bluuebunny/crossref_metadata_2025 huggingface dataset:
The impact of bisphenol S on bovine granulosa and theca cells
Authors: Campen KA , Lavallee M , Combelles CMH
Published: January 2018

Contents

Bisphenol S (BPS) is an endocrine‐disrupting chemical with multiple potential mechanisms of action, including as an oestrogen receptor agonist. BPS is increasingly used in plastics and thermal receipts as a substitute for bisphenol A, which has been phased out due to concerns about human health implications. The ability of BPS to alter female reproductive function in mammals has not been widely studied, despite the importance of normal hormone signalling for female reproduction. The aim of this study was to investigate how BPS (in a wide range of doses, including very low doses) affects granulosa cell and theca cell steroid hormone production and cell viability in the bovine. Granulosa cell oestradiol production was stimulated when cells were exposed to 100 μM BPS under basal conditions, but there was no effect of BPS when cells were stimulated with follicle‐stimulating hormone (FSH). Additionally, there was no effect of BPS on granulosa cell progesterone production or cell viability under basal or FSH‐stimulated conditions. BPS did not affect theca cell androstenedione or progesterone production, or theca cell viability under basal or luteinizing hormone‐stimulated conditions. This study suggests for the first time that BPS may alter oestradiol production by bovine granulosa cells, albeit at a concentration that is unlikely to be physiologically relevant. Further studies are needed to determine the effects of BPS on the bovine oocyte and on other functions of follicular cells.
Effect of local scrotal heating on the expression of tight junction‐associated molecule Occludin in boar testes
Authors: Zhang Z , Fan X , Xi H , Ji R , Shen H , Shi A , He J
Published: January 2018

Contents

The aim of this study was to determine whether local scrotal heating (42°C, for 1 hr) had an effect on the expression of tight junction (TJ)‐associated molecule Occludin in boar testes. Adult boars (Landrace, n = 6) were used and randomly divided into two groups (n = 3 each). Three boars were given local scrotal exposure to 42°C for approximately 1 h with a home‐made electric blanket of controlled temperature as local scrotal heating group, the other three boars received no heat treatment and were left at standard room temperature as control group. After 6 hr, all boars were castrated and the testes were harvested. qRT‐PCR, Western blotting and immunohistochemistry were used to explore the expression and localization of Occludin. qRT‐PCR and Western blotting showed that the protein and mRNA levels of Occludin significantly decreased in local scrotal heating group as compared to the control. Furthermore, immunoreactivity staining of Occludin was localized at the sites of the blood–testis barrier (BTB) and formed an almost consecutive and strong immunoreactivity strand in the control, while Occludin was limited to Sertoli cells (SCs) and no obvious immunoreactivity strand was present in local scrotal heating group. These data indicated that local scrotal heating decreased the expression of TJ‐associated molecule Occludin, which may be involved in heat‐induced spermatogenesis damage.
Exercise desaturation and oxygen therapy in ILD and COPD: Similarities, differences and therapeutic relevance
Authors: McDonald Christine F.
Published: January 2018

See related Article
Characterization of biologic response modifiers in the supernatant of conventional, refrigerated, and cryopreserved platelets
Authors: Johnson Lacey , Tan Shereen , Jenkins Emily , Wood Ben , Marks Denese C.
Published: January 2018

BACKGROUND

Alternatives to room temperature storage of platelets (PLTs) are of interest to support blood banking logistics. The aim of this study was to compare the presence of biologic response modifiers (BRMs) in PLT concentrates stored under conventional room temperature conditions with refrigerated or cryopreserved PLTs.

STUDY DESIGN AND METHODS

A three‐arm pool‐and‐split study was carried out using buffy coat–derived PLTs stored in 30% plasma/70% SSP+. The three matched treatment arms were as follows: room temperature (20‐24°C), cold (2‐6°C), and cryopreserved (–80°C with DMSO). Liquid‐stored PLTs were tested over a 21‐day period, while cryopreserved PLTs were tested immediately after thawing and reconstitution in 30% plasma/70% SSP+ and after storage at room temperature.

RESULTS

Coagulation factor activity was comparable between room temperature and cold PLTs, with the exception of protein S, while cryopreserved PLTs had reduced Factor (F)V and FVIII activity. Cold‐stored PLTs retained α‐granule proteins better than room temperature or cryopreserved PLTs. Cryopreservation resulted in 10‐fold higher microparticle generation than cold‐stored PLTs, but both groups contained significantly more microparticles than those stored at room temperature. The supernatant from both cold and cryopreserved PLTs initiated faster clot formation and thrombin generation than room temperature PLTs.

CONCLUSION

Cold storage and cryopreservation alter the composition of the soluble fraction of stored PLTs. These differences in coagulation proteins, cytokines, and microparticles likely influence both the hemostatic capacity of the components and the auxiliary functions.
Reviewer Acknowledgements
Authors: Young James
Published: January 2018

