bluuebunny/crossref_metadata_2025 huggingface dataset:
Circovirus Transport Proceeds via Direct Interaction of the Cytoplasmic Dynein IC1 Subunit with the Viral Capsid Protein
Authors: Cao Jingjing , Lin Cui , Wang Huijuan , Wang Lun , Zhou Niu , Jin Yulan , Liao Min , Zhou Jiyong
Published: December 2014

Microtubule transport of circovirus from the periphery of the cell to the nucleus is essential for viral replication in early infection. How the microtubule is recruited to the viral cargo remains unclear. In this study, we observed that circovirus trafficking is dependent on microtubule polymerization and that incoming circovirus particles colocalize with cytoplasmic dynein and endosomes. However, circovirus binding to dynein was independent of the presence of microtubular α-tubulin and translocation of cytoplasmic dynein into the nucleus. The circovirus capsid (Cap) subunit enhanced microtubular acetylation and directly interacted with intermediate chain 1 (IC1) of dynein. N-terminal residues 42 to 100 of the Cap viral protein were required for efficient binding to the dynein IC1 subunit and for retrograde transport. Knockdown of IC1 decreased virus transport and replication. These results demonstrate that Cap is a direct ligand of the cytoplasmic dynein IC1 subunit and an inducer of microtubule α-tubulin acetylation. Furthermore, Cap recruits the host dynein/microtubule machinery to facilitate transport toward the nucleus by an endosomal mechanism distinct from that used for physiological dynein cargo.

IMPORTANCE
Incoming viral particles hijack the intracellular trafficking machinery of the host in order to migrate from the cell surface to the replication sites. Better knowledge of the interaction between viruses and virus proteins and the intracellular trafficking machinery may provide new targets for antiviral therapies. Currently, little is known about the molecular mechanisms of circovirus transport. Here, we report that circovirus particles enter early endosomes and utilize the microtubule-associated molecular motor dynein to travel along microtubules. The circovirus capsid subunit enhances microtubular acetylation, and N-terminal residues 42 to 100 directly interact with the dynein IC1 subunit during retrograde transport. These findings highlight a mechanism whereby circoviruses recruit dynein for transport to the nucleus via the dynein/microtubule machinery.
A Viable Recombinant Rhabdovirus Lacking Its Glycoprotein Gene and Expressing Influenza Virus Hemagglutinin and Neuraminidase Is a Potent Influenza Vaccine
Authors: Ryder Alex B. , Buonocore Linda , Vogel Leatrice , Nachbagauer Raffael , Krammer Florian , Rose John K.
Published: December 2014

The emergence of novel influenza viruses that cause devastating human disease is an ongoing threat and serves as an impetus for the continued development of novel approaches to influenza vaccines. Influenza vaccine development has traditionally focused on producing humoral and/or cell-mediated immunity, often against the viral surface glycoproteins hemagglutinin (HA) and neuraminidase (NA). Here, we describe a new vaccine candidate that utilizes a replication-defective vesicular stomatitis virus (VSV) vector backbone that lacks the native G surface glycoprotein gene (VSVΔG). The expression of the H5 HA of an H5N1 highly pathogenic avian influenza virus (HPAIV), A/Vietnam/1203/04 (VN1203), and the NA of the mouse-adapted H1N1 influenza virus A/Puerto Rico/8/34 (PR8) in the VSVΔG vector restored the ability of the recombinant virus to replicate in cell culture, without the requirement for the addition of trypsin. We show here that this recombinant virus vaccine candidate was nonpathogenic in mice when given by either the intramuscular or intranasal route of immunization and that the
in vivo
replication of VSVΔG-H5N1 is profoundly attenuated. This recombinant virus also provided protection against lethal H5N1 infection after a single dose. This novel approach to vaccination against HPAIVs may be widely applicable to other emerging strains of influenza virus.

IMPORTANCE
Preparation for a potentially catastrophic influenza pandemic requires novel influenza vaccines that are safe, can be produced and administered quickly, and are effective, both soon after administration and for a long duration. We have created a new influenza vaccine that utilizes an attenuated vesicular stomatitis virus (VSV) vector, to deliver and express influenza virus proteins against which vaccinated animals develop potent antibody responses. The influenza virus hemagglutinin and neuraminidase proteins, expressed on the surface of VSV particles, allowed this vaccine to grow in cell culture and induced a potent antibody response in mice that was effective against infection with a lethal influenza virus. The mice showed no adverse reactions to the vaccine, and they were protected against an otherwise lethal influenza infection after only 14 days postvaccination and after as many as 140 days postvaccination. The ability to rapidly produce this safe and effective vaccine in cell culture is additionally advantageous.
Suppression of Transforming Growth Factor β Receptor 2 and Smad5 Is Associated with High Levels of MicroRNA miR-155 in the Oral Mucosa during Chronic Simian Immunodeficiency Virus Infection
Authors: George Jeffy , Lewis Mark G. , Renne Rolf , Mattapallil Joseph J.
Published: December 2014

