Ticagrelor alone versus ticagrelor plus aspirin from month 1 to month 12 after percutaneous coronary intervention in patients with acute coronary syndromes (ULTIMATE-DAPT): a randomised, placebo-controlled, double-blind clinical trial.

BACKGROUND: Following percutaneous coronary intervention with stent placement to treat acute coronary syndromes, international clinical guidelines generally recommend dual antiplatelet therapy with aspirin plus a P2Y12 receptor inhibitor for 12 months to prevent myocardial infarction and stent thrombosis. However, data on single antiplatelet therapy with a potent P2Y12 inhibitor earlier than 12 months after percutaneous coronary intervention for patients with an acute coronary syndrome are scarce. The aim of this trial was to assess whether the use of ticagrelor alone, compared with ticagrelor plus aspirin, could reduce the incidence of clinically relevant bleeding events without an accompanying increase in major adverse cardiovascular or cerebrovascular events (MACCE). METHODS: In this randomised, placebo-controlled, double-blind clinical trial, patients aged 18 years or older with an acute coronary syndrome who completed the IVUS-ACS study and who had no major ischaemic or bleeding events after 1-month treatment with dual antiplatelet therapy were randomly assigned to receive oral ticagrelor (90 mg twice daily) plus oral aspirin (100 mg once daily) or oral ticagrelor (90 mg twice daily) plus a matching oral placebo, beginning 1 month and ending at 12 months after percutaneous coronary intervention (11 months in total). Recruitment took place at 58 centres in China, Italy, Pakistan, and the UK. Patients were required to remain event-free for 1 month on dual antiplatelet therapy following percutaneous coronary intervention with contemporary drug-eluting stents. Randomisation was done using a web-based system, stratified by acute coronary syndrome type, diabetes, IVUS-ACS randomisation, and site, using dynamic minimisation. The primary superiority endpoint was clinically relevant bleeding (Bleeding Academic Research Consortium [known as BARC] types 2, 3, or 5). The primary non-inferiority endpoint was MACCE (defined as the composite of cardiac death, myocardial infarction, ischaemic stroke, definite stent thrombosis, or clinically driven target vessel revascularisation), with an expected event rate of 6·2% in the ticagrelor plus aspirin group and an absolute non-inferiority margin of 2·5 percentage points between 1 month and 12 months after percutaneous coronary intervention. The two co-primary endpoints were tested sequentially; the primary superiority endpoint had to be met for hypothesis testing of the MACCE outcome to proceed. All principal analyses were assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT03971500, and is completed. FINDINGS: Between Sept 21, 2019, and Oct 27, 2022, 3400 (97·0%) of the 3505 participants in the IVUS-ACS study were randomly assigned (1700 patients to ticagrelor plus aspirin and 1700 patients to ticagrelor plus placebo). 12-month follow-up was completed by 3399 (>99·9%) patients. Between month 1 and month 12 after percutaneous coronary intervention, clinically relevant bleeding occurred in 35 patients (2·1%) in the ticagrelor plus placebo group and in 78 patients (4·6%) in the ticagrelor plus aspirin group (hazard ratio [HR] 0·45 [95% CI 0·30 to 0·66]; p<0·0001). MACCE occurred in 61 patients (3·6%) in the ticagrelor plus placebo group and in 63 patients (3·7%) in the ticagrelor plus aspirin group (absolute difference -0·1% [95% CI -1·4% to 1·2%]; HR 0·98 [95% CI 0·69 to 1·39]; pnon-inferiority<0·0001, psuperiority=0·89). INTERPRETATION: In patients with an acute coronary syndrome who had percutaneous coronary intervention with contemporary drug-eluting stents and remained event-free for 1 month on dual antiplatelet therapy, treatment with ticagrelor alone between month 1 and month 12 after the intervention resulted in a lower rate of clinically relevant bleeding and a similar rate of MACCE compared with ticagrelor plus aspirin. Along with the results from previous studies, these findings show that most patients in this population can benefit from superior clinical outcomes with aspirin discontinuation and maintenance on ticagrelor monotherapy after 1 month of dual antiplatelet therapy. FUNDING: The Chinese Society of Cardiology, the National Natural Scientific Foundation of China, and the Jiangsu Provincial & Nanjing Municipal Clinical Trial Project. TRANSLATION: For the Mandarin translation of the abstract see Supplementary Materials section.