International Journal of Social Science Studies (IJSSS) would like to acknowledge the following reviewers for their assistance with peer review of manuscripts for this issue. Many authors, regardless of whether IJSSS publishes their work, appreciate the helpful feedback provided by the reviewers. Their comments and suggestions were of great help to the authors in improving the quality of their papers. Each of the reviewers listed below returned at least one review for this issue.Reviewers for Volume 6, Number 2 Agboola O. Paul, Universiti Teknologi Malaysia, MalaysiaAhmet Yıkmış, Abant Izzet Baysal Univeersity, TurkeyAmany Albert, Beni-Suef University, EgyptAnastasia Panagakos, Cosumnes River College, USAAntónio Calha, Polytechnic Institute of Portalegre, PortugalBo Li, St Ambrose University, USAE.Ozan Aksoz, Anadolu University, TurkeyJehu Onyekwere Nnaji, University of Naples II, Italy and Globe Visions Network Italy, ItalyJohn Boulard Forkuor , Kwame Nkrumah University of Science and Technology (KNUST) , GhanaJulia M. Mack, Gannon University, USAMohammad Naji Shah Mohammadi, Kuala Lumpur, MalaysiaQingzhi Huan, Peking University, ChinaRasa Poceviciene, Siauliai University, LithuaniaRemigiusz Kijak, "University of Warsaw", PolandSandro Serpa, University of the Azores, PortugalShariq aziz butt, Superior University Lahore, PakistanValentina Evangelista, G. d’Annunzio University, ItalyXian-Liang Tian, Zhongnan University of Economics and Law, ChinaYanzhe Zhang, Jilin University, China, China/Australia
An Investigation between Multiple Intelligences and Learning Styles
Authors: Şener Sabriye , Çokçalışkan Ayten
Published: January 2018

Exploring learning style and multiple intelligence type of learners can enable the students to identify their strengths and weaknesses and learn from them. It is also very important for teachers to understand their learners’ learning styles and multiple intelligences since they can carefully identify their goals and design activities that can teach to the different intelligences, and design student-centered activities. This study aims to reveal secondary school students’ multiple intelligences and learning styles. It also aims to describe gender differences and the relationship between learning styles and multiple intelligences of the students. The research study employed a quantitative research design and the data were collected from the students of a state school in the winter term of 2015-2016 Education Year. The data were gathered by means of the two instruments: The Perceptual Learning-Style Preference Questionnaire (PLSPQ), and the Multiple Intelligence Inventory. It was observed that the students had almost all these types of learning styles but mostly they were found to be tactile and auditory learners. The three intelligence groups: Naturalistic, Visual and Kinesthetic intelligences types received the highest score. The analyses also indicated that there was a significant difference between males and females. It was seen that most of the intelligence types and learning styles had a moderate positive correlation.
Examination of the Views of High School Teachers and Students with Regard to Discipline Perception and Discipline Problems
Authors: Sadik Fatma , Yalcin Onur
Published: January 2018

This research is a qualitative study comparatively examining the views of high school teachers and students related to discipline perception and discipline problems. The study has been realized at a vocational school during the 2014/2015 school term. Maximum diversity and criterion sampling methods have been followed for the formation of the study groups with 18 teachers and 16 students. The data collected through semi-structured interview forms has been evaluated by content analysis. As a result of the study, it has been observed that the teachers define discipline as a wholistic system, self-control and providing the necessary learning environment, while the students define it as self-control, obeying the rules and respect. The participating teachers, who agreed on the idea that discipline does not mean bullying or passivizing the individuals, described rudeness, lack of interest in the lesson and misbehavior as disciplinary problems. According to the teachers, not fulfilling the responsibilities and rudeness; according to the students, preventing the course from running and not being interested in the course are the most experienced discipline problems at their respective schools. Pursuant to the acquired results, the students differ from the teachers by thinkink that behavior such as not obeying the directives, using hazardous items and harming the environment/objects are the most common problems.
Critical Theory-Based Approaches in Geography Teaching Departments in Turkey
Authors: Bilgili Münür
Published: January 2018

The aim of this study is to understand the relationships between critical theory-based approaches and its implementations in geography teaching departments in Turkey. Critical theory dates back to 1930s and has developed over time aiming to deal with institutions, culture and society through critical lens. Currently, critical theory-based research designs and research paradigms inspire a large number of books, articles especially in qualitative researches due to their beneficial outcomes for the vulnerable, the poor and the othered segments of society with which critical researches are mainly concerned.In the study, firstly it was described critical theory and critical research characteristics. Secondly, human geography and critical research relationships covered. Thirdly, human geography courses in geography teaching departments in Turkey explained in connection with critical theory. The relationships between these courses, critical theory and critical research were tried to explore. The study emphasized the importance of critical theory in courses in human geography considering far-reaching effects of critical theory on humanities, social sciences and art studies. Human geography has and should have close connections with other disciplines and sub-disciplines drawing on multiple theories, concepts and approaches.
Contradictory Explorative Assessment. Multimodal Teacher/Student Interaction in Scandinavian Digital Learning Environments
Authors: Kjällander Susanne
Published: January 2018

Assessment in the much-discussed digital divide in Scandinavian technologically advanced schools, is the study object of this article. Interaction is studied to understand assessment; and to see how assessment can be didactically designed to recognise students´ learning. With a multimodal, design theoretical perspective on learning teachers’ and students’ modes are documented and analysed. Illustrated in the article, is how the subject design aims at an expert level, while formative assessment aims at a novice level leaving students without adequate guidance. Despite this, summative assessment aims at an expert level and is at times contradictory. A concluding suggestion is that assessment in a digital learning environment can be designed exploratory to encompass students’ new knowledge and to embrace their multimodal signs of learning, or much of what is learned will be ignored.
The Rescue of French Jews during the Second World War as Reflected in Two Novels: The Nightingale by Kristin Hannah and the Velvet Hours by Alyson Richman
Authors: Dori Nitsa
Published: January 2018

