Steering them softly with a quality label? A case study analysis of a patient channelling strategy without financial incentives.

Steering patients to lower priced and/or higher quality providers can increase the value of a healthcare system. In a managed care setting, health insurers may use financial incentives for this purpose. However, introducing cost-sharing differences among providers may cause enrolee discontent, which may result in disenrollment. Simply informing and guiding enrolees to preferred providers without financial incentives may therefore be an attractive alternative for insurers. But the effectiveness of such a soft channelling strategy is unclear. This paper investigates whether a Dutch health insurer's strategy of designating preferred hospitals for breast cancer surgery and for inguinal hernia repair affected its enrolees' hospital choices. In October 2008, preferred hospitals received a quality label ('TopCare') because of their high-quality performances in previous years. The insurer recommended these hospitals to enrolees without a financial incentive. Individual patient-level claims data from the insurer over a 5-year period (2006-2010) and a conditional logit choice model was used. Our study samples for breast cancer surgery and inguinal hernia repair included 7985 and 17,292 patients, respectively. It is found that for both procedures, patients ex ante already had a certain preference for the hospitals designated by the insurer as top-quality providers, even when considering possible additional travel time. Also, for both procedures, patient choice did not differ significantly before and after the launch of the TopCare label. The quality label did not increase patient demand for preferred hospitals. Thus, the insurer's strategy to steer patients to preferred hospital alternatives without a financial incentive was not effective.

Pyridoxal 5'-Phosphate Biosynthesis by Pyridox-(am)-ine 5'-Phosphate Oxidase: Species-Specific Features.

Enzymes reliant on pyridoxal 5'-phosphate (PLP), the metabolically active form of vitamin B6, hold significant importance in both biology and medicine. They facilitate various biochemical reactions, particularly in amino acid and neurotransmitter metabolisms. Vitamin B6 is absorbed by organisms in its non-phosphorylated form and phosphorylated within cells via pyridoxal kinase (PLK) and pyridox-(am)-ine 5'-phosphate oxidase (PNPOx). The flavin mononucleotide-dependent PNPOx enzyme converts pyridoxine 5'-phosphate and pyridoxamine 5'-phosphate into PLP. PNPOx is vital for both biosynthesis and salvage pathways in organisms producing B6 vitamers. However, for those depending on vitamin B6 as a nutrient, PNPOx participates only in the salvage pathway. Transferring the PLP produced via PNPOx to client apo-enzymes is indispensable for their catalytic function, proper folding and targeting of specific organelles. PNPOx activity deficiencies due to inborn errors lead to severe neurological pathologies, particularly neonatal epileptic encephalopathy. PNPOx maintains PLP homeostasis through highly regulated mechanisms, including structural alterations throughout the catalytic cycle and allosteric PLP binding, influencing substrate transformation at the active site. Elucidation at the molecular level of the mechanisms underlying PNPOx activity deficiencies is a requirement to develop personalized approaches to treat related disorders. Finally, despite shared features, the few PNPOx enzymes molecularly and functionally studied show species-specific regulatory properties that open the possibility of targeting it in pathogenic organisms.

Two separate pathways underlie NADH and succinate oxidation in swine heart mitochondria: Kinetic evidence on the mobile electron carriers.

We have investigated NADH and succinate aerobic oxidation in frozen and thawed swine heart mitochondria. Simultaneous oxidation of NADH and succinate showed complete additivity under a variety of experimental conditions, suggesting that the electron fluxes originating from NADH and succinate are completely independent and do not mix at the level of the so-called mobile diffusible components. We ascribe the results to mixing of the fluxes at the level of cytochrome c in bovine mitochondria: the Complex IV flux control coefficient in NADH oxidation was high in swine mitochondria but very low in bovine mitochondria, suggesting a stronger interaction of cytochrome c with the supercomplex in the former. This was not the case in succinate oxidation, in which Complex IV exerted little control also in swine mitochondria. We interpret the data in swine mitochondria as restriction of the NADH flux by channelling within the I-III2-IV supercomplex, whereas the flux from succinate shows pool mixing for both Coenzyme Q and probably cytochrome c. The difference between the two types of mitochondria may be ascribed to different lipid composition affecting the cytochrome c binding properties, as suggested by breaks in Arrhenius plots of Complex IV activity occurring at higher temperatures in bovine mitochondria.

