In situ observation of thermal-driven structural transitions of a ß-NaYF4 single nanoparticle aided with correlative cathodoluminescence electron microscopy.

NaYF4 systems have been widely studied as up-conversion host matrices, and their phase transitions are flexible and worth investigating in great detail. Herein, the evolution of morphology and crystal structure of a Eu3+-doped ß-NaYF4 single nanoparticle heated in an air atmosphere was investigated using in situ transmission electron microscopy (TEM). The annealing process revealed that the hexagonal ß-NaYF4 phase undergoes sequential transformations into high-temperature cubic phases at both 350 °C and 500 °C. The emission characteristics of Eu3+ in the single nanoparticle after heating treatment were also analyzed using Correlative Cathodoluminescence Electron Microscopy (CCLEM). The results of CCLEM suggest a gradual decrease followed by a subsequent increase in structural symmetry. A comprehensive spectroscopic and structural analysis encapsulates the entire transformation process as NaYF4 → YOF → Y2O3. In situ energy dispersive spectroscopy analyses (EDS) support this reaction process. The aforementioned technique yields correlative lattice-resolved TEM images and nanoscale spectroscopic information, which can be employed to assess the structure-function relationships on the nanoscale.

Efficacy and Safety of Acoramidis in Transthyretin Amyloid Cardiomyopathy.

BACKGROUND: Transthyretin amyloid cardiomyopathy is characterized by the deposition of misfolded monomeric transthyretin (TTR) in the heart. Acoramidis is a high-affinity TTR stabilizer that acts to inhibit dissociation of tetrameric TTR and leads to more than 90% stabilization across the dosing interval as measured ex vivo. METHODS: In this phase 3, double-blind trial, we randomly assigned patients with transthyretin amyloid cardiomyopathy in a 2:1 ratio to receive acoramidis hydrochloride at a dose of 800 mg twice daily or matching placebo for 30 months. Efficacy was assessed in the patients who had an estimated glomerular filtration rate of at least 30 ml per minute per 1.73 m2 of body-surface area. The four-step primary hierarchical analysis included death from any cause, cardiovascular-related hospitalization, the change from baseline in the N-terminal pro-B-type natriuretic peptide (NT-proBNP) level, and the change from baseline in the 6-minute walk distance. We used the Finkelstein-Schoenfeld method to compare all potential pairs of patients within strata to generate a P value. Key secondary outcomes were death from any cause, the 6-minute walk distance, the score on the Kansas City Cardiomyopathy Questionnaire-Overall Summary, and the serum TTR level. RESULTS: A total of 632 patients underwent randomization. The primary analysis favored acoramidis over placebo (P<0.001); the corresponding win ratio was 1.8 (95% confidence interval [CI], 1.4 to 2.2), with 63.7% of pairwise comparisons favoring acoramidis and 35.9% favoring placebo. Together, death from any cause and cardiovascular-related hospitalization contributed more than half the wins and losses to the win ratio (58% of all pairwise comparisons); NT-proBNP pairwise comparisons yielded the highest ratio of wins to losses (23.3% vs. 7.0%). The overall incidence of adverse events was similar in the acoramidis group and the placebo group (98.1% and 97.6%, respectively); serious adverse events were reported in 54.6% and 64.9% of the patients. CONCLUSIONS: In patients with transthyretin amyloid cardiomyopathy, the receipt of acoramidis resulted in a significantly better four-step primary hierarchical outcome containing components of mortality, morbidity, and function than placebo. Adverse events were similar in the two groups. (Funded by BridgeBio Pharma; ATTRibute-CM ClinicalTrials.gov number, NCT03860935.).

Dynamic Weighting Network for Person Re-Identification.