Two primary concepts are usually mentioned when analyzing the attitude of the French towards the Jews during the Second World War: anti-Semitism and rescue. Paldiel divides the types of help offered by the rescuers during the Second World War into four: a hiding place, impersonating a non-Jew, escape, and helping children. The two novels, The Nightingale and The Velvet Hours were written at around the same time and share many common themes: rigid father-daughter relations, becoming orphaned, unwanted pregnancy, and pioneering women leaders. The ethnic origin of both authors is also the same, but the primary purpose of this article is to discuss the setting of both novels: the Second World War; in France, and the heroic deed occurring in the two books: saving Jews from the threat of the Nazi invader. We will examine each book separately and then discuss the points common to both – points that will evolve into a discussion and conclusions.
A Distinctive Platform System to Study the Effects of a Vestibular Prosthesis on Nonhuman Primate Postural Control
Authors: Thompson Lara A. , Haburcakova Csilla , Lewis Richard F.
Published: January 2018

The purpose of this paper is to describe novel experiments and methodologies utilizing a distinctive balance platform system to investigate postural responses for moderate to severe vestibular loss and invasive vestibular prosthesis-assisted nonhuman primates (rhesus monkeys). For several millions of vestibular loss sufferers in the U.S., daily living is severely affected in that common everyday tasks, such as getting out of bed at night, maintaining balance on a moving bus, or walking on an uneven surface, may cause a loss of stability leading to falls and injury. Aside from loss of balance, blurred vision and vertigo (perceived spinning sensation) are also debilitating in vestibular-impaired individuals. Although the need for vestibular rehabilitative solutions is apparent, postural responses for a broad range of peripheral vestibular function, and for various stationary and moving support conditions, have not been systematically investigated. For the investigation of implants and prostheses that are being developed toward implementation in humans, nonhuman primates are a key component. The measurement system used in this research was unique. Our platform system facilitated the study of rhesus monkey posture for stationary support surface conditions (quiet stance and head turns) and for dynamic support surface conditions (pseudorandom roll tilts of the support surface). Further, the platform system was used to systematically study postural responses that will serve as baseline measures for future vestibular-focused human and nonhuman primate posture studies.
Dynamic Analysis for the Rotor Drop Process and Its Application to a Horizontal Rotor-Active Magnetic Bearing System in Helium Gas
Authors: Yulan Zhao , Xingnan Liu , Guojun Yang , Zhengang Shi , Lei Zhao
Published: January 2018

The high-temperature gas-cooled reactor pebble-bed modular (HTR-PM) has been proposed by the Institute of Nuclear and New Energy Technology of Tsinghua University, in which the active magnetic bearings (AMBs) are equipped to support the high-speed rotor in the helium circulator system. In the case of AMB failures, emergencies, or overload conditions, the auxiliary bearing is applied as the backup protector to provide temporary mechanical support and displacement constraint for the dropping rotor. A detailed dynamic model is established to reveal the behavior of the dropping rotor. This model is able to describe the rotor displacement and inclination around each axis. The left and right rotor orbits are revealed. Dropping experiments are also carried out to reveal the actual behavior of the dropping rotor in helium. The predicted and experimental results will benefit further study, design, and application of the auxiliary bearing in HTR-PM helium circulator.
Mathieu's Equation and Its Generalizations: Overview of Stability Charts and Their Features
Authors: Kovacic Ivana , Rand Richard , Mohamed Sah Si
Published: January 2018

This work is concerned with Mathieu's equation—a classical differential equation, which has the form of a linear second-order ordinary differential equation (ODE) with Cosine-type periodic forcing of the stiffness coefficient, and its different generalizations/extensions. These extensions include: the effects of linear viscous damping, geometric nonlinearity, damping nonlinearity, fractional derivative terms, delay terms, quasiperiodic excitation, or elliptic-type excitation. The aim is to provide a systematic overview of the methods to determine the corresponding stability chart, its structure and features, and how it differs from that of the classical Mathieu's equation.
A Review of Intent Detection, Arbitration, and Communication Aspects of Shared Control for Physical Human–Robot Interaction
Authors: Losey Dylan P. , McDonald Craig G. , Battaglia Edoardo , O'Malley Marcia K.
Published: January 2018

As robotic devices are applied to problems beyond traditional manufacturing and industrial settings, we find that interaction between robots and humans, especially physical interaction, has become a fast developing field. Consider the application of robotics in healthcare, where we find telerobotic devices in the operating room facilitating dexterous surgical procedures, exoskeletons in the rehabilitation domain as walking aids and upper-limb movement assist devices, and even robotic limbs that are physically integrated with amputees who seek to restore their independence and mobility. In each of these scenarios, the physical coupling between human and robot, often termed physical human robot interaction (pHRI), facilitates new human performance capabilities and creates an opportunity to explore the sharing of task execution and control between humans and robots. In this review, we provide a unifying view of human and robot sharing task execution in scenarios where collaboration and cooperation between the two entities are necessary, and where the physical coupling of human and robot is a vital aspect. We define three key themes that emerge in these shared control scenarios, namely, intent detection, arbitration, and feedback. First, we explore methods for how the coupled pHRI system can detect what the human is trying to do, and how the physical coupling itself can be leveraged to detect intent. Second, once the human intent is known, we explore techniques for sharing and modulating control of the coupled system between robot and human operator. Finally, we survey methods for informing the human operator of the state of the coupled system, or the characteristics of the environment with which the pHRI system is interacting. At the conclusion of the survey, we present two case studies that exemplify shared control in pHRI systems, and specifically highlight the approaches used for the three key themes of intent detection, arbitration, and feedback for applications of upper limb robotic rehabilitation and haptic feedback from a robotic prosthesis for the upper limb.
Discussion of “A Review of Intent Detection, Arbitration, and Communication Aspects of Shared Control for Physical Human–Robot Interaction” (Losey, D. P., McDonald, C. G., Battaglia, E., and O'Malley, M. K., 2018, ASME Appl. Mech. Rev., 70(1), p. 010804)
Authors: Schmiedeler James P. , Wensing Patrick M.
Published: January 2018