Chronic human immunodeficiency virus and simian immunodeficiency virus (HIV and SIV) infections are characterized by mucosal inflammation in the presence of anti-inflammatory cytokines such as transforming growth factor β (TGFβ). The mechanisms for refractiveness to TGFβ are not clear. Here we show that the expression of microRNA miR-155 was significantly upregulated in the oropharyngeal mucosa during chronic SIV infection and was coincident with downregulation of TGFβ receptor 2 (TGFβ-R2) and SMAD5, key TGFβ signaling genes that harbor putative target sites for miR-155. Ectopic expression of miR-155in vitrowas found to significantly downregulate TGFβ-R2 and Smad5 expression, suggesting a role for miR-155 in the suppression of TGFβ-R2 and SMAD5 genesin vivo. The downregulation of TGFβ signaling genes by miR-155 likely contributes to the nonresponsiveness to TGFβ during SIV infection and may inadvertently aid in increased immune activation during HIV and SIV infections.
The Epstein-Barr Virus BamHI C Promoter Is Not Essential for B Cell Immortalization
In Vitro
, but It Greatly Enhances B Cell Growth Transformation
Authors: Tierney Rosemary J. , Nagra Jasdeep , Rowe Martin , Bell Andrew I. , Rickinson Alan B.
Published: December 2014

Epstein-Barr virus (EBV) infection of B cells leads to the sequential activation of two viral promoters, Wp and Cp, resulting in the expression of six EBV nuclear antigens (EBNAs) and the viral Bcl2 homologue BHRF1. The viral transactivator EBNA2 is required for this switch from Wp to Cp usage during the initial stages of infection. EBNA2-dependent Cp transcription is mediated by the EBNA2 response element (E2RE), a region that contains at least two binding sites for cellular factors; one of these sites, CBF1, interacts with RBP-JK, which then recruits EBNA2 to the transcription initiation complex. Here we demonstrate that the B cell-specific transcription factor BSAP/Pax5 binds to a second site, CBF2, in the E2RE. Deletion of the E2RE in the context of a recombinant virus greatly diminished levels of Cp-initiated transcripts during the initial stages of infection but did not affect the levels of Wp-initiated transcripts or EBNA mRNAs. Consistent with this finding, viruses deleted for the E2RE were not markedly impaired in their ability to induce B cell transformation
in vitro
. In contrast, a larger deletion of the entire Cp region did reduce EBNA mRNA levels early after infection and subsequently almost completely ablated lymphoblastoid cell line (LCL) outgrowth. Notably, however, rare LCLs could be established following infection with Cp-deleted viruses, and these were indistinguishable from wild-type-derived LCLs in terms of steady-state EBV gene transcription. These data indicate that, unlike Wp, Cp is dispensable for the virus' growth-transforming activity.

IMPORTANCE
Epstein-Barr virus (EBV), a B lymphotropic herpesvirus etiologically linked to several B cell malignancies, efficiently induces B cell proliferation leading to the outgrowth of lymphoblastoid cell lines (LCLs). The initial stages of this growth-transforming infection are characterized by the sequential activation of two viral promoters, Wp and Cp, both of which appear to be preferentially active in target B cells. In this work, we have investigated the importance of Cp activity in initiating B cell proliferation and maintaining LCL growth. Using recombinant viruses, we demonstrate that while Cp is not essential for LCL outgrowth
in vitro
, it enhances transformation efficiency by >100-fold. We also show that Cp, like Wp, interacts with the B cell-specific activator protein BSAP/Pax5. We suggest that EBV has evolved this two-promoter system to ensure efficient colonization of the host B cell system
in vivo
.
Pathogenicity and Transmissibility of Novel Reassortant H3N2 Influenza Viruses with 2009 Pandemic H1N1 Genes in Pigs
Authors: Ma Jingjiao , Shen Huigang , Liu Qinfang , Bawa Bhupinder , Qi Wenbao , Duff Michael , Lang Yuekun , Lee Jinhwa , Yu Hai , Bai Jianfa , Tong Guangzhi , Hesse Richard A. , Richt Jürgen A. , Ma Wenjun
Published: December 2014

At least 10 different genotypes of novel reassortant H3N2 influenza viruses with 2009 pandemic H1N1 [A(H1N1)pdm09] gene(s) have been identified in U.S. pigs, including the H3N2 variant with a single A(H1N1)pdm09 M gene, which has infected more than 300 people. To date, only three genotypes of these viruses have been evaluated in animal models, and the pathogenicity and transmissibility of the other seven genotype viruses remain unknown. Here, we show that three H3N2 reassortant viruses that contain 3 (NP, M, and NS) or 5 (PA, PB2, NP, M, and NS) genes from A(H1N1)pdm09 were pathogenic in pigs, similar to the endemic H3N2 swine virus. However, the reassortant H3N2 virus with 3 A(H1N1)pdm09 genes and a recent human influenza virus N2 gene was transmitted most efficiently among pigs, whereas the reassortant H3N2 virus with 5 A(H1N1)pdm09 genes was transmitted less efficiently than the endemic H3N2 virus. Interestingly, the polymerase complex of reassortant H3N2 virus with 5 A(H1N1)pdm09 genes showed significantly higher polymerase activity than those of endemic and reassortant H3N2 viruses with 3 A(H1N1)pdm09 genes. Further studies showed that an avian-like glycine at position 228 at the hemagglutinin (HA) receptor binding site is responsible for inefficient transmission of the reassortant H3N2 virus with 5 A(H1N1)pdm09 genes. Taken together, our results provide insights into the pathogenicity and transmissibility of novel reassortant H3N2 viruses in pigs and suggest that a mammalian-like serine at position 228 in the HA is critical for the transmissibility of these reassortant H3N2 viruses.

