The association between triglyceride glucose-body mass index and all-cause mortality in critically ill patients with atrial fibrillation: a retrospective study from MIMIC-IV database.

BACKGROUND: The TyG-BMI index, which is a reliable indicator of insulin resistance (IR), has been found to have a significant correlation with the occurrence of cardiovascular events. However, there still lacks study on the TyG-BMI index and prognosis in patients with atrial fibrillation (AF). The objective of the present study was to evaluate the relationship between TyG-BMI index at admission to ICU and all-cause mortality in critically ill patients with AF. METHODS: The patient's data were extracted from Medical Information Mart for Intensive Care IV(MIMIC-IV) database. All patients were divided into four groups according to TyG-BMI index. Outcomes include primary and secondary endpoints, with the primary endpoint being the 30-day and 365-day all-cause mortality and the secondary endpoint being the 90-day and 180-day all-cause mortality. TyG-BMI index was quartile and Kaplan-Meier curve was used to compare the outcome of each group. Cox proportional-hazards regression model and restricted cubic splines (RCS) were conducted to assess the relationship between TyG-BMI index and outcomes. RESULTS: Out of a total of 2509 participants, the average age was 73.26 ± 11.87 years, with 1555 (62.0%) being males. Patients with lower level of TyG-BMI had higher risk of 30-day, 90-day, 180-day and 365-day all-cause mortality, according to the Kaplan-Meier curves (log-rank P < 0.001). In addition, cox proportional-hazards regression analysis revealed that the risk of 30-day, 90-day, 180-day and 365-day all-cause mortality was significantly higher in the lowest quartile of TyG-BMI. Meanwhile, the RCS analysis indicated that L-typed relationships between TyG-BMI index and all-cause mortality, with inflection points at 223.60 for 30-day and 255.02 for 365-day all-cause mortality, respectively. Compared to patients with TyG-BMI levels below the inflection points, those with higher levels had a 1.8% lower risk for 30-day all-cause mortality (hazard ratio [HR] 0.982, 95% confidence interval [CI] 0.9676-0.988) and 1.1% lower risk for 365-day all-cause mortality (HR 0.989, 95% CI 0.986-0.991). CONCLUSION: In critically ill patients with AF, a lower TyG-BMI level is significantly associated with a higher risk of 30-day, 90-day, 180-day and 365-day all-cause mortality. TyG-BMI index could be used as a valid indicator for grading and treating patients with AF in the ICU.

Predicting simultaneously fields of soot temperature and volume fraction in laminar sooting flames from soot radiation measurements - a convolutional neural networks approach.

An original convolutional neural network, i.e. U-net approach, has been designed to retrieve simultaneously local soot temperature and volume fraction fields from line-of-sight measurements of soot radiation fields. A five-stage U-net architecture is established and detailed. Based on a set of N2 diluted ethylene non-premixed flames, the minimum batch size requirement for U-net model training is discussed and the U-net model prediction ability is validated for the first time by fields provided by the modulated absorption emission (MAE) technique documenting the N2 diluted flame. Additionally, the U-net model's flexibility and robustness to noise are also quantitatively studied by introducing 5% & 10% Gaussian random noises into training together with the testing data. Eventually, the U-net predictive results are directly contrasted with those of Bayesian optimized back propagation neural network (BPNN) in terms of testing score, prediction absolute error (AE), soot parameter field smoothness, and time cost.

Discovery and optimization of heteroaryl piperazines as potent and selective PI3Kδ inhibitors.

A high-throughput screening (HTS) campaign identified a class of heteroaryl piperazines with excellent baseline affinity and selectivity for phosphoinositide 3-kinase δ (PI3Kδ) over closely related isoforms. Rapid evaluation and optimization of structure-activity relationships (SAR) for this class, leveraging the modular nature of this scaffold, facilitated development of this hit class into a series of potent and selective inhibitors of PI3Kδ. This effort culminated in the identification of 29, which displayed excellent potency in enzyme and cell-based assays, as well as favorable pharmacokinetic and off-target profiles.

