41 research outputs found
Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial
Background:
Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke.
Methods:
We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30â50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515.
Findings:
Patients were screened between July 1, 2015, and Nov 24, 2016. 10â793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68â0·90), which indicated that albiglutide was superior to placebo (p<0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (<1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (<1%) deaths in the albiglutide group.
Interpretation:
In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes.
Funding:
GlaxoSmithKline
The PREDICTS database: a global database of how local terrestrial biodiversity responds to human impacts
Biodiversity continues to decline in the face of increasing anthropogenic pressures
such as habitat destruction, exploitation, pollution and introduction of
alien species. Existing global databases of speciesâ threat status or population
time series are dominated by charismatic species. The collation of datasets with
broad taxonomic and biogeographic extents, and that support computation of
a range of biodiversity indicators, is necessary to enable better understanding of
historical declines and to project â and avert â future declines. We describe and
assess a new database of more than 1.6 million samples from 78 countries representing
over 28,000 species, collated from existing spatial comparisons of
local-scale biodiversity exposed to different intensities and types of anthropogenic
pressures, from terrestrial sites around the world. The database contains
measurements taken in 208 (of 814) ecoregions, 13 (of 14) biomes, 25 (of 35)
biodiversity hotspots and 16 (of 17) megadiverse countries. The database contains
more than 1% of the total number of all species described, and more than
1% of the described species within many taxonomic groups â including flowering
plants, gymnosperms, birds, mammals, reptiles, amphibians, beetles, lepidopterans
and hymenopterans. The dataset, which is still being added to, is
therefore already considerably larger and more representative than those used
by previous quantitative models of biodiversity trends and responses. The database
is being assembled as part of the PREDICTS project (Projecting Responses
of Ecological Diversity In Changing Terrestrial Systems â www.predicts.org.uk).
We make site-level summary data available alongside this article. The full database
will be publicly available in 2015
Hydrophobic/Hydrophilic Interplay in 1,2,4âTriazoleâ or CarboxylateâBased Molybdenum(VI) Oxide Hybrids: A Step Toward Development of ReactionâInduced SelfâSeparating Catalysts
2-(4H-1,2,4-triazol-4-yl)acetic acid (trglyH) and (dl)-4-methyl-2-(4H-1,2,4-triazol-4-yl)pentanoic acid (trleuH) were used as ligands for the development of MoO3 coordination hybrids for catalytic applications. Coordination polymers [Mo2O6(Htrgly)] ·H2O (1) and [MoO3(trleuH)] · 0.5H2O (2) were prepared and structurally characterized. Compound 1 adopts a structure in which edge-sharing MoO6 octahedra are organized in a ribbon motif via Ό3-O bridges. The Htrgly ligand exists as a zwitterion: - CO2- links two Mo(VI) in a Ό2-η1 : η1 mode, while
positively charged triazolium is left uncoordinated. In 2, Mo atoms are joined in a chain through ÎŒ2-O. The more hydrophobic trleuH appears in a nonionized form and its [N- N] sites serve as a âclampâ for supporting the [-OMo(O)2-OMo(O)2(tr)2]n sequence. The complexes were explored for liquid phase catalytic epoxidation of cis-cyclooctene, using H2O2 or tert-butylhydroperoxide as oxidants. The hybrids showed good catalytic activity, and 2 behaved as a reaction-induced self-separating catalyst for olefin epoxidation with H2O2, presenting advantages of homogeneous and heterogeneous catalysis .publishe
Functionalized Adamantane Tectons Used in the Design of Mixed-Ligand Copper(II) 1,2,4-Triazolyl/Carboxylate MetalâOrganic Frameworks
