bluuebunny/crossref_metadata_2025 huggingface dataset:
Extensive Within-Host Diversity in Fecally Carried Extended-Spectrum-Beta-Lactamase-Producing Escherichia coli Isolates: Implications for Transmission Analyses
Authors: Stoesser N. , Sheppard A. E. , Moore C. E. , Golubchik T. , Parry C. M. , Nget P. , Saroeun M. , Day N. P. J. , Giess A. , Johnson J. R. , Peto T. E. A. , Crook D. W. , Walker A. S.
Published: April 2015

Studies of the transmission epidemiology of antimicrobial-resistant
Escherichia coli
, such as strains harboring extended-spectrum beta-lactamase (ESBL) genes, frequently use selective culture of rectal surveillance swabs to identify isolates for molecular epidemiological investigation. Typically, only single colonies are evaluated, which risks underestimating species diversity and transmission events. We sequenced the genomes of 16
E. coli
colonies from each of eight fecal samples (
n =
127 genomes; one failure), taken from different individuals in Cambodia, a region of high ESBL-producing
E. coli
prevalence. Sequence data were used to characterize both the core chromosomal diversity of
E. coli
isolates and their resistance/virulence gene content as a proxy measure of accessory genome diversity. The 127
E. coli
genomes represented 31 distinct sequence types (STs). Seven (88%) of eight subjects carried ESBL-positive isolates, all containing
bla
CTX-M
variants. Diversity was substantial, with a median of four STs/individual (range, 1 to 10) and wide genetic divergence at the nucleotide level within some STs. In 2/8 (25%) individuals, the same
bla
CTX-M
variant occurred in different clones, and/or different
bla
CTX-M
variants occurred in the same clone. Patterns of other resistance genes and common virulence factors, representing differences in the accessory genome, were also diverse within and between clones. The substantial diversity among intestinally carried ESBL-positive
E. coli
bacteria suggests that fecal surveillance, particularly if based on single-colony subcultures, will likely underestimate transmission events, especially in high-prevalence settings.
Analytical and Clinical Evaluation of the PathoNostics AsperGenius Assay for Detection of Invasive Aspergillosis and Resistance to Azole Antifungal Drugs during Testing of Serum Samples
Authors: White P. Lewis , Posso Raquel B. , Barnes Rosemary A.
Published: April 2015

The commercially developed PathoNostics AsperGenius species assay is a multiplex real-time PCR capable of detecting aspergillosis and genetic markers associated with azole resistance. The assay is validated for testing bronchoalveolar lavage fluids, replacing the requirement for culture and benefiting patient management. Application of this assay to less invasive, easily obtainable samples (e.g., serum) might be advantageous. The aim of this study was to determine the analytical and clinical performance of the AsperGenius species and resistance assays for testing serum samples. For the analytical evaluations, serum samples were spiked with various concentrations of
Aspergillus
genomic DNA for extraction, following international recommendations. For the clinical study, 124 DNA extracts from 14 proven/probable invasive aspergillosis (IA) cases, 2 possible IA cases, and 33 controls were tested. The resistance assay was performed on
Aspergillus fumigatus
PCR-positive samples when a sufficient fungal burden was evident. The limits of detection of the species and resistance assays for
A. fumigatus
DNA were 10 and ≥75 genomes/sample, respectively. Nonreproducible detection at lower burdens was achievable for all markers. With a positivity threshold of 39 cycles, the sensitivity and specificity of the species assay were 78.6% and 100%, respectively. For 7 IA cases, at least one genetic region potentially associated with azole resistance was successfully amplified, although no resistance markers were detected in this small cohort. The AsperGenius assay provides good clinical performance with the added ability to detect azole resistance directly from noninvasive samples. While the available burden will limit application, it remains a significant advancement in the diagnosis and management of aspergillosis.
Mixed Infections and Rifampin Heteroresistance among Mycobacterium tuberculosis Clinical Isolates
Authors: Zheng Chao , Li Song , Luo Zhongyue , Pi Rui , Sun Honghu , He Qingxia , Tang Ke , Luo Mei , Li Yuqing , Couvin David , Rastogi Nalin , Sun Qun
Published: April 2015

Mixed infections and heteroresistance of
Mycobacterium tuberculosis
contribute to the difficulty of diagnosis, treatment, and control of tuberculosis. However, there is still no proper solution for these issues. This study aimed to investigate the potential relationship between mixed infections and heteroresistance and to determine the high-risk groups related to these factors. A total of 499 resistant and susceptible isolates were subjected to spoligotyping and 24-locus variable-number tandem repeat methods to analyze their genotypic lineages and the occurrence of mixed infections. Two hundred ninety-two randomly selected isolates were sequenced on their
rpoB
gene to examine mutations and heteroresistance. The results showed that 12 patients had mixed infections, and the corresponding isolates belonged to Manu2 (
n
= 8), Beijing (
n
= 2), T (
n
= 1), and unknown (
n
= 1) lineages. Manu2 was found to be significantly associated with mixed infections (odds ratio, 47.72; confidence interval, 9.68 to 235.23;
P
< 0.01). Four isolates (1.37%) were confirmed to be heteroresistant, which was caused by mixed infections in three (75%) isolates; these belonged to Manu2. Additionally, 3.8% of the rifampin-resistant isolates showing no mutation in the
rpoB
gene were significantly associated with mixed infections (χ
2
, 56.78;
P
< 0.01). This study revealed for the first time that Manu2 was the predominant group in the cases of mixed infections, and this might be the main reason for heteroresistance and a possible mechanism for isolates without any mutation in the
rpoB
gene to become rifampin resistant. Further studies should focus on this lineage to clarify its relevance to mixed infections.
Mutation and Recombination Frequencies Reveal a Biological Contrast within Strains of Cucumber Mosaic Virus
Authors: Pita Justin S. , Morris Viktoriya , Roossinck Marilyn J.
Published: April 2015

