bluuebunny/crossref_metadata_2025 huggingface dataset:
2D radially compensating excitation pulse in combination with an internal transceiver antenna for 3D MRI of the rectum at 7 T
Authors: van Kalleveen I. M. L. , Kroeze H. , Sbrizzi A. , Boer V. O. , Reerink O. , Philippens M. E. P. , van de Berg C. A. T. , Luijten P. R. , Klomp D. W. J.
Published: June 2016

Purpose:

The high precession frequency in ultrahigh field MRI coincides with reduced RF penetration, increased RF power deposition and consequently can lead to reduced scan efficiency. However, the shorter wavelength enables the use of efficient antennas rather than loop coils. In fact, ultrathin monopole antennas have been demonstrated at 7 T, which fit in natural cavities like the rectum in the human body. As the RF field generated by the antenna provides an extremely nonuniform B1 field, the use of conventional RF pulses will lead to severe image distortions and highly nonuniform contrast. However, using the two predominant dimensions (orthogonal to the antenna), 2D RF pulses can be designed that counteract the nonuniform B1 into uniform flip angles. In this study the authors investigate the use of an ultrathin antenna not only for reception, but also for transmission in 7 T MRI of the rectum.

Methods:

The 2D radially compensating excitation (2D RACE) pulse was designed in matlab. SAR calculations between the 2D RACE pulse and an adiabatic RF pulse (BIR‐4) have been obtained, to visualize the gain in decreasing the SAR when using the 2D RACE pulse instead of an adiabatic RF pulse. The authors used the 7 T whole body MR system in combination with an internally placed monopole antenna used for transceiving and obtained 3D gradient echo images with a conventional sinc pulse and with the 2D RACE pulse. For extra clarity, they also reconstructed an image where the receive field of the antenna was removed.

Results:

Comparing the results of the SAR simulations of the 2D RACE pulse with a BIR‐4 pulse shows that for low flip angles (θ < 41°) the SAR can be decreased with a factor of 4.8 or even more, when using the 2D RACE pulse. Relative to a conventional sinc excitation, the 2D RACE pulse achieves more uniform flip angle distributions than a BIR‐4 pulse with a smaller SAR increase (16 × versus 64 ×).

Conclusions:

The authors have shown that the 2D RACE pulse provides more homogeneous flip angles for gradient echo sequences when compared to a conventional sinc pulse albeit at increased SAR. However, when compared to adiabatic RF pulses, as shown by simulations, the SAR of the 2D RACE pulse can be an order of magnitude less. Phantom and in vivo human rectum images are obtained to demonstrate that the 2D RACE pulse can provide a uniform excitation while transmitting with a single ultrathin endorectal antenna at 7 T. The combination of thin rectal antennas with efficient uniform transmit can open up new possibilities in high resolution imaging of rectal cancer.
Optical interference with digital holograms
Authors: Gossman David , Perez-Garcia Benjamin , Hernandez-Aranda Raul I. , Forbes Andrew
Published: June 2016

In 1804, Thomas Young reported the observation of fringes in the intensity of light, and attributed it to the concept of interference between coherent sources. In this paper, we revisit this famous experiment and show how it can easily be demonstrated with digital holography. We look closely at the concept of interference with light and ask, “fringes in what?” We then show that depending on how light interferes, fringe patterns in observables other than intensity can be seen. We explain this conceptually and demonstrate it experimentally. We provide a holistic approach to the topic, aided by modern laboratory practices for a straightforward demonstration of the underlying physics.
Resource Letter QI-1: Quantum Information
Authors: Strauch Frederick W.
Published: June 2016

This Resource Letter surveys the history and modern developments in the field of quantum information. It is written to guide advanced undergraduates, beginning graduate students, and other new researchers to the theoretical and experimental aspects of this field. The topics covered include quantum states and processes, quantum coding and cryptography, quantum computation, the experimental implementation of quantum information processing, and the role of quantum information in the fundamental properties and foundations of physical theories.
Young Children’s Energy Expenditure and Moderate-to-vigorous Physical Activity on Weekdays and Weekends
Authors: Lee Jung Eun , Stodden David F. , Gao Zan
Published: June 2016

Background:

Few studies have examined young children’s leisure- and school-based energy expenditure (EE) and moderateto-vigorous physical activity (MVPA). The purpose of this study was to explore children’s estimated EE rates and time spent in MVPA in 3 time segments: at-school, after-school, and weekends.

Methods:

A total of 187 second and third grade children from 2 elementary schools participated in the study. Accelerometers were used to assess children’s 5-day EE and MVPA. Multiple 2 (Grade) × 2 (Gender) ANOVAs with repeated measures (Time) were conducted to examine the differences in the outcome variables.

Results:

Significant time effects on EE and MVPA were revealed. Children’s EE rate and minutes in MVPA per day were higher during after school and weekends than at school.

