bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of co‐substrate sorbitol different feeding strategies on human growth hormone production by recombinant Pichia pastoris
Authors: Çalık Pınar , Bozkurt Bahar , Zerze Gül H. , İnankur Bahar , Bayraktar Eda , Boy Erdem , Orman Mehmet Ali , Açık Eda , Özdamar Tunçer H.
Published: December 2012

BACKGROUND

Effects of co‐substrate sorbitol different feeding strategies on recombinant human growth hormone (rhGH) production by Pichia pastoris hGH‐Mut+ were investigated by eight designed experiments grouped as: (i) fed‐batch methanol feeding without the co‐substrate; (ii) fed‐batch methanol feeding with pulse sorbitol feeding; (iii) fed‐batch methanol feeding together with fed‐batch sorbitol feeding at t = 0–15 h, followed by fed‐batch methanol feeding; and (iv) fed‐batch methanol and sorbitol feeding at t = 0–30 h, followed with fed‐batch methanol feeding.

RESULTS

The highest rhGH and cell concentrations were achieved, respectively, as 0.64 g L−1 and 105 g L−1 at t = 42 h of induction phase, with the strategy where methanol was fed to the system at a pre‐determined feeding rate of μM0=0.03 h−1, and sorbitol concentration was kept at 50 g L−1 at t = 0–15 h of the rhGH production phase where the specific growth rate on sorbitol was μS0=0.025 h−1. The overall cell and product yield on total substrate were found as 0.26 g g−1 and 2.26 mg g−1, respectively.

CONCLUSION

This work demonstrates that co‐carbon source, sorbitol, feeding strategy is as important as methanol feeding strategy in recombinant protein production by Mut+ strains of P. pastoris. © 2012 Society of Chemical Industry
The integration of flow reactors into synthetic organic chemistry
Authors: Baxendale Ian R.
Published: December 2012

The material presented in this review is based upon discussions and interactions with members of the Department of Chemistry and Biochemistry within the University of Windsor, Ontario, Canada. This article explores the changing face of chemical synthesis with regard to the impact of flow based chemical processing technologies. Highlighted works from the Innovative Technology Centre (ITC), Cambridge, UK, are used to illustrate the alternative synthetic practices available to modern research chemists. The dominant theme of the review is the synergistic effects encountered by combining the advantages of continuous processing regimes with the power of immobilized reagents and scavenger systems for multi‐step organic chemistry. © 2012 Society of Chemical Industry
Comparison of local sine wave modeling with harmonic phase analysis for the assessment of myocardial strain
Authors: Miller Christopher A. , Borg Alex , Clark David , Steadman Christopher D. , McCann Gerry P. , Clarysse Patrick , Croisille Pierre , Schmitt Matthias
Published: December 2012

Purpose

To compare local sine‐wave modeling (SinMod) with harmonic phase analysis (HARP), for assessment of left ventricular (LV) circumferential strain (εcc) from tagged cardiovascular magnetic resonance images.

Materials and Methods

Mid‐ventricular spatial modulation of magnetization was performed in 60 participants (15 each with hypertrophic, dilated or ischemic cardiomyopathy and 15 healthy controls) at 1.5 Tesla. Global and segmental peak transmural εcc were measured using HARP and SinMod. Repeated measurements were performed on 25% of examinations to assess observer variability. Effect of contrast was assessed in 10 additional patients.

Results

SinMod showed a high level of agreement with HARP for global εcc (mean difference −0.02, 95% limits of agreement −6.46 to 6.43%). Agreement was much lower for segmental εcc. Both methods showed excellent observer agreement for global εcc (intraclass correlation coefficient >0.75). Observer agreement for segmental εcc was also excellent with SinMod, but was significantly lower with HARP. Analysis time was significantly shorter using SinMod. Pre‐ and postcontrast εcc measurements were not significantly different using either technique, although postcontrast measurements showed greater variability with HARP.

Conclusion

SinMod and HARP‐based measurements of global εcc have a high level of agreement, but segmental agreement is substantially lower. SinMod has generally lower observer variability, is faster and is less affected by contrast, but requires further validation. J. Magn. Reson. Imaging 2013;38:320–328. © 2012 Wiley Periodicals, Inc.
Inter‐ and intra‐rater reproducibility of quantitative dynamic contrast enhanced MRI using TWIST perfusion data in a uterine fibroid model
Authors: Davenport Matthew S. , Heye Tobias , Dale Brian M. , Horvath Jeffrey J. , Breault Steven R. , Feuerlein Sebastian , Bashir Mustafa R. , Boll Daniel T. , Merkle Elmar M.
Published: December 2012

Purpose

To determine the reproducibility of TWIST‐derived (Time‐Resolved Angiography with Interleaved Stochastic Trajectories) quantitative dynamic contrast enhanced (DCE) MRI in a uterine fibroid model.

Materials and Methods

The institutional review board approved this retrospective study. Dynamic contrast‐enhanced TWIST datasets from 15 randomly selected 1.5 Tesla pelvic MR studies were postprocessed. Five readers recorded kinetic parameters (Ktrans [volume transfer constant], ve [extracellular extravascular space volume], kep [flux rate constant], iAUC [initial area under the gadolinium‐time curve]) of the largest uterine fibroid using three region‐of‐interest (ROI) selection methods. Measurements were randomized and repeated three times, and measures of reproducibility were calculated.

