bluuebunny/crossref_metadata_2025_split huggingface dataset:
Iron Restriction to Clinical Isolates of Candida albicans by the Novel Chelator DIBI Inhibits Growth and Increases Sensitivity to AzolesIn VitroandIn Vivoin a Murine Model of Experimental Vaginitis
Authors: Savage Kimberley A. , Parquet Maria del Carmen , Allan David S. , Davidson Ross J. , Holbein Bruce E. , Lilly Elizabeth A. , Fidel Paul L. 
Published: May 2018

ABSTRACTCandida albicansis an important opportunistic pathogen causing various human infections that are often treated with azole antifungals. The U.S. CDC now regards developing candidal antifungal resistance as a threat, creating a need for new and more effective antifungal treatments. Iron is an essential nutrient for all living cells, and there is growing evidence that interference with iron homeostasis ofC. albicanscan improve its response to antifungals. This study was aimed at establishing whether withholding iron by currently used medical iron chelators and the novel chelator DIBI could restrict growth and also enhance the activity of azoles against clinical isolates ofC. albicans. DIBI, but not deferoxamine or deferiprone, inhibited the growth ofC. albicansat relatively low concentrationsin vitro, and this inhibition was reversed by iron addition. DIBI in combination with various azoles demonstrated stronger growth inhibition than the azoles alone and greatly prolonged the inhibition of cell multiplication. In addition, the administration of DIBI along with fluconazole (FLC) to mice inoculated with an FLC-sensitive isolate in a model of experimentalC. albicansvaginitis showed a markedly improved clearance of infection. These results suggest that iron chelation by DIBI has the potential to enhance azole efficacy for the treatment of candidiasis.
A New Family of Capsule Polymerases Generates Teichoic Acid-Like Capsule Polymers in Gram-Negative Pathogens
Authors: Litschko Christa , Oldrini Davide , Budde Insa , Berger Monika , Meens Jochen , Gerardy-Schahn Rita , Berti Francesco , Schubert Mario , Fiebig Timm 
Published: May 2018

ABSTRACT

Group 2 capsule polymers represent crucial virulence factors of Gram-negative pathogenic bacteria. They are synthesized by enzymes called capsule polymerases. In this report, we describe a new family of polymerases that combine glycosyltransferase and hexose- and polyol-phosphate transferase activity to generate complex poly(oligosaccharide phosphate) and poly(glycosylpolyol phosphate) polymers, the latter of which display similarity to wall teichoic acid (WTA), a cell wall component of Gram-positive bacteria. Using modeling and multiple-sequence alignment, we showed homology between the predicted polymerase domains and WTA type I biosynthesis enzymes, creating a link between Gram-negative and Gram-positive cell wall biosynthesis processes. The polymerases of the new family are highly abundant and found in a variety of capsule-expressing pathogens such as
Neisseria meningitidis
,
Actinobacillus pleuropneumoniae
,
Haemophilus influenzae
,
Bibersteinia trehalosi
, and
Escherichia coli
with both human and animal hosts. Five representative candidates were purified, their activities were confirmed using nuclear magnetic resonance (NMR) spectroscopy, and their predicted folds were validated by site-directed mutagenesis.

IMPORTANCE
Bacterial capsules play an important role in the interaction between a pathogen and the immune system of its host. During the last decade, capsule polymerases have become attractive tools for the production of capsule polymers applied as antigens in glycoconjugate vaccine formulations. Conventional production of glycoconjugate vaccines requires the cultivation of the pathogen and thus the highest biosafety standards, leading to tremendous costs. With regard to animal husbandry, where vaccines could avoid the extensive use of antibiotics, conventional production is not sufficiently cost-effective. In contrast, enzymatic synthesis of capsule polymers is pathogen-free and fast, offers high stereo- and regioselectivity, and works with high efficacy. The new capsule polymerase family described here vastly increases the toolbox of enzymes available for biotechnology purposes. Representatives are abundantly found in human pathogens but also in animal pathogens, paving the way for the exploitation of polymerases for the development of a new generation of vaccines for animal husbandry.
Rational Design of Biosafety Level 2-Approved, Multidrug-Resistant Strains of Mycobacterium tuberculosis through Nutrient Auxotrophy
Authors: Vilchèze Catherine , Copeland Jacqueline , Keiser Tracy L. , Weisbrod Torin , Washington Jacqueline , Jain Paras , Malek Adel , Weinrick Brian , Jacobs William R. 
Published: May 2018