Intravascular ultrasound-guided versus angiography-guided percutaneous coronary intervention in acute coronary syndromes (IVUS-ACS): a two-stage, multicentre, randomised trial.

BACKGROUND: Intravascular ultrasound-guided percutaneous coronary intervention has been shown to result in superior clinical outcomes compared with angiography-guided percutaneous coronary intervention. However, insufficient data are available concerning the advantages of intravascular ultrasound guidance for patients with an acute coronary syndrome. This trial aimed to investigate whether the use of intravascular ultrasound guidance, as compared with angiography guidance, improves the outcomes of percutaneous coronary intervention with contemporary drug-eluting stents in patients presenting with an acute coronary syndrome. METHODS: In this two-stage, multicentre, randomised trial, patients aged 18 years or older and presenting with an acute coronary syndrome at 58 centres in China, Italy, Pakistan, and the UK were randomly assigned to intravascular ultrasound-guided percutaneous coronary intervention or angiography-guided percutaneous coronary intervention. Patients, follow-up health-care providers, and assessors were masked to random assignment; however, staff in the catheterisation laboratory were not. The primary endpoint was target vessel failure, a composite of cardiac death, target vessel myocardial infarction, or clinically driven target vessel revascularisation at 1 year after randomisation. This trial is registered at ClinicalTrials.gov, NCT03971500, and is completed. FINDINGS: Between Aug 20, 2019 and Oct 27, 2022, 3505 patients with an acute coronary syndrome were randomly assigned to intravascular ultrasound-guided percutaneous coronary intervention (n=1753) or angiography-guided percutaneous coronary intervention (n=1752). 1-year follow-up was completed in 3504 (>99·9%) patients. The primary endpoint occurred in 70 patients in the intravascular ultrasound group and 128 patients in the angiography group (Kaplan-Meier rate 4·0% vs 7·3%; hazard ratio 0·55 [95% CI 0·41-0·74]; p=0·0001), driven by reductions in target vessel myocardial infarction or target vessel revascularisation. There were no significant differences in all-cause death or stent thrombosis between groups. Safety endpoints were also similar in the two groups. INTERPRETATION: In patients with an acute coronary syndrome, intravascular ultrasound-guided implantation of contemporary drug-eluting stents resulted in a lower 1-year rate of the composite outcome of cardiac death, target vessel myocardial infarction, or clinically driven revascularisation compared with angiography guidance alone. FUNDING: The Chinese Society of Cardiology, the National Natural Scientific Foundation of China, and Jiangsu Provincial & Nanjing Municipal Clinical Trial Project. TRANSLATION: For the Mandarin translation of the abstract see Supplementary Materials section.

Proton-coupled electron transfer of macrocyclic ring hydrogenation: The chlorinphlorin.

SignificanceThe chemical reduction of unsaturated bonds occurs by hydrogenation with H2 as the reductant. Conversely, in biology, the unavailability of H2 engenders the typical reduction of unsaturated bonds with electrons and protons from different cofactors, requiring olefin hydrogenation to occur by proton-coupled electron transfer (PCET). Moreover, the redox noninnocence of tetrapyrrole macrocycles furnishes unusual PCET intermediates, including the phlorin, which is an intermediate in tetrapyrrole ring reductions. Whereas the phlorin of a porphyrin is well established, the phlorin of a chlorin is enigmatic. By controlling the PCET reactivity of a chlorin, including the use of a hangman functionality to manage the proton transfer, the formation of a chlorinphlorin by PCET is realized, and the mechanism for its formation is defined.

An Asymmetric Layer Structure Enables Robust Multifunctional Wearable Bacterial Cellulose Composite Film with Excellent Electrothermal/Photothermal and EMI Shielding Performance.

Highly robust flexible multifunctional film with excellent electromagnetic interference shielding and electrothermal/photothermal characteristics are highly desirable for aerospace, military, and wearable devices. Herein, an asymmetric gradient multilayer structured bacterial cellulose@Fe3O4/carbon nanotube/Ti3C2Tx (BC@Fe3O4/CNT/Ti3C2Tx) multifunctional composite film is fabricated with simultaneously demonstrating fast Joule response, excellent EMI shielding effectiveness (EMI SE) and photothermal conversion properties. The asymmetric gradient 6-layer composite film with 40% of Ti3C2Tx possesses excellent mechanical performance with exceptional tensile strength (76.1 MPa), large strain (14.7%), and good flexibility. This is attributed to the asymmetric gradient multilayer structure designed based on the hydrogen bonding self-assembly strategy between Ti3C2Tx and BC. It achieved an EMI SE of up to 71.3 dB, which is attributed to the gradient "absorption-reflection-reabsorption" mechanism. Furthermore, this composite film also exhibits excellent low-voltage-driven Joule heating (up to 80.3 °C at 2.5 V within 15 s) and fast-response photothermal performance (up to 101.5 °C at 1.0 W cm-2 within 10 s), which is attributed to the synergistic effect of heterostructure. This work demonstrates the fabrication of multifunctional bacterial cellulose@Fe3O4/carbon nanotube/Ti3C2Tx composite film has promising potentials for next-generation wearable electronic devices in energy conversion, aerospace, and artificial intelligence.