Recent
in planta
studies have shown that strains Fny and LS of
Cucumber mosaic virus
(CMV) display differential genetic diversities, Fny and LS having higher and lower mutation frequencies, respectively (J. S. Pita and M. J. Roossinck, J Virol 87:790–797, 2012
http://dx.doi.org/10.1128/JVI.01891-12
). In this article, we show that these virus strains have differential recombination frequencies as well. However, the high-diversity Fny strain is a low-recombination virus, whereas the very-low-diversity LS strain is instead a high-recombination virus. Unlike the mutation frequency that was determined by both RNAs 1 and 2, the control elements of recombination frequency reside predominantly within RNA 2, specifically within the 2a gene.

IMPORTANCE
Recombination is an important mechanism in virus evolution that can lead to increased or decreased variation and is a major player in virus speciation events that can lead to emerging viruses. Although viral genomes show very frequent evidence of recombination, details of the mechanism involved in these events are still poorly understood. We show here that the reciprocal effects of high mutation frequency and low recombination frequency (and
vice versa
) involve the RNA-dependent RNA polymerase of the virus, and we speculate that these evolutionary events are related to differences in processivity for two strains of the same virus.
ORF45-Mediated Prolonged c-Fos Accumulation Accelerates Viral Transcription during the Late Stage of Lytic Replication of Kaposi's Sarcoma-Associated Herpesvirus
Authors: Li Xiaojuan , Du Shumin , Avey Denis , Li Yuqing , Zhu Fanxiu , Kuang Ersheng
Published: April 2015

Kaposi's sarcoma-associated herpesvirus (KSHV) encodes multiple viral proteins that activate extracellular signal-regulated kinase (ERK)–mitogen-activated protein kinase (MAPK) cascades. One of these viral proteins, ORF45, mediates sustained ERK-p90 ribosomal S6 kinase (RSK) activation during KSHV lytic replication and facilitates viral translation through the phosphorylation of a eukaryotic translation initiation factor, eIF4B. The importance of ERK-RSK activation for KSHV viral transcription has been shown; however, which transcription factor senses the sustained MAPK signaling and leads to viral transcription remains poorly understood. Here we show that the presence of ORF45 leads to the prolonged accumulation of c-Fos during the late stage of KSHV lytic replication through ERK-RSK-dependent phosphorylation and stabilization and that the depletion of c-Fos disrupts viral lytic transcription. Genome-wide screening revealed that c-Fos directly binds to multiple viral gene promoters and enhances viral transcription. Mutation of the ERK-RSK phosphorylation sites of c-Fos restrains KSHV lytic gene expression and virion production. These results indicate that the prolonged accumulation of c-Fos promotes the progression of viral transcription from early to late stages and accelerates viral lytic replication upon sustained ORF45-ERK-RSK activation during the KSHV lytic life cycle.

IMPORTANCE
During KSHV lytic replication, transient activation and sustained activation of ERK-RSK induce viral immediate early (IE) transcription and late transcription, respectively. Studies have revealed that ERK-RSK activates several transcription factors involved in IE gene expression, including Ets, AP-1, CREB, and C/EBP, which lead to the transient ERK-RSK activation-dependent IE transcription. Whereas c-Fos acts as a sensor of sustained ERK-RSK activation, ORF45-ERK-RSK signaling mediates c-Fos phosphorylation and accumulation during late KSHV lytic replication, consequently promoting viral transcription through the direct binding of c-Fos to multiple KSHV promoters. This finding indicates that c-Fos mediates distinct viral transcriptional progression following sustained ERK-RSK signaling during the KSHV lytic life cycle.
A Single Dose of an Avian H3N8 Influenza Virus Vaccine Is Highly Immunogenic and Efficacious against a Recently Emerged Seal Influenza Virus in Mice and Ferrets
Authors: Baz Mariana , Paskel Myeisha , Matsuoka Yumiko , Zengel James R. , Cheng Xing , Treanor John J. , Jin Hong , Subbarao Kanta
Published: April 2015