IMPORTANCE
Swine influenza is a highly contagious zoonotic disease that threatens animal and public health. Introduction of 2009 pandemic H1N1 virus [A(H1N1)pdm09] into swine herds has resulted in novel reassortant influenza viruses in swine, including H3N2 and H1N2 variants that have caused human infections in the United States. We showed that reassortant H3N2 influenza viruses with 3 or 5 genes from A(H1N1)pdm09 isolated from diseased pigs are pathogenic and transmissible in pigs, but the reassortant H3N2 virus with 5 A(H1N1)pdm09 genes displayed less efficient transmissibility than the endemic and reassortant H3N2 viruses with 3 A(H1N1)pdm09 genes. Further studies revealed that an avian-like glycine at the HA 228 receptor binding site of the reassortant H3N2 virus with 5 A(H1N1)pdm09 genes is responsible for less efficient transmissibility in pigs. Our results provide insights into viral pathogenesis and the transmission of novel reassortant H3N2 viruses that are circulating in U.S. swine herds and warrant future surveillance.
Lymph Node but Not Intradermal Injection Site Macrophages Are Critical for Germinal Center Formation and Antibody Responses to Rabies Vaccination
Authors: Lytle Andrew G. , Shen Shixue , McGettigan James P.
Published: December 2014

Replication-deficient rabies virus (RABV)-based vaccines induce rapid and potent antibody responses via T cell-independent and T cell-dependent mechanisms. To further investigate early events in vaccine-induced antibody responses against RABV infections, we studied the role of macrophages as mediators of RABV-based vaccine immunogenicity. In this report, we show that a recombinant matrix gene-deleted RABV-based vaccine (rRABV-ΔM) infects and activates primary murine macrophages
in vitro
. Immunization of mice with live RABV-based vaccines results in accumulation of macrophages at the site of immunization, which suggests that macrophages in tissues support the development of effective anti-RABV B cell responses. However, we show that draining lymph node macrophages, but not macrophages at the site of immunization, are essential for the generation of germinal center B cells, follicular T helper cells, and RABV-specific antibodies. Our findings have implications for the design of new RABV-based vaccines for which early immunological events are important for the protection against RABV in postexposure settings.

IMPORTANCE
More than two-thirds of the world's population live in regions where rabies is endemic. Postexposure prophylaxis is the primary means of treating humans. Identifying immunological principles that guide the development of rapid and potent antibody responses against rabies infections will greatly increase our ability to produce more-effective rabies vaccines. Here we report that macrophages in the draining lymph node, but not in the tissue at the site of immunization are important for vaccine-induced antibody responses to rabies. Information gleaned from this study may help guide the development of a single-dose vaccine against rabies infections.
Natural Killer Cells Can Inhibit the Transmission of Human Cytomegalovirus in Cell Culture by Using Mechanisms from Innate and Adaptive Immune Responses
Authors: Wu Zeguang , Sinzger Christian , Reichel Johanna Julia , Just Marlies , Mertens Thomas
Published: December 2014

Human cytomegalovirus (HCMV) transmission within the host is important for the pathogenesis of HCMV diseases. Natural killer (NK) cells are well known to provide a first line of host defense against virus infections. However, the role of NK cells in the control of HCMV transmission is still unknown. Here, we provide the first experimental evidence that NK cells can efficiently control HCMV transmission in different cell types. NK cells engage different mechanisms to control the HCMV transmission both via soluble factors and by cell contact. NK cell-produced interferon gamma (IFN-γ) suppresses HCMV production and induces resistance of bystander cells to HCMV infection. The UL16 viral gene contributes to an immune evasion from the NK cell-mediated control of HCMV transmission. Furthermore, the efficacy of the antibody-dependent NK cell-mediated control of HCMV transmission is dependent on a CD16-158V/F polymorphism. Our findings indicate that NK cells may have a clinical relevance in HCMV infection and highlight the need to consider potential therapeutic strategies based on the manipulation of NK cells.

IMPORTANCEHuman cytomegalovirus (HCMV) infects 40% to 100% of the human population worldwide. After primary infection, mainly in childhood, the virus establishes a lifelong persistence with possible reactivations. Most infections remain asymptomatic; however, HCMV represents a major health problem since it is the most frequent cause of infection-induced birth defects and is responsible for high morbidity and mortality in immunocompromised patients. The immune system normally controls the infection by antibodies and immune effector cells. One type of effector cells are the natural killer (NK) cells, which provide a rapid response to virus-infected cells. NK cells participate in viral clearance by inducing the death of infected cells. NK cells also secrete antiviral cytokines as a consequence of the interaction with an infected cell. In this study, we investigated the mechanisms by which NK cells control HCMV transmission, from the perspectives of immune surveillance and immune evasion.
The Unusual Fold of Herpes Simplex Virus 1 UL21, a Multifunctional Tegument Protein
Authors: Metrick Claire M. , Chadha Pooja , Heldwein Ekaterina E.
Published: December 2014

UL21 is a conserved protein in the tegument of alphaherpesviruses and has multiple important albeit poorly understood functions in viral replication and pathogenesis. To provide a roadmap for exploration of the multiple roles of UL21, we determined the crystal structure of its conserved N-terminal domain from herpes simplex virus 1 to 2.0-Å resolution, which revealed a novel sail-like protein fold. Evolutionarily conserved surface patches highlight residues of potential importance for future targeting by mutagenesis.
Virus Evolution toward Limited Dependence on Nonessential Functions of the Host: the Case of Bacteriophage SPP1
Authors: Cvirkaite-Krupovic Virginija , Carballido-López Rut , Tavares Paulo
Published: December 2014