A unifying description of the shared control architecture within the field of physical human–robot interaction (pHRI) facilitates the education of those being introduced to the field and the framing of new contributions to it. The authors' review of shared control within pHRI proposes such a unifying framework composed of three pillars. First, intent detection addresses the robot's interpretation of human goals, representing one-way communication. Second, arbitration manages the respective roles of the human and robot in the shared control. Third, feedback is the mechanism by which the robot returns information to the human, representing one-way communication in the opposite direction. Interpreting existing contributions through the lens of this framework brings out the importance of mechanical design, modeling, and state-based control.
Ultralow power artificial synapses using nanotextured magnetic Josephson junctions
Authors: Schneider Michael L. , Donnelly Christine A. , Russek Stephen E. , Baek Burm , Pufall Matthew R. , Hopkins Peter F. , Dresselhaus Paul D. , Benz Samuel P. , Rippard William H.
Published: January 2018

Clustered ferromagnetic Josephson junctions form ultralow energy synaptic elements.
An optical authentication system based on imaging of excitation-selected lanthanide luminescence
Authors: Carro-Temboury Miguel R. , Arppe Riikka , Vosch Tom , Sørensen Thomas Just
Published: January 2018

Random patterns of lanthanide(III) ion–doped zeolites were used to create a tamper-proof optical authentication system.
Cross-stream migration of active particles
Authors: Katuri Jaideep , Uspal William E. , Simmchen Juliane , Miguel-López Albert , Sánchez Samuel
Published: January 2018

Active spheres swimming in a flow near a surface spontaneously adopt an orientation that allows them to swim across streamlines.
Programming a crystalline shape memory polymer network with thermo- and photo-reversible bonds toward a single-component soft robot
Authors: Jin Binjie , Song Huijie , Jiang Ruiqi , Song Jizhou , Zhao Qian , Xie Tao
Published: January 2018

Programming a shape memory polymer network with thermo- and photo-reversible bonds toward a single-component soft robot.
Supersaturated calcium carbonate solutions are classical
Authors: Henzler Katja , Fetisov Evgenii O. , Galib Mirza , Baer Marcel D. , Legg Benjamin A. , Borca Camelia , Xto Jacinta M. , Pin Sonia , Fulton John L. , Schenter Gregory K. , Govind Niranjan , Siepmann J. Ilja , Mundy Christopher J. , Huthwelker Thomas , De Yoreo James J.
Published: January 2018

Ions and ion pairs are the species that lead to CaCO
3
nucleation.
Emergent hydrodynamic bound states between magnetically powered micropropellers
Authors: Martinez-Pedrero Fernando , Navarro-Argemí Eloy , Ortiz-Ambriz Antonio , Pagonabarraga Ignacio , Tierno Pietro
Published: January 2018

Propelling microparticles in viscous fluid form long-living bound states maintained by hydrodynamic interactions.
Witnessing eigenstates for quantum simulation of Hamiltonian spectra
Authors: Santagati Raffaele , Wang Jianwei , Gentile Antonio A. , Paesani Stefano , Wiebe Nathan , McClean Jarrod R. , Morley-Short Sam , Shadbolt Peter J. , Bonneau Damien , Silverstone Joshua W. , Tew David P. , Zhou Xiaoqi , O’Brien Jeremy L. , Thompson Mark G.
Published: January 2018

We introduce the concept of an eigenstate witness and use it to find energies of quantum systems with quantum computers.
Collisions of ultracold
23
Na
87
Rb molecules with controlled chemical reactivities
Authors: Ye Xin , Guo Mingyang , González-Martínez Maykel L. , Quéméner Goulven , Wang Dajun
Published: January 2018

An experiment on ultracold polar molecules shows that there is more to be understood besides ultracold chemical reactions.
Population Pharmacokinetics of Cefotaxime and Dosage Recommendations in Children with Sickle Cell Disease
Authors: Maksoud Elsa , Koehl Berengere , Facchin Aude , Ha Phuong , Zhao Wei , Kaguelidou Florentia , Benkerrou Malika , Mariani Patricia , Faye Albert , Lorrot Mathie , Jacqz-Aigrain Evelyne
Published: January 2018

