bluuebunny/crossref_metadata_2025 huggingface dataset:
The Effect of Size and Location of Tears in the Supraspinatus Tendon on Potential Tear Propagation
Authors: Thunes James , Matthew Miller R. , Pal Siladitya , Damle Sameer , Debski Richard E. , Maiti Spandan
Published: June 2015

Rotator cuff tears are a common problem in patients over the age of 50 yr. Tear propagation is a potential contributing factor to the failure of physical therapy for treating rotator cuff tears, thus requiring surgical intervention. However, the evolution of tears within the rotator cuff is not well understood yet. The objective of this study is to establish a computational model to quantify initiation of tear propagation in the supraspinatus tendon and examine the effect of tear size and location. A 3D finite element (FE) model of the supraspinatus tendon was constructed from images of a healthy cadaveric tendon. A tear of varying length was placed at six different locations within the tendon. A fiber-reinforced Mooney–Rivlin material model with spatial variation in material properties along the anterior–posterior (AP) axis was utilized to obtain the stress state of the computational model under uniaxial stretch. Material parameters were calibrated by comparing computational and experimental stress–strain response and used to validate the computational model. The stress state of the computational model was contrasted against the spatially varying material strength to predict the critical applied stretch at which a tear starts propagating further. It was found that maximum principal stress (as well as the strain) was localized at the tips of the tear. The computed critical stretch was significantly lower for the posterior tip of the tear than for the anterior tip suggesting a propensity to propagate posteriorly. Onset of tear propagation was strongly correlated with local material strength and stiffness in the vicinity of the tear tip. Further, presence of a stress-shielded zone along the edges of the tear was observed. This study illustrates the complex interplay between geometry and material properties of tendon up to the initiation of tear propagation. Future work will examine the evolution of tears during the propagation process as well as under more complex loading scenarios.
Graph-Based Simplification of Feature-Based Three-Dimensional Computer-Aided Design Models for Preserving Connectivity
Authors: Kwon Soonjo , Chul Kim Byung , Mun Duhwan , Han Soonhung
Published: June 2015

The required level of detail (LOD) of a three-dimensional computer-aided design (3D CAD) model differs according to its purpose. It is therefore important that users are able to simplify a highly complex 3D CAD model and create a low-complexity one. The simplification of a 3D CAD model requires the application of a simplification operation and evaluation metrics for the geometric elements of the 3D CAD model. The evaluation metrics are used to select those elements that should be removed. The simplification operation removes selected elements in order to simplify the 3D CAD model. In this paper, we propose the graph-based simplification of feature-based 3D CAD models using a method that preserves connectivity. First, new evaluation metrics that consider the discrimination priority among several simplification criteria are proposed. Second, a graph-based refined simplification operation that prevents the separation of a feature-based 3D CAD model into multiple volumes is proposed. Finally, we verify the proposed method by implementing a prototype system and performing simplification experiments using feature-based 3D CAD models.
Biomechanical Properties of Human Ascending Thoracic Aortic Dissections
Authors: Babu Anju R. , Byju Achu G. , Gundiah Namrata
Published: June 2015

Thoracic aortic dissections are associated with a significant risk of morbidity and mortality, and currently challenge our understanding of the biomechanical factors leading to their initiation and propagation. We quantified the biaxial mechanical properties of human type A dissections (n = 16) and modeled the stress–strain data using a microstructurally motivated form of strain energy function. Our results show significantly higher stiffness for dissected tissues as compared to control aorta without arterial disease. Higher stiffness of dissected tissues did not, however, correlate with greater aortic diameter measured prior to surgery nor were there any age dependent differences in the tissue properties.
High Rake Angle Orthogonal Machining of Highly Ordered Pyrolytic Graphite Parallel to the Basal Plane
Authors: Jayasena B. , Subbiah S. , Reddy C. D.
Published: June 2015

High rake angle orthogonal machining of highly ordered pyrolytic graphite (HOPG) parallel to the basal plane was carried out to synthesize few layers of graphene. The quality of the graphite sheets was found to be an alliance of any pre-existing defects in the HOPG and the nature of the machining process itself. Presence of pre-existing defects such as kinks and discontinuous layers were observed during the lateral examination of HOPG structure prior to machining. Evidence of flat, folded, and rolled structures were found in exfoliated graphite sheets in addition to defects such as two types of kink bands. Multiple spikes in measured cutting forces were seen during machining due to disturbances in tool movement. Molecular dynamic simulations were carried out to support the argument that specific pre-existing defects such as discontinuous layers cause the marked disturbances during machining.
Pulsed laser assisted synthesis of Ho3+/Yb3+ codoped CaMoO4 nanocolloid and its upconversion luminescence
Authors: Cho Kyoungwon , Choi Jaeha , Mhin Sungwook , Kim Kang Min , Lee Jung-Il , Ryu Jeong Ho
Published: June 2015

The authors report a novel synthetic route for Ho3+/Yb3+ codoped calcium molybdate (CaMoO4) nanoparticles by pulsed laser ablation in ethanol. Well-dispersed Ho3+/Yb3+ codoped CaMoO4 nanocolloid was prepared without any surfactant. Crystallographic information, microstructure, and the upconversion (UC) luminescent properties of the nanocolloid were investigated. Under the excitation at 980 nm, Ho3+/Yb3+ codoped CaMoO4 nanocolloid exhibited strong yellow emission visible to the naked eyes, which is the combination of green emission near 542 nm and strong red emission around 656 nm. Based on the pump power dependence, UC mechanism of Ho3+/Yb3+ codoped CaMoO4 nanocolloid was discussed in detail.
Magnetoelectric domain control in multiferroic TbMnO
3
Authors: Matsubara Masakazu , Manz Sebastian , Mochizuki Masahito , Kubacka Teresa , Iyama Ayato , Aliouane Nadir , Kimura Tsuyoshi , Johnson Steven L. , Meier Dennis , Fiebig Manfred
Published: June 2015