All viruses are obligate intracellular parasites and depend on certain host cell functions for multiplication. However, the extent of such dependence and the exact nature of the functions provided by the host cell remain poorly understood. Here, we investigated if nonessential
Bacillus subtilis
genes are necessary for multiplication of bacteriophage SPP1. Screening of a collection of 2,514 single-gene knockouts of nonessential
B. subtilis
genes yielded only a few genes necessary for efficient SPP1 propagation. Among these were genes belonging to the
yuk
operon, which codes for the Esat-6-like secretion system, including the SPP1 receptor protein YueB. In addition, we found that SPP1 multiplication was negatively affected by the absence of two other genes,
putB
and
efp
. The gene
efp
encodes elongation factor P, which enhances ribosome activity by alleviating translational stalling during the synthesis of polyproline-containing proteins. PutB is an enzyme involved in the proline degradation pathway that is required for infection in the post-exponential growth phase of
B. subtilis
, when the bacterium undergoes a complex genetic reprogramming. The
putB
knockout shortens significantly the window of opportunity for SPP1 infection during the host cell life cycle. This window is a critical parameter for competitive phage multiplication in the soil environment, where
B. subtilis
rarely meets conditions for exponential growth. Our results in combination with those reported for other virus-host systems suggest that bacterial viruses have evolved toward limited dependence on nonessential host functions.

IMPORTANCE
A successful viral infection largely depends on the ability of the virus to hijack cellular machineries and to redirect the flow of building blocks and energy resources toward viral progeny production. However, the specific virus-host interactions underlying this fundamental transformation are poorly understood. Here, we report on the first systematic analysis of virus-host cross talk during bacteriophage infection in Gram-positive bacteria. We show that lytic bacteriophage SPP1 is remarkably independent of nonessential genes of its host,
Bacillus subtilis
, with only a few cellular genes being necessary for efficient phage propagation. We hypothesize that such limited dependence of the virus on its host results from a constant “evolutionary arms race” and might be much more widespread than currently thought.
Recombinant Subgroup B Human Respiratory Syncytial Virus Expressing Enhanced Green Fluorescent Protein Efficiently Replicates in Primary Human Cells and Is Virulent in Cotton Rats
Authors: Lemon Ken , Nguyen D. Tien , Ludlow Martin , Rennick Linda J. , Yüksel Selma , van Amerongen Geert , McQuaid Stephen , Rima Bert K. , de Swart Rik L. , Duprex W. Paul
Published: December 2014

Human respiratory syncytial virus (HRSV) is the most important viral cause of severe respiratory tract disease in infants. Two subgroups (A and B) have been identified, which cocirculate during, or alternate between, yearly epidemics and cause indistinguishable disease. Existing
in vitro
and
in vivo
models of HRSV focus almost exclusively on subgroup A viruses. Here, a recombinant (r) subgroup B virus (rHRSV
B05
) was generated based on a consensus genome sequence obtained directly from an unpassaged clinical specimen from a hospitalized infant. An additional transcription unit containing the gene encoding enhanced green fluorescent protein (EGFP) was introduced between the phosphoprotein and matrix genes (position 5) of the genome to generate rHRSV
B05
EGFP(5). The recombinant viruses replicated efficiently in both HEp-2 cells and in well-differentiated normal human bronchial cells grown at air-liquid interface. Intranasal infection of cotton rats (
Sigmodon hispidus
) resulted in high numbers of EGFP
+
cells in epithelia of the nasal septum and conchae. When administered in a relatively large inoculum volume, the virus also replicated efficiently in bronchiolar epithelial cells and spread extensively in both the upper and lower respiratory tracts. Virus replication was not observed in ciliated epithelial cells of the trachea. This is the first virulent rHRSV strain with the genetic composition of a currently circulating wild-type virus.
In vivo
tracking of infected cells by means of EGFP fluorescence in the absence of cytopathic changes increases the sensitivity of virus detection in HRSV pathogenesis studies.

IMPORTANCE
Virology as a discipline has depended on monitoring cytopathic effects following virus culture
in vitro
. However, wild-type viruses isolated from patients often do not cause significant changes to infected cells, necessitating blind passage. This can lead to genetic and phenotypic changes and the generation of high-titer, laboratory-adapted viruses with diminished virulence in animal models of disease. To address this, we determined the genome sequence of an unpassaged human respiratory syncytial virus from a sample obtained directly from an infected infant, assembled a molecular clone, and recovered a wild-type recombinant virus. Addition of a gene encoding enhanced green fluorescent protein allowed this wild-type virus to be tracked in primary human cells and living animals in the absence of significant cytopathic effects. Imaging of fluorescent cells proved to be a highly valuable tool for monitoring the spread of virus and may help improve assays for evaluating novel intervention strategies.
Ultrasonography of fractures in sports medicine
Authors: Hoffman Douglas F , Adams Erik , Bianchi Stefano
Published: December 2014

High-resolution ultrasound is emerging as an important imaging modality in fracture assessment due to its availability, ease of use and multiplanar capabilities. Its usefulness includes injury assessment for the presence of a fracture when obtaining radiographs is not immediately available, detecting occult fractures not revealed on radiographs, and diagnosing bone stress injury before radiographic changes. Sonographic evaluation of bone, however, has limitations and should always be coupled with radiographs and possibly advanced imaging modalities such as CT and MR when clinically indicated.
Deliberative democracy and cancer screening consent: a randomised control trial of the effect of a community jury on men's knowledge about and intentions to participate in PSA screening
Authors: Thomas Rae , Glasziou Paul , Rychetnik Lucie , Mackenzie Geraldine , Gardiner Robert , Doust Jenny
Published: December 2014

Objective

Prostate-specific antigen (PSA) screening is controversial. A community jury allows presentation of complex information and may clarify how participants view screening after being well-informed. We examined whether participating in a community jury had an effect on men's knowledge about and their intention to participate in PSA screening.

