bluuebunny/crossref_metadata_2025_split huggingface dataset:
TREATMENT SWITCHING IN CANCER TRIALS: ISSUES AND PROPOSALS
Authors: Henshall Chris , Latimer Nicholas R. , Sansom Lloyd , Ward Robyn L. 
Published: September 2016

Objectives:Treatment switching occurs when patients in a randomized clinical trial switch from the treatment initially assigned to them to another treatment, typically from the control to experimental treatment. This study discusses the issues this raises and possible approaches to addressing them in trials of cancer drugs.Methods:Stakeholders from around the world were invited to a 1.5-day Workshop in Adelaide, Australia. This study attempts to capture the key points from the discussion and the perspectives of the various stakeholder groups, but is not a formal consensus statement.Results:Treatment switching raises challenging ethical issues with arguments for and against allowing it. It is increasingly common in cancer drug trials and presents challenges for the interpretation of results by regulators, clinicians, patients, and payers. Proposals are offered for good practice in the design, management, and analysis of trials and wider development programs for cancer drugs in which treatment switching has occurred or is likely to. Recommendations are also offered for further action to improve understanding of the importance and challenges of treatment switching and to promote agreement between key stakeholders on guidelines and other steps to address these challenges.Conclusions:The handling of treatment switching in trials is of concern to all stakeholders. On the basis of the discussions at the Adelaide International Workshop, there would appear to be common ground on approaches to addressing treatment switching in cancer trials and scope for the development of formal guidelines to inform the work of regulators, payers, industry, trial designers and other stakeholders.
COST-EFFECTIVENESS ANALYSIS OF HERPES ZOSTER VACCINATION IN ITALIAN ELDERLY PERSONS
Authors: Coretti Silvia , Codella Paola , Romano Federica , Ruggeri Matteo , Cicchetti Americo 
Published: September 2016

Objectives:Herpes zoster (HZ) is characterized by a painful skin rash. Its main complication is postherpetic neuralgia (PHN), pain persisting or occurring after the rash onset. HZ treatment aims to reduce acute pain, impede the onset complications, and disease progression. The aim of this study was to assess the cost-effectiveness of HZ vaccination compared with no vaccination strategy, within the Italian context.Methods:The natural history of HZ and PHN was mapped through a Markov model with lifetime horizon. A population of patients aged between 60 and 79 years was hypothesized. Third party payer (Italian National Health Service, I-NHS) and societal perspectives were adopted. Data were derived from literature.Results and Conclusions:The incremental cost-effectiveness ratio of the vaccination equaled EUR 11,943 per quality-adjusted life-year (QALY) under the I-NHS perspective and EUR 11,248 per QALY under the societal perspective. Considering a cost-effectiveness threshold of EUR 30,000/QALY, the multi-way sensitivity analysis showed that vaccination is cost-effective regardless of the perspective adopted, in 99 percent of simulations.
SCIENTIFIC AND SOCIAL VALUE JUDGMENTS FOR ORPHAN DRUGS IN HEALTH TECHNOLOGY ASSESSMENT
Authors: Nicod Elena , Kanavos Panos 
Published: September 2016

Objectives: We explore how broader aspects of a treatment's value and the impact of the condition on patients not captured by routine health technology assessment (HTA) methods using clinical and economic evidence, defined as “other considerations,” may influence HTA processes in different settings.Methods: Countries included were England, Scotland, Sweden, and France. Data sources were the publicly available reports on HTA recommendations. Ten drugs with European Medicines Agency orphan designation and appraised in England were selected. Qualitative thematic analysis was used to systematically identify and code all “other considerations” based on a previously developed methodological framework, which also coded whether it was provided by stakeholders, and how it influenced the decision.Results: A classification framework of scientific and social value judgments was developed and used throughout the study. A total of 125 “other considerations” were identified and grouped into ten subcategories based on the information provided. Eighteen to 100 percent of these, depending on the agency, were put forward as one of the main reasons for the final decision potentially contributing to accepting a higher incremental cost-effectiveness ratio or uncertain evidence. Some of these were nonquantified or nonelicited and pertained to the assessor's judgment. A taxonomy of these value judgments was created to be used in future cases. Results also contributed to better defining the determinants of social value and improving accountability for reasonableness.Conclusions: The systematic identification of the scientific and social value judgments enables to better understanding the dimensions of value, which can be used to improve their transparency and consistent use across decisions and settings.
‘Unwomanly practices’: Poaching Crime, Gender and the Female Offender in Nineteenth-Century Britain
Authors: OSBORNE HARVEY 
Published: September 2016