H3N8 influenza viruses are a commonly found subtype in wild birds, usually causing mild or no disease in infected birds. However, they have crossed the species barrier and have been associated with outbreaks in dogs, pigs, donkeys, and seals and therefore pose a threat to humans. A live attenuated, cold-adapted (ca) H3N8 vaccine virus was generated by reverse genetics using the wild-type (wt) hemagglutinin (HA) and neuraminidase (NA) genes from the A/blue-winged teal/Texas/Sg-00079/2007 (H3N8) (tl/TX/079/07) wt virus and the six internal protein gene segments from thecainfluenza A virus vaccine donor strain, A/Ann Arbor/6/60ca(H2N2), the backbone of the licensed seasonal live attenuated influenza vaccine. One dose of the tl/TX/079/07cavaccine induced a robust neutralizing antibody response against the homologous (tl/TX/079/07) and two heterologous influenza viruses, including the recently emerged A/harbor seal/New Hampshire/179629/2011 (H3N8) and A/northern pintail/Alaska/44228-129/2006 (H3N8) viruses, and conferred robust protection against the homologous and heterologous influenza viruses. We also analyzed human sera against the tl/TX/079/07 H3N8 avian influenza virus and observed low but detectable antibody reactivity in elderly subjects, suggesting that older H3N2 influenza viruses confer some cross-reactive antibody. The latter observation was confirmed in a ferret study. The safety, immunogenicity, and efficacy of the tl/TX/079/07cavaccine in mice and ferrets support further evaluation of this vaccine in humans for use in the event of transmission of an H3N8 avian influenza virus to humans. The human and ferret serology data suggest that a single dose of the vaccine may be sufficient in older subjects.

IMPORTANCEAlthough natural infection of humans with an avian H3N8 influenza virus has not yet been reported, this influenza virus subtype has already crossed the species barrier and productively infected mammals. Pandemic preparedness is an important public health priority. Therefore, we generated a live attenuated avian H3N8 vaccine candidate and demonstrated that a single dose of the vaccine was highly immunogenic and protected mice and ferrets against homologous and heterologous H3N8 avian viruses.
Human Cytomegalovirus Infection Dysregulates the Localization and Stability of NICD1 and Jag1 in Neural Progenitor Cells
Authors: Li Xiao-Jun , Liu Xi-Juan , Yang Bo , Fu Ya-Ru , Zhao Fei , Shen Zhang-Zhou , Miao Ling-Feng , Rayner Simon , Chavanas Stéphane , Zhu Hua , Britt William J. , Tang Qiyi , McVoy Michael A. , Luo Min-Hua
Published: April 2015

Human cytomegalovirus (HCMV) infection of the developing fetus frequently results in major neural developmental damage. In previous studies, HCMV was shown to downregulate neural progenitor/stem cell (NPC) markers and induce abnormal differentiation. As Notch signaling plays a vital role in the maintenance of stem cell status and is a switch that governs NPC differentiation, the effect of HCMV infection on the Notch signaling pathway in NPCs was investigated. HCMV downregulated mRNA levels of Notch1 and its ligand, Jag1, and reduced protein levels and altered the intracellular localization of Jag1 and the intracellular effector form of Notch1, NICD1. These effects required HCMV gene expression and appeared to be mediated through enhanced proteasomal degradation. Transient expression of the viral tegument proteins of pp71 and UL26 reduced NICD1 and Jag1 protein levels endogenously and exogenously. Given the critical role of Notch signaling in NPC growth and differentiation, these findings reveal important mechanisms by which HCMV disturbs neural cell developmentin vitro. Similar eventsin vivomay be associated with HCMV-mediated neuropathogenesis during congenital infection in the fetal brain.

IMPORTANCECongenital human cytomegalovirus (HCMV) infection is the leading cause of birth defects that primarily manifest as neurological disabilities. Neural progenitor cells (NPCs), key players in fetal brain development, are the most susceptible cell type for HCMV infection in the fetal brain. Studies have shown that NPCs are fully permissive for HCMV infection, which causes neural cell loss and premature differentiation, thereby perturbing NPC fate. Elucidation of virus-host interactions that govern NPC proliferation and differentiation is critical to understanding neuropathogenesis. The Notch signaling pathway is critical for maintaining stem cell status and functions as a switch for differentiation of NPCs. Our investigation into the impact of HCMV infection on this pathway revealed that HCMV dysregulates Notch signaling by altering expression of the Notch ligand Jag1, Notch1, and its active effector in NPCs. These results suggest a mechanism for the neuropathogenesis induced by HCMV infection that includes altered NPC differentiation and proliferation.
Murine Immune Responses to Virus-Like Particle-Associated Pre- and Postfusion Forms of the Respiratory Syncytial Virus F Protein
Authors: McGinnes Cullen Lori , Schmidt Madelyn R. , Kenward Sarah A. , Woodland Robert T. , Morrison Trudy G.
Published: April 2015

Virus-like particles (VLPs) built on the Newcastle disease virus (NDV) core proteins, NP and M, and containing two chimeric proteins, F/F and H/G, composed of respiratory syncytial virus (RSV) fusion protein (F) and glycoprotein (G) ectodomains fused to the transmembrane and cytoplasmic domains of the NDV F and HN proteins, respectively, stimulate durable, protective RSV neutralizing antibodies in mice. Here, we report the properties of VLPs constructed to contain mutant RSV F protein ectodomains stabilized in prefusion (pre-F/F) or postfusion (post-F/F) configurations. The structures of the chimeric proteins assembled into VLPs were verified immunologically by their reactivities with a conformationally restricted anti-F protein monoclonal antibody. Following immunization of mice, without adjuvant, pre-F/F-containing VLPs induced significantly higher neutralizing antibody titers than the post-F/F-containing VLPs or the wild-type F/F-containing VLPs after a single immunization but not after prime and boost immunization. The specificities of anti-F IgG induced by the two mutant VLPs were assessed by enzyme-linked immunosorbent assay (ELISA) using soluble forms of the prefusion and postfusion forms of the F protein as targets. While both types of VLPs stimulated similar levels of IgG specific for the soluble postfusion F protein, titers of IgG specific for prefusion F induced by the pre-F/F-containing VLPs were higher than those induced by post-F/F-containing VLPs. Thus, VLPs containing a stabilized prefusion form of the RSV F protein represent a promising RSV vaccine candidate.

