Type 1 diabetes, its complications, and non-ischemic cardiomyopathy: a mendelian randomization study of European ancestry.

BACKGROUND: Type 1 diabetes (T1D) is a significant risk factor for a range of cardiovascular diseases. Nonetheless, the causal relationship between T1D and non-ischemic cardiomyopathy (NICM) remains to be elucidated. Furthermore, the mechanisms responsible for the progression from T1D to NICM have not been definitively characterized. OBJECTIVE: The aim of this study was to conduct a Mendelian randomization (MR) study to investigate the causal effects of T1D and its complications on the development of NICM. Additionally, this study aimed to conduct a mediation analysis to identify potential mediators within this correlation. METHODS: Genetic variants were used as instrumental variables for T1D. The summary data for T1D were obtained from two genome-wide association study datasets. The summary data for T1D with complications and NICM were obtained from the Finnish database. Two-sample MR, multivariable MR and mediation MR were conducted in this study. RESULTS: The study revealed a causal association between T1D, T1D with complications, and NICM (with odds ratios of 1.02, 95% CI 1.01-1.04, p = 1.17e-04 and 1.03, 95% CI 1.01-1.05, p = 3.15e-3). Even after adjusting for confounding factors such as body mass index and hypertension, T1D remained statistically significant (with odds ratio of 1.02, 95% CI 1.01-1.04, p = 1.35e-4). Mediation analysis indicated that monokine induced by gamma interferon may play a mediating role in the pathogenesis of T1D-NICM (mediation effect indicated by odds ratio of 1.005, 95% CI 1.001-1.01, p = 4.9e-2). CONCLUSION: The study demonstrates a causal relationship between T1D, its complications, and NICM. Additionally, monokine induced by gamma interferon may act as a potential mediator in the pathogenesis of T1D-NICM.

Proteomic Characterization of Peritoneal Extracellular Vesicles in a Mouse Model of Peritoneal Fibrosis.

Peritoneal fibrosis progression is regarded as a significant cause of the loss of peritoneal function, markedly limiting the application of peritoneal dialysis (PD). However, the pathogenesis of peritoneal fibrosis remains to be elucidated. Tissue-derived extracellular vesicles (EVs) change their molecular cargos to adapt the environment alteration, mediating intercellular communications and play a significant role in organ fibrosis. Hence, we performed, for the first time, four-dimensional label-free quantitative liquid chromatography-tandem mass spectrometry proteomic analyses on EVs from normal peritoneal tissues and PD-induced fibrotic peritoneum in mice. We demonstrated the alterations of EV concentration and protein composition between normal control and PD groups. A total of 2339 proteins containing 967 differentially expressed proteins were identified. Notably, upregulated proteins in PD EVs were enriched in processes including response to wounding and leukocyte migration, which participated in the development of fibrosis. In addition, EV proteins of the PD group exhibited unique metabolic signature compared with those of the control group. The glycolysis-related proteins increased in PD EVs, while oxidative phosphorylation and fatty acid metabolism-related proteins decreased. We also evaluated the effect of cell-type specificity on EV proteins, suggesting that mesothelial cells mainly cause the alterations in the molecular composition of EVs. Our study provided a useful resource for further validation of the key regulator or therapeutic target of peritoneal fibrosis.

Nickel-Catalyzed Regio- and Enantioselective Borylative Coupling of Terminal Alkenes with Alkyl Halides Enabled by an Anionic Bisoxazoline Ligand.

Chiral boronic esters are a class of versatile building blocks. We describe herein an asymmetric nickel-catalyzed borylative coupling of terminal alkenes with nonactivated alkyl halides. The success of this asymmetric reaction is ascribed to the application of a chiral anionic bisoxazoline ligand. This study provides a three-component strategy to access α- and ß-stereogenic boronic esters from easily accessible starting materials. This protocol is characterized by mild reaction conditions, wide substrate scope and high regio- and enantioselectivity. We also showcase the value of this method in simplifying the synthesis of several drug molecules. Mechanistic studies suggest that the generation of enantioenriched boronic esters bearing an α-stereogenic center results from a stereoconvergent process, while the enantioselectivity-controlling step in the generation of boronic esters with a ß-stereocenter is switched to the olefin migratory insertion step due to coordination of an ester group.

