The Value of Medical Innovation Versus Industry Rewards.

Objectives: This article provides systematic evidence on the share of the value of health generated by drugs and other healthcare goods and services that accrue to patients on the demand side versus the manufacturers on the supply side.

Methods: We exploit a large data set with > 9000 cost-effectiveness measures for various interventions, which we convert into measures of the shares of the value of improved health appropriated by the supply side using literature estimates of how patients value gains in health.

Results: We find that if patients value a quality-adjusted life-year at $450 000 the median share appropriated for drugs on the supply side is approximately 6% and has declined at 0.

Development of an evaluation framework and assessment tools to assess the foot and mouth disease (FMD) control policies and their implementation in the proposed FMD-free zone in Thailand.

This paper proposes an evaluation framework and assessment tools for use in the evaluation of the current foot and mouth disease (FMD) control policies in Thailand and their implementation in the eastern region of the country (the proposed FMD-free zone). To develop the framework and assessment tools this study identified: a) the essential elements of a successful FMD control programme; b) stakeholders who are affected by the FMD control programme; and c) relevant Department of Livestock Development regulations and documents. These regulations and documents were used as the foundation for development of the framework and assessment tools.

Dicarboxylic esters: Useful tools for the biocatalyzed synthesis of hybrid compounds and polymers.

Dicarboxylic acids and their derivatives (esters and anhydrides) have been used as acylating agents in lipase-catalyzed reactions in organic solvents. The synthetic outcomes have been dimeric or hybrid derivatives of bioactive natural compounds as well as functionalized polyesters.

Ambulance nurses' experiences of nursing critically ill and injured children: A difficult aspect of ambulance nursing care.

Background: Ambulance nurses work daily in both emergency and non-emergency situations that can be demanding. One emotionally demanding situation for ambulance nurses is to nurse children who are ill.

Aim: The aim of this study was to describe ambulance nurses' experiences of nursing critically ill or injured children.

Rational engineering of Candida antarctica lipase B for selective monoacylation of diols.

The enzyme Candida antarctica lipase B was subjected to site directed mutagenesis suggested by molecular modelling. The selectivity for the enzyme increased towards a range of diols over their corresponding monoesters as an effect of the mutations.

Rational redesign of Candida antarctica lipase B for the ring opening polymerization of D,D-lactide.

Based on molecular modelling, the enzyme Candida antarctica lipase B was redesigned as a catalyst for the ring opening polymerization of D,D-lactide. Two mutants with 90-fold increased activity as compared to the wild-type enzyme were created. In a preparative synthesis of poly(D,D-lactide) the mutants greatly improved the rate and the degree of polymerization.

Mutated variant of Candida antarctica lipase B in (S)-selective dynamic kinetic resolution of secondary alcohols.

An (S)-selective dynamic kinetic resolution of secondary alcohols, employing a mutated variant of Candida antarctica lipase B (CalB) gave products in 84-88% yield and in 90-97% ee.

Substrate conformations set the rate of enzymatic acrylation by lipases.

Acrylates represent a class of alpha,beta-unsaturated compounds of high industrial importance. We investigated the influence of substrate conformations on the experimentally determined reaction rates of the enzyme-catalysed transacylation of methyl acrylate and derivatives by ab initio DFT B3LYP calculations and molecular dynamics simulations. The results supported a least-motion mechanism upon the sp(2) to sp(3) substrate transition to reach the transition state in the enzyme active site.

Suppression of water as a nucleophile in Candida antarctica lipase B catalysis.

A water tunnel in Candida antarctica lipase B that provides the active site with substrate water is hypothesized. A small, focused library created in order to prevent water from entering the active site through the tunnel was screened for increased transacylation over hydrolysis activity. A single mutant, S47L, in which the inner part of the tunnel was blocked, catalysed the transacylation of vinyl butyrate to 20 mM butanol 14 times faster than hydrolysis.

Guidelines for reporting of biocatalytic reactions.

Enzymes and whole cells are being increasingly applied in research and industry, but the adoption of biocatalysis relies strongly on useful scientific literature. Unfortunately, too many published papers lack essential information needed to reproduce and understand the results. Here, members of the scientific committee of the European Federation of Biotechnology Section on Applied Biocatalysis (ESAB) provide practical guidelines for reporting experiments.

Mutant lipase-catalyzed kinetic resolution of bulky phenyl alkyl sec-alcohols: a thermodynamic analysis of enantioselectivity.

The size of the stereoselectivity pocket of Candida antarctica lipase B limits the range of alcohols that can be resolved with this enzyme. These steric constrains have been changed by increasing the size of the pocket by the mutation W104A. The mutated enzyme has good activity and enantioselectivity toward bulky secondary alcohols, such as 1-phenylalkanols, with alkyl chains up to eight carbon atoms.

Enzymatic one-pot route to telechelic polypentadecalactone epoxide: synthesis, UV curing, and characterization.

In an enzymatic one-pot procedure immobilized lipase B from Candida antarctica was used to synthesize semicrystalline diepoxy functional macromonomers based on glycidol, pentadecalactone, and adipic acid. By changing the stoichiometry of the building blocks, macromonomers of controlled molecular weight from 1400 to 2700 g mol(-1) could be afforded. The enzyme-catalyzed reaction went to completion (conversion >or=95%) within 24 h at 60 degrees C.