Fast generation of calculated ADF-EDX scattering cross-sections under channelling conditions.

Advanced materials often consist of multiple elements which are arranged in a complicated structure. Quantitative scanning transmission electron microscopy is useful to determine the composition and thickness of nanostructures at the atomic scale. However, significant difficulties remain to quantify mixed columns by comparing the resulting atomic resolution images and spectroscopy data with multislice simulations where dynamic scattering needs to be taken into account. The combination of the computationally intensive nature of these simulations and the enormous amount of possible mixed column configurations for a given composition indeed severely hamper the quantification process. To overcome these challenges, we here report the development of an incoherent non-linear method for the fast prediction of ADF-EDX scattering cross-sections of mixed columns under channelling conditions. We first explain the origin of the ADF and EDX incoherence from scattering physics suggesting a linear dependence between those two signals in the case of a high-angle ADF detector. Taking EDX as a perfect incoherent reference mode, we quantitatively examine the ADF longitudinal incoherence under different microscope conditions using multislice simulations. Based on incoherent imaging, the atomic lensing model previously developed for ADF is now expanded to EDX, which yields ADF-EDX scattering cross-section predictions in good agreement with multislice simulations for mixed columns in a core-shell nanoparticle and a high entropy alloy. The fast and accurate prediction of ADF-EDX scattering cross-sections opens up new opportunities to explore the wide range of ordering possibilities of heterogeneous materials with multiple elements.

Mechanisms and Effects of Substrate Channelling in Enzymatic Cascades.

Substrate or metabolite channelling is a transfer of intermediates produced by one enzyme to the sequential enzyme of a reaction cascade or metabolic pathway, without releasing them entirely into bulk. Despite an enormous effort and more than three decades of research, substrate channelling remains the subject of continuing debates and active investigation. Herein, we review the benefits and mechanisms of substrate channelling in vivo and in vitro. We discuss critically the effects that substrate channelling can have on enzymatic cascades, including speeding up or slowing down reaction cascades and protecting intermediates from sequestration and enzymes' surroundings from toxic or otherwise detrimental intermediates. We also discuss how macromolecular crowding affects substrate channelling and point out the galore of open questions.

Understanding, controlling and optimising the cooling of waste thermal treatment beds including STARx Hottpads.

STARx (Self-sustaining Treatment for Active Remediation ex situ) is a thermal treatment strategy for contaminated soils and organic wastes. Key to this technology is that organics are embedded in porous matrix beds (e.g. sand). STARx induces a self-sustaining smouldering combustion front that traverses the bed, burning away the embedded contaminants/wastes. The time and cost effectiveness of this technology is largely dictated by the time required for cooling of the hot, clean, porous matrix bed that remains after treatment. This study is the first to explore the cooling of these beds. A suite of novel simulations investigated the influence of key parameters on bed-cooling time. The results reveal that cooling time decreased nearly linearly with decreases of volume-averaged bed temperature and bed bulk density. Increased injection air fluxes led to the non-linear decrease of cooling time. Also, cooling time was negatively impacted by bed temperature inhomogeneity, which influenced preferential air flow through cooler regions of the bed, bypassing hotter regions. From these results, using lower bulk density bed materials, increased air fluxes and enhancing wall insulation to improve bed temperature homogeneity were identified as system optimisations to reduce cooling times. While the aim of this research is to improve the STARx cooling process, the results are also highly applicable to many similar engineering systems that involve hot porous bed cooling.

Cardiovascular events and all-cause mortality in patients with chronic obstructive pulmonary disease using olodaterol and other long-acting beta2-agonists.

