Pharmacokinetics of articaine hydrochloride and its metabolite articainic acid after subcutaneous administration in red deer (Cervus elaphus)

“This is an Accepted Manuscript of an article published by Taylor & Francis in New Zealand Veterinary Journal on 23 October 2017, available online: https://www.tandfonline.com/doi/full/10.1080/00480169.2017.1391141”Publishe

Ab initio study of magnetism at the TiO2/LaAlO3 interface

In this paper we study the possible relation between the electronic and magnetic structure of the TiO2/LaAlO3 interface and the unexpected magnetism found in undoped TiO2 films grown on LaAlO$_3$. We concentrate on the role played by structural relaxation and interfacial oxygen vacancies. LaAlO3 has a layered structure along the (001) direction with alternating LaO and AlO2 planes, with nominal charges of +1 and -1, respectively. As a consequence of that, an oxygen deficient TiO2 film with anatase structure will grow preferently on the AlO2 surface layer. We have therefore performed ab-initio calculations for superlattices with TiO2/AlO2 interfaces with interfacial oxygen vacancies. Our main results are that vacancies lead to a change in the valence state of neighbour Ti atoms but not necessarily to a magnetic solution and that the appearance of magnetism depends also on structural details, such as second neighbor positions. These results are obtained using both the LSDA and LSDA+U approximations.Comment: Accepted for publication in Journal of Materials Scienc

The interface between silicon and a high-k oxide

The ability to follow Moore's Law has been the basis of the tremendous success of the semiconductor industry in the past decades. To date, the greatest challenge for device scaling is the required replacement of silicon dioxide-based gate oxides by high-k oxides in transistors. Around 2010 high-k oxides are required to have an atomically defined interface with silicon without any interfacial SiO2 layer. The first clean interface between silicon and a high-K oxide has been demonstrated by McKee et al. Nevertheless, the interfacial structure is still under debate. Here we report on first-principles calculations of the formation of the interface between silicon and SrTiO3 and its atomic structure. Based on insights into how the chemical environment affects the interface, a way to engineer seemingly intangible electrical properties to meet technological requirements is outlined. The interface structure and its chemistry provide guidance for the selection process of other high-k gate oxides and for controlling their growth. Our study also shows that atomic control of the interfacial structure can dramatically improve the electronic properties of the interface. The interface presented here serves as a model for a variety of other interfaces between high-k oxides and silicon.Comment: 10 pages, 2 figures (one color

The Architectural Design Rules of Solar Systems based on the New Perspective

On the basis of the Lunar Laser Ranging Data released by NASA on the Silver Jubilee Celebration of Man Landing on Moon on 21st July 1969-1994, theoretical formulation of Earth-Moon tidal interaction was carried out and Planetary Satellite Dynamics was established. It was found that this mathematical analysis could as well be applied to Star and Planets system and since every star could potentially contain an extra-solar system, hence we have a large ensemble of exoplanets to test our new perspective on the birth and evolution of solar systems. Till date 403 exoplanets have been discovered in 390 extra-solar systems. I have taken 12 single planet systems, 4 Brown Dwarf - Star systems and 2 Brown Dwarf pairs. Following architectural design rules are corroborated through this study of exoplanets. All planets are born at inner Clarke Orbit what we refer to as inner geo-synchronous orbit in case of Earth-Moon System. By any perturbative force such as cosmic particles or radiation pressure, the planet gets tipped long of aG1 or short of aG1. Here aG1 is inner Clarke Orbit. The exoplanet can either be launched on death spiral as CLOSE HOT JUPITERS or can be launched on an expanding spiral path as the planets in our Solar System are. It was also found that if the exo-planet are significant fraction of the host star then those exo-planets rapidly migrate from aG1 to aG2 and have very short Time Constant of Evolution as Brown Dwarfs have. This vindicates our basic premise that planets are always born at inner Clarke Orbit. This study vindicates the design rules which had been postulated at 35th COSPAR Scientific Assembly in 2004 at Paris, France, under the title ,New Perspective on the Birth & Evolution of Solar Systems.Comment: This paper has been reported to Earth,Moon and Planets Journal as MOON-S-09-0007

What guidance are researchers given on how to present network meta-analyses to end-users such as policymakers and clinicians? A systematic review

