Evidence review : liraglutide for the treatment of type 2 diabetes

This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of liraglutide in the treatment of type 2 diabetes mellitus, based upon the manufacturer’s submission to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal process. The manufacturer proposed the use of liraglutide as a second or third drug in patients with type 2 diabetes whose glycaemic control was unsatisfactory with metformin, with or without a second oral glucose-lowering drug. The submission included six manufacturer-sponsored trials that compared the efficacy of liraglutide against other glucose-lowering agents. Not all of the trials were relevant to the decision problem. The most relevant were Liraglutide Effects and Actions in Diabetes 5 (LEAD-5) (liraglutide used as part of triple therapy and compared against insulin glargine) and LEAD-6 [liraglutide in triple therapy compared against another glucagon-like peptide-1 agonist, exenatide]. Five of the six trials were published in full and one was then unpublished. Two doses of liraglutide, 1.2 and 1.8 mg, were used in some trials, but in the two comparisons in triple therapy, against glargine and exenatide, only the 1.8-mg dose was used. Liraglutide in both doses was found to be clinically effective in lowering blood glucose concentration [glycated haemoglobin (HbA1c)], reducing weight (unlike other glucose-lowering agents, such as sulphonylureas, glitazones and insulins, which cause weight gain) and also reducing systolic blood pressure (SBP). Hypoglycaemia was uncommon. The ERG carried out meta-analyses comparing the 1.2- and 1.8-mg doses of liraglutide, which suggested that there was no difference in control of diabetes, and only a slight difference in weight loss, insufficient to justify the extra cost. The cost-effectiveness analysis was carried out using the Center for Outcomes Research model. The health benefit was reported as quality-adjusted life-years (QALYs). The manufacturer estimated the cost-effectiveness to be £15,130 per QALY for liraglutide 1.8 mg compared with glargine, £10,054 per QALY for liraglutide 1.8 mg compared with exenatide, £10,465 per QALY for liraglutide 1.8 mg compared with sitagliptin, and £9851 per QALY for liraglutide 1.2 mg compared with sitagliptin. The ERG conducted additional sensitivity analyses and concluded that the factors that carried most weight were: in the comparison with glargine, the direct utility effects of body mass index (BMI) changes and SBP, with some additional contribution from HbA1c in the comparison with exenatide, HbA1c, with some additional effects from cholesterol and triglycerides in the comparison with sitagliptin, HbA1c and direct utility effects of BMI changes. The European Medicines Agency has approved liraglutide in dual therapy with other oral glucose-lowering agents. NICE guidance recommends the use of liraglutide 1.2 mg in triple therapy when glycaemic control remains or becomes inadequate with a combination of two oral glucose-lowering drugs. The use of liraglutide 1.2 mg in a dual therapy is indicated only in patients who are intolerant of, or have contraindications to, three oral glucose-lowering drugs. The use of liraglutide 1.8 mg was not approved by NICE. The ERG recommends research into the (currently unlicensed) use of liraglutide in combination with long-acting insulin

An overview of the research evidence on ethnicity and communication in healthcare

• The aim of the present study was to identify and review the available research evidence on 'ethnicity and communication' in areas relevant to ensuring effective provision of mainstream services (e.g. via interpreter, advocacy and translation services); provision of services targeted on communication (e.g. speech and language therapy, counselling, psychotherapy); consensual/ participatory activities (e.g. consent to interventions), and; procedures for managing and planning for linguistic diversity

Metabolic modeling and analysis of the metabolic switch in Streptomyces coelicolor

Background The transition from exponential to stationary phase in Streptomyces coelicolor is accompanied by a major metabolic switch and results in a strong activation of secondary metabolism. Here we have explored the underlying reorganization of the metabolome by combining computational predictions based on constraint-based modeling and detailed transcriptomics time course observations. Results We reconstructed the stoichiometric matrix of S. coelicolor, including the major antibiotic biosynthesis pathways, and performed flux balance analysis to predict flux changes that occur when the cell switches from biomass to antibiotic production. We defined the model input based on observed fermenter culture data and used a dynamically varying objective function to represent the metabolic switch. The predicted fluxes of many genes show highly significant correlation to the time series of the corresponding gene expression data. Individual mispredictions identify novel links between antibiotic production and primary metabolism. Conclusion Our results show the usefulness of constraint-based modeling for providing a detailed interpretation of time course gene expression data

First observation of Bs0 → D*s2+Xμ-ν decays

Using data collected with the LHCb detector in proton–proton collisions at a centre-of-mass energy of 7 TeV, the semileptonic decays B0s→D+sXμ−ν and B0s→D0K+Xμ−ν are detected. Two structures are observed in the D0K+ mass spectrum at masses consistent with the known Ds1(2536)+ and D∗s22573)+ mesons. The measured branching fractions relative to the total B0s semileptonic rate are B(B0s→D∗+s2Xμ−ν)/B(B0s→Xμ−ν) = (3.3±1.0±0.4)%, and B(B0s→D+s1Xμ−ν)/B(B0s→Xμ−ν) = (5.4±1.2±0.5)%, where the first uncertainty is statistical and the second is systematic. This is the first observation of the D∗+s2 state in B0s decays; we also measure its mass and width