Results

The intra‐rater coefficients of variation (CVs, brackets indicate 95% confidence intervals) varied from 4.6% to 7.6% (Ktrans 7.6% [6.1%, 9.1%], kep 7.2% [5.9%, 8.5%], ve 4.6% [3.8%, 5.4%], and iAUC 7.2% [6.1%, 8.3%]). ve was the most reproducible (P < 0.05). Inter‐rater reproducibility was significantly (P < 0.05) greater for the large ROI method (range of intraclass correlation coefficients [ICCs] = 0.80–0.98 versus 0.48–0.63 [user‐defined ROI] versus 0.41–0.69 [targeted ROI]). The uterine fibroid accounted for the greatest fraction of variance for the large ROI method (range across kinetic parameters: 83–98% versus 56–69% [user‐defined ROI] versus 47–74% [targeted ROI]). The reader accounted for the greatest fraction of variance for the user‐defined ROI method (0.4–14.1% versus 0.1–3.0% [large ROI] versus <0.1–1.5% [targeted ROI]).

Conclusion

Changes in TWIST‐derived DCE‐MRI kinetic parameters of up to 9–15% may be attributable to measurement error. Large DCE‐MRI regions of interest are the most reproducible across multiple readers. J. Magn. Reson. Imaging 2013;38:329–335. © 2012 Wiley Periodicals, Inc.
Separation of isomeric disaccharides by traveling wave ion mobility mass spectrometry using CO2 as drift gas
Authors: Fasciotti Maíra , Sanvido Gustavo B. , Santos Vanessa G. , Lalli Priscila M. , McCullagh Michael , de Sá Gilberto F. , Daroda Romeu J. , Peter Martin G. , Eberlin Marcos N.
Published: December 2012

The use of CO2 as a massive and polarizable drift gas is shown to greatly improve peak‐to‐peak resolution (Rp‐p), as compared with N2, for the separation of disaccharides in a Synapt G2 traveling wave ion mobility cell. Near or baseline Rp‐p was achieved for three pairs of sodiated molecules of disaccharide isomers, that is, cellobiose and sucrose (Rp‐p = 0.76), maltose and sucrose (Rp‐p = 1.04), and maltose and lactose (Rp‐p = 0.74). Ion mobility mass spectrometry using CO2 as the drift gas offers therefore an attractive alternative for fast and efficient separation of isomeric disaccharides. Copyright © 2012 John Wiley & Sons, Ltd.
High friction moments in large hard‐on‐hard hip replacement bearings in conditions of poor lubrication
Authors: Bishop Nicholas E. , Hothan Arne , Morlock Michael M.
Published: December 2012

Disappointing clinical results for large diameter metal replacement bearings for the hip are related to compromised lubrication due to poor cup placement, which increases wear as well as friction moments. The latter can cause overload of the implant–bone interfaces and the taper junction between head and stem. We investigated the influence of lubrication conditions on friction moments in modern hip bearings. Friction moments for large diameter metal and ceramic bearings were measured in a hip simulator with cup angles varying from 0° to 60°. Two diameters were tested for each bearing material, and measurements were made in serum and in dry conditions, representing severely compromised lubrication. Moments were lower for the ceramic bearings than for the metal bearings in lubricated conditions, but approached those for metal bearings at high cup inclination. In dry conditions, friction moments increased twofold to 12 Nm for metal bearings. For ceramic bearings, the increase was more than fivefold to over 25 Nm. Although large diameter ceramic bearings demonstrate an improvement in friction characteristics in the lubricated condition, they could potentially replicate problems currently experienced due to high friction moments in metal bearings once lubrication is compromised. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31: 807–813, 2013
Synthesis of Maleimide‐Functionalyzed HPMA‐Copolymers and in vitro Characterization of the aRAGE‐ and Human Immunoglobulin (huIgG)–Polymer Conjugates
Authors: Tappertzhofen Kristof , Metz Verena V. , Hubo Mario , Barz Matthias , Postina Rolf , Jonuleit Helmut , Zentel Rudolf
Published: December 2012

Herein the synthesis of antibody–polymer conjugates, with a quite narrow dispersity based on the polymer HPMA, are reported. These conjugates are synthesized by coupling antibodies to maleimide‐functionalized poly(N‐(2‐hydroxypropyl)‐methacrylamide) (poly‐HPMA) copolymers derived through reversible addition‐fragmentation chain transfer (RAFT) polymerization of pentafluorophenyl methacrylate via the intermediate step of an activated ester polymer. We develop a protocol that allows the attachment of two different model antibodies, monoclonal anti‐RAGE (receptor for advanced glycation end‐products) antibody, and polyclonal human immunoglobulin (huIgG). Modification of the antibody and conjugation is monitored by SDS‐PAGE electrophoresis. Preserved affinity is demonstrated by Western Blott and cell‐uptake analysis, for example, to cells of the immune system.