IMPORTANCE
The development of vaccines for respiratory syncytial virus has been hampered by a lack of understanding of the requirements for eliciting high titers of neutralizing antibodies. The results of this study suggest that particle-associated RSV F protein containing mutations that stabilize the structure in a prefusion conformation may stimulate higher titers of protective antibodies than particles containing F protein in a wild-type or postfusion conformation. These findings indicate that the prefusion F protein assembled into VLPs has the potential to produce a successful RSV vaccine candidate.
Studies on the Contribution of Human Cytomegalovirus UL21a and UL97 to Viral Growth and Inactivation of the Anaphase-Promoting Complex/Cyclosome (APC/C) E3 Ubiquitin Ligase Reveal a Unique Cellular Mechanism for Downmodulation of the APC/C Subunits APC1, APC4, and APC5
Authors: Clark Elizabeth , Spector Deborah H.
Published: April 2015

Human cytomegalovirus (HCMV) deregulates the cell cycle by several means, including inactivation of the
a
naphase-
p
romoting
c
omplex/
c
yclosome (APC/C) E3 ubiquitin ligase. Viral proteins UL97 and UL21a, respectively, affect the APC/C by phosphorylation of APC/C coactivator Cdh1 and by inducing the degradation of subunits APC4 and APC5, which along with APC1 form the APC/C platform subcomplex. The aim of this study was to further characterize the mechanism of APC/C inactivation and define the relative contributions of UL21a and UL97 to APC/C substrate accumulation and to viral growth. We show that in uninfected cells, UL21a but not UL97 can disrupt APC/C function, leading to the accumulation of substrates. We find that UL21a is necessary and sufficient to induce the degradation of APC1, in addition to the previously reported APC4 and APC5. We also demonstrate that there is a previously unreported cellular mechanism for a specific decrease in the levels of all three platform subunits, APC1, APC4, and APC5, upon the depletion of any one of these subunits or of subunit APC8. Finally, we show that at a low multiplicity of infection, either UL97 or UL21a can partially complement a growth-defective mutant virus lacking both UL21a and UL97, with significantly greater benefit afforded by the expression of both proteins. This double mutant also can be partially rescued by inactivation of the APC/C using small interfering RNAs against specific subunits. These results further our understanding of HCMV's interaction with the cell cycle machinery and reveal a new cellular pattern of APC/C subunit downmodulation.

IMPORTANCE
HCMV lytic infection subverts the host cell cycle machinery in multiple ways. A major effect is inactivation of the APC/C, which plays a central role in the control of cell cycle progression. This study provides further insight into the mechanism of inactivation. We discovered that the APC1 subunit, which along with APC4 and APC5 form the platform subcomplex of the APC/C, is an additional target of the degradation induced by HCMV protein UL21a. This study also shows for the first time that there is a unique cellular process in uninfected cells whereby depletion of APC1, APC4, APC5, or APC8 recapitulates the pattern of HCMV-mediated APC/C subunit degradation.
Identification of Cholesterol 25-Hydroxylase as a Novel Host Restriction Factor and a Part of the Primary Innate Immune Responses against Hepatitis C Virus Infection
Authors: Xiang Yu , Tang Jing-Jie , Tao Wanyin , Cao Xuezhi , Song Bao-Liang , Zhong Jin
Published: April 2015

Hepatitis C virus (HCV), a single-stranded positive-sense RNA virus of the
Flaviviridae
family, causes chronic liver diseases, including hepatitis, cirrhosis, and cancer. HCV infection is critically dependent on host lipid metabolism, which contributes to all stages of the viral life cycle, including virus entry, replication, assembly, and release. 25-Hydroxycholesterol (25HC) plays a critical role in regulating lipid metabolism, modulating immune responses, and suppressing viral pathogens. In this study, we showed that 25HC and its synthesizing enzyme cholesterol 25-hydroxylase (CH25H) efficiently inhibit HCV infection at a postentry stage. CH25H inhibits HCV infection by suppressing the maturation of SREBPs, critical transcription factors for host lipid biosynthesis. Interestingly, CH25H is upregulated upon poly(I·C) treatment or HCV infection in hepatocytes, which triggers type I and III interferon responses, suggesting that the CH25H induction constitutes a part of host innate immune response. To our surprise, in contrast to studies in mice, CH25H is not induced by interferons in human cells and knockdown of STAT-1 has no effect on the induction of CH25H, suggesting CH25H is not an interferon-stimulated gene in humans but rather represents a primary and direct host response to viral infection. Finally, knockdown of CH25H in human hepatocytes significantly increases HCV infection. In summary, our results demonstrate that CH25H constitutes a primary innate response against HCV infection through regulating host lipid metabolism. Manipulation of CH25H expression and function should provide a new strategy for anti-HCV therapeutics.

