bluuebunny/crossref_metadata_2025_split huggingface dataset:
Enhanced Neutralizing Antibody Response Induced by Respiratory Syncytial Virus Prefusion F Protein Expressed by a Vaccine Candidate
Authors: Liang Bo , Surman Sonja , Amaro-Carambot Emerito , Kabatova Barbora , Mackow Natalie , Lingemann Matthias , Yang Lijuan , McLellan Jason S. , Graham Barney S. , Kwong Peter D. , Schaap-Nutt Anne , Collins Peter L. , Munir Shirin 
Published: July 2015

ABSTRACT
Respiratory syncytial virus (RSV) and human parainfluenza virus type 3 (HPIV3) are the first and second leading viral agents of severe respiratory tract disease in infants and young children worldwide. Vaccines are not available, and an RSV vaccine is particularly needed. A live attenuated chimeric recombinant bovine/human PIV3 (rB/HPIV3) vector expressing the RSV fusion (F) glycoprotein from an added gene has been under development as a bivalent vaccine against RSV and HPIV3. Previous clinical evaluation of this vaccine candidate suggested that increased genetic stability and immunogenicity of the RSV F insert were needed. This was investigated in the present study. RSV F expression was enhanced 5-fold by codon optimization and by modifying the amino acid sequence to be identical to that of an early passage of the original clinical isolate. This conferred a hypofusogenic phenotype that presumably reflects the original isolate. We then compared vectors expressing stabilized prefusion and postfusion versions of RSV F. In a hamster model, prefusion F induced increased quantity and quality of RSV-neutralizing serum antibodies and increased protection against wild-type (wt) RSV challenge. In contrast, a vector expressing the postfusion F was less immunogenic and protective. The genetic stability of the RSV F insert was high and was not affected by enhanced expression or the prefusion or postfusion conformation of RSV F. These studies provide an improved version of the previously well-tolerated rB/HPIV3-RSV F vaccine candidate that induces a superior RSV-neutralizing serum antibody response.

IMPORTANCE
Respiratory syncytial virus (RSV) and human parainfluenza virus type 3 (HPIV3) are two major causes of pediatric pneumonia and bronchiolitis. The rB/HPIV3 vector expressing RSV F protein is a candidate bivalent live vaccine against HPIV3 and RSV. Previous clinical evaluation indicated the need to increase the immunogenicity and genetic stability of the RSV F insert. Here, we increased RSV F expression by codon optimization and by modifying the RSV F amino acid sequence to conform to that of an early passage of the original isolate. This resulted in a hypofusogenic phenotype, which likely represents the original phenotype before adaptation to cell culture. We also included stabilized versions of prefusion and postfusion RSV F protein. Prefusion RSV F induced a larger quantity and higher quality of RSV-neutralizing serum antibodies and was highly protective. This provides an improved candidate for further clinical evaluation.
Microplitis demolitor Bracovirus Proviral Loci and Clustered Replication Genes Exhibit Distinct DNA Amplification Patterns during Replication
Authors: Burke Gaelen R. , Simmonds Tyler J. , Thomas Sarah A. , Strand Michael R. 
Published: July 2015

ABSTRACT

Polydnaviruses are large, double-stranded DNA viruses that are beneficial symbionts of parasitoid wasps. Polydnaviruses in the genus
Bracovirus
(BVs) persist in wasps as proviruses, and their genomes consist of two functional components referred to as proviral segments and nudivirus-like genes. Prior studies established that the DNA domains where proviral segments reside are amplified during replication and that segments within amplified loci are circularized before packaging into nucleocapsids. One DNA domain where nudivirus-like genes are located is also amplified but never packaged into virions. We recently sequenced the genome of the braconid
Microplitis demolitor
, which carries
M. demolitor
bracovirus (MdBV). Here, we took advantage of this resource to characterize the DNAs that are amplified during MdBV replication using a combination of Illumina and Pacific Biosciences sequencing approaches. The results showed that specific nucleotide sites identify the boundaries of amplification for proviral loci. Surprisingly, however, amplification of loci 3, 4, 6, and 8 produced head-to-tail concatemeric intermediates; loci 1, 2, and 5 produced head-to-head/tail-to-tail concatemers; and locus 7 yielded no identified concatemers. Sequence differences at amplification junctions correlated with the types of amplification intermediates the loci produced, while concatemer processing gave rise to the circularized DNAs that are packaged into nucleocapsids. The MdBV nudivirus-like gene cluster was also amplified, albeit more weakly than most proviral loci and with nondiscrete boundaries. Overall, the MdBV genome exhibited three patterns of DNA amplification during replication. Our data also suggest that PacBio sequencing could be useful in studying the replication intermediates produced by other DNA viruses.