ABSTRACT

Multidrug-resistant (MDR) tuberculosis, defined as tuberculosis resistant to the two first-line drugs isoniazid and rifampin, poses a serious problem for global tuberculosis control strategies. Lack of a safe and convenient model organism hampers progress in combating the spread of MDR strains of
Mycobacterium tuberculosis
. We reasoned that auxotrophic MDR mutants of
M. tuberculosis
would provide a safe means for studying MDR
M. tuberculosis
without the need for a biosafety level 3 (BSL3) laboratory. Two different sets of triple auxotrophic mutants of
M. tuberculosis
were generated, which were auxotrophic for the nutrients leucine, pantothenate, and arginine or for leucine, pantothenate, and methionine. These triple auxotrophic strains retained their acid-fastness, their ability to generate both a drug persistence phenotype and drug-resistant mutants, and their susceptibility to plaque-forming mycobacterial phages. MDR triple auxotrophic mutants were obtained in a two-step fashion, selecting first for solely isoniazid-resistant or rifampin-resistant mutants. Interestingly, selection for isoniazid-resistant mutants of the methionine auxotroph generated isolates with single point mutations in
katG
, which encodes an isoniazid-activating enzyme, whereas similar selection using the arginine auxotroph yielded isoniazid-resistant mutants with large deletions in the chromosomal region containing
katG
. These
M. tuberculosis
MDR strains were readily sterilized by second-line tuberculosis drugs and failed to kill immunocompromised mice. These strains provide attractive candidates for
M. tuberculosis
biology studies and drug screening outside the BSL3 facility.

IMPORTANCE
Elimination of
Mycobacterium tuberculosis
, the bacterium causing tuberculosis, requires enhanced understanding of its biology in order to identify new drugs against drug-susceptible and drug-resistant
M. tuberculosis
as well as uncovering novel pathways that lead to
M. tuberculosis
death. To circumvent the need for a biosafety level 3 (BSL3) laboratory when conducting research on
M. tuberculosis
, we have generated drug-susceptible and drug-resistant triple auxotrophic strains of
M. tuberculosis
suitable for use in a BSL2 laboratory. These strains originate from a double auxotrophic
M. tuberculosis
strain, H37Rv Δ
panCD
Δ
leuCD
, which was reclassified as a BSL2 strain based on its lack of lethality in immunocompromised and immunocompetent mice. A third auxotrophy (methionine or arginine) was introduced via deletion of
metA
or
argB
, respectively, since
M. tuberculosis
Δ
metA
and
M. tuberculosis
Δ
argB
are unable to survive amino acid auxotrophy and infect their host. The resulting triple auxotrophic
M. tuberculosis
strains retained characteristics of
M. tuberculosis
relevant for most types of investigations.
Thrombectomy 24 hours after stroke: beyond DAWN
Authors: Desai Shashvat M , Haussen Diogo C , Aghaebrahim Amin , Al-Bayati Alhamza R , Santos Roberta , Nogueira Raul G , Jovin Tudor G , Jadhav Ashutosh P 
Published: May 2018

Background and purposeThe results of the DAWN trial support the benefit of thrombectomy in patients with anterior circulation large vessel occlusion (LVO) acute stroke presenting within 6–24 hours from time last known well (TLKW). We sought to evaluate the characteristics and outcomes of patients who met DAWN criteria but underwent thrombectomy beyond 24 hours of TLKW.MethodsA retrospective review of endovascular thrombectomy databases at three comprehensive stroke centers was performed to identify all patients who received thrombectomy beyond 24 hours of TLKW and otherwise met the DAWN criteria. Baseline characteristics, efficacy, and safety outcomes were compared with patients in the DAWN trial intervention arm.ResultsTwenty-one patients met the inclusion criteria. Rates of successful reperfusion (mTICI2b–3: 81% vs 84%, P=0.72), 90-day functional independence (modified Rankin Scale score 0–2, 43% vs 48%, P=0.68), and symptomatic intracranial hemorrhage (5% vs 6%, P=0.87) were comparable across the two groups.ConclusionThrombectomy appears to be safe and feasible in patients with acute ischemic stroke due to LVO meeting all DAWN trial criteria but treated beyond 24 hours of TLKW with outcomes comparable to patients in the DAWN trial intervention arm. Further studies are warranted to validate these findings.
Should flavours be banned in cigarettes and e-cigarettes? Evidence on adult smokers and recent quitters from a discrete choice experiment
Authors: Buckell John , Marti Joachim , Sindelar Jody L 
Published: May 2018

Objectives
To provide the policy-relevant estimates of impacts of alternative flavour bans on preferences and demand for cigarettes and e-cigarettes in adult smokers and recent quitters.