IMPORTANCE
Recent studies have expanded the critical roles of oxysterols in regulating immune response and antagonizing viral pathogens. Here, we showed that one of the oxysterols, 25HC and its synthesizing enzyme CH25H efficiently inhibit HCV infection at a postentry stage via suppressing the maturation of transcription factor SREBPs that regulate lipid biosynthesis. Furthermore, we found that CH25H expression is upregulated upon poly(I·C) stimulation or HCV infection, suggesting CH25H induction constitutes a part of host innate immune response. Interestingly, in contrast to studies in mice showing that
ch25h
is an interferon-stimulated gene, CH25H cannot be induced by interferons in human cells but rather represents a primary and direct host response to viral infection. Our studies demonstrate that the induction of CH25H represents an important host innate response against virus infection and highlight the role of lipid effectors in host antiviral strategy.
Accumulation of Cytotoxic CD16+NK Cells in Simian Immunodeficiency Virus-Infected Lymph Nodes Associated withIn SituDifferentiation and Functional Anergy
Authors: Schafer Jamie L. , Li Haiying , Evans Tristan I. , Estes Jacob D. , Reeves R. Keith
Published: April 2015

Recent evidence suggests that even in treated infections, human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) replication may continue in lymph nodes (LN), serving as a potential virus reservoir. Here we investigated the effects of lentivirus infection on natural killer (NK) cell frequencies, phenotypes, and functions in naive and acutely or chronically SIVmac239-infected rhesus macaques. Compared to that in naive animals, we observed a 3-fold-greater frequency of cytotoxic CD16+CD56−NK cells in LN of chronically infected macaques. However, NK cells did not appear to be trafficking to LN, as homing markers CD62L and CCR7 did not increase on circulating NK cells during infection. LN NK cells demonstrated enhanced cytotoxicity in acute infection, with 2-fold increases in perforin expression and 3-fold increases in CD107a expression following mitogen stimulation. Lysis of K562 cells by LN NK cells from acutely infected animals was greater than lysis by preinfection samples from the same animals. LN NK cells from chronically infected animals lysed K562 cells more efficiently than LN NK cells from uninfected animals, but importantly, surrogate markers of cytotoxicity in infected macaques were disproportionately greater thanex vivokilling. Furthermore, Tim-3, an indicator of activation and/or exhaustion, was upregulated 3-fold on LN NK cells in chronically infected animals. Collectively, these data suggest that LN NK cells are skewed toward a cytotoxic phenotype during SIV infection but may become dysfunctional and exhausted in chronic disease.

IMPORTANCEThe accumulation of CD16+CD56−NK cells in the SIV-infected lymph node without changes in NK homing to the LN could suggest that these cells are differentiatingin situ. Surprisingly, this increase in frequency of the cytotoxic subset of NK cells is not accompanied by an increase of similar magnitude in the cytolytic function of LN lymphocytes. This functional modulation, together with the higher Tim-3 expression observed on LN NK cells isolated from chronically infected animals than on those from naive macaques, is indicative of an exhausted phenotype. This exhaustion could contribute to the robust replication of HIV and SIV in the LN during acute and chronic stages of infection, allowing the survival of infected cells and maintenance of a viral reservoir.
Improving the care of children with urinary tract infection: use of a clinical decision proforma
Authors: Leach Daniel
Published: April 2015

Urinary tract infection (UTI) is a common and important clinical problem in children. Follow up imaging is indicated in some cases to reduce the risk of long-term harm from UTI and sometimes to help guide acute management. Overuse of imaging may be harmful due to radiation exposure, as well as increasing demand on services and budgets. On the other hand under-use of imaging may leave children vulnerable to renal damage and long-term morbidity. Accepted standards propose an imaging strategy specific to age and type of UTI. The complexity of the guideline makes compliance with the standards challenging.

The aim of this project was to assess current practice for imaging of children with UTI managed at The Royal Oldham Hospital and to improve compliance with accepted standards through the use of a proforma to aid clinical decision making, supported by an education programme. A retrospective audit was performed over a 6 month period both prior to and after the intervention. The baseline audit found 57.7% of children treated for UTI (n=26) had imaging compliant with the accepted standards, which improved to 75.9% (n=29) on post-measurement. The percentage of inappropriate investigations reduced from 52.4% to 10.5%. The percentage of missed investigations reduced from 35.0% to 32.0%. The proforma was used and filed in 40% of cases where practice was in line with accepted standards. It was not used in any of the cases where practice deviated.

In conclusion, a clear clinical decision aid, supported by an education programme, can significantly improve compliance with accepted standards for imaging of children with UTI. This may also be transferable to other scenarios where guidelines exist but have reduced efficacy due to complexity and/or lack of understanding.
Enhanced recovery clinical education programme improves quality of post-operative care
Authors: McDonald Ruth
Published: April 2015

Quality is the driving principle of Enhanced Recovery (ER). It improves the patient experience by getting patients better sooner and changes clinical practice to make care safer and more efficient. As a consequence of ER patients spend less time in hospital.

A successful ER programme began to fail after organisational restructuring and staff changes. Patients did not meet their ER goals and length of stay (LOS) increased. An ER nurse was appointed to get the programme back on track.

This involved a multidisciplinary approach to an ER clinical education programme. The programme aimed to develop knowledge of the physiology of post-operative recovery and the evidence underpinning the interventions required. This was considered crucial to secure longer term staff engagement while avoiding unthinking protocol driven compliance. Success of the education programme was measured by improved outcomes in patient LOS and readmission statistics.

