Deel IV: de belastingplichtige

Analyse van de toepassingsvoorwaarden om als belastingplichtige inzake de BTW te worden beschouwd.

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Deel II: Europeesrechtelijke aspecten inzake BTW

Algemene analyse van de Europeesrechtelijke uitgangspunten bij de invoering van BTW-reglementering

http://ift.tt/2e53G25

Fiscale transparantie: toerekening van inkomsten: een onderzoek naar de classificatie van grensoverschrijdende samenwerkingsverbanden

Commerciële editie van proefschrift voor de graad van doctor in de rechten

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Belgium

Belgian report for a book comparing the domestic tax legislation concerning surcharges and penalties of different European states.

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Veroordeling excess profit rulings: effectief verboden staatssteun?

Analyse van veroordeling Belgische Excess Profit Rulings door Europese Commissie

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Fiscaal Compendium: internationaal fiscaal recht

Een algemeen overzicht van de internationale fiscaliteit aan de hand van een bespreking van de artikelen uit het OESO-Modelverdrag, met bijzondere aandacht voor Belgische implementatie en afwijkingen.

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Tax avoidance revisited: exploring the boundaries of anti-avoidance rules in the EU BEPS context

Analysis of Belgian anti-avoidance rules in tax legislation

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Condamnation des 'excess profit rulings': s'agit-il bien d'une aide d' Etat prohibée?

Analyse de la conviction des excess profit rulings en Belgique par la Commission Européenne.

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Kieback: when Schumacker emigrates ...

Analysis of the income tax consequences for a source state, when a foreign worker emigrates from his residence state to a third state.

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Criticality on the international scene: quo vadis?

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Extending the Geographical Scope of the ENP: The Neighbours of the EU’s Neighbours

The concept of the "neighbours of the EU's neighbours" appeared for the first time within the 2006 communication of the European Commission on "strengthening the ENP"1, the main idea being to "look beyond the Union's immediate neighbourhood" and to see if bridges could be built between the areas covered by the latter and Africa, Central Asia and the Gulf.

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Microbial community abundance vs. activity in anaerobic digestion in relation to salt stress

Not applicable

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Libres propos sur la Méditerranée, le Maroc et l’Union européenne en hommage au professeur Abdallah Saaf

Hommage au Prof. Abdallah Saaf Libres propos sur les relations euro-méditerranéennes

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Classification of foreign entities for corporate income tax purposes

Analysis of how foreign entities (mostly corporations) are being dealth with for domestic income tax purposes.

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Belgium

A general description of the (domestic/foreign) entities being submitted to Belgian income tax.

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Belgium

European and international constraints when dealing with income taxation of foreign entities

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Deel IV: de belastingplichtige

Analyse van de toepassingsvoorwaarden om als belastingplichtige inzake de BTW te worden beschouwd.

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Deel II: Europeesrechtelijke aspecten inzake BTW

Algemene analyse van de Europeesrechtelijke uitgangspunten bij de invoering van BTW-reglementering

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Fiscale transparantie: toerekening van inkomsten: een onderzoek naar de classificatie van grensoverschrijdende samenwerkingsverbanden

Commerciële editie van proefschrift voor de graad van doctor in de rechten

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Primary human renal-derived tubular epithelial cells fail to recognize and suppress BK virus infection.

Background: BK polyomavirus (BKV)-associated nephropathy is a threat to kidney allograft survival affecting up to 15% of renal transplant patients. Previous studies revealed that tubular epithelial cells (TEC) show a limited response towards BKV infection. Here we investigated the interplay between BKV and TEC in more detail. In particular, we questioned whether BKV suppresses and/or evades antiviral responses. Methods: Human primary tubular epithelial cells (TEC) and peripheral blood mononuclear cells were infected with BKV Dunlop strain or other viruses. Moreover, TEC were stimulated with genomic double-stranded (ds)DNA or interferons (IFN). Viral replication and cellular responses were measured using quantitative real time PCR and multiplex assay. Results: BKV infection of primary human TEC did not induce an antiviral response, whereas infection with influenza A virus, herpes simplex virus 1, or cytomegalovirus induced a strong antiviral response measured by upregulation of interferon-stimulated genes, such as CXCL10 and DAI. In addition, intracellular delivery of dsDNA or stimulation with IFN did elicit a rapid and pronounced response. However, BKV infection did not affect dsDNA-induced gene expression, indicating BKV did not modulate the antiviral response. Prestimulation of primary TEC with IFN[alpha] or dsDNA did not hamper replication of BKV, whereas influenza and HSV-1 replication were clearly reduced. In contrast, BKV infection of leukocytes did elicit an antiviral response. Conclusion: BKV specifically evades innate immunity in TEC and is not susceptible to an intrinsic interferon response, which may facilitate latent presence of the virus in this cell type. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

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C-C Chemokine Receptor type 2 (CCR2)-Dependent Migration of Myeloid-Derived Suppressor Cells in Protection of Islet Transplants.