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Temperature‐Regulated Fluorescence Characteristics of Supramolecular Assemblies Formed By a Smart Polymer and a Conjugated Polyelectrolyte
Authors: Inal Sahika , Kölsch Jonas D. , Chiappisi Leonardo , Kraft Mario , Gutacker Andrea , Janietz Dietmar , Scherf Ullrich , Gradzielski Michael , Laschewsky André , Neher Dieter
Published: December 2012

Aqueous mixtures of a coumarin‐labeled non‐ionic thermoresponsive copolymer and a cationic polythiophene exhibit marked changes in their fluorescence properties upon heating. At room temperature, emission from the label is significantly quenched due to energy transfer to the conjugated polyelectrolyte. Heating the mixture reduces the energy‐transfer efficiency markedly, resulting in a clearly visible change of the emission color. Although the two macromolecules associate strongly at room temperature, the number of interacting sites is largely reduced upon the phase transition. Crucially, the intermolecular association does not suppress the responsiveness of the smart polymer, meaning that this concept should be applicable to chemo‐ or bioresponsive polymers with optical read‐out, for example, as a sensor device.
Oxidation‐Responsive Polymers: Which Groups to Use, How to Make Them, What to Expect From Them (Biomedical Applications)
Authors: Lallana Enrique , Tirelli Nicola
Published: December 2012

Dramatic physical changes may take place upon the occurrence of oxidation reactions in a polymer, for example, solubilization or crosslinking. These effects can be used to perform responsive actions such as modulating the release kinetics of a drug with the extent of oxidation. The relevance of oxidation‐responsive applications to the biomedical/pharmaceutical field is discussed, starting from a review of chemical groups that can respond to physiologically occurring oxidants. An overview of the preparative processes of polymers containing groups such as metallocenes, (poly)pyridyl metal complexes, polyconjugated sequences, thiols, thioethers (sulfides), and stannanes is presented, and the mechanisms of oxidative response are reviewed.
Bioinspired Photo‐Core‐Crosslinked and Noncovalently Connected Micelles From Functionalized Polystyrene and Poly(ethylene oxide) Homopolymers
Authors: Wu Yi‐Chen , Wu Yu‐Shian , Kuo Shiao‐Wei
Published: December 2012

In this paper, we report a simple and effective method for the preparation of stable core‐crosslinked micelles after the self‐assembly of thymine‐functionalized polystyrene (PVBT) and adenine‐terminated poly(ethylene oxide) (PEO‐A) homopolymers, and subsequent bioinspired photo‐crosslinking of the thymine units in PVBT. We obtained “graft‐like” copolymers from the interactions of PEO‐A with the PVBT chains through complementary multiple hydrogen bonding in a common solvent (dimethylformamide) after the addition of selective solvents (H2O and MeCN for PVBT and PEO‐A, respectively). Stable micelles featuring PVBT as the core and PEO‐A as the shell were formed via selective solvent pairs; they were clearly visualized using transmission electronic microscopy and staining techniques. The shapes and sizes of the core/shell micelle structures did not change after exposure to UV light, revealing the enhanced dimensional stability of these photo‐core‐crosslinked micelles.
Rejuvenation, Aging, and Confinement Effects in Atactic‐Polystyrene Films Subjected to Oscillatory Shear
Authors: Hudzinskyy Dmytro , Michels Matthias A. J. , Lyulin Alexey V.
Published: December 2012

Molecular‐dynamics simulations of 5 nm‐thick atactic‐polystyrene films have been used to study the influence of cyclic‐shear deformation on the stress–strain behavior and local segmental mobility. Upon cyclic yield the stress–strain behavior of the films slowly evolves towards a steady state which is characterized by a decrease of the maximum stress and by an enhanced dissipative process. Immediately after plastic deformation the storage modulus is decreased and the loss modulus is increased as compared with their initial values. Such changes in the viscoelastic moduli reflect the mechanical rejuvenation of a polymer glass. This mechanical rejuvenation of polymers is connected to the increase in the simulated segmental mobility, which is calculated for the entire film as well as in different layers.

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Manufacturing and Distribution Strategies, Distribution Channels, and Transaction Costs: The Case of Parallel Imported Automobiles
Authors: Yeung Godfrey , Mok Vincent
Published: December 2012

We examine how constraints on transnational corporations' official distribution channels, asset specificity, and bounded rationality of franchise dealers and parallel traders contribute to the sustainability of the parallel importation of automobiles. The manufacturing and distribution strategies employed by transnational corporations considerably add to the regional differences in the pricing and availability of specific models, as well as vehicle specifications. These necessary conditions enable opportunistic parallel traders to engage in arbitrage. The asset specificity of franchise dealers, bounded rationality, and opportunism of dealers and arbitrageurs sustain the parallel importation of automobiles. Copyright © 2012 John Wiley & Sons, Ltd.
Asymmetric Price Adjustments in Airlines
Authors: Escobari Diego
Published: December 2012

This paper uses a unique daily time series data set to investigate the asymmetric response of airline prices to capacity costs driven by demand fluctuations. We use a Markov regime‐switching model with time‐varying transition probabilities to capture the time variation in the response. The results show strong evidence of asymmetric price adjustments: positive cost shifts have a large positive effect, whereas negative cost shifts have no effect. The asymmetry is also explained by summer travel but not by the size of cost shifts. The findings show the importance of consumer heterogeneity and capacity constraints as a source of asymmetric responses. Copyright © 2012 John Wiley & Sons, Ltd.
Levodopa improves motor deficits but can further disrupt cognition in a macaque parkinson model
Authors: Schneider Jay S. , Pioli Elsa Y. , Jianzhong Yang , Li Qin , Bezard Erwan
Published: December 2012

Background

Levodopa effectively relieves motor symptoms in Parkinson's disease (PD), but has had inconsistent effects on cognition, even worsening some aspects of cognitive functioning. Therefore, remediation of PD cognitive deficits is a major unmet need. However, drug development efforts have been hampered by lack of an animal model in which motor and cognitive deficits can be examined simultaneously.

Methods

Cynomolgus monkeys were trained to perform cognitive tasks and then chronically exposed to MPTP to slowly produce cognitive and motor deficits of parkinsonism.