Design

Random allocation to either a 2-day community jury or a control group, with preassessment, postassessment and 3-month follow-up assessment.

Setting

Participants from the Gold Coast (Australia) recruited via radio, newspaper and community meetings.

Participants

Twenty-six men aged 50–70 years with no previous diagnosis of prostate cancer.

Intervention

The control group (n=14) received factsheets on PSA screening. Community jury participants (n=12) received the same factsheets and further information about screening for prostate cancer. In addition, three experts presented information on PSA screening: a neutral scientific advisor provided background information, one expert emphasised the potential benefits of screening and another expert emphasised the potential harms. Participants discussed information, asked questions to the experts and deliberated on personal and policy decisions.

Main outcome and measures

Our primary outcome was change in individual intention to have a PSA screening test. We also assessed knowledge about screening for prostate cancer.

Results

Analyses were conducted using intention-to-treat. Immediately after the jury, the community jury group had less intention-to-screen for prostate cancer than men in the control group (effect size=−0.6 SD, p=0.05). This was sustained at 3-month follow-up. Community jury men also correctly identified PSA test accuracy and considered themselves more informed (effect size=1.2 SD, p<0.001).

Conclusions

Evidence-informed deliberation of the harms and benefits of PSA screening effects men's individual choice to be screened for prostate cancer. Community juries may be a valid method for eliciting target group input to policy decisions.

Trial registration number

Australian and New Zealand Clinical Trials Registry (ACTRN12612001079831).
Effectiveness of new legislation on partial sickness benefit on work participation: a quasi-experiment in Finland
Authors: Kausto Johanna , Viikari-Juntura Eira , Virta Lauri J , Gould Raija , Koskinen Aki , Solovieva Svetlana
Published: December 2014

Objectives

To examine the effect of the new legislation on partial sickness benefit on subsequent work participation of Finns with long-term sickness absence. Additionally, we investigated whether the effect differed by sex, age or diagnostic category.

Design

A register-based quasi-experimental study compared the intervention (partial sick leave) group with the comparison (full sick leave) group regarding their pre-post differences in the outcome. The preintervention and postintervention period each consisted of 365 days.

Setting

Nationwide, individual-level data on the beneficiaries of partial or full sickness benefit in 2008 were obtained from national sickness insurance, pension and earnings registers.

Participants

1738 persons in the intervention and 56 754 persons in the comparison group.

Outcome

Work participation, measured as the proportion (%) of time within 365 days when participants were gainfully employed and did not receive either partial or full ill-health-related or unemployment benefits.

Results

Although work participation declined in both groups, the decline was 5% (absolute difference-in-differences) smaller in the intervention than in the comparison group, with a minor sex difference. The beneficial effect of partial sick leave was seen especially among those aged 45–54 (5%) and 55–65 (6%) and in mental disorders (13%). When the groups were rendered more exchangeable (propensity score matching on age, sex, diagnostic category, income, occupation, insurance district, work participation, sickness absence, rehabilitation periods and unemployment, prior to intervention and their interaction terms), the effects on work participation were doubled and seen in all age groups and in other diagnostic categories than traumas.

Conclusions

The results suggest that the new legislation has potential to increase work participation of the population with long-term sickness absence in Finland. If applied in a larger scale, partial sick leave may turn out to be a useful tool in reducing withdrawal of workers from the labour market due to health reasons.
Adverse events in patients with return emergency department visits
Authors: Calder Lisa , Pozgay Anita , Riff Shena , Rothwell David , Youngson Erik , Mojaverian Naghmeh , Cwinn Adam , Forster Alan
Published: December 2014

Objectives

This study describes the proportion of emergency department (ED) returns within 7 days due to adverse events, defined as adverse outcomes related to healthcare received.

Design

Prospective cohort study.

Setting

We used an electronically triggered adverse event surveillance system at a tertiary care ED from May to June 2010 to examine ED returns within 7 days of index visit.

Participants

One of three trained nurses determined whether the visit was related to index emergency care. For such records, one of three trained emergency physicians conducted adverse event determinations.

Main outcome measure

We determined adverse event type and severity and analysed the data with descriptive statistics, χ2tests and logistic regression.

Results

Of 13 495 index ED visits, 923 (6.8%) were followed by ED returns within 7 days. The median age of all patients was 47 years and 52.8% were women. After nursing review, 211 cases required physician review. Of these, 53 visits were adverse events (positive predictive value (PPV)=5.7%, 95% CI 4.4% to 7.4%) and 30 (56.6%) were preventable. Common adverse event types involved management, diagnostic or medication issues. We observed one potentially preventable death and 58.5% of adverse events resulting in transient disability. The PPV of a modified trigger with a cut-off of return within 72 h, resulting in admission was 11.9% (95% CI 6.8% to 18.9%).

Conclusions

Our electronic trigger efficiently identified adverse events among 12% of patients with ED returns within 72 h, requiring hospital admission. Given the high degree of preventability of the identified adverse events, this trigger also holds promise as a performance measurement tool.
High body mass index and allergies in schoolchildren: the French six cities study
Authors: Saadeh Danielle , Salameh Pascale , Caillaud Denis , Charpin Denis , de Blay Frédéric , Kopferschmitt Christine , Lavaud François , Annesi-Maesano Isabella , Baldi Isabelle , Raherison Chantal
Published: December 2014

Background

The prevalence of allergic diseases such as asthma, allergic rhinitis and atopic dermatitis is increasing rapidly worldwide, especially among children and in western countries. This coincides with an increase in body mass index (BMI), which might be a major risk factor for atopic diseases.