Background: Islet transplantation is a promising therapeutic approach for restore the physical response to blood glucose in type 1 diabetes. Current chronic use of immunosuppressive reagents for preventing islet allograft rejection is associated with severe complications. In addition, many of the immunosuppressive drugs are diabetogenic. The induction of transplant tolerance to eliminate the dependency on immunosuppression is ideal, but remains challenging. Methods: Addition of hepatic stellate cells allowed generation of myeloid-derived suppressor cells (MDSC) from precursors in mouse bone marrow. Migration of MDSC was examined in an islet allograft transplant model by tracking the systemic administered MDSC from CD45.1 congenic mice. Results: The generated MDSC were expressed C-C chemokine receptor type 2 (CCR2), which was enhanced by exposure to interferon-[gamma]. A single systemic administration of MDSC markedly prolonged survival of islet allografts without requirement of immunosuppression. Tracking the administered MDSC showed that they promptly migrated to the islet graft sites, at which point they exerted potent immune suppressive activity by inhibiting CD8+ T cells, enhancing T regulatory T cell activity. MDSC generated from CCR2-/- mice failed to be mobilized and lost tolerogenic activity in vivo, but sustained suppressive activity in vitro. Conclusion: MDSC migration was dependent on expression of CCR2, while CCR2 does not directly participate in immune suppression. Expression of CCR2 needs to be closely monitored for quality control purpose when MDSC are generated in vitro for immune therapy. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

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Effectiveness of preemptive therapy for Cytomegalovirus disease in pediatric liver transplantation.

Background: Most pediatric liver transplantation (LT) centers administer long courses of prophylaxis against Cytomegalovirus (CMV) without evidence of benefit and with significant drug exposure and costs. We aimed at evaluating overall outcomes, direct and putative indirect effects of CMV, possible impact of viremia and risk factors for CMV infection in pediatric LT recipients managed with ganciclovir-based preemptive therapy (PET). Methods: The records of all the children who underwent LT between 2008 and 2014 were retrospectively analyzed. Results: One-hundred children were included. Three children had CMV disease; no CMV-related death or graft loss was recorded. The only identified risk factor for CMV infection was the donor/recipient serostatus [OR: 17.23 (95%CI: 1.88-157.87); P=0.012], while viremia per se did not worsen LT outcomes, such as the incidence of acute rejection, EBV infection, sepsis, biliary and vascular complications, nor graft dysfunction/loss or death at 3 and 5 years after LT. When compared with a historical cohort of children receiving ganciclovir prophylaxis, PET did not differ from prophylaxis for any of the selected outcomes, but was rather associated with lower antiviral drug exposure (6.4 +/- 13 vs 38.6 +/- 14 days, P

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Totally laparoscopic right hepatectomy for living donor liver transplantation. Analysis of a preliminary experience on 5 consecutive cases.

Background: The pure laparoscopic approach in right hepatectomy (LRH) for living donor liver transplantation (LDLT) is a controversial issue. Some authors have reported the procedure to be feasible but surgical outcomes and impact on short and long-term morbidity rates are yet to be determined. The aim of this study is to present the results of a preliminary 5 consecutive cases series of LRH for LDLT and to compare it with a successive cohort of open right hepatectomies (ORH) for LDLT. Methods: From May 2013 to October 2015, 5 consecutive donors underwent LRH for LDLT in our center. The previous last 10 ORH for LDLT were selected for comparison. Special care was taken to include all adverse events. Each patient[spacing acute]s complications were graded with the Clavien-Dindo Classification and scored with the Comprehensive Complication Index (CCI). Results: All 5 consecutive donors completed a pure laparoscopic procedure. All allografts (open and laparoscopically procured) were successfully transplanted with no primary graft failures. Only 2 Clavien-Dindo Grade-I complications occurred in the LRH donors, while ORH donors had 10 Grade I, 2 Grade II and 1 Grade IIIa complications in the short term (

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Ex Situ Perfusion of Human Limb Allografts for 24 Hours.