Methods
A best–best discrete choice experiment (DCE) is used to elicit smokers’ and recent quitters’ preferences for flavours, price, health impact and nicotine level in cigarettes and e-cigarettes. Choice of tobacco products and an opt-out option were examined. An efficient design yielded 36 choice sets. Exploded logit choice models were estimated. Flavour bans are modelled by restricting flavour coefficients in the estimated model.

Setting and participants
A sample of 2031 adult smokers and recent quitters was recruited to complete an online survey and DCE.

Results
Current smokers and recent quitters, on average, prefer cigarettes and menthol cigarettes over flavoured e-cigarettes. However, there is substantial preference heterogeneity by younger adults (ages 18–25), race/ethnicity and respondents with higher education. Our predictions suggest that a ban on menthol cigarettes would produce the greatest reduction in the choice of cigarettes (−5.2%), but with an accompanying increase in e-cigarettes use (3.8%). In contrast, banning flavours in e-cigarettes, while allowing menthol in cigarettes would result in the greatest increase in the selection of cigarettes (8.3%), and a decline in the use of e-cigarettes (−11.1%). A ban on all flavours, but tobacco in both products would increase ‘opting-out’ the most (5.2%) but would also increase choice of cigarettes (2.7%) and decrease choice of e-cigarettes (−7.9%).

Conclusions
A ban on flavoured e-cigarettes alone would likely increase the choice of cigarettes in smokers, arguably the more harmful way of obtaining nicotine, whereas a ban on menthol cigarettes alone would likely be more effective in reducing the choice of cigarettes. A ban on all flavours in both products would likely reduce the smoking/vaping rates, but the use of cigarettes would be higher than in the status quo. Policy-makers should use these results to guide the choice of flavour bans in light of their stance on the potential health impacts both products.
The beneficial effect of natural antioxidants from olive oil with fig and date palm fruit extracts on biochemical and hematological parameters in rats during diethylnitrosamine-induced carcinogenesis
Authors: Fathy Abdallah H. , Bashandy Mohamed A. , Bashandy Samir A. , Mansour Ahmed M. 
Published: May 2018

Diethylnitrosamine (DEN) is a well-known carcinogen. The aim of our study was to determine the role of olive oil (7 g/kg) with fig (1 g/kg) (OF) and (or) date palm (1 g/kg) (D) fruit extracts during DEN treatment of male Wistar rats. The OF–DEN and (or) D–DEN groups were given oral antioxidants daily for two weeks before and during DEN treatment (21 weeks).The DEN-treated group showed dramatic results for all investigated parameters as compared with the control rats. All OF–DEN and D–DEN groups showed significant improvement in hepatic thiobarbituric acid reactive substances, reduced glutathione, and nitric oxide concentration in the liver tissue, in addition to improvement in serum vascular endothelial growth factor level, alpha-fetoprotein, lipid profile, lipid risk ratios, and the hematological parameters as compared with the DEN-treated group.In conclusion, the administration of OF and (or) D fruit extracts to DEN-treated rats resulted in a considerable improvement in the investigated biochemical and hematological parameters. In addition, the combined OFD treatments showed greater improvements revealing the synergistic effect of the combination.
Wave equations in conformal gravity
Authors: Du Juan-Juan , Wang Xue-Jing , He You-Biao , Yang Si-Jiang , Li Zhong-Heng 
Published: May 2018

We study the wave equation governing massless fields of all spins (s = 0, [Formula: see text], 1, [Formula: see text] and 2) in the most general spherical symmetric metric of conformal gravity. The equation is separable, the solution of the angular part is a spin-weighted spherical harmonic, and the radial wave function may be expressed in terms of solutions of the Heun equation which has four regular singular points. We also consider various special cases of the metric and find that the angular wave functions are the same for all cases, the actual shape of the metric functions affects only the radial wave function. It is interesting to note that each radial equation can be transformed into a known ordinary differential equation (i.e. Heun equation, or confluent Heun equation, or hypergeometric equation). The results show that there are analytic solutions for all the wave equations of massless spin fields in the spacetimes of conformal gravity. This is amazing because exact solutions are few and far between for other spacetimes.
Allee optimal control of a system in ecology
Authors: Trélat Emmanuel , Zhu Jiamin , Zuazua Enrique 
Published: May 2018