© 2014 Sullivan et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Introduction: Network meta-analyses (NMAs) are complex methodological approaches that may be challenging for non-technical end-users, such as policymakers and clinicians, to understand. Consideration should be given to identifying optimal approaches to presenting NMAs that help clarify analyses. It is unclear what guidance researchers currently have on how to present and tailor NMAs to different end-users. Methods: A systematic review of NMA guidelines was conducted to identify guidance on how to present NMAs. Electronic databases and supplementary sources were searched for NMA guidelines. Presentation format details related to sample formats, target audiences, data sources, analysis methods and results were extracted and frequencies tabulated. Guideline quality was assessed following criteria developed for clinical practice guidelines. Results: Seven guidelines were included. Current guidelines focus on how to conduct NMAs but provide limited guidance to researchers on how to best present analyses to different end-users. None of the guidelines provided reporting templates. Few guidelines provided advice on tailoring presentations to different end-users, such as policymakers. Available guidance on presentation formats focused on evidence networks, characteristics of individual trials, comparisons between direct and indirect estimates and assumptions of heterogeneity and/or inconsistency. Some guidelines also provided examples of figures and tables that could be used to present information. Conclusions: Limited guidance exists for researchers on how best to present NMAs in an accessible format, especially for non-technical end-users such as policymakers and clinicians. NMA guidelines may require further integration with end-users' needs, when NMAs are used to support healthcare policy and practice decisions. Developing presentation formats that enhance understanding and accessibility of NMAs could also enhance the transparency and legitimacy of decisions informed by NMAs.The Canadian Institute of Health Research (CIHR) Drug Safety and Effectiveness Network (Funding reference number – 116573)

Interface properties and built-in potential profile of a LaCr O3/SrTi O3 superlattice determined by standing-wave excited photoemission spectroscopy

LaCrO3(LCO)/SrTiO3(STO) heterojunctions are intriguing due to a polar discontinuity along [001], exhibiting two distinct and controllable charged interface structures [(LaO)+/(TiO2)0 and (SrO)0/(CrO2)-] with induced polarization, and a resulting depth-dependent potential. In this study, we have used soft- and hard-x-ray standing-wave excited photoemission spectroscopy (SW-XPS) to quantitatively determine the elemental depth profile, interface properties, and depth distribution of the polarization-induced built-in potentials. We observe an alternating charged interface configuration: a positively charged (LaO)+/(TiO2)0 intermediate layer at the LCOtop/STObottom interface and a negatively charged (SrO)0/(CrO2)- intermediate layer at the STOtop/LCObottom interface. Using core-level SW data, we have determined the depth distribution of species, including through the interfaces, and these results are in excellent agreement with scanning transmission electron microscopy and electron energy-loss spectroscopy mapping of local structure and composition. SW-XPS also enabled deconvolution of the LCO and STO contributions to the valence-band (VB) spectra. Using a two-step analytical approach involving first SW-induced core-level binding-energy shifts and then VB modeling, the variation in potential across the complete superlattice is determined in detail. This potential is in excellent agreement with density functional theory models, confirming this method as a generally useful tool for interface studies

Multiple Neural Oscillators and Muscle Feedback Are Required for the Intestinal Fed State Motor Program

After a meal, the gastrointestinal tract exhibits a set of behaviours known as the fed state. A major feature of the fed state is a little understood motor pattern known as segmentation, which is essential for digestion and nutrient absorption. Segmentation manifests as rhythmic local constrictions that do not propagate along the intestine. In guinea-pig jejunum in vitro segmentation constrictions occur in short bursts together with other motor patterns in episodes of activity lasting 40–60 s and separated by quiescent episodes lasting 40–200 s. This activity is induced by luminal nutrients and abolished by blocking activity in the enteric nervous system (ENS). We investigated the enteric circuits that regulate segmentation focusing on a central feature of the ENS: a recurrent excitatory network of intrinsic sensory neurons (ISNs) which are characterized by prolonged after-hyperpolarizing potentials (AHPs) following their action potentials. We first examined the effects of depressing AHPs with blockers of the underlying channels (TRAM-34 and clotrimazole) on motor patterns induced in guinea-pig jejunum, in vitro, by luminal decanoic acid. Contractile episode durations increased markedly, but the frequency and number of constrictions within segmenting bursts and quiescent period durations were unaffected. We used these observations to develop a computational model of activity in ISNs, excitatory and inhibitory motor neurons and the muscle. The model predicted that: i) feedback to ISNs from contractions in the circular muscle is required to produce alternating activity and quiescence with the right durations; ii) transmission from ISNs to excitatory motor neurons is via fast excitatory synaptic potentials (EPSPs) and to inhibitory motor neurons via slow EPSPs. We conclude that two rhythm generators regulate segmentation: one drives contractions within segmentation bursts, the other the occurrence of bursts. The latter depends on AHPs in ISNs and feedback to these neurons from contraction of the circular muscle

A structurally distinct TGF-β mimic from an intestinal helminth parasite potently induces regulatory T cells

Helminth parasites defy immune exclusion through sophisticated evasion mechanisms, including activation of host immunosuppressive regulatory T (Treg) cells. The mouse parasite Heligmosomoides polygyrus can expand the host Treg population by secreting products that activate TGF-β signalling, but the identity of the active molecule is unknown. Here we identify an H. polygyrus TGF-β mimic (Hp-TGM) that replicates the biological and functional properties of TGF-β, including binding to mammalian TGF-β receptors and inducing mouse and human Foxp3+ Treg cells. Hp-TGM has no homology with mammalian TGF-β or other members of the TGF-β family, but is a member of the complement control protein superfamily. Thus, our data indicate that through convergent evolution, the parasite has acquired a protein with cytokine-like function that is able to exploit an endogenous pathway of immunoregulation in the host