Conclusions:

Although children were more active outside of school, their MVPA during weekdays and weekends still fell far short of the recommended level of 60 minutes/day.
Is There Potential for Repurposing Statins as Novel Antimicrobials?
Authors: Hennessy Emma , Adams Claire , Reen F. Jerry , O'Gara Fergal
Published: June 2016

Statins are members of a class of pharmaceutical widely used to reduce high levels of serum cholesterol. In addition, statins have so-called “pleiotropic effects,” which include inflammation reduction, immunomodulation, and antimicrobial effects. An increasing number of studies are emerging which detail the attenuation of bacterial growth and
in vitro
and
in vivo
virulence by statin treatment. In this review, we describe the current information available concerning the effects of statins on bacterial infections and provide insight regarding the potential use of these compounds as antimicrobial therapeutic agents.
Isavuconazole Is Effective for the Treatment of Experimental Cryptococcal Meningitis
Authors: Wiederhold Nathan P. , Kovanda Laura , Najvar Laura K. , Bocanegra Rosie , Olivo Marcos , Kirkpatrick William R. , Patterson Thomas F.
Published: June 2016

We evaluated the efficacy of isavuconazole against cryptococcal meningitis. Treatment with either oral isavuconazole (120 mg/kg and 240 mg/kg twice a day [BID]) or fluconazole as the positive control significantly improved survival in mice infected intracranially with either
Cryptococcus neoformans
USC1597 or H99 and significantly reduced brain fungal burdens for both isolates. Concentrations of isavuconazole in plasma and brain tissue also demonstrated that the greatest improvements in survival and fungal burden were associated with elevated exposures.
Isolation and Characterization of NDM-Positive Escherichia coli from Municipal Wastewater in Jeddah, Saudi Arabia
Authors: Mantilla-Calderon David , Jumat Muhammad Raihan , Wang Tiannyu , Ganesan Pugalenthi , Al-Jassim Nada , Hong Pei-Ying
Published: June 2016

The emergence of resistance to last-resort antibiotics is a public health concern of global scale. Besides direct person-to-person propagation, environmental pathways might contribute to the dissemination of antibiotic-resistant bacteria and antibiotic resistance genes (ARGs). Here, we describe the incidence of
bla
NDM-1
, a gene conferring resistance to carbapenems, in the wastewater of the city of Jeddah, Saudi Arabia, over a 1-year period.
bla
NDM-1
was detected at concentrations ranging from 10
4
to 10
5
copies/m
3
of untreated wastewater during the entire monitoring period. These results indicate the ubiquity and high incidence of
bla
NDM-1
in the local wastewater. To track the bacteria carrying
bla
NDM-1
, we isolated
Escherichia coli
PI7, a strain of sequence type 101 (ST101), from wastewater around the Hajj event in October 2013. Genome sequencing of this strain revealed an extensive repertoire of ARGs as well as virulence and invasive traits. These traits were further confirmed by antibiotic resistance profiling and
in vitro
cell internalization in HeLa cell cultures. Given that this strain remains viable even after a certain duration in the sewerage, and that Jeddah lacks a robust sanitary infrastructure to fully capture all generated sewage, the presence of this bacterium in the untreated wastewater represents a potential hazard to the local public health. To the best of our knowledge, this is the first report of a
bla
NDM-1
-positive
E. coli
strain isolated from a nonnosocomial environment in Saudi Arabia and may set a priority concern for the need to establish improved surveillance for carbapenem-resistant
E. coli
in the country and nearby regions.
In Vitro
and
In Vivo
Assessments of Cardiovascular Effects with Omadacycline
Authors: Tanaka S. Ken , Villano Stephen
Published: June 2016

Omadacycline is a first-in-class aminomethylcycline antibiotic with a broad spectrum of activity against Gram-positive and Gram-negative aerobes and anaerobes and atypical bacterial pathogens. A series of nonclinical studies, including mammalian pharmacologic receptor binding studies, human ether-a-go-go-related gene (hERG) channel binding studies, studies of the effects on
ex vivo
sinoatrial (SA) node activity, and studies of
in vivo
effects on cardiovascular function in the cynomolgus monkey, was undertaken to assess the cardiovascular risk potential. Omadacycline was found to bind almost exclusively to the muscarinic subtype 2 acetylcholine receptor (M
2
), and in the SA node model it antagonized the effect of a pan-muscarinic agonist (carbamylcholine) in a concentration-dependent manner. Omadacycline exhibited no effect on hERG channel activity at 100 μg/ml (179.5 μM), with a 25% inhibitory concentration of 166 μg/ml (298.0 μM). Omadacycline had no effect on QTc in conscious monkeys at doses up to 40 mg/kg of body weight. Overall, omadacycline appears to attenuate the parasympathetic influence on the heart rate but has a low potential to induce cardiac arrhythmia or to have clinically significant cardiovascular toxicity.
Predictors of Inadequate Linezolid Concentrations after Standard Dosing in Critically Ill Patients
Authors: Taubert Max , Zoller Michael , Maier Barbara , Frechen Sebastian , Scharf Christina , Holdt Lesca-Miriam , Frey Lorenz , Vogeser Michael , Fuhr Uwe , Zander Johannes
Published: June 2016

Adequate linezolid blood concentrations have been shown to be associated with an improved clinical outcome. Our goal was to assess new predictors of inadequate linezolid concentrations often observed in critically ill patients. Fifty-two critically ill patients with severe infections receiving standard dosing of linezolid participated in this prospective observational study. Serum samples (median, 32 per patient) were taken on four consecutive days, and total linezolid concentrations were quantified. Covariates influencing linezolid pharmacokinetics were identified by multivariate analysis and a population pharmacokinetic model. Target attainment (area under the concentration-time curve over 12 h [AUC
12
]/MIC ratio of >50; MIC = 2 mg/liter) was calculated for both the study patients and a simulated independent patient group (
n
= 67,000). Target attainment was observed for only 36% of the population on both days 1 and 4. Independent covariates related to significant decreases of linezolid concentrations included higher weight, creatinine clearance rates, and fibrinogen and antithrombin concentrations, lower concentrations of lactate, and the presence of acute respiratory distress syndrome (ARDS). Linezolid clearance was increased in ARDS patients (by 82%) and in patients with elevated fibrinogen or decreased lactate concentrations. In simulated patients, most covariates, including fibrinogen and lactate concentrations and weight, showed quantitatively minor effects on target attainment (difference of ≤9% between the first and fourth quartiles of the respective parameters). In contrast, the presence of ARDS had the strongest influence, with only ≤6% of simulated patients reaching this target. In conclusion, the presence of ARDS was identified as a new and strong predictor of insufficient linezolid concentrations, which might cause treatment failure. Insufficient concentrations might also be a major problem in patients with combined alterations of other covariate parameters. (This study has been registered at ClinicalTrials.gov under registration number NCT01793012.)
Wild-Type and Non-Wild-Type Mycobacterium tuberculosis MIC Distributions for the Novel Fluoroquinolone Antofloxacin Compared with Those for Ofloxacin, Levofloxacin, and Moxifloxacin
Authors: Yu Xia , Wang Guirong , Chen Suting , Wei Guomei , Shang Yuanyuan , Dong Lingling , Schön Thomas , Moradigaravand Danesh , Parkhill Julian , Peacock Sharon J. , Köser Claudio U. , Huang Hairong
Published: June 2016

