bluuebunny/crossref_metadata_2025_split huggingface dataset:
Petrobactin Is Exported from
Bacillus anthracis
by the RND-Type Exporter ApeX
Authors: Hagan A. K. , Tripathi A. , Berger D. , Sherman D. H. , Hanna P. C. 
Published: September 2017

ABSTRACT

Bacillus anthracis
—a Gram-positive, spore-forming bacterium—causes anthrax, a highly lethal disease with high bacteremia titers. Such rapid growth requires ample access to nutrients, including iron. However, access to this critical metal is heavily restricted in mammals, which requires
B. anthracis
to employ petrobactin, an iron-scavenging small molecule known as a siderophore. Petrobactin biosynthesis is mediated by
asb
gene products, and import of the iron-bound (holo)-siderophore into the bacterium has been well studied. In contrast, little is known about the mechanism of petrobactin export following its production in
B. anthracis
cells. Using a combination of bioinformatics data, gene deletions, and laser ablation electrospray ionization mass spectrometry (LAESI-MS), we identified a resistance-nodulation-cell division (RND)-type transporter, termed ApeX, as a putative petrobactin exporter. Deletion of
apeX
abrogated export of intact petrobactin, which accumulated inside the cell. However, growth of Δ
apeX
mutants in iron-depleted medium was not affected, and virulence in mice was not attenuated. Instead, petrobactin components were determined to be exported through a different protein, which enables iron transport sufficient for growth, albeit with a slightly lower affinity for iron. This is the first report to identify a functional siderophore exporter in
B. anthracis
and the
in vivo
functionality of siderophore components. Moreover, this is the first application of LAESI-MS to sample a virulence factor/metabolite directly from bacterial culture media and cell pellets of a human pathogen.

IMPORTANCE
Bacillus anthracis
requires iron for growth and employs the siderophore petrobactin to scavenge this trace metal during infections. While we understand much about petrobactin biosynthesis and ferric petrobactin import, how apo-petrobactin (iron free) is exported remains unknown. This study used a combination of bioinformatics, genetics, and mass spectrometry to identify the petrobactin exporter. After screening 17 mutants with mutations of candidate exporter genes, we identified the
a
po-
p
etrobactin
ex
porter (termed ApeX) as a member of the resistance-nodulation-cell division (RND) family of transporters. In the absence of ApeX, petrobactin accumulates inside the cell while continuing to export petrobactin components that are capable of transporting iron. Thus, the loss of ApeX does not affect the ability of
B. anthracis
to cause disease in mice. This has implications for treatment strategies designed to target and control pathogenicity of
B. anthracis
in humans.
Strategies for research engagement of clinicians in allied health (STRETCH): a mixed methods research protocol
Authors: Mickan Sharon , Wenke Rachel , Weir Kelly , Bialocerkowski Andrea , Noble Christy 
Published: September 2017

IntroductionAllied health professionals (AHPs) report positive attitudes to using research evidence in clinical practice, yet often lack time, confidence and skills to use, participate in and conduct research. A range of multifaceted strategies including education, mentoring and guidance have been implemented to increase AHPs’ use of and participation in research. Emerging evidence suggests that knowledge brokering activities have the potential to support research engagement, but it is not clear which knowledge brokering strategies are most effective and in what contexts they work best to support and maintain clinicians’ research engagement.Methods and analysisThis protocol describes an exploratory concurrent mixed methods study that is designed to understand how allied health research fellows use knowledge brokering strategies within tailored evidence-based interventions, to facilitate research engagement by allied health clinicians. Simultaneously, a realist approach will guide a systematic process evaluation of the research fellows’ pattern of use of knowledge brokering strategies within each case study to build a programme theory explaining which knowledge brokering strategies work best, in what contexts and why. Learning and behavioural theories will inform this critical explanation.Ethics and disseminationAn explanation of how locally tailored evidence-based interventions improve AHPs use of, participation in and leadership of research projects will be summarised and shared with all participating clinicians and within each case study. It is expected that local recommendations will be developed and shared with medical and nursing professionals in and beyond the health service, to facilitate building research capacity in a systematic and effective way.
Changes in admission thresholds in English emergency departments
Authors: Wyatt Steven , Child Kieran , Hood Andrew , Cooke Matthew , Mohammed Mohammed A 
Published: September 2017

