Evaluating the cost-effectiveness of insulin detemir versus neutral protamine Hagedorn insulin in patients with type 1 or type 2 diabetes in the UK using a short-term modeling approach

Background: To estimate the short-term cost-effectiveness of insulin detemir (IDet) versus neutral protamine Hagedorn (NPH) insulin based on the incidence of non-severe hypoglycemia and changes in body weight in subjects with type 1 diabetes (T1D) or type 2 diabetes (T2D) in the UK. Methods: A model was developed to evaluate cost-effectiveness based on non-severe hypoglycemia, body mass index, and pharmacy costs over 1 year. Published rates of non-severe hypoglycemia were employed in the T1D and T2D analyses, while reduced weight gain with IDet was modeled in the T2D analysis only. Effectiveness was calculated in terms of quality-adjusted life expectancy using published utility scores. Pharmacy costs were captured using published prices and defined daily doses. Costs were expressed in 2016 pounds sterling (GBP). Sensitivity analyses were performed (including probabilistic sensitivity analysis). Results: In T1D, IDet was associated with fewer non-severe hypoglycemic events than NPH insulin (126.7 versus 150.8 events per person-year), leading to an improvement of 0.099 quality-adjusted life years (QALYs). Costs with IDet were GBP 60 higher, yielding an incremental cost-effectiveness ratio (ICER) of GBP 610 per QALY gained. In T2D, mean non-severe hypoglycemic event rates and body weight were lower with IDet than NPH insulin, leading to a total incremental utility of 0.120, accompanied by an annual cost increase of GBP 171, yielding an ICER of GBP 1,422 per QALY gained for IDet versus NPH insulin. Conclusion: Short-term health economic evaluation showed IDet to be a cost-effective alternative to NPH insulin in the UK due to lower rates of non-severe hypoglycemia (T1D and T2D) and reduced weight gain (T2D only)

Prolonged prothrombotic effects of antecedent hypoglycemia in individuals with type 2 diabetes

OBJECTIVE Hypoglycemia has been linked to persistent increases in cardiovascular (CV) mortality in type 2 diabetes after the event. Our aim was to examine acute and downstream effects of hypoglycemia on markers of thrombosis risk and inflammation in type 2 diabetes. RESEARCH DESIGN AND METHODS Twelve individuals with type 2 diabetes with no history of CV disease and 11 age- and BMI-matched volunteers without diabetes underwent paired hyperinsulinemic-euglycemic (glucose 6 mmol/L for two 60-min periods) and hypoglycemic (glucose 2.5 mmol/L for two 60-min periods) clamps on separate occasions on day 0. Fibrin clot properties, platelet reactivity, and inflammatory markers were measured at baseline, end of and after recovery from the initial clamp, day 1, and day 7 using validated assays and electron microscopy. RESULTS Euglycemic hyperinsulinemia reduced platelet reactivity, decreased fibrin clot density, and improved fibrinolytic efficiency in both groups. Platelet reactivity and aggregation increased during acute hypoglycemia in both groups, resolving at recovery. In type 2 diabetes, clot lysis times and clot maximum absorbance increased up to day 7 (P = 0.002 and 0.001 vs. euglycemia, respectively), but clots from control subjects without diabetes showed limited changes. Fibrin network density increased Δ 1.15 ± 0.28 fibers/μm2 at day 7 after the hypoglycemic clamp (P < 0.01 for glycemic arm), whereas fibrinogen and complement C3 increased after hypoglycemia up to day 7 in type 2 diabetes only. CONCLUSIONS Antecedent hypoglycemia has acute and persistent prothrombotic effects, lasting at least 7 days, that were enhanced in individuals with type 2 diabetes. These findings identify mechanisms by which hypoglycemia might increase short- and medium-term risk of CV mortality

Evaluation of sesamum gum as an excipient in matrix tablets

In developing countries modern medicines are often beyond the affordability of the majority of the population. This is due to the reliance on expensive imported raw materials despite the abundance of natural resources which could provide an equivalent or even an improved function. The aim of this study was to investigate the potential of sesamum gum (SG) extracted from the leaves of Sesamum radiatum (readily cultivated in sub-Saharan Africa) as a matrix former. Directly compressed matrix tablets were prepared from the extract and compared with similar matrices of HPMC (K4M) using theophylline as a model water soluble drug. The compaction, swelling, erosion and drug release from the matrices were studied in deionized water, 0.1 N HCl (pH 1.2) and phosphate buffer (pH 6.8) using USP apparatus II. The data from the swelling, erosion and drug release studies were also fitted into the respective mathematical models. Results showed that the matrices underwent a combination of swelling and erosion, with the swelling action being controlled by the rate of hydration in the medium. SG also controlled the release of theophylline similar to the HPMC and therefore may have use as an alternative excipient in regions where Sesamum radiatum can be easily cultivated

Measurement of the correlation between flow harmonics of different order in lead-lead collisions at √sNN = 2.76 TeV with the ATLAS detector