Background: Vascularized composite allografts, particularly hand and forearm, have limited ischemic tolerance following procurement. In bilateral hand transplantations, this demands a 2 team approach and expedited transfer of the allograft, limiting the recovery to a small geographic area. Ex situ perfusion may be an alternative allograft preservation method to extend allograft survival time. This is a short report of 5 human limbs maintained for 24 hours with ex situ perfusion. Methods: Upper limbs were procured from brain-dead organ donors. Following recovery, the brachial artery was cannulated and flushed with 10 000U of heparin. The limb was then attached to a custom-made, near-normothermic (30-33[degrees]C) ex situ perfusion system composed of a pump, reservoir, and oxygenator. Perfusate was plasma-based with a hemoglobin concentration of 4-6 g/dL. Results: Average warm ischemia time was 76 minutes. Perfusion was maintained at an average systolic pressure of 93+/-2 mmHg, flow 310+/-20 mL/min, and vascular resistance 153+/-16 mmHg/L/min. Average oxygen consumption was 1.1+/-0.2 mL/kg/min. Neuromuscular electrical stimulation continually displayed contraction until the end of perfusion and histology showed no myocyte injury. Conclusions: Human limb allografts appeared viable after 24 hours of near-normothermic ex situ perfusion. While these results are early and need validation with transplantation, this technology has promise for extending allograft storage times. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

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Oral nitrite circumvents antiseptic mouthwash-induced disruption of enterosalivary circuit of nitrate and promotes nitrosation and blood pressure lowering effect

Publication date: Available online 18 October 2016
Source:Free Radical Biology and Medicine
Author(s): Lucas C. Pinheiro, Graziele C. Ferreira, Jefferson H. Amaral, Rafael L. Portella, Sandra de O.C. Tella, Madla A. Passos, Jose E. Tanus-Santos
The nitric oxide (NO^•) metabolites nitrite and nitrate exert antihypertensive effects by mechanisms that involve gastric formation of S-nitrosothiols. However, while the use of antiseptic mouthwash (AM) is known to attenuate the responses to nitrate by disrupting its enterosalivary cycle, there is little information about whether AM attenuates the effects of orally administered nitrite. We hypothesized that the antihypertensive effects of orally administered nitrite would not be prevented by AM because, in contrast to oral nitrate, oral nitrite could promote S-nitrosothiols formation in the stomach without intereference by AM. Chronic effects of oral nitrite or nitrate were studied in two-kidney, one-clip (2K1C) hypertensive rats (and normotensive controls) treated with AM (or vehicle) once/day. We found that orally administered nitrite exerts antihypertensive effects that were not affected by AM. This finding contrasts with lack of antihypertensive responses to oral nitrate in 2K1C hypertensive rats treated with AM. Nitrite and nitrate treatments increased plasma nitrites, nitrates, and S-nitrosothiols concentrations. However, while treatment with AM attenuated the increases in plasma nitrite concentrations after both nitrite and nitrate treatments, AM attenuated the increases in S-nitrosothiols in nitrate-treated rats, but not in nitrite-treated rats. Moreover, AM attenuated vascular S-nitrosylation (detected by the SNO-RAC method) after nitrate, but not after nitrite treatment. Significant correlations were found between the hypotensive responses and S-nitrosothiols, and vascular S-nitrosylation levels. These results show for the first time that oral nitrite exerts antihypertensive effects notwithstanding the fact that antiseptic mouthwash disrupts the enterosalivary circulation of nitrate. Our results support a major role for S-nitrosothiols formation resulting in vascular S-nitrosylation as a key mechanism for the antihypertensive effects of both oral nitrite and nitrate.

Graphical abstract

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Degradation of the cytostatic 5-Fluorouracil in water by Fenton and photo-assisted oxidation processes

Abstract

Cytostatics are part of the forefront research topics due to their high prescription, high toxicity, and the lack of effective solutions to stop their entrance and spread in the environment. Among them, 5-Fluorouracil (5-Fu) has received particular attention because is one of the most prescribed active substances in chemotherapy worldwide. The degradation of 5-Fu by advanced oxidation processes (AOPs) is a poorly addressed topic, and this work brings valuable inputs concerning this matter. Herein, the efficacy of Fenton's process in the degradation of 5-Fu is explored for the first time; the study of the main variables and its successful application to the treatment of real wastewaters is demonstrated. Moreover, hydrogen peroxide-based and photo-assisted techniques (direct photolysis, photodegradation with H₂O₂ and photo-Fenton) are also investigated for purposes of comparison. Under the best operation conditions obtained (T = 30 °C, [Fe²⁺]₀ = 0.5 mM; [H₂O₂]₀ = 240 mM and pH = 3 for [5-Fu]₀ = 0.38 mM), 5-Fu was completely eliminated after 2 h of Fenton's reaction and about 50 % of mineralization was reached after 8 h. The best performance was obtained by the photo-Fenton process, with 5-Fu mineralization level as high as 67 %, using an iron dose within the legal limits required for direct water discharge. Toxicity (towards Vibrio fischeri) of the effluents that resulted from the application of the above-mentioned AOPs was also evaluated; it was found that the degradation products generated from the photo-assisted processes are less toxic than the parent compound, putting into evidence the relevance of such technologies for degradation of cytostatics like 5-Fu.