Visualizing ferroelectric domains

Multiferroic materials support intertwined ferromagnetic and ferroelectric orders, with the magnetic field capable of controlling the electric order and vice versa. Matsubara
et al.
used second harmonic generation microscopy to visualize what happens to the ferroelectric domains in the multiferroic TbMnO
3
when an externally applied magnetic field changes the direction of electric polarization by 90°. Unexpectedly, the domain walls, initially parallel to the polarization vector, did not change their shape or position. The resulting transition from neutral to charged domain walls may help in the development of future ferroelectric devices.

Science
, this issue p.
1112
Hawaii's governor proposes telescope swap
Authors: Cho Adrian , Loomis Ilima
Published: June 2015

Thirty Meter Telescope can move forward, but existing instruments must be culled.
Understanding our origins
The Strange Case of the Rickety Cossack And Other Cautionary Tales from Human Evolution
Ian Tattersall
Palgrave Macmillan, 2015. 256 pp.
Authors: Milam Erika Lorraine
Published: June 2015

How a long tradition of exceptionalism distorted our perception of human evolution.
Slippery when dry
Authors: Hone James , Carpick Robert W.
Published: June 2015

Stiff nanodiamond particles encapsulated in graphene can substantially reduce friction for water-free macroscopic surfaces

[Also see Report by

Berman
et al.

]
Controlling friction atom by atom
Authors: Meyer Ernst
Published: June 2015

A cold-atom system is used to probe atomic friction on the scale of single atoms

[Also see Report by

Bylinskii
et al.

]
Invisible barriers to dispersal
Authors: Kleypas Joan
Published: June 2015

Physiological properties constrain future range expansions of marine organisms

[Also see Reports by

Deutsch
et al.

and

Muir
et al.

]
TH17-Mediated Protection against Pneumococcal Carriage by a Whole-Cell Vaccine Is Dependent on Toll-Like Receptor 2 and Surface Lipoproteins
Authors: Moffitt K. , Howard A. , Martin S. , Cheung E. , Herd M. , Basset A. , Malley R.
Published: June 2015

A pneumococcal whole-cell vaccine (WCV) confers TH17-mediated immunogenicity and reduces nasopharyngeal (NP) carriage in mice. Activation of Toll-like receptor 2 (TLR2) has been shown to be important for generating TH17 responses, and several lipidated pneumococcal proteins have TLR2-activating properties. Here we investigated the roles of TLR2 and lipidation of proteins in WCV-induced interleukin-17A (IL-17A) responses and protection against NP carriage. Immunization ofTlr2−/−mice with WCV conferred significantly lower IL-17A levels and reduced protection against NP carriage, compared to wild-type (WT) mice, suggesting that host TLR2 engagement is required for effective immunity and protection elicited by WCV immunization. Using a WCV with deletion oflgt, the gene encoding the enzyme required for lipidation and membrane attachment of prolipoproteins, we show that lipidation and membrane localization of these proteins are critical for the immunogenicity and protective efficacy of the WCV. To evaluate the roles of diacylglyceryl transferase (Lgt)-mediated processes in the recall of WCV-induced protective responses, we colonized WCV-immunized animals with a strain in whichlgtwas deleted. WCV-immunized animals still had significantly reduced colonization burdens, compared to control animals, which suggests that lipidation and membrane localization of pneumococcal prolipoproteins are less critical for the recall of the immune responses elicited by WCV immunization than for the priming of such responses. Elucidation of underlying immune mechanisms and the optimal characteristics of WCV formulations can help guide vaccine development and enhance our understanding of host-pneumococcus interactions.
Bacillus anthracis Capsular Conjugates Elicit Chimpanzee Polyclonal Antibodies That Protect Mice from Pulmonary Anthrax
Authors: Chen Zhaochun , Schneerson Rachel , Lovchik Julie A. , Dai Zhongdong , Kubler-Kielb Joanna , Agulto Liane , Leppla Stephen H. , Purcell Robert H.
Published: June 2015

The immunogenicity of
Bacillus anthracis
capsule (poly-γ-
d
-glutamic acid [PGA]) conjugated to recombinant
B. anthracis
protective antigen (rPA) or to tetanus toxoid (TT) was evaluated in two anthrax-naive juvenile chimpanzees. In a previous study of these conjugates, highly protective monoclonal antibodies (MAbs) against PGA were generated. This study examines the polyclonal antibody response of the same animals. Preimmune antibodies to PGA with titers of >10
3
were detected in the chimpanzees. The maximal titer of anti-PGA was induced within 1 to 2 weeks following the 1st immunization, with no booster effects following the 2nd and 3rd immunizations. Thus, the anti-PGA response in the chimpanzees resembled a secondary immune response. Screening of sera from nine unimmunized chimpanzees and six humans revealed antibodies to PGA in all samples, with an average titer of 10
3
. An anti-PA response was also observed following immunization with PGA-rPA conjugate, similar to that seen following immunization with rPA alone. However, in contrast to anti-PGA, preimmune anti-PA antibody titers and those following the 1st immunization were ≤300, with the antibodies peaking above 10
4
following the 2nd immunization. The polyclonal anti-PGA shared the MAb 11D epitope and, similar to the MAbs, exerted opsonophagocytic killing of
B. anthracis
. Most important, the PGA-TT–induced antibodies protected mice from a lethal challenge with virulent
B. anthracis
spores. Our data support the use of PGA conjugates, especially PGA-rPA targeting both toxin and capsule, as expanded-spectrum anthrax vaccines.
Serological Correlates of Protection against a GII.4 Norovirus
Authors: Atmar Robert L. , Bernstein David I. , Lyon G. Marshall , Treanor John J. , Al-Ibrahim Mohamed S. , Graham David Y. , Vinjé Jan , Jiang Xi , Gregoricus Nicole , Frenck Robert W. , Moe Christine L. , Chen Wilbur H. , Ferreira Jennifer , Barrett Jill , Opekun Antone R. , Estes Mary K. , Borkowski Astrid , Baehner Frank , Goodwin Robert , Edmonds Anthony , Mendelman Paul M.
Published: June 2015