Sodium-glucose cotransporter 2 inhibitor may not prevent atrial fibrillation in patients with heart failure: a systematic review.

BACKGROUND: Atrial fibrillation (AF) and heart failure (HF) frequently coexist because of their similar pathological basis. However, whether sodium-glucose cotransporter 2 inhibitor (SGLT2i), a novel class of anti-HF medication, decreases the risk of AF in HF patients remains unclear. OBJECTIVES: The aim of this study was to assess the relationship between SGLT2i and AF in HF patients. METHODS: A meta-analysis of randomized controlled trails evaluating the effects of SGLT2i on AF in HF patients was performed. PubMed and ClinicalTrails.gov were searched for eligible studies until 27 November 2022. The risk of bias and quality of evidence were assessed through the Cochrane tool. Pooled risk ratio of AF for SGLT2i versus placebo in eligible studies was calculated. RESULTS: A total of 10 eligible RCTs examining 16,579 patients were included in the analysis. AF events occurred in 4.20% (348/8292) patients treated with SGLT2i, and in 4.57% (379/8287) patients treated with placebo. Meta-analysis showed that SGLT2i did not significantly reduce the risk of AF (RR 0.92; 95% CI 0.80-1.06; p = 0.23) in HF patients when compared to placebo. Similar results remained in the subgroup analyses, regardless of the type of SGLT2i, the type of HF, and the duration of follow-up. CONCLUSIONS: Current evidences showed that SGLT2i may have no preventive effects on the risk of AF in patients with HF. TRANSLATIONAL PERSPECTIVE: Despite HF being one of the most common heart diseases and conferring increased risk for AF, affective prevention of AF in HF patients is still unresolved. The present meta-analysis demonstrated that SGLT2i may have no preventive effects on reducing AF in patients with HF. How to effectively prevent and early detect the occurrence of AF is worth discussing.

The increase of Nrf2 m6A modification induced by FTO downregulation promotes hippocampal neuron injury and aggravates the progression of epilepsy in a rat model.

Epilepsy is a common chronic neurological disorder characterized by widespread neuronal death. The purpose of this study was to investigate the role of nuclear factor erythroid 2-related factor 2 (Nrf2) m6A methylation in epilepsy. To create epileptic models, the rats were given Lithium chloride and pilocarpine, and isolated primary rat hippocampal neurons were cultured in an Mg2+ -free medium. The frequency of seizures was recorded in the epilepsy group of rats. The functional tests included TUNEL, MTT, and flow cytometry. Mechanistically, RNA degradation assay, RNA immunoprecipitation, and methylated RNA immunoprecipitation were performed. In epileptic models, Nrf2 and fat mass and obesity-associated (FTO) levels were downregulated, whereas YT521-B homology (YTH) domain family protein 2 (YTHDF2) was upregulated. Additionally, in epileptic models, there was a rise in the m6A methylation level of Nrf2 mRNA. Overexpressing FTO increased cell viability and reduced apoptosis, but Nrf2 interference reversed these effects. Meanwhile, FTO overexpression decreased the m6A methylation of Nrf2 mRNA. Moreover, YTHDF2 bound to Nrf2 mRNA and decreased its stability. Furthermore, FTO overexpression reduced seizure frequency in rats and inhibited hippocampal neuron apoptosis via lowering the m6A methylation level of Nrf2 mRNA. Overexpressing FTO reduced m6A methylation of Nrf2 mRNA, increased cell viability, suppressed apoptosis, and slowed the progression of epileptic diseases, which is linked to YTHDF2 binding to m6A-modified Nrf2 and promoting its degradation, as well as downregulating Nrf2 expression in hippocampal neurons.

Design and synthesis of novel anti-multidrug-resistant staphylococcus aureus derivatives of glycyrrhetinic acid by blocking arginine biosynthesis, metabolic and H2S biogenesis.