Transfemoral transcatheter aortic valve replacement with VitaFlowTM valve for pure native aortic regurgitation in patients with high surgical risk: Rationale and design of a prospective, multicenter, and randomized SEASON-AR trial.

BACKGROUND: Previous studies primarily demonstrated that transfemoral transcatheter aortic valve replacement (TAVR) with self-expanding valve appeared to be a safe and feasible treatment for patients with pure native aortic regurgitation (AR). However, the routine application of transfemoral TAVR for pure AR patients lacks support from randomized trials. TRIAL DESIGN: SEASON-AR trial is a prospective, multicenter, randomized, controlled, parallel-group, open-label trial, involving at least 20 sites in China, aiming to enroll 210 patients with pure native severe AR and high surgical risk. All enrolled patients are randomly assigned in a 1:1 fashion to undergo transfemoral TAVR with VitaFlowTM valve and receive guideline-directed medical therapy (GDMT) or to receive GDMT alone. The primary endpoint is the rate of major adverse cardiac events (MACE) at 12 months after the procedure, defined by the composite of all-cause mortality, disabling stroke, and rehospitalization for heart failure. The major secondary endpoints encompass various measures, including procedure-related complications, device success, 6-minute walk distance, and the occurrence of each individual component of the primary endpoint. After hospital discharge, follow-up was conducted through clinical visits or telephone contact at 1, 6, and 12 months. The follow-up will continue annually until 5 years after the index procedure to assess the long-term outcomes. CONCLUSION: SEASON-AR trial is the first study designed to investigate the clinical efficacy and safety of transfemoral TAVR with a self-expanding valve in patients with pure native severe AR with inoperable or high-risk, as compared to medical treatment only.

PCSK9 Inhibitor Added to High-Intensity Statin Therapy to Prevent Cardiovascular Events in Patients with Acute Coronary Syndrome after Percutaneous Coronary Intervention: A Randomized, Double- Blind, Placebo-Controlled, Multicenter SHAWN Study.

BACKGROUND: It is currently uncertain whether the combination of a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor and high-intensity statin treatment can effectively reduce cardiovascular events in patients with acute coronary syndrome (ACS) who have undergone percutaneous coronary intervention (PCI) for culprit lesions. METHODS: This study protocol describes a double-blind, randomized, placebo-controlled, multicenter study aiming to investigate the efficacy and safety of combining a PCSK9 inhibitor with high-intensity statin therapy in patients with ACS following PCI. A total of 1212 patients with ACS and multiple lesions will be enrolled and randomly assigned to receive either PCSK9 inhibitor plus high-intensity statin therapy or high-intensity statin monotherapy. The randomization process will be stratified by sites, diabetes, initial presentation and use of stable (≥4 weeks) statin treatment at presentation. PCSK 9 inhibitor or its placebo is injected within 4 hours after PCI for the culprit lesion. The primary endpoint is the composite of cardiovascular death, myocardial infarction, stroke, re-hospitalization due to ACS or heart failure, or any ischemia-driven coronary revascularization at one-year follow-up between two groups. Safety endpoints mean PCSK 9 inhibitor and statin intolerance. CONCLUSION: The SHAWN study has been specifically designed to evaluate the effectiveness and safety of adding a PCSK9 inhibitor to high-intensity statin therapy in patients who have experienced ACS following PCI. The primary objective of this study is to generate new evidence regarding the potential benefits of combining a PCSK9 inhibitor with high-intensity statin treatment in reducing cardiovascular events among these patients.

Self-Assembly of Sulfate-Containing Peptides Sequesters VEGF for Inhibiting Cancer Cell Invasion.