The Allee threshold of an ecological system distinguishes the sign of population growth either towards extinction or to carrying capacity. In practice, human interventions can tune the Allee threshold for instance thanks to the sterile male technique and the mating disruption. In this paper, we address various control problems for a system described by a diffusion–reaction equation regulating the Allee threshold, viewed as a real parameter determining the unstable equilibrium of the bistable nonlinear reaction term. We prove that this system is the mean field limit of an interacting system of particles in which the individual behaviour is driven by stochastic laws. Numerical simulations of the stochastic process show that the propagation of population is governed by travelling wave solutions of the macroscopic reaction–diffusion system, which model the fact that solutions, in bounded space domains, reach asymptotically an equilibrium configuration. An optimal control problem for the macroscopic model is then introduced with the objective of steering the system to a target travelling wave. Using well-known analytical results and stability properties of travelling waves, we show that well-chosen piecewise constant controls allow to reach the target approximately in sufficiently long time. We then develop a direct computational method and show its efficiency for computing such controls in various numerical simulations. Finally, we show the effectiveness of the obtained macroscopic optimal controls in the microscopic system of interacting particles and we discuss their advantage when addressing situations that are out of reach for the analytical methods. We conclude the paper with some open problems and directions for future research.
Healthcare Resource Use and Cost Implications in the MOMENTUM 3 Long-Term Outcome Study
Authors: Mehra Mandeep R. , Salerno Christopher , Cleveland Joseph C. , Pinney Sean , Yuzefpolskaya Melana , Milano Carmelo A. , Itoh Akinobu , Goldstein Daniel J. , Uriel Nir , Gulati Sanjeev , Pagani Francis D. , John Ranjit , Adamson Robert , Bogaev Roberta , Thohan Vinay , Chuang Joyce , Sood Poornima , Goates Scott , Silvestry Scott C. 
Published: May 2018

Background:
The MOMENTUM 3 trial compares the centrifugal HeartMate 3 (HM3) with the axial HeartMate II (HMII) continuous-flow left ventricular assist system in patients with advanced heart failure, irrespective of the intended goal of therapy. The trial’s 2-year clinical outcome (n=366) demonstrated superiority of the HM3 for the primary end point (survival free of a disabling stroke or reoperation to replace or remove a malfunctioning pump). This analysis evaluates health resource use and cost implications of the observed differences between the 2 devices while patients were enrolled in the trial.

Methods:
We analyzed all hospitalizations and their associated costs occurring after discharge from the implant hospitalization until censoring (study withdrawal, heart transplantation, and pump exchange with a nonstudy device or death). Each adjudicated episode of hospital-based care was used to calculate costs (device-attributable and non–device-attributable event costs), estimated by using trial data and payer administrative claims databases. Cost savings stratified by subgroups (study outcome [transplant, death, or ongoing on device], intended goal of therapy, type of insurance, or sex) were also assessed.

Results:

In 366 randomly assigned patients, 361 comprised the as-treated group (189 in the HM3 group and 172 in the HMII group), of whom 337 (177 in the HM3 group and 160 in the HMII group) were successfully discharged following implantation. The HM3 arm experienced fewer total hospitalizations per patient-year (HM3: 2.1±0.2 versus HMII: 2.7±0.2;
P
=0.015) and 8.3 fewer hospital days per patient-year on average (HM3: 17.1 days versus HMII: 25.5 days;
P
=0.003). These differences were driven by patients hospitalized for suspected pump thrombosis (HM3: 0.6% versus HMII: 12.5%;
P
<0.001) and stroke (HM3: 2.8% versus HMII: 11.3%;
P
=0.002). Controlled for time spent in the study (average cumulative cost per patient-year), postdischarge HM3 arm costs were 51% lower than with the HMII (HM3: $37 685±4251 versus HMII: $76 599±11 889,
P
<0.001) and similar in either bridge to transplant or destination therapy intent.

Conclusions:
In this 2-year outcome economic analysis of the MOMENTUM 3 trial, the HM3 demonstrated a reduction in rehospitalizations, hospital days spent during rehospitalizations, and a significant cost savings following discharge in comparison with the HMII left ventricular assist system, irrespective of the intended goal of therapy.