Results

Administration of L‐dopa to these animals dose dependently improved motor functioning, but did not significantly improve cognitive performance. At doses that maximally improved motor function, additional cognitive deficits were observed. The present model of MPTP‐induced parkinsonism recapitulates important motor and cognitive aspects of PD. Results with L‐dopa mirror data derived from PD patients.

Conclusion

This model should allow more efficient testing of potential PD therapeutics to evaluate motor and cognitive functions simultaneously. © 2012 Movement Disorder Society
Levodopa does not change cerebral vasoreactivity in Parkinson's disease
Authors: Krainik Alexandre , Maillet Audrey , Fleury Vanessa , Sahin Mehmet , Troprès Irène , Lamalle Laurent , Thobois Stephane , Fraix Valerie , Villien Marjorie , Warnking Jan , Pollak Pierre , Pinto Serge , Krack Paul
Published: December 2012

The aim of this work was to study cerebral vasoreactivity to hypercapnia in Parkinson's disease (PD) before and after levodopa administration. The prospective study was conducted in 20 patients presenting with PD, using 3T blood oxygenation level‐dependent (BOLD) functional MRI (fMRI) covering the whole brain. The hypercapnic stimulus was block‐designed using carbogen inhalation, a gas mixture of 7% CO2 and 93% O2, before (OFF) and 60 minutes after administration of a suprathreshold (120%) therapeutic L‐dopa dose (ON). Ten age‐matched controls were enrolled for between‐group comparisons. Analyses were conducted with a random effects model and corrected for multiple comparisons. No adverse reaction to the hypercapnic stimulus was reported. However, 10 patients and 2 controls were excluded because of incomplete protocol realization, inappropriate hypercapnic stimulus, or excessive movements, leaving 10 patients and 8 controls for further analyses. The hypercapnic stimulus increased whole‐brain BOLD signal of 1.48% ± 0.06% (mean ± standard error) in controls, 1.59% ± 0.05% in patients OFF, and 1.62% ± 0.09% in patients ON. Regions of interest analyses showed a signal increase in gray matter of 2.60% ± 0.16% in controls, 2.89% ± 0.21% in patients OFF, and 2.87% ± 0.12% in patients ON. No global or regional significant difference was detected, when comparing patients OFF and ON L‐dopa, or between patients and controls. Contrary to Alzheimer's disease, the vasoreactivity to hypercapnia was normal in PD before and after L‐dopa administration, compared to controls. This negative result is an important finding, especially for neuroscientists using fMRI to investigate motricity and cognition, discarding a significant confounding effect. © 2012 Movement Disorder Society
Atherosclerotic Risk Factors, Vascular Cognitive Impairment, and Alzheimer Disease
Authors: Kovacic Jason C. , Fuster Valentin
Published: December 2012

The involvement of vascular factors in Alzheimer dementia was first appreciated over 100 years ago. Recently, significant advances in our understanding of these brain‐vascular relationships have taken place. Vascular cognitive impairment is now recognized as a distinct group of interrelated vascular‐based neurological insults that can accumulate and lead to dementia. Importantly, the pathology of vascular cognitive impairment extends far beyond brain destruction wrought by major stroke. Other subtle changes may also arise that contribute to vascular cognitive impairment and dementia, including subclinical stroke, white‐matter changes such as hyperintensities and lipohyalinosis, small lacunar infarcts, cerebral hypoperfusion, and compromise of the blood‐brain barrier. In this review we critically examine the emerging body of evidence that relates atherosclerotic risk factors, brain functioning, and Alzheimer disease. Mt Sinai J Med 79:664–673, 2012. © 2012 Mount Sinai School of Medicine
Evaluating Efficacy of Pharmaceutical Interventions in Atherosclerosis: Role of Magnetic Resonance Imaging and Positron Emission Tomography
Authors: Hyafil Fabien , Feldman Laurent , Le Guludec Dominique , Fayad Zahi A.
Published: December 2012

The rate of acute complications of atherosclerosis (acute myocardial infarction, ischemic stroke) has continuously decreased over the last 20 years in Western countries. This is largely explained by improvements in the reduction and treatment of cardiovascular risk factors and by the increasing number of patients who benefit from preventive treatments such as antiplatelet, lipid‐lowering, or antihypertensive drugs. This means also that, when testing new drugs aimed at either halting or even reversing the progression of atherosclerotic plaques, a large number of patients will need to be included in clinical trials to demonstrate an improvement in patient outcome with the drugs. Pharmaceutical companies are therefore looking for early surrogate markers that could be evaluated in a small number of patients to predict the beneficial effects of new drugs on atherosclerotic plaques before moving to costly clinical trials with a large number of patients. In this review, we will discuss the place of atherosclerotic plaque imaging with magnetic resonance imaging and positron emission tomography for the evaluation of new antiatherosclerotic drugs. Mt Sinai J Med 79:689–704, 2012. © 2012 Mount Sinai School of Medicine
Amyloid Neuropathies
Authors: Shin Susan C. , Robinson‐Papp Jessica
Published: December 2012