During the four months of the clinical education programme there were no significant changes in monthly LOS. At six months post implementation of the programme there was a reduction in LOS of 0.6 days compared to the previous six months. At 12 months there was a reduction in 1.1 days compared with previous 12 months. There was a mean reduction of 28 day readmissions for all elective gynaecology surgery of 1.1 patients per month in the 12 months post programme implementation compared to the 12 months before. Delivering a multidisciplinary participatory education programme improved overall understanding of ER, and achieved sustained improvement in ER for patient benefit.
The impact of job strain on smoking cessation and relapse in the Canadian population: a cohort study
Authors: Rowe Daniel J , Dunn James R , Muntaner Carles
Published: April 2015

Background

The aim of this study is to investigate the impact of job strain, as measured by the Karasek demand/control model (DCM), on smoking cessation and relapse in a representative general population sample.

Methods

A secondary analysis of data from the Canadian National Population Health Survey (NPHS) was undertaken. Daily smokers and former daily smokers (n=1287 and 1184, respectively) at cycle 1 (1994/1995) of the NPHS were followed up at cycle 2 (1996/1997). Measures of job strain (the independent variables) were based on data from cycle 1, predicting smoking status at cycle 2. Logistic regression analysis was employed in two ways. Individuals were stratified into job strain quartiles while continuous measures were also employed in separate analyses for job strain and its component dimensions.

Results

In the quartile analysis, no effect of job strain was observed on the likelihood of cessation, while a non-linear effect was observed on the likelihood of relapse, although this relationship lost significance (p>0.05 and <0.10) after controlling for personal characteristics. No effect was observed using the continuous measure of job strain or the continuous measure of job demand on either cessation or relapse. For job control, no effect was observed on the likelihood of cessation, but increased control was found to decrease the likelihood of relapse in the unadjusted model only.

Conclusions

Psychosocial work environments may be too diverse for uniform trends in the relationship between job stress and smoking behaviour to emerge in a population sample. Future research should avoid use of the scaled-down DCM instrument where possible.
Integrating reproductive health services into HIV care: strategies for successful implementation in a low-resource HIV clinic in Lilongwe, Malawi
Authors: Phiri Sam , Feldacker Caryl , Chaweza Thomas , Mlundira Linly , Tweya Hannock , Speight Colin , Samala Bernadette , Kachale Fannie , Umpierrez Denise , Haddad Lisa
Published: April 2015

Background

Lighthouse Trust operates two public HIV testing, treatment and care clinics in Lilongwe, Malawi, caring for over 26 000 people living with HIV, 23 000 of whom are on antiretroviral treatment (ART). In August 2010, Lighthouse Trust piloted a step-wise integration of sexual and reproductive health (SRH) services into routine HIV care at its Lighthouse clinic site. The objectives were to increase uptake of family planning (FP), promote long-term reversible contraceptive methods, and increase access, screening and treatment for cervical cancer using visual inspection with acetic acid.

Methods and results

Patients found integrated SRH/ART services acceptable; service availability appeared to increase uptake. Between August 2010 and May 2014, over 6000 women at Lighthouse received FP education messages. Of 859 women who initiated FP, 55% chose depot medroxyprogesterone acetate, 19% chose an intrauterine contraceptive device, 14% chose oral contraceptive pills, and 12% chose an implant. By May 2014, 21% of eligible female patients received cervical cancer screening: 11% (166 women) had abnormal cervical findings during screening for cervical cancer and underwent further treatment.

Conclusions

Several lessons were learned in overcoming initial concerns about integration. First, our integrated services required minimal additional resources over those needed for provision of HIV care alone. Second, patient flow improved during implementation, reducing a barrier for clients seeking multiple services. Lastly, analysis of routine data showed that the proportion of women using some form of modern contraception was 45% higher at Lighthouse than at Lighthouse's sister clinic where services were not integrated (42% vs 29%), providing further evidence for promotion of SRH/ART integration.
From bench to bedside: utility of the rabbit elastase aneurysm model in preclinical studies of intracranial aneurysm treatment
Authors: Brinjikji Waleed , Ding Yong H , Kallmes David F , Kadirvel Ramanathan
Published: April 2015

Preclinical studies are important in helping practitioners and device developers improve techniques and tools for endovascular treatment of intracranial aneurysms. Thus an understanding of the major animal models used in such studies is important. The New Zealand rabbit elastase induced arterial aneurysm of the common carotid artery is one of the most commonly used models in testing the safety and efficacy of new endovascular devices. In this review we discuss: (1) the various techniques used to create the aneurysm, (2) complications of aneurysm creation, (3) natural history of the arterial aneurysm, (4) histopathologic and hemodynamic features of the aneurysm, (5) devices tested using this model, and (6) weaknesses of the model. We demonstrate how preclinical studies using this model are applied in the treatment of intracranial aneurysms in humans. The model has similar hemodynamic, morphological, and histologic characteristics to human aneurysms, and demonstrates similar healing responses to coiling as human aneurysms. Despite these strengths, however, the model does have many weaknesses, including the fact that the model does not emulate the complex inflammatory processes affecting growing and ruptured aneurysms. Furthermore, the extracranial location of the model affects its ability to be used in preclinical safety assessments of new devices. We conclude that the rabbit elastase model has characteristics that make it a simple and effective model for preclinical studies on the endovascular treatment of intracranial aneurysms, but further work is needed to develop aneurysm models that simulate the histopathologic and morphologic characteristics of growing and ruptured aneurysms.
One Health and a world of opportunity
Authors: Reeve‐Johnson Lloyd
Published: April 2015