Noroviruses are the leading cause of acute gastroenteritis worldwide, and norovirus vaccine prevention strategies are under evaluation. The immunogenicity of two doses of bivalent genogroup 1 genotype 1 (GI.1)/GII.4 (50 μg of virus-like particles [VLPs] of each strain adjuvanted with aluminum hydroxide and 3-
O
-desacyl-4′monophosphoryl lipid A [MPL]) norovirus vaccine administered to healthy adults in a phase 1/2 double-blind placebo-controlled trial was determined using virus-specific serum total antibody enzyme-linked immunosorbent assay (ELISA), IgG, IgA, and histoblood group antigen (HBGA)-blocking assays. Trial participants subsequently received an oral live virus challenge with a GII.4 strain, and the vaccine efficacy results were reported previously (D. I. Bernstein et al., J Infect Dis 211:870–878, 2014, doi:
10.1093/infdis/jiu497
). This report assesses the impact of prechallenge serum antibody levels on infection and illness outcomes. Serum antibody responses were observed in vaccine recipients by all antibody assays, with first-dose seroresponse frequencies ranging from 88 to 100% for the GI.1 antigen and from 69 to 84% for the GII.4 antigen. There was little increase in antibody levels after the second vaccine dose. Among the subjects receiving the placebo, higher prechallenge serum anti-GII.4 HBGA-blocking and IgA antibody levels, but not IgG or total antibody levels, were associated with a lower frequency of virus infection and associated illness. Notably, some placebo subjects without measurable serum antibody levels prechallenge did not become infected after norovirus challenge. In vaccinees, anti-GII.4 HBGA-blocking antibody levels of >1:500 were associated with a lower frequency of moderate-to-severe vomiting or diarrheal illness. In this study, prechallenge serum HBGA antibody titers correlated with protection in subjects receiving the placebo; however, other factors may impact the likelihood of infection and illness after virus exposure. (This study is registered at ClinicalTrials.gov under registration number NCT1609257.)
Creation of an In-House Matrix-Assisted Laser Desorption Ionization–Time of Flight Mass Spectrometry Corynebacterineae Database Overcomes Difficulties in Identification of Nocardia farcinica Clinical Isolates
Authors: Paściak Mariola , Dacko Władysław , Sikora Joanna , Gurlaga Danuta , Pawlik Krzysztof , Miękisiak Grzegorz , Gamian Andrzej
Published: June 2015

Nocardiosis is a rare disease that is caused by Gram-positive actinobacteria of the
Nocardia
genus and affects predominantly immunocompromised patients. In its disseminated form, it has a predilection for the central nervous system and is associated with high mortality rates. Therefore, prompt identification of the pathogen is critical. Matrix-assisted laser desorption ionization–time of flight (MALDI-TOF) mass spectrometry is a relatively novel technique used for identification of microorganisms. In this work, an upgraded MALDI-TOF Biotyper database containing
Corynebacterineae
representatives of strains deposited in the Polish Collection of Microorganisms was created and used for identification of the strain isolated from a nocardial brain abscess, mimicking a brain tumor, in an immunocompetent patient. Testing with the API Coryne system initially incorrectly identified
Rhodococcus
sp., while chemotaxonomic tests, especially mycolic acid analysis, enabled correct
Nocardia
identification only at the genus level. Subsequent sequence analysis of 16S rRNA and
secA1
genes confirmed the identification. To improve the accuracy of the results, an in-house database was constructed using optimized parameters; with the use of the database, the strain was eventually identified as
Nocardia farcinica
. Clinical laboratories processing various clinical strains can upgrade a commercial database to improve and to accelerate the results obtained. This is especially important in the case of
Nocardia
, for which valid microbial diagnosis remains challenging; reference laboratories are often required to identify and to survey these rare actinobacteria.
A Novel Quantitative Sampling Technique for Detection and Monitoring of Clostridium difficile Contamination in the Clinical Environment
Authors: Ali Shanom , Muzslay Monika , Wilson Peter
Published: June 2015