Abstract:Studies of poaching in the nineteenth century have tended to understate the involvement of women in this archetypal rural crime. This article will suggest that female offending was both more significant and more widespread than previously assumed, but it will also highlight how in a variety of complex ways dominant conceptions of gender shaped perceptions of female poachers and often influenced their treatment before the courts. It will argue that alongside more widely effectual assumptions about appropriate male and female spheres and behaviours, the response of the authorities to female poachers was also shaped by powerful and increasingly culturally embedded notions about the sexually exclusive nature of hunting.
Economic Growth and Biological Innovation: The Development of the European Dairy Sector, 1865–1940
Authors: ADELL ISMAEL HERNÁNDEZ , PUJOL-ANDREU JOSEP 
Published: September 2016

Abstract:In this article we discuss an aspect of economic growth that has not been the subject of much consideration in economic and agrarian history to date: the effect of biological innovations on farming development between the mid nineteenth century and the 1930s. We have focused on dairy farming for two reasons. Firstly, dairy farming played a relevant economic role in a number of European regions during this period. Secondly, one of its products, liquid milk, was probably the most significant food during the early stages of the European nutrition transition. We present new statistical data for the evolution of dairy farming in different Northern European countries as well as Spain, and evaluate the impact of cattle population and milk yields in each case. We also link milk yields and the availability of fodder, but special attention is paid to the breeds kept and techniques for their improvement. The article shows that cattle improvement played a significant role in Central and Northern Europe from the mid nineteenth century, but that this was not the case in Spain. Improvement through inbreeding was soon discarded in Spain, absorbent crossbreeding failed, and the sector became dependent on foreign imports of bulls and cows, first from Switzerland and later from Holland. By taking these factors into consideration we can better understand why the dairy sector in Mediterranean Europe did not really begin until the late nineteenth century and why it stagnated in the wake of the First World War.
Analysis of the sequence of ITS1 and ITS2 regions of Three Mentha species
Authors: Apostolova Elena , Todorov Krasimir , Dimitrova-Dyulgerova Ivanka , Stoyanov Plamen , Mladenov Rumen , Yahubyan Galina , Naimov Samir 
Published: September 2016

AbstractMentha (Nepetoideae, Lamiaceae) is a taxonomically complex genus consisting of 29 species and 11 different hybrids including a number of economically important species among them medical plants used for more than 250 years. Because of its high incidence of polyploidy, diverse morphology, high degree of chromosome number variations and interspecies hybridization, Mentha is considered to be a taxonomical challenge. In this paper, we describe cloning and sequencing of internal transcribed spacers (ITS) 1 and 2 of three mint species: Mentha aquatic L., Mentha longifolia L. (Huds) and Mentha piperita L., collected from natural habitats of Bulgaria. The applicability of ITS1 and ITS2 for molecular fingerprinting and further comparative studies, including the newly obtained ITS1 and ITS2 sequences, was tested in phylogenetic analysis of all eight Mentha species, found in Bulgarian flora.
Asymmetric cyanation of imines via dipeptide-derived organophosphine dual-reagent catalysis
Authors: Wang Hong-Yu , Zheng Chang-Wu , Chai Zhuo , Zhang Jia-Xing , Zhao Gang 
Published: September 2016