BackgroundThe most common route to a hospital bed in an emergency is via an Emergency Department (ED). Many recent initiatives and interventions have the objective of reducing the number of unnecessary emergency admissions. We aimed to assess whether ED admission thresholds had changed over time taking account of the casemix of patients arriving at ED.MethodsWe conducted a retrospective cross-sectional analysis of more than 20 million attendances at 47 consultant-led EDs in England between April 2010 and March 2015. We used mixed-effects logistic regression to estimate the odds of a patient being admitted to hospital and the impact of a range of potential explanatory variables. Models were developed and validated for four attendance subgroups: ambulance-conveyed children, walk-in children, ambulance-conveyed adults and walk-in adults.Results23.8% of attendances were for children aged under 18 years, 49.7% were female and 30.0% were conveyed by ambulance. The number of ED attendances increased by 1.8% per annum between April 2010–March 2011 (year 1) and April 2014–March 2015 (year 5). The proportion of these attendances that were admitted to hospital changed negligiblybetween year 1 (27.0%) and year 5 (27.5%). However, after adjusting for patient and attendance characteristics, the odds of admission over the 5-year period had reduced by 15.2% (95% CI 13.4% to 17.0%) for ambulance-conveyed children, 22.6% (95% CI 21.7% to 23.5%) for walk-in children, 20.9% (95% CI 20.4% to 21.5%) for ambulance conveyed adults and 22.9% (95% CI 22.4% to 23.5%) for walk-in adults.ConclusionsThe casemix-adjusted odds of admission via ED to NHS hospitals in England have decreased since April 2010. EDs are admitting a similar proportion of patients to hospital despite increases in the complexity and acuity of presenting patients. Without these threshold changes, the number of emergency admissions would have been 11.9% higher than was the case in year 5.
TP73DNA methylation and upregulation of ΔNp73 are associated with an adverse prognosis in breast cancer
Authors: Gomez Laura C , Sottile Mayra L , Guerrero-Gimenez Martin E , Zoppino Felipe C M , Redondo Analia L , Gago Francisco E , Orozco Javier I , Tello Olga M , Roqué Maria , Nadin Silvina B , Marzese Diego M , Vargas-Roig Laura M 
Published: September 2017

AimAccumulated evidence suggests that aberrant methylation of theTP73gene and increased levels of ΔNp73 in primary tumours correlate with poor prognosis. However, little is known regarding the transcriptional and functional regulation of theTP73gene in breast cancer. The aim of the present study was to determine the expression of the ΔNp73 isoform, its relationship with DNA methylation ofTP73and their clinical prognostic significance in breast cancer patients.MethodsTP73gene methylation was studied in TCGA datasets and in 70 invasive ductal breast carcinomas (IDCs). The expression of p73 isoforms was evaluated by immunohistochemistry (IHC) and Western blot and correlated with clinicopathological variables and clinical outcome.ResultsWe observed that the methylation of diverse CpG islands ofTP73differed significantly between molecular subtypes. An inverse correlation was found between p73 protein expression and the methylation status of theTP73gene. The expression of exon 3’ of p73 (only expressed in ΔNp73) was significantly higher in patients with wild-type p53. Immunohistochemical analysis revealed that all p73 isoforms were localised in both the nuclear and cytoplasmic compartments. We confirmed a positive association between the expression of ∆Np73 and high histological grade.ConclusionsOur findings suggest that high expression of ΔNp73 could be used to determine the aggressiveness of IDCs and could be incorporated in the pathologist’s report.
Sustainability of TNF-blocker tapering in rheumatoid arthritis over 3 years: long-term follow-up of the STRASS (Spacing of TNF-blocker injections in Rheumatoid ArthritiS Study) randomised controlled trial
Authors: Sigaux Johanna , Bailly Florian , Hajage David , Mariette Xavier , Morel Jacques , Gandjbakhch Frédérique , Foltz Violaine , Gossec Laure , Tubach Florence , Fautrel Bruno 
Published: September 2017