The pharmacokinetic profile of most drugs is dependent on the patient's covariates and may be influenced by the disease. Cefotaxime is frequently prescribed in pediatric patients with sickle cell disease (SCD), characterized by vaso-occlusive complications, chronic hemolytic anemia, and a defective immunological function predisposing the individual to severe infection. Data on the impact of the disease on the disposition of cefotaxime are missing. In the present study, our aims were to determine cefotaxime pharmacokinetics when prescribed to children with SCD for suspected or proven bacterial infection, identify significant covariates, and perform Monte Carlo simulations to optimize the drug dosage. Cefotaxime serum concentrations were measured in 78 pediatric SCD patients receiving cefotaxime intravenously at a daily dose of 200 mg/kg of body weight in three or four divided doses over 30 min. A total of 107 concentrations were available for pharmacokinetic analysis. A population pharmacokinetic model was developed with NONMEM software and used for Monte Carlo simulations. Cefotaxime concentrations ranged from 0.05 to 103.7 mg/liter. Cefotaxime pharmacokinetics were best described by a one-compartment model: the median estimated weight-normalized volume of distribution and clearance were 0.42 liter/kg (range, 0.2 to 1.1 liter/kg) and 0.38 liter/h/kg (range, 0.1 to 1.2 liter/h/kg). Cefotaxime clearance increased by 22% in patients with acute chest syndrome. Dosing optimization, performed using EUCAST MIC susceptibility breakpoints, showed that a dose of 100 mg/kg/6 h should be used, depending on the patient's characteristics and clinical presentation, in order to reach a value of the percentage of time that the drug concentration exceeded the MIC under steady-state pharmacokinetic conditions of 80% in 80% of the patients when targeting sensitive Gram-positive cocci and Gram-negative bacilli with MICs of 1 mg/liter or below.
Roles of Three Cryptococcus neoformans and Cryptococcus gattii Efflux Pump-Coding Genes in Response to Drug Treatment
Authors: Chang Miwha , Sionov Edward , Khanal Lamichhane Ami , Kwon-Chung Kyung J. , Chang Yun C.
Published: January 2018

Cryptococcus neoformans
and
Cryptococcus gattii
species complexes are the etiologic agents of cryptococcosis. We have deciphered the roles of three ABC transporters, Afr1, Afr2, and Mdr1, in the representative strains of the two species,
C. neoformans
H99 and
C. gattii
R265. Deletion of
AFR1
in H99 and R265 drastically reduced the levels of resistance to three xenobiotics and three triazoles, suggesting that Afr1 is the major drug efflux pump in both strains. Fluconazole susceptibility was not affected when
AFR2
or
MDR1
was deleted in both strains. However, when these genes were deleted in combination with
AFR1
, a minor additive effect in susceptibility toward several drugs was observed. Deletion of all three genes in both strains caused further increases in susceptibility toward fluconazole and itraconazole, suggesting that Afr2 and Mdr1 augment Afr1 function in pumping these triazoles. Intracellular accumulation of Nile Red significantly increased in
afr1Δ
mutants of both strains, but rhodamine 6G accumulation increased only in the
mdr1Δ
mutant of H99. Thus, the three efflux pumps play different roles in the two strains when exposed to different azoles and xenobiotics.
AFR1
and
AFR2
expression was upregulated in H99 and R265 when treated with fluconazole. However,
MDR1
expression was upregulated only in R265 under the same conditions. We screened a library of transcription factor mutants and identified several mutants that manifested either altered fluconazole sensitivity or an increase in the frequency of fluconazole heteroresistance. Gene expression analysis suggests that the three efflux pumps are regulated independently by different transcription factors in response to fluconazole exposure.
A Multicenter, Randomized, Double-Blind, Phase 2 Study of the Efficacy and Safety of Plazomicin Compared with Levofloxacin in the Treatment of Complicated Urinary Tract Infection and Acute Pyelonephritis
Authors: Connolly Lynn E. , Riddle Valerie , Cebrik Deborah , Armstrong Eliana S. , Miller Loren G.
Published: January 2018

Increasing antimicrobial resistance among uropathogens limits treatment options for patients with complicated urinary tract infection (cUTI). Plazomicin, a new aminoglycoside, has
in vitro
activity against multidrug-resistant
Enterobacteriaceae
, including isolates resistant to currently available aminoglycosides, as well as extended-spectrum β-lactamase-producing and carbapenem-resistant
Enterobacteriaceae
. We evaluated the efficacy and safety of plazomicin in a double-blind, comparator-controlled, phase 2 study in adults with cUTI or acute pyelonephritis. Patients were randomized 1:1:1 to receive intravenous plazomicin (10 or 15 mg/kg of body weight) or intravenous levofloxacin (750 mg) once daily for 5 days. Coprimary efficacy endpoints were microbiological eradication at the test of cure (TOC; 5 to 12 days after the last dose) in the modified intent-to-treat (MITT) and microbiologically evaluable (ME) populations. Overall, 145 patients were randomized to treatment. In the groups receiving plazomicin at 10 mg/kg, plazomicin at 15 mg/kg, and levofloxacin, microbiological eradication rates were, respectively, 50.0% (6 patients with microbiological eradication at TOC/12 patients treated [95% confidence interval {CI}, 21.1 to 78.9%]), 60.8% (31/51 [95% CI, 46.1 to 74.2%]), and 58.6% (17/29 [95% CI, 38.9 to 76.5%]) in the MITT population and 85.7% (6/7 [95% CI, 42.1 to 99.6%]), 88.6% (31/35 [95% CI, 73.3 to 96.8%]), and 81.0% (17/21 [95% CI, 58.1 to 94.6%]) in the ME population. In the MITT population, 66.7% (95% CI, 34.9 to 90.1%), 70.6% (95% CI, 56.2 to 82.5%), and 65.5% (95% CI, 45.7 to 82.1%) of the patients in the three groups, respectively, were assessed by the investigator to be clinically cured at TOC. Adverse events were reported in 31.8%, 35.1%, and 47.7% of the patients in the three groups, respectively. Serum creatinine values were generally stable over the course of the study. No plazomicin-treated patients with evaluable audiometry data had postbaseline sensorineural, conductive, or mixed hearing loss. In summary, plazomicin demonstrated microbiological and clinical success and an overall safety profile supportive of further clinical development. (This study has been registered at ClinicalTrials.gov under identifier NCT01096849.)
Antibiotic Susceptibility and Genotyping of Mycobacterium avium Strains That Cause Pulmonary and Disseminated Infection
Authors: Uchiya Kei-ichi , Asahi Shoki , Futamura Kazunori , Hamaura Hiromitsu , Nakagawa Taku , Nikai Toshiaki , Ogawa Kenji
Published: January 2018

