Impact of physical activity on surrogate markers of cardiovascular disease in the haemodialysis population.

Background: The haemodialysis (HD) population is sedentary, with substantial cardiovascular disease risk. In the general population, small increases in daily step count associate with significant reductions in cardiovascular mortality. This study explores the relationship between daily step count and surrogate markers of cardiovascular disease, including left ventricular ejection fraction (LVEF) and native T1 (a marker of diffuse myocardial fibrosis), within the HD population.

Implementation and engagement of the SMART Work & Life sitting reduction intervention: an exploratory analysis on intervention effectiveness.

Background: To enhance the impact of interventions, it is important to understand how intervention engagement relates to study outcomes. We report on the level of implementation and engagement with the SMART Work & Life (SWAL) programme (delivered with (SWAL plus desk) and without a height-adjustable desk (SWAL)) and explore the effects of different levels of this on change in daily sitting time in comparison to the control group.

Methods: The extent of intervention delivery by workplace champions and the extent of engagement by champions and participants (staff) with each intervention activity was assessed by training attendance logs, workplace champion withdrawal dates, intervention activities logs and questionnaires.

A systematic review of simulation studies which compare existing statistical methods to account for non-compliance in randomised controlled trials.

Introduction: Non-compliance is a common challenge for researchers and may reduce the power of an intention-to-treat analysis. Whilst a per protocol approach attempts to deal with this issue, it can result in biased estimates. Several methods to resolve this issue have been identified in previous reviews, but there is limited evidence supporting their use.

Incorporation of patient and public involvement in statistical methodology research: a survey assessing current practices and attitudes of researchers.

Background: Patient and public involvement (PPI) ensures that research is designed and conducted in a manner that is most beneficial to the individuals whom it will impact. It has an undisputed place in applied research and is required by many funding bodies. However, PPI in statistical methodology research is more challenging and work is needed to identify where and how patients and the public can meaningfully input in this area.

Discovery of (BMS-986172) as a Highly Potent MGAT2 Inhibitor that Achieved Targeted Efficacious Exposures at a Low Human Dose for the Treatment of Metabolic Disorders.

A series of dihydropyridinone (DHP) compounds was prepared and evaluated for MGAT2 activity. The efforts led to the identification of novel tetrazolones with potent MGAT2 inhibitory activity and favorable profiles. Further tests of select analogues in mouse models revealed significant reduction in food intake and body weight.

Branched-chain keto acids inhibit mitochondrial pyruvate carrier and suppress gluconeogenesis in hepatocytes.

Branched-chain amino acid (BCAA) metabolism is linked to glucose homeostasis, but the underlying signaling mechanisms are unclear. We find that gluconeogenesis is reduced in mice deficient of Ppm1k, a positive regulator of BCAA catabolism, which protects against obesity-induced glucose intolerance. Accumulation of branched-chain keto acids (BCKAs) inhibits glucose production in hepatocytes.

Whole Body Distribution of Labile Coenzymes and Antioxidants in a Mouse Model as Visualized Using H NMR Spectroscopy.

Coenzyme A, acetyl coenzyme A, coenzymes of cellular energy, coenzymes of redox reactions, and antioxidants mediate biochemical reactions fundamental to the functioning of all living cells. There is an immense interest in measuring them routinely in biological specimens to gain insights into their roles in cellular functions and to help characterize the biological status. However, it is challenging to measure them ex vivo as they are sensitive to specimen harvesting, extraction, and measurement conditions.

Amino acid primed mTOR activity is essential for heart regeneration.

Heart disease is the leading cause of death with no method to repair damaged myocardium due to the limited proliferative capacity of adult cardiomyocytes. Curiously, mouse neonates and zebrafish can regenerate their hearts via cardiomyocyte de-differentiation and proliferation. However, a molecular mechanism of why these cardiomyocytes can re-enter cell cycle is poorly understood.

Evaluation of Warfarin Use in Patients With Mental Health Conditions in a Rural Community Health Center System.