Recently, hybrid Convolution-Transformer architectures have become popular due to their ability to capture both local and global image features and the advantage of lower computational cost over pure Transformer models. However, directly embedding a Transformer can result in the loss of convolution-based features, particularly fine-grained features. Therefore, using these architectures as the backbone of a re-identification task is not an effective approach. To address this challenge, we propose a feature fusion gate unit that dynamically adjusts the ratio of local and global features. The feature fusion gate unit fuses the convolution and self-attentive branches of the network with dynamic parameters based on the input information. This unit can be integrated into different layers or multiple residual blocks, which will have varying effects on the accuracy of the model. Using feature fusion gate units, we propose a simple and portable model called the dynamic weighting network or DWNet, which supports two backbones, ResNet and OSNet, called DWNet-R and DWNet-O, respectively. DWNet significantly improves re-identification performance over the original baseline, while maintaining reasonable computational consumption and number of parameters. Finally, our DWNet-R achieves an mAP of 87.53%, 79.18%, 50.03%, on the Market1501, DukeMTMC-reID, and MSMT17 datasets. Our DWNet-O achieves an mAP of 86.83%, 78.68%, 55.66%, on the Market1501, DukeMTMC-reID, and MSMT17 datasets.

Effect of the angiotensin-receptor-neprilysin inhibitor in heart failure patients with left ventricular ejection fraction higher than 40.

The angiotensin-receptor-neprilysin inhibitor (ARNI) reduced cardiovascular deaths and heart failure hospitalization in patients with heart failure of reduced ejection fraction (HFrEF). Its role in non-HFrEF patients was not clear. This study aims to answer this question.In this retrospective study, we enrolled 928 patients diagnosed with non-HFrEF, 492 of them received angiotensin converting enzyme inhibitor (ACEI) and the rest 436 received angiotensin-receptor-neprilysin inhibitor. Outcomes were compared by Kaplan-Meier survival analysis and various clinical parameters were investigated using Cox multivariable analysis, followed by interaction analysis. Minnesota living with heart failure Questionnaire (MLHFQ) was employed as one of the criteria to assess heart failure outcome.The cardiovascular (CV) death or HF hospitalization at 24 months occurred in 49 patients in ACEI group compared with 31 in ARNI group (Hazard Ratio (HR): 1.231, 95% confidence Interval (CI): 1.080-2.460, P = .031). And ARNI showed better prognosis of HF hospitalization (HR: 1.283, 95%CI: 1.065-1.360, P = .038). Cumulative Kaplan-Meier estimates of endpoints, ARNI could reduce the incidence of CV death or HF hospitalization (P = .042) and HF hospitalization (P = .035). The stratified analysis revealed that participants with age less than 70 years old had a lower incidence of CV death or HF hospitalization (HR: 1.194, 95%CI: 1.011-1992, P = .031) after treated with ARNI. Patients received diuretics could benefit from ARNI (HR: 1.383, 95%CI: 1.082-1.471, P = .019). Similar results were also observed in patients with heart rate lower than 90 bpm (HR: 1.556, 95%CI: 1.045-2.386, P = .003) and patients with atrial fibrillation history (HR: 1.873, 95%CI: 1.420-2.809, P = .011). ARNI could improve the quality of life both from the total, emotional and physical aspects.ARNI is an efficacy treatment strategy to improve the outcome and quality of life in patients with non-HFrEF.

Efficacy and Safety of Different Antiplatelet Strategies in Survivors of Myocardial Infarction With Acute Coronary Syndrome.

PURPOSE: Many patients with acute coronary syndrome may experience recurrent myocardial infarction although they are receiving optional therapy, but they are still associated with poor clincial outcomes. The goal of this study was to assess different antiplatelet strategies in these patients. METHODS: This retrospective trial compared ticagrelor (180-mg loading dose, 90-mg BID maintenance dose) and clopidogrel (300- to 600-mg loading dose, 150-mg daily maintenance dose) for the prevention of cardiovascular events in 1083 patients with acute coronary syndrome and recurrent myocardial infarction admitted to the hospital undergoing percutaneous coronary intervention. FINDINGS: At the 24-month follow-up, a major adverse cardiovascular and cerebrovascular event (MACCE) occurred in 10.5% of patients receiving ticagrelor compared with 13.2% in the clopidogrel group (P = 0.023). Meanwhile, ticagrelor caused a higher rate of minor bleeding (18.1% vs 15.3%; P = 0.008). A survival analysis showed that ticagrelor decreased the incidence of MACCE (log-rank test, P < 0.001) and all-cause death (log-rank test, P = 0.001). The advantage of ticagrelor was also presented according to analysis of Seattle Angina Questionnaire scores. IMPLICATIONS: In patients with recurrent myocardial infarction, the ticagrelor antiplatelet strategy significantly reduced the MACCE rate without increasing the risk of major bleeding, although patients did have a higher risk of minor bleeding.