Mycobacterium avium
subsp.
hominissuis
mainly causes disseminated infection in immunocompromised hosts, such as individuals with human immunodeficiency virus (HIV) infection, and pulmonary infection in immunocompetent hosts. However, many aspects of the different types of
M. avium
subsp.
hominissuis
infection remain unclear. We examined the antibiotic susceptibilities and genotypes of
M. avium
subsp.
hominissuis
isolates from different hosts by performing drug susceptibility testing using eight antibiotics (clarithromycin, rifampin, ethambutol, streptomycin, kanamycin, amikacin, ethionamide, and levofloxacin) and variable-number tandem-repeat (VNTR) typing analysis for 46 isolates from the sputa of HIV-negative patients with pulmonary
M. avium
subsp.
hominissuis
disease without previous antibiotic treatment and 30 isolates from the blood of HIV-positive patients with disseminated
M. avium
subsp.
hominissuis
disease. Interestingly, isolates from pulmonary
M. avium
subsp.
hominissuis
disease patients were more resistant to seven of the eight drugs, with the exception being rifampin, than isolates from HIV-positive patients. Moreover, VNTR typing analysis showed that the strains examined in this study were roughly classified into three clusters, and the genetic distance from reference strain 104 for isolates from pulmonary
M. avium
subsp.
hominissuis
disease patients was statistically significantly different from that for isolates from HIV-positive patients (
P
= 0.0018), suggesting that
M. avium
subsp.
hominissuis
strains that cause pulmonary and disseminated disease have genetically distinct features. Significant differences in susceptibility to seven of the eight drugs, with the exception being ethambutol, were noted among the three clusters. Collectively, these results suggest that an association between the type of
M. avium
subsp.
hominissuis
infection, drug susceptibility, and the VNTR genotype and the properties of
M. avium
subsp.
hominissuis
strains associated with the development of pulmonary disease are involved in higher levels of antibiotic resistance.
Norepinephrine in Combination with Antibiotic Therapy Increases both the Bacterial Replication Rate and Bactericidal Activity
Authors: Ambrose Paul G. , VanScoy Brian D. , Adams John , Fikes Steven , Bader Justin C. , Bhavnani Sujata M. , Rubino Christopher M.
Published: January 2018

We previously demonstrated that the rate and extent of an antimicrobial agent's bactericidal effects were coupled to the bacterial replication rate, the latter of which was modulated with the sodium chloride concentration. Herein, we describe the results from a 24-h one-compartment
in vitro
infection model study that was designed to demonstrate that an antimicrobial agent's bactericidal effects could be amplified when it is administered with a pharmaceutical agent that increases the bacterial replication rate. The antimicrobial and growth-promoting agents selected were levofloxacin and norepinephrine, respectively. The challenge isolate was
Escherichia coli
JMI 21711R (levofloxacin MIC, 8 mg/liter). Within the
in vitro
infection model, a human levofloxacin concentration-time profile (half-life, 7 h) was simulated and the challenge isolate was subjected to an ineffective monotherapy exposure (free-drug area under the concentration-time curve over 24 h divided by the MIC [AUC/MIC] ratio of 6) with and without norepinephrine as a continuous infusion (275 mg/liter). Samples were collected from the model during the course of the study for bacterial density determinations and drug concentration assay using liquid chromatography-tandem mass spectrometry (LC-MS/MS). As expected, the norepinephrine and no-treatment control arms failed immediately, followed by the levofloxacin monotherapy arm, which failed slowly over time. The levofloxacin-epinephrine regimen resulted in a 2-log
10
CFU reduction in bacterial density over the first 6 to 8 h of the study, which was followed by regrowth of a highly levofloxacin-resistant subpopulation (MIC, 64 mg/liter). These data demonstrate that increasing the rate of bacterial replication with a pharmaceutical product in combination with antimicrobial therapy represents an opportunity to increase the rate and magnitude of bactericidal effect.
A 10-Year Comparative Analysis Shows that Increasing Prevalence of Rifampin-Resistant Mycobacterium tuberculosis in China Is Associated with the Transmission of Strains Harboring Compensatory Mutations
Authors: Huo Fengmin , Luo Jingjing , Shi Jin , Zong Zhaojing , Jing Wei , Dong Wenzhu , Dong Lingling , Ma Yifeng , Liang Qian , Shang Yuanyuan , Huang Hairong , Pang Yu
Published: January 2018