With the soaring number of multidrug-resistant bacteria, it is imperative to develop novel efficient antibacterial agents and discovery new antibacterial pathways. Herein, we designed and synthesized a series of structurally novel glycyrrhetinic acid (GA) derivatives against multidrug-resistant Staphylococcus aureus (MRSA). The in vitro antibacterial activity of these compounds was evaluated using the microbroth dilution method, agar plate coating experiments and real-time growth curves, respectively. Most of the target derivatives showed moderate antibacterial activity against Staphylococcus aureus (S. aureus) and MRSA (MIC = 3.125-25 µM), but inactivity against Escherichia coli (E. Coli) and Pseudomonas aeruginosa (P. aeruginosa) (MIC > 200 µM). Among them, compound 11 had the strongest antibacterial activity against MRSA, with an MIC value of 3.125 µM, which was 32 times and 64 times than the first-line antibiotics penicillin and norfloxacin, respectively. Additionally, transcriptomic (RNA-seq) and quantitative polymerase chain reaction (qPCR) analysis revealed that the antibacterial mechanism of compound 11 was through blocking the arginine biosynthesis and metabolic and the H2S biogenesis. Importantly, compound 11 was confirmed to have good biocompatibility through the in vitro hemolysis tests, cytotoxicity assays and the in vivo quail chicken chorioallantoic membrane (qCAM) experiments. Current study provided new potential antibacterial candidates from glycyrrhetinic acid derivatives for clinical treatment of MRSA infections.

Naturally occurring anti-PP1PK in a Chinese individual with p phenotype: A case based on compound heterozygosity including one novel allele.

BACKGROUND: The null phenotype in P1PK blood group, known as "p," is extremely rare in the whole world. Individuals of p phenotype spontaneously form anti-PP1PK isoantibody. Here, we report a case of p phenotype with naturally occurring anti-PP1PK isoantibodies in a Chinese individual. STUDY DESIGN AND METHODS: Serology tests, containing alloantibodies screening and identification, were conducted to demonstrate the phenotype in P1PK blood group. The genotype of A4GALT gene was identified by haplotypes separation and sequencing. RESULTS: The serological assay demonstrated the p phenotype of the proband, presenting with 1:64 titer of anti-PP1PK . The sequencing data revealed a compound heterozygote consisting of A4GALT*P1.01 with c.343A>T and a novel allele based on A4GALT*01N.05 with an addition polymorphism c.100G>A. The sequence of the novel allele has been submitted to GenBank and the accession number OM912503 was assigned. CONCLUSION: Our study demonstrates a case of naturally occurring anti-PP1Pk in a Chinese individual with p phenotype, which is based on compound heterozygosity including one novel allele. As the proband is a young lady, monitoring the titer of anti-PP1PK and early initiation of medical intervention are essential after her pregnancy.

Phase Behavior of Internal Mixtures of Hydrocarbon-like Primary Organic Aerosol and Secondary Aerosol Based on Their Differences in Oxygen-to-Carbon Ratios.

The phase behavior, the number and type of phases, in atmospheric particles containing mixtures of hydrocarbon-like organic aerosol (HOA) and secondary organic aerosol (SOA) is important for predicting their impacts on air pollution, human health, and climate. Using a solvatochromic dye and fluorescence microscopy, we determined the phase behavior of 11 HOA proxies (O/C = 0-0.29) each mixed with 7 different SOA materials generated in environmental chambers (O/C 0.4-1.08), where O/C represents the average oxygen-to-carbon atomic ratio. Out of the 77 different HOA + SOA mixtures studied, we observed two phases in 88% of the cases. The phase behavior was independent of relative humidity over the range between 90% and <5%. A clear trend was observed between the number of phases and the difference between the average O/C ratios of the HOA and SOA components (ΔO/C). Using a threshold ΔO/C of 0.265, we were able to predict the phase behavior of 92% of the HOA + SOA mixtures studied here, with one-phase particles predicted for ΔO/C < 0.265 and two-phase particles predicted for ΔO/C ≥ 0.265. The threshold ΔO/C value provides a relatively simple and computationally inexpensive framework for predicting the number of phases in internal SOA and HOA mixtures in atmospheric models.

Synthesis and biological activity evaluation of podophyllotoxin-linked bile acid derivatives as potential anti-liver cancer agents.