Peripheral neuropathy is a common complication of many of the systemic amyloidoses. Although the cause of neuropathy is not entirely clear, it is likely related to amyloid deposition within the nerve. This may lead to focal, multifocal, or diffuse neuropathies involving sensory, motor and/or autonomic fibers. The presenting symptoms depend on the distribution of nerves affected. One of the most common phenotypes is sensorimotor polyneuropathy, which is characterized by symptoms of neuropathic pain, numbness, and in advanced cases weakness. Symptoms begin in the feet and ultimately progress to the proximal legs and hands. The most common focal neuropathy is a median neuropathy at the wrist, clinically known as carpal tunnel syndrome. Carpal tunnel symptoms may include pain and sensory disturbances in the lateral palm and fingers; hand weakness may ensue if the focal neuropathy is severe. Autonomic neuropathy may affect a variety of organ systems such as the cardiovascular, gastrointestinal, and genitourinary systems. Symptoms may be non‐specific making the diagnosis of autonomic neuropathy more difficult to identify. However, it is important to recognize and distinguish autonomic neuropathy from diseases of the end‐organs themselves. This article reviews the inherited and acquired amyloidoses that affect the peripheral nervous system including familial amyloid polyneuropathy, and primary, secondary and senile amyloidosis. We emphasize the clinical presentation of the neurologic aspects of these diseases, physical examination findings, appropriate diagnostic evaluation, treatment and prognosis. Mt Sinai J Med 79:733–748, 2012. © 2012 Mount Sinai School of Medicine
Cancer recording and mortality in the General Practice Research Database and linked cancer registries
Authors: Boggon Rachael , van Staa Tjeerd P. , Chapman Michael , Gallagher Arlene M. , Hammad Tarek A. , Richards Mike A.
Published: December 2012

Purpose

Large electronic datasets are increasingly being used to evaluate healthcare delivery. The aim of this study was to compare information held by cancer registries with that of the General Practice Research Database (GPRD).

Methods

A convenience sample of 101 020 patients aged 40+ years drawn from GPRD formed the primary data source. This cohort was derived from a larger sample originally established for a cohort study of diabetes. GPRD records were linked with those from cancer registries in the National Cancer Data Repository (NCDR). Concordance between the two datasets was then evaluated. For cases recorded only on one dataset, validation was sought from other datasets (Hospital Episode Statistics and death registration) and by detailed analysis of a subset of GPRD records.

Results

A total of 5797 cancers (excluding non‐melanomatous skin cancer) were recorded on GPRD. Of these cases, 4830 were also recorded on NCDR (concordance rate of 83.3%). Of the 976 cases recorded on GPRD but not on NCDR, 528 were present also in the hospital records or death certificates. Of the 341 cases recorded on NCDR but not on GPRD, 307 were recorded in these other two datasets. Rates of concordance varied by cancer type. Cancer registries recorded larger numbers of patients with lung, colorectal, and pancreatic cancers, whereas GPRD recorded more haematological cancers and melanomas. As expected, GPRD recorded significantly more non‐melanomatous skin cancer. Concordance decreased with increasing age.

Conclusion

Although concordance levels were reasonably high, the findings from this study can be used to direct efforts for better recording in both datasets. Copyright © 2012 Crown copyright.
An automated tool for detecting medication overuse based on the electronic health records
Authors: Salmasian Hojjat , Freedberg Daniel E , Abrams Julian A , Friedman Carol
Published: December 2012

Purpose

Medication overuse is a serious concern in healthcare as it leads to increased expenditures, side effects, and morbidities. Identifying overuse is only possible through excluding appropriate indications that are primarily mentioned in unstructured notes. We developed a framework for automatic identification of medication overuse and applied it to proton pump inhibitors (PPIs).

Methods

We first created an indications knowledge base using data from drug labels, clinical guidelines, expert opinion, and other sources. We also obtained the list of current problems for 200 randomly selected inpatients who received PPIs using a natural language processing system and the discharge summaries of those patients. These problems were checked against the indications knowledge base to identify overuse candidates. Two gastroenterologists manually reviewed the notes and identified cases of overuse. Results from the automated framework were compared with the manual review.

Results

Reviewers had high interrater reliability in finding indications (agreement = 92.1%, Cohen's κ = 0.773). In 137 notes included in the final analysis, our system identified indications with a sensitivity of 74% (95%CI = 59–86) and specificity of 95% (95%CI = 87–98). In cases of appropriate use where the automated system also found one or more indications, it always included the correct indication.

Conclusions

We created an automated system that can identify established indications of medication use in electronic health records with high accuracy. It can provide clinical decision support for identifying potential overuse of PPIs and could be useful for reducing overuse and encouraging better documentation of indications. Copyright © 2012 John Wiley & Sons, Ltd.
Synthesis, characterization, and CO2 permeation properties of acetylene‐terminated polyimide membranes
Authors: Kanehashi Shinji , Onda Masaki , Shindo Ryohei , Sato Shuichi , Kazama Shingo , Nagai Kazukiyo
Published: December 2012

A novel fluorine‐containing telechelic polyimide end‐capped with acetylene group which derived from 4,4‐(hexafluoroisopropylidene) diphthalic anhydride (6FDA), 3,4‐diaminodiphenyl ether (DADE), and 4‐(2‐phenylethynyl) phthalic anhydride (PEPA) was synthesized using polycondensation. The physical and CO2 permeation properties of its crosslinked membranes prepared by the cyclotrimerization reaction of the acetylene groups at the polymer chain end using tantalum (V) chloride (TaCl5) as a catalyst under thermal treatment was investigated in terms of CO2‐induced membrane plasticization. The crosslinked membranes showed a gel content in organic solvent, which was good solvent of noncrosslinked membranes, and improved their thermal stability. Based on the measurement of the high‐pressure time dependence on CO2 permeation, the crosslinked 6FDA–DADE–PEPA membranes exhibited more resistance to CO2‐induced plasticization than noncrosslinked 6FDA–DADE and thermal treated 6FDA–DADE–PEPA. Furthermore, the increase in TaCl5 content resulted in more resistance to plasticization. The cyclotrimerization reaction of the acetylene groups at the polymer chain ends using a transition metal catalyst under thermal treatment was found to be more effective than conventional thermal treatments for suppressing membrane plasticization without the membrane densification. POLYM. ENG. SCI., 2013. © 2012 Society of Plastics Engineers
Accelerated irradiance and temperature cycle test for amorphous silicon photovoltaic devices
Authors: Igari Sanekazu , Takahisa Kiyoshi
Published: December 2012

