This study compared the blood pressure‐lowering effect of ertugliflozin (1, 5, 25 mg), hydrochlorothiazide (HCTZ; 12.5 mg) and placebo in 194 patients with type 2 diabetes mellitus and hypertension ...for 4 weeks using ambulatory blood pressure monitoring. Endpoints (change from baseline to week 4) were: 24‐h mean systolic blood pressure (SBP; primary); daytime, night‐time, seated predose SBP, 24‐h, daytime, night‐time, seated predose diastolic blood pressure, 24‐h urinary glucose excretion and fasting plasma glucose (FPG; secondary). Safety and tolerability were monitored. Significant decreases in placebo‐corrected 24‐h mean SBP (−3.0 to −4.0 mmHg) were recorded for all doses of ertugliflozin (for HCTZ, this was −3.2 mmHg). Daytime, but not night‐time SBP was consistently reduced. Ertugliflozin produced dose‐dependent significant decreases in FPG and increases in urinary glucose excretion. No notable changes in plasma renin activity or urinary aldosterone were seen. The most common adverse events were urinary tract infection, genital fungal infection, upper respiratory tract infection and musculoskeletal pain.
Aim
To investigate the efficacy and safety of ertugliflozin, in a phase II dose‐ranging study, in patients with type 2 diabetes mellitus (T2DM) inadequately controlled on metformin.
Methods
A total ...of 328 patients mean T2DM duration, 6.3 years; mean glycated haemoglobin (HbA1c), 8.1% were randomized to once‐daily ertugliflozin (1, 5, 10, 25 mg), sitagliptin (100 mg) or placebo, for 12 weeks. The primary efficacy endpoint was change from baseline to week 12 in HbA1c concentration and the secondary efficacy endpoints were changes from baseline to week 12 in body weight, fasting plasma glucose (FPG) and systolic/diastolic blood pressure (SBP/DBP). Safety and tolerability were also monitored.
Results
Ertugliflozin (1–25 mg/day) produced significant reductions in HbA1c concentration placebo‐corrected least‐squares mean (LSM) −0.45% (1 mg) to −0.72% (25 mg); p ≤ 0.002, similar to sitagliptin (−0.76%; p = 0.0001), FPG (LSM −1.17 to −1.90 mmol/l; p < 0.0001) and body weight (−1.15 to −2.15%; p < 0.0001). The LSM SBP decreased by −3.4 to −4.0 mmHg from baseline with ertugliflozin 5–25 mg/day. No reductions in body weight or blood pressure were observed with sitagliptin. After randomization, 2.7% of patients (9/328) withdrew because of adverse events (AEs); the frequency of AEs was evenly distributed across groups. No dose‐related increase in AE frequency occurred with ertugliflozin. Hypoglycaemia was reported in 5 (1.5%) randomized participants (all in the ertugliflozin group). The frequency of urinary tract infection was 3.2% for ertugliflozin (pooled across groups), 1.8% for sitagliptin, 7.4% for placebo, and the frequency of genital fungal infections was 3.7% for ertugliflozin (pooled) versus 1.9% for placebo.
Conclusion
Ertugliflozin (1–25 mg/day) improved glycaemic control, body weight and blood pressure in patients with T2DM suboptimally controlled on metformin, and was well tolerated.
► Formation of stoichiometric SiO2 layer with lowest density after chlorine oxidation ► KCN/HCN passivation contributes to formation of SiN, SiO and SiOH bonds at the expense of SiCl bonds. ► SiCN ...could not be identified due to overlapping of detected signal with absorption induced by CO2.