Antofloxacin (AFX) is a novel fluoroquinolone that has been approved in China for the treatment of infections caused by a variety of bacterial species. We investigated whether it could be repurposed for the treatment of tuberculosis by studying its
in vitro
activity. We determined the wild-type and non-wild-type MIC ranges for AFX as well as ofloxacin (OFX), levofloxacin (LFX), and moxifloxacin (MFX), using the microplate alamarBlue assay, of 126 clinical
Mycobacterium tuberculosis
strains from Beijing, China, of which 48 were OFX resistant on the basis of drug susceptibility testing on Löwenstein-Jensen medium. The MIC distributions were correlated with mutations in the quinolone resistance-determining regions of
gyrA
(
Rv0006
) and
gyrB
(
Rv0005
). Pharmacokinetic/pharmacodynamic (PK/PD) data for AFX were retrieved from the literature. AFX showed lower MIC levels than OFX but higher MIC levels than LFX and MFX on the basis of the tentative epidemiological cutoff values (ECOFFs) determined in this study. All strains with non-wild-type MICs for AFX harbored known resistance mutations that also resulted in non-wild-type MICs for LFX and MFX. Moreover, our data suggested that the current critical concentration of OFX for Löwenstein-Jensen medium that was recently revised by the World Health Organization might be too high, resulting in the misclassification of phenotypically non-wild-type strains with known resistance mutations as wild type. On the basis of our exploratory PK/PD calculations, the current dose of AFX is unlikely to be optimal for the treatment of tuberculosis, but higher doses could be effective.
p53 Mediates Colistin-Induced Autophagy and Apoptosis in PC-12 Cells
Authors: Zhang Ling , Xie Daoyuan , Chen Xueping , Hughes Maria L. R. , Jiang Guozheng , Lu Ziyin , Xia Chunli , Li Li , Wang Jinli , Xu Wei , Sun Yuan , Li Rui , Wang Rui , Qian Feng , Li Jian , Li Jichang
Published: June 2016

The mechanism of colistin-induced neurotoxicity is still unknown. Our recent study (L. Zhang, Y. H. Zhao, W. J. Ding, G. Z. Jiang, Z. Y. Lu, L. Li, J. L. Wang, J. Li, and J. C. Li, Antimicrob Agents Chemother 59:2189–2197, 2015,
http://dx.doi.org/10.1128/AAC.04092-14
; H. Jiang, J. C. Li, T. Zhou, C. H. Wang, H. Zhang, and H. Wang, Int J Mol Med 33:1298–1304, 2014,
http://dx.doi.org/10.3892/ijmm.2014.1684
) indicates that colistin induces autophagy and apoptosis in rat adrenal medulla PC-12 cells, and there is interplay between both cellular events. As an important cellular stress sensor, phosphoprotein p53 can trigger cell cycle arrest and apoptosis and regulate autophagy. The aim of the present study was to investigate the involvement of the p53 pathway in colistin-induced neurotoxicity in PC-12 cells. Specifically, cells were treated with colistin (125 μg/ml) in the absence and presence of a p53 inhibitor, pifithrin-α (PFT-α; 20 nM), for 12 h and 24 h, and the typical hallmarks of autophagy and apoptosis were examined by fluorescence/immunofluorescence microscopy and electron microscopy, real-time PCR, and Western blotting. The results indicate that colistin had a stimulatory effect on the expression levels of the target genes and proteins involved in autophagy and apoptosis, including LC3-II/I, p53, DRAM (damage-regulated autophagy modulator), PUMA (p53 upregulated modulator of apoptosis), Bax, p-AMPK (activated form of AMP-activated protein kinase), and caspase-3. In contrast, colistin appeared to have an inhibitory effect on the expression of p-mTOR (activated form of mammalian target of rapamycin), which is another target protein in autophagy. Importantly, analysis of the levels of p53 in the cells treated with colistin revealed an increase in nuclear p53 at 12 h and cytoplasmic p53 at 24 h. Pretreatment of colistin-treated cells with PFT-α inhibited autophagy and promoted colistin-induced apoptosis. This is the first study to demonstrate that colistin-induced autophagy and apoptosis are associated with the p53-mediated pathway.
Discovery of Antischistosomal Drug Leads Based on Tetraazamacrocyclic Derivatives and Their Metal Complexes
Authors: Khan M. O. Faruk , Keiser Jennifer , Amoyaw P. N. A. , Hossain Mohammad F. , Vargas Mireille , Le Justin G. , Simpson Natalie C. , Roewe Kimberly D. , Freeman TaRynn N. Carder , Hasley Travis R. , Maples Randall D. , Archibald Stephen J. , Hubin Timothy J.
Published: June 2016