Podophyllotoxin's undifferentiated cytotoxicity and poor selectivity limit its clinical application. To improve above disadvantages, conjugation of bile acids with podophyllotoxin could improve cell line selectivity of liver cancer to achieve clinical translation further. Enlightened by the bile acids' moiety magic characters, thirty podophyllotoxin-linked bile acid derivatives had been designed and synthesized. The cytotoxicity of these compounds in vitro was evaluated on HepG2, HCT-116, A549 and MDCK cell lines. After conjunction with bile acids, most of the derivatives (IC50 = 0.066-0.831 µM) were more potent against above three types of tumor cells than Etoposide (VP-16, IC50 = 4.319-41.080 µM) and exhibited similar antitumor activity compared with doxorubicin (DOX, IC50 = 0.230-0.745 µM). Moreover, structure-activity relationship displayed the length of the linker chain between podophyllotoxin and bile acids affected the cytotoxicity. Especially, compound 23 exhibited strong activity against HepG2 cell lines (IC50 = 0.188 ± 0.01 µM) than MDCK cell lines (IC50 = 4.780 ± 0.50 µM) and its SI (IC50MDCK/IC50HepG2) value of compound 23 was 25.4. Further antitumor mechanism studies showed that compound 23 acted as Topo Ⅱ inhibition and induced cell apoptosis with S cell cycle arrest. In particular, compound 23 showed valid antitumor efficacy at 10 mg/kg by intraperitoneal administration with a tumor inhibition rate of 60.9% in the Hepa1-6 xenograft mice model. The current research displayed that introduction of bile acids contributed to improve selectivity and activity to cell, and compound 23 could be a promising anti-tumor candidate.

Monocyte to High-Density Lipoprotein Cholesterol Ratio Is Associated with Subclinical Left Cardiac Remodeling and Dysfunction in Type 2 Diabetes Mellitus.

Chronic inflammation is involved in the development of heart failure (HF) in type 2 diabetes mellitus (T2DM). However, reliable and easily accessible biomarker of subclinical left cardiac remodeling and dysfunction remains a challenge.Overall, 1020 patients with T2DM without overt HF were enrolled from May 2019 to April 2020. Monocyte to high-density lipoprotein ratio (MHR) was calculated by blood monocyte count divided by high-density lipoprotein cholesterol. Left cardiac structure and function were assessed using transthoracic echocardiography. Univariate and multivariate linear regression analyses were used to estimate the association of MHR (Lg transferred) with echocardiographic parameters. We found that septal wall thickness (SWT), left ventricular internal end-diastole dimension (LVIDd), and left ventricular mass index (LVMI) raised with increasing MHR (P = 0.002 for SWT, P < 0.001 for LVIDd, and P = 0.001 for LVMI). Declined trends were shown in ejection fraction (EF) (P = 0.016), E velocity (P = 0.037), E/A ratio (P = 0.009), and tissue Doppler e' (P < 0.001), and elevating trend was observed in E/e' (P < 0.001). In multivariate regression analysis, MHR (Lg transferred) was positively associated with LVIDd (ß = 0.031; P = 0.016), LVMI (ß = 0.073; P = 0.014), and E/e' (ß = 0.331; P < 0.001), whereas it was negatively associated with EF (ß = -0.086; P = 0.007), E/A (ß = -0.072; P = 0.009), and e' (ß = -0.332; P < 0.001).MHR could be a practical biomarker for indicating subclinical cardiac remodeling and dysfunction in T2DM, due to low cost and easy availability.

[Material basis of Rhei Radix et Rhizoma-Coptidis Rhizoma combination in alleviating "bitter-cold" properties based on supramolecular chemistry of Chinese medicine].