In this work, we conducted bacterial population profile studies to assess trends of rifampin (RIF) resistance of
Mycobacterium tuberculosis
isolates collected across China from 2005 to 2015. Totals of 273 and 269 randomly selected
M. tuberculosis
isolates from 2005 and 2015, respectively, were analyzed. The rates of RIF resistance (36.4%), isoniazid resistance (39.0%), and levofloxacin resistance (25.7%) in 2015 were significantly higher than those in 2005 (28.2%, 30.0%, and 15.4%, respectively;
P
< 0.05). Genotypic data revealed 256 (95.2%) Beijing-type isolates in 2015, a rate significantly higher than that in 2005 (86.4%) (
P
< 0.01). A higher proportion of mutations was identified within the rifampin resistance-determining region (RRDR) of
rpoB
in isolates from 2015 (99.0%) than in 2005 isolates (85.7%,
P
< 0.01). In addition, a significantly higher proportion of RIF-resistant isolates carrying compensatory mutations was observed in 2015 (31.6%) than in 2005 (7.8%). Notably, the great majority of these compensatory mutations (91.9%) were observed in isolates that harbored a mutation of codon 531 of the
rpoB
gene. In conclusion, our data demonstrate that resistance to RIF, isoniazid, and levofloxacin has become significantly more prevalent during the past decade. In addition, the prevalence of the Beijing genotype significantly increased from 2005 to 2015. Notably, a significantly increased frequency of strains with mutations in
rpoC
or
rpoA
is observed among those that have codon 531 mutations, which suggests that they may be compensatory and may play a role in facilitating transmission.
Evaluation of a System-Specific Function To Describe the Pharmacokinetics of Benzylpenicillin in Term Neonates Undergoing Moderate Hypothermia
Authors: Bijleveld Yuma A. , de Haan Timo R. , van der Lee Johanna H. , Groenendaal Floris , Dijk Peter H. , van Heijst Arno , de Jonge Rogier C. J. , Dijkman Koen P. , van Straaten Henrica L. M. , Rijken Monique , Zonnenberg Inge A. , Cools Filip , Zecic Alexandra , Nuytemans Debbie H. G. M. , van Kaam Anton H. , Mathôt Ron A. A. ,   PharmaCool study group, Brouwer Mieke J. , van den Broek Marcel P. , Rademaker Carin M. A. , Liem Djien , Steiner Katerina , Simons Sinno H. P. , Bos Annelies A. , Mulder-de Tollenaer S. M. , Jebbink-Akkerman L. J. M. Groot , Sonnaert Michel , Camfferman Fleur Anne
Published: January 2018

The pharmacokinetic (PK) properties of intravenous (i.v.) benzylpenicillin in term neonates undergoing moderate hypothermia after perinatal asphyxia were evaluated, as they have been unknown until now. A system-specific modeling approach was applied, in which our recently developed covariate model describing developmental and temperature-induced changes in amoxicillin clearance (CL) in the same patient study population was incorporated into a population PK model of benzylpenicillin with
a priori
birthweight (BW)-based allometric scaling. Pediatric population covariate models describing the developmental changes in drug elimination may constitute system-specific information and may therefore be incorporated into PK models of drugs cleared through the same pathway. The performance of this system-specific model was compared to that of a reference model. Furthermore, Monte-Carlo simulations were performed to evaluate the optimal dose. The system-specific model performed as well as the reference model. Significant correlations were found between CL and postnatal age (PNA), gestational age (GA), body temperature (TEMP), urine output (UO; system-specific model), and multiorgan failure (reference model). For a typical patient with a GA of 40 weeks, BW of 3,000 g, PNA of 2 days (TEMP, 33.5°C), and normal UO (2 ml/kg/h), benzylpenicillin CL was 0.48 liter/h (interindividual variability [IIV] of 49%) and the volume of distribution of the central compartment was 0.62 liter/kg (IIV of 53%) in the system-specific model. Based on simulations, we advise a benzylpenicillin i.v. dose regimen of 75,000 IU/kg/day every 8 h (q8h), 150,000 IU/kg/day q8h, and 200,000 IU/kg/day q6h for patients with GAs of 36 to 37 weeks, 38 to 41 weeks, and ≥42 weeks, respectively. The system-specific model may be used for other drugs cleared through the same pathway accelerating model development.
Pharmacokinetics of Tedizolid in an Obese Patient after Bariatric Surgery
Authors: Grégoire Matthieu , Libois Julia Brochard , Waast Denis , Gaborit Benjamin , Dauty Marc , Deslandes Guillaume , Dailly Eric , Touchais Sophie , Boutoille David , Grégoire Nicolas , Couet William
Published: January 2018

An obese woman was treated with oral tedizolid 200 mg once daily for pseudoarthrosis 10 years after Roux-en-Y bypass surgery. Total plasma peak concentration was 2.12 mg/liter 3 h after intake, and area under the concentration-time curve from 0 to 24 h (AUC
0–24
) was 28.3 mg/liter · h. The AUC
0–24
/MIC ratio for unbound concentrations and for sensitive
Staphylococcus
and
Streptococcus
strains was ≥10.8, higher than the target ratio of 3. These results support the use of tedizolid without adjustment after bariatric surgery.
Enhanced Ex Vivo Plasmodium vivax Intraerythrocytic Enrichment and Maturation for Rapid and Sensitive Parasite Growth Assays
Authors: Rangel Gabriel W. , Clark Martha A. , Kanjee Usheer , Lim Caeul , Shaw-Saliba Kathryn , Menezes Maria José , Mascarenhas Anjali , Chery Laura , Gomes Edwin , Rathod Pradipsinh K. , Ferreira Marcelo U. , Duraisingh Manoj T.
Published: January 2018