Heparan sulfate proteoglycans (HSPGs) play a crucial role in regulating cancer growth and migration by mediating interactions with growth factors. In this study, we developed a self-assembling peptide (S1) containing a sulfate group to simulate the contiguous sulfated regions (S-domains) in heparan sulfate for growth factor binding, aiming to sequester growth factors like VEGF. Spectral and structural studies as well as simulation studies suggested that S1 self-assembled into nanostructures similar to the heparan sulfate chains and effectively bound to VEGF. On cancer cell surfaces, S1 self-assemblies sequestered VEGF, leading to a reduction in VEGF levels in the medium, consequently inhibiting cancer cell growth, invasion, and angiogenesis. This study highlights the potential of self-assembling peptides to emulate extracellular matrix functions, offering insights for future cancer therapeutic strategies.

Estimated Pulse Wave Velocity Predicts All-Cause and Cardiovascular-Cause Mortality in Individuals With Hypertension　- Findings From a National Health and Nutrition Examination Study 1999-2018.

BACKGROUND: This study aimed to investigate the association between estimated pulse wave velocity (ePWV) and mortality outcomes among individuals with hypertension.Methods and Results: Based on the National Health and Nutrition Examination Survey (NHANES) 1999-2018, a total of 14,396 eligible participants with hypertension were enrolled. The ePWV was calculated using the equation based on blood pressure and age. The mortality outcomes of included participants were directly acquired from the National Death Index database. The multivariable Cox regression analysis was used to examine the relationship between ePWV and mortality outcomes. Moreover, the restricted cubic spline (RCS) was also used to explore this relationship. Receiver operating characteristics curves (ROC) were adopted to evaluate the prognostic ability of ePWV for predicting mortality outcomes of patients with hypertension. The median follow-up duration was 10.8 years; individuals with higher an ePWV had higher risks of mortality from both all causes (HR: 2.79, 95% CI: 2.43-3.20) and cardiovascular diseases (HR: 3.41, 95% CI: 2.50-4.64). After adjusting for confounding factors, each 1 m/s increase in ePWV was associated with a 43% increase in all-cause mortality risk (HR: 1.43, 95% CI: 1.37-1.48) and a 54% increase in cardiovascular mortality risk (HR: 1.54, 95% CI: 1.43-1.66). CONCLUSIONS: This study indicates that ePWV is a novel prognostic indicator for predicting the risks of mortality among patients with hypertension.

Examining dynamic developmental trends: the interrelationship between age-friendly environments and healthy aging in the Chinese population-evidence from China Health and Retirement Longitudinal Study, 2011-2018.

BACKGROUND: The objective of this research is to investigate the dynamic developmental trends between Age-Friendly Environments (AFE) and healthy aging in the Chinese population. METHODS: This study focused on a sample of 11,770 participants from the CHARLS and utilized the ATHLOS Healthy Aging Index to assess the level of healthy aging among the Chinese population. Linear mixed model (LMM) was used to explore the relationship between AFE and healthy aging. Furthermore, a cross-lagged panel model (CLPM) and a random-intercept cross-lagged panel model (RI-CLPM) were used to examine the dynamic developmental trends of healthy aging, taking into account both Between-Person effects and Within-Person effects. RESULTS: The results from LMM showed a positive correlation between AFE and healthy aging (ß = 0.087, p < 0.001). There was a positive interaction between the geographic distribution and AFE (central region * AFE: ß = 0.031, p = 0.038; eastern region * AFE: ß = 0.048, p = 0.003). In CLPM and RI-CLPM, the positive effect of healthy aging on AFE is a type of Between-Person effects (ß ranges from 0.147 to 0.159, p < 0.001), while the positive effect of AFE on healthy aging is Within-Person effects (ß ranges from 0.021 to 0.024, p = 0.004). CONCLUSION: Firstly, individuals with high levels of healthy aging are more inclined to actively participate in the development of appropriate AFE compared to those with low levels of healthy aging. Furthermore, by encouraging and guiding individuals to engage in activities that contribute to building appropriate AFE, can elevate their AFE levels beyond the previous average level, thereby improving their future healthy aging levels. Lastly, addressing vulnerable groups by reducing disparities and meeting their health needs effectively is crucial for fostering healthy aging in these populations.

A fully digital workflow to design anterior guidance for an implant-supported single crown using a modified patient-specific motion technique.