Praziquantel (PZQ) is the only drug available for the treatment of schistosomiasis, and since its large-scale use might be associated with the onset of resistance, new antischistosomal drugs should be developed. A series of 26 synthetic tetraazamacrocyclic derivatives and their metal complexes were synthesized, characterized, and screened for antischistosomal activity by application of a phased screening program. The compounds were first screened against newly transformed schistosomula (NTS) of harvested
Schistosoma mansoni
cercariae, then against adult worms, and finally,
in vivo
using the mouse model of
S. mansoni
infection. At a concentration of 33 μM, incubation with a total of 12 compounds resulted in the mortality of NTS at the 62% to 100% level. Five of these showing 100% inhibition of viability of NTS at 10 μM were selected for further screening for determination of the 50 inhibitory concentrations (IC
50
s) against both NTS and adult worms. Against NTS, all 5 compounds showed IC
50
s comparable to the IC
50
of the standard drug, PZQ (0.87 to 9.65 μM for the 5 compounds versus 2.20 μM for PZQ). Three of these, which are the bisquinoline derivative of cyclen and its Fe
2+
and Mn
2+
complexes, showed micromolar IC
50
s (1.62 μM, 1.34 μM, and 4.12 μM, respectively, versus 0.10 μM for PZQ) against adult worms.
In vivo
, the worm burden reductions were 12.3%, 88.4%, and 74.5%, respectively, at a single oral dose of 400 mg/kg of body weight. The Fe
2+
complex exhibited activity
in vivo
comparable to that of PZQ, pointing to the discovery of a novel drug lead for schistosomiasis.
Efficacy of a Novel Tricyclic Topoisomerase Inhibitor in a Murine Model of Neisseria gonorrhoeae Infection
Authors: Savage Victoria J. , Charrier Cédric , Salisbury Anne-Marie , Box Helen , Chaffer-Malam Nathan , Huxley Anthony , Kirk Ralph , Noonan Gary M. , Mohmed Sarfraz , Craighead Mark W. , Ratcliffe Andrew J. , Best Stuart A. , Stokes Neil R.
Published: June 2016

There is an urgent need for new antibiotics to treat multidrug-resistant
Neisseria gonorrhoeae
. In this report, the microbiology,
in vivo
pharmacokinetics, and efficacy of REDX05931, a representative novel tricyclic topoisomerase inhibitor, were evaluated. REDX05931 demonstrated high oral bioavailability in mice and reduced
N. gonorrhoeae
infection after a single dose in a mouse model of gonorrhea. These data support the potential of this series of small molecules as a new treatment for drug-resistant gonorrheal infections.
Transcriptional Profiling of Mycobacterium tuberculosis Exposed toIn VitroLysosomal Stress
Authors: Lin Wenwei , de Sessions Paola Florez , Teoh Garrett Hor Keong , Mohamed Ahmad Naim Nazri , Zhu Yuan O. , Koh Vanessa Hui Qi , Ang Michelle Lay Teng , Dedon Peter C. , Hibberd Martin Lloyd , Alonso Sylvie
Published: June 2016

Increasing experimental evidence supports the idea thatMycobacterium tuberculosishas evolved strategies to survive within lysosomes of activated macrophages. To further our knowledge ofM. tuberculosisresponse to the hostile lysosomal environment, we profiled the global transcriptional activity ofM. tuberculosiswhen exposed to the lysosomal soluble fraction (SF) prepared from activated macrophages. Transcriptome sequencing (RNA-seq) analysis was performed using various incubation conditions, ranging from noninhibitory to cidal based on the mycobacterial replication or killing profile. Under inhibitory conditions that led to the absence of apparent mycobacterial replication,M. tuberculosisexpressed a unique transcriptome with modulation of genes involved in general stress response, metabolic reprogramming, respiration, oxidative stress, dormancy response, and virulence. The transcription pattern also indicates characteristic cell wall remodeling with the possible outcomes of increased infectivity, intrinsic resistance to antibiotics, and subversion of the host immune system. Among the lysosome-specific responses, we identified theglgE-mediated 1,4 α-glucan synthesis pathway and a defined group of VapBC toxin/anti-toxin systems, both of which represent toxicity mechanisms that potentially can be exploited for killing intracellular mycobacteria. A meta-analysis including previously reported transcriptomic studies in macrophage infection andin vitrostress models was conducted to identify overlapping and nonoverlapping pathways. Finally, the Tap efflux pump-encoding geneRv1258cwas selected for validation. AnM. tuberculosis ΔRv1258cmutant was constructed and displayed increased susceptibility to killing by lysosomal SF and the antimicrobial peptide LL-37, as well as attenuated survival in primary murine macrophages and human macrophage cell line THP-1.
The Type Three Secretion System 2-Encoded Regulator EtrB Modulates Enterohemorrhagic Escherichia coli Virulence Gene Expression
Authors: Luzader Deborah H. , Willsey Graham G. , Wargo Matthew J. , Kendall Melissa M.
Published: June 2016

Enterohemorrhagic
Escherichia coli
O157:H7 (EHEC) is a foodborne pathogen that causes bloody diarrhea and hemolytic uremic syndrome throughout the world. A defining feature of EHEC pathogenesis is the formation of attaching and effacing (AE) lesions on colonic epithelial cells. Most of the genes that code for AE lesion formation, including a type three secretion system (T3SS) and effectors, are carried within a chromosomal pathogenicity island called the locus of enterocyte effacement (LEE). In this study, we report that a putative regulator, which is encoded in the cryptic
E. coli
type three secretion system 2 (ETT2) locus and herein renamed EtrB, plays an important role in EHEC pathogenesis. The
etrB
gene is expressed as a monocistronic transcript, and EtrB autoregulates expression. We provide evidence that EtrB directly interacts with the
ler
regulatory region to activate LEE expression and promote AE lesion formation. Additionally, we mapped the EtrB regulatory circuit in EHEC to determine a global role for EtrB. EtrB is regulated by the transcription factor QseA, suggesting that these proteins comprise a regulatory circuit important for EHEC colonization of the gastrointestinal tract.
AlgU Controls Expression of Virulence Genes in Pseudomonas syringae pv. tomato DC3000
Authors: Markel Eric , Stodghill Paul , Bao Zhongmeng , Myers Christopher R. , Swingle Bryan
Published: June 2016