Plasmodium vivax
chloroquine resistance has been documented in nearly every region where this malaria-causing parasite is endemic. Unfortunately,
P. vivax
resistance surveillance and drug discovery are challenging due to the low parasitemias of patient isolates and poor parasite survival through
ex vivo
maturation that reduce the sensitivity and scalability of current
P. vivax
antimalarial assays. Using cryopreserved patient isolates from Brazil and fresh patient isolates from India, we established a robust enrichment method for
P. vivax
parasites. We next performed a medium screen for formulations that enhance
ex vivo
survival. Finally, we optimized an isotopic metabolic labeling assay for measuring
P. vivax
maturation and its sensitivity to antimalarials. A KCl Percoll density gradient enrichment method increased parasitemias from small-volume
ex vivo
isolates by an average of >40-fold. The use of Iscove's modified Dulbecco's medium for
P. vivax ex vivo
culture approximately doubled the parasite survival through maturation. Coupling these with [
3
H]hypoxanthine metabolic labeling permitted sensitive and robust measurements of parasite maturation, which was used to measure the sensitivities of Brazilian
P. vivax
isolates to chloroquine and several novel antimalarials. These techniques can be applied to rapidly and robustly assess the
P. vivax
isolate sensitivities to antimalarials for resistance surveillance and drug discovery.
Methanogens Are Major Contributors to Nitrogen Fixation in Soils of the Florida Everglades
Authors: Bae Hee-Sung , Morrison Elise , Chanton Jeffrey P. , Ogram Andrew
Published: January 2018

The objective of this study was to investigate the interaction of the nitrogen (N) cycle with methane production in the Florida Everglades, a large freshwater wetland. This study provides an initial analysis of the distribution and expression of N-cycling genes in Water Conservation Area 2A (WCA-2A), a section of the marsh that underwent phosphorus (P) loading for many years due to runoff from upstream agricultural activities. The elevated P resulted in increased primary productivity and an N limitation in P-enriched areas. Results from quantitative real-time PCR (qPCR) analyses indicated that the N cycle in WCA-2A was dominated by
nifH
and
nirK
/
S
, with an increasing trend in copy numbers in P-impacted sites. Many
nifH
sequences (6 to 44% of the total) and
nifH
transcript sequences (2 to 49%) clustered with the methanogenic
Euryarchaeota
, in stark contrast to the proportion of core gene sequences representing
Archaea
(≤0.27% of SSU rRNA genes) for the WCA-2A microbiota. Notably, archaeal
nifH
gene transcripts were detected at all sites and comprised a significant proportion of total
nifH
transcripts obtained from the unimpacted site, indicating that methanogens are actively fixing N
2
. Laboratory incubations with soils taken from WCA-2A produced
nifH
transcripts with the production of methane from H
2
plus CO
2
and acetate as electron donors and carbon sources. Methanogenic N
2
fixation is likely to be an important, although largely unrecognized, route through which fixed nitrogen enters the anoxic soils of the Everglades and may have significant relevance regarding methane production in wetlands.

IMPORTANCE
Wetlands are the most important natural sources of the greenhouse gas methane, and much of that methane emanates from (sub)tropical peatlands. Primary productivity in these peatlands is frequently limited by the availability of nitrogen or phosphorus; however, the response to nutrient limitations of microbial communities that control biogeochemical cycling critical to ecosystem function may be complex and may be associated with a range of processes, including methane production. We show that many, if not most, of the methanogens in the peatlands of the Florida Everglades possess the
nifH
gene and actively express it for N
2
fixation coupled with methanogenesis. These findings indicate that archaeal N
2
fixation would play crucial role in methane emissions and overall N cycle in subtropical wetlands suffering N limitation.
Novel Cell Wall Hydrolase CwlC from Bacillus thuringiensis Is Essential for Mother Cell Lysis
Authors: Chen Xiaomin , Gao Tantan , Peng Qi , Zhang Jie , Chai Yunrong , Song Fuping
Published: January 2018

In this study, a sporulation-specific gene (tentatively named
cwlC
) involved in mother cell lysis in
Bacillus thuringiensis
was characterized. The encoded CwlC protein consists of an N-terminal
N
-acetylmuramoyl-
l
-alanine amidase (Mur
N
Ac-LAA) domain and a C-terminal amidase02 domain. The recombinant histidine-tagged CwlC proteins purified from
Escherichia coli
were able to directly bind to and digest the
B. thuringiensis
cell wall. The CwlC point mutations at the two conserved glutamic acid residues (Glu-24 and Glu-140) shown to be critical for the catalytic activity in homologous amidases resulted in a complete loss of cell wall lytic activity, suggesting that CwlC is an
N
-acetylmuramoyl-
l
-alanine amidase. Results of transcriptional analyses indicated that
cwlC
is transcribed as a monocistronic unit and that its expression is dependent on sporulation sigma factor K (σ
K
). Deletion of
cwlC
completely blocked mother cell lysis during sporulation without impacting the sporulation frequency, Cry1Ac protein production, and insecticidal activity. Taken together, our data suggest that CwlC is an essential cell wall hydrolase for
B. thuringiensis
mother cell lysis during sporulation. Engineered
B. thuringiensis
strains targeting
cwlC
, which allows the crystal inclusion to remain encapsulated in the mother cell at the end of sporulation, may have the potential to become more effective biological control agents in agricultural applications since the crystal inclusion remains encapsulated in the mother cell at the end of sporulation.

IMPORTANCE
Mother cell lysis has been well studied in
Bacillus subtilis
, which involves three distinct yet functionally complementary cell wall hydrolases. In this study, a novel cell wall hydrolase, CwlC, was investigated and found to be essential for mother cell lysis in
Bacillus thuringiensis
. CwlC of
B. thuringiensis
only shows 9 and 21% sequence identity with known
B. subtilis
mother cell hydrolases CwlB and CwlC, respectively, suggesting that mechanisms of mother cell lysis may differ between
B. subtilis
and
B. thuringiensis
. The
cwlC
gene deletion completely blocked the release of spores and crystals from the mother cell without affecting insecticidal activity. This may provide a new effective strategy for crystal encapsulation against UV light inactivation.