AbstractOver the past few decades, enantioselective phosphine organocatalysis has evolved rapidly into a highly efficient catalytic strategy for a range of useful reactions. However, as restricted by the traditional catalytic modes, some important reactions, such as asymmetric Strecker-type reactions, have thus far been out of reach of this strategy. Reported herein is an application of enantioselective phosphine organocatalysis for asymmetric Strecker-type reactions, enabled by a dual-reagent catalyst system in which the key organophosphorus zwitterion intermediate, generated in situ by mixing a chiral dipeptide-derived multifunctional organophosphine with methyl acrylate, is used as a highly efficient chiral Lewis base catalyst. The high efficiency of this catalytic system is demonstrated in the asymmetric cyanation of isatin-derived ketimines and azomethine aldimines as well as in the kinetic resolution of racemic 3-substituted azomethines. Mechanistic studies provide experimental evidence for the intermediacy of the putative zwitterion and its role as a catalytically active Lewis base.
Observation of acceleration and deceleration in gigaelectron-volt-per-metre gradient dielectric wakefield accelerators
Authors: O’Shea B. D. , Andonian G. , Barber S. K. , Fitzmorris K. L. , Hakimi S. , Harrison J. , Hoang P. D. , Hogan M. J. , Naranjo B. , Williams O. B. , Yakimenko V. , Rosenzweig J. B. 
Published: September 2016

AbstractThere is urgent need to develop new acceleration techniques capable of exceeding gigaelectron-volt-per-metre (GeV m−1) gradients in order to enable future generations of both light sources and high-energy physics experiments. To address this need, short wavelength accelerators based on wakefields, where an intense relativistic electron beam radiates the demanded fields directly into the accelerator structure or medium, are currently under intense investigation. One such wakefield based accelerator, the dielectric wakefield accelerator, uses a dielectric lined-waveguide to support a wakefield used for acceleration. Here we show gradients of 1.347±0.020 GeV m−1 using a dielectric wakefield accelerator of 15 cm length, with sub-millimetre transverse aperture, by measuring changes of the kinetic state of relativistic electron beams. We follow this measurement by demonstrating accelerating gradients of 320±17 MeV m−1. Both measurements improve on previous measurements by and order of magnitude and show promise for dielectric wakefield accelerators as sources of high-energy electrons.
The electrophotonic silicon biosensor
Authors: Juan-Colás José , Parkin Alison , Dunn Katherine E. , Scullion Mark G. , Krauss Thomas F. , Johnson Steven D. 
Published: September 2016

AbstractThe emergence of personalized and stratified medicine requires label-free, low-cost diagnostic technology capable of monitoring multiple disease biomarkers in parallel. Silicon photonic biosensors combine high-sensitivity analysis with scalable, low-cost manufacturing, but they tend to measure only a single biomarker and provide no information about their (bio)chemical activity. Here we introduce an electrochemical silicon photonic sensor capable of highly sensitive and multiparameter profiling of biomarkers. Our electrophotonic technology consists of microring resonators optimally n-doped to support high Q resonances alongside electrochemical processes in situ. The inclusion of electrochemical control enables site-selective immobilization of different biomolecules on individual microrings within a sensor array. The combination of photonic and electrochemical characterization also provides additional quantitative information and unique insight into chemical reactivity that is unavailable with photonic detection alone. By exploiting both the photonic and the electrical properties of silicon, the sensor opens new modalities for sensing on the microscale.
Hidden lattice instabilities as origin of the conductive interface between insulating LaAlO3 and SrTiO3
Authors: Lee P. W. , Singh V. N. , Guo G. Y. , Liu H.-J. , Lin J.-C. , Chu Y.-H. , Chen C. H. , Chu M.-W. 
Published: September 2016

AbstractThe metallic interface between insulating LaAlO3 and SrTiO3 opens up the field of oxide electronics. With more than a decade of researches on this heterostructure, the origin of the interfacial conductivity, however, remains unsettled. Here we resolve this long-standing puzzle by atomic-scale observation of electron-gas formation for screening hidden lattice instabilities, rejuvenated near the interface by epitaxial strain. Using atomic-resolution imaging and electron spectroscopy, the generally accepted notions of polar catastrophe and cation intermixing for the metallic interface are discounted. Instead, the conductivity onset at the critical thickness of 4-unit cell LaAlO3 on SrTiO3 substrate is accompanied with head-to-head ferroelectric-like polarizations across the interface due to strain-rejuvenated ferroelectric-like instabilities in the materials. The divergent depolarization fields of the head-to-head polarizations cast the interface into an electron reservoir, forming screening electron gas in SrTiO3 with LaAlO3 hosting complementary localized holes. The ferroelectric-like polarizations and electron–hole juxtaposition reveal the cooperative nature of metallic LaAlO3/SrTiO3.
Real-time observation of DNA recognition and rejection by the RNA-guided endonuclease Cas9
Authors: Singh Digvijay , Sternberg Samuel H. , Fei Jingyi , Doudna Jennifer A. , Ha Taekjip 
Published: September 2016