Current methods for designing anterior guidance of anterior fixed prostheses are either complicated or lack accuracy. The article describes a fully digital workflow to design individualized anterior guidance of an implant-supported single crown by using a modified patient-specific motion technique. The technique aims to optimize the digital occlusal design workflow, thereby improving the occlusal fit and long-term stability of anterior fixed prostheses.

Sirtuin 2 Exerts Regulatory Functions on Radiation-Induced Myocardial Fibrosis in Mice by Mediating H3K27 Acetylation of Galectin-3 Promoter.

Background: Sirtuin 2 (SIRT2) and galectin-3 have been shown to protect the heart against fibrosis. However, their impacts on radiation-induced myocardial fibrosis (RIMF) remain to be elucidated. To deepen this understanding, the current study sought to explore the effects of SIRT2 and galectin-3 on RIMF and the underlying mechanisms. Methods: Galectin-3 knockout mice were obtained, and a radiation-induced heart damage (RIHD) mouse model was induced by local radiation exposure to the heart. Lentivirus transfection was then performed, and heart function, fibrosis of heart tissues, and levels of SIRT2, galectin-3, and fibrosis-related markers collagen type-I/-III and matrix metalloproteinase (MMP)2/MMP9 were respectively assessed by echocardiography, hematoxylin-eosin and Masson staining, reverse transcription-quantitative polymerase chain reaction, Western blot, and immunofluorescence staining. Additionally, Western blot and chromatin immunoprecipitation were used to test H3K27 acetylation levels and the binding of H3K27ac to galectin-3, respectively. Results: After radiation exposure, heart tissues from the galectin-3 knockout mice had a smaller fibrotic area compared to normal mice, with reduced expression levels of collagen type-I/-III and MMP2/MMP9. SIRT2 was down-regulated and galectin-3 was up-regulated after RIHD treatment. The histone deacetylase inhibitor sirtinol promoted galectin-3 expression and H3K27 acetylation in a time-dependent manner, and increased H3K27ac enrichment in the galectin-3 promoter. Overexpression of SIRT2 down-regulated H3K27ac, collagen type-I/-III, and MMP2/MMP9 expression levels, and reduced the fibrotic area in mouse heart tissues. However, these effects were reversed by the additional overexpression of galectin-3. Conclusions: SIRT2 facilitates deacetylation of H3K27 to inhibit galectin-3 transcription, thus ameliorating RIMF in mice.

Hierarchical Self-Assembly of Multidimensional Functional Materials from Sequence-Defined Peptoids.

Hierarchical self-assembly represents a powerful strategy for the fabrication of functional materials across various length scales. However, achieving precise formation of functional hierarchical assemblies remains a significant challenge and requires a profound understanding of molecular assembly interactions. In this study, we present a molecular-level understanding of the hierarchical assembly of sequence-defined peptoids into multidimensional functional materials, including twisted nanotube bundles serving as a highly efficient artificial light harvesting system. By employing synchrotron-based powder X-ray diffraction and analyzing single crystal structures of model compounds, we elucidated the molecular packing and mechanisms underlying the assembly of peptoids into multidimensional nanostructures. Our findings demonstrate that incorporating aromatic functional groups, such as tetraphenyl ethylene (TPE), at the termini of assembling peptoid sequences promotes the formation of twisted bundles of nanotubes and nanosheets, thus enabling the creation of a highly efficient artificial light harvesting system. This research exemplifies the potential of leveraging sequence-defined synthetic polymers to translate microscopic molecular structures into macroscopic assemblies. It holds promise for the development of functional materials with precisely controlled hierarchical structures and designed functions.

A Double Open-Shelled Au43 Nanocluster with Increased Catalytic Activity and Stability.

Atomically precise metal nanoclusters (NCs) are an intriguing class of crystalline solids with unique physicochemical properties derived from tunable structures and compositions. Most atomically precise NCs require closed-shells and coordinatively saturated surface metals in order to be stable. Herein, we report Au43(C≡CtBu)20 and Au42Ag1(C≡CtBu)20, which feature open electronic and geometric shells, leading to both paramagnetism (23 valence e-) and enhanced catalytic activity from a single coordinatively unsaturated surface metal. The Au-alkynyl surface motifs of these NCs form five helical stripes around the inner Au12 kernel, imparting chirality and high thermal stability. Density functional theory (DFT) calculations suggest that there are minimal energy differences between the open-shelled NCs and hypothetical closed-shell systems and that the open-shelled electronic configuration gives rise to the largest band gap, which is known to promote cluster stability. Furthermore, we highlight how coordinatively unsaturated surface metals create active sites for the catalytic oxidation of benzyl alcohol to benzaldehyde, leading to high selectivity and increased conversion. This work represents the first example of an atomically precise Au NC with a double open-shelled structure and provides a promising platform for investigating the magnetic and catalytic properties of noble metal nanoparticles.