PURPOSE: We examined the effect of olodaterol on the risk of myocardial ischaemia, cardiac arrhythmia, and all-cause mortality compared with use of other long-acting beta2-agonists (LABAs). Channelling bias was also explored. METHODS: This Danish population-based cohort study used data linked from registries of hospital diagnoses, outpatient dispensings, and deaths. It included patients (aged ≥40 years) with a diagnosis of chronic obstructive pulmonary disease (COPD) who initiated olodaterol or another LABA. Using matching and propensity score (PS) stratification, we calculated adjusted incidence rate ratios (IRRs) using Poisson regression, followed by several additional analyses to evaluate and control channelling bias. RESULTS: The IRRs of cardiac arrhythmias or myocardial ischaemia among users of olodaterol (n = 14 239) compared to users of other LABAs (n = 51 167) ranged from 0.96 to 1.65 in various analyses, although some estimates had low precision. Initial analysis suggested an increased risk for death with olodaterol compared with other LABAs (IRR, 1.63; 95% CI, 1.44-1.84). Because olodaterol prescribing was associated with COPD severity, the mortality association was attenuated by using different methods of tighter confounding control: the IRRs were 1.26 (95% CI, 0.97-1.64) among LABA-naïve LABA/LAMA users without recent COPD hospitalisation; 1.27 (95% CI, 1.03-1.57) in a population with additional trimming from the tails of the PS distribution; and 1.32 (95% CI, 1.19-1.48) after applying overlap-weights analysis. CONCLUSIONS: Olodaterol users had a similar risk for cardiac arrhythmias or myocardial ischaemia as other LABA users. The observed excess all-cause mortality associated with olodaterol use could be due to uncontrolled channelling bias.

A Nanopore Sensing Assay Resolves Cascade Reactions in a Multienzyme System.

Enzymatic cascade reactions are widely used to synthesize complex molecules from simple precursors. The major underlying mechanism of cascade reactions is substrate channelling, where intermediates of different enzymatic steps are not in equilibrium with the bulk solution. Here, we report a nanopore sensing assay that allows accurate quantification of all the reaction intermediates and the product of an artificial three-enzyme system. A DNA-peptide complex is used as the initial substrate which undergoes sequential enzymatic cleavages in solution. All the temporal changes of the intermediates and product can be obtained through nanopore translocation recordings. Furthermore, we find that in a confined environment such as liposome, substrate channelling occurs between two sets of the three enzymes. Our results demonstrate a novel and powerful approach to determine and quantify substrate channelling effects, which is potentially useful for designing and evaluating multienzyme systems.

Whole-beam self-focusing in fusion-relevant plasma.

Fast ignition inertial confinement fusion requires the production of a low-density channel in plasma with density scale-lengths of several hundred microns. The channel assists in the propagation of an ultra-intense laser pulse used to generate fast electrons which form a hot spot on the side of pre-compressed fusion fuel. We present a systematic characterization of an expanding laser-produced plasma using optical interferometry, benchmarked against three-dimensional hydrodynamic simulations. Magnetic fields associated with channel formation are probed using proton radiography, and compared to magnetic field structures generated in full-scale particle-in-cell simulations. We present observations of long-lived, straight channels produced by the Habara-Kodama-Tanaka whole-beam self-focusing mechanism, overcoming a critical barrier on the path to realizing fast ignition. This article is part of a discussion meeting issue 'Prospects for high gain inertial fusion energy (part 2)'.

Atomically resolved tomographic reconstruction of nanoparticles from single projection: Influence of amorphous carbon support.