Identification of quinazoline based inhibitors of IRAK4 for the treatment of inflammation.

Interleukin-1 receptor associated kinase 4 (IRAK4) has been implicated in IL-1R and TLR based signaling. Therefore selective inhibition of the kinase activity of this protein represents an attractive target for the treatment of inflammatory diseases. Medicinal chemistry optimization of high throughput screening (HTS) hits with the help of structure based drug design led to the identification of orally-bioavailable quinazoline based IRAK4 inhibitors with excellent pharmacokinetic profile and kinase selectivity. These highly selective IRAK4 compounds show activity in vivo via oral dosing in a TLR7 driven model of inflammation.

Identification of N-(1H-pyrazol-4-yl)carboxamide inhibitors of interleukin-1 receptor associated kinase 4: Bicyclic core modifications.

IRAK4 plays a critical role in the IL-1R and TLR signalling, and selective inhibition of the kinase activity of the protein represents an attractive target for the treatment of inflammatory diseases. A series of permeable N-(1H-pyrazol-4-yl)carboxamides was developed by introducing lipophilic bicyclic cores in place of the polar pyrazolopyrimidine core of 5-amino-N-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamides. Replacement of the pyrazolo[1,5-a]pyrimidine core with the pyrrolo[2,1-f][1,2,4]triazine, the pyrrolo[1,2-b]pyridazine, and thieno[2,3-b]pyrazine cores guided by cLogD led to the identification of highly permeable IRAK4 inhibitors with excellent potency and kinase selectivity.

Potent benzoazepinone γ-secretase modulators with improved bioavailability.

The triazolyl amide γ-secretase modulators are potent alternatives to the cinnamyl amides that have entered the clinic for the treatment of Alzheimer's disease. Herein we build on the lead benzoazepinones described in our prior communication with imidazomethoxyarene moiety alternatives that offer opportunities to fine tune physical properties as well as address hERG binding and PK. Both half-life and bioavailability were significantly improved, especially in dog, with robust brain Aß42 lowering maintained in both transgenic mouse and rat.

Lead optimization of 4,4-biaryl piperidine amides as γ-secretase inhibitors.

Alzheimer's disease is a major unmet medical need with pathology characterized by extracellular proteinaceous plaques comprised primarily of ß-amyloid. γ-Secretase is a critical enzyme in the cellular pathway responsible for the formation of a range of ß-amyloid peptides; one of which, Aß42, is believed to be responsible for the neuropathological features of the disease. Herein, we report 4,4 disubstituted piperidine γ-secretase inhibitors that were optimized for in vitro cellular potency and pharmacokinetic properties in vivo. Key agents were further characterized for their ability to lower cerebral Aß42 production in an APP-YAC mouse model. This structural series generally suffered from sub-optimal pharmacokinetics but hypothesis driven lead optimization enabled the discovery of γ-secretase inhibitors capable of lowering cerebral Aß42 production in mice.

The role of circadian clocks in metabolic disease.

The circadian clock is a highly conserved timing system, resonating physiological processes to 24-hour environmental cycles. Circadian misalignment is emerging as a risk factor of metabolic disease. The molecular clock resides in all metabolic tissues, the dysfunction of which is associated with perturbed energy metabolism. In this article, we will review current knowledge about molecular mechanisms of the circadian clock and the role of clocks in the physiology and pathophysiology of metabolic tissues.

A Comparison of Doxycycline and Amoxicillin Containing Quadruple Eradication Therapy for Treating Helicobacter pylori-Infected Duodenal Ulcers: A Multicenter, Opened, Randomized Controlled Trial in China.