Bistriazoles, 1,3-bis(1,2,4-triazol-4-yl)propane (tr2pr) and 1,3-bis(1,2,4-triazol-4-yl)adamantane (tr2ad), were examined in combination with the rigid tetratopic 1,3,5,7-adamantanetetracarboxylic acid (H4-adtc) platform for the construction of neutral heteroleptic copper(II) metalâorganic frameworks. Two coordination polymers, [{Cu4(OH)2(H2O)2}{Cu4(OH)2}(tr2pr)2(H-adtc)4]·2H2O (1) and [Cu4(OH)2(tr2ad)2(H-adtc)2(H2O)2]·3H2O (2), were synthesized and structurally characterized. In complexes 1 and 2, the N1,N2-1,2,4-triazolyl (tr) and ÎŒ3-OHâ groups serve as complementary bridges between adjacent metal centers supporting the tetranuclear dihydroxo clusters. The structure of 1 represents a unique association of two different kinds of centrosymmetrical {Cu4(OH)2} units in a tight 3D framework, while in compound 2, another configuration type of acentric tetranuclear metal clusters is organized in a layered 3,6-hexagonal motif. In both cases, the {Cu4(OH)2} secondary building block and trideprotonated carboxylate H-adtc3â can be viewed as covalently bound six- and three-connected nodes that define the net topology. The tr ligands, showing ÎŒ3- or ÎŒ4-binding patterns, introduce additional integrating links between the neighboring {Cu4(OH)2} fragments. A variable-temperature magnetic susceptibility study of 2 demonstrates strong antiferromagnetic intracluster coupling (J1 = â109 cmâ1 and J2 = â21 cmâ1), which combines for the bulk phase with a weak antiferromagnetic intercluster interaction (zj = â2.5 cmâ1)
A Molybdenum Trioxide Hybrid Decorated by 3-(1,2,4-Triazol-4-yl)adamantane-1-carboxylic Acid: A Promising Reaction-Induced Self-Separating (RISS) Catalyst
3-(1,2,4-Triazol-4-yl)adamantane-1-carboxylic acid (tradcH), a heterobifunctional organic ligand in which carboxylic acid and 1,2,4-triazole groups are united through a rigid 1,3-adamantanediyl spacer, was employed for the synthesis of a MoVI oxide organic hybrid. The ligand crystallized from water as tradcH·H2O (1), possessing a two-dimensional hydrogen-bonding network, and from ethanol as a cyclic molecular solvate with the composition (tradcH)3·2EtOH (2). Treatment of tradcH with MoO3 under hydrothermal conditions afforded a new Mo trioxide hybrid, [MoO3(tradcH)]·H2O (3), which was structurally characterized. In 3, the molybdenum atoms form a polymeric zigzag chain of {Ό2-O-MoO2}n which is supported by double triazole bridges, while the carboxylic acid termini are left uncoordinated. The coordination environment of the Mo centers appears as distorted cis-{MoN2O4} octahedra. The hybrid exhibits high thermal stability (up to 270 °C) and was employed for a relatively broad scope of catalytic oxidation reactions in the liquid phase. Its catalytic behavior may be compared to a reversible mutation, featuring the best sides of homogeneous and heterogeneous catalysis. The original solid material converts into soluble active species, and the latter revert to the original material upon completion of the catalytic reaction, precipitating and allowing straightforward catalyst separation/reuse (like a heterogeneous catalyst). This catalyst was explored for a chemical reaction scope covering sulfoxidation, oxidative alcohol dehydrogenation, aldehyde oxidation, and olefin epoxidation, using hydrogen peroxide as an eco-friendly oxidant that gives water as a coproduct.publishe
Composition Space Analysis in the Development of Copper Molybdate Hybrids Decorated by a Bifunctional Pyrazolyl/1,2,4-Triazole Ligand
A bitopic ligand, 4-(3,5-dimethylpyrazol-4-yl)-1,2,4-triazole (Hpz-tr) (1), containing two different heterocyclic moieties was employed for the design of copper(II)âmolybdate solids under hydrothermal conditions. In the multicomponent CuII/Hpz-tr/MoVI system, a diverse set of coordination hybrids, [Cu(Hpz-tr)2SO4]·3H2O (2), [Cu(Hpz-tr)Mo3O10] (3), [Cu4(OH)4(Hpz-tr)4Mo8O26]·6H2O (4), [Cu(Hpz-tr)2Mo4O13] (5), and [Mo2O6(Hpz-tr)]·H2O (6), was prepared and characterized. A systematic investigation of these systems in the form of a ternary crystallization diagram approach was utilized to show the influence of the molar ratios of starting reagents, the metal (CuII and MoVI) sources, the temperature, etc., on the reaction products outcome. Complexes 2â4 dominate throughout a wide crystallization range of the composition triangle, while the other two compounds 5 and 6 crystallize as minor phases in a narrow concentration range. In the crystal structures of 2â6, the organic ligand behaves as a short [NâN]-triazole linker between metal centers Cu···Cu in 2â4, Cu···Mo in 5, and Mo···Mo in 6, while the pyrazolyl function remains uncoordinated. This is the reason for the exceptional formation of low-dimensional coordination motifs: 1D for 2, 4, and 6 and 2D for 3 and 5. In all cases, the pyrazolyl group is involved in H bonding (H-donor/H-acceptor) and is responsible for ÏâÏ stacking, thus connecting the chain and layer structures in more complicated H-bonding architectures. These compounds possess moderate thermal stability up to 250â300 °C. The magnetic measurements were performed for 2â4, revealing in all three cases antiferromagnetic exchange interactions between neighboring CuII centers and long-range order with a net moment below Tc of 13 K for compound 4