Cabazitaxel for Hormone-Relapsed Metastatic Prostate Cancer Previously Treated With a Docetaxel-Containing Regimen: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

As part of its single technology appraisal (STA) process, the National Institute for Health and Care Excellence (NICE) invited the company that manufactures cabazitaxel (Jevtana(®), Sanofi, UK) to submit evidence for the clinical and cost effectiveness of cabazitaxel for treatment of patients with metastatic hormone-relapsed prostate cancer (mHRPC) previously treated with a docetaxel-containing regimen. The School of Health and Related Research Technology Appraisal Group at the University of Sheffield was commissioned to act as the independent Evidence Review Group (ERG). The ERG produced a critical review of the evidence for the clinical and cost effectiveness of the technology based upon the company's submission to NICE. Clinical evidence for cabazitaxel was derived from a multinational randomised open-label phase III trial (TROPIC) of cabazitaxel plus prednisone or prednisolone compared with mitoxantrone plus prednisone or prednisolone, which was assumed to represent best supportive care. The NICE final scope identified a further three comparators: abiraterone in combination with prednisone or prednisolone; enzalutamide; and radium-223 dichloride for the subgroup of people with bone metastasis only (no visceral metastasis). The company did not consider radium-223 dichloride to be a relevant comparator. Neither abiraterone nor enzalutamide has been directly compared in a trial with cabazitaxel. Instead, clinical evidence was synthesised within a network meta-analysis (NMA). Results from TROPIC showed that cabazitaxel was associated with a statistically significant improvement in both overall survival and progression-free survival compared with mitoxantrone. Results from a random-effects NMA, as conducted by the company and updated by the ERG, indicated that there was no statistically significant difference between the three active treatments for both overall survival and progression-free survival. Utility data were not collected as part of the TROPIC trial, and were instead taken from the company's UK early access programme. Evidence on resource use came from the TROPIC trial, supplemented by both expert clinical opinion and a UK clinical audit. List prices were used for mitoxantrone, abiraterone and enzalutamide as directed by NICE, although commercial in-confidence patient-access schemes (PASs) are in place for abiraterone and enzalutamide. The confidential PAS was used for cabazitaxel. Sequential use of the advanced hormonal therapies (abiraterone and enzalutamide) does not usually occur in clinical practice in the UK. Hence, cabazitaxel could be used within two pathways of care: either when an advanced hormonal therapy was used pre-docetaxel, or when one was used post-docetaxel. The company believed that the former pathway was more likely to represent standard National Health Service (NHS) practice, and so their main comparison was between cabazitaxel and mitoxantrone, with effectiveness data from the TROPIC trial. Results of the company's updated cost-effectiveness analysis estimated a probabilistic incremental cost-effectiveness ratio (ICER) of £45,982 per quality-adjusted life-year (QALY) gained, which the committee considered to be the most plausible value for this comparison. Cabazitaxel was estimated to be both cheaper and more effective than abiraterone. Cabazitaxel was estimated to be cheaper but less effective than enzalutamide, resulting in an ICER of £212,038 per QALY gained for enzalutamide compared with cabazitaxel. The ERG noted that radium-223 is a valid comparator (for the indicated sub-group), and that it may be used in either of the two care pathways. Hence, its exclusion leads to uncertainty in the cost-effectiveness results. In addition, the company assumed that there would be no drug wastage when cabazitaxel was used, with cost-effectiveness results being sensitive to this assumption: modelling drug wastage increased the ICER comparing cabazitaxel with mitoxantrone to over £55,000 per QALY gained. The ERG updated the company's NMA and used a random effects model to perform a fully incremental analysis between cabazitaxel, abiraterone, enzalutamide and best supportive care using PASs for abiraterone and enzalutamide. Results showed that both cabazitaxel and abiraterone were extendedly dominated by the combination of best supportive care and enzalutamide. Preliminary guidance from the committee, which included wastage of cabazitaxel, did not recommend its use. In response, the company provided both a further discount to the confidential PAS for cabazitaxel and confirmation from NHS England that it is appropriate to supply and purchase cabazitaxel in pre-prepared intravenous-infusion bags, which would remove the cost of drug wastage. As a result, the committee recommended use of cabazitaxel as a treatment option in people with an Eastern Cooperative Oncology Group performance status of 0 or 1 whose disease had progressed during or after treatment with at least 225 mg/m(2) of docetaxel, as long as it was provided at the discount agreed in the PAS and purchased in either pre-prepared intravenous-infusion bags or in vials at a reduced price to reflect the average per-patient drug wastage