An accelerated irradiance and temperature cycle test (AITCT) has been developed as a method to evaluate the long‐term performance stability of amorphous silicon (a‐Si) photovoltaic (PV) devices. The AITCT simulates the daily light–dark cycle in 6 min (0.1 h). It also simulates the annual temperature cycle while controlling the temperature at 45 °C above the average monthly outdoor ambient temperature. This allows the influence of the day–night cycle and seasonal variation to be included in the acceleration factor for single‐junction a‐Si PV devices. The initial degradation and seasonal variation of performance of a‐Si PV devices simulated by the AITCT agreed well with experimental results of 4‐year outdoor exposure. Subsequent tests with the AITCT equivalent of 30‐year outdoor exposure revealed that rapid degradation in the efficiency of a‐Si PV devices would not occur by repeating the cyclic changes corresponding to seasonal variations following the initial degradation. The AITCT is able to accelerate further recovery in addition to light‐induced degradation. Furthermore, the AITCT is applicable to other PV devices with light‐intensity dependencies related to light‐induced degradation as well as thermal recovery dependencies, such as multi‐junction PV devices consisting of a‐Si layers and other materials. This point will be discussed. Copyright © 2012 John Wiley & Sons, Ltd.
Influence of the substrate material on the surface morphology of electrochemically deposited ZnO layers
Authors: Dimova‐Malinovska Doriana , Lovchinov Konstantin , Ganchev Maxim , Angelov Orlin , Graff Joachim Seland , Ulyashin Alexander
Published: December 2012

In this paper we report results of fabrication of ordered ZnO nanorods (NRs) or nanowalls (NWs) electrochemically deposited on different highly conductive substrates. The following types of conductive substrates have been used: (i) highly doped p‐type multi‐crystalline Si, and (ii) copper thin plates. The influence of a seeding Ag layer deposited on multi‐Si substrates on the growth of ZnO NRs has been studied as well. It is observed that morphology of the deposited ZnO structures depends strongly on the type of the substrate used. It is found that ZnO structures with different shapes, such as NRs, nanotubes or NWs can be grown on top of highly conductive substrates used in this work. It is observed that optical reflection of the deposited layers depends on the substrate used as well as on the time of the electrochemical deposition of ZnO layers. It was found that: (i) for ZnO NWs/Cu structures, diffused reflection exhibit strong enhancement compared to pure Cu substrate; (ii) in case of ZnO NRs/Si structures reflection is decreased compared to that for pure Si substrate. Possible applications of ZnO NRs or NWs‐based structures for the processing of advanced Si‐based solar cells are discussed.
Erratum: Theoretical analysis of free carrier absorption in the cavity of a quantum cascade laser
Authors: Bogdanov Andrey , Suris Robert
Published: December 2012

Expression for the frequency at which free carrier absorption is the same for the volume and surface mode is slightly changed.
Fragmentation patterns of protonated amino acids formed by atmospheric pressure chemical ionization
Authors: Choi Sung‐Seen , Song Min Ju , Kim Ok‐Bae , Kim Yeowool
Published: December 2012

RATIONALE

Dissociation reactions of protonated amino acids (AAs) can be used as models for the fragmentation of protonated peptides. Atmospheric pressure chemical ionization mass spectrometry (APCI‐MS) provides a great deal of structural information in a short analysis time.

METHODS

In APCI‐MS, the fragmentation patterns can be obtained by varying the cone voltage and some fragment ions are produced that can be used to identify the structure of an analyte. In general, the fragmentation of AAs has used liquid chromatography/tandem mass spectrometry (LC/MS/MS). However, we studied the fragmentation of protonated AAs using a single quadrupole mass spectrometer.

RESULTS

The principal fragment ions were [M + H – H2O – CO]+, [M + H – H2O]+, and [M + H – NH3]+. AAs that only generated [M + H – H2O – CO]+ were alanine, glycine, histidine, isoleucine, leucine, proline, phenylalanine, and valine. AAs that generated [M + H – H2O]+ and [M + H – H2O – CO]+ were aspartic acid, glutamic acid, serine, and threonine, while AAs that generated [M + H – NH3]+ and [M + H – H2O – CO]+ were asparagine, cysteine, glutamine, methionine, tryptophan, and tyrosine. Arginine and lysine generated [M + H – H2O]+ and [M + H – NH3]+.

