Long-term glycaemic control with metformin– sulphonylurea–pioglitazone triple therapy in PROactive (PROactive 17)

peer reviewedAims We assessed the long-term glycaemic effects and the safety profile of triple therapy with the addition of pioglitazone vs. placebo in patients with Type 2 diabetes treated with combined metformin–sulphonylurea therapy in the PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive). Methods In a post-hoc analysis, we identified patients treated with metformin plus sulphonylurea combination therapy and not receiving insulin at baseline (n = 1314). In those patients, we compared the effects of pioglitazone (force-titrated to 45 mg⁄ day, n = 654) vs. placebo (n = 660) on glycated haemoglobin (HbA1c) reduction, concomitant changes in medications and initiation of permanent insulin use (defined as daily insulin use for a period of ‡ 90 days or ongoing use at death ⁄ final visit). Results Significantly greater reductions in HbA1c and greater proportions of patients with HbA1c at target were noted with pioglitazone vs, placebo, despite a decrease in the use of other oral glucose-lowering agents. Therewas an approximate twofold increase in progression to permanent insulin use in the placebo group vs. the pioglitazone group: 31.1 vs. 16.1%, respectively, when added to combination therapy. The overall safety of themetformin–sulphonylurea–pioglitazone triple therapy was good. Conclusions Intensifying an existing dual oral therapy regimen to a triple oral regimen by adding pioglitazone to the classical metformin–sulphonylurea combination resulted in sustained improvements in glycaemic control and reduced progression to insulin therapy. The advantages and disadvantages of adding pioglitazone instead of adding basal insulin should be assessed further

Computer-controlled apparatus for automated development of continuous flow methods

An automated apparatus to assist in the development of analytical continuous flow methods is described. The system is capable of controlling and monitoring a variety of pumps, valves, and detectors through an IBM PC-AT compatible computer. System components consist of two types of peristaltic pumps (including a multiple pump unit), syringe pumps, electrically and pneumatically actuated valves, and an assortment of spectrophotometric and electrochemical detectors. Details of the interface circuitry are given where appropriate. To demonstrate the utility of the system, an automatically generated response surface is presented for the flow injection determination of iron(II) by its reaction with 1,10-phenanthroline

Hybridised multigrid preconditioners for a compatible finite element dynamical core

Compatible finite element discretisations for the atmospheric equations of motion have recently attracted considerable interest. Semi-implicit timestepping methods require the repeated solution of a large saddle-point system of linear equations. Preconditioning this system is challenging since the velocity mass matrix is non-diagonal, leading to a dense Schur complement. Hybridisable discretisations overcome this issue: weakly enforcing continuity of the velocity field with Lagrange multipliers leads to a sparse system of equations, which has a similar structure to the pressure Schur complement in traditional approaches. We describe how the hybridised sparse system can be preconditioned with a non-nested two-level preconditioner. To solve the coarse system, we use the multigrid pressure solver that is employed in the approximate Schur complement method previously proposed by the some of the authors. Our approach significantly reduces the number of solver iterations. The method shows excellent performance and scales to large numbers of cores in the Met Office next-generation climate- and weather prediction model LFRic.Comment: 24 pages, 13 figures, 5 tables; accepted for publication in Quarterly Journal of the Royal Meteorological Societ

Presence of anti-eukaryotic initiation factor-2B, anti-RuvBL1/2 and anti-synthetase antibodies in patients with anti-nuclear antibody negative systemic sclerosis

Objectives: Autoantibodies targeting ubiquitously expressed nuclear antigens can be identified in most patients with SSc. Cytoplasmic autoantibodies (in otherwise ANA-negative sera) targeting eukaryotic initiation factor-2B (anti-eIF2B) have recently been identified in SSc with clinical associations to dcSSc disease and interstitial lung disease (ILD), although the majority of samples originated from a tertiary SSc-ILD centre. We investigated the prevalence and clinical associations of recently described SSc-specific (including anti-eIF2B) and other cytoplasmic autoantibodies in ANA-negative sera obtained from a large representative SSc cohort.Methods: ANA-negative sera from the Scleroderma Family Registry and DNA Repository underwent indirect immunofluorescence, radiolabelled protein immunoprecipitation (± immunodepletion) to identify anti-eIF2B and other CTD-related autoantibodies. The clinical phenotype of positive samples was evaluated.Results: Immunoprecipitation was performed on 128 ANA-negative samples (obtained from 3249 SSc patients). Anti-eIF2B antibodies were present in nine patients (7%), the majority of whom had dcSSc (8/9). SSc-ILD was present in all anti-eIF2B patients for whom chest imaging was available (7/9). Anti-synthetase autoantibodies (targeting PL12, PL7, OJ and Zo) were identified in seven patients (5.5%), all of whom fulfilled the 2013 ACR/EULAR classification criteria for SSc and had evidence of SSc-ILD where relevant outcomes were available for evaluation. Anti-RuvBL1/2 antibodies were identified in two patients with SSc-overlap syndromes.Conclusion: Anti-eIF2B antibodies are cytoplasmic SSc-specific autoantibodies with strong clinical associations with dcSSc and SSc-ILD found in ANA-negative sera. Anti-synthetase autoantibodies, and other recently discovered SSc-specific antibodies such as anti-RuvBL1/2, can also be identified in ANA-negative SSc.</p