Plant-pathogenic bacteria are able to integrate information about their environment and adjust gene expression to provide adaptive functions. AlgU, an extracytoplasmic function (ECF) sigma factor encoded byPseudomonas syringae, controls expression of genes for alginate biosynthesis and genes involved with resisting osmotic and oxidative stress. AlgU is active while these bacteria are associated with plants, where its presence supports bacterial growth and disease symptoms. We found that AlgU is an important virulence factor forP. syringaepv. tomato DC3000 but that alginate production is dispensable for disease in host plants. This implies that AlgU regulates additional genes that facilitate bacterial pathogenesis. We used transcriptome sequencing (RNA-seq) to characterize the AlgU regulon and chromatin immunoprecipitation sequencing (ChIP-seq) to identify AlgU-regulated promoters associated with genes directly controlled by this sigma factor. We found that in addition to genes involved with alginate and osmotic and oxidative stress responses, AlgU regulates genes with known virulence functions, including components of the Hrp type III secretion system, virulence effectors, and thehrpLandhrpRStranscription regulators. These data suggest thatP. syringaepv. tomato DC3000 has adapted to use signals that activate AlgU to induce expression of important virulence functions that facilitate survival and disease in plants.

IMPORTANCEPlant immune systems produce antimicrobial and bacteriostatic conditions in response to bacterial infection. Plant-pathogenic bacteria are adapted to suppress and/or tolerate these conditions; however, the mechanisms controlling these bacterial systems are largely uncharacterized. The work presented here provides a mechanistic explanation for howP. syringaepv. tomato DC3000 coordinates expression of multiple genetic systems, including those dedicated to pathogenicity, in response to environmental conditions. This work demonstrates the scope of AlgU regulation inP. syringaepv. tomato DC3000 and characterizes the promoter sequence regulated by AlgU in these bacteria.
The Na
+
-Translocating NADH:Quinone Oxidoreductase Enhances Oxidative Stress in the Cytoplasm of Vibrio cholerae
Authors: Muras Valentin , Dogaru-Kinn Paul , Minato Yusuke , Häse Claudia C. , Steuber Julia
Published: June 2016

We searched for a source of reactive oxygen species (ROS) in the cytoplasm of the human pathogen
Vibrio cholerae
and addressed the mechanism of ROS formation using the dye 2′,7′-dichlorofluorescein diacetate (DCFH-DA) in respiring cells. By comparing
V. cholerae
strains with or without active Na
+
-translocating NADH:quinone oxidoreductase (Na
+
-NQR), this respiratory sodium ion redox pump was identified as a producer of ROS
in vivo
. The amount of cytoplasmic ROS detected in
V. cholerae
cells producing variants of Na
+
-NQR correlated well with rates of superoxide formation by the corresponding membrane fractions. Membranes from wild-type
V. cholerae
showed increased superoxide production activity (9.8 ± 0.6 μmol superoxide min
−1
mg
−1
membrane protein) compared to membranes from the mutant lacking Na
+
-NQR (0.18 ± 0.01 μmol min
−1
mg
−1
). Overexpression of plasmid-encoded Na
+
-NQR in the
nqr
deletion strain resulted in a drastic increase in the formation of superoxide (42.6 ± 2.8 μmol min
−1
mg
−1
). By analyzing a variant of Na
+
-NQR devoid of quinone reduction activity, we identified the reduced flavin adenine dinucleotide (FAD) cofactor of cytoplasmic NqrF subunit as the site for intracellular superoxide formation in
V. cholerae
. The impact of superoxide formation by the Na
+
-NQR on the virulence of
V. cholerae
is discussed.

IMPORTANCE
In several studies, it was demonstrated that the Na
+
-NQR in
V. cholerae
affects virulence in a yet unknown manner. We identified the reduced FAD cofactor in the NADH-oxidizing NqrF subunit of the Na
+
-NQR as the site of superoxide formation in the cytoplasm of
V. cholerae
. Our study provides the framework to understand how reactive oxygen species formed during respiration could participate in the regulated expression of virulence factors during the transition from aerobic to microaerophilic (intestinal) habitats. This hypothesis may turn out to be right for many other pathogens which, like
V. cholerae
, depend on the Na
+
-NQR as the sole electrogenic NADH dehydrogenase.
Prevalence of chronic pain in the UK: a systematic review and meta-analysis of population studies
Authors: Fayaz A , Croft P , Langford R M , Donaldson L J , Jones G T
Published: June 2016

Objectives

There is little consensus regarding the burden of pain in the UK. The purpose of this review was to synthesise existing data on the prevalence of various chronic pain phenotypes in order to produce accurate and contemporary national estimates.

Design

Major electronic databases were searched for articles published after 1990, reporting population-based prevalence estimates of chronic pain (pain lasting >3 months), chronic widespread pain, fibromyalgia and chronic neuropathic pain. Pooled prevalence estimates were calculated for chronic pain and chronic widespread pain.