The horizontal transmission of
Clostridium difficile
in the hospital environment is difficult to establish. Current methods to detect
C. difficile
spores on surfaces are not quantitative, lack sensitivity, and are protracted. We propose a novel rapid method to detect and quantify
C. difficile
contamination on surfaces. Sponge swabbing was compared to contact plate sampling to assess the
in vitro
recovery of
C. difficile
ribotype 027 contamination (∼10
0
, 10
1
, or 10
2
CFU of spores) from test surfaces (a bed rail, a stainless steel sheet, or a polypropylene work surface). Sponge swab contents were concentrated by vacuum filtration, and the filter membrane was plated onto selective agar. The efficacy of each technique for the recovery of
C. difficile
from sites in the clinical environment that are touched at a high frequency was evaluated. Contact plates recovered 19 to 32% of the total contamination on test surfaces, whereas sponge swabs recovered 76 to 94% of the total contamination, and contact plates failed to detect
C. difficile
contamination below a detection limit of 10 CFU/25 cm
2
(0.4 CFU/cm
2
). In use, contact plates failed to detect
C. difficile
contamination (0/96 contact plates; 4 case wards), while sponge swabs recovered
C. difficile
from 29% (87/301) of the surfaces tested in the clinical environment. Approximately 74% (36/49) of the area in the vicinity of the patient was contaminated (∼1.34 ± 6.88 CFU/cm
2
C. difficile
spores). Reservoirs of
C. difficile
extended to beyond the areas near the patient: a dirty utility room sink (2.26 ± 5.90 CFU/cm
2
), toilet floor (1.87 ± 2.40 CFU/cm
2
), and chair arm (1.33 ± 4.69 CFU/cm
2
).
C. difficile
was present on floors in ∼90% of case wards. This study highlights that sampling with a contact plate may fail to detect
C. difficile
contamination and result in false-negative reporting. Our sponge sampling technique permitted the rapid and quantitative measurement of
C. difficile
contamination on surfaces with a sensitivity (limit, 0 CFU) greater than that which is otherwise possible. This technique could be implemented for routine surface hygiene monitoring for targeted cleaning interventions and as a tool to investigate routes of patient-patient transmission in the clinical environment.
Nocardia Septic Arthritis Complicating an Anterior Cruciate Ligament Repair
Authors: Yong Elaine X. L. , Cheong Elaine Y. L. , Boutlis Craig S. , Chen Darren B. , Liu Eunice Y.-T. , McKew Genevieve L.
Published: June 2015

Nocardia
infection following anterior cruciate ligament (ACL) allograft reconstruction is a rare occurrence. We report a case of
Nocardia
infection of an allograft ACL reconstruction and septic arthritis of the knee joint due to an organism most similar to the novel
Nocardia
species
Nocardia aobensis
.
Long-Range HIV Genotyping Using Viral RNA and Proviral DNA for Analysis of HIV Drug Resistance and HIV Clustering
Authors: Novitsky Vlad , Zahralban-Steele Melissa , McLane Mary Fran , Moyo Sikhulile , van Widenfelt Erik , Gaseitsiwe Simani , Makhema Joseph , Essex M.
Published: June 2015

The goal of the study was to improve the methodology of HIV genotyping for analysis of HIV drug resistance and HIV clustering. Using the protocol of Gall et al. (A. Gall, B. Ferns, C. Morris, S. Watson, M. Cotten, M. Robinson, N. Berry, D. Pillay, and P. Kellam, J Clin Microbiol 50:3838–3844, 2012, doi:10.1128/JCM.01516-12), we developed a robust methodology for amplification of two large fragments of viral genome covering about 80% of the unique HIV-1 genome sequence. Importantly, this method can be applied to both viral RNA and proviral DNA amplification templates, allowing genotyping in HIV-infected subjects with suppressed viral loads (e.g., subjects on antiretroviral therapy [ART]). The two amplicons cover critical regions across the HIV-1 genome (includingpolandenv), allowing analysis of mutations associated with resistance to protease inhibitors, reverse transcriptase inhibitors (nucleoside reverse transcriptase inhibitors [NRTIs] and nonnucleoside reverse transcriptase inhibitors [NNRTIs]), integrase strand transfer inhibitors, and virus entry inhibitors. The two amplicons generated span 7,124 bp, providing substantial sequence length and numbers of informative sites for comprehensive phylogenic analysis and greater refinement of viral linkage analyses in HIV prevention studies. The long-range HIV genotyping from proviral DNA was successful in about 90% of 212 targeted blood specimens collected in a cohort where the majority of patients had suppressed viral loads, including 65% of patients with undetectable levels of HIV-1 RNA loads. The generated amplicons could be sequenced by different methods, such as population Sanger sequencing, single-genome sequencing, or next-generation ultradeep sequencing. The developed method is cost-effective—the cost of the long-range HIV genotyping is under $140 per subject (by Sanger sequencing)—and has the potential to enable the scale up of public health HIV prevention interventions.
A Novel Solid Medium for Culturing Mycobacterium tuberculosis Isolates from Clinical Specimens
Authors: Asmar S. , Chatellier S. , Mirande C. , van Belkum A. , Canard I. , Raoult D. , Drancourt M.
Published: June 2015