Transferring and Retaining of Different Polyaniline Nanofeatures via Electrophoretic Deposition for Enhanced Sensing Performance.

Nanofeatured polyaniline (PANI) electrodes have demonstrated impressive sensing performance due to the enhanced electrolyte diffusion and ion transport. However, the retaining of these nanostructures on substrates via electrophoretic deposition (EPD) faces an insurmountable challenge from the involved dedoping process. Here, camphorsulfonic acid is utilized with high steric effects to dope PANI (PANI-CSA) that can be directly used EPD without involving a dedoping process. Five different nanofeatures (sea cucumber-like, nanofiber, amorphous, nanotube, and nanorod) are synthesized, and they have been all successfully transferred onto indium tin oxide substrate in a formic acid/acetonitrile system, namely a morphology memory effect. The mechanism of retaining these nanofeatures is revealed, which is realized via the processes of dissolution of PANI-CSA, codoping and solvation, and reassembly of basic units into the original nanofeature. The enhanced protonation level by the codoping of formic acid and solvation of acetonitrile plays the key role in retaining these nanofeatures. This method is also applicable to transfer PANI/gold nanorod composites (PANI-CSA/AuNRs). The PANI-CSA/AuNRs electrode as an ascorbic acid sensor has shown an excellent sensing performance with a sensitivity up to 872.7 µA mm-1 cm-2 and a detection limit of as low as 0.18 × 10-6 m.

Pyrene-Based Self-Assembling Peptide for Ratiometric Detection of Heparin.

Heparin is a commonly used anticoagulant in clinical practice; however, excessive heparin can cause serious adverse reactions. Convenient and accurate detection of heparin levels is thus very important. In this research, a pyrene-based self-assembling fluorescent peptide PyFFRRR was designed for simple, selective, and efficient heparin detection. The guanidine groups in the arginine residues of PyFFRRR bind tightly with heparin, which is highly sulfated, through electrostatic interactions. Charge neutralization facilitated the self-assembly of PyFFRRR, resulting in its spectral response changing from deep blue monomer fluorescence to green excimer fluorescence. PyFFRRR exhibited excellent sensitivity and selectivity for ratiometric detection of heparin. The binding mechanism was investigated by using spectral and simulation tools, and structural observation. Finally, PyFFRRR was employed in human serum samples for ratiometric detection of heparin.

Clinical and ultrasonic risk factors for high-volume central lymph node metastasis in cN0 papillary thyroid microcarcinoma: A retrospective study and meta-analysis.

OBJECTIVE: Papillary thyroid microcarcinoma (PTMC) comprises more than 50% of all newly detected cases of papillary thyroid carcinoma (PTC). High-volume lymph node metastasis (involving >5 lymph nodes) (hv-LNM) is associated with PTMC recurrence. In half of the clinically node-negative (cN0) PTMC patients, central lymph node metastasis (CLNM) is pathologically present. However, clinical risk factors for high-volume CLNM (hv-CLNM) in cN0 PTMC have not been defined well. Therefore, we aimed to obtain evidence for hv-CLNM risk factors in cN0 PTMC. DESIGN: Data on patients who visited our hospital between January 2020 and December 2021 were collected; a preoperative diagnosis of cN0 and a postoperative pathological confirmation of PTMC were obtained. After filtering by inclusion versus exclusion criteria, the obtained data (N = 2268) were included in the meta-analysis. Relevant studies published as of 10 April 2022, were identified from the Web of Science, PubMed, WANFANG, and CNKI databases. These eligible studies were included in the meta-analysis and the association between clinicopathological factors and hv-CLNM in cN0 PTMC was assessed. SPSS and MetaXL were used for statistical analyses. RESULTS: The meta-analysis included 10 previous studies (11,734 patients) and 2268 patients enroled in our hospital for a total of 14,002 subjects. The results of which suggested that younger age (<40, odds ratio [OR] = 3.28, 95% confidence interval [CI] = 2.75-3.92, p < .001 or <45 odds ratio [OR] = 2.93, 95% CI = 2.31-3.72, p < .001), male sex (OR = 2.81, 95% CI = 2.25-3.52, p < .001), tumour size >5 mm (OR = 1.85, 95% CI = 1.39-2.47, p < .001), multifocality (OR = 1.88, 95% CI = 1.56-2.26, p < .001), extrathyroidal extension (OR = 2.58, 95% CI = 2.02-3.30, p < .001), capsule invasion (OR = 2.02, 95% CI = 1.46-2.78, p < .001), microcalcification (OR = 3.25, 95% CI = 2.42-4.36, p < .001) and rich blood flow (OR = 1.65, 95% CI = 1.21-2.25, p = .002) were the significant factors related to an elevated hv-CLNM risk in cN0 PTMC patients. Hashimoto thyroiditis (OR = 0.76, 95% CI = 0.55-1.07, p = .114), irregular margin (versus regular margin, OR = 0.96, 95% CI = 0.68-1.33, p = .787) and hypoechoic (versus nonhypoechoic, OR = 1.27, 95% CI = 0.84-1.92, p = .261) showed no significant association with hv-CLNM. CONCLUSIONS: Younger age, tumour size >5 mm, males, extrathyroidal extension, multifocality, microcalcification, capsular invasion, and rich blood flow were the significant clinicopathological risk factors for hv-CLNM risk in cN0 PTMC patients. These predictors may compensate for the sensitivity of imaging diagnosis in the preoperative period, thus helping in the effective identification of PTMCs with an invasive phenotype.