IMPORTANCE
Polydnaviruses are of fundamental interest because they provide a novel example of viruses evolving into beneficial symbionts. All polydnaviruses are associated with insects called parasitoid wasps, which are of additional applied interest because many are biological control agents of pest insects. Polydnaviruses in the genus
Bracovirus
(BVs) evolved ∼100 million years ago from an ancestor related to the baculovirus-nudivirus lineage but have also established many novelties due to their symbiotic lifestyle. These include the fact that BVs are transmitted only vertically as proviruses and produce replication-defective virions that package only a portion of the viral genome. Here, we studied
Microplitis demolitor
bracovirus (MdBV) and report that its genome exhibits three distinct patterns of DNA amplification during replication. We also identify several previously unknown features of BV genomes that correlate with these different amplification patterns.
Insights into Chronic Wasting Disease and Bovine Spongiform Encephalopathy Species Barriers by Use of Real-Time Conversion
Authors: Davenport Kristen A. , Henderson Davin M. , Bian Jifeng , Telling Glenn C. , Mathiason Candace K. , Hoover Edward A. 
Published: July 2015

ABSTRACT

The propensity for transspecies prion transmission is related to the structural characteristics of the enciphering and new host PrP, although the exact mechanism remains incompletely understood. The effects of variability in prion protein on cross-species prion transmission have been studied with animal bioassays, but the influence of prion protein structure versus that of host cofactors (e.g., cellular constituents, trafficking, and innate immune interactions) remains difficult to dissect. To isolate the effects of protein-protein interactions on transspecies conversion, we used recombinant PrP
C
and real-time quaking-induced conversion (RT-QuIC) and compared chronic wasting disease (CWD) and classical bovine spongiform encephalopathy (cBSE) prions. To assess the impact of transmission to a new species, we studied feline CWD (fCWD) and feline BSE (i.e., feline spongiform encephalopathy [FSE]). We cross-seeded fCWD and FSE into each species' full-length, recombinant PrP
C
and measured the time required for conversion to the amyloid (PrP
Res
) form, which we describe here as the rate of amyloid conversion. These studies revealed the following: (i) CWD and BSE seeded their homologous species' PrP best; (ii) fCWD was a more efficient seed for feline rPrP than for white-tailed deer rPrP; (iii) conversely, FSE more efficiently converted bovine than feline rPrP; (iv) and CWD, fCWD, BSE, and FSE all converted human rPrP, although not as efficiently as homologous sCJD prions. These results suggest that (i) at the level of protein-protein interactions, CWD adapts to a new species more readily than does BSE and (ii) the barrier preventing transmission of CWD to humans may be less robust than estimated.

IMPORTANCE
We demonstrate that bovine spongiform encephalopathy prions maintain their transspecies conversion characteristics upon passage to cats but that chronic wasting disease prions adapt to the cat and are distinguishable from the original prion. Additionally, we showed that chronic wasting disease prions are effective at seeding the conversion of normal human prion protein to an amyloid conformation, perhaps the first step in crossing the species barrier.
The Gut-Associated Lymphoid Tissues in the Small Intestine, Not the Large Intestine, Play a Major Role in Oral Prion Disease Pathogenesis
Authors: Donaldson David S. , Else Kathryn J. , Mabbott Neil A. 
Published: July 2015