IntroductionWe have limited data on the sustainability of tumour necrosis factor (TNF)-blocker tapering in rheumatoid arthritis (RA) in remission over the long term in real-life settings. This study aimed to assess the probability of sustained dose reduction of TNF-blockers in an observational 3-year extended follow-up of the Spacing of TNF-blocker injections in Rheumatoid ArthritiS Study (STRASS), a randomised controlled trial comparing progressive TNF-blocker injections (spacing arm (S-arm) to maintenance arm (M-arm)) in patients with RA in stable remission.MethodsIn 2015, clinical data for the completer population were retrospectively collected at 1, 2 and 3 years after the end of the trial. The endpoints were the proportion of patients free of a biological disease-modifying antirheumatic drug (bDMARD) treatment, a sustainably spaced injection of TNF-blockers and a full-dose regimen as well as the mean dose of bDMARD intake and treatment switch rate.ResultsOverall, 96 patients (76.8% of the completers) had data available up to 3 years; 11.5% discontinued TNF-blockers (5.8% vs 18.2% in the M-arm and S-arm, p=0.06), 30.2% had a tapered regimen (28.8% vs 31.8%, p=0.76) and 37.5% retained a full dose (44.2% vs 29.5%, p=0.14). The mean TNF-blocker dose quotient was 66% of the full dose (74% vs 58% in the M-arm and S-arm, p=0.06); 20.8% switched to another bDMARD (21.2% vs 20.5%, p=0.94).ConclusionSustained TNF-blocker de-escalation or withdrawal is achievable in 41% of patients over 3 years with limited dose reduction. Optimal strategies remain to be determined to maintain remission after TNF-blocker tapering or discontinuation.
Two cases of embolic pneumonia associated with udder cleft dermatitis in dairy cattle from the same farm
Authors: Turner Andrea , Wood Sarah , Millar Michael 
Published: September 2017

Two Holstein cows from the same farm were presented within eight months of each other with malaise, milk drop and dyspnoea. Both cows had active or historic udder cleft dermatitis (UCD) lesions. Clinical examination and diagnostic tests led to an initial diagnosis of chronic suppurative pneumonia in both cows. The cases were poorly responsive to antibiotic treatment and died or were euthanased, 18 and 16 days respectively, after presentation. Postmortem examination of each case resulted in the diagnosis of embolic pneumonia associated with UCD. In both cases, UCD lesions, which were considered insignificant by the farmer and the veterinarian, are thought to have been the initiating source of infection. It is important that both farmers and vets are made aware of the possible severe consequences of udder cleft lesions and that early detection strategies for UCD and udder cleft lesions are adopted and implemented on‐farm.
TOP2A and EZH2 Provide Early Detection of an Aggressive Prostate Cancer Subgroup
Authors: Labbé David P. , Sweeney Christopher J. , Brown Myles , Galbo Phillip , Rosario Spencer , Wadosky Kristine M. , Ku Sheng-Yu , Sjöström Martin , Alshalalfa Mohammed , Erho Nicholas , Davicioni Elai , Karnes R. Jeffrey , Schaeffer Edward M. , Jenkins Robert B. , Den Robert B. , Ross Ashley E. , Bowden Michaela , Huang Ying , Gray Kathryn P. , Feng Felix Y. , Spratt Daniel E. , Goodrich David W. , Eng Kevin H. , Ellis Leigh 
Published: September 2017

Abstract
Purpose: Current clinical parameters do not stratify indolent from aggressive prostate cancer. Aggressive prostate cancer, defined by the progression from localized disease to metastasis, is responsible for the majority of prostate cancer–associated mortality. Recent gene expression profiling has proven successful in predicting the outcome of prostate cancer patients; however, they have yet to provide targeted therapy approaches that could inhibit a patient's progression to metastatic disease.
Experimental Design: We have interrogated a total of seven primary prostate cancer cohorts (n = 1,900), two metastatic castration-resistant prostate cancer datasets (n = 293), and one prospective cohort (n = 1,385) to assess the impact of TOP2A and EZH2 expression on prostate cancer cellular program and patient outcomes. We also performed IHC staining for TOP2A and EZH2 in a cohort of primary prostate cancer patients (n = 89) with known outcome. Finally, we explored the therapeutic potential of a combination therapy targeting both TOP2A and EZH2 using novel prostate cancer–derived murine cell lines.
Results: We demonstrate by genome-wide analysis of independent primary and metastatic prostate cancer datasets that concurrent TOP2A and EZH2 mRNA and protein upregulation selected for a subgroup of primary and metastatic patients with more aggressive disease and notable overlap of genes involved in mitotic regulation. Importantly, TOP2A and EZH2 in prostate cancer cells act as key driving oncogenes, a fact highlighted by sensitivity to combination-targeted therapy.
Conclusions: Overall, our data support further assessment of TOP2A and EZH2 as biomarkers for early identification of patients with increased metastatic potential that may benefit from adjuvant or neoadjuvant targeted therapy approaches. Clin Cancer Res; 23(22); 7072–83. ©2017 AACR.
Variation in Management of Patients With Obstructive Coronary Artery Disease: Insights From the Veterans Affairs Clinical Assessment and Reporting Tool (VA CART) Program
Authors: Sandhu Amneet , Stanislawski Maggie A. , Grunwald Gary K. , Guinn Kathryn , Valle Javier , Matlock Daniel , Ho P. Michael , Maddox Thomas M. , Bradley Steven M. 
Published: September 2017

Background
Little is known about facility‐level variation in the use of revascularization procedures for the management of stable obstructive coronary artery disease. Furthermore, it is unknown if variation in the use of coronary revascularization is associated with use of other cardiovascular procedures.

Methods and Results

We evaluated all elective coronary angiograms performed in the Veterans Affairs system between September 1, 2007, and December 31, 2011, using the Clinical Assessment and Reporting Tool and identified patients with obstructive coronary artery disease. Patients were considered managed with revascularization if they received percutaneous coronary intervention (PCI) or coronary artery bypass grafting within 30 days of diagnosis. We calculated risk‐adjusted facility‐level rates of overall revascularization,
PCI
, and coronary artery bypass grafting. In addition, we determined the association between facility‐level rates of revascularization and post‐
PCI
stress testing. Among 15 650 patients at 51 Veterans Affairs sites who met inclusion criteria, the median rate of revascularization was 59.6% (interquartile range, 55.7%–66.7%). Across all facilities, risk‐adjusted rates of overall revascularization varied from 41.5% to 88.1%, rate of
PCI
varied from 23.2% to 80.6%, and rate of coronary artery bypass graftingvariedfrom 7.5% to 36.5%. Of 6179 patients who underwent elective
PCI
, the median rate of stress testing in the 2 years after
PCI
was 33.7% (interquartile range, 30.7%–47.1%). There was no evidence of correlation between facility‐level rate of revascularization and follow‐up stress testing.

Conclusions

Within the Veterans Affairs system, we observed large facility‐level variation in rates of revascularization for obstructive coronary artery disease, with variation driven primarily by
PCI
. There was no association between facility‐level use of revascularization and follow‐up stress testing, suggesting use rates are specific to a particular procedure and not a marker of overall facility‐level use.
Sensibility and Uncertainties Analysis method dedicated to home energy management problem
Authors: Le Minh-Hoang , Ploix Stephane 
Published: September 2017

This paper focuses on the energy management problem applied to residential sector. The studied optimization problem is defined as the optimal management of production and consumption activities in buildings. A scheduling problem is identified to adjust the energy consumption to both the energy cost and the users’ comfort. The optimization procedure of energy management is based on available predictions (weather forecast, users habit, etc.). These predictions are not entirely known data of the optimization problem because of uncertainties. Parametric uncertainties are introduced in the home energy management problem in order to provide robust energy allocation. To improve the taking into account of uncertainties of prediction and the energy management problems, a Sensibility and Uncertainties Analysis method based on the procedure Branch & Bound and the multi-parametric linear programming is proposed. After a description of general principles and main steps, this algorithm is applied to various energy flow management problems in a smart platform. Practical application: The problem of energy management in buildings is described as the optimization problem which is defined to adjust the energy consumption of buildings in order to reach equilibrium between production and consumption on the grid. This home energy management problem has been modeled with a lot of parameters that are uncertain data. This is generally the case in modeling. This is particularly true in the energy management problem because of the high sensitivity of the decision (the energy allocation) to the data. The proposed approach permits to analyze the sensitivity of the solutions according to uncertain parameters. Then the impact of an uncertainty can be analyzed. Each family of solutions can be used to quantify locally the stability of a robust solution over the uncertainties.
Effect of Loading on In Vivo Tibiofemoral and Patellofemoral Kinematics of Healthy and ACL-Reconstructed Knees
Authors: Kaiser Jarred M. , Vignos Michael F. , Kijowski Richard , Baer Geoffrey , Thelen Darryl G. 
Published: September 2017

Background: Although knees that have undergone anterior cruciate ligament reconstruction (ACLR) often exhibit normal laxity on clinical examination, abnormal kinematic patterns have been observed when the joint is dynamically loaded during whole body activity. This study investigated whether abnormal knee kinematics arise with loading under isolated dynamic movements. Hypothesis: Tibiofemoral and patellofemoral kinematics of ACLR knees will be similar to those of the contralateral uninjured control knee during passive flexion-extension, with bilateral differences emerging when an inertial load is applied. Study Design: Controlled laboratory study. Methods: The bilateral knees of 18 subjects who had undergone unilateral ACLR within the past 4 years were imaged by use of magnetic resonance imaging (MRI). Their knees were cyclically (0.5 Hz) flexed passively. Subjects then actively flexed and extended their knees against an inertial load that induced stretch-shortening quadriceps contractions, as seen during the load acceptance phase of gait. A dynamic, volumetric, MRI sequence was used to track tibiofemoral and patellofemoral kinematics through 6 degrees of freedom. A repeated-measures analysis of variance was used to compare secondary tibiofemoral and patellofemoral kinematics between ACLR and healthy contralateral knees during the passive and active extension phases of the cyclic motion. Results: Relative to the passive motion, inertial loading induced significant shifts in anterior and superior tibial translation, internal tibial rotation, and all patellofemoral degrees of freedom. As hypothesized, tibiofemoral and patellofemoral kinematics were bilaterally symmetric during the passive condition. However, inertial loading induced bilateral differences, with the ACLR knees exhibiting a significant shift toward external tibial rotation. A trend toward greater medial and anterior tibial translation was seen in the ACLR knees. Conclusion: This study demonstrates that abnormal knee kinematic patterns in ACLR knees emerge during a simple, active knee flexion-extension task that can be performed in an MRI scanner. Clinical Relevance: It is hypothesized that abnormal knee kinematics may alter cartilage loading patterns and thereby contribute to increased risk for osteoarthritis. Recent advances in quantitative MRI can be used to detect early cartilage degeneration in ACLR knees. This study demonstrates the feasibility of identifying abnormal ACLR kinematics by use of dynamic MRI, supporting the combined use of dynamic and quantitative MRI to investigate the proposed link between knee motion, cartilage contact, and early biomarkers of cartilage degeneration.
The Usefulness of Submaximal Exercise Gas Exchange in Pulmonary Arterial Hypertension: A Case Series
Authors: Woods Paul R. , Frantz Robert P. , Johnson Bruce D. 
Published: September 2017

Introduction Submaximal exercise gas exchange may be a useful tool to track responses to therapy in pulmonary arterial hypertension (PAH) patients. Methods Three patients diagnosed with idiopathic PAH, on differing therapies, were included. Standard clinical tests (echocardiography; 6 minute walk) were performed pre and 3-5 months after treatment. Gas exchange was measured during 3 minutes of step exercise at both time points. Results Gas exchange variables, end tidal CO2 (PETCO2) and the ratio of ventilation to CO2 production (VE/VCO2), during submaximal exercise were able to track patient responses to therapy over a 3-5 month period. Two patients demonstrated positive improvements, with an increased PETCO2 and decreased VE/VCO2 during light exercise, in response to an altered therapeutic regime. The third patient had a worsening of gas exchange (decreased PETCO2 and increased VE/VCO2) following no changes in the medical regime from the baseline visit. Conclusion Gas exchange variables measured during light submaximal exercise, such as PETCO2 and VE/VCO2, may be able to better detect small changes in functional status following treatment and could, therefore, be a useful tool to track disease severity in PAH patients. Further study is required to determine the clinical usefulness of these gas exchange variables.