Minor enantiomer recycling: metal catalyst, organocatalyst and biocatalyst working in concert.

A minor enantiomer recycling one-pot procedure employing two reinforcing chiral catalysts has been developed. Continuous regeneration of the achiral starting material is effected via selective enzyme-catalyzed hydrolysis of the minor product enantiomer from Lewis acid-Lewis base catalyzed addition of acyl cyanides to prochiral aldehydes in a two-phase solvent system. The process provides O-acylated cyanohydrins in close to perfect enantioselectivities, higher than those obtained in the direct process, and in high yields.

Lactone size dependent reactivity in Candida antarctica lipase B: a molecular dynamics and docking study.

Size matters: Lactones have extensively been studied as monomers in enzymatic polymerization reactions. Large lactones showed an unexpectedly high reactivity in these reactions. A combination of docking and molecular dynamics studies have been used to explain this high reactivity in terms of productive binding due to the transoid nature of the ester bond in these substrates.

Systematic comparison of HEA and HEMA as initiators in enzymatic ring-opening polymerizations.

Two initiators containing a cleavable ester bond were compared in the lipase-catalyzed ROP of CL and PDL. The results show that transesterification reactions are present at high rates throughout the enzymatic ROP and start at low conversion. HEA and HEMA displayed similar reaction efficiencies as initiators (acyl acceptors) in the enzymatic ROP.

Direct epoxidation in Candida antarctica lipase B studied by experiment and theory.

Candida antarctica lipase B (CALB) is a promiscuous serine hydrolase that, besides its native function, catalyzes different side reactions, such as direct epoxidation. A single-point mutant of CALB demonstrated a direct epoxidation reaction mechanism for the epoxidation of alpha,beta-unsaturated aldehydes by hydrogen peroxide in aqueous and organic solution. Mutation of the catalytically active Ser105 to alanine made the previously assumed indirect epoxidation reaction mechanism impossible.

Expression of Candida antarctica lipase B in Pichia pastoris and various Escherichia coli systems.

Candida antarctica lipase B (CALB) carrying a point mutation, N74S, resulting in a non-glycosylated protein was actively expressed in Pichia pastoris yielding 44 mg/L which was similar to that of the glycosylated CALB wild type expressed in P. pastoris. Hence, the major obstacle in the Escherichia coli expression of CALB is not the lack of glycosylation.

Lipase catalyzed HEMA initiated ring-opening polymerization: in situ formation of mixed polyester methacrylates by transesterification.

2-Hydroxyethyl methacrylate (HEMA) was used as initiator for the enzymatic ring-opening polymerization (ROP) of omega-pentadecalactone (PDL) and epsilon-caprolactone (CL). The lipase B from Candida antarctica was found to catalyze the cleavage of the ester bond in the HEMA end group of the formed polyesters, resulting in two major transesterification processes, methacrylate transfer and polyester transfer. This resulted in a number of different polyester methacrylate structures, such as polymers without, with one, and with two methacrylate end groups.

Solvent as a competitive inhibitor for Candida antarctica lipase B.

In enzyme-catalyzed reactions, the choice of solvent often has a marked effect on the reaction outcome. In this paper, it is shown that solvent effects could be explained by the ability of the solvent to act as a competitive inhibitor to the substrate. Experimentally, the effect of six solvents, 2-pentanone, 3-pentanone, 2-methyl-2-pentanol, 3-methyl-3-pentanol, 2-methylpentane and 3-methylpentane, was studied in a solid/gas reactor.

Enzyme promiscuity: mechanism and applications.

Introductory courses in biochemistry teach that enzymes are specific for their substrates and the reactions they catalyze. Enzymes diverging from this statement are sometimes called promiscuous. It has been suggested that relaxed substrate and reaction specificities can have an important role in enzyme evolution; however, enzyme promiscuity also has an applied aspect.

High-throughput synthesis and analysis of acylated cyanohydrins.

The yields and optical purities of products obtained from chiral Lewis acid/Lewis base-catalysed additions of alpha-ketonitriles to prochiral aldehydes could be accurately determined by an enzymatic method. The amount of remaining aldehyde was determined after its reduction to an alcohol, whilst the two product enantiomers were analysed after subsequent hydrolysis first by the (S)-selective Candida antarctica lipase B and then by the unselective pig liver esterase. The method could be used for analysis of products obtained from a number of aromatic aldehydes and aliphatic ketonitriles.

A water molecule in the stereospecificity pocket of Candida antarctica lipase B enhances enantioselectivity towards pentan-2-ol.

The effect of water activity on enzyme-catalyzed enantioselective transesterification was studied by using a solid/gas reactor. The experimental results were compared with predictions from molecular modelling. The system studied was the esterification of pentan-2-ol with methylpropanoate as acyl donor and lipase B from Candida antarctica as catalyst.

Highly enantioselective kinetic resolution of two tertiary alcohols using mutants of an esterase from Bacillus subtilis.

Enzyme-catalyzed kinetic resolutions of secondary alcohols are a standard procedure today and several lipases and esterases have been described to show high activity and enantioselectivity. In contrast, tertiary alcohols and their esters are accepted only by a few biocatalysts. Only lipases and esterases with a conserved GGG(A)X-motif are active, but show low activity combined with low enantioselectivity in the hydrolysis of tertiary alcohol esters.