The laboratory diagnosis of tuberculosis usually relies on culture-based isolation of the causative
Mycobacterium tuberculosis
bacteria. We developed and evaluated the performance of MOD9, a new blood-free derivative of the MOD4 solid medium on which we previously reported for the isolation and culture of mycobacteria. First, inoculation of Lowenstein-Jensen medium with 21
M. tuberculosis
isolates at 10
5
, 10
3
, and 10 CFU yielded colonies in 5.7 ± 1.5 days, 7.6 ± 0.8 days, and 10.8 ± 1.7 days versus 1.5 ± 0.4 days, 3.5 ± 0.6 days, and 4.9 ± 1 days in MOD9 (
P
< 0.05, Student's
t
test). Further, the time to detectable growth of
M. tuberculosis
was measured on MOD9 and Lowenstein-Jensen media after duplicate inoculation of 250 clinical specimens decontaminated with 0.7% chlorhexidine. The contamination rate was 1.6% (4/250) on MOD9 versus 4.4% (11/250) on Lowenstein-Jensen medium (
P
= 0.11, Fisher's exact test). Chlorhexidine-MOD9 yielded 38/250 (15.2%) isolates versus 32/250 (12.8%) isolates for the chlorhexidine-LJ (
P
= 0.5195, Fisher's exact test). All together, eight
M. tuberculosis
isolates were cultured solely from chlorhexidine-MOD9, and two
M. tuberculosis
isolates were cultured solely from chlorhexidine-LJ. The time to detection was 9.8 ± 3.9 (range, 5 to 18) days for chlorhexidine-MOD9 versus 17.4 ± 5.9 (range, 10 to 35) days for chlorhexidine-LJ (
P
< 0.05, Student's
t
test). These data indicate the superiority of the MOD9 medium over the standard LJ medium following chlorhexidine decontamination for the recovery of
M. tuberculosis
.
Thioredoxin 2 Is a Novel E2-Interacting Protein That Inhibits the Replication of Classical Swine Fever Virus
Authors: Li Su , Wang Jinghan , He Wen-Rui , Feng Shuo , Li Yongfeng , Wang Xiao , Liao Yajin , Qin Hua-Yang , Li Lian-Feng , Dong Hong , Sun Yuan , Luo Yuzi , Qiu Hua-Ji
Published: June 2015

The E2 protein of classical swine fever virus (CSFV) is an envelope glycoprotein that is involved in virus attachment and entry. To date, the E2-interacting cellular proteins and their involvement in viral replication have been poorly documented. In this study, thioredoxin 2 (Trx2) was identified to be a novel E2-interacting partner using yeast two-hybrid screening from a porcine macrophage cDNA library. Trx2 is a mitochondrion-associated protein that participates in diverse cellular events. The Trx2-E2 interaction was further confirmed by glutathione
S
-transferase (GST) pulldown,
in situ
proximity ligation, and laser confocal assays. The thioredoxin domain of Trx2 and the asparagine at position 37 (N37) in the E2 protein were shown to be critical for the interaction. Silencing of the Trx2 expression in PK-15 cells by small interfering RNAs significantly promotes CSFV replication, and conversely, overexpression of Trx2 markedly inhibits viral replication of the wild-type (wt) CSFV and to a greater extent that of the CSFV N37D mutant, which is defective in binding Trx2. The wt CSFV but not the CSFV N37D mutant was shown to reduce the Trx2 protein expression in PK-15 cells. Furthermore, we demonstrated that Trx2 increases nuclear factor kappa B (NF-κB) promoter activity by promoting the nuclear translocation of the p65 subunit of NF-κB. Notably, activation of the NF-κB signaling pathway induced by tumor necrosis factor alpha (TNF-α) significantly inhibits CSFV replication in PK-15 cells, whereas blocking the NF-κB activation in Trx2-overexpressing cells no longer suppresses CSFV replication. Taken together, our findings reveal that Trx2 inhibits CSFV replication via the NF-κB signaling pathway.

IMPORTANCE
Thioredoxin 2 (Trx2) is a mitochondrion-associated protein that participates in diverse cellular events, such as antioxidative and antiapoptotic processes and the modulation of transcription factors. However, little is known about the involvement of Trx2 in viral replication. Here, we investigated, for the first time, the role of Trx2 in the replication of classical swine fever virus (CSFV), a devastating pestivirus of pigs. By knockdown and overexpression, we showed that Trx2 negatively regulates CSFV replication. Notably, we demonstrated that Trx2 inhibits CSFV replication by promoting the nuclear translocation of the p65 subunit of NF-κB, a key regulator of the host's innate immunity and inflammatory response. Our findings reveal a novel role of Trx2 in the host's antiviral response and provide new insights into the complex mechanisms by which CSFV interacts with the host cell.
mRNA Capping by Venezuelan Equine Encephalitis Virus nsP1: Functional Characterization and Implications for Antiviral Research
Authors: Li Changqing , Guillén Jaime , Rabah Nadia , Blanjoie Alexandre , Debart Françoise , Vasseur Jean-Jacques , Canard Bruno , Decroly Etienne , Coutard Bruno
Published: June 2015

Alphaviruses are known to possess a unique viral mRNA capping mechanism involving the viral nonstructural protein nsP1. This enzyme harbors methyltransferase (MTase) and nsP1 guanylylation (GT) activities catalyzing the transfer of the methyl group from
S
-adenosylmethionine (AdoMet) to the N7 position of a GTP molecule followed by the formation of an m
7
GMP-nsP1 adduct. Subsequent transfer of m
7
GMP onto the 5′ end of the viral mRNA has not been demonstrated
in vitro
yet. Here we report the biochemical characterization of Venezuelan equine encephalitis virus (VEEV) nsP1. We have developed enzymatic assays uncoupling the different reactions steps catalyzed by nsP1. The MTase and GT reaction activities were followed using a nonhydrolyzable GTP (GIDP) substrate and an original Western blot assay using anti-m
3
G/m
7
G-cap monoclonal antibody, respectively. The GT reaction is stimulated by
S
-adenosyl-
l
-homocysteine (Ado-Hcy), the product of the preceding MTase reaction, and metallic ions. The covalent linking between nsP1 and m
7
GMP involves a phosphamide bond between the nucleotide and a histidine residue. Final guanylyltransfer onto RNA was observed for the first time with an alphavirus nsP1 using a 5′-diphosphate RNA oligonucleotide whose sequence corresponds to the 5′ end of the viral genome. Alanine scanning mutagenesis of residues H37, H45, D63, E118, Y285, D354, R365, N369, and N375 revealed their respective roles in MT and GT reactions. Finally, the inhibitory effects of sinefungin, aurintricarboxylic acid (ATA), and ribavirin triphosphate on MTase and capping reactions were investigated, providing possible avenues for antiviral research.