Chlorine oxidation is important methods for improvement of many properties such as passivation of mobile oxide charge, breakdown strength or enhancement of the minority-carrier lifetime in the underlying silicon. In this study we consider effects influencing the density of SiO2 layers formed by three different methods: thermal oxidation at 850°C, low temperature oxidation method by use of nitric acid – HNO3 (NAOS) and HClO4 afterward passivated with KCN/HCN solutions. Thicknesses of SiO2 layers determined by both capacitance–voltage (C–V) and XPS revealed fast oxidation rate compared with samples prepared by thermal oxidation. FT IR measurement showed that all absorption spectra are almost similar. Higher absorption of the sample prepared in HClO4 was observed. No SiCl bonds were visible. Calculated atomic density of the SiO2 layer obtained from IR measurements was lowest for sample formed in HClO4. Chlorine oxidation results in higher oxidation rate (higher thickness) and formation of stoichiometric SiO2 layer with lower density. Following KCN/HCN passivation causes formation of SiN, SiO and SiOH bonds at the expense of SiCl bonds.
An oriented hypergraph is an oriented incidence structure that allows for the generalization of graph theoretic concepts to integer matrices through its locally signed graphic substructure. The ...locally graphic behaviors are formalized in the subobject classifier of incidence hypergraphs. Moreover, the injective envelope is calculated and shown to contain the class of uniform hypergraphs — providing a combinatorial framework for the entries of incidence matrices. A multivariable all-minors characteristic polynomial is obtained for both the determinant and permanent of the oriented hypergraphic Laplacian and adjacency matrices arising from any integer incidence matrix. The coefficients of each polynomial are shown to be submonic maps from the same family into the injective envelope limited by the subobject classifier. These results provide a unifying theorem for oriented hypergraphic matrix-tree-type and Sachs-coefficient-type theorems. Finally, by specializing to bidirected graphs, the trivial subclasses for the degree-k monomials of the Laplacian are shown to be in one-to-one correspondence with k-arborescences.
This paper considers the difficulty in the set-system approach to generalizing graph theory. These difficulties arise categorically as the category of set-system hypergraphs is shown not to be ...cartesian closed and lacks enough projective objects, unlike the category of directed multigraphs (i.e., quivers). The category of incidence hypergraphs is introduced as a “graph-like” remedy for the set-system issues so that hypergraphs may be studied by their locally graphic behavior via homomorphisms that allow an edge of the domain to be mapped into a subset of an edge in the codomain. Moreover, it is shown that the category of quivers embeds into the category of incidence hypergraphs via a logical functor that is the inverse image of an essential geometric morphism between the topoi. Consequently, the quiver exponential is shown to be simply represented using incidence hypergraph homomorphisms.
Interventional closure of left atrial appendage (LAAC) represents an alternative for stroke prevention in patients with non-valvular atrial fibrillation. Whether LAAC may affect metabolomic pathways ...has not been investigated yet. This study evaluates the impact of LAAC on the metabolism of essential amino acids, kynurenine and creatinine.
Peripheral blood samples of prospectively enrolled patients undergoing successful LAAC were taken before (T0) and 6 months after (T1, mid-term follow-up). Targeted metabolomic profiling was performed using electrospray ionization liquid chromatography–mass spectrometry (ESI-LC-MS/MS) and MS/MS measurements focusing on metabolism of essential amino acids.
44 patients with non-valvular AF (mean CHA2DS2-VASc score 4, mean HAS-BLED score 4) were enrolled. Changes in metabolites of essential amino acids, myocardial contraction and bioenergetic efficacy, such as phenylalanine (percentage change 8.2%, p = 0.006), tryptophan (percentage change 20.3%, p = 0.0006), tyrosine (percentage change 20.2%, p = 0.0001), creatinine (percentage change 7.2%, p > 0.05) and kynurenine (percentage change 8.3%, p = 0.0239) were found at mid-term follow-up.
LAAC may affect the metabolism of essential amino acids and bioenergetic efficacy.