Objectives

To study the relationship between high BMI and allergic diseases, as well as skin-prick test (SPT) positivity and exercise-induced asthma (EIA) in 6733 randomly selected schoolchildren aged 9–11 years in the French Six Cities Study.

Methods

A cross-sectional study was carried out in Bordeaux, Clermont-Ferrand, Créteil, Marseille, Reims and Strasbourg. Parental questionnaires based on the International Study on Asthma and Allergies in Childhood (ISAAC) were used to collect information on allergic diseases and potential risk factors. Skin-prick testing to common allergens was performed to identify the existence of an allergic hypersensitivity and an exercise test was also performed to assess EIA. Height and weight were collected by trained investigators. After computing the BMI (weight/height squared), the International Obesity Task Force (IOTF) cut-offs were used to define overweight and obesity. The children were also classified as wheezing or non-wheezing.

Results

After adjustment for confounding factors, lifetime asthma was associated with high BMI among non-wheezing children (adjusted OR, aOR=1.98, 95% CI (1.06 to 3.70)). In addition, lifetime and past-year allergic rhinitis was associated with high BMI in wheezing children (aOR=1.63, (1.09 to 2.45) and aOR=2.20, (1.13 to 4.27)). However, high BMI was not significantly associated with eczema, SPT positivity or EIA.

Conclusions

This study shows a positive association between high BMI and lifetime asthma in non-wheezing children. High BMI was also associated with lifetime and past-year allergic rhinitis. Further studies are needed to provide causal evidence.
The Manchester Acute Coronary Syndromes (MACS) decision rule: validation with a new automated assay for heart-type fatty acid binding protein
Authors: Body Richard , Burrows Gillian , Carley Simon , Lewis Philip S
Published: December 2014

Objective

The Manchester Acute Coronary Syndromes (MACS) decision rule may enable acute coronary syndromes to be immediately ‘ruled in’ or ‘ruled out’ in the emergency department. The rule incorporates heart-type fatty acid binding protein (h-FABP) and high sensitivity troponin T levels. The rule was previously validated using a semiautomated h-FABP assay that was not practical for clinical implementation. We aimed to validate the rule with an automated h-FABP assay that could be used clinically.

Methods

In this prospective diagnostic cohort study we included patients presenting to the emergency department with suspected cardiac chest pain. Serum drawn on arrival was tested for h-FABP using an automated immunoturbidimetric assay (Randox) and high sensitivity troponin T (Roche). The primary outcome, a diagnosis of acute myocardial infarction (AMI), was adjudicated based on 12 h troponin testing. A secondary outcome, major adverse cardiac events (MACE; death, AMI, revascularisation or new coronary stenosis), was determined at 30 days.

Results

Of the 456 patients included, 78 (17.1%) had AMI and 97 (21.3%) developed MACE. Using the automated h-FABP assay, the MACS rule had the same C-statistic for MACE as the original rule (0.91; 95% CI 0.88 to 0.92). 18.9% of patients were identified as ‘very low risk’ and thus eligible for immediate discharge with no missed AMIs and a 2.3% incidence of MACE (n=2, both coronary stenoses). 11.1% of patients were classed as ‘high-risk’ and had a 92.0% incidence of MACE.

Conclusions

Our findings validate the performance of a refined MACS rule incorporating an automated h-FABP assay, facilitating use in clinical settings. The effectiveness of this refined rule should be verified in an interventional trial prior to implementation.

Trial registration number

UK CRN 8376.
Epidemiology of non-fatal US emergency room visits for road crashes involving pedestrians in wheelchairs
Authors: Kraemer John D
Published: December 2014

This study aims to quantify and describe the risk of non-fatal pedestrian injury among persons who use wheelchairs in the US. Cases of pedestrian injury between 2002 and 2010 among persons using wheelchairs were identified in the National Electronic Injury Surveillance System to generate national injury estimates. Between 2002 and 2010, an estimated 9348 (95% CI 4912 to 13 784) people were treated in emergency departments for non-fatal pedestrian injuries sustained while using wheelchairs. Using wheelchair-use denominators calculated from the Survey of Income and Program Participation, this equates to an incidence rate of 31.3 (95% CI 16.4 to 46.1) per 100 000 person-years. Injury risk was 3.5 times higher for men than women (p<0.001). Contusions, abrasions, and lacerations (42.7%) and fractures (16.4%) were most common. The head and neck (24.7%) and lower extremities (28.4%) were most often injured. A fifth (21.4%) of injuries required hospitalisation, and 89.2% occurred in traffic on public roadways.
Bone-specific alkaline phosphatase by immunoassay or electrophoresis: their use in clinical practice
Authors: Ahmed Farhan , Gibbons Stephen M
Published: December 2014

Background

Measurement of bone-specific alkaline phosphatase (BALP) may be useful in diagnosing and monitoring metabolic bone disease. This study aimed to evaluate the BALP immunoassay and compare it with electrophoresis (densitometry) for the quantitation of BALP.

Methods

Metra BALP immunoassay kits were used for the method comparison. BALP was also quantitated by electrophoresis (densitometry) in seven patients with active Paget's disease.