The present study aimed to explore the material basis of Rhei Radix et Rhizoma-Coptidis Rhizoma combination in alleviating "bitter-cold" properties based on the supramolecular chemistry of Chinese medicine.Dynamic light scattering and scanning/transmission electron microscopy were used to characterize the morphological characteristics of supramolecules in the decoction of Rhei Radix et Rhizoma and Coptidis Rhizoma.The chemical composition of supramolecules, as well as the dissolution and release processes of supramolecules and the medicinal components of Coptidis Rhizoma decoction, was determined by the high-performance liquid chromatography-mass spectrometry.The differences in "bitter-cold" medicinal properties between Rhei Radix et Rhizoma decoction, Coptidis Rhizoma decoction, and co-decoction were analyzed by sensory evaluation, electronic tongue, mouse diarrhea model, and pathological indicators.The anthraquinones/tannins and alkaloids interacted to form supramolecules with a scale of about 400 nm when Rhei Radix et Rhizoma and Coptidis Rhizoma were decocted together, which delayed the dissolution and release of the active components represented by berberine. Compared with the consequence of single drug administration at 4 g·kg~(-1), the combination of the two drugs at 8 g·kg~(-1) significantly alleviated the "bitter-cold" properties.The effective components interacted to form supramolecules in the co-decoction of Rhei Radix et Rhizoma and Coptidis Rhizoma, which affected the dissolution and release of the effective components of Chinese medicinal decoction, thereby alleviating the "bitter-cold" properties.The findings of this study provide a new idea for revealing the scientific compatibility of Rhei Radix et Rhizoma and Coptidis Rhizoma.

Hybrid Genome Assembly and Gene Repertoire of the Root Endophyte Clitopilus hobsonii QYL-10 (Entolomataceae, Agaricales, Basidiomycetes).

Clitopilus hobsonii (Entolomataceae, Agaricales, Basidiomycetes) is a common soil saprotroph. There is also evidence that C. hobsonii can act as a root endophyte benefitting tree growth. Here, we report the genome assembly of C. hobsonii QYL-10, isolated from ectomycorrhizal root tips of Quercus lyrata. The genome size is 36.93 Mb, consisting of 13 contigs (N50 = 3.3 Mb) with 49.2% GC content. Of them, 10 contigs approached the length of intact chromosomes, and three had telomeres at one end only. BUSCO analysis reported a completeness score of 98.4%, using Basidiomycota_odb10 lineage data. Combining ab-initio, RNA-seq data, and homology-based predictions, we identified 12,710 protein-coding genes. Approximately, 1.43 Mb of transposable elements (3.88% of the assembly), 36 secondary metabolite biosynthetic gene clusters, and 361 genes encoding putative carbohydrate-active enzymes were identified. This genomic resource will allow functional studies aimed to characterize the symbiotic interactions between C. hobsonii and its host trees and will also provide a valuable foundation for further research on comparative genomics of the Entolomataceae.[Formula: see text] Copyright © 2021 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.

Hepatocyte TNF Receptor-Associated Factor 6 Aggravates Hepatic Inflammation and Fibrosis by Promoting Lysine 6-Linked Polyubiquitination of Apoptosis Signal-Regulating Kinase 1.

Activation of apoptosis signal-regulating kinase 1 (ASK1) is a key driving force of the progression of nonalcoholic steatohepatitis (NASH) and represents an attractive therapeutic target for NASH treatment. However, the molecular and cellular mechanisms underlying ASK1 activation in the pathogenesis of NASH remain incompletely understood. In this study, our data unequivocally indicated that hyperactivated ASK1 in hepatocytes is a potent inducer of hepatic stellate cell (HSC) activation by promoting the production of hepatocyte-derived factors. Our previous serial studies have shown that the ubiquitination system plays a key role in regulating ASK1 activity during NASH progression. Here, we further demonstrated that tumor necrosis factor receptor-associated factor 6 (TRAF6) promotes lysine 6 (Lys6)-linked polyubiquitination and subsequent activation of ASK1 to trigger the release of robust proinflammatory and profibrotic factors in hepatocytes, which, in turn, drive HSC activation and hepatic fibrosis. Consistent with the in vitro findings, diet-induced liver inflammation and fibrosis were substantially attenuated in Traf6+/- mice, whereas hepatic TRAF6 overexpression exacerbated these abnormalities. Mechanistically, Lys6-linked ubiquitination of ASK1 by TRAF6 facilitates the dissociation of thioredoxin from ASK1 and N-terminal dimerization of ASK1, resulting in the boosted activation of ASK1-c-Jun N-terminal kinase 1/2 (JNK1/2)-mitogen-activated protein kinase 14(p38) signaling cascade in hepatocytes. Conclusion: These results suggest that Lys6-linked polyubiquitination of ASK1 by TRAF6 represents a mechanism underlying ASK1 activation in hepatocytes and a key driving force of proinflammatory and profibrogenic responses in NASH. Thus, inhibiting Lys6-linked polyubiquitination of ASK1 may serve as a potential therapeutic target for NASH treatment.