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Calcium polysulphide, its applications and emerging risk of environmental pollution—a review article

Abstract

Easy availability, preparation technique, and economic value make calcium polysulphide (CaS_x ) a very useful inorganic chemical for various field and industrial applications. In this article, disparate applications of CaS_x solution have been reviewed to suggest potential and future consolidation. This article also encompasses the physiochemical properties and production of CaS_x solution, with critical appraisal on research focusing on CaS_x application in agriculture industries and removal of potentially toxic elements (PTEs) from the environment. The kinetics of CaS_x , technical issues associated with optimization of its dosage and environmental fate is also discussed in detail. This study covers almost all of the peer-reviewed research that has been performed since 1914. Some of the critiques in this article include the lack of integration between the exposure effect and the efficiency of treatment method, effects of oxidizing environments on the long-term performance of CaS_x solution, and kinetics of CaS_x solution with the PTEs. The working model of CaS_x with PTEs is still system dependent, and therefore cannot be used with other applications. The kinetics of CaS_x is described in detail with various phase stoichiometric reactions. Environmental fate is discussed based on applications, government reports, peer-reviewed articles and kinetics of CaS_x , which provides a clear picture of emerging contaminants in the environment in relation to the insect resistance and ecotoxicology. Real time, lab based research articles are needed to identify toxicity limits of CaS_x in environment in order to describe its effective permissible limit in environmental system. This review article provides a risk assessment of environmental pollution by CaS_x based on its physicochemical characteristic, stoichiometry, kinetics, field, and industrial applications.

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A modeling approach to direct interspecies electron transfer process in anaerobic transformation of ethanol to methane

Abstract

Recent studies have shown that direct interspecies electron transfer (DIET) plays an important part in contributing to methane production from anaerobic digestion. However, so far anaerobic digestion models that have been proposed only consider two pathways for methane production, namely, acetoclastic methanogenesis and hydrogenotrophic methanogenesis, via indirect interspecies hydrogen transfer, which lacks an effective way for incorporating DIET into this paradigm. In this work, a new mathematical model is specifically developed to describe DIET process in anaerobic digestion through introducing extracellular electron transfer as a new pathway for methane production, taking anaerobic transformation of ethanol to methane as an example. The developed model was able to successfully predict experimental data on methane dynamics under different experimental conditions, supporting the validity of the developed model. Modeling predictions clearly demonstrated that DIET plays an important role in contributing to overall methane production (up to 33 %) and conductive material (i.e., carbon cloth) addition would significantly promote DIET through increasing ethanol conversion rate and methane production rate. The model developed in this work will potentially enhance our current understanding on syntrophic metabolism via DIET.

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Technoeconomic perspectives on sustainable CO 2 capture and utilization

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Role of C16, angiopoietin-1 and regeneration gene protein 2 in attenuating inflammation in an experimental rat model of autoimmune encephalomyelitis

Abstract

Multiple sclerosis (MS) is a chronic neurological disorder that affects the central nervous system (CNS), and results in CNS inflammation and damage to myelin. In this study, we examined the possible synergistic effects of C16, angiopoietin-1 (Ang-1) and regeneration gene protein 2 (Reg-2) in alleviating inflammation in an acute experimental autoimmune encephalomyelitis (EAE) model. We employed multiple histological, morphological and iconographic assays to examine the effect of those drugs on disease onset, clinical scores and behavioral deficits. Our results demonstrated that triple combination therapy was more efficient than the monotherapy in EAE treatment. The triple therapy significantly delayed the onset of motor symptoms, reduced disease severity, attenuated inflammatory cell infiltration and suppressed the secretion of proinflammatory cytokines. Additionally, treatment increased anti-inflammatory cytokines expression, inhibited reactive astrocytes proliferation, reduced demyelination and axonal loss, and finally reduced the neural death. Specifically, Reg-2 administration rescued oligodendrocytes and neuronal axons mainly by direct neurotrophic effects, while C16+Ang-1 (C+A) mainly improved the inflammatory milieu. In conclusion, our study suggests a possible synergistic effect through targeting a variety of pathways in relieving the clinical symptoms of inflammation in acute EAE model. Therefore, using molecules that target different molecular pathways can be beneficial for exploring novel therapeutic approaches for MS treatment.

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3D vs. 2D imaging in laparoscopic surgery—an advantage? Results of standardised black box training in laparoscopic surgery

Abstract

Purpose

3D imaging is an upcoming technology in laparoscopic surgery, and recent studies have shown that the modern 3D technique is superior in an experimental setting.