Results

Immunoassay results did not correlate well with densitometrically quantitated BALP, as there was a statistically significant (p<0.01), negative bias (22%) for results obtained by immunoassay compared with those derived by densitometry. Possible interference in the immunoassay with other isoforms of alkaline phosphatase (ALP) such as liver, placental and intestinal was also observed. The Metra BALP immunoassay is quoted as having an upper dynamic limit of 140 U/L and recommends that samples only require dilution above this level; we observed inconsistent results upon dilution of samples below this level.

Conclusions

Immunoassay and electrophoresis did not correlate well for BALP quantitation. Possible interference with other isoforms of ALP was observed with the BALP immunoassay. The accuracy of the BALP immunoassay is questionable at higher concentrations.
Neurological outcomes and cure rates of embolization of brain arteriovenous malformations with n-butyl cyanoacrylate or Onyx: a meta-analysis
Authors: Elsenousi Abdussalam , Aletich Victor A , Alaraj Ali
Published: December 2014

Background

In the past decade, preoperative endovascular embolization of cerebral arteriovenous malformations (AVMs) became an essential tool in the treatment of these entities. With the current expansion of technology and wide incorporation of new devices, the indications for the use of endovascular embolization have expanded to include embolization for cure. This has been facilitated by the wide use of the new liquid embolic agents (ethylene-vinyl alcohol co-polymer (EVOH)) in addition to n-butyl cyanoacrylate (NBCA). The aim of this study was to review the current published literature for these two agents and report on permanent neurological injuries and cure rate.

Methods

Published literature citing embolization results for AVMs using liquid embolic agents was reviewed. Papers reporting on permanent complication rates and complete angiographic cure were reviewed. A meta-analysis was performed based on these two variables for the two embolic agents.

Results

103 studies met the selection criteria. Poor neurological outcomes for NBCA and EVOH were 5.2% and 6.8%, respectively (OR 1.4; p=0.56). AVM complete obliteration rate was seen in 13.7% in the NBCA group and in 24% in the EVOH group (OR 1.9). This OR decreased to 1.35 in the subgroup analysis for patients treated after the year 2000.

Conclusions

NBCA continues to have a trend towards lower permanent complication rates, but EVOH had higher angiographic cure rates. The recent literature has demonstrated an increase in the cure rate of AVMs with endovascular embolization techniques yet with a possible increase in permanent neurological deficits and mortality.
Infarct growth despite full reperfusion in endovascular therapy for acute ischemic stroke
Authors: Haussen Diogo C , Nogueira Raul G , Elhammady Mohamed Samy , Yavagal Dileep R , Aziz-Sultan Mohammad Ali , Johnson Jeremiah N , Gaynor Brandon G , Jen Shyian , Dehkharghani Seena , Peterson Eric C
Published: December 2014

Aim

To explore the predictors of infarct core expansion despite full reperfusion after intra-arterial therapy (IAT).

Methods

We retrospectively reviewed 604 consecutive patients who underwent IAT for anterior circulation large vessel occlusion acute ischemic stroke in two tertiary centers (2008–2013/2010–2013). Sixty patients selected by MRI or CT perfusion presenting within <24 h of onset with modified Thrombolysis In Cerebral Infarction (mTICI) grade 3 or 2c reperfusion were included. Significant infarct growth (SIG) was defined as infarct expansion >11.6 mL.

Results

Mean age was 67.0±13.7 years, 56% were men. Mean National Institute of Health Stroke Scale (NIHSS) score was 16.2±6.1, time from onset to puncture was 6.8±3.1 h, and procedure length was 1.3±0.6 h. MRI was used for baseline core analysis in 43% of patients. Mean baseline infarct volume was 17.1±19.1 mL, absolute infarct growth was 30.6±74.5 mL, and final infarct volume was 47.7±77.7 mL. Overall, 35% of patients had SIG. Three of 21 patients (14%) treated with stent-retrievers had SIG compared with 14 of 39 (36%) with first-generation devices. Eight of 21 patients (38%) with intravenous tissue plasminogen activator (IV t-PA) had infarct growth compared with 25/39 (64%) without. 23% of patients with SIG had a modified Rankin Scale score ≤2 at 3 months compared with 48% of those without SIG. Multivariate logistic regression indicated that race affected infarct growth. Use of IV t-PA (p=0.03) and stent-retrievers (p=0.03) were independently and inversely correlated with SIG.

Conclusions

Despite full reperfusion, infarct growth is relatively frequent and may explain poor clinical outcomes in this setting. Ethnicity was found to influence SIG. Use of IV t-PA and stent-retrievers were associated with less infarct core expansion.
Alfred J Luessenhop and the dawn of a new superspecialty: endovascular neurosurgery
Authors: Maiti Tanmoy Kumar , Bir Shyamal Chandra , Bollam Papireddy , Nanda Anil
Published: December 2014

Endovascular neurosurgery, or interventional neuroradiology, has developed rapidly over the last 50 years and has posed a challenge to the established mode of open surgery. Alfred J Luessenhop, an American neurosurgeon, is credited with the first embolization of a cranial arteriovenous malformation and the first intracranial arterial catheterization to occlude an aneurysm. This review describes the life and work of the surgeon who can be regarded as the father of endovascular neurosurgery.
Nasal cryptococcoma causing severe meningitis in a dog in the UK
Authors: Martinez Lorena , Beltran Elsa , Rasotto Roberta , Berlato Davide , Holloway Andrew
Published: December 2014