Background: Increased antibiotic resistance is one of the major factors contributing to the failure of H. pylori eradication. This study aimed to compare the efficacy and safety of doxycycline and amoxicillin, both critical components for bismuth-based quadruple therapy, for the first-line treatment of H. pylori-infected duodenal ulcers. Methods: An open, randomized case-controlled, multicenter trial was conducted in seven hospitals in China. A total of 184 eligible participants were divided into an IDFB (ilaprazole 5 mg, doxycycline 100 mg, furazolidone 100 mg, and bismuth 220 mg bid) or IAFB (ilaprazole 5 mg, amoxicillin 1000 mg, furazolidone 100 mg, and bismuth 220 mg bid) group for 14 days. Both groups were administrated with ilaprazole 5 mg qd for another 14 days. The main outcome was an H. pylori eradication rate; secondary outcomes were ulcer healing, relief of symptoms, and incidence of adverse effects. Results: The H. pylori eradication rates were 85.9% (95% CI 78.6−93.9) in the IDFB vs. 84.8% (95% CI 77.3−92.3) in the IAFB group in ITT analysis (p > 0.05), and 92.9% (95% CI 87.4−98.5) vs. and 91.8% (95% CI 85.8−97.7) in PP analysis (p > 0.05). The overall ulcer healing rates of IDFB and IAFB were 79.1% and 84.7% (p > 0.05), both effective in relieving symptoms. Only nine participants had adverse reactions in this trial (4/92 in IDFB and 5/92 in IAFB). Conclusion: A bismuth quadruple regimen containing doxycycline or amoxicillin could be an effective and safe treatment for H. pylori eradication, while doxycycline replacement is an alternative for participants with penicillin allergy.

Discovery of MK-4688: an Efficient Inhibitor of the HDM2-p53 Protein-Protein Interaction.

Identification of low-dose, low-molecular-weight, drug-like inhibitors of protein-protein interactions (PPIs) is a challenging area of research. Despite the challenges, the therapeutic potential of PPI inhibition has driven significant efforts toward this goal. Adding to recent success in this area, we describe herein our efforts to optimize a novel purine carboxylic acid-derived inhibitor of the HDM2-p53 PPI into a series of low-projected dose inhibitors with overall favorable pharmacokinetic and physical properties. Ultimately, a strategy focused on leveraging known binding hot spots coupled with biostructural information to guide the design of conformationally constrained analogs and a focus on efficiency metrics led to the discovery of MK-4688 (compound 56), a highly potent, selective, and low-molecular-weight inhibitor suitable for clinical investigation.

Projected Dose Optimization of Amino- and Hydroxypyrrolidine Purine PI3Kδ Immunomodulators.

The approvals of idelalisib and duvelisib have validated PI3Kδ inhibitors for the treatment for hematological malignancies driven by the PI3K/AKT pathway. Our program led to the identification of structurally distinct heterocycloalkyl purine inhibitors with excellent isoform and kinome selectivity; however, they had high projected human doses. Improved ligand contacts gave potency enhancements, while replacement of metabolic liabilities led to extended half-lives in preclinical species, affording PI3Kδ inhibitors with low once-daily predicted human doses. Treatment of C57BL/6-Foxp3-GDL reporter mice with 30 and 100 mg/kg/day of 3c (MSD-496486311) led to a 70% reduction in Foxp3-expressing regulatory T cells as observed through bioluminescence imaging with luciferin, consistent with the role of PI3K/AKT signaling in Treg cell proliferation. As a model for allergic rhinitis and asthma, treatment of ovalbumin-challenged Brown Norway rats with 0.3 to 30 mg/kg/day of 3c gave a dose-dependent reduction in pulmonary bronchoalveolar lavage inflammation eosinophil cell count.

Lessons from the Total Synthesis of (±) Phalarine: Insights Into the Mechanism of the Pictet-Spengler Reaction.