Methods

All 14 members of the Asklepios Klinik Langen Department of Visceral and Thoracic Surgery, as well as two gynaecologists, were asked to undertake 2D vs. 3D laparoscopic black box skill training. The black box training was adapted to the "fundamentals of laparoscopic surgery" programme provided by the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES). First, the participants categorised themselves as beginner, advanced or expert in laparoscopic surgery. Then, they were randomised in terms of whether the black box training commenced with 2D or 3D vision. The exercises included peg transfer with the dominant hand and the non-dominant hand (with and without transfer between the graspers), needle capping and cutting a sutured knot. The time taken to complete these exercises was measured. After the training, each participant was asked to describe his/her personal impression of the imaging systems employed.

Results

Overall, for the participants in all groups, the time required for all exercises showed a significant advantage for 3D imaging (3D vs. 2D; Wilcoxon matched pair test; mean 68.0 ± 94.9 s (3D) vs. 90.1 ± 69.4 s (2D); p = 0.002). Regarding the subgroups, the experts significantly improved their time in completing the exercises in 3D vs. 2D by a margin of 25.8 % (mean 30.8 ± 20.1 s (3D) vs. 41.5 ± 25.0 s (2D); p = 0.010). In the group of advanced surgeons, the results were similar, showing an improvement of 23.6 % for 3D, but without significance (mean 61.5 ± 41.1 s (3D) vs. 80.4 ± 72.8 s (2D); p = 0.123). The results for the beginner group also showed an improvement in the 3D exercises of 24.8 %; here, the result also showed a trend towards 3D but did not reach significance (mean 93.9 ± 90.7 s (3D) vs. 124.8 ± 118.72 (2D); p = 0.062).

Conclusion

In our opinion, 3D imaging could be an advantage in laparoscopic surgery, especially in the surgical education of upcoming surgical generations. To determine whether these ex vivo results can be transferred to the clinical situation, our group has initiated a randomised controlled study.

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Issue Information - TOC

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Issue Information - Journal Information

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Isosmotic is not always isotonic: the five-minute version

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Winter course in physiology: a successful example of continuing education for secondary school teachers in Brazil

In international surveys, Brazilian students have been consistently ranking low in science. Continuing education for secondary school teachers is certainly a way to change this situation. To update teachers and provide teaching and learning experiences for graduate students, our department organized a "Winter Course in Physiology" where schoolteachers had the opportunity to attend lectures that were offered by graduate students and participate in discussions on teaching and learning strategies and their applicability, considering different schools and student age groups. This work evaluated the ways in which the Winter Course in Physiology improves continuing education for secondary school teachers. Graduate students prepared, presented, and discussed with the audience the concepts, content, and topics of the program, which were previously presented to the organizing committee and a supervising professor. Potential participants were recruited based on their curriculum vitae and a letter of intent. During the course, they completed a questionnaire that graded different aspects of course organization and lectures. The results indicated that the Winter Course was positively evaluated. Most topics received a grade of ≥4.0, considering a range of 1.0 (low) to 5.0 (high). In a followup, both the participants and instructors reported positive impacts on their overall knowledge in physiology. Schoolteachers reported improvements in the performance and participation of their students. In conclusion, the results suggested that the Winter Course is a good way to promote continuing education for schoolteachers and promote university outreach. It also provided an important experience for graduate students to develop teaching skills.

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Physiology and pathophysiology of potassium homeostasis

Total body potassium content and proper distribution of potassium across the cell membrane is of critical importance for normal cellular function. Potassium homeostasis is maintained by several different methods. In the kidney, total body potassium content is achieved by alterations in renal excretion of potassium in response to variations in intake. Insulin and beta-adrenergic tone play critical roles in maintaining the internal distribution of potassium under normal conditions. Despite homeostatic pathways designed to maintain potassium levels within the normal range, disorders of altered potassium homeostasis are common. The clinical approach to designing effective treatments relies on understanding the pathophysiology and regulatory influences which govern the internal distribution and external balance of potassium. Here we provide an overview of the key regulatory aspects of normal potassium physiology. This review is designed to provide an overview of potassium homeostasis as well as provide references of seminal papers to guide the reader into a more in depth discussion of the importance of potassium balance. This review is designed to be a resource for educators and well-informed clinicians who are teaching trainees about the importance of potassium balance.

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The Impact of Phase Retention on the Structural and Optoelectronic Properties of Metal Halide Perovskites

The extent to which the soft structural properties of metal halide perovskites affect their optoelectronic properties is unclear. X-ray diffraction and micro-photoluminescence measurements are used to show that there is a coexistence of both tetragonal and orthorhombic phases through the low-temperature phase transition, and that cycling through this transition can lead to structural changes and enhanced optoelectronic properties.

