Glycaemic control and hypoglycaemia benefits with insulin glargine 300 U/mL extend to people with type 2 diabetes and mild-to-moderate renal impairment

Aim: To investigate the impact of renal function on the safety and efficacy of insulin glargine 300 U/mL (Gla-300) and insulin glargine 100 U/mL (Gla-100). Materials and Methods: A meta-analysis was performed using pooled 6-month data from the EDITION 1, 2 and 3 trials (N = 2496). Eligible participants, aged ≥18 years with a diagnosis of type 2 diabetes (T2DM), were randomized to receive once-daily evening injections of Gla-300 or Gla-100. Pooled results were assessed by two renal function subgroups: estimated glomerular filtration rate (eGFR) <60 and ≥60 mL/min/1.73 m2 . Results: The decrease in glycated haemoglobin (HbA1c) after 6 months and the proportion of individuals with T2DM achieving HbA1c targets were similar in the Gla-300 and Gla-100 groups, for both renal function subgroups. There was a reduced risk of nocturnal (12:00-5:59 AM) confirmed (≤3.9 mmol/L [≤70 mg/dL]) or severe hypoglycaemia with Gla-300 in both renal function subgroups (eGFR <60 mL/min/1.73 m2 : relative risk [RR] 0.76 [95% confidence interval {CI} 0.62-0.94] and eGFR ≥60 mL/min/1.73 m2 : RR 0.75 [95% CI 0.67-0.85]). For confirmed (≤70 mg/dL [≤3.9 mmol/L]) or severe hypoglycaemia at any time of day (24 hours) the hypoglycaemia risk was lower with Gla-300 vs Gla-100 in both the lower (RR 0.94 [95% CI 0.86-1.03]) and higher (RR 0.90 [95% CI 0.85-0.95]) eGFR subgroups. Conclusions: Gla-300 provided similar glycaemic control to Gla-100, while indicating a reduced overall risk of confirmed (≤3.9 and <3.0 mmol/L [≤70 and <54 mg/dL]) or severe hypoglycaemia, with no significant difference between renal function subgroups

Conditional symmetries and the canonical quantization of constrained minisuperspace actions: The Schwarzschild case

A conditional symmetry is defined, in the phase space of a quadratic in velocities constrained action, as a simultaneous conformal symmetry of the supermetric and the superpotential. It is proven that such a symmetry corresponds to a variational (Noether) symmetry. The use of these symmetries as quantum conditions on the wave function entails a kind of selection rule. As an example, the minisuperspace model ensuing from a reduction of the Einstein-Hilbert action by considering static, spherically symmetric configurations and r as the independent dynamical variable is canonically quantized. The conditional symmetries of this reduced action are used as supplementary conditions on the wave function. Their integrability conditions dictate, at the first stage, that only one of the three existing symmetries can be consistently imposed. At a second stage one is led to the unique Casimir invariant, which is the product of the remaining two, as the only possible second condition on Ψ. The uniqueness of the dynamical evolution implies the need to identify this quadratic integral of motion to the reparametrization generator. This can be achieved by fixing a suitable parametrization of the r-lapse function, exploiting the freedom to arbitrarily rescale it. In this particular parametrization the measure is chosen to be the determinant of the supermetric. The solutions to the combined Wheeler-DeWitt and linear conditional symmetry equations are found and seen to depend on the product of the two &quot;scale factors&quot;. © 2013

Towards canonical quantum gravity for G1 geometries in 2+1 dimensions with a Λ-term

The canonical analysis and subsequent quantization of the (2+1)-dimensional action of pure gravity plus a cosmological constant term is considered, under the assumption of the existence of one spacelike Killing vector field. The proper imposition of the quantum analogues of two linear (momentum) constraints reduces an initial collection of state vectors, consisting of all smooth functionals of the components (and/or their derivatives) of the spatial metric, to particular scalar smooth functionals. The demand that the midi-superspace metric (inferred from the kinetic part of the quadratic (Hamiltonian) constraint) must define on the space of these states an induced metric whose components are given in terms of the same states, which is made possible through an appropriate re-normalization assumption, severely reduces the possible state vectors to three unique (up to general coordinate transformations) smooth scalar functionals. The quantum analogue of the Hamiltonian constraint produces a Wheeler-DeWitt equation based on this reduced manifold of states, which is completely integrated. © 2008 IOP Publishing Ltd

Towards canonical quantum gravity for 3+1 geometries admitting maximally symmetric two-dimensional surfaces

The canonical decomposition of all 3+1 geometries admitting two-dimensional space-like surfaces is exhibited as a generalization of a previous work. A proposal, consisting of a specific renormalization Assumption and an accompanying Requirement, which has been put forward in the 2+1 case is now generalized to 3+1 dimensions. This enables the canonical quantization of these geometries through a generalization of Kucha&apos;s quantization scheme in the case of infinite degrees of freedom. The resulting Wheeler-DeWitt equation is based on a renormalized manifold parameterized by three smooth scalar functionals. The entire space of solutions to this equation is analytically given, a fact that is entirely new to the present case. This is made possible through the exploitation of the residual freedom in the choice of the third functional, which is left by the imposition of the Requirement, and is proven to correspond to a general coordinate transformation in the renormalized manifold. © 2010 IOP Publishing Ltd