Mental health conditions (MHCs) may affect a patient's ability to comply with requirements necessary for safe warfarin use. To describe warfarin control, defined as time in therapeutic range (TTR), for patients with and without MHCs receiving care through a pharmacist-driven anticoagulation service within a rural community health center system. Retrospective cohort study of patients on warfarin between January 1, 2014, and December 31, 2017.

Screening Hit to Clinical Candidate: Discovery of BMS-963272, a Potent, Selective MGAT2 Inhibitor for the Treatment of Metabolic Disorders.

MGAT2 inhibition is a potential therapeutic approach for the treatment of metabolic disorders. High-throughput screening of the BMS internal compound collection identified the aryl dihydropyridinone compound (hMGAT2 IC = 175 nM) as a hit. Compound had moderate potency against human MGAT2, was inactive vs mouse MGAT2 and had poor microsomal metabolic stability.

Discovery and structure activity relationships of 7-benzyl triazolopyridines as stable, selective, and reversible inhibitors of myeloperoxidase.

Myeloperoxidase (MPO) is a heme peroxidase found in neutrophils, monocytes and macrophages that efficiently catalyzes the oxidation of endogenous chloride into hypochlorous acid for antimicrobial activity. Chronic MPO activation can lead to indiscriminate protein modification causing tissue damage, and has been associated with chronic inflammatory diseases, atherosclerosis, and acute cardiovascular events. Triazolopyrimidine 5 is a reversible MPO inhibitor; however it suffers from poor stability in acid, and is an irreversible inhibitor of the DNA repair protein methyl guanine methyl transferase (MGMT).

Identification of RIPK3 Type II Inhibitors Using High-Throughput Mechanistic Studies in Hit Triage.

Necroptosis has been implicated in a variety of disease states, and RIPK3 is one of the kinases identified to play a critical role in this signaling pathway. In an effort to identify RIPK3 kinase inhibitors with a novel profile, mechanistic studies were incorporated at the hit triage stage. Utilization of these assays enabled identification of a Type II DFG-out inhibitor for RIPK3, which was confirmed by protein crystallography.

Identification of Reversible Small Molecule Inhibitors of Endothelial Lipase (EL) That Demonstrate HDL-C Increase In Vivo.

Endothelial lipase (EL) hydrolyzes phospholipids in high-density lipoprotein (HDL) resulting in reduction in plasma HDL levels. Studies with murine transgenic, KO, or loss-of-function variants strongly suggest that inhibition of EL will lead to sustained plasma high-density lipoprotein cholesterol (HDL-C) increase and, potentially, a reduced cardiovascular disease (CVD) risk. Herein, we describe the discovery of a series of oxadiazole ketones, which upon optimization, led to the identification of compound .

Fear of Missing Out and Relational Aggression on Facebook.

The use of social networking sites has been associated with fear of missing out (FOMO), which is characterized by perceiving others as having more rewarding lives. This study investigated whether FOMO is related to Facebook relational aggression through a desire to avoid inferiority and engagement in manipulative behaviors. Facebook users ( = 190, 87 percent women) completed an online survey assessing FOMO, striving to avoid inferiority, interpersonal manipulation, and Facebook relational aggression.

Do physical activity levels differ by number of children at home in women aged 25-44 in the general population?

Objectives: While physical activity is important for health, many women do not meet recommended levels, particularly mothers. The purpose of this study was to assess whether physical activity levels differ by number of children at home in women aged 25-44 in the general US population.

Methods: This cross-sectional analysis used 2017 Behavioral Risk Factor Surveillance System data for females aged 25-44 (N = 6266) from California, Colorado, New York, Texas, and Utah.

Identification of substituted benzothiazole sulfones as potent and selective inhibitors of endothelial lipase.

A low level of high density lipoprotein (HDL) is an independent risk factor for cardiovascular disease. HDL reduces inflammation and plays a central role in reverse cholesterol transport, where cholesterol is removed from peripheral tissues and atherosclerotic plaque. One approach to increase plasma HDL is through inhibition of endothelial lipase (EL).

Targeting NAD Metabolism as Interventions for Mitochondrial Disease.