Ethnicity : UK colorectal cancer screening pilot : final report

27. In summary, the overall evaluation of the UK Pilot has demonstrated that key parameters of test and programme performance observed in randomised studies of FOBt screening can be repeated in population-based pilot programmes. However, our study provides strong evidence of very low CRC screening uptake for ethnic groups in the Pilot area. This is coupled with a very low uptake of colonoscopy for individuals from ethnic groups with a positive FOBt result. 28. It has long been acknowledged that a diverse population may require diverse responses. Following the implementation of the Race Relations Amendment Act 2000, there has been a statutory duty laid upon all NHS agencies to ‘have due regard to the need to eliminate unlawful discrimination’, and to make explicit consideration of the implications for racial equality of every action or policy. 29. Because the observed overall outcomes in the UK Pilot generally compare favourably with the results of previous randomised trials of FOBt screening, the main Evaluation Group has concluded that benefits observed in the trials should be repeatable in a national roll-out. 30. However, our study indicates that any national colorectal cancer screening programme would need to very carefully consider the implications of ethnicity for roll-out, and develop a strategic plan on how best to accommodate this at both a national and local level. Based on our findings, consideration will clearly need to be given to improved access and screening service provision for ethnic minorities. 31. In order to ensure adequate CRC screening provision for a diverse UK population, and to address the explicit implications for racial equality highlighted by our findings, interventions now urgently need to be evaluated to improve access for ethnic minorities. This work should be undertaken as part of the second round of CRC screening currently underway in the English Pilot

Measurement of the Bs0-Bs0 oscillation frequency δms in Bs0→Ds-(3)π decays

The Bs0-Bs0 oscillation frequency δms is measured with 36 pb-1 of data collected in pp collisions at s=7TeV by the LHCb experiment at the Large Hadron Collider. A total of 1381 Bs0→Ds-π+ and Bs0→Ds-π+π-π + signal decays are reconstructed, with average decay time resolutions of 44 fs and 36 fs, respectively. An oscillation signal with a statistical significance of 4.6σ is observed. The measured oscillation frequency is δm s=17.63±0.11(stat)±0.02(syst)ps -1

Study of beauty hadron decays into pairs of charm hadrons

First observations of the decays Λb 0 → Λc +D(s) - are reported using data corresponding to an integrated luminosity of 3fb-1 collected at 7 and 8 TeV center-of-mass energies in proton-proton collisions with the LHCb detector. In addition, the most precise measurement of the branching fraction B(Bs 0→D+Ds -) is made and a search is performed for the decays B(s) 0→Λc +Λc -. The results obtained are B(Λb 0→Λc +D-)/ B(Λb 0→Λc +D s -)=0.042±0.003(stat)±0.003(syst), [B(Λb 0→Λc +D s -)/B(B̄0→D+D s -)]/[B(Λb 0→Λ c +π-)/B(B̄0→D +π-)]=0.96±0.02(stat)±0.06(syst),B(B s 0→D+Ds -)/ B(B̄0→D+Ds -)=0. 038±0.004(stat)±0.003(syst),B(B̄0→Λ c +Λc -)/B(B̄ 0→D+Ds -)<0.0022[95%C.L.], B(Bs 0→Λc +Λ c -)/B(Bs 0→D+D s -)<0.30[95%C.L.]. Measurement of the mass of the Λb 0 baryon relative to the B̄0 meson gives M(Λb 0)-M(B̄0)=339. 72±0.24(stat)±0.18(syst)MeV/c2. This result provides the most precise measurement of the mass of the Λb 0 baryon to date

Observation of the suppressed ADS modes B± → [π±K-/+ π+π-]D K± and B± → [π± K-/+π+π-]Dπ±

An analysis of and B± → DK± and B± → Dπ± decays is presented where the D meson is reconstructed in the four-body final state K± π-/+π+π-. Using LHCb data corresponding to an integrated luminosity of 1.0 fb-1, first observations are made of the suppressed ADS modes B± →[π± K-/+π+π-]DK± and B± → [π± K-/+π+π-]Dπ± with a significance of 5.1 sigma and greater than 10 sigma, respectively. Measurements of CP asymmetries and CP-conserving ratios of partial widths from this family of decays are also performed. The magnitude of the ratio between the suppressed and favoured B± → DK ± amplitudes is determined to be rKB = 0.097 ± 0.011

First observation of the decay B0s→ϕK∗0

The first observation of the decay B0s→ϕK∗0 is reported. The analysis is based on a data sample corresponding to an integrated luminosity of 1.0 fb−1 of pp collisions at s√=7 TeV, collected with the LHCb detector. A yield of 30 ± 6 B0s→(K+K−)(K−π+) decays is found in the mass windows 1012.5 < M (K + K −) < 1026.5 MeV/c 2 and 746 < M(K − π +) < 1046 MeV/c 2. The signal yield is found to be dominated by B0s→ϕK∗0 decays, and the corresponding branching fraction is measured to be B(B0s→ϕK∗0) = (1.10 ± 0.24 (stat) ± 0.14 (syst) ± 0.08 (f d /f s )) × 10−6, where the uncertainties are statistical, systematic and from the ratio of fragmentation fractions f d /f s which accounts for the different production rate of B 0 and B0s mesons. The significance of B0s→ϕK∗0 signal is 6.1 standard deviations. The fraction of longitudinal polarization in B0s→ϕK∗0 decays is found to be f 0 = 0.51 ± 0.15 (stat) ± 0.07 (syst)

Effective lifetime measurements in the B-s(0) -> K+K-, B-0 -> K+pi(-) and B-s(0) -> pi K-+(-) decays

Measurements of the effective lifetimes in the View the MathML source, B0→K+π− and View the MathML source decays are presented using 1.0 fb−1 of pp collision data collected at a centre-of-mass energy of 7 TeV by the LHCb experiment. The analysis uses a data-driven approach to correct for the decay time acceptance. This is the most precise determination to date of the effective lifetime in the View the MathML source decay and provides constraints on contributions from physics beyond the Standard Model to the View the MathML source mixing phase and the width difference ΔΓs