AbstractBinding specificity of Cas9–guide RNA complexes to DNA is important for genome-engineering applications; however, how mismatches influence target recognition/rejection kinetics is not well understood. Here we used single-molecule FRET to probe real-time interactions between Cas9–RNA and DNA targets. The bimolecular association rate is only weakly dependent on sequence; however, the dissociation rate greatly increases from <0.006 s−1 to >2 s−1 upon introduction of mismatches proximal to protospacer-adjacent motif (PAM), demonstrating that mismatches encountered early during heteroduplex formation induce rapid rejection of off-target DNA. In contrast, PAM-distal mismatches up to 11 base pairs in length, which prevent DNA cleavage, still allow formation of a stable complex (dissociation rate <0.006 s−1), suggesting that extremely slow rejection could sequester Cas9–RNA, increasing the Cas9 expression level necessary for genome-editing, thereby aggravating off-target effects. We also observed at least two different bound FRET states that may represent distinct steps in target search and proofreading.
Towards optical polarization control of laser-driven proton acceleration in foils undergoing relativistic transparency
Authors: Gonzalez-Izquierdo Bruno , King Martin , Gray Ross J. , Wilson Robbie , Dance Rachel J. , Powell Haydn , Maclellan David A. , McCreadie John , Butler Nicholas M. H. , Hawkes Steve , Green James S. , Murphy Chris D. , Stockhausen Luca C. , Carroll David C. , Booth Nicola , Scott Graeme G. , Borghesi Marco , Neely David , McKenna Paul 
Published: September 2016

AbstractControl of the collective response of plasma particles to intense laser light is intrinsic to relativistic optics, the development of compact laser-driven particle and radiation sources, as well as investigations of some laboratory astrophysics phenomena. We recently demonstrated that a relativistic plasma aperture produced in an ultra-thin foil at the focus of intense laser radiation can induce diffraction, enabling polarization-based control of the collective motion of plasma electrons. Here we show that under these conditions the electron dynamics are mapped into the beam of protons accelerated via strong charge-separation-induced electrostatic fields. It is demonstrated experimentally and numerically via 3D particle-in-cell simulations that the degree of ellipticity of the laser polarization strongly influences the spatial-intensity distribution of the beam of multi-MeV protons. The influence on both sheath-accelerated and radiation pressure-accelerated protons is investigated. This approach opens up a potential new route to control laser-driven ion sources.
De novo large rare copy-number variations contribute to conotruncal heart disease in Chinese patients
Authors: Mak Christopher C Y , Chow Pak Cheong , Liu Anthony P Y , Chan Kelvin Y K , Chu Yoyo W Y , Mok Gary T K , Leung Gordon K C , Yeung Kit San , Chau Adolphus K T , Lowther Chelsea , Scherer Stephen W , Marshall Christian R , Bassett Anne S , Chung Brian H Y 
Published: September 2016