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Digital derasars in diaspora: a critical examination of Jain Ritual online

Over the last decades, researchers in the fields of media studies and sociology have described how technological change in general, and the rise in ICT more recently, impacts upon migrants' daily lives. Studies on the transformations and adaptations that new media can cause in modes of religious practice and authority in different traditions have followed. However, the relation between Jainism and new media, although mentioned in the work of John E. Cort and Peter Flügel on Jain modernism, has as yet not been fully delved into. For Jains, especially those living in the diaspora, the new possibilities and modalities new media bring on a social and communicative level seem to be clear. But does the Internet also impact upon Jain religious praxis? Based on a structural analysis of more than 300 Jain websites hosted worldwide, alongside a series of in-depth interviews with Jains living in Belgium and the USA, this chapter will specifically address online ritual practices. It will describe the services offered by a selection of Jain websites and subsequently analyse their reception and potential use in the daily religious routines of Jains in the diaspora. In doing so, it will provide an exemplary case study of the different aspects, functions, and limitations of computer-mediated ritual, opening up the possibility of comparative studies with other (South Asian) traditions.

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Denominal location and locatum verbs in Kavalan

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Greening and producing: an economic assessment framework for integrating trees in cropping systems

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Ballasting the Hanse. Baltoscandian Erratic Cobbles in the Later Medieval Port Landscape of Bruges.

The find of a remarkable group of vividly coloured rounded cobbles on the fields and in the monuments of the late-Medieval outer ports of Bruges has initiated a multi-disciplinary research into the function, provenance and wider economic meaning of these exotic stones. Geological examination demonstrates that the stones can be considered as ballast of varied lithological nature. A substantial part are constituted by glacial erratics which have been collected along the Baltoscandian shores. Another group can be traced to the NE-British coasts. Because of the clustering of stones at Hoeke, specific attention is drawn to the connections between Bruges and the Hanse, and to the Hanseatic settlement of Hoeke which hosted the staple of stockfisch and various other Hanseatic activities. The paper adds to the discussion of ballast stone as a meaningful archaeological object category, in particularly when studied in a broader methodological context including archaeological, geological and historical research.

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Escherichia coli O157:H7 and lactoferrin modulate immunity in cattle

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Preclinical Characterization and Human Microdose Pharmacokinetics of ITMN-8187, a Non-Macrocyclic Inhibitor of the Hepatitis C Virus NS3 Protease [PublishAheadOfPrint]

The current paradigm for the treatment of chronic hepatitis C virus (HCV) infection involves combinations of agents which act directly on steps of the HCV lifecycle. Here we report the preclinical characteristics of ITMN-8187, a non-macrocyclic inhibitor of the NS3/4A HCV protease. X-ray crystallographic studies of ITMN-8187 and simeprevir binding to NS3/4A protease demonstrated good agreement between structures. Low nanomolar biochemical potency was maintained against NS3/4A derived from HCV genotypes 1, 2b, 4, 5, and 6. In cell-based potency assays, half-maximal reduction of genotype 1a and 1b HCV replicon RNA was afforded by 11 and 4 nM doses of ITMN-8187, respectively. Combinations of ITMN-8187 with other direct-acting antiviral agents in vitro displayed additive antiviral efficacy. A 30 mg/kg dose of ITMN-8187 administered for 4 days yielded significant viral load reductions through Day 5 in a chimeric mouse model of HCV. A 3 mg/kg oral dose administered to rats, dogs, or monkeys yielded plasma concentrations 16 hours after dosing that exceeded the half-maximal effective concentration of ITMN-8187. Human microdose pharmacokinetics showed low inter-subject variability and prolonged oral absorption with first-order elimination kinetics compatible with once-daily dosing. These preclinical characteristics compare favorably with those of other NS3/4A inhibitors approved for the treatment of chronic HCV infection.

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Acinetobacter baumannii ATCC 19606 carries GIsul2 in a genomic island located in the chromosome [PublishAheadOfPrint]

During the course of routine antibiotic resistance testing, we noticed that Acinetobacter baumannii ATCC 19606, which was isolated prior to 1948 (1) and is often used in genetic studies, is resistant to the sulphonamide compound sulfamethoxazole, minimal inhibitory concentration (MIC) >128 mg/L....

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Evaluating polymyxin B-based combinations against carbapenem-resistant Escherichia coli in time-kill studies and in a hollow-fiber infection model [PublishAheadOfPrint]

Objectives: Polymyxin B-based combinations have emerged as a mainstay treatment against carbapenem-resistant Escherichia coli (CREC). We investigated the activity of polymyxin B-based two-antibiotic combinations against CREC using time-kill studies (TKS) and validated the findings in a hollow fiber infection model (HFIM).