Correlations between the elliptic or triangular flow coefficients vm (m=2 or 3) and other flow harmonics vn (n=2 to 5) are measured using √sNN=2.76 TeV Pb+Pb collision data collected in 2010 by the ATLAS experiment at the LHC, corresponding to an integrated luminosity of 7 μb−1. The vm−vn correlations are measured in midrapidity as a function of centrality, and, for events within the same centrality interval, as a function of event ellipticity or triangularity defined in a forward rapidity region. For events within the same centrality interval, v3 is found to be anticorrelated with v2 and this anticorrelation is consistent with similar anticorrelations between the corresponding eccentricities, ε2 and ε3. However, it is observed that v4 increases strongly with v2, and v5 increases strongly with both v2 and v3. The trend and strength of the vm−vn correlations for n=4 and 5 are found to disagree with εm−εn correlations predicted by initial-geometry models. Instead, these correlations are found to be consistent with the combined effects of a linear contribution to vn and a nonlinear term that is a function of v22 or of v2v3, as predicted by hydrodynamic models. A simple two-component fit is used to separate these two contributions. The extracted linear and nonlinear contributions to v4 and v5 are found to be consistent with previously measured event-plane correlations

Search for vectorlike B quarks in events with one isolated lepton, missing transverse momentum, and jets at √s = 8 TeV with the ATLAS detector

A search has been performed for pair production of heavy vectorlike down-type (B) quarks. The analysis explores the lepton-plus-jets final state, characterized by events with one isolated charged lepton (electron or muon), significant missing transverse momentum, and multiple jets. One or more jets are required to be tagged as arising from b quarks, and at least one pair of jets must be tagged as arising from the hadronic decay of an electroweak boson. The analysis uses the full data sample of pp collisions recorded in 2012 by the ATLAS detector at the LHC, operating at a center-of-mass energy of 8 TeV, corresponding to an integrated luminosity of 20.3 fb −1 . No significant excess of events is observed above the expected background. Limits are set on vectorlike B production, as a function of the B branching ratios, assuming the allowable decay modes are B → Wt/Zb/Hb. In the chiral limit with a branching ratio of 100% for the decay B → Wt, the observed (expected) 95% C.L. lower limit on the vectorlike B mass is 810 GeV (760 GeV). In the case where the vectorlike B quark has branching ratio values corresponding to those of an SU(2) singlet state, the observed (expected) 95% C.L. lower limit on the vectorlike B mass is 640 GeV (505 GeV). The same analysis, when used to investigate pair production of a colored, charge 5/3 exotic fermion T 5/3 , with subsequent decay T 5/3 → Wt, sets an observed (expected) 95% C.L. lower limit on the T 5/3 mass of 840 GeV (780 GeV)

Mutations in CDC45, Encoding an Essential Component of the Pre-initiation Complex, Cause Meier-Gorlin Syndrome and Craniosynostosis

DNA replication precisely duplicates the genome to ensure stable inheritance of genetic information. Impaired licensing of origins of replication during the G1 phase of the cell cycle has been implicated in Meier-Gorlin syndrome (MGS), a disorder defined by the triad of short stature, microtia, and a/hypoplastic patellae. Biallelic partial loss-of-function mutations in multiple components of the pre-replication complex (preRC; ORC1, ORC4, ORC6, CDT1, or CDC6) as well as de novo stabilizing mutations in the licensing inhibitor, GMNN, cause MGS. Here we report the identification of mutations in CDC45 in 15 affected individuals from 12 families with MGS and/or craniosynostosis. CDC45 encodes a component of both the pre-initiation (preIC) and CMG helicase complexes, required for initiation of DNA replication origin firing and ongoing DNA synthesis during S-phase itself, respectively, and hence is functionally distinct from previously identified MGS-associated genes. The phenotypes of affected individuals range from syndromic coronal craniosynostosis to severe growth restriction, fulfilling diagnostic criteria for Meier-Gorlin syndrome. All mutations identified were biallelic and included synonymous mutations altering splicing of physiological CDC45 transcripts, as well as amino acid substitutions expected to result in partial loss of function. Functionally, mutations reduce levels of full-length transcripts and protein in subject cells, consistent with partial loss of CDC45 function and a predicted limited rate of DNA replication and cell proliferation. Our findings therefore implicate the preIC as an additional protein complex involved in the etiology of MGS and connect the core cellular machinery of genome replication with growth, chondrogenesis, and cranial suture homeostasis

M100 and NGC 6951: Morphological Clues to Central Dynamics

Original paper can be found at: http://www.astrosociety.org/pubs/cs/070-112.html--Copyright Astronomical Society of the PacificHigh-resolution optical and NIR observations are used to constrain a dynamical model of the circumnuclear star forming (SF) region in the barred galaxy M100 (NGC 4321). Small leading arms observed in our K-band image of the nuclear region have been reproduced in numerical modeling of M100, a galaxy with a double inner Lindblad resonance (ILR). We also present preliminary optical and NIR observations of NGC 6951: a barred galaxy with circumnuclear SF showing a distinctly different behavior to M100 at 2.2um