A five‐year‐old neutered male Staffordshire bull terrier was referred with a one‐month history of lethargy and ataxia. Neurolocalisation was to the left forebrain with suspected increased intracranial pressure. MRI demonstrated a mass lesion in the caudal right and left nasal cavities extending through the cribriform plate into the rostral cranial fossa infiltrating the left olfactory bulb and left frontal lobe. Severe diffuse meningitis of the brain and cranial cervical spinal cord characterised by disseminated avidly enhancing meningeal nodules was present. At postmortem examination, the mass was multilobulated and firm; histologically, it was composed of pyogranulomatous and eosinophilic inflammation associated with large numbers of encapsulated yeast‐like organisms, consistent with a nasal cryptococcoma. Fungal culture from a nasal swab confirmed Cryptococcus neoformans species. To the authors’ knowledge, this is the first case reported in the UK of a dog with nasal cryptococcoma causing severe meningitis.
On the Lie subalgebra of Killing–Milne and Killing–Cartan vector fields in Newtonian spacetime
Authors: Chamel Nicolas
Published: December 2014

The Galilean (and more generally Milne) invariance of Newtonian theory allows for Killing vector fields of a general kind, whereby the Lie derivative of a field is not required to vanish but only to be cancellable by some infinitesimal Galilean (respectively Milne) gauge transformation. In this paper, it is shown that both the Killing–Milne vector fields, which preserve the background Newtonian spacetime structure and the Killing–Cartan vector fields, which in addition preserve the gravitational field, form a Lie subalgebra.
Circular geodesic of Bardeen and Ayon–Beato–Garcia regular black-hole and no-horizon spacetimes
Authors: Stuchlík Zdeněk , Schee Jan
Published: December 2014

In this paper, we study circular geodesic motion of test particles and photons in the Bardeen and Ayon–Beato–Garcia (ABG) geometry describing spherically symmetric regular black-hole or no-horizon spacetimes. While the Bardeen geometry is not exact solution of Einstein's equations, the ABG spacetime is related to self-gravitating charged sources governed by Einstein's gravity and nonlinear electrodynamics. They both are characterized by the mass parameter m and the charge parameter g. We demonstrate that in similarity to the Reissner–Nordstrom (RN) naked singularity spacetimes an antigravity static sphere should exist in all the no-horizon Bardeen and ABG solutions that can be surrounded by a Keplerian accretion disc. However, contrary to the RN naked singularity spacetimes, the ABG no-horizon spacetimes with parameter g/m > 2 can contain also an additional inner Keplerian disc hidden under the static antigravity sphere. Properties of the geodesic structure are reflected by simple observationally relevant optical phenomena. We give silhouette of the regular black-hole and no-horizon spacetimes, and profiled spectral lines generated by Keplerian rings radiating at a fixed frequency and located in strong gravity region at or nearby the marginally stable circular geodesics. We demonstrate that the profiled spectral lines related to the regular black-holes are qualitatively similar to those of the Schwarzschild black-holes, giving only small quantitative differences. On the other hand, the regular no-horizon spacetimes give clear qualitative signatures of their presence while compared to the Schwarschild spacetimes. Moreover, it is possible to distinguish the Bardeen and ABG no-horizon spacetimes, if the inclination angle to the observer is known.
PREDICTABILITY AND MARKET EFFICIENCY IN AGRICULTURAL FUTURES MARKETS: A PERSPECTIVE FROM PRICE–VOLUME CORRELATION BASED ON WAVELET COHERENCY ANALYSIS
Authors: HE LING-YUN , WEN XING-CHUN
Published: December 2014

In this paper, we use a time-frequency domain technique, namely, wavelet squared coherency, to examine the associations between the trading volumes of three agricultural futures and three different forms of these futures' daily closing prices, i.e. prices, returns and volatilities, over the past several years. These agricultural futures markets are selected from China as a typical case of the emerging countries, and from the US as a representative of the developed economies. We investigate correlations and lead–lag relationships between the trading volumes and the prices to detect the predictability and efficiency of these futures markets. The results suggest that the information contained in the trading volumes of the three agricultural futures markets in China can be applied to predict the prices or returns, while that in US has extremely weak predictive power for prices or returns. We also conduct the wavelet analysis on the relationships between the volumes and returns or volatilities to examine the existence of the two "stylized facts" proposed by Karpoff [J. M. Karpoff, The relation between price changes and trading volume: A survey, J. Financ. Quant. Anal.22(1) (1987) 109–126]. Different markets in the two countries perform differently in reproducing the two stylized facts. As the wavelet tools can decode nonlinear regularities and hidden patterns behind price–volume relationship in time-frequency space, different from the conventional econometric framework, this paper offers a new perspective into the market predictability and efficiency.
REDUCED-ORDER MODELS FOR THE IMPLIED VARIANCE UNDER LOCAL VOLATILITY
Authors: SACHS EKKEHARD W. , SCHNEIDER MARINA
Published: December 2014

Implied volatility is a key value in financial mathematics. We discuss some of the pros and cons of the standard ways to compute this quantity, i.e. numerical inversion of the well-known Black–Scholes formula or asymptotic expansion approximations, and propose a new way to directly calculate the implied variance in a local volatility framework based on the solution of a quasilinear degenerate parabolic partial differential equation. Since the numerical solution of this equation may lead to large nonlinear systems of equations and thus high computation times compared to the classical approaches, we apply model order reduction techniques to achieve computational efficiency. Our method of choice for the derivation of a reduced-order model (ROM) will be proper orthogonal decomposition (POD). This strategy is additionally combined with the discrete empirical interpolation method (DEIM) to deal with the nonlinear terms. Numerical results prove the quality of our approach compared to other methods.