Nanoparticles have a wide range of applications due to their unique geometry and arrangement of atoms. For a precise structure-property correlation, information regarding atomically resolved 3D structures of nanoparticles is utmost beneficial. Though modern aberration-corrected transmission electron microscopes can resolve atoms with the sub-angstrom resolution, an atomic-scale 3D reconstruction of a nanoparticle using Scanning Transmission Electron Microscopy (STEM) based tomographic method faces hurdles due to high electron irradiation damage and "missing-wedge". Instead, inline 3D holography based tomographic reconstructions from single projection registered at low electron doses is more suitable for defining atomic positions at nanostructures. Nanoparticles are generally supported on amorphous carbon film for Transmission Electron Microscopy (TEM) experiments. However, neglecting the influence of carbon film on the tomographic reconstruction of the nanoparticle may lead to ambiguity. To address this issue, the effect of amorphous carbon support was quantitatively studied using simulations and experiments and it was revealed that increasing thickness and/or density of carbon support increases distortion in tomograms.

Synthetic protein scaffolds for the colocalisation of co-acting enzymes.

Nature relies on complexes of colocated enzymes to efficiently perform multiple catalytic steps. Such enzyme colocalisation promotes substrate channelling, enhances the activity of multiple synergistically acting enzymes and avoids the loss of potentially toxic intermediates. The industrial biotechnology field develops sophisticated methods to mimic natural colocalisation mechanisms to produce increasingly complex bio-based chemicals. Synthetic protein scaffolds are an advanced way to achieve colocalisation of multiple enzymes in one protein complex. The backbone scaffold is composed of multiple domains that are either separated by linkers or fused to self-assembling proteins. Enzymes are recruited to this scaffold by fusing them to domains that bind to orthogonal domains in the scaffold. A particular feature of synthetic protein scaffolds is the control over spatial organisation and enzyme stoichiometry. Several successful examples of synthetic protein scaffolds have been reported, yet the optimisation of such multi-enzyme complexes is a multiparametric, and therefore often empirical process. This review focusses on pioneering scaffolding examples and elaborates on each parameter influencing the activity of these multi-enzyme complexes. Advances in this field are expected to result in a growing catalogue of chemicals that can be produced starting from cheap and widely available renewable materials.

Metrology of crystal defects through intensity variations in secondary electrons from the diffraction of primary electrons in a scanning electron microscope.

Understanding defects and their roles in plastic deformation and device reliability is important for the development of a wide range of novel materials for the next generation of electronic and optoelectronic devices. We introduce the use of gaseous secondary electron detectors in a variable pressure scanning electron microscope for non-destructive imaging of extended defects using electron channelling contrast imaging. We demonstrate that all scattered electrons, including the secondary electrons, can provide diffraction contrast as long as the sample is positioned appropriately with respect to the incident electron beam. Extracting diffraction information through monitoring the modulation of the intensity of secondary electrons as a result of diffraction of the incident electron beam, opens up the possibility of performing low energy electron channelling contrast imaging to characterise low atomic weight and ultra-thin film materials. Our methodology can be adopted for large area, nanoscale structural characterisation of a wide range of crystalline materials including metals and semiconductors, and we illustrate this using the examples of aluminium nitride and gallium nitride. The capability of performing electron channelling contrast imaging, using the variable pressure mode, extends the application of this technique to insulators, which usually require conducting coatings on the sample surface for traditional scanning electron microscope based microstructural characterisation.

Distinguishing space groups by electron channelling: centrosymmetric full-Heusler or non-centrosymmetric half-Heusler?

X-ray emission under electron-channelling conditions is used to distinguish between a non-centrosymmetric half-Heusler and a centrosymmetric full-Heusler crystal. For TiCo1.5+xSn the space-group determination based on a Rietveld refinement procedure became challenging for increasing Co content (x > 0.2), while electron channelling proved successful for higher Co content (x = 0.35). This technique can be used on crystals as small as (10 nm)3.

Lignin biosynthesis: old roads revisited and new roads explored.