Facultative symbiosis with a saprotrophic soil fungus promotes potassium uptake in American sweetgum trees.

Several species of soil free-living saprotrophs can sometimes establish biotrophic symbiosis with plants, but the basic biology of this association remains largely unknown. Here, we investigate the symbiotic interaction between a common soil saprotroph, Clitopilus hobsonii (Agaricomycetes), and the American sweetgum (Liquidambar styraciflua). The colonized root cortical cells were found to contain numerous microsclerotia-like structures. Fungal colonization led to increased plant growth and facilitated potassium uptake, particularly under potassium limitation (0.05 mM K+ ). The expression of plant genes related to potassium uptake was not altered by the symbiosis, but colonized roots contained the transcripts of three fungal genes with homology to K+ transporters (ACU and HAK) and channel (SKC). Heterologously expressed ChACU and ChSKC restored the growth of a yeast K+ -uptake-defective mutant. Upregulation of ChACU transcript under low K+ conditions (0 and 0.05 mM K+ ) compared to control (5 mM K+ ) was demonstrated in planta and in vitro. Colonized plants displayed a larger accumulation of soluble sugars under 0.05 mM K+ than non-colonized plants. The present study suggests reciprocal benefits of this novel tree-fungus symbiosis under potassium limitation mainly through an exchange of additional carbon and potassium between both partners.

Terahertz coded-aperture imaging for moving targets based on an incoherent detection array.

Terahertz coded-aperture imaging relies on sequential coding and sampling. Its capturing speed is limited by the switching rate of the coded-aperture antenna; therefore, it is not suitable for capturing moving targets. In this paper, we focus on imaging for moving targets using the terahertz coded-aperture imaging technique. An incoherent detection array is adopted to replace sequential sampling by spatial sampling, therefore improving the capturing speed significantly. Then, a signal processing method based on phase retrieval and image enhancement is proposed to reconstruct targets with improved quality. Numerical experimental results verify the effectiveness of the method.

SLC17A3 rs9379800 and Ischemic Stroke Susceptibility at the Northern Region of Malaysia.

OBJECTIVES: The relationships of Paired Like Homeodomain 2 (PITX2), Ninjurin 2 (NINJ2), TWIST-Related Protein 1 (TWIST1), Ras Interacting Protein 1 (Rasip1), Solute Carrier Family 17 Member 3 (SLC17A3), Methylmalonyl Co-A Mutase (MUT) and Fer3 Like BHLH Transcription Factor (FERD3L) polymorphisms and gene expression with ischemic stroke have yet to be determined in Malaysia. Hence, this study aimed to explore the associations of single nucleotide polymorphisms (SNPs) and gene expression with ischemic stroke risk among population who resided at the Northern region of Malaysia. MATERIALS AND METHODS: Study subjects including 216 ischemic stroke patients and 203 healthy controls were recruited upon obtaining ethical clearance. SNP genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism assays. Gene expression levels were quantified by real-time polymerase chain reaction assays. Statistical and genetic analyses were conducted with SPSS version 22.2, PLINK version 1.07 and multifactor dimensionality reduction software. RESULTS: Study subjects with G allele, CG or GG genotypes of SLC17A3 rs9379800 demonstrated increased risk of ischemic stroke with the odds ratios ranging from 1.76-fold to 3.14-fold (p<0.05). When stratified study subjects according to the ethnicity, SLC17A3 rs9379800 G allele and CG genotype contributed to 2.14- and 2.96-fold of ischemic stroke risk among Malay population significantly, in the multivariate analysis (p<0.05). However, no significant associations were observed for PITX2, NINJ2, TWIST1, Rasip1, and MUT polymorphisms with ischemic stroke risk in the multivariate analysis for the pooled cases and controls as well as when stratified them according to the ethnicity. Lower mRNA expression levels of Rasip1, SLC17A3, MUT and FERD3L were observed among cases (p<0.05). After FDR adjustment, the mRNA level of SLC17A3 remained significantly associated with ischemic stroke among Malay population (q=0.034). CONCLUSION: In conclusion, this study suggests that SLC17A3 rs9379800 polymorphism and its gene expression contribute to significant ischemic stroke risk among Malaysian population, particularly the Malay who resided at the Northern Region of the country. Our findings can provide useful information for the future diagnosis, management and treatment of ischemic stroke patients.