ABSTRACTPrion diseases are infectious neurodegenerative disorders characterized by accumulations of abnormally folded cellular prion protein in affected tissues. Many natural prion diseases are acquired orally, and following exposure, the early replication of some prion isolates upon follicular dendritic cells (FDC) within gut-associated lymphoid tissues (GALT) is important for the efficient spread of disease to the brain (neuroinvasion). Prion detection within large intestinal GALT biopsy specimens has been used to estimate human and animal disease prevalence. However, the relative contributions of the small and large intestinal GALT to oral prion pathogenesis were unknown. To address this issue, we created mice that specifically lacked FDC-containing GALT only in the small intestine. Our data show that oral prion disease susceptibility was dramatically reduced in mice lacking small intestinal GALT. Although these mice had FDC-containing GALT throughout their large intestines, these tissues were not early sites of prion accumulation or neuroinvasion. We also determined whether pathology specifically within the large intestine might influence prion pathogenesis. Congruent infection with the nematode parasiteTrichuris murisin the large intestine around the time of oral prion exposure did not affect disease pathogenesis. Together, these data demonstrate that the small intestinal GALT are the major early sites of prion accumulation and neuroinvasion after oral exposure. This has important implications for our understanding of the factors that influence the risk of infection and the preclinical diagnosis of disease.IMPORTANCEMany natural prion diseases are acquired orally. After exposure, the accumulation of some prion diseases in the gut-associated lymphoid tissues (GALT) is important for efficient spread of disease to the brain. However, the relative contributions of GALT in the small and large intestines to oral prion pathogenesis were unknown. We show that the small intestinal GALT are the essential early sites of prion accumulation. Furthermore, congruent infection with a large intestinal helminth (worm) around the time of oral prion exposure did not affect disease pathogenesis. This is important for our understanding of the factors that influence the risk of prion infection and the preclinical diagnosis of disease. The detection of prions within large intestinal GALT biopsy specimens has been used to estimate human and animal disease prevalence. However, our data suggest that using these biopsy specimens may miss individuals in the early stages of oral prion infection and significantly underestimate the disease prevalence.
Aspergillus
Biofilm
In Vitro
and
In Vivo
Authors: Beauvais Anne , Latgé Jean-Paul 
Published: July 2015

ABSTRACT

In vivo, Aspergillus fumigatus
grows as a typical biofilm with hyphae covered by an extracellular matrix (ECM) composed of polysaccharides, galactomannan, and galactosaminogalactan. α1,3 glucans and melanin are also constitutive of the ECM in aspergilloma but not in invasive aspergillosis.
In vitro
, two biofilm models were established to mimic the
in vivo
situation. The first model (model 1) uses submerged liquid conditions and is characterized by slow growth, while the second model (model 2) uses agar medium and aerial conditions and is characterized by rapid growth. The composition of the ECM was studied only in the second model and has been shown to be composed of galactomannan, galactosaminogalactan (GAG), and α1,3 glucans, melanin, antigens, and hydrophobins. The presence of extracellular DNA was detected in model 1 biofilm but not in model 2. Transcriptomic analysis employing both biofilm models showed upregulation of genes coding for proteins involved in the biosynthesis of secondary metabolites, adhesion, and drug resistance. However, most data on
A. fumigatus
biofilms have been obtained
in vitro
and should be confirmed using
in vivo
animal models. There is a need for new therapeutic antibiofilm strategies that focus on the use of combination therapy, since biofilm formation poses an important clinical problem due to their resistance to antifungal agents. Furthermore,
in vivo
investigations of
A. fumigatus
biofilms that incorporate the associated microbiota are needed. Such studies will add another layer of complexity to our understanding of the role of
A. fumigatus
biofilm during lung invasion.
Sustained virological response and its treatment predictors in hepatitis C virus genotype 4 compared to genotypes 1, 2, and 3: a meta-analysis
Authors: Yee Brittany E , Nguyen Nghia H , Zhang Bing , Lin Derek , Vutien Philip , Wong Carrie R , Lutchman Glen A , Nguyen Mindie H 
Published: July 2015