Clinical Trial Registration:

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT02224755.
Money in Classical Islam: Legal Theory and Economic Practice
Authors: Oberauer Norbert 
Published: May 2018

AbstractThe present study examines the conception of money in classical Islamic law,
specifically the relationship between scholarly discourses on money and actual
economic practice. I shall argue that the theoretical concept of money was to
some extent a fiction. Muslim jurists conceived of money in terms of a
three-tier currency system that involved gold dinars, silver dirhams and copper
fulūs. The market was much more complex. A wide
range of coins of various metallic content, weight and value circulated. In the
first part of the study I describe the complexity of Islamic money markets. In
the second part, I investigate how scholars reacted to the gap between theory
and practice and posit some tentative conclusions about the relationship between
Islamic law and practice.
Missing the Muscles? Mediation by Conditionality in Bosnia and Herzegovina
Authors: Richter Solveig 
Published: May 2018

AbstractIn October 2009, the European Union, in conjunction with the United States, launched a high-level mediation effort in Butmir, Bosnia and Herzegovina, to reform the political structure of the state. Since 2005, the constitution which was included in the Dayton Peace Accord has been widely perceived as dysfunctional. In two negotiation rounds, theEUand theUSput a comprehensive proposal on the table and showed strong leverage. However, the talks ended without a tangible result. To explain this failure, a theoretical model is developed based on both mediation and Europeanization literature to explore mediation by conditionality as a type of ‘directive mediation’ in a systematic way. Contrary to the argument that theEUlacked muscle, it is argued that pre-conditions for political conditionality were not fulfilled and strong leverage proved ineffective and counterproductive. These results question conditionality as an effective mediation strategy when state-building is contested between local parties.
EU Mediation in Egypt: The Limits of Reactive Conflict Management
Authors: Pinfari Marco 
Published: May 2018

AbstractThis article reviewsEU’s mediation attempts in Egypt between 2011 and 2013. After presenting the main challenges and opportunities ofEUmediation in the Middle East-North Africa (MENA) neighborhood,EUinterventions in Egypt are discussed in relation to the 25 January 2011 revolution, during the presidency of Mohammed Morsi, and after the 3 July 2013 coup d’état, focusing specifically on the choice of mediation styles and their timing. It is argued that three contextual conditions that are typical of the crises that erupt during failed democratic transitions – their fast pace, their eminently domestic nature and significant power asymmetries between the main parties involved – exacerbate the structural problems that theEUfaces when intervening in countries that are not current or potential candidates for accession. The analysis ofEUmediation styles during Egypt’s transition provides a critical perspective onEU’s foreign policy making after the Treaty of Lisbon.
Diagnostic performance of CT, MRI, and their combined use for the assessment of the direct cranial or intracranial extension of malignant head and neck tumors
Authors: Choi Hye Yeon , Yoon Dae Young , Kim Eun Soo , Baek Sora , Lim Kyoung Ja , Seo Young Lan , Yun Eun Joo 
Published: May 2018

Background Preoperative radiological evaluation of the cranial or intracranial extension of malignant head and neck tumors is critical in the planning of curative surgery. Purpose To assess the diagnostic accuracy of computed tomography (CT) combined with magnetic resonance imaging (MRI), compared to CT or MRI alone in diagnosing the direct cranial or intracranial extension of malignant head and neck tumors, using histopathologic results as the reference standard. Material and Methods CT and MRI images in 41 patients with malignant head and neck tumors abutting the skull were retrospectively reviewed. The images were evaluated for the presence or absence of skull invasion (erosion/destruction of the skull), dural invasion (nodular dural enhancement), and brain invasion (enhancing brain lesion with or without brain swelling/edema). The results of the CT alone, MRI alone, and CT combined with MRI were compared with the histopathologic findings. Results Of the 41 patients studied, ten had no invasion, eight had skull invasion, 17 had dural invasion, and six had brain invasion by tumor. The sensitivity/specificity/accuracy of CT alone, MRI alone, and CT combined with MRI for diagnosing intracranial extension were 78.0%/100%/94.5%, 85.4%/80.5%/93.9%, and 95.1%/100%/98.8%, respectively. The sensitivity of CT combined with MRI was significantly higher than those of CT alone ( P = 0.0156) and MRI alone ( P = 0.0313). Conclusion CT combined with MRI is a more sensitive tool for the diagnosis of the direct cranial or intracranial extension of malignant head and neck tumors than CT alone and MRI alone.