Methods: TKS was conducted using 5 clinical CREC strains at 5 log₁₀ CFU/mL against 10 polymyxin B-based two-antibiotic combinations at maximum clinically achievable concentrations. A HFIM simulating polymyxin B (30,000U/kg/day) and tigecycline (100mg every 12h) dosing regimens alone and in combination was conducted against two CREC strains at 5 log₁₀ CFU/mL over 120h. Emergence of resistance was quantified using antibiotic-containing media. Phenotypic characterization (growth rate, stability of resistant phenotypes) of the resistant isolates were performed.

Results: All five CRECs strains harbored carbapenemases. Polymyxin B and tigecycline MICs ranged from 0.5mg/L–2mg/L and 0.25mg/L–8mg/L respectively. All antibiotics alone did not have bactericidal activity at 24h in the TKS, except for polymyxin B against two strains. In combination TKS, only polymyxin B+ tigecycline demonstrated both bactericidal activity and synergy in two out of five strains. In the HFIM, polymyxin B alone was bactericidal against both CREC strains before regrowth was observed at 8h. Phenotypically stable polymyxin B-resistant mutants were observed for both strains, with reduced growth rate observed in one strain. Tigecycline alone resulted in slow reduction in bacterial counts. Polymyxin B+ tigecycline resulted in rapid and sustained bactericidal killing up to 120h.

Conclusions: Polymyxin B+ tigecycline is a promising combination against CREC. The clinical relevance of our results warrants further investigations.

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Pharmacokinetic/Pharmacodynamic Modeling and Simulation of Cefiderocol, a Parenteral Siderophore Cephalosporin, for Dose Adjustment based on Renal Function [PublishAheadOfPrint]

The novel parenteral siderophore cephalosporin, cefiderocol, exhibits potent efficacy against most Gram-negative bacteria including carbapenem-resistant strains. Since cefiderocol is primarily excreted via the kidneys, this study was conducted to develop a population pharmacokinetic (PK) model to determine dose adjustment based on renal function.

Population PK models were developed based on cefiderocol concentration data in plasma, urine and dialysate with a non-linear mixed effects model approach. Monte-Carlo simulations were conducted to calculate the probability of target attainment (PTA) of fraction of time during the dosing interval where the free drug concentration in plasma exceeds the minimum inhibitory concentration (MIC) (T_f>MIC) for a MIC range of 0.25 to 16 μg/mL. For the simulations, dose regimens were selected to compare cefiderocol exposure among groups with different levels of renal function.

The developed models well described the PK of cefiderocol for each renal-function group. A dose of 2 g every 8 hours with 3-hr infusion provided >90% PTA for 75% T_f>MIC for an MIC of ≤4 μg/mL for patients with normal renal function, while a more frequent dose (every 6 hours) could be used for patients with augmented renal function. A reduced dose and/or extended dosing interval were selected for patients with impaired renal function. A supplemental dose immediately after intermittent hemodialysis was proposed for patients requiring intermittent hemodialysis.

The PK of cefiderocol could be adequately modeled and the Modeling and Simulation approach suggested dose regimens based on renal function ensuring drug exposure with adequate bactericidal effect.

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Escherichia coli probiotic strain ED1a in pigs has a limited impact on the gut carriage of extended-spectrum beta-lactamase-producing E. coli [PublishAheadOfPrint]

Four trials were conducted to evaluate the impact of Escherichia coli probiotic strain ED1a (EcED1a) administration to pigs on the gut carriage or survival in manure of extended-spectrum beta-lactamase-producing E. coli. Groups of pigs were orally inoculated with strain E. coli M63 (EcM63) carrying the bla_CTX-M-1 gene (n=84) or used as control (n=26). In the first two trials, eight days later, 24 of 40 EcM63 inoculated pigs were given EcED1a orally for six days. In the third trial, 10 EcM63 inoculated pigs were given either EcED1a or probiotic E. coli Nissle 1917 (EcN) for five days. In the fourth trial, EcED1a was given to a sow and its 12 piglets, the latter, as well as 12 piglets which did not received EcED1a, then being inoculated with EcM63. Fecal shedding of cefotaxime-resistant Enterobacteriaceae (CTX-RE) was studied by culture and bla_CTX-M-1 genes were quantified by PCR. The persistence of CTX-RE in manure samples from inoculated pigs, or inoculated in vitro with EcM63 with or without probiotics was studied. Results showed that EcM63and EcED1a were good gut colonizers. The reduction in fecal excretion of CTX-RE in EcED1a-treated pigs compared to non-treated pigs was usually inferior to 1 log10 CFU and mainly observed during the probiotic administration period. The results obtained with EcN did not differ significantly from those with EcED1a. CTX-RE survival did not differ significantly in manures with or without probiotics. In conclusion, in our experimental conditions, EcED1a and EcN could not durably prevent CTX-RE colonization of the pig gut.