BackgroundPegylated interferon and ribavirin (PEG-IFN+RBV) may be more cost-effective than direct-acting antivirals in resource-limited settings. Current literature suggests sustained virological response (SVR) in hepatitis C virus genotype 4 (HCV-4) is similar to genotype 1 (HCV-1), but worse than 2 and 3 (HCV-2/3). However, few studies have compared treatment response between these groups and these have been limited by small sample sizes with heterogeneous designs. We performed a meta-analysis of SVR predictors in HCV-4 versus HCV-1, 2, and 3 patients treated with PEG-IFN+RBV.MethodsIn November 2013, we searched for ‘genotype 4’ in MEDLINE/EMBASE databases and scientific conferences. We included original articles with ≥25 treatment-naïve HCV-4 and comparisons to HCV-1, 2, and/or 3 patients treated with PEG-IFN+RBV. Random effects modelling was used with heterogeneity defined by Cochrane Q-test (p value<0.10) and I2statistic (>50%).ResultsFive studies with 20 014 patients (899 HCV-4; 12 033 HCV-1; and 7082 HCV-2/3 patients) were included. SVR was 53% (CI 43% to 62%) for HCV-4, 44% (CI 40% to 47%) for HCV-1; and 73% (CI 58% to 84%) for HCV-2/3. SVR with EVR (early virological response) was 75% (CI 61% to 86%) in HCV-4; 64% (CI 46% to 79%) in HCV-1; and 85% (CI 71% to 93%) in HCV-2/3. SVR without EVR was 10% (CI 6% to 17%) for HCV-4; 13% (CI 12% to 15%) for HCV-1; and 23% (CI 16% to 33%) for HCV-2/3.ConclusionsSVR rates are similar in HCV-4 (∼50%) and HCV-1 (∼40%). Lack of EVR is a good stopping rule for HCV-4 and HCV-1 since only 10% subsequently achieve SVR. In HCV-4 patients with EVR, three-quarters can expect to achieve SVR with PEG-IFN+RBV.
Evaluation of the fidelity of an interactive face-to-face educational intervention to improve general practitioner management of back pain
Authors: French Simon D , Green Sally E , Francis Jill J , Buchbinder Rachelle , O'Connor Denise A , Grimshaw Jeremy M , Michie Susan 
Published: July 2015

ObjectivesImplementation intervention effects can only be fully realised and understood if they are faithfully delivered. However the evaluation of implementation intervention fidelity is not commonly undertaken. The IMPLEMENT intervention was designed to improve the management of low back pain by general medical practitioners. It consisted of a two-session interactive workshop, including didactic presentations and small group discussions by trained facilitators. This study aimed to evaluate the fidelity of the IMPLEMENT intervention by assessing: (1) observed facilitator adherence to planned behaviour change techniques (BCTs); (2) comparison of observed and self-reported adherence to planned BCTs and (3) variation across different facilitators and different BCTs.DesignThe study compared planned and actual, and observed versus self-assessed delivery of BCTs during the IMPLEMENT workshops.MethodWorkshop sessions were audiorecorded and transcribed verbatim. Observed adherence of facilitators to the planned intervention was assessed by analysing the workshop transcripts in terms of BCTs delivered. Self-reported adherence was measured using a checklist completed at the end of each workshop session and was compared with the ‘gold standard’ of observed adherence using sensitivity and specificity analyses.ResultsThe overall observed adherence to planned BCTs was 79%, representing moderate-to-high intervention fidelity. There was no significant difference in adherence to BCTs between the facilitators. Sensitivity of self-reported adherence was 95% (95% CI 88 to 98) and specificity was 30% (95% CI 11 to 60).ConclusionsThe findings suggest that the IMPLEMENT intervention was delivered with high levels of adherence to the planned intervention protocol.Trial registration numberThe IMPLEMENT trial was registered in the Australian New Zealand Clinical Trials Registry, ACTRN012606000098538 (http://www.anzctr.org.au/trial_view.aspx?ID=1162).
Prospective cohort study protocol to describe the transfer of patients from intensive care units to hospital wards
Authors: Buchner Denise L , Bagshaw Sean M , Dodek Peter , Forster Alan J , Fowler Robert A , Lamontagne François , Turgeon Alexis F , Potestio Melissa , Stelfox Henry T 
Published: July 2015