The furanobisindole alkaloid, phalarine, possesses a unique structural framework within the alkaloid family of natural products. Our laboratory recently disclosed the racemic total synthesis of phalarine, featuring an efficient azaspiroindolenine rearrangement; this achievement is revisited in detail. Upon completion of the first-generation total synthesis, we explored some interesting mechanism-level issues with regard to the key azaspiroindolenine rearrangement. These investigations provided valuable insights into the mechanism of racemization during the azaspiroindolenine rearrangement en route to synthetic phalarine. In addition, in the course of these studies, we demonstrated the Pictet-Spengler capture reaction for C(2)-aryl indoles, and successfully isolated the elusive azaspiroindolenine intermediate of the Pictet-Spengler reaction. Key insights into the remarkably subtle stereoelectronics that govern this rearrangement for C(2)-arylated indoles are discussed.

Piperazinyl pyrimidine derivatives as potent gamma-secretase modulators.

The development of a novel series of piperazinyl pyrimidines as gamma-secretase modulators for potential use in the treatment of Alzheimer's disease is disclosed herein. Optimization of a screening hit provided a series of potent gamma-secretase modulators with >180-fold in vitro selectivity over inhibition of Notch cleavage.

Purine derivatives as potent gamma-secretase modulators.

The development of a novel series of purines as gamma-secretase modulators for potential use in the treatment of Alzheimer's disease is disclosed herein. Optimization of a previously disclosed pyrimidine series afforded a series of potent purine-based gamma-secretase modulators with 300- to 2000-fold in vitro selectivity over inhibition of Notch cleavage and that selectively reduces Alphabeta42 in an APP-YAC transgenic mouse model.

Common Variants in the ARG1 Gene Contribute to the Risk of Dilated Cardiomyopathy in the Han Chinese Population.

Background: Arginase I, encoded by the ARG1 gene, is an enzyme that catalyzes the conversion of arginine to ornithine in the urea cycle; mutations in this gene has recently been reported to be associated with dilated cardiomyopathy (DCM) in Pakistan. The present study aimed to investigate the relationship between ARG1 gene mutations and DCM in the Han Chinese population. Methods: A total of 488 DCM cases and 924 matched-healthy controls were recruited. All subjects were genotyped for 12 tag single nucleotide polymorphisms (SNPs) within the ARG1 gene. Genetic association studies, including SNP and haplotype analyses, were performed. Further analyses were conducted to examine the correlations between the associated SNPs and specific clinical characteristics. Results: Only the rs2781666 and rs2781667 loci in the ARG1 gene were found to be significantly associated with DCM compared to the healthy controls. The risk of DCM at both of these loci for T allele carriers was ∼1.42-fold higher than that for carriers of the alternative alleles. There were significant differences in end-diastolic interventricular septal diameter, end-diastolic left ventricular posterior wall diameter, left ventricular end-diastolic diameter, left ventricular end-systolic diameter, and left ventricular ejection fraction among the genotype distributions of both SNPs. Furthermore, we found that the T alleles at the rs2781666 and rs2781667 loci were significantly associated with DCM in gender subgroups and the subgroup of patients <58 years of age. The haplotype T-T (rs2781666-rs2781667) also showed a significant association with DCM. Conclusion: Our results support the hypothesis that alleles and haplotypes of the ARG1 gene are significantly involved in the etiology of DCM in the Han Chinese population, but further research is necessary to elucidate the mechanism governing this association.

Correlation between alterations of gut microbiota and miR-122-5p expression in patients with type 2 diabetes mellitus.