Inhaled Beta2-Agonists Increase In-Hospital Mortality in ICU Patients with Heart Failure.

The impact of beta2-agonists (B2As) on heart failure (HF) remains controversial. This study aimed to investigate whether inhaled B2As increased in-hospital mortality in ICU patients with HF.The Multiparameter Intelligent Monitoring in Intensive Care III database was initially searched to identify adult patients (≥ 18 years old) with HF in ICU. Then, patients using or not using inhaled B2As were matched using propensity score matching on a 1:1 basis to control for baseline confounders. In-hospital mortality was compared between the two groups, and logistic regression analysis was performed to assess the association between B2As and in-hospital mortality.The initial search retrieved 2345 eligible patients with HF from the database. After propensity score matching, 705 pairs of patients were included in the final analysis. Patients using B2As had markedly higher in-hospital mortality than those not using B2As (4.68% versus 2.27%; P = 0.013). In the multivariate logistic regression analysis, B2A use (odd ratios (OR), 2.471; 95% confidence interval (CI), 1.289-4.734; P = 0.006), stroke (OR, 4.581; 95% CI, 1.621-12.948; P = 0.004), and simplified acute physiology score II (SAPS-II) scores (OR, 1.090; 95% CI, 1.064-1.116; P < 0.001) were significantly associated with increased risk of in-hospital mortality, whereas renin angiotensin system inhibitor use (OR, 0.396; 95% CI, 0.202-0.778; P = 0.007) was significantly associated with decreased risk of in-hospital mortality. Subgroup analysis further indicated that the association between B2A use and mortality was significant only in patients with HF without chronic pulmonary disease (OR, 2.427; 95% CI, 1.351-4.362; P = 0.003), but not in those with chronic pulmonary disease (OR, 2.094; 95% CI, 0.582-7.537; P = 0.258).In ICU patients with HF but without chronic pulmonary disease, the use of inhaled B2As is associated with increased in-hospital mortality.

[Explore antioxidant quality markers of Hippophae tibetana based on "dry-method + wet-method" technology].

The cross combination of dry-method(network pharmacology analysis) and wet-method(high-resolution mass spectro-metry with antioxidation experiment) was used to predict antioxidant quality markers(Q-markers) of Hippophae tibetana. Ultra-high performance liquid chromatography coupled with hybrid quadrupole-orbitrap mass spectrometry(UPLC-Q-Exactive Orbitrap-MS) was developed to rapidly separate and identify the chemical constituents in H. tibetana. Then in DPPH free radicals and superoxide anion scavenging experiment, the antioxidant activity of the four different polar parts with extracts of petroleumether, ethyl acetate, n-butanol and water was evaluated. Network pharmacology method was used for functional enrichment and pathway analysis to screen antioxidant-related components and preliminarily explain the mechanism of action. On this basis, multi-source information was integrated to predict the antioxidant Q-markers. The results showed that 51 components in H. tibetana were identified, including 18 flavonoids, 14 terpenoids, 6 alkaloids, 4 coumarins and phenylpropanoids, 3 volatile components and 2 polyphenols. The antioxidant capacity of different fractions: ethyl acetate > n-butanol > water > petroleum ether. The medicine mainly acted on PI3 K-Akt and FoxO signaling pathways to perform antioxidant effects through flavonoids such as quercetin, luteolin and kaempferol. According to the results of dry-method and wet-method, quercetin, luteolin and kaempferol, the representatives of poly-hydroxy flavone, may be the antioxidant Q-markers of H. tibetana. In this study, with the antioxidant Q-markers of H. tibetana as an example, an investigation model of predicting Q-marker was discussed based on the ternary system of composition, function and informatics, providing a scientific basis for the establishment of quality evaluation standards for H. tibetana.