IMPORTANCE
Emergence or reemergence of alphaviruses represents a serious health concern, and the elucidation of their replication mechanisms is a prerequisite for the development of specific inhibitors targeting viral enzymes. In particular, alphaviruses are able, through an original reaction sequence, to add to their mRNA a cap required for their protection against cellular nucleases and initiation of viral proteins translation. In this study, the capping of a 5′ diphosphate synthetic RNA mimicking the 5′ end of an alphavirus mRNA was observed
in vitro
for the first time. The different steps for this capping are performed by the nonstructural protein 1 (nsP1). Reference compounds known to target the viral capping inhibited nsP1 enzymatic functions, highlighting the value of this enzyme in antiviral development.
Robust Protection against Highly Virulent Foot-and-Mouth Disease Virus in Swine by Combination Treatment with Recombinant Adenoviruses Expressing Porcine Alpha and Gamma Interferons and Multiple Small Interfering RNAs
Authors: Kim Su-Mi , Park Jong-Hyeon , Lee Kwang-Nyeong , Kim Se-Kyung , You Su-Hwa , Kim Taeseong , Tark Dongseob , Lee Hyang-Sim , Seo Min-Goo , Kim Byounghan
Published: June 2015

Because the currently available vaccines against foot-and-mouth disease (FMD) provide no protection until 4 to 7 days postvaccination, the only alternative method to halt the spread of the FMD virus (FMDV) during outbreaks is the application of antiviral agents. Combination treatment strategies have been used to enhance the efficacy of antiviral agents, and such strategies may be advantageous in overcoming viral mechanisms of resistance to antiviral treatments. We have developed recombinant adenoviruses (Ads) for the simultaneous expression of porcine alpha and gamma interferons (Ad-porcine IFN-αγ) as well as 3 small interfering RNAs (Ad-3siRNA) targeting FMDV mRNAs encoding nonstructural proteins. The antiviral effects of Ad-porcine IFN-αγ and Ad-3siRNA expression were tested in combination in porcine cells, suckling mice, and swine. We observed enhanced antiviral effects in porcine cells and mice as well as robust protection against the highly pathogenic strain O/Andong/SKR/2010 and increased expression of cytokines in swine following combination treatment. In addition, we showed that combination treatment was effective against all serotypes of FMDV. Therefore, we suggest that the combined treatment with Ad-porcine IFN-αγ and Ad-3siRNA may offer fast-acting antiviral protection and be used with a vaccine during the period that the vaccine does not provide protection against FMD.

IMPORTANCE
The use of current foot-and-mouth disease (FMD) vaccines to induce rapid protection provides limited effectiveness because the protection does not become effective until a minimum of 4 days after vaccination. Therefore, during outbreaks antiviral agents remain the only available treatment to confer rapid protection and reduce the spread of foot-and-mouth disease virus (FMDV) in livestock until vaccine-induced protective immunity can become effective. Interferons (IFNs) and small interfering RNAs (siRNAs) have been reported to be effective antiviral agents against FMDV, although the virus has associated mechanisms of resistance to type I interferons and siRNAs. We have developed recombinant adenoviruses for the simultaneous expression of porcine alpha and gamma interferons (Ad-porcine IFN-αγ) as well as 3 small interfering RNAs (Ad-3siRNA) to enhance the inhibitory effects of these antiviral agents observed in previous studies. Here, we show enhanced antiviral effects against FMDV by combination treatment with Ad-porcine IFN-αγ and Ad-3siRNA to overcome the mechanisms of resistance of FMDV in swine.
Mapping of a Region of the PA-X Protein of Influenza A Virus That Is Important for Its Shutoff Activity
Authors: Oishi Kohei , Yamayoshi Seiya , Kawaoka Yoshihiro
Published: June 2015

Influenza A virus PA-X comprises an N-terminal PA endonuclease domain and a C-terminal PA-X-specific domain. PA-X reduces host and viral mRNA accumulation via its endonuclease function. Here, we found that the N-terminal 15 amino acids, particularly six basic amino acids, in the C-terminal PA-X-specific region are important for PA-X shutoff activity. These six basic amino acids enabled a PA deletion mutant to suppress protein expression at a level comparable to that of wild-type PA-X.
Gestational age and adolescent mental health: evidence from Hong Kong's ‘Children of 1997’ birth cohort
Authors: Wang Hui , Leung Gabriel M , Lam HS , Schooling C Mary
Published: June 2015

Background

Preterm, and more recently early term, birth has been identified as a risk factor for poor health. Whether the sequelae of late preterm or early term birth extends to poor mental health and well-being in adolescence is unclear and has not been systematically assessed.

Method

Linear regression was used to assess the adjusted associations of gestational age (very/moderate preterm (<34 weeks, n=85), late preterm (34–36 weeks, n=305), early term (37–38 weeks, n=2228), full term (39–40 weeks, n=4018), late term (41 weeks, n=809), post-term (≥42 weeks, n=213)) with self-reported self-esteem at ∼11 years (n=6935), parent-reported Rutter score assessing the common emotional and behavioural problems at ∼7 years (n=6292) and ∼11 years (n=5596) and self-reported depressive symptoms at ∼13 years (n=5795) in a population-representative Hong Kong Chinese birth cohort ‘Children of 1997’ where gestational age has little social patterning.