BACKGROUND: To investigate the correlation between gut microbiota and circulating microRNAs (miRNAs) in patients with primary diagnosis of type 2 diabetes mellitus (T2DM) and to explore the possible mechanisms of miRNA-gut microbiota crosstalke network in the regulation of the insulin signaling pathway and glucose homeostasis in T2DM. METHODS: T2DM patients and normal controls were recruited. Fasting plasma and fecal samples were collected from the subjects, and their biochemical indexes including fasting blood glucose (FBG), glycated hemoglobin (HbAlc), cholesterol (TC), total triglycerides (TG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), and insulin were recorded. The variations in intestinal microbiota in the two groups were analyzed using 16S rRNA third-generation sequencing technology, and the differential expression of miRNAs between the groups was screened using miRNA high-throughput sequencing. The correlation and association between specifically changed intestinal microbiota and miRNA expressions were analyzed using a combination of bioinformatics analysis and statistical methods. Finally, 16S functional gene prediction analysis and target gene enrichment pathway analysis were carried out to predict relevant gut microbiota and miRNAs. RESULTS: Compared with normal controls, the biochemical indexes of HAlbc, FBG, TG, TC, LDL, HDL, and insulin were significantly different in T2DM patients (P<0.001, P<0.001, P=0.0125, P=0.98, P<0.001 P=0.022, and P=0.0013, respectively). The two groups also showed significantly different intestinal microbiota distribution and miRNA expression characteristics, including in the counts of Bacteriodes. uniformis and Phascolarctobacterium. Faecium (P=0.023, 0.031), which were negatively correlated (P=0.014, FC = -2.36) with the expression levels of serum miR-122-5p (r=-0.68, -0.60, P=0.01, 0.01). CONCLUSIONS: This study discovered specific gut microbiota and miRNA characteristics in patients with a primary diagnosis of T2DM. A negative correlation between miR-122-5p and the intestinal bacteria Bacteriodes. uniformis and Phascolarctobacterium. Faecium was also revealed, suggesting that the crosstalke between miRNA and gut microbiota may regulate the insulin secretion and signal transduction by controling key genes of glucose metabolism during the development of T2DM.

Effect of large dosage of Prunella on Hashimoto's thyroiditis: A protocol of systematic review and meta-analysis of randomized clinical trials.

INTRODUCTION: Hashimoto's Thyroiditis (HT) is one of the common autoimmune diseases, which can lead to thyroid reduction, increase the risk of tumor, and seriously affect women's reproductive health. Many other autoimmune diseases are easy to occur, seriously harming people's health.large dose herb Prunella or compound prescription contain large dose Prunella for treatment of HT has already been confirmed. However, due to the lack of evidence, there is no specific method or suggestion, it is necessary to carry out a systematic evaluation on Prunella and provide effective evidence for further research. METHODS AND ANALYSIS: The following databases will be searched from their inception to October 2020: Electronic database includes PubMed, Embase, Cochrane Library, Web of Science, Nature, Science online, Chinese Biomedical Database WangFang, VIP medicine information, and China National Knowledge Infrastructure. MAIN RESULTS: serum thyroid peroxidase antibody (TPOAb), thyroid globulin antibody (TGAb), other results: serum thyroid stimulating hormone (TSH), serum free triiodothyronine (FT3), serum free thyroid hormone (FT4). Data will be extracted by 2 researchers independently, risk of bias of the meta-analysis will be evaluated based on the Cochrane Handbook for Systematic Reviews (SR)of Interventions. All data analysis will be conducted by data statistics software Review Manager V.5.3. and Stata V.12.0. RESULTS: The results of this study will systematically evaluate the efficacy and safety of large dose prunella salicorrhizae in the intervention of people with HT. CONCLUSION: The systematic review of this study will summarize the current published evidence of large dose prunella for the treatment of HT, which can further guide the promotion and application of it. ETHICS AND COMMUNICATION: This study is a systematic review, the outcomes are based on the published evidence, so examination and agreement by the ethics committee are not required in this study. We intend to publish the study results in a journal or conference presentations.Open Science Fra mework (OSF) registration number:October 21, 2020.osf.io/fcyqp. (https://osf.io/fcyqp).

Matrix Gla protein regulates adipogenesis and is serum marker of visceral adiposity.