Impact of long-term glucose variability on coronary atherosclerosis progression in patients with type 2 diabetes: a 2.3 year follow-up study.

BACKGROUND: Glycemic variability (GV) confers a risk of cardiovascular events. In this study, we aimed to investigate whether long-term GV has an impact on coronary atherosclerosis progression in patients with type 2 diabetes mellitus (T2DM). METHODS: A total of 396 patients with T2DM who had coronary computed tomography angiography and laboratory data available at baseline and for follow-up evaluations [median 2.3 (1.8-3.1) years] were included. Fasting plasma glucose (FPG) was measured every 1-3 months, and HbA1c was measured quarterly. The coefficient of variation (CV) of HbA1c and FPG were calculated as measures of GV. Quantitative assessment of coronary plaques was performed by measuring the annual change and progression rate of total plaque volume (TPV). Significant progression was defined as annual TPV progression ≥ 15%. Multivariable regression analyses were used to assess the effects of GV on atherosclerosis progression. RESULTS: In the 396 patients, the annual change in TPV was 12.35 ± 14.23 mm3, and annual progression rate was 13.36 ± 12.69%. There were 143 (36.11%) patients with significant progression, and they had a significantly higher CV-HbA1c (P < 0.001) and CV-FPG (P < 0.001) than those without significant progression. In multivariable regression analyses, both CV-HbA1c and CV-FPG were independent predictors of annual change in TPV [CV-HbA1c: ß = 0.241 (0.019-0.462), P = 0.034; CV-FPG: ß = 0.265 (0.060-0.465), P = 0.012], annual TPV progression [CV-HbA1c: ß = 0.214 (0.023-0.405), P = 0.029; CV-FPG: ß = 0.218 (0.037-0.399), P = 0.019], and significant atherosclerosis progression [CV-HbA1c: odds ratio [OR] = 1.367 (1.149-1.650), P = 0.010; CV-FPG: OR = 1.321 (1.127-1.634), P = 0.013]. CONCLUSIONS: Long-term GV is associated with accelerated progression of coronary atherosclerosis independent of conventional risk factors in patients with T2DM. Trial registration ClinicalTrials.gov (NCT02587741), October 27, 2015; retrospectively registered.

Renin-Angiotensin System Inhibitors for the Prevention of Atrial Fibrillation Recurrence After Ablation　- A Meta-Analysis.

BACKGROUND: Atrial fibrillation (AF) recurrence remains a tricky problem in patients undergoing ablation. This meta-analysis aimed to summarize the current literature to clarify whether renin-angiotensin system inhibitors (RASIs) prevent AF recurrence after ablation.Methods and Results:Relevant studies were searched on Pubmed and EMBASE through December 2019. Pooled relative risk (RR) of AF recurrence was calculated. Subgroup analyses according to study design, race, and follow-up duration were further performed. A total of 15 studies examining 4,300 patients were included, with 3 randomized controlled trials and 12 cohort studies. Overall analysis showed that RASIs significantly reduced AF recurrence after ablation (RR=0.83; 95% confidence interval (CI) 0.70-0.98, P=0.028; I2=68.9%). Subgroup analysis further indicated that positive results were found in randomized controlled trials (RR=0.51, 95% CI 0.37-0.70, P<0.001; I2=4%), studies conducted in Asia (RR=0.59, 95% CI 0.46-0.76, P<0.001; I2=30.7%), and studies with follow-up duration ≥1 year (RR=0.82, 95% CI 0.70-0.95, P=0.01; I2=59.1%); negative results were found in cohort studies, studies conducted in Europe or the USA, and studies with follow-up duration <1 year. CONCLUSIONS: RASIs can potentially prevent AF recurrence after ablation under selected conditions. However, more studies are required to confirm this finding due to the variation in current evidence.