Betulonic acid regulates oviduct epithelial cell inflammation through the TLR4, MAPK, and JAK/STAT signalling pathways.

CONTEXT: Infertility is a common disease among women of childbearing age and seriously endangers the reproductive health of human beings. AIMS: We aimed to study the active effect and mechanism of betulonic acid (BTA) on tubal inflammatory infertility. METHODS: An inflammatory model was established in isolated rat oviduct epithelial cells. Immunofluorescence of cytokeratin 18 was performed in cells. The therapeutic effect of BTA on cells was observed. Subsequently, we added JAK/STAT inhibitor AG490 and MAPK inhibitor U0126 and measured the levels of inflammatory factors via enzyme-linked immunosorbent assay and qRT-PCR. CCK-8 assay was applied to test cell proliferation, whereas flow cytometry was used to measure apoptosis. The levels of TLR4, IκBα, JAK1, JAK2, JAK3, Tyk2, STAT3, p38, ERK and the phosphorylation of p65 were determined by Western blotting. KEY RESULTS: Betulonic acid inhibited the activation of TLR4 and NF-κB signalling pathways, and significantly downregulated IL-1ß, IL-6, and TNF-α, with high doses being the most effective. Furthermore, high-dose BTA promoted the proliferation of oviduct epithelial cells and inhibited apoptosis. In addition, BTA inhibited the activation of JAK/STAT signalling pathway to perform effectively in oviduct epithelial cells inflammation. The addition of AG490 led to the inhibition of the JAK/STAT signalling pathway. BTA also inhibited the activation of MAPK signalling pathway in oviduct epithelial cells inflammation. Under U0126 treatment, the inhibition of proteins in MAPK pathway by BTA was weakened. CONCLUSIONS: Therefore, BTA inhibited the TLR, JAK/STAT and MAPK signalling pathways. IMPLICATIONS: Our study provided a new therapeutic strategy for infertility caused by oviduct inflammation.

An active glutamine/α-ketoglutarate/HIF-1α axis prevents pregnancy loss by triggering decidual IGF1+GDF15+NK cell differentiation.

Deficiency of decidual NK (dNK) cell number and function has been widely regarded as an important cause of spontaneous abortion. However, the metabolic mechanism underlying the crosstalk between dNK cells and embryonic trophoblasts during early pregnancy remains largely unknown. Here, we observed that enriched glutamine and activated glutaminolysis in dNK cells contribute to trophoblast invasion and embryo growth by insulin-like growth factor-1 (IGF-1) and growth differentiation factor-15 (GDF-15) secretion. Mechanistically, these processes are dependent on the downregulation of EGLN1-HIF-1α mediated by α-ketoglutarate (α-KG). Blocking glutaminolysis with the GLS inhibitor BPTES or the glutamate dehydrogenase inhibitor EGCG leads to early embryo implantation failure, spontaneous abortion and/or fetal growth restriction in pregnant mice with impaired trophoblast invasion. Additionally, α-KG supplementation significantly alleviated pregnancy loss mediated by defective glutaminolysis in vivo, suggesting that inactivated glutamine/α-ketoglutarate metabolism in dNK cells impaired trophoblast invasion and induced pregnancy loss.