AbstractConotruncal heart anomalies (CTDs) are particularly prevalent congenital heart diseases (CHD) in Hong Kong. We surveyed large (>500 kb), rare (<1% frequency in controls) copy-number variations (CNVs) in Chinese patients with CTDs to identify potentially disease-causing variations. Adults who tested negative for 22q11.2 deletions were recruited from the adult CHD clinic in Hong Kong. Using a stringent calling criteria, high-confidence CNV calls were obtained, and a large control set comprising 3,987 Caucasian and 1,945 Singapore Chinese subjects was used to identify rare CNVs. Ten large rare CNVs were identified, and 3 in 108 individuals were confirmed to harbour de novo CNVs. All three patients were syndromic with a more complex phenotype, and each of these CNVs overlapped regions likely to be important in CHD. One was a 611 kb deletion at 17p13.3, telomeric to the Miller–Dieker syndrome (MDS) critical region, overlapping the NXN gene. Another was a 5 Mb deletion at 13q33.3, within a previously described critical region for CHD. A third CNV, previously unreported, was a large duplication at 2q22.3 overlapping the ZEB2 gene. The commonly reported 1q21.1 recurrent duplication was not observed in this Chinese cohort. We provide detailed phenotypic and genotypic descriptions of large rare genic CNVs that may represent CHD loci in the East Asian population. Larger samples of Chinese origin will be required to determine whether the genome-wide distribution differs from that found in predominantly European CHD cohorts.
P2X-mediated AMPA receptor internalization and synaptic depression is controlled by two CaMKII phosphorylation sites on GluA1 in hippocampal neurons
Authors: Pougnet Johan-Till , Compans Benjamin , Martinez Audrey , Choquet Daniel , Hosy Eric , Boué-Grabot Eric 
Published: September 2016

AbstractPlasticity at excitatory synapses can be induced either by synaptic release of glutamate or the release of gliotransmitters such as ATP. Recently, we showed that postsynaptic P2X2 receptors activated by ATP released from astrocytes downregulate synaptic AMPAR, providing a novel mechanism by which glial cells modulate synaptic activity. ATP- and lNMDA-induced depression in the CA1 region of the hippocampus are additive, suggesting distinct molecular pathways. AMPARs are homo-or hetero-tetramers composed of GluA1-A4. Here, we first show that P2X2-mediated AMPAR inhibition is dependent on the subunit composition of AMPAR. GluA3 homomers are insensitive and their presence in heteromers alters P2X-mediated inhibition. Using a mutational approach, we demonstrate that the two CaMKII phosphorylation sites S567 and S831 located in the cytoplasmic Loop1 and C-terminal tail of GluA1 subunits, respectively, are critical for P2X2-mediated AMPAR inhibition recorded from co-expressing Xenopus oocytes and removal of surface AMPAR at synapses of hippocampal neurons imaged by the super-resolution dSTORM technique. Finally, using phosphorylation site-specific antibodies, we show that P2X-induced depression in hippocampal slices produces a dephosphorylation of the GluA1 subunit at S567, contrary to NMDAR-mediated LTD. These findings indicate that GluA1 phosphorylation of S567 and S831 is critical for P2X2-mediated AMPAR internalization and ATP-driven synaptic depression.
Deep brain stimulation of the subthalamic nucleus modulates sensitivity to decision outcome value in Parkinson’s disease
Authors: Seymour Ben , Barbe Michael , Dayan Peter , Shiner Tamara , Dolan Ray , Fink Gereon R. 
Published: September 2016

AbstractDeep brain stimulation (DBS) of the subthalamic nucleus in Parkinson’s disease is known to cause a subtle but important adverse impact on behaviour, with impulsivity its most widely reported manifestation. However, precisely which computational components of the decision process are modulated is not fully understood. Here we probe a number of distinct subprocesses, including temporal discount, outcome utility, instrumental learning rate, instrumental outcome sensitivity, reward-loss trade-offs, and perseveration. We tested 22 Parkinson’s Disease patients both on and off subthalamic nucleus deep brain stimulation (STN-DBS), while they performed an instrumental learning task involving financial rewards and losses, and an inter-temporal choice task for financial rewards. We found that instrumental learning performance was significantly worse following stimulation, due to modulation of instrumental outcome sensitivity. Specifically, patients became less sensitive to decision values for both rewards and losses, but without any change to the learning rate or reward-loss trade-offs. However, we found no evidence that DBS modulated different components of temporal impulsivity. In conclusion, our results implicate the subthalamic nucleus in a modulation of outcome value in experience-based learning and decision-making in Parkinson’s disease, suggesting a more pervasive role of the subthalamic nucleus in the control of human decision-making than previously thought.