Results

Of the 1737 articles generated through our searches, 19 studies matched our inclusion criteria, presenting data from 139 933 adult residents of the UK. The prevalence of chronic pain, derived from 7 studies, ranged from 35.0% to 51.3% (pooled estimate 43.5%, 95% CIs 38.4% to 48.6%). The prevalence of moderate-severely disabling chronic pain (Von Korff grades III/IV), based on 4 studies, ranged from 10.4% to 14.3%. 12 studies stratified chronic pain prevalence by age group, demonstrating a trend towards increasing prevalence with increasing age from 14.3% in 18–25 years old, to 62% in the over 75 age group, although the prevalence of chronic pain in young people (18–39 years old) may be as high as 30%. Reported prevalence estimates were summarised for chronic widespread pain (pooled estimate 14.2%, 95% CI 12.3% to 16.1%; 5 studies), chronic neuropathic pain (8.2% to 8.9%; 2 studies) and fibromyalgia (5.4%; 1 study). Chronic pain was more common in female than male participants, across all measured phenotypes.

Conclusions

Chronic pain affects between one-third and one-half of the population of the UK, corresponding to just under 28 million adults, based on data from the best available published studies. This figure is likely to increase further in line with an ageing population.
Direct inpatient burden caused by foot-related conditions: a multisite point-prevalence study
Authors: Lazzarini Peter A , Hurn Sheree E , Kuys Suzanne S , Kamp Maarten C , Ng Vanessa , Thomas Courtney , Jen Scott , Kinnear Ewan M , d'Emden Michael C , Reed Lloyd
Published: June 2016

Objective

The aims of this point-prevalence study were to investigate a representative inpatient population to determine the prevalence of people admitted to hospital for the reason of a foot-related condition, and identify associated independent factors.

Methods

Participants were adult inpatients in 5 different representative hospitals, admitted for any reason on the day of data collection. Maternity, mental health and cognitively impaired inpatients were excluded. Participants were surveyed on a range of self-reported demographic, social determinant, medical history, foot disease history, self-care, footwear, past foot treatment prior to hospitalisation and reason for admission variables. Physical examinations were performed to clinically diagnose a range of foot disease and foot risk factor variables. Independent factors associated with being admitted to hospital for the primary or secondary reason of a foot-related condition were analysed using multivariate logistic regression.

Results

Overall, 733 participants were included; mean (SD) age 62 (19) years, male 55.8%. Foot-related conditions were the primary reason for admission in 54 participants (7.4% (95% CI 5.7% to 9.5%)); 36 for foot disease (4.9%), 15 foot trauma (2.1%). Being admitted for the primary reason of a foot-related condition was independently associated with foot infection, critical peripheral arterial disease, foot trauma and past foot treatment by a general practitioner and surgeon (p<0.01). Foot-related conditions were a secondary reason for admission in 28 participants (3.8% (2.6% to 5.6%)), and were independently associated with diabetes and current foot ulcer (p<0.01).

Conclusions

This study, the first in a representative inpatient population, suggests the direct inpatient burden caused by foot-related conditions is significantly higher than previously appreciated. Findings indicate 1 in every 13 inpatients was primarily admitted because of a foot-related condition with most due to foot disease or foot trauma. Future strategies are recommended to investigate and intervene in the considerable inpatient burden caused by foot-related conditions.
Disclosing victimisation to healthcare professionals in Sweden: a constructivist grounded theory study of experiences among men exposed to interpersonal violence
Authors: Simmons Johanna , Brüggemann Adrianus Jelmer , Swahnberg Katarina
Published: June 2016

Objective

To develop a theoretical model concerning male victims' processes of disclosing experiences of victimisation to healthcare professionals in Sweden.

Design

Qualitative interview study.

Setting

Informants were recruited from the general population and a primary healthcare centre in Sweden.

Participants

Informants were recruited by means of theoretical sampling among respondents in a previous quantitative study. Eligible for this study were men reporting sexual, physical and/or emotional violence victimisation by any perpetrator and reporting that they either had talked to a healthcare provider about their victimisation or had wanted to do so.

Method

Constructivist grounded theory. 12 interviews were performed and saturation was reached after 9.

Results

Several factors influencing the process of disclosing victimisation can be recognised from previous studies concerning female victims, including shame, fear of negative consequences of disclosing, specifics of the patient–provider relationship and time constraints within the healthcare system. However, this study extends previous knowledge by identifying strong negative effects of adherence to masculinity norms for victimised men and healthcare professionals on the process of disclosing. It is also emphasised that the process of disclosing cannot be separated from other, even seemingly unrelated, circumstances in the men's lives.

Conclusions

The process of disclosing victimisation to healthcare professionals was a complex process involving the men's experiences of victimisation, adherence to gender norms, their life circumstances and the dynamics of the actual healthcare encounter.
Cross-sectional study of coeliac autoimmunity in a population of Vietnamese children
Authors: Zanella Sara , De Leo Luigina , Nguyen-Ngoc-Quynh Le , Nguyen-Duy Bo , Not Tarcisio , Tran-Thi-Chi Mai , Phung-Duc Son , Le-Thanh Hai , Malaventura Cristina , Vatta Serena , Ziberna Fabiana , Mazzocco Martina , Volpato Stefano , Phung-Tuyet Lan , Le-Thi-Minh Huong , Borgna-Pignatti Caterina
Published: June 2016

Objective

The prevalence of coeliac disease (CD) in Vietnam is unknown. To fill this void, we assessed the prevalence of serological markers of CD autoimmunity in a population of children in Hanoi.

Setting

The outpatient blood drawing laboratory of the largest paediatric hospital in North Vietnam was used for the study, which was part of an international project of collaboration between Italy and Vietnam.