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Safety, Tolerability, and Pharmacokinetics of MEDI4893, an Investigational, ExtendedHalf-Life, Anti-Staphylococcus aureus Alpha-Toxin Human Monoclonal Antibody, in Healthy Adults [PublishAheadOfPrint]

MEDI4893 is an investigational immunoglobulin G1_K monoclonal antibody that specifically binds to and neutralizes alpha-toxin, a key Staphylococcus aureus virulence factor. A triple–amino acid substitution, M252Y/S254T/T256E, was engineered into the MEDI4893 Fc region to extend its serum half-life. A phase 1, double-blind, dose escalation study was designed to evaluate the safety, tolerability, pharmacokinetics, anti–alpha-toxin neutralizing activity, and anti-drug antibody (ADA) response of MEDI4893 following a single intravenous infusion in healthy adults 18–65 years of age. Thirty-three subjects were randomly assigned to receive MEDI4893 at 225 mg (n = 3), 750 mg (n = 3), 2,250 mg (n = 8), or 5,000 mg (n = 12) or placebo (n = 7) and were followed for 360 days. Adverse events were mild or moderate in severity; none were serious. MEDI4893 peak serum concentration increased dose proportionally from 77.2 μg/mL (225 mg) to 1,784 μg/mL (5,000 mg). Area under the concentration–time curve from 0 to 360 days also increased dose proportionally, from 4,840 μg•day/mL (225 mg) to 91,493 μg•day/mL (5,000 mg), indicating linear pharmacokinetics. MEDI4893's terminal half-life was estimated as 80–112 days, approximately fourfold longer than those of other human immunoglobulin G antibodies. Alpha-toxin–neutralizing activity in serum correlated highly with MEDI4893 concentrations in serum. Three adults tested positive transiently for ADA on day 151 without impact on MEDI4893 serum concentrations or safety profile; no subjects exhibited serum ADA at the study end. These data support continued development of MEDI4893 for the prevention of S. aureus-mediated pneumonia.

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Population Pharmacokinetics and Target Attainment of Ertapenem in Plasma and Tissue Assessed via Microdialysis in Morbidly Obese Patients after Laparoscopic Visceral Surgery [PublishAheadOfPrint]

Ertapenem provides broad-spectrum activity against many pathogens relevant for prophylaxis and treatment of infections in morbidly obese patients undergoing surgery. However, its pharmacokinetics and tissue penetration in these patients are not well defined. We assessed the population pharmacokinetics and target attainment for ertapenem in plasma, subcutaneous tissue and peritoneal fluid of morbidly obese patients. Six female patients (BMI: 43.7-55.9 kg/m²) received 1,000mg ertapenem as 15-min infusions at 0 and 26h. On day 2, unbound ertapenem concentration profiles in plasma, subcutaneous tissue, and peritoneal fluid were measured by microdialysis; total plasma concentrations were additionally quantified. The probability of attaining a target of the unbound ertapenem concentrations above the MIC for at least 40% of the dosing interval was predicted via Monte Carlo simulations. The population pharmacokinetic model contained two disposition compartments and simultaneously described all concentrations. For unbound ertapenem, total clearance was 12.3L/h (21.6% CV for between patient variability) and volume of distribution at steady-state 57.8L in patients with 53kg fat-free mass. The area under the ertapenem concentration time curve (AUC) was 49% lower in subcutaneous tissue and 25% lower in peritoneal fluid compared to the unbound AUC in plasma. Tissue penetration was rapid (equilibration half-life <15min) and, in subcutaneous tissue, variable. Short-term ertapenem infusions (1,000 mg every 24h) achieved robust (>90%) target attainment probabilities for MICs up to 1 mg/L in plasma, 0.25 to 0.5 mg/L in subcutaneous tissue, and 0.5 mg/L in peritoneal fluid. Ertapenem presents an attractive choice for many pathogens relevant to morbidly obese patients undergoing surgery.

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Evaluation of the Carba NP test in Oregon, 2013 [PublishAheadOfPrint]

Carbapenem-resistant Enterobacteriaceae (CRE) are an urgent public health threat. We evaluated the capacity of the Carba NP test to detect carbapenemase production in 206 isolates: 143 Enterobacteriaceae identified by Oregon's CRE surveillance in 2013 and 63 known carbapenemase-positive organisms. Overall, test sensitivity and specificity were 89% (59/66; 95% CI 81-97%) and 100% (140/140; 95% CI 98-100%), respectively. All KPC, NDM-1, VIM, and IMP-producers but no (0/7) OXA-48-like strains were Carba NP-positive prior to a post-hoc protocol modification. We subsequently incorporated Carba NP into Oregon's CRE screening algorithm.

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