Leigh syndrome is a mitochondrial disease characterized by neurological disorders, metabolic abnormality and premature death. There is no cure for Leigh syndrome; therefore, new therapeutic targets are urgently needed. In Ndufs4-KO mice, a mouse model of Leigh syndrome, we found that Complex I deficiency led to declines in NAD levels and NAD redox imbalance.

Sulfonylated Benzothiazoles as Inhibitors of Endothelial Lipase.

Endothelial lipase (EL) selectively metabolizes high density lipoprotein (HDL) particles. Inhibition of EL has been shown to increase HDL concentration in preclinical animal models and was targeted as a potential treatment of atherosclerosis. We describe the introduction of an α-sulfone moiety to a benzothiazole series of EL inhibitors resulting in increased potency versus EL.

Potent Triazolopyridine Myeloperoxidase Inhibitors.

Myeloperoxidase (MPO) generates reactive oxygen species that potentially contribute to many chronic inflammatory diseases. A recently reported triazolopyrimidine MPO inhibitor was optimized to improve acid stability and remove methyl guanine methyl transferase (MGMT) activity. Multiple synthetic routes were explored that allowed rapid optimization of a key benzyl ether side chain.

Extending the Scope of H NMR Spectroscopy for the Analysis of Cellular Coenzyme A and Acetyl Coenzyme A.

Coenzyme A (CoA) and acetyl-coenzyme A (acetyl-CoA) are ubiquitous cellular molecules, which mediate hundreds of anabolic and catabolic reactions including energy metabolism. Highly sensitive methods including absorption spectroscopy and mass spectrometry enable their analysis, albeit with many limitations. To date, however, NMR spectroscopy has not been used to analyze these important molecules.

Discovery and synthesis of tetrahydropyrimidinedione-4-carboxamides as endothelial lipase inhibitors.

Endothelial lipase (EL) inhibitors have been shown to elevate HDL-C levels in pre-clinical murine models and have potential benefit in prevention and treatment of cardiovascular diseases. Modification of the 1-ethyl-3-hydroxy-1,5-dihydro-2H-pyrrol-2-one (DHP) lead, 1, led to the discovery of a series of potent tetrahydropyrimidinedione (THP) EL inhibitors. Synthesis and SAR studies including modification of the amide group, together with changes on the pyrimidinone core led to a series of arylcycloalkyl, indanyl, and tetralinyl substituted 5-amino or 5-hydroxypyrimidinedione-4-carboxamides.

Triazolopyrimidines identified as reversible myeloperoxidase inhibitors.

Myeloperoxidase, a mammalian peroxidase involved in the immune system as an anti-microbial first responder, can produce hypochlorous acid in response to invading pathogens. Myeloperoxidase has been implicated in several chronic pathological diseases due to the chronic production of hypochlorous acid, as well as other reactive radical species. A high throughput screen and triaging protocol was developed to identify a reversible inhibitor of myeloperoxidase toward the potential treatment of chronic diseases such as atherosclerosis.

PK/PD Disconnect Observed with a Reversible Endothelial Lipase Inhibitor.

Screening of a small set of nonselective lipase inhibitors against endothelial lipase (EL) identified a potent and reversible inhibitor, -(3-(3,4-dichlorophenyl)propyl)-3-hydroxy-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide (; EL IC = 61 nM, EL IC = 454 nM). Deck mining identified a related hit, -(3-(3,4-dichlorophenyl)propyl)-4-hydroxy-1-methyl-5-oxo-2,5-dihydro-1-pyrrole-3-carboxamide (; EL IC = 41 nM, EL IC = 1760 nM). Both compounds were selective against lipoprotein lipase (LPL) but nonselective versus hepatic lipase (HL).

Development of endocytosis, degradative activity, and antigen processing capacity during GM-CSF driven differentiation of murine bone marrow.

Dendritic cells (DC) are sentinels of the immune system, alerting and enlisting T cells to clear pathogenic threats. As such, numerous studies have demonstrated their effective uptake and proteolytic activities coupled with antigen processing and presentation functions. Yet, less is known about how these cellular mechanisms change and develop as myeloid cells progress from progenitor cells to more differentiated cell types such as DC.