Thioredoxin Reductase 2 Synergizes with Cytochrome c, Somatic to Alleviate Doxorubicin-Induced Oxidative Stress in Cardiomyocytes and Mouse Myocardium.

Doxorubicin (DOX) may cause multiple side effects, which include cardiotoxicity. Hence, to ascertain the impact of thioredoxin reductase 2 (TXNRD2) and cytochrome c, somatic (CYCS) on DOX-induced oxidative stress (OS) in cardiomyocytes and mouse myocardium, this study was implemented. DOX was utilized to treat cardiomyocytes and mice, and TXNRD2 and CYCS expression in cell supernatant and mouse myocardial tissues was detected. TXNRD2 and/or CYCS were overexpressed in DOX-induced cardiomyocytes and mice. In cardiomyocytes, cell viability and the levels of reactive oxygen species (ROS), superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA), and glutathione (GSH) were measured. In mice, pathologic changes of the heart, ejection fraction (EF), fractional shortening (FS), and heart weight (HW) /tibial length (TL) ratio, and the contents of lactic dehydrogenase (LDH), creatine kinase-MB (CK-MB), and cardiac troponin I (cTnI) were analyzed. To assess the binding between TXNRD2 and CYCS, coimmunoprecipitation and glutathione S-transferase pull-down assays were performed. TXNRD2 and CYCS were downregulated in DOX-treated cardiomyocytes and mice. Mechanistically, TXNRD2 interacted with CYCS. Overexpression of TXNRD2 or CYCS augmented viability and SOD, CAT, and GSH levels but reduced ROS and MDA contents in DOX-induced cardiomyocytes, which was further facilitated by simultaneous overexpression of TXNRD2 or CYCS. Moreover, TXNRD2 or CYCS upregulation improved the pathologic changes in myocardial tissues, along with increases in EF, FS, and HW/TL ratio of the heart and SOD, CAT, and GSH levels and decreases in LDH, CK-MB, cTnI, ROS, and MDA levels. TXNRD2 coordinated with CYCS to alleviate DOX-induced OS in cardiomyocytes and mouse myocardium.

Downregulation of MicroRNA-29-3p Following Percutaneous Coronary Intervention: An Implication of YY1/IRAK1 Pathway in the Post-Vascular Injury Inflammation.

This study explored the expression of microRNA (miR)-29b-3p following percutaneous coronary intervention (PCI) and the implication of its downstream Yin Yang 1 (YY1)/interleukin (IL)-1 receptor-associated kinase 1 (IRAK1) pathway in post-vascular injury inflammation. Blood samples were collected for analysis of plasma miR-29b-3p from patients with acute coronary syndrome before surgery, 1 day after PCI, and 30 days after PCI. Lipopolysaccharide (LPS)-treated human coronary artery endothelial cells (HCAECs) were transfected with miR-29b-3p mimic/inhibitor or YY1 shRNA and underwent viability tests. Enzyme-linked immunosorbent assay was performed to detect the levels of soluble vascular cell adhesion molecule-1 (sVCAM-1), IL-1ß, IL-6, and tumor necrosis factor (TNF)-α in serum and cell culture supernatant. Dual-luciferase reporter and RNA/chromatin immunoprecipitation were used to confirm the targeting relationships among miR-29b-3p, YY1, and IRAK1. A rat model of intraluminal injury of the common femoral artery was established to address the role of miR-29b-3p and relevant mechanisms. miR-29b-3p was lowly expressed, and sVCAM-1, IL-1ß, IL-6, and TNF-α were upregulated 1 day after PCI and 24 h after LPS treatment. miR-29b-3p overexpression or YY1 knockdown alleviated LPS-induced inflammatory responses and improved the viability of HCAECs. miR-29b-3p inhibition aggravated LPS-induced inflammatory injury in HCAECs. miR-29b-3p bound to YY1 mRNA and inhibited the expression of YY1 protein. YY1 bound to the IRAK1 promoter and activated the transcription of IRAK1. Upregulation of miR-29b-3p suppressed the inflammatory response after intraluminal injury of the common femoral artery in rats. In conclusion, dysregulation of the YY1/IRAK1 pathway via miR-29b-3p downregulation may be implicated in post-vascular injury inflammation.