Improved Efficacy of a Gene Optimised Adenovirus-based Vaccine for Venezuelan Equine Encephalitis Virus

<p>Abstract</p> <p>Background</p> <p>Optimisation of genes has been shown to be beneficial for expression of proteins in a range of applications. Optimisation has increased protein expression levels through improved codon usage of the genes and an increase in levels of messenger RNA. We have applied this to an adenovirus (ad)-based vaccine encoding structural proteins (E3-E2-6K) of Venezuelan equine encephalitis virus (VEEV).</p> <p>Results</p> <p>Following administration of this vaccine to Balb/c mice, an approximately ten-fold increase in antibody response was elicited and increased protective efficacy compared to an ad-based vaccine containing non-optimised genes was observed after challenge.</p> <p>Conclusion</p> <p>This study, in which the utility of optimising genes encoding the structural proteins of VEEV is demonstrated for the first time, informs us that including optimised genes in gene-based vaccines for VEEV is essential to obtain maximum immunogenicity and protective efficacy.</p

A comparison of sex offenders and other types of offenders referred to intellectual disability forensic services

This study compared 131 sex offenders with ID and 346 other types of offenders with ID using case file records. All the females in the study were non sexual offenders. Significantly more sexual offenders were referred from court and criminal justice services while significantly fewer were referred from secondary healthcare. A higher percentage of sex offenders had some form of legal status at time of referral. Greater proportions of non sexual offenders were referred for aggression, damage to property, substance abuse and fire setting while only the sex offenders had an index sex offence. For previous offending, the non sexual offenders had higher rates of aggression, cruelty and neglect of children, property damage and substance abuse while the sexual offenders had higher rates of previous sexual offending. For psychiatric disturbance and adversity in childhood, only ADHD showed a significant difference between groups with the non sexual offenders recording higher rates

Investigating High-Energy Proton-Induced Reactions on Spherical Nuclei: Implications for the Pre-Equilibrium Exciton Model

A number of accelerator-based isotope production facilities utilize 100- to 200-MeV proton beams due to the high production rates enabled by high-intensity beam capabilities and the greater diversity of isotope production brought on by the long range of high-energy protons. However, nuclear reaction modeling at these energies can be challenging because of the interplay between different reaction modes and a lack of existing guiding cross section data. A Tri-lab collaboration has been formed among the Lawrence Berkeley, Los Alamos, and Brookhaven National Laboratories to address these complexities by characterizing charged-particle nuclear reactions relevant to the production of established and novel radioisotopes. In the inaugural collaboration experiments, stacked-targets of niobium foils were irradiated at the Brookhaven Linac Isotope Producer (E$_p$=200 MeV) and the Los Alamos Isotope Production Facility (E$_p$=100 MeV) to measure $^{93}$Nb(p,x) cross sections between 50 and 200 MeV. The measured cross-section results were compared with literature data as well as the default calculations of the nuclear model codes TALYS, CoH, EMPIRE, and ALICE. We developed a standardized procedure that determines the reaction model parameters that best reproduce the most prominent reaction channels in a physically justifiable manner. The primary focus of the procedure was to determine the best parametrization for the pre-equilibrium two-component exciton model. This modeling study revealed a trend toward a relative decrease for internal transition rates at intermediate proton energies (E$_p$=20-60 MeV) in the current exciton model as compared to the default values. The results of this work are instrumental for the planning, execution, and analysis essential to isotope production.Comment: 37 pages, 62 figures. Revised version, published in Physical Review

Blocking TLR7- and TLR9-mediated IFN-α Production by Plasmacytoid Dendritic Cells Does Not Diminish Immune Activation in Early SIV Infection

Persistent production of type I interferon (IFN) by activated plasmacytoid dendritic cells (pDC) is a leading model to explain chronic immune activation in human immunodeficiency virus (HIV) infection but direct evidence for this is lacking. We used a dual antagonist of Toll-like receptor (TLR) 7 and TLR9 to selectively inhibit responses of pDC but not other mononuclear phagocytes to viral RNA prior to and for 8 weeks following pathogenic simian immunodeficiency virus (SIV) infection of rhesus macaques. We show that pDC are major but not exclusive producers of IFN-α that rapidly become unresponsive to virus stimulation following SIV infection, whereas myeloid DC gain the capacity to produce IFN-α, albeit at low levels. pDC mediate a marked but transient IFN-α response in lymph nodes during the acute phase that is blocked by administration of TLR7 and TLR9 antagonist without impacting pDC recruitment. TLR7 and TLR9 blockade did not impact virus load or the acute IFN-α response in plasma and had minimal effect on expression of IFN-stimulated genes in both blood and lymph node. TLR7 and TLR9 blockade did not prevent activation of memory CD4+ and CD8+ T cells in blood or lymph node but led to significant increases in proliferation of both subsets in blood following SIV infection. Our findings reveal that virus-mediated activation of pDC through TLR7 and TLR9 contributes to substantial but transient IFN-α production following pathogenic SIV infection. However, the data indicate that pDC activation and IFN-α production are unlikely to be major factors in driving immune activation in early infection. Based on these findings therapeutic strategies aimed at blocking pDC function and IFN-α production may not reduce HIV-associated immunopathology. © 2013 Kader et al

Should Controls With Respiratory Symptoms Be Excluded From Case-Control Studies of Pneumonia Etiology? Reflections From the PERCH Study.

Many pneumonia etiology case-control studies exclude controls with respiratory illness from enrollment or analyses. Herein we argue that selecting controls regardless of respiratory symptoms provides the least biased estimates of pneumonia etiology. We review 3 reasons investigators may choose to exclude controls with respiratory symptoms in light of epidemiologic principles of control selection and present data from the Pneumonia Etiology Research for Child Health (PERCH) study where relevant to assess their validity. We conclude that exclusion of controls with respiratory symptoms will result in biased estimates of etiology. Randomly selected community controls, with or without respiratory symptoms, as long as they do not meet the criteria for case-defining pneumonia, are most representative of the general population from which cases arose and the least subject to selection bias

Altered engagement of the speech motor network is associated with reduced phonological working memory in autism

Nonword repetition, a common clinical measure of phonological working memory, involves component processes of speech perception, working memory, and speech production. Autistic children often show behavioral challenges in nonword repetition, as do many individuals with communication disorders. It is unknown which subprocesses of phonological working memory are vulnerable in autistic individuals, and whether the same brain processes underlie the transdiagnostic difficulty with nonword repetition. We used functional magnetic resonance imaging (fMRI) to investigate the brain bases for nonword repetition challenges in autism. We compared activation during nonword repetition in functional brain networks subserving speech perception, working memory, and speech production between neurotypical and autistic children. Autistic children performed worse than neurotypical children on nonword repetition and had reduced activation in response to increasing phonological working memory load in the supplementary motor area. Multivoxel pattern analysis within the speech production network classified shorter vs longer nonword-repetition trials less accurately for autistic than neurotypical children. These speech production motor-specific differences were not observed in a group of children with reading disability who had similarly reduced nonword repetition behavior. These findings suggest that atypical function in speech production brain regions may contribute to nonword repetition difficulties in autism.R01 DC011339 - NIDCD NIH HHS; R21 DC017576 - