bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Monte Carlo study on the collimation of pencil beam scanning proton therapy beams
Authors: Charlwood Frances C. , Aitkenhead Adam H. , Mackay Ranald I. 
Published: February 2016

Purpose:The lateral edge of a proton therapy beam is commonly used to achieve conformality to the treatment volume where critical structures reside close to the target. However, when treating shallow depths, the lateral edge of a pencil beam scanning (PBS) system may be broader than that of a double scattered (DS) system. Use of a range‐shifter to degrade the beam and allow treatment of very shallow depths further blurs the lateral edge. The authors investigate the potential use of a collimator with a PBS system for delivery of 3D uniform dose–volumes to a water‐tank phantom, identifying the key factors controlling the width of the lateral edge.Methods:The geant4 application for tomographic emission (gate) Monte Carlo (MC) environment was used, following validation against previously published data. Key parameters for PBS beams were investigated to assess their impact on the lateral edge of both monoenergetic beams and uniform dose–volumes. These parameters included nozzle‐to‐surface distance (NSD), vacuum window‐to‐surface distance (VSD), use of a range‐shifter, and spot optimization parameters.Results:The lateral edge of an uncollimated PBS beam is particularly sensitive to VSD and NSD. While use of a range‐shifter blurs the lateral edge, collimation allows the edge to be sharpened to between 2 and 4 mm depending on the depth of the target. Optimization of the spot weightings alone can provide a penumbral width close to that of a single spot, but also leads to poorer uniformity near the edge of the target volume.Conclusions:Collimation of PBS beams should be considered for superficial targets particularly for beams delivered through a range‐shifter, since the resultant sharpening of the lateral edge will allow improved sparing of adjacent normal tissues. Further work is needed to develop collimators which are integrated into both nozzle designs and planning system optimization algorithms.
Technical Note: Relationships between gamma criteria and action levels: Results of a multicenter audit of gamma agreement index results
Authors: Crowe Scott B. , Sutherland Bess , Wilks Rachael , Seshadri Venkatakrishnan , Sylvander Steven , Trapp Jamie V. , Kairn Tanya 
Published: February 2016

Purpose:The aim of this work was to use a multicenter audit of modulated radiotherapy quality assurance (QA) data to provide a practical examination of gamma evaluation criteria and action level selection. The use of the gamma evaluation method for patient‐specific pretreatment QA is widespread, with most commercial solutions implementing the method.Methods:Gamma agreement indices were calculated using the criteria 1%/1 mm, 2%/2 mm, 2%/3 mm, 3%/2 mm, 3%/3 mm, and 5%/3 mm for 1265 pretreatment QA measurements, planned at seven treatment centers, using four different treatment planning systems, delivered using three different delivery systems (intensity‐modulated radiation therapy, volumetric‐modulated arc therapy, and helical tomotherapy) and measured using three different dose measurement systems. The sensitivity of each pair of gamma criteria was evaluated relative to the gamma agreement indices calculated using 3%/3 mm.Results:A linear relationship was observed for 2%/2 mm, 2%/3 mm, and 3%/2 mm. This result implies that most beams failing at 3%/3 mm would also fail for those criteria, if the action level was adjusted appropriately. Some borderline plans might be passed or failed depending on the relative priority (tighter tolerance) used for dose difference or distance to agreement evaluation. Dosimeter resolution and treatment modality were found to have a smaller effect on the results of QA measurements than the number of dimensions (2D or 3D) over which the gamma evaluation was calculated.Conclusions:This work provides a method (and a large sample of results) for calculating equivalent action levels for different gamma evaluation criteria. This work constitutes a valuable guide for clinical decision making and a means to compare published gamma evaluation results from studies using different evaluation criteria. More generally, the data provided by this work support the recommendation that gamma criteria that specifically prioritize the property of greatest clinical importance for each treatment modality of anatomical site should be selected when using gamma evaluations for modulated radiotherapy QA. It is therefore suggested that departments using the gamma evaluation as a QA analysis tool should consider the relative importance of dose difference and distance to agreement, when selecting gamma evaluation criteria.
Mechanistic Analysis of the Effect of Deamidation on the Immunogenicity of Anthrax Protective Antigen
Authors: Verma Anita , Ngundi Miriam M. , Burns Drusilla L. 
Published: February 2016

ABSTRACT
The spontaneous modification of proteins, such as deamidation of asparagine residues, can significantly affect the immunogenicity of protein-based vaccines. Using a “genetically deamidated” form of recombinant protective antigen (rPA), we have previously shown that deamidation can decrease the immunogenicity of rPA, the primary component of new-generation anthrax vaccines. In this study, we investigated the biochemical and immunological mechanisms by which deamidation of rPA might decrease the immunogenicity of the protein. We found that loss of the immunogenicity of rPA vaccine was independent of the presence of adjuvant. We assessed the effect of deamidation on the immunodominant neutralizing B-cell epitopes of rPA and found that these epitopes were not significantly affected by deamidation. In order to assess the effect of deamidation on T-cell help for antibody production elicited by rPA vaccine, we examined the ability of the wild-type and genetically deamidated forms of rPA to serve as hapten carriers. We found that when wild-type and genetically deamidated rPA were modified to similar extents with 2,4-dinitrophenyl hapten (DNP) and then used to immunize mice, higher levels of anti-DNP antibodies were elicited by wild-type DNP-rPA than those elicited by the genetically deamidated DNP-rPA, indicating that wild-type rPA elicits more T-cell help than the genetically deamidated form of the protein. These results suggest that a decrease in the ability of deamidated rPA to elicit T-cell help for antibody production is a possible contributor to its lower immunogenicity.
Evaluation of an IgG Enzyme-Linked Immunosorbent Assay as a Serological Assay for Detection of Mycoplasma bovis Infection in Feedlot Cattle
Authors: Wawegama Nadeeka K. , Markham Philip F. , Kanci Anna , Schibrowski Meghan , Oswin Sally , Barnes Tamsin S. , Firestone Simon M. , Mahony Timothy J. , Browning Glenn F. 
Published: February 2016

ABSTRACTMycoplasma bovisis a pathogen of emerging significance in cattle throughout the world that is causing a range of diseases, including mastitis, arthritis, and pneumonia. The limited availability and efficacy of current diagnostic and prophylactic tools for its control and its increasing antimicrobial resistance are contributing to its increasing importance in beef and dairy cattle. We have developed an indirect IgG enzyme-linked immunosorbent assay (ELISA) based on a recombinant fragment of the MilA protein and have shown its potential as an effective diagnostic tool. To more comprehensively estimate the diagnostic sensitivity and specificity of this IgG ELISA for detection of infection withM. bovisin cattle and to define a suitable cutoff for use in the field, we further assessed its performance in experimentally infected calves in a closed beef herd and by applying Bayesian latent class modeling to laboratory testing results from 7,448 cattle entering Australian feedlots. The most effective cutoff points were estimated to be 68.6 antibody units (AU) for experimentally infected calves and to be 58.7 AU for a closed adult herd. Under field conditions, in feedlot cattle the globally optimal cutoff was estimated to be 105 AU. At this cutoff, the diagnostic sensitivity was 94.3% (95% probability interval [PI], 89.9% to 99.6%) with a diagnostic specificity of 94.4% (95% PI, 90.3% to 99.6%). Applying this 105 AU cutoff, 13.1% of cattle were seropositive for infection withM. bovison entry into feedlots, and 73.5% were seropositive when followed up approximately 6 weeks later suggesting a high risk of infection shortly after entry into feedlots.
Development of Rapid Enzyme-Linked Immunosorbent Assays for Detection of Antibodies to Burkholderia pseudomallei
Authors: Suttisunhakul Vichaya , Wuthiekanun Vanaporn , Brett Paul J. , Khusmith Srisin , Day Nicholas P. J. , Burtnick Mary N. , Limmathurotsakul Direk , Chantratita Narisara 
Published: February 2016

ABSTRACT

Burkholderia pseudomallei
, the causative agent of melioidosis, is an environmental bacillus found in northeast Thailand. The mortality rate of melioidosis is ∼40%. An indirect hemagglutination assay (IHA) is used as a reference serodiagnostic test; however, it has low specificity in areas where the background seropositivity of healthy people is high. To improve assay specificity and reduce the time for diagnosis, four rapid enzyme-linked immunosorbent assays (ELISAs) were developed using two purified polysaccharide antigens (O-polysaccharide [OPS] and 6-deoxyheptan capsular polysaccharide [CPS]) and two crude antigens (whole-cell [WC] antigen and culture filtrate [CF] antigen) of
B. pseudomallei
. The ELISAs were evaluated using serum samples from 141 culture-confirmed melioidosis patients from Thailand along with 188 healthy donors from Thailand and 90 healthy donors from the United States as controls. The areas under receiver operator characteristic curves (AUROCC) using Thai controls were high for the OPS-ELISA (0.91), CF-ELISA (0.91), and WC-ELISA (0.90), while those of CPS-ELISA (0.84) and IHA (0.72) were lower. AUROCC values using U.S. controls were comparable to those of the Thai controls for all ELISAs except IHA (0.93). Using a cutoff optical density (OD) of 0.87, the OPS-ELISA had a sensitivity of 71.6% and a specificity of 95.7% for Thai controls; for U.S. controls, specificity was 96.7%. An additional 120 serum samples from tuberculosis, scrub typhus, or leptospirosis patients were evaluated in all ELISAs and resulted in comparable or higher specificities than using Thai healthy donors. Our findings suggest that antigen-specific ELISAs, particularly the OPS-ELISA, may be useful for serodiagnosis of melioidosis in areas where it is endemic and nonendemic.
Multicenter Matrix-Assisted Laser Desorption Ionization–Time of Flight Mass Spectrometry Study for Identification of Clinically Relevant Nocardia spp
Authors: Blosser Sara J. , Drake Steven K. , Andrasko Jennifer L. , Henderson Christina M. , Kamboj Kamal , Antonara Stella , Mijares Lilia , Conville Patricia , Frank Karen M. , Harrington Susan M. , Balada-Llasat Joan-Miquel , Zelazny Adrian M. 
Published: February 2016

ABSTRACT

This multicenter study analyzed
Nocardia
spp., including extraction, spectral acquisition, Bruker matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS) identification, and score interpretation, using three
Nocardia
libraries, the Bruker, National Institutes of Health (NIH), and The Ohio State University (OSU) libraries, and compared the results obtained by each center. A standardized study protocol, 150
Nocardia
isolates, and NIH and OSU
Nocardia
MALDI-TOF MS libraries were distributed to three centers. Following standardized culture, extraction, and MALDI-TOF MS analysis, isolates were identified using score cutoffs of ≥2.0 for species/species complex-level identification and ≥1.8 for genus-level identification. Isolates yielding a score of <2.0 underwent a single repeat extraction and analysis. The overall score range for all centers was 1.3 to 2.7 (average, 2.2 ± 0.3), with common species generally producing higher average scores than less common ones. Score categorization and isolate identification demonstrated 86% agreement between centers; 118 of 150 isolates were correctly identified to the species/species complex level by all centers. Nine strains (6.0%) were not identified by any center, and six (4.0%) of these were uncommon species with limited library representation. A categorical score discrepancy among centers occurred for 21 isolates (14.0%). There was an overall benefit of 21.2% from repeat extraction of low-scoring isolates and a center-dependent benefit for duplicate spotting (range, 2 to 8.7%). Finally, supplementation of the Bruker
Nocardia
MALDI-TOF MS library with both the OSU and NIH libraries increased the genus-level and species-level identification by 18.2% and 36.9%, respectively. Overall, this study demonstrates the ability of diverse clinical microbiology laboratories to utilize MALDI-TOF MS for the rapid identification of clinically relevant
Nocardia
spp. and to implement MALDI-TOF MS libraries developed by single laboratories across institutions.
Matrix-Assisted Laser Desorption Ionization–Time of Flight Mass Spectrometry Accelerates Pathogen Identification and May Confer Benefit in the Outcome of Peritoneal Dialysis-Related Peritonitis
Authors: Lin Wei-Hung , Hwang Jyh-Chang , Tseng Chin-Chung , Chang Yu-Tzu , Wu An-Bang , Yan Jing-Jou , Wu Jiunn-Jong , Wang Ming-Cheng 
Published: February 2016

ABSTRACT

Matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS) and conventional standard methods were compared for time to pathogen identification and impact on clinical outcomes in peritoneal dialysis-related peritonitis patients. The MALDI-TOF MS method identified the causative microorganisms earlier (average time saved, 64 h for all pathogens), and patients had a shorter hospital stay (mean ± standard deviation, 5.2 ± 4.8 days versus 8.2 ± 4.5 days,
P
= 0.001).
Domain Organization of Vaccinia Virus Helicase-Primase D5
Authors: Hutin Stephanie , Ling Wai Li , Round Adam , Effantin Gregory , Reich Stefan , Iseni Frédéric , Tarbouriech Nicolas , Schoehn Guy , Burmeister Wim Pascal 
Published: February 2016

ABSTRACT

Poxviridae
are viruses with a large linear double-stranded DNA genome coding for up to 250 open reading frames and a fully cytoplasmic replication. The double-stranded DNA genome is covalently circularized at both ends. Similar structures of covalently linked extremities of the linear DNA genome are found in the African swine fever virus (asfarvirus) and in the
Phycodnaviridae
. We are studying the machinery which replicates this peculiar genome structure. From our work with vaccinia virus, we give first insights into the overall structure and function of the essential poxvirus virus helicase-primase D5 and show that the active helicase domain of D5 builds a hexameric ring structure. This hexamer has ATPase and, more generally, nucleoside triphosphatase activities that are indistinguishable from the activities of full-length D5 and that are independent of the nature of the base. In addition, hexameric helicase domains bind tightly to single- and double-stranded DNA. Still, the monomeric D5 helicase construct truncated within the D5N domain leads to a well-defined structure, but it does not have ATPase or DNA-binding activity. This shows that the full D5N domain has to be present for hexamerization. This allowed us to assign a function to the D5N domain which is present not only in D5 but also in other viruses of the nucleocytoplasmic large DNA virus (NCLDV) clade. The primase domain and the helicase domain were structurally analyzed via a combination of small-angle X-ray scattering and, when appropriate, electron microscopy, leading to consistent low-resolution models of the different proteins.

IMPORTANCE
Since the beginning of the 1980s, research on the vaccinia virus replication mechanism has basically stalled due to the absence of structural information. As a result, this important class of pathogens is less well understood than most other viruses. This lack of information concerns in general viruses of the NCLDV clade, which use a superfamily 3 helicase for replication, as do poxviruses. Here we provide for the first time information about the domain structure and DNA-binding activity of D5, the poxvirus helicase-primase. This result not only refines the current model of the poxvirus replication fork but also will lead in the long run to a structural basis for antiviral drug design.
Influenza A Virus Dysregulates Host Histone Deacetylase 1 That Inhibits Viral Infection in Lung Epithelial Cells
Authors: Nagesh Prashanth Thevkar , Husain Matloob 
Published: February 2016

ABSTRACTViruses dysregulate the host factors that inhibit virus infection. Here, we demonstrate that human enzyme, histone deacetylase 1 (HDAC1) is a new class of host factor that inhibits influenza A virus (IAV) infection, and IAV dysregulates HDAC1 to efficiently replicate in epithelial cells. A time-dependent decrease in HDAC1 polypeptide level was observed in IAV-infected cells, reducing to <50% by 24 h of infection. A further depletion (97%) of HDAC1 expression by RNA interference increased the IAV growth kinetics, increasing it by >3-fold by 24 h and by >6-fold by 48 h of infection. Conversely, overexpression of HDAC1 decreased the IAV infection by >2-fold. Likewise, a time-dependent decrease in HDAC1 activity, albeit with slightly different kinetics to HDAC1 polypeptide reduction, was observed in infected cells. Nevertheless, a further inhibition of deacetylase activity increased IAV infection in a dose-dependent manner. HDAC1 is an important host deacetylase and, in addition to its role as a transcription repressor, HDAC1 has been lately described as a coactivator of type I interferon response. Consistent with this property, we found that inhibition of deacetylase activity either decreased or abolished the phosphorylation of signal transducer and activator of transcription I (STAT1) and expression of interferon-stimulated genes, IFITM3, ISG15, and viperin in IAV-infected cells. Furthermore, the knockdown of HDAC1 expression in infected cells decreased viperin expression by 58% and, conversely, the overexpression of HDAC1 increased it by 55%, indicating that HDAC1 is a component of IAV-induced host type I interferon antiviral response.IMPORTANCEInfluenza A virus (IAV) continues to significantly impact global public health by causing regular seasonal epidemics, occasional pandemics, and zoonotic outbreaks. IAV is among the successful human viral pathogens that has evolved various strategies to evade host defenses, prevent the development of a universal vaccine, and acquire antiviral drug resistance. A comprehensive knowledge of IAV-host interactions is needed to develop a novel and alternative anti-IAV strategy. Host produces a variety of factors that are able to fight IAV infection by employing various mechanisms. However, the full repertoire of anti-IAV host factors and their antiviral mechanisms has yet to be identified. We have identified here a new host factor, histone deacetylase 1 (HDAC1) that inhibits IAV infection. We demonstrate that HDAC1 is a component of host innate antiviral response against IAV, and IAV undermines HDAC1 to limit its role in antiviral response.
Broad Anti-Hepatitis C Virus (HCV) Antibody Responses Are Associated with Improved Clinical Disease Parameters in Chronic HCV Infection
Authors: Swann Rachael E. , Cowton Vanessa M. , Robinson Mark W. , Cole Sarah J. , Barclay Stephen T. , Mills Peter R. , Thomson Emma C. , McLauchlan John , Patel Arvind H. 
Published: February 2016

ABSTRACT

During hepatitis C virus (HCV) infection, broadly neutralizing antibody (bNAb) responses targeting E1E2 envelope glycoproteins are generated in many individuals. It is unclear if these antibodies play a protective or a pathogenic role during chronic infection. In this study, we investigated whether bNAb responses in individuals with chronic infection were associated with differences in clinical presentation. Patient-derived purified serum IgG was used to assess the breadth of HCV E1E2 binding and the neutralization activity of HCV pseudoparticles. The binding and neutralization activity results for two panels bearing viral envelope proteins representing either an intergenotype or an intragenotype 1 group were compared. We found that the HCV load was negatively associated with strong cross-genotypic E1E2 binding (
P
= 0.03). Overall, we observed only a modest correlation between total E1E2 binding and neutralization ability. The breadth of intergenotype neutralization did not correlate with any clinical parameters; however, analysis of individuals with genotype 1 (gt1) HCV infection (
n
= 20), using an intragenotype pseudoparticle panel, found a strong association between neutralization breadth and reduced liver fibrosis (
P
= 0.006). A broad bNAb response in our cohort with chronic infection was associated with a single nucleotide polymorphism (SNP) in the
HLA-DQB1
gene (
P
= 0.038), as previously reported in a cohort with acute disease. Furthermore, the bNAbs in these individuals targeted more than one region of E2-neutralizing epitopes, as assessed through cross-competition of patient bNAbs with well-characterized E2 antibodies. We conclude that the bNAb responses in patients with chronic gt1 infection are associated with lower rates of fibrosis and host genetics may play a role in the ability to raise such responses.

IMPORTANCE
Globally, there are 130 million to 150 million people with chronic HCV infection. Typically, the disease is progressive and is a major cause of severe liver cirrhosis and hepatocellular carcinoma. While it is known that neutralizing antibodies have a role in spontaneous clearance during acute infection, little is known about their role in chronic infection. In the present work, we investigated the antibody response in a cohort of chronically infected individuals and found that a broadly neutralizing antibody response is protective and is associated with reduced levels of liver fibrosis and cirrhosis. We also found an association between SNPs in class II HLA genes and the presence of a broadly neutralizing response, indicating that antigen presentation may be important for the production of HCV-neutralizing antibodies.
Mobile revolution: a requiem for bleeps?
Authors: Martin Guy , Janardhanan Pradeep , Withers Tristan , Gupta Sanjay 
Published: February 2016

AbstractObjectivesEffective communication is a vital part of good clinical care. Traditionally bleep systems have been used as the mainstay of communication. Mobile technology is increasingly seen as a quicker, easier and more reliable method of communication. Our objective was to assess the use of mobile devices within a typical National Health Service (NHS) hospital, discuss potential benefits and pitfalls, and develop suggestions for future improvements.MethodsA survey of 600 hospital doctors was conducted in a large NHS district general hospital between 1 May and 30 June 2015. The questionnaire explored the patterns of use, attitudes and impact of mobile communication, and identified potential risks and benefits of its wider adoption within the NHS.Results92% of doctors use their personal mobile for hospital-related work. 95% share their personal number with colleagues, and 64% have it available through hospital switchboard. 77% use their personal mobile to discuss patient matters, and 48% are prevented from communicating effectively due to poor signal within the hospital. 90% are contacted when not at work on a weekly or daily basis regarding patients. 73% feel that traditional bleeps should be replaced with new mobile technologies.ConclusionsMobile phone usage is very common among doctors, and is the preferred method of communication within the hospital. Mobile technology has the potential to revolutionise communication and clinical care and should be embraced. The introduction of new technology will inevitably change existing hospital dynamics, and consequently may create a new set of challenges that will require further work to explore in the future.