Lignin is a major component of secondarily thickened plant cell walls and is considered to be the second most abundant biopolymer on the planet. At one point believed to be the product of a highly controlled polymerization procedure involving just three potential monomeric components (monolignols), it is becoming increasingly clear that the composition of lignin is quite flexible. Furthermore, the biosynthetic pathways to the major monolignols also appear to exhibit flexibility, particularly as regards the early reactions leading to the formation of caffeic acid from coumaric acid. The operation of parallel pathways to caffeic acid occurring at the level of shikimate esters or free acids may help provide robustness to the pathway under different physiological conditions. Several features of the pathway also appear to link monolignol biosynthesis to both generation and detoxification of hydrogen peroxide, one of the oxidants responsible for creating monolignol radicals for polymerization in the apoplast. Monolignol transport to the apoplast is not well understood. It may involve passive diffusion, although this may be targeted to sites of lignin initiation/polymerization by ordered complexes of both biosynthetic enzymes on the cytosolic side of the plasma membrane and structural anchoring of proteins for monolignol oxidation and polymerization on the apoplastic side. We present several hypothetical models to illustrate these ideas and stimulate further research. These are based primarily on studies in model systems, which may or may not reflect the major lignification process in forest trees.

Insights into image contrast from dislocations in ADF-STEM.

Competitive mechanisms contribute to image contrast from dislocations in annular dark-field scanning transmission electron microscopy (ADF-STEM). A clear theoretical understanding of the mechanisms underlying the ADF-STEM contrast is therefore essential for correct interpretation of dislocation images. This paper reports on a systematic study of the ADF-STEM contrast from dislocations in a GaN specimen, both experimentally and computationally. Systematic experimental ADF-STEM images of the edge-character dislocations reveal a number of characteristic contrast features that are shown to depend on both the angular detection range and specific position of the dislocation in the sample. A theoretical model based on electron channelling and Bloch-wave scattering theories, supported by numerical simulations based on Grillo's strain-channelling equation, is proposed to elucidate the physical origin of such complex contrast phenomena.

Advice from the health insurer as a channelling strategy: a natural experiment at a Dutch health insurance company.

BACKGROUND: In a health care system based on managed competition it is important that health insurers are able to channel their enrolees to preferred care providers. However, enrolees are often very negative about financial incentives and any limitations in their choice of care provider. Therefore, a Dutch health insurance company conducted an experiment to study the effectiveness of a new method of channelling their enrolees. This method entails giving enrolees advise on which physiotherapists to choose when they call customer service. Offering this advice as an extra service is supposed to improve service quality ratings. Objective of this study is to evaluate this channelling method on effectiveness and the impact on service quality ratings. METHODS: In this experiment, one of the health insurer's customer service call teams (pilot team) began advising enrolees on their choice of physiotherapist. Three data sources were used. Firstly, all enrolees who called customer service received an online questionnaire in order to measure their evaluation of the quality of service. Enrolees who were offered advice received a slightly different questionnaire which, in addition, asked about whether they intended to follow the advice they were offered. Multilevel regression analysis was conducted to analyse the difference in service quality ratings between the pilot team and two comparable customer service teams before and after the implementation of the channelling method. Secondly, employees logged each call, registering, if they offered advice, whether the enrolee accepted it, and if so, which care provider was advised. Thirdly, data from the insurance claims were used to see if enrolees visited the recommended physiotherapist. RESULTS: The results of the questionnaire show that enrolees responded favorably to being offered advice on the choice of physiotherapist. Furthermore, 45% of enrolees who received advice and then went on to visit a care provider, followed the advice. The service quality ratings were higher compared to control groups. However, it could not be determined whether this effect was entirely due to the intervention. CONCLUSIONS: Channelling enrolees towards preferred care providers by offering advice on their choice of care provider when they call customer service is successful. The effect on service quality seems positive, although a causal relationship could not be determined.

Preferential prescribing and utilization trends of diabetes medications among patients with renal impairment: Emerging role of linagliptin and other dipeptidyl peptidase 4 inhibitors.