Objective Matrix Gla protein (MGP) is a potent calcification inhibitor. Mgp-/- mice display increased proportion of brown adipose tissue. However, whether MGP is involved in fat metabolism remains unclear. This study aims to investigate the involvement. Methods Expression of adipocyte differentiation markers was examined by RT-qPCR. Adipocyte formation was assessed by Oil Red staining. Serum triglyceride, cholesterol, and desphosphorylated-uncarboxylated MGP (dp-ucMGP) were quantified by ELISA. Visceral fat was detected by bioelectrical impedance analysis. Results MGP is highly expressed in visceral fat. MGP expression is induced during preadipocyte differentiation. Knockout of MGP leads to retardation of 3T3-L1 differentiation. Intracellular triglyceride amount is impaired while glycerol release is increased in MGP-depleted cells. Serum dp-ucMGP level is significantly increased in individual with higher visceral fat index (VFI) and waist height ratio (WHtR), but not body mass index (BMI). Additionally, dp-ucMGP positively correlates to low-density lipoprotein cholesterol (LDL-C) level. Conclusions MGP is involved in fat metabolism and serum inactive MGP level is associated with visceral fat. Our study uncovers for the first time the link between MGP and fat metabolism, and sheds light on the potential of dp-ucMGP as a novel serum marker.

Increased Respiratory Modulation of Blood Pressure in Hypertensive Patients.

OBJECTIVE: Although the important role of respiratory modulation of the cardiovascular system in the development of hypertension has been demonstrated in animal studies, little research has assessed this modulation in essential hypertensive patients. We aimed to explore whether respiratory-related variations in cardiovascular variables are changed in hypertensive patients and their potential relationships with the respiratory pattern. METHODS: Respiration, ECG, and beat-to-beat blood pressure (BP) were simultaneously measured in 46 participants (24 hypertensive patients and 22 normotensive participants) during rest and a mental arithmetic task (MAT). Respiratory-triggered averaging and orthogonal subspace projection methods were used to assess the respiratory modulations of BP and heart rate (HR). Respiratory parameters including inspiratory time, expiratory time, respiratory rate and their variabilities were also characterized. RESULTS: The inspiratory time, expiratory time, respiratory rate and their variabilities were not different between hypertensive and normotensives. Additionally, the modulation of HR by respiration was also similar between the two groups. Hypertensive patients exhibited an amplified respiratory modulation of systolic BP (SBP), as assessed from the amplitude of respiratory-related changes and the percentage of the power of respiratory-related variation, and also reflected from the temporal pattern of respiratory modulation of SBP. The exaggerated respiratory-related variation of SBP in hypertensive patients accounted for ≈23% of the total power of SBP, producing an absolute change of ≈4.5 mmHg in SBP. MAT was characterized by decreased inspiratory time and increased variabilities of expiratory time and respiratory rate with no changes in the amplitude of respiratory modulations. CONCLUSION: Hypertensive patients had excessive respiratory modulation of SBP, despite having similar respiratory pattern with normotensives. These findings highlight the importance of respiratory influence in BP variation and suggest that respiratory modulation of SBP may have prognostic information for cardiovascular events in hypertensive patients.

Structure Overhaul Affords a Potent Purine PI3Kδ Inhibitor with Improved Tolerability.

PI3Kδ catalytic activity is required for immune cell activation, and has been implicated in inflammatory diseases as well as hematological malignancies in which the AKT pathway is overactive. A purine PI3Kδ inhibitor bearing a benzimidazolone-piperidine motif was found to be poorly tolerated in dog, which was attributed to diffuse vascular injury. Several strategies were implemented to mitigate this finding, including reconstruction of the benzimidazolone-piperidine selectivity motif. Structure-based design led to the identification of O- and N-linked heterocycloalkyls, with pyrrolidines being particularly ligand efficient and kinome selective, and having an improved safety pharmacology profile. A representative was advanced into a dog tolerability study where it was found to be well tolerated, with no histopathological evidence of vascular injury.