Results

Very/moderate preterm birth was associated with higher Rutter subscore for hyperactivity (ß coefficients 0.5, 95% CI 0.01 to 1.00) at ∼7 years but not at ∼11 years, adjusted for sex, age, socio-economic position, parents’ age at birth, birth order and secondhand smoke exposure. Similarly adjusted, late preterm, early term, late term and post-term birth were not associated with self-esteem or depressive symptoms.

Conclusions

In a population-representative birth cohort from a non-Western-developed setting, gestational age had few associations with mental health and well-being in adolescence, whereas very preterm birth was specifically associated with hyperactivity in childhood. Inconsistencies with studies from Western settings suggest setting specific unmeasured confounding may underlie any observed associations.
Catheter ablation targeting Purkinje potentials controlled ventricular fibrillation in a patient with a malignant lymphoma occurring in the ventricular septum
Authors: Nakabayashi Keisuke , Sugiura Ryo , Oka Toshiaki
Published: June 2015

Malignant lymphoma is known to cause various types of arrhythmia, including ventricular fibrillation. However, radiofrequency catheter ablation of ventricular fibrillation associated with malignant lymphoma has never been reported. We describe the case of a 53-year-old man with refractory ventricular fibrillation that was associated with malignant lymphoma. Electrophysiological testing revealed that a Purkinje potential appeared before ventricular contraction at the tumour site. We successfully treated the ventricular fibrillation with radiofrequency catheter ablation, using the Purkinje potential as an indicator. Physicians should consider this treatment if ventricular fibrillation cannot be controlled using other strategies.
Is traditional Chinese medicine recommended in Western medicine clinical practice guidelines in China? A systematic analysis
Authors: Ren Jun , Li Xun , Sun Jin , Han Mei , Yang Guo-Yan , Li Wen-Yuan , Robinson Nicola , Lewith George , Liu Jian-Ping
Published: June 2015

Background

Evidence-based medicine promotes and relies on the use of evidence in developing clinical practice guidelines (CPGs). The Chinese healthcare system includes both traditional Chinese medicine (TCM) and Western medicine, which are expected to be equally reflected in Chinese CPGs.

Objective

To evaluate the inclusion of TCM-related information in Western medicine CPGs developed in China and the adoption of high level evidence.

Methods

All CPGs were identified from the China Guideline Clearinghouse (CGC), which is the main Chinese organisation maintaining the guidelines issued by the Ministry of Health of China, the Chinese Medical Association and the Chinese Medical Doctors’ Association.

TCM-related contents were extracted from all the CPGs identified. Extracted information comprised the institution issuing the guideline, date of issue, disease, recommendations relating to TCM, evidence level of the recommended content and references supporting the recommendations.

Results

A total of 604 CPGs were identified, only a small number of which (74/604; 12%) recommended TCM therapy and only five guidelines (7%) had applied evidence grading. The 74 CPGs involved 13 disease systems according to the International Classification of Diseases 10th edition. TCM was mainly recommended in the treatment part of the guidelines (73/74, 99%), and more than half of the recommendations (43/74, 58%) were related to Chinese herbal medicine (single herbs or herbal treatment based on syndrome differentiation).

Conclusions

Few Chinese Western medicine CPGs recommend TCM therapies and very few provide evidence grading for the TCM recommendation. We suggest that future guideline development should be based on systematic searches for evidence to support CPG recommendations and involve a multidisciplinary approach including TCM expertise.
Do patterns of mental healthcare predict treatment failure in young people with schizophrenia? Evidence from an Italian population-based cohort study
Authors: Corrao Giovanni , Soranna Davide , Merlino Luca , Monzani Emiliano , Viganò Caterina , Lora Antonio
Published: June 2015

Objective

Little is known about the practice of predicting community-based care effectiveness of patients affected by schizophrenic disorders. We assessed predictors of treatment failure in a large sample of young people affected by schizophrenia.

Methods

A cohort of 556 patients aged 18–35 years who were originally diagnosed with schizophrenia during 2005–2009 in a Mental Health Service (MHS) of the Italian Lombardy Region was identified. Intensity of mental healthcare received during the first year after index visit (exposure) was measured by patients’ regularity in MHS attendance and the length of time covered with antipsychotic drug therapy. Patients were followed from index visit until 2012 for identifying hospital admission for mental disorder (outcome). A proportional hazards model was fitted to estimate the HR and 95% CIs for the exposure-outcome association, after adjusting for several covariates. A set of sensitivity analyses were performed in order to account for sources of systematic uncertainty.

Results

During follow-up, 144 cohort members experienced the outcome. Compared with patients on low coverage with antipsychotic drugs (≤4 months), those on intermediate (5–8 months) and high (≥9 months) coverage, had HRs (95% CI) of 0.94 (0.64 to 1.40) and 0.69 (0.48 to 0.98), respectively. There was no evidence that regular attendance at the MHS affected the outcome.

Conclusions

Patients in the early phase of schizophrenia and their families should be cautioned about the possible consequences of poor antipsychotic adherence. Physicians and decision makers should increase their contribution towards improving mental healthcare.
The ETTAA study protocol: a UK-wide observational study of ‘Effective Treatments for Thoracic Aortic Aneurysm’
Authors: Sastry Priya , Hughes Victoria , Hayes Paul , Vallabhaneni Srinivasa , Sharples Linda , Thompson Matt , Catarino Pedro , Moorjani Narain , Vale Luke , Gray Joanne , Cook Andrew , Elefteriades John A , Large Stephen R
Published: June 2015

Introduction

Chronic thoracic aortic aneurysm (CTAA) affecting the arch or descending aorta is an indolent but life-threatening condition with a rising prevalence as the UK population ages. Treatment may be in the form of open surgical repair (OSR) surgery, endovascular stent grafting (ESG) or best medical therapy (BMT). Currently, there is no consensus on the best management strategy, and no UK-specific economic studies that assess outcomes beyond the chosen procedure, but this is required in the context of greater demand for treatment and limited National Health Service (NHS) resources.

