considered in interpreting the trial. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03797651.