IntroductionThe transfer of patient care between the intensive care unit (ICU) and the hospital ward is associated with increased risk of medical error and adverse events. This study will describe patient transfer from ICU to hospital ward by documenting (1) patient, family and provider experiences related to ICU transfer, (2) communication between stakeholders involved in ICU transfer, (3) adverse events that follow ICU transfer and (4) opportunities to improve ICU to hospital ward transfer.MethodsThis is a mixed methods prospective observational study of ICU to hospital ward transfer practices in 10 ICUs across Canada. We will recruit 50 patients at each site (n=500) who are transferred from ICU to hospital ward, and distribute surveys to enrolled patients, family members, and healthcare providers (ICU and ward physicians and nurses) after patient transfer. A random sample of 6 consenting study participants (patients, family members, healthcare providers) from each study site (n=60) will be offered an opportunity to participate in interviews to further describe stakeholders’ experience with ICU to hospital ward transfer. We will abstract information from patient health records to identify clinical data and use of transfer tools, and identify adverse events that are related to the transfer.Ethics and DisseminationResearch ethics board approval has been obtained at the coordinating study centre (UofC REB13-0021) and 5 study sites (UofA Pro00050646; UBC-PHC H14-01667; Sunnybrook 336-2014; QCH 14-07; Sherbrooke 14-172). Dissemination of the findings will provide a comprehensive description of transfer from ICU to hospital ward in Canada including the uptake of validated or local transfer tools, a conceptual framework of the experiences and needs of stakeholders in the ICU transfer process, a summary of adverse events experienced by patients after transfer from ICU to hospital ward, and opportunities to guide quality improvement efforts.
Inverting multispectral thermal time-series images of volcanic eruptions for lava emplacement models
Authors: Barnie T. D. , Oppenheimer C. 
Published: July 2015

Abstract
We present a novel method for interpreting time series of multispectral observations of volcanic eruptions. We show how existing models relating to radiance and area emplacement can be generalized into an integration-convolution of a Net Area Emplacement (NAE) function and a cooling function, assuming all surfaces follow the same cooling curve. The NAE describes the variation in the rate of emplacement of hot material with time and temperature, while the cooling function describes the cooling of a hot surface with time. Discretizing the integration-convolution equation yields an underdetermined matrix equation that we solve using second-order Tikhonov regularization to stabilize the solution. We test the inversion by modelling plausible NAE surfaces, calculating the radiances, adding noise and inverting for the original surface. Three or more spectral bands are required to capture the overall shape of the NAE, and recovering specific quantities is difficult. Single wavebands that yield flat kernels recover the total area emplacement curve (rate of increase of hot area – the integral of the NAE with respect to temperature) surprisingly well due to their property of conserving NAE, suggesting novel methods for calculating area emplacement rates (and effusion rates) from time series of satellite images and radiometer measurements.
Where Can Colorectal Cancer Screening Interventions Have the Most Impact?
Authors: Siegel Rebecca L. , Sahar Liora , Robbins Anthony , Jemal Ahmedin 
Published: July 2015

Abstract
Background: Although colorectal cancer death rates in the United States have declined by half since 1970, large geographic disparities persist. Spatial identification of high-risk areas can facilitate targeted screening interventions to close this gap.
Methods: We used the Getis-Ord Gi* statistic within ArcGIS to identify contemporary colorectal cancer “hotspots” (spatial clusters of counties with high rates) based on county-level mortality data from the national vital statistics system. Hotspots were compared with the remaining aggregated counties (non-hotspot United States) by plotting trends from 1970 to 2011 and calculating rate ratios (RR). Trends were quantified using joinpoint regression.
Results: Spatial mapping identified three distinct hotspots in the contemporary United States where colorectal cancer death rates were elevated. The highest rates were in the largest hotspot, which encompassed 94 counties in the Lower Mississippi Delta [Arkansas (17), Illinois (16), Kentucky (3), Louisiana (6), Mississippi (27), Missouri (15), and Tennessee (10)]. During 2009 to 2011, rates here were 40% higher than the non-hotspot United States [RR, 1.40; 95% confidence interval (CI), 1.34–1.46], despite being 18% lower during 1970 to 1972 (RR, 0.82; 95% CI, 0.78–0.86). The elevated risk was similar in blacks and whites. Notably, rates among black men in the Delta increased steadily by 3.5% per year from 1970 to 1990, and have since remained unchanged. Rates in hotspots in west central Appalachia and eastern Virginia/North Carolina were 18% and 9% higher, respectively, than the non-hotspot United States during 2009 to 2011.
Conclusions: Advanced spatial analysis revealed large pockets of the United States with excessive colorectal cancer death rates.
Impact: These well-defined areas warrant prioritized screening intervention. Cancer Epidemiol Biomarkers Prev; 24(8); 1151–6. ©2015 AACR.