Glycaemic control and hypoglycaemia benefits with insulin glargine 300 U/mL extend to people with type 2 diabetes and mild-to-moderate renal impairment

Aim: To investigate the impact of renal function on the safety and efficacy of insulin glargine 300 U/mL (Gla-300) and insulin glargine 100 U/mL (Gla-100). Materials and Methods: A meta-analysis was performed using pooled 6-month data from the EDITION 1, 2 and 3 trials (N = 2496). Eligible participants, aged ≥18 years with a diagnosis of type 2 diabetes (T2DM), were randomized to receive once-daily evening injections of Gla-300 or Gla-100. Pooled results were assessed by two renal function subgroups: estimated glomerular filtration rate (eGFR) <60 and ≥60 mL/min/1.73 m2 . Results: The decrease in glycated haemoglobin (HbA1c) after 6 months and the proportion of individuals with T2DM achieving HbA1c targets were similar in the Gla-300 and Gla-100 groups, for both renal function subgroups. There was a reduced risk of nocturnal (12:00-5:59 AM) confirmed (≤3.9 mmol/L [≤70 mg/dL]) or severe hypoglycaemia with Gla-300 in both renal function subgroups (eGFR <60 mL/min/1.73 m2 : relative risk [RR] 0.76 [95% confidence interval {CI} 0.62-0.94] and eGFR ≥60 mL/min/1.73 m2 : RR 0.75 [95% CI 0.67-0.85]). For confirmed (≤70 mg/dL [≤3.9 mmol/L]) or severe hypoglycaemia at any time of day (24 hours) the hypoglycaemia risk was lower with Gla-300 vs Gla-100 in both the lower (RR 0.94 [95% CI 0.86-1.03]) and higher (RR 0.90 [95% CI 0.85-0.95]) eGFR subgroups. Conclusions: Gla-300 provided similar glycaemic control to Gla-100, while indicating a reduced overall risk of confirmed (≤3.9 and <3.0 mmol/L [≤70 and <54 mg/dL]) or severe hypoglycaemia, with no significant difference between renal function subgroups

On the Hong-Krahn-Szego inequality for the p-Laplace operator

Given an open set $\Omega$, we consider the problem of providing sharp lower bounds for $\lambda_2(\Omega)$, i.e. its second Dirichlet eigenvalue of the p-Laplace operator. After presenting the nonlinear analogue of the Hong-Krahn-Szego inequality, asserting that the disjoint unions of two equal balls minimize the second eigenvalue among open sets of given measure, we improve this spectral inequality by means of a quantitative stability estimate. The extremal cases p = 1 and p = $\infty$ are considered as well. Copyright 2012 Springer-Verlag Berlin Heidelberg

Genetic variant predictors of gene expression provide new insight into risk of colorectal cancer

Genome-wide association studies have reported 56 independently associated colorectal cancer (CRC) risk variants, most of which are non-coding and believed to exert their effects by modulating gene expression. The computational method PrediXcan uses cis-regulatory variant predictors to impute expression and perform gene-level association tests in GWAS without directly measured transcriptomes. In this study, we used reference datasets from colon (n = 169) and whole blood (n = 922) transcriptomes to test CRC association with genetically determined expression levels in a genome-wide analysis of 12,186 cases and 14,718 controls. Three novel associations were discovered from colon transverse models at FDR ≤ 0.2 and further evaluated in an independent replication including 32,825 cases and 39,933 controls. After adjusting for multiple comparisons, we found statistically significant associations using colon transcriptome models with TRIM4 (discovery P = 2.2 × 10− 4, replication P = 0.01), and PYGL (discovery P = 2.3 × 10− 4, replication P = 6.7 × 10− 4). Interestingly, both genes encode proteins that influence redox homeostasis and are related to cellular metabolic reprogramming in tumors, implicating a novel CRC pathway linked to cell growth and proliferation. Defining CRC risk regions as one megabase up- and downstream of one of the 56 independent risk variants, we defined 44 non-overlapping CRC-risk regions. Among these risk regions, we identified genes associated with CRC (P &amp;lt; 0.05) in 34/44 CRC-risk regions. Importantly, CRC association was found for two genes in the previously reported 2q25 locus, CXCR1 and CXCR2, which are potential cancer therapeutic targets. These findings provide strong candidate genes to prioritize for subsequent laboratory follow-up of GWAS loci. This study is the first to implement PrediXcan in a large colorectal cancer study and findings highlight the utility of integrating transcriptome data in GWAS for discovery of, and biological insight into, risk loci. © 2019, The Author(s)

Correction to: Genetic variant predictors of gene expression provide new insight into risk of colorectal cancer (Human Genetics, (2019), 138, 4, (307-326), 10.1007/s00439-019-01989-8)

Every author has erroneously been assigned to the affiliation “62”. The affiliation 62 belongs to the author Graham Casey. © 2019, Springer-Verlag GmbH Germany, part of Springer Nature