Presence of anti-eukaryotic initiation factor-2B, anti-RuvBL1/2 and anti-synthetase antibodies in patients with anti-nuclear antibody negative systemic sclerosis

Objectives: Autoantibodies targeting ubiquitously expressed nuclear antigens can be identified in most patients with SSc. Cytoplasmic autoantibodies (in otherwise ANA-negative sera) targeting eukaryotic initiation factor-2B (anti-eIF2B) have recently been identified in SSc with clinical associations to dcSSc disease and interstitial lung disease (ILD), although the majority of samples originated from a tertiary SSc-ILD centre. We investigated the prevalence and clinical associations of recently described SSc-specific (including anti-eIF2B) and other cytoplasmic autoantibodies in ANA-negative sera obtained from a large representative SSc cohort.Methods: ANA-negative sera from the Scleroderma Family Registry and DNA Repository underwent indirect immunofluorescence, radiolabelled protein immunoprecipitation (± immunodepletion) to identify anti-eIF2B and other CTD-related autoantibodies. The clinical phenotype of positive samples was evaluated.Results: Immunoprecipitation was performed on 128 ANA-negative samples (obtained from 3249 SSc patients). Anti-eIF2B antibodies were present in nine patients (7%), the majority of whom had dcSSc (8/9). SSc-ILD was present in all anti-eIF2B patients for whom chest imaging was available (7/9). Anti-synthetase autoantibodies (targeting PL12, PL7, OJ and Zo) were identified in seven patients (5.5%), all of whom fulfilled the 2013 ACR/EULAR classification criteria for SSc and had evidence of SSc-ILD where relevant outcomes were available for evaluation. Anti-RuvBL1/2 antibodies were identified in two patients with SSc-overlap syndromes.Conclusion: Anti-eIF2B antibodies are cytoplasmic SSc-specific autoantibodies with strong clinical associations with dcSSc and SSc-ILD found in ANA-negative sera. Anti-synthetase autoantibodies, and other recently discovered SSc-specific antibodies such as anti-RuvBL1/2, can also be identified in ANA-negative SSc.</p

(1R,2R,3S,6aS,7R,8R,9S,12aS)-1,2,3,7,8,9-Hexahydroxy­perhydro­dipyrido[1,2-a:1′,2′-d]pyrazine-6,12-dione

The crystal structure of the title compound, C12H18N2O8, exists as O—H⋯O hydrogen-bonded layers of mol­ecules running parallel to the ab plane. Each mol­ecule is a donor and acceptor for six hydrogen bonds. The absolute stereochemistry was determined by the use of d-glucuronolactone as the starting material

1-(1-Carboxy­methyl-1,4-anhydro-2,3-O-isopropyl­idene-α-d-erythrofuranos­yl)thymine

X-Ray crystallography unequivocally determined the stereochemistry of the thymine base in the title compound, C14H18N2O7. The absolute stereochemistry was determined from the use of d-ribose as the starting material. There are two independent mol­ecules in the asymmetric unit (Z′ = 2) which exist as N—H⋯O hydrogen-bonded pairs in the crystal structure

2-O-Benzhydryl-3,4-(S)-O-benzyl­idene-d-lyxono-1,4-lactone

X-ray crystallography unequivocally showed that protection of the free hydroxyl group of 3,5-O-benzyl­idene-d-lyxono-1,4-lactone with diphenyl­diazo­methane proceeded with retention of configuration to give the title compound, C25H22O5. The crystal structure consists of layers of inter­locked mol­ecules lying parallel to the a axis

3,4-O-Isopropyl­idene-2-C-methyl-d-galactonolactone

X-ray crystallography unequivocally confirmed the stereochemistry of the 2-C-methyl group in the title mol­ecule, C10H16O6, in which the 1,5-lactone ring exists in a boat conformation. The use of d-galactose in the synthesis determined the absolute stereochemistry. The crystal exists as O—H⋯O hydrogen-bonded layers in the ab plane, with each mol­ecule acting as a donor and acceptor for two hydrogen bonds