In the course of his career, work has taken Lloyd Reeve‐Johnson to more than 100 countries and he has lived on four continents while collaborating on One Health issues. His career has included clinical practice, pharmaceutical research, tertiary academia and entrepreneurial business. He believes all these avenues are open to veterinary graduates
Retrospective weight-of-evidence analysis identifies substrate change as the apparent cause of recruitment failure in the upper Columbia River white sturgeon (Acipenser transmontanus)
Authors: McAdam D. Steven O.
Published: April 2015

A weight-of-evidence evaluation of the potential cause of white sturgeon (Acipenser transmontanus) recruitment failure in the upper Columbia River evaluated 12 recruitment-failure hypotheses based on nine criteria. Recruitment-failure timing was estimated by identifying breakpoints in the hindcasted recruitment time series for three of four spatially distinct groups. Observed spatial and temporal recruitment decline patterns were then compared with expected patterns for each hypothesis (e.g., flow, temperature, turbidity, contaminants, and changes to the riverine fish community). The weight-of-evidence evaluation also considered criteria including coherence with theoretical, factual, and biological evidence and responses to impact reversal. Recruitment failure began about 1968, coincident with the initiation of upstream mainstem flow regulation. An 8- or 9-year lag in the recruitment decline of the Waneta group was particularly informative for hypothesis evaluations. The identification of increased fine substrates at spawning sites as the most plausible explanation for chronic recruitment failure has important implications regarding the apparent life stages affected and potential restoration approaches.
Identification and quantification of heteroscedasticity in stock–recruitment relationships
Authors: Panikian Garo , Cussens James , Pitchford Jonathan W.
Published: April 2015

Nonconstant variance (heteroscedasticity) in the stock–recruitment (S-R) relationship is proposed as an important factor in sustainable fisheries management, but its reliable estimation from noisy populations is problematic. We developed methods for both frequentist and Bayesian approaches to test whether we can accurately estimate the degree of heteroscedasticity in 90 published S-R populations. We estimated the confidence interval for the heteroscedastic regression model via a parametric bootstrap approach and the credible interval for the Bayesian method via a Markov chain Monte Carlo sampling algorithm. We found strong evidence of negative heteroscedasticity in several stocks, regardless of the statistical paradigm, the details of density dependence, and the methods used to generate the original populations. This statistical framework, together with its associated freely available software, provides an efficient and reliable setting for assessing heteroscedasticity of the S-R relationship in fisheries.
Resveratrol ameliorates cisplatin-induced oxidative injury in New Zealand rabbits
Authors: Cigremis Yilmaz , Akgoz Muslum , Ozen Hasan , Karaman Musa , Kart Asım , Gecer Murat , Atalan Gultekin
Published: April 2015

This study investigated the preventive role of resveratrol in cisplatin-induced nephrotoxicity. The study used groups of New Zealand rabbits that were treated as follows: group C (cisplatin treated), group R (resveratrol treated), group R+C (resveratrol + cisplatin treatment), and group E (control group). Kidney levels of glutathione were significantly lower in group C than in groups E and R, whereas glutathione levels in group R+C were found to be similar to the control values. Malondialdehyde levels in group C were significantly higher than in groups E and R. However, malondialdehyde levels in group R+C were similar to group E. Kidney levels of nitric oxide were significantly higher in the cisplatin group than in the control, whereas nitric oxide levels were at basal values in group R+C. Cisplatin treatment significantly reduced kidney levels of glutathione peroxidase, superoxide dismutase, and catalase activity compared with those of group E, whereas resveratrol treatment significantly increased levels of glutathione peroxidase, superoxide dismutase, and catalase activity in group R+C. However, cisplatin injection did not affect mRNA levels of glutathione peroxidase, superoxide dismutase, or catalase enzymes. Histopathological and immunohistochemical analyses indicated that cisplatin caused kidney damage, which was mostly prevented by resveratrol treatment. In conclusion, resveratrol ameliorates cisplatin-induced oxidative injury in the kidney of rabbit.
Study of the anti-angiogenic effects of cardiolipin by the aortic ring assay
Authors: Carnevale Matthew L. , Bergdahl Andreas
Published: April 2015

Cardiolipin (CL), a phospholipid found in the inner mitochondrial membrane in all cell types, is critical for the function of the electron transport chain. The role of CL is not fully understood, but it is assumed that the molecule maintains membrane potential and architecture and compensates for alterations in homeostasis that could affect the energy metabolism. The objective of this project was to determine the effects of increasing CL concentrations on angiogenic sprouting by using the aortic ring assay model. For this, 5-day-old C57Bl/6 pups were euthanized by cervical dislocation prior to removal of the aortas. The vessels were cleaned, cut in 0.5 mm wide rings, and placed in a collagen growth matrix supplemented with CL. The results revealed a highly significant reduction of sprout growth (both length and quantity) at low, physiological concentrations. In conclusion, the results of this study demonstrate that CL significantly reduces microvessel formation and that it could potentially provide an interesting novel therapeutic target for angiogenesis.
Bounds on Kaluza–Klein states from EWPT and direct searches at the LHC
Authors: Accomando Elena
Published: April 2015