Composition Space Analysis in the Development of Copper Molybdate Hybrids Decorated by a Bifunctional Pyrazolyl/1,2,4-Triazole Ligand
A bitopic ligand, 4-(3,5-dimethylpyrazol-4-yl)-1,2,4-triazole (Hpz-tr) (1), containing two different heterocyclic moieties was employed for the design of copper(II)âmolybdate solids under hydrothermal conditions. In the multicomponent CuII/Hpz-tr/MoVI system, a diverse set of coordination hybrids, [Cu(Hpz-tr)2SO4]·3H2O (2), [Cu(Hpz-tr)Mo3O10] (3), [Cu4(OH)4(Hpz-tr)4Mo8O26]·6H2O (4), [Cu(Hpz-tr)2Mo4O13] (5), and [Mo2O6(Hpz-tr)]·H2O (6), was prepared and characterized. A systematic investigation of these systems in the form of a ternary crystallization diagram approach was utilized to show the influence of the molar ratios of starting reagents, the metal (CuII and MoVI) sources, the temperature, etc., on the reaction products outcome. Complexes 2â4 dominate throughout a wide crystallization range of the composition triangle, while the other two compounds 5 and 6 crystallize as minor phases in a narrow concentration range. In the crystal structures of 2â6, the organic ligand behaves as a short [NâN]-triazole linker between metal centers Cu···Cu in 2â4, Cu···Mo in 5, and Mo···Mo in 6, while the pyrazolyl function remains uncoordinated. This is the reason for the exceptional formation of low-dimensional coordination motifs: 1D for 2, 4, and 6 and 2D for 3 and 5. In all cases, the pyrazolyl group is involved in H bonding (H-donor/H-acceptor) and is responsible for ÏâÏ stacking, thus connecting the chain and layer structures in more complicated H-bonding architectures. These compounds possess moderate thermal stability up to 250â300 °C. The magnetic measurements were performed for 2â4, revealing in all three cases antiferromagnetic exchange interactions between neighboring CuII centers and long-range order with a net moment below Tc of 13 K for compound 4
Unprecedented Trapping of Difluorooctamolybdate Anions within an α-Polonium Type Coordination Network
New fluorinated hybrid solids [Mo2F2O5(tr2pr)] (1), [Co3(tr2pr)2(MoO4)2F2]·7H2O (2), and [Co3(H2O)2(tr2pr)3(Mo8O26F2)]·3H2O (3) (tr2pr = 1,3-bis(1,2,4-triazol-4-yl)propane) were prepared from the reaction systems consisting of Co(OAc)2/CoF2 and MoO3/(NH4)6Mo7O24, as CoII and MoVI sources, in water (2) or in aqueous HF (1, 3) employing mild hydrothermal conditions. The tr2pr ligand serves as a conformationally flexible tetradentate donor. In complex 1, the octahedrally coordinated Mo atoms are linked in the discrete corner-sharing {Mo2(ÎŒ2-O)F2O4N4} unit in which a pair of tr-heterocycles (tr = 1,2,4-triazole) is arranged in cis-positions opposite to âmolybdenylâ oxygen atoms. The antiâanti conformation type of tr2pr facilitates the tight zigzag chain packing motif. The crystal structure of the mixed-anion complex salt 2 consists of trinuclear [Co3(ÎŒ3-MoO4)2(ÎŒ2-F)2] units self-assembling in CoII-undulating chains (Co···Co 3.0709(15) and 3.3596(7) Ă
), which are cross-linked by tr2pr in layers. In 3, containing condensed oxyfluoromolybdate species, linear centrosymmetric [Co3(ÎŒ2-tr)6]6+ SBUs are organized at distances of 10.72â12.45 Ă
in an α-Po-like network using bitopic tr-linkers. The octahedral {N6} and {N3O3} environments of the central and peripheral cobalt atoms, respectively, are filled by triazole N atoms, water molecules, and coordinating [Mo8O26F2]6â anions. Acting as a tetradentate O-donor, each difluorooctamolybdate anion anchors four [Co3(ÎŒ2-tr)6]6+ units through their peripheral Co-sites, which consequently leads to a novel type of a two-nodal 4,10-c net with the SchlaÌfli symbol {32.43.5}{34.420.516.65}. The 2D and 3D coordination networks of 2 and 3, respectively, are characterized by significant overall antiferromagnetic exchange interactions (J/k) between the CoII spin centers on the order of â8 and â4 K. The [Mo8O26F2]6â anion is investigated in detail by quantum chemical calculations