Participants

Children having blood drawn for any reason were included. Exclusion criteria were age younger than 2 years, acquired or congenital immune deficiency and inadequate sample. A total of 1961 children (96%) were enrolled (838 females, 1123 males, median age 5.3 years).

Outcomes

Primary outcome was the prevalence of positive autoimmunity to both IgA antitransglutaminase antibodies (anti-tTG) assessed with an ELISA test and antiendomysial antibodies (EMA). Secondary outcome was the prevalence of CD predisposing human leucocyte antigens (HLA) (HLA DQ2/8) in the positive children and in a random group of samples negative for IgA anti-tTG.

Results

The IgA anti-tTG test was positive in 21/1961 (1%; 95% CI 0.61% to 1.53%); however, EMA antibodies were negative in all. HLA DQ2/8 was present in 7/21 (33%; 95% CI 14.5% to 56.9%) of the anti-tTG-positive children and in 72/275 (26%; 95% CI 21% to 32%) of those who were negative.

Conclusions

Coeliac autoimmunity is rare in Vietnam, although prevalence of HLA DQ2/8 is similar to that of other countries. We hypothesise that the scarce exposure to gluten could be responsible for these findings.
β-Adrenoreceptor agonists in the management of pain associated with renal colic: a systematic review
Authors: Tabner Andrew John , Johnson Graham David , Fakis Apostolos , Surtees Jane , Lennon Robert Iain
Published: June 2016

Objectives

To determine whether β-adrenoreceptor agonists are effective analgesics for patients with renal colic through a systematic review of the literature.

Setting

Adult emergency departments or acute assessment units.

Participants

Human participants with proven or suspected renal colic.

Interventions

β-adrenoreceptor agonists.

Outcome measures

Primary: level of pain at 30 min following administration of the β-agonist.Secondary: level of pain at various time points following β-agonist administration; length of hospital stay; analgesic requirement; stone presence, size and position; degree of hydronephrosis.

Results

256 records were screened and 4 identified for full-text review. No articles met the inclusion criteria.

Conclusions and implications

There is no evidence to support or refute the proposed use of β-agonists for analgesia in patients with renal colic. Given the biological plausibility and existing literature base, clinical trials investigating the use of β-adrenoreceptor agonists in the acute setting for treatment of the pain associated with renal colic are recommended.

Trial registration number

CRD42015016266.
Consultants as victims of bullying and undermining: a survey of Royal College of Obstetricians and Gynaecologists consultant experiences
Authors: Shabazz Tariq , Parry-Smith William , Oates Sharon , Henderson Steven , Mountfield Joanna
Published: June 2016

Objective

To explore incidents of bullying and undermining among obstetrics and gynaecology (O&G) consultants in the UK, to add another dimension to previous research and assist in providing a more holistic understanding of the problem in medicine.

Design

Questionnaire survey.

Setting

Royal College of Obstetricians and Gynaecologists (RCOG).

Participants

O&G consultant members/fellows of the RCOG working in the UK.

Main outcome measures

Measures included a typology of 4 bullying and undermining consequences from major to coping.

Results

There was a 28% (664) response rate of whom 44% (229) responded that they had been persistently bullied or undermined. Victims responded that bullying and undermining is carried out by those senior or at least close in the hierarchy. Of the 278 consultants who answered the question on ‘frequency of occurrence’, 50% stated that bullying and undermining occurs on half, or more, of all encounters with perpetrators and two-thirds reported that it had lasted more than 3 years. The reported impact on professional and personal life spans a wide spectrum from suicidal ideation, depression and sleep disturbance, and a loss of confidence. Over half reported problems that could compromise patient care. When victims were asked if the problem was being addressed, 73% of those that responded stated that it was not.

Conclusions

Significant numbers of consultants in O&G in the UK are victims of bullying and undermining behaviour that puts their own health and patient care at risk. New interventions to tackle the problem, rather than its consequences, are required urgently, together with greater commitment to supporting such interventions.
Protocol for an open-label, single-arm trial of HIV pre-exposure prophylaxis (PrEP) among people at high risk of HIV infection: the NSW Demonstration ProjectPRELUDE
Authors: Vaccher S , Grulich A , McAllister J , Templeton D J , Bloch M , McNulty A , Holden J , Poynten I M , Prestage G , Zablotska I
Published: June 2016

Introduction

Despite a number of HIV prevention strategies, the number of new HIV infections remains high. In Australia, over three-quarters of new HIV diagnoses are in gay and bisexual men (GBM). Pre-exposure prophylaxis (PrEP) has been shown to be effective at preventing new HIV infections in several randomised trials. ThePRELUDEstudy aims to evaluate the implementation of PrEP in healthcare settings in New South Wales (NSW), Australia, among a sample of high-risk adults.

Methods and analysis

PRELUDEis an ongoing open-label, single-arm demonstration project, conducted in public and private clinics across NSW, Australia. Enrolment began in November 2014. The study is designed for 300 high-risk participants—mainly GBM and heterosexual women. Participants receive daily oral PrEP, composed of emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF), for up to 2.5 years. Quarterly study visits include testing for HIV and sexually transmitted infections (STIs), assessment of ongoing eligibility and side effects, and self-reported adherence. Following each study visit, online behavioural surveys are administered to collect information on medication adherence, risk behaviours and attitudes. Blood samples will be collected in a subset of patients 1, 6 and 12 months after PrEP initiation to measure FTC/TDF concentrations. Analyses using longitudinal regression models will focus on feasibility, adherence, safety, tolerability and effects of PrEP on behaviour. This study will inform PrEP policy and guide the implementation of PrEP in Australia in people at high risk of HIV.