We review the present bounds on Kaluza–Klein (KK)-excitations of Standard Model gauge bosons, predicted by TeV size extra dimensions, which have been set by the ElectroWeak Precision Test (EWPT) and recently by the direct searches performed at the CERN Large Hadron Collider (LHC). Concerning the theoretical framework we present results for the Non-Universal Extra Dimension (NUED) model with matter localized at the boundaries and all gauge bosons propagating into the bulk and acquiring KK-excitations. We also discuss its simplified version, NUED(EW), where only the ElectroWeak SM gauge bosons are allowed to propagate in the extra dimension, and its next-to-minimal version ElectroWeak Universal Extra Dimension (UED)(EW) where SU(3) is localized on the brane while the SU(2)×U(1) particle content fully propagates into the bulk.
Exact treatment of the relativistic double ring-shaped Kratzer potential using the quantum Hamilton–Jacobi formalism
Authors: Gharbi A. , Touloum S. , Bouda A.
Published: April 2015

We study the Klein–Gordon equation with noncentral and separable potential under the condition of equal scalar and vector potentials and we obtain the corresponding relativistic quantum Hamilton–Jacobi equation. The application of the quantum Hamilton–Jacobi formalism to the double ring-shaped Kratzer potential leads to its relativistic energy spectrum as well as the corresponding eigenfunctions.
Post-Buckling of Piezoelectric Thin Plates
Authors: Krommer Michael , Irschik Hans
Published: April 2015

In the present paper, the geometrically nonlinear behavior of piezoelastic thin plates is studied. First, the governing equations for the electromechanically coupled problem are derived based on the von Karman–Tsien kinematic assumption. Here, the Berger approximation is extended to the coupled piezoelastic problem. The general equations are then reduced to a single nonlinear partial differential equation for the special case of simply supported polygonal edges. The nonlinear equations are approximated by using a problem-oriented Ritz Ansatz in combination with a Galerkin procedure. Based on the resulting equations the buckling and post-buckling behavior of a polygonal simply supported plate is studied in a nondimensional form, where the special geometry of the polygonal plate enters via the eigenvalues of a Helmholtz problem with Dirichlet boundary conditions. Single term as well as multi-term solutions are discussed including the effects of piezoelectric actuation and transverse force loadings upon the solution. Novel results concerning the buckling, snap through and snap buckling behavior are presented.
Bond Characterization of Steel-CFRP with Carbon Nanotube Modified Epoxy Adhesive via Pull-off Tests
Authors: Korayem Asghar H. , Liu Yan Ming , Zhao Xiao Ling , Duan Wen Hui
Published: April 2015

This paper presents an experimental investigation of the bond strength between carbon fiber reinforced polymer (CFRP) and steel substrate by utilizing the pull-off test and scanning electron microscope (SEM) analysis. A series of pull-off experiments was conducted by using three types of CFRP (CFRP sheets and CFRP laminates with/without woven mesh) and two types of epoxy adhesive (ductile and brittle epoxy adhesive) with/without carbon nanotube (CNT) modification. Pull-off samples with CFRP laminates possess higher (about double) bond strength than that of samples with CFRP sheets, due to the good saturation of fibers in the laminates. The steel-CFRP bond with ductile epoxy adhesive (Araldite 2011) is found to have about 16% higher bond strength when compared to that of brittle epoxy (MBrace Saturant), even though the tensile strength of Araldite 2011 is about 40% less than that of MBrace Saturant. Also, it is shown that modified epoxy with CNTs is more efficient than neat epoxy for bonding CFRP to steel at a moderately elevated temperature, and increasing the bond strength about twofold.
Application of Kalman Filtering Methods to Online Real-Time Structural Identification: A Comparison Study
Authors: Askari Mohsen , Li Jianchun , Samali Bijan
Published: April 2015

System identification refers to the process of building or improving mathematical models of dynamical systems from the observed experimental input–output data. In the area of civil engineering, the estimation of the integrity of a structure under dynamic loadings and during service condition has become a challenge for the engineering community. Therefore, there has been a great deal of attention paid to online and real-time structural identification, especially when input–output measurement data are contaminated by high-level noise. Among real-time identification methods, one of the most successful and widely used algorithms for estimation of system states and parameters is the Kalman filter and its various nonlinear extensions such as extended Kalman filter (EKF), Iterated EKF (IEKF), the recently developed unscented Kalman filter (UKF) and Iterated UKF (IUKF). In this paper, an investigation has been carried out on the aforementioned techniques for their effectiveness and efficiencies through a highly nonlinear single degree of freedom (SDOF) structure as well as a two-storey linear structure. Although IEKF is an improved version of EKF, results show that IUKF generally produces better results in terms of structural parameters and state estimation than UKF and IEKF. Also IUKF is more robust to noise levels compared to the other approaches.
Microwell arrays reveal cellular heterogeneity during the clonal expansion of transformed human cells
Authors: Chang Tim C. , Tang Weiliang , Koh William Jen Hoe , Rettie Alexander J.E. , Emond Mary J. , Monnat Raymond J. , Folch Albert
Published: April 2015

We developed micromolded microwell arrays to study the proliferation and senescence of single cells. Microwell arrays were designed to be compatible with conventional cell culture protocols to simplify cell loading, cell culture, and imaging. We demonstrated the utility of these arrays by measuring the proliferation and senescence of isogenic cells which expressed or had been depleted of the human Werner syndrome protein. Our results allowed us to reveal cell-to-cell heterogeneity in proliferation in WRN+ and WRN-depleted fibroblasts during clonal growth.