Derivation and Evaluation of the Ischemic Risk Model in High-Risk Chinese Patients Undergoing Percutaneous Coronary Intervention for Acute Coronary Syndrome.

PURPOSE: Coronary artery disease is the top cause of death among the Chinese population. With the establishment of a Chinese prediction model, it is urgent to assess factors related to the prognosis of patients with acute coronary syndrome at extremely high risk. METHODS: In this retrospective study, we enrolled 601 patients assessed as being of extremely high risk, according to specific criteria from the China-PAR (Prediction for Atherosclerotic Cardiovascular Disease Risk) project, and investigated various clinical parameters using Cox multivariate analysis to establish a risk nomogram. C-index and calibration curves were involved to assess the internal identification. By using the all-cause death risk model, we stratified patients by risk level and compared the effects of clopidogrel and ticagrelor on end points. FINDINGS: We identified several factors, including body mass index, angiopathy, smoking status, ß-blocker usage, history of myocardial infarction, total number of stents, and usage of antiplatelet agents, related to ischemic end points, all-cause death, cardiovascular events, and cardiac death. A C-index of >0.7 and the calibration curve demonstrated good concordance. In a subsequent analysis, we used the all-cause death model to stratify patients by risk level, and compared the effects of clopidogrel and ticagrelor. In the subgroup with a 2-year death rate of >50%, ticagrelor showed a positive effect (P = 0.045), but in the subgroup with a 2-year death rate of <50%, the difference between clopidogrel and ticagrelor was not significant. Considering the duration of effect of antiplatelet agents, we also compared these 2 agents at 1-year follow up, with ticagrelor showing no advantage. IMPLICATIONS: We determined the probability of ischemic risk in patients at extremely high ischemic risk and developed new risk models for this specific group. Ticagrelor, compared with clopidogrel, may improve the prognosis of patients at high risk for death after 2 years.

Partial deficiency of DNA-PKcs increases ionizing radiation-induced mutagenesis and telomere instability in human cells.

The correct repair of DNA double-strand breaks (DSBs) is essential to maintaining the integrity of the genome. Misrepair of DSBs is detrimental to cells and organisms, leading to gene mutation, chromosomal aberration, and cancer development. Nonhomologous end-joining (NHEJ) is one of the principal rejoining processes in most higher eukaryotic cells. NHEJ is facilitated by DNA-dependent protein kinase (DNA-PK), which is composed of a catalytic subunit, DNA-PKcs, and the heterodimeric DNA binding regulatory complex Ku70/86. Null mutation of DNA-PKcs leads to immunodeficiency, chromosomal aberration, gene mutation, telomeric end-capping failure, and cancer predisposition in animals and cells. However, it is unknown whether partial deficiency of DNA-PKcs as might occur in a fraction of the population (e.g., heterozygotes), influences cellular function. Using small interfering RNA (siRNA) transfection, we established partial deficiency of DNA-PKcs in human cells, ranging from 4 to 85% of control levels. Our results reveal for the first time, that partial deficiency of DNA-PKcs leads to increased ionizing radiation (IR)-induced mutagenesis, cell killing, and telomere dysfunction. Radiation mutagenesis was increased inversely with DNA-PKcs protein level, with the most pronounced effect being observed in cells with protein levels below 50% of controls. A small but statistically significant increase in IR-induced cell killing was observed as DNA-PKcs levels decreased, over the entire range of protein levels. Frequencies of IR-induced telomere-DSB fusion was increased at levels of DNA-PKcs as low as approximately 50%, similar to what would be expected in heterozygous individuals. Taken together, our results suggest that even partial deficiency of DNA repair proteins may represent a considerable risk to genomic stability.