Fixed-dose combination therapy for type 2 diabetes:sitagliptin plus pioglitazone

Type 2 diabetes is typically associated with insulin resistance and dysfunction of insulin-secreting pancreatic beta-cells. Addressing these defects often requires therapy with a combination of differently acting antidiabetic agents. A potential novel combination in development brings together the dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin with the thiazolidinedione pioglitazone into a fixed-dose single-tablet combination. The former component acts mainly to increase prandial insulin secretion; the latter improves insulin sensitivity.

Statnote 30 : The one-way analysis of variance (ANOVA):fixed effects model

In Statnote 9, we described a one-way analysis of variance (ANOVA) ‘random effects’ model in which the objective was to estimate the degree of variation of a particular measurement and to compare different sources of variation in space and time. The illustrative scenario involved the role of computer keyboards in a University communal computer laboratory as a possible source of microbial contamination of the hands. The study estimated the aerobic colony count of ten selected keyboards with samples taken from two keys per keyboard determined at 9am and 5pm. This type of design is often referred to as a ‘nested’ or ‘hierarchical’ design and the ANOVA estimated the degree of variation: (1) between keyboards, (2) between keys within a keyboard, and (3) between sample times within a key. An alternative to this design is a 'fixed effects' model in which the objective is not to measure sources of variation per se but to estimate differences between specific groups or treatments, which are regarded as 'fixed' or discrete effects. This statnote describes two scenarios utilizing this type of analysis: (1) measuring the degree of bacterial contamination on 2p coins collected from three types of business property, viz., a butcher’s shop, a sandwich shop, and a newsagent and (2) the effectiveness of drugs in the treatment of a fungal eye infection.

On bandwidth request mechanism with piggyback in fixed IEEE 802.16 networks

This paper investigates the random channel access mechanism specified in the IEEE 802.16 standard for the uplink traffic in a Point-to-MultiPoint (PMP) network architecture. An analytical model is proposed to study the impacts of the channel access parameters, bandwidth configuration and piggyback policy on the performance. The impacts of physical burst profile and non-saturated network traffic are also taken into account in the model. Simulations validate the proposed analytical model. It is observed that the bandwidth utilization can be improved if the bandwidth for random channel access can be properly configured according to the channel access parameters, piggyback policy and network traffic.

Performance comparison of OFDM bandwidth request schemes in fixed IEEE 802.16 networks

IEEE 802.16 standard specifies two contention based bandwidth request schemes working with OFDM physical layer specification in point-to-multipoint (PMP) architecture, the mandatory one used in region-full and the optional one used in region-focused. This letter presents a unified analytical model to study the bandwidth efficiency and channel access delay performance of the two schemes. The impacts of access parameters, available bandwidth and subchannelization have been taken into account. The model is validated by simulations. The mandatory scheme is observed to perform closely to the optional one when subchannelization is active for both schemes.

Service differentiation for the bandwidth request scheme in fixed IEEE 802.16 networks

IEEE 802.16 standards have been developed as one of the technical solutions for broadband wireless access systems. It has high data rate, large network coverage, flexible QoS schemes and cheap network deployment. Various flexible mechanisms related to QoS provisioning have been specified for uplink traffic at the medium access control (MAC) layer in the standards. Among the mechanisms, contention based bandwidth request scheme can be used to indicate bandwidth demands to the base station for the non-real-time polling and besteffort services. These two services are used for most application with unknown traffic characteristics. Due to the diverse QoS requirements of those applications, service differentiation (SD) is anticipated over the contention based bandwidth request scheme. In this paper we investigate the SD with the bandwidth request scheme by means of assigning different channel access parameters and bandwidth allocation priorities. The effectiveness of the differentiation schemes are evaluated by simulations. It is observed that the initial backoff window can be efficient in SD, and if combined with the bandwidth allocation priority, the SD performances will be better. ©2008 IEEE.

Fixed bed downdraft gasification of paper industry wastes

The two main wastes generated from secondary fibre paper mills are rejects (composed mainly of plastics and fibres) and de-inking sludge, both of which are evolved from the pulping process during paper manufacture. The current practice for the disposal of these wastes is either by land-spreading or land-filling. This work explores the gasification of blends of pre-conditioned rejects and de-inking sludge pellets with mixed wood chips in an Imbert type fixed bed downdraft gasifier with a maximum feeding capacity of 10kg/h. The producer gases evolved would generate combined heat and power (CHP) in an internal combustion engine. The results show that as much as 80wt.% of a brown paper mill's rejects (consisting of 20wt.% mixed plastics and 80wt.% paper fibres) could be successfully gasified in a blend with 20wt.% mixed wood chips. The producer gas composition was 16.24% H, 23.34% CO, 12.71% CO 5.21% CH and 42.49% N (v/v%) with a higher heating value of 7.3MJ/Nm. After the removal of tar and water condensate the producer gas was of sufficient calorific value and flow rate to power a 10kWe gas engine. Some blends using rejects from other mill types were not successful, and the limiting factor was usually the agglomeration of plastics present within the fuel.

Fixed-dose single tablet antidiabetic combinations

Combinations of two or more oral agents with different mechanisms of action are often used for the management of hyperglycaemia in type 2 diabetes. While these combinations have customarily been taken as separate tablets, several fixed-dose single tablet combinations are now available. These are based on bioequivalence with the separate tablets, giving similar efficacy to the separate tablets and necessitating the same cautions and contraindications that apply to each active component. Fixed-dose combinations can offer convenience, reduce the pill burden and simplify administration regimens for the patient. They increase patient adherence compared with equivalent combinations of separate tablets, and this is associated with some improvements in glycaemic control. Presently available antidiabetic fixed-dose combinations include metformin combined with a sulphonylurea, thiazolidinedione, dipeptidylpeptidase-4 inhibitor or meglitinide as well as thiazolidinedione-sulphonylurea combinations, each at a range of dosage strengths to facilitate titration. Anticipated future expansion of multiple drug regimens for diabetes management is likely to increase the use of fixed-dose single tablet combinations. © 2009 Blackwell Publishing Ltd.