Methods and analysis

This is a prospective, multicentre observational study with statistical and economic modelling of patients with CTAA affecting the arch or descending aorta. We aim to gain an understanding of how treatments are currently chosen, and to determine the clinical effectiveness and cost-effectiveness of the three available treatment strategies (BMT, ESG and OSR). This will be achieved by: (1) following consecutive patients who are referred to the teams collaborating in this proposal and collecting data regarding quality of life (QoL), medical events and hospital stays over a maximum of 5 years; (2) statistical analysis of the comparative effectiveness of the three treatments; and (3) economic modelling of the comparative cost-effectiveness of the three treatments. Primary study outcomes are: aneurysm growth, QoL, freedom from reintervention, freedom from death or permanent neurological injury, incremental cost per quality-adjusted life year gained.

Ethics and dissemination

The study will generate an evidence base to guide patients and clinicians to determine the indications and timing of treatment, as well as informing healthcare decision-makers about which treatments the NHS should provide. The study has achieved ethical approval and will be disseminated primarily in the form of a Health Technology Assessment monograph at its completion.

Trial registration number

ISRCTN04044627.
Associations between safety culture and employee engagement over time: a retrospective analysis
Authors: Daugherty Biddison Elizabeth Lee , Paine Lori , Murakami Peter , Herzke Carrie , Weaver Sallie J
Published: June 2015

With the growth of the patient safety movement and development of methods to measure workforce health and success have come multiple modes of assessing healthcare worker opinions and attitudes about work and the workplace. Safety culture, a group-level measure of patient safety-related norms and behaviours, has been proposed to influence a variety of patient safety outcomes. Employee engagement, conceptualised as a positive, work-related mindset including feelings of vigour, dedication and absorption in one's work, has also demonstrated an association with a number of important worker outcomes in healthcare. To date, the relationship between responses to these two commonly used measures has been poorly characterised. Our study used secondary data analysis to assess the relationship between safety culture and employee engagement over time in a sample of >50 inpatient hospital units in a large US academic health system. With >2000 respondents in each of three time periods assessed, we found moderate to strong positive correlations (r=0.43–0.69) between employee engagement and four Safety Attitudes Questionnaire domains. Independent collection of these two assessments may have limited our analysis in that minimally different inclusion criteria resulted in some differences in the total respondents to the two instruments. Our findings, nevertheless, suggest a key area in which healthcare quality improvement efforts might be streamlined.
What do patients want from their endoscopy experience? The importance of measuring and understanding patient attitudes to their care
Authors: Tierney M , Bevan R , Rees C J , Trebble T M
Published: June 2015

Understanding and addressing patient attitudes to their care facilitates their engagement and attendance, improves the quality of their experience and the appropriate utilisation of resources. Gastrointestinal endoscopy is a commonly performed medical procedure that can be associated with patient anxiety and apprehension. Measuring patient attitudes to endoscopy can be undertaken through a number of approaches with contrasting benefits and limitations. Methodological validation is necessary for accurate interpretation of results and avoiding bias. Retrospective post-procedure questionnaires measuring satisfaction are easily undertaken but have limited value, particularly in directing service improvements. Patient experience questionnaires indicate areas of poor care but may reflect the clinician's not the patient's perspective. Directly assessing patient priorities and expectations identifies what is important to patients in their healthcare experience (patient-reported value) that can also provide a basis for other forms of evaluation. Published studies of patient attitudes to their endoscopy procedure indicate the importance of ensuring that endoscopists and their staff control patient discomfort, have adequate technical skill and effectively communicate with their patient relating to the procedure and results. Environmental factors, including noise, privacy and the single-sex environment, are considered to have less value. There are contrasting views on patient attitudes to waiting times for the procedure. Implementing patient-centred care in endoscopy requires an understanding of what patients want from their healthcare experience. The results from available studies suggest implications for current practice that relate to the training and practice of the endoscopist and their staff.
A systematic review of measurement tools of health and well-being for evaluating community-based interventions
Authors: Dronavalli Mithilesh , Thompson Sandra C
Published: June 2015

Background

Those interested in evaluating the effectiveness of community interventions on health and well-being need information about what tools are available and best suited to measure improvements that could be attributed to the intervention.

This study evaluated published measurement tools of health and well-being that have the potential to be used before and after an intervention.

Methods

A literature search of health and sociological databases was undertaken for articles that utilised measurement tools in community settings to measure overall health, well-being or quality of life. Articles were considered potentially relevant because they included use of measurement tools related to general health or well-being. These tools were evaluated by further searching of the literature to assess each tool's properties including: reliability; validity; responsiveness; length; use in cross-cultural settings; global health or well-being assessment; use of subjective measures; clarity and cost. A composite score was made based on the average rating of all fields.

Results

Of 958 abstracts that were screened, 123 articles were extracted for review. From those articles, 27 measurement tools were selected and assessed. Based on the composite score assessing across all domains, five tools were rated as excellent.

Conclusions

While tools may need to be selected for particular aims and interventions, a range of potential well-described tools already exist and should be considered for use in preference to ad hoc or bespoke tools. Any of the five tools rated as excellent are recommended to assess the impact of a community intervention.