CONCLUSIONS

The relative abundances of the fragment ions increased with increase in the cone voltage. The experimental results were explained by the favorability of the intermediate structure and the stability of the fragment ion structure. The specific fragmentation patterns could be used for differentiating underivatized AAs. Copyright © 2012 John Wiley & Sons, Ltd.
Detection systems for mass spectrometry imaging: A perspective on novel developments with a focus on active pixel detectors
Authors: Jungmann Julia H. , Heeren Ron M. A.
Published: December 2012

Instrumental developments for imaging and individual particle detection for biomolecular mass spectrometry (imaging) and fundamental atomic and molecular physics studies are reviewed. Ion‐counting detectors, array detection systems and high mass detectors for mass spectrometry (imaging) are treated. State‐of‐the‐art detection systems for multi‐dimensional ion, electron and photon detection are highlighted. Their application and performance in three different imaging modes – integrated, selected and spectral image detection – are described. Electro‐optical and microchannel‐plate‐based systems are contrasted. The analytical capabilities of solid‐state pixel detectors – both charge coupled device (CCD) and complementary metal oxide semiconductor (CMOS) chips – are introduced. The Medipix/Timepix detector family is described as an example of a CMOS hybrid active pixel sensor. Alternative imaging methods for particle detection and their potential for future applications are investigated. Copyright © 2012 John Wiley & Sons, Ltd.
Fragmentation studies of SIRT1‐activating drugs and their detection in human plasma for doping control purposes
Authors: Höppner Sebastian , Schänzer Wilhelm , Thevis Mario
Published: December 2012

RATIONALE

The efficiency of Sirtuin1, a major target for the treatment of various metabolic disorders such as inflammation and type 2 diabetes mellitus, can be modulated via low molecular mass SIRT1 activators (e.g. resveratrol, SRT1720, and SRT2104).The administration of such compounds results in increased deacetylation of substrates including p53, FOXO1, and PGC1alpha, potentially leading to an improved physical performance. Consequently, proactive and preventive anti‐doping measures are required and an assay dedicated to serum and plasma was desirable.

METHODS

Model substances of emerging SIRT1 drug candidates were obtained and synthesized and their mass spectrometric behavior following positive or negative electrospray ionization and collision‐induced dissociation was elucidated using low and high resolution/high accuracy (tandem) mass spectrometry. Subsequently, a screening and confirmation procedure necessitating 100 μL of plasma was established employing liquid chromatography/tandem mass spectrometry (LC/MS/MS) based on diagnostic ion transitions recorded in multiple reaction monitoring mode. Sample preparation consisted of the addition of two deuterated internal standards (D8‐SRT1720 and D4‐resveratrol) to the plasma specimen and subsequent protein precipitation.

RESULTS

Characteristic product ions indicative of the core structures of the model analytes were characterized and utilized for the development of a multi‐analyte LC/MS/MS detection method applicable to sports drug testing programs. The doping control assay was validated with regard to specificity, limits of detection (0.1–1 ng/mL), recoveries (90–98%), intraday and interday precisions (2–18%), and ion suppression/enhancement effects.

CONCLUSIONS

The fragmentation pathways of SRT1720 and 4 SIRT1 activator models based on a common thiazole‐imidazole nucleus as well as two different complementary activators (SIRT1 activator 3 and CAY10602), comprising a quinoxaline core, were studied. The resulting information was used to establish and validate a sports drug testing methodology relevant for an efficient and timely anti‐doping procedure, targeting a new class of emerging therapeutics possessing significant potential for misuse in elite and amateur sport. Copyright © 2012 John Wiley & Sons, Ltd.
A novel approach to the analysis of SUMOylation with the independent use of trypsin and elastase digestion followed by database searching utilising consecutive residue addition to lysine
Authors: Chicooree Navin , Griffiths John R. , Connolly Yvonne , Tan Chong‐Teik , Malliri Angeliki , Eyers Claire E. , Smith Duncan L.
Published: December 2012

RATIONALE

Identification of sites of protein SUMOylation is of great importance due its functional diversity within the cell. To date, most approaches to this problem rely on site‐directed mutagenesis and/or highly specialised mass spectrometry approaches. We present a novel alternative approach to the site mapping of SUMOylation using trypsin and elastase digestion, routine mass spectrometry and an unbiased isotag database searching strategy.

METHODS

SUMOylated protein samples were digested with a number of enzymes and the resulting peptides separated using liquid chromatography. Analysis was carried out on both linear ion trap Orbitrap and quadrupole‐time‐of‐flight (Q‐TOF)‐based mass spectrometers equipped with electrospray ionisation. The data files were subsequently searched using the Mascot algorithm with multiple variable tag modifications corresponding to SUMO‐derived fragments. The utility of this approach was demonstrated with di‐SUMO 2, di‐SUMO 3, SUMO 1‐RanGap418‐587 1 and an enriched population of SUMOylated proteins.

RESULTS

Unbiased database searches led to the identification of a number of analytically useful isotags ranging in length from two to four residues. Isopeptide fragments were generated including QTGG (di‐SUMO‐2/3), TGG (di‐SUMO‐2/3) and GG (SUMO‐1). The method was validated by successfully mapping a number of sites of SUMO modification on SUMO‐modified proteins enriched from a cell lysate.

CONCLUSIONS

This combination of relaxed enzyme specificity, shortened isotag generation and unbiased database searching enabled confident identification of novel analytically useful SUMOylated isopeptides without a requirement for mutagenesis. Copyright © 2012 John Wiley & Sons, Ltd.
Negative ion fragmentations of disulfide‐containing cross‐linking reagents are competitive with aspartic acid side‐chain‐induced cleavages
Authors: Calabrese Antonio N. , Wang Tianfang , Bowie John H. , Pukala Tara L.
Published: December 2012

RATIONALE

It has been shown that the disulfide moiety in the chemical cross‐linking reagent dithiobis(succinimidyl)propionate (DSP), which is similar in structure to the natural cystine disulfide, cleaves preferentially to the peptide backbone in the negative ion mode. However, the tandem mass (MS/MS) spectra of peptides in the negative ion mode are often dominated by products arising from low‐energy, side‐chain‐induced processes, which may compete with any facile cross‐linker fragmentations and complicate identification of chemical cross‐links in a complex mixture.