ClinicalTrials.gov Identifier: NCT02985463
•Successful left atrial appendage closure (LAAC) might affect the metabolism of essential amino acids and kynurenine•Pathophysiological alterations due to LAAC include ongoing myocardial contraction, local stretch and device-related neo-endothelization•Changes of these metabolites might reveal the impact of LAAC on bioenergetic efficacy
An oriented hypergraph is an oriented incidence structure that generalizes and unifies graph and hypergraph theoretic results by examining its locally signed graphic substructure. In this paper we ...obtain a combinatorial characterization of the coefficients of the characteristic polynomials of oriented hypergraphic Laplacian and adjacency matrices via a signed hypergraphic generalization of basic figures of graphs. Additionally, we provide bounds on the determinant and permanent of the Laplacian matrix, characterize the oriented hypergraphs in which the upper bound is sharp, and demonstrate that the lower bound is never achieved.
Patients with non-valvular atrial fibrillation (AF) and a high risk for oral anticoagulation can be treated by percutaneous implantation of left atrial appendage occlusion devices (LAAC) to reduce ...the risk of cardio-embolic stroke. This study evaluates whether LAAC may influence lipid metabolism, which has never been investigated before. Patients with successful LAAC were included consecutively. Venous peripheral blood samples of patients were collected immediately before (T0, baseline) and 6 months after (T1, mid-term) LAAC. A targeted metabolomics approach based on electrospray ionization liquid chromatography-mass spectrometry (ESI-LC-MS/MS) and MS/MS measurements was performed. A total of 34 lipids revealed a significant change from baseline to mid-term follow-up after successful LAAC. Subgroup analysis revealed confounding influence by gender, age, diabetes mellitus type II, body mass index, left ventricular ejection fraction, creatinine and NT-proBNP. After multivariable adjustment within logistic regression models, these 34 lipids were still significantly altered after LAAC. Successful percutaneous LAAC may affect lipid metabolism and thereby may potentially affect pro-atherogenic and cardio-toxic effects.
An oriented hypergraph is a hypergraph where each vertex-edge incidence is given a label of +1 or -1. We define the adjacency, incidence and Laplacian matrices of an oriented hypergraph and study ...each of them. We extend several matrix results known for graphs and signed graphs to oriented hypergraphs. New matrix results that are not direct generalizations are also presented. Finally, we study a new family of matrices that contains walk information.
► We explore the relationship between product designs and organizational designs. ► We compare open source software with software developed by commercial firms. ► We measure modularity by capturing ...the level of coupling between components. ► We find that loosely coupled organizations tend to develop more modular products. ► The differences in modularity are substantial—up to a factor of six in our sample.
A variety of academic studies argue that a relationship exists between the structure of an organization and the design of the products that this organization produces. Specifically, products tend to “mirror” the architectures of the organizations in which they are developed. This dynamic occurs because the organization's governance structures, problem solving routines and communication patterns constrain the space in which it searches for new solutions. Such a relationship is important, given that product architecture has been shown to be an important predictor of product performance, product variety, process flexibility and even the path of industry evolution.
We explore this relationship in the software industry. Our research takes advantage of a natural experiment, in that we observe products that fulfill the same function being developed by very different organizational forms. At one extreme are commercial software firms, in which the organizational participants are tightly-coupled, with respect to their goals, structure and behavior. At the other, are open source software communities, in which the participants are much more loosely-coupled by comparison. The mirroring hypothesis predicts that these different organizational forms will produce products with distinctly different architectures. Specifically, loosely-coupled organizations will develop more modular designs than tightly-coupled organizations. We test this hypothesis, using a sample of matched-pair products.
We find strong evidence to support the mirroring hypothesis. In all of the pairs we examine, the product developed by the loosely-coupled organization is significantly more modular than the product from the tightly-coupled organization. We measure modularity by capturing the level of coupling between a product's components. The magnitude of the differences is substantial—up to a factor of six, in terms of the potential for a design change in one component to propagate to others. Our results have significant managerial implications, in highlighting the impact of organizational design decisions on the technical structure of the artifacts that these organizations subsequently develop.
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