Ethics and dissemination

The study will be conducted in accordance with the Declaration of Helsinki. All patients will provide written informed consent prior to participation in the study. Publications relating to each of the primary end points will be gradually released after 12 months of follow-up is complete.

Trial registration number

NCT02206555; Pre-results.
Prevalence and predictors of hospital prealerting in acute stroke: a mixed methods study
Authors: Sheppard J P , Lindenmeyer A , Mellor R M , Greenfield S , Mant J , Quinn T , Rosser A , Sandler D , Sims D , Ward M , McManus R J
Published: June 2016

Background

Thrombolysis can significantly reduce the burden of stroke but the time window for safe and effective treatment is short. In patients travelling to hospital via ambulance, the sending of a ‘prealert’ message can significantly improve the timeliness of treatment.

Objective

Examine the prevalence of hospital prealerting, the extent to which prealert protocols are followed and what factors influence emergency medical services (EMS) staff's decision to send a prealert.

Methods

Cohort study of patients admitted to two acute stroke units in West Midlands (UK) hospitals using linked data from hospital and EMS records. A logistic regression model examined the association between prealert eligibility and whether a prealert message was sent. In semistructured interviews, EMS staff were asked about their experiences of patients with suspected stroke.

Results

Of the 539 patients eligible for this study, 271 (51%) were recruited. Of these, only 79 (29%) were eligible for prealerting according to criteria set out in local protocols but 143 (53%) were prealerted. Increasing number of Face, Arm, Speech Test symptoms (1 symptom, OR 6.14, 95% CI 2.06 to 18.30, p=0.001; 2 symptoms, OR 31.36, 95% CI 9.91 to 99.24, p<0.001; 3 symptoms, OR 75.84, 95% CI 24.68 to 233.03, p<0.001) and EMS contact within 5 h of symptom onset (OR 2.99, 95% CI 1.37 to 6.50 p=0.006) were key predictors of prealerting but eligibility for prealert as a whole was not (OR 1.92, 95% CI 0.85 to 4.34 p=0.12). In qualitative interviews, EMS staff displayed varying understanding of prealert protocols and described frustration when their interpretation of the prealert criteria was not shared by ED staff.

Conclusions

Up to half of the patients presenting with suspected stroke in this study were prealerted by EMS staff, regardless of eligibility, resulting in disagreements with ED staff during handover. Aligning the expectations of EMS and ED staff, perhaps through simplified prealert protocols, could be considered to facilitate more appropriate use of hospital prealerting in acute stroke.
BET 1: Does apnoeic oxygenation reduce the risk of desaturation in patients requiring endotracheal intubation?
Authors: Denton Gavin , Howard Laura
Published: June 2016

A shortcut review of the literature was carried out to establish whether the use of apnoeic oxygenation technique during endotracheal intubation reduces the incidence of critical desaturation. Four trials were found to be directly relevant to the three-part question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these papers are tabulated. The clinical bottom line is that there is emerging evidence that the use of apnoeic oxygenation decreases the incidence of critical desaturation during endotracheal intubation. Due to the heterogeneity of trials, however, further well-constructed and emergency department (ED)-based studies are probably warranted before conclusion can be drawn for daily emergency medicine practice.
Implementation of a teaching programme to improve doctors’ awareness of DVLA guidelines: a multicentre study
Authors: Maruthappu Mahiben , Sykes Mark , Green Ben L , Watson Robert , Gollop Nicholas D , Shalhoub Joseph , Ng Ka Ying Bonnie
Published: June 2016

Introduction

Over half of the UK population holds a driver’s licence. Driver and Vehicle Licensing Authority (DVLA) guidelines are available for conditions from most specialties. Despite this, no focused training occurs in the undergraduate or postgraduate setting. We evaluate the impact of a teaching programme to improve guideline awareness.

Methods

A 25-point questionnaire was designed using the current DVLA guidelines. Five questions were included for the following fields: neurology, cardiology, drug and alcohol abuse, visual disorders and respiratory. This was distributed to doctors in training at five hospitals. Four weeks later, a single-session teaching programme was implemented. The questionnaire was redistributed. Preintervention and postintervention scores were compared using the Wilcoxon rank sum test.

Results

139 preteaching and 144 post-teaching questionnaires were completed. Implementation of a single-session teaching programme significantly improved the knowledge of DVLA guidelines in all five areas explored. Median scores: neurology, preteaching 40%, post-teaching 100%, p<0.001; cardiology, 0%, 100%, p<0.001; drug and alcohol misuse, 0%, 100%, p<0.001; visual disorders, 40%, 100%, p<0.001; respiratory disorders, 20%, 100%, p<0.001; and overall, 28%, 92%, p<0.001.

Conclusions

Knowledge of DVLA guidelines among our cohort was poor. Implementation of a single-session teaching programme can significantly improve guideline knowledge and awareness, serving as a cost-effective intervention.
Congenital venous aneurysm of the right external jugular vein in a great dane
Authors: Lefebvre Michael , Merveille Anne‐Christine , Rizza Maïlis , Heimann Marianne , Claeys Stephanie
Published: June 2016

An 11‐month‐old entire female great dane was presented for a painless swelling on the ventral right side of its neck. Fine needle aspiration of the mass revealed the presence of blood. Ultrasonographic examination revealed an anechoic subcutaneous tubular structure consistent with a jugular aneurysm. Surgery consisted in ligature of the right external jugular vein and excision of the aneurysm. No intraoperative complication occurred. Jugular aneurysm has been rarely reported in dogs. Venous aneurysms may be the result of several processes including tumours, inflammation, trauma, or may appear spontaneously or congenitally. Surgical excision is the treatment of choice due to the risk of thrombosis or possible rupture.