METHODS

Two disulfide‐containing crosslinking reagents similar to DSP, but with varying spacer arm lengths, were synthesized and the MS/MS spectra of several model peptides cross‐linked with these reagents were investigated. Theoretical calculations were used to describe the energetics of the cross‐linker fragmentations as well as several low‐energy side‐chain‐induced fragmentations which compete with disulfide cleavages.

RESULTS

Altering the spacer arm length of the cross‐linker, such that there is one methylene group less than in DSP, results in a more facile cleavage process, whilst the opposite is true when a methylene group is added. Of the low‐energy side‐chain‐induced fragmentations studied, only those from aspartic acid compete significantly with those of the cross‐linker disulfide.

CONCLUSIONS

Low‐energy cleavage processes from aspartic acid that compete with cross‐linker fragmentations occur in the negative ion MS/MS spectra of the cross‐linked peptides, irrespective of the spacer arm length. Other fragmentation pathways do not significantly interfere with low‐energy disulfide cleavage, making the presence of additional product ions in the MS/MS spectrum diagnostic for the presence of aspartic acid. Copyright © 2012 John Wiley & Sons, Ltd.
Study on the intermediate ions formed by glutathione peroxidase mimic 2,2'‐ditellurobis(2‐deoxy‐β‐cyclodextrin) by electrospray ionization mass spectrometry
Authors: Jiao Aiquan , Yang Na , Xu Xueming , Jin Zhengyu
Published: December 2012

RATIONALE

2,2'‐Ditellurobis(2‐deoxy‐β‐cyclodextrin) (2‐TeCD) is one of the most well‐known glutathione peroxidase (GPx) mimics. However, because the critical reaction intermediates had not previously been isolated or directly detected due to its short lifetime, the catalytic mechanism of 2‐TeCD is not very clear and further experiments are needed to characterize each of the intermediates in the catalytic cycle.

METHODS

Using electrospray ionization mass (and tandem) spectrometry (ESI‐MS and ESI‐MS/MS) experiments, the decomposition of hydrogen peroxide at the expense of glutathione (GSH) catalyzed by 2‐TeCD was monitored on‐line.

RESULTS

The key intermediates were successfully intercepted and structurally characterized for the first time by coupling a microreactor on‐line to the ESI ion source, which permitted the fast screening of intermediates directly from solution.

CONCLUSIONS

The catalytic mechanism of 2‐TeCD catalysis has been elaborated based on mass spectrometric data and exerted its peroxidase activity via tellurol, tellurenic acid, and tellurosulfide, in analogy with natural GPX. Copyright © 2012 John Wiley & Sons, Ltd.
Distribution‐free models for longitudinal count responses with overdispersion and structural zeros
Authors: Yu Q. , Chen R. , Tang W. , He H. , Gallop R. , Crits‐Christoph P. , Hu J. , Tu X.M.
Published: December 2012

Overdispersion and structural zeros are two major manifestations of departure from the Poisson assumption when modeling count responses using Poisson log‐linear regression. As noted in a large body of literature, ignoring such departures could yield bias and lead to wrong conclusions. Different approaches have been developed to tackle these two major problems. In this paper, we review available methods for dealing with overdispersion and structural zeros within a longitudinal data setting and propose a distribution‐free modeling approach to address the limitations of these methods by utilizing a new class of functional response models. We illustrate our approach with both simulated and real study data. Copyright © 2012 John Wiley & Sons, Ltd.
Agile coaching for global software development
Authors: Paasivaara Maria , Lassenius Casper
Published: December 2012

This paper presents a case study on building a successful agile coaching team focusing on global software development projects in an international Nordic‐based software company. We describe how the team of eight coaches was built, and how the coaches work together as a team using agile practices, such as weekly iterations, backlogs, and daily stand‐ups. Furthermore, we describe their ‘deep and narrow’ approach to working closely with case projects, and the benefits to the coached projects. We describe the main challenges in building the coaching activities in a globally distributed company. The paper concludes with a set of lessons learned for coaching globally distributed projects and a discussion of the future plans for scaling up coaching by building a global coaching network within the company. We collected the data using 13 semi‐structured interviews of the coaching team members, and personnel from four coached case projects. Copyright © 2012 John Wiley & Sons, Ltd.
Inter‐Cloud architectures and application brokering: taxonomy and survey
Authors: Grozev Nikolay , Buyya Rajkumar
Published: December 2012

Although Cloud computing itself has many open problems, researchers in the field have already made the leap to envision Inter‐Cloud computing. Their goal is to achieve better overall Quality of Service (QoS), reliability and cost efficiency by utilizing multiple clouds. Inter‐Cloud research is still in its infancy, and the body of knowledge in the area has not been well defined yet. In this work, we propose and motivate taxonomies for Inter‐Cloud architectures and application brokering mechanisms. We present a detailed survey of the state of the art in terms of both academic and industry developments (20 projects), and we fit each project onto the discussed taxonomies. We discuss how the current Inter‐Cloud environments facilitate brokering of distributed applications across clouds considering their nonfunctional requirements. Finally, we analyse the existing works and identify open challenges and trends in the area of Inter‐Cloud application brokering. Copyright © 2012 John Wiley & Sons, Ltd.