OBJECTIVES: Although many newer diabetes medications have become available in the last decade, most have not been widely studied in populations with chronic kidney disease under routine care. Linagliptin, a recently marketed dipeptidyl peptidase 4 (DPP-4) inhibitor, is the only agent in the U.S. that does not require dose adjustment in patients with diabetes mellitus type 2 (T2DM) and renal impairment. We sought to describe baseline kidney function and other key characteristics among patients with diabetes mellitus type 2 (T2DM) initiating linagliptin and other diabetes medications, and to explore prescribing patterns among T2DM patients with moderate to severe renal impairment before and after the launch of linagliptin. DESIGN: Using a population-based cohort study design nested in a large U.S. commercial healthcare dataset linked to laboratory values, we described characteristics of T2DM patients initiating linagliptin and other diabetes medications between May 2011 (launch of linagliptin) and September 2015. We also explored prescribing trends among T2DM patients with moderate to severe renal impairment (ICD-9 diagnosis code 585.3x-6x) who initiated linagliptin and other diabetes medications between January 2006 to September 2015 (before and after the launch of linagliptin). PATIENTS: We identified 1,174,476 T2DM patients initiating a diabetes medication (28,900 linagliptin initiators) between 05/2011-09/2015. We also identified 100,847 T2DM patients with moderate to severe renal impairment initiating a diabetes agent between 01/2006-09/2015. RESULTS AND CONCLUSION: Among patients initiating newer diabetes medications between 05/2011-09/2015, those initiating linagliptin had the highest prevalence of moderate to severe renal impairment, suggesting preferential prescribing in routine care. DPP-4 inhibitors overall were among the most frequently chosen agents among T2DM patients with moderate to severe renal impairment between 01/2006-09/2015. Further investigation of the safety and effectiveness of DPP-4 inhibitors in routine care of T2DM patients with renal impairment is needed to either corroborate or discourage current prescribing patterns.

A menu of electron probes for optimising information from scanning transmission electron microscopy.

We assess a selection of electron probes in terms of the spatial resolution with which information can be derived about the structure of a specimen, as opposed to the nominal image resolution. Using Ge [001] as a study case, we investigate the scattering dynamics of these probes and determine their relative merits in terms of two qualitative criteria: interaction volume and interpretability. This analysis provides a 'menu of probes' from which an optimum probe for tackling a given materials science question can be selected. Hollow cone, vortex and spherical wave fronts are considered, from unit cell to Ångstrom size, and for different defocus and specimen orientations.

The Molybdenum Cofactor Biosynthesis Network: In vivo Protein-Protein Interactions of an Actin Associated Multi-Protein Complex.

Survival of plants and nearly all organisms depends on the pterin based molybdenum cofactor (Moco) as well as its effective biosynthesis and insertion into apo-enzymes. To this end, both the central Moco biosynthesis enzymes are characterized and the conserved four-step reaction pathway for Moco biosynthesis is well-understood. However, protection mechanisms to prevent degradation during biosynthesis as well as transfer of the highly oxygen sensitive Moco and its intermediates are not fully enlightened. The formation of protein complexes involving transient protein-protein interactions is an efficient strategy for protected metabolic channelling of sensitive molecules. In this review, Moco biosynthesis and allocation network is presented and discussed. This network was intensively studied based on two in vivo interaction methods: bimolecular fluorescence complementation (BiFC) and split-luciferase. Whereas BiFC allows localisation of interacting partners, split-luciferase assay determines interaction strengths in vivo. Results demonstrate (i) interaction of Cnx2 and Cnx3 within the mitochondria and (ii) assembly of a biosynthesis complex including the cytosolic enzymes Cnx5, Cnx6, Cnx7, and Cnx1, which enables a protected transfer of intermediates. The whole complex is associated with actin filaments via Cnx1 as anchor protein. After biosynthesis, Moco needs to be handed over to the specific apo-enzymes. A potential pathway was discovered. Molybdenum-containing enzymes of the sulphite oxidase family interact directly with Cnx1. In contrast, the xanthine oxidoreductase family acquires Moco indirectly via a Moco binding protein (MoBP2) and Moco sulphurase ABA3. In summary, the uncovered interaction matrix enables an efficient transfer for intermediate and product protection via micro-compartmentation.