Anti-obesity fixed-dose combinations

The management of hypertension, dyslipidaemia and hyperglycaemia often requires multiple medications that combine two or more agents with different modes of action to give additive efficacy. In some situations lower doses of two agents with different modes of action can achieve greater efficacy than a high dose of one agent. This is achieved by addressing different pathophysiological features of the disease, whilst at the same time producing fewer side effects than a high dose of one agent. Several examples of this have been described for combinations of blood glucose-lowering therapies in type 2 diabetes. However, the pill burden associated with multiple medications can reduce patient adherence and compromise the potential value of the treatments. To reduce the number of daily doses, single-tablet (‘fixed-dose’) combinations have been introduced to offer greater convenience. There are several ant-diabetic FDCs, mostly combining metformin with another type of glucose-lowering agent. The UK has been less enthusiastic about FDCs than many other parts of the world, and does not have most of these combinations available. One of the concerns expressed about FDCs is a reduced flexibility to select desired doses of the two agents for dose titration. However, in practise the variety of dosage strengths for most FDCs matches the dosages available as separate tablets. Another concern has been the preference to add drugs one at a time to be able to attribute any adverse effects. In most cases the FDC is used when a second drug has been added to a monotherapy that is already a component of the FDC, so it is only the same as adding one agent but without increasing the pill burden.

A simulation study of service differentiation for the bandwidth request scheme in fixed IEEE 802.16 network

Various flexible mechanisms related to quality of service (QoS) provisioning have been specified for uplink traffic at the medium access control (MAC) layer in the IEEE 802.16 standards. Among the mechanisms, contention based bandwidth request scheme can be used to indicate bandwidth demands to the base station for the non-real-time polling and best-effort services. These two services are used for most applications with unknown traffic characteristics. Due to the diverse QoS requirements of those applications, service differentiation (SD) is anticipated over the contention based bandwidth request scheme. In this paper we investigate the SD with the bandwidth request scheme by means of assigning different channel access parameters and bandwidth allocation priorities at different packets arrival probability. The effectiveness of the differentiation schemes is evaluated by simulations. It is observed that the initial backoff window can be efficient in SD, and if combined with the bandwidth allocation priority, the SD performances will be better.

Injectable hydrogels with high fixed charge density and swelling pressure for nucleus pulposus repair:biomimetic glycosaminoglycan analogues

The load-bearing biomechanical role of the intervertebral disc is governed by the composition and organization of its major macromolecular components, collagen and aggrecan. The major function of aggrecan is to maintain tissue hydration, and hence disc height, under the high loads imposed by muscle activity and body weight. Key to this role is the high negative fixed charge of its glycosaminoglycan side chains, which impart a high osmotic pressure to the tissue, thus regulating and maintaining tissue hydration and hence disc height under load. In degenerate discs, aggrecan degrades and is lost from the disc, particularly centrally from the nucleus pulposus. This loss of fixed charge results in reduced hydration and loss of disc height; such changes are closely associated with low back pain. The present authors developed biomimetic glycosaminoglycan analogues based on sulphonate-containing polymers. These biomimetics are deliverable via injection into the disc where they polymerize in situ, forming a non-degradable, nuclear "implant" aimed at restoring disc height to degenerate discs, thereby relieving back pain. In vitro, these glycosaminoglycan analogues possess appropriate fixed charge density, hydration and osmotic responsiveness, thereby displaying the capacity to restore disc height and function. Preliminary biomechanical tests using a degenerate explant model showed that the implant adapts to the space into which it is injected and restores stiffness. These hydrogels mimic the role taken by glycosaminoglycans in vivo and, unlike other hydrogels, provide an intrinsic swelling pressure, which can maintain disc hydration and height under the high and variable compressive loads encountered in vivo. © 2013 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Economic efficiency when prices are not fixed:disentangling quantity and price efficiency

This paper proposes an approach to compute cost efficiency in contexts where units can adjust input quantities and to some degree prices so that through their joint determination they can minimise the aggregate cost of the outputs they secure. The model developed is based on the data envelopment analysis (DEA) framework and can accommodate situations where the degree of influence over prices ranges from minimal to considerable. When units cannot influence prices at all the model proposed reduces to the standard cost efficiency DEA model for the case where prices are taken as exogenous. In addition to the cost efficiency model, we introduce an additive decomposition of potential cost savings into a quantity and a price component, based on Bennet indicators. © 2014 Elsevier Ltd.

Continuous Dependence of Solutions of Quasidifferential Equations with Non-Fixed Time of Impulses

In this article on quasidifferential equation with non-fixed time of impulses we consider the continuous dependence of the solutions on the initial conditions as well as the mappings defined by these equations. We prove general theorems for quasidifferential equations from which follows corresponding results for differential equations, differential inclusion and equations with Hukuhara derivative.

Generalized Variational Inequalities for Upper Hemicontinuous and Demi Operators with Applications to Fixed Point Theorems in Hilbert Spaces

∗ The final version of this paper was sent to the editor when the author was supported by an ARC Small Grant of Dr. E. Tarafdar.

Integral Manifolds and Perturbations of the Nonlinear Part of Systems of Autonomous Differential Equations with Impulses at Fixed Moments

* This investigation was supported by the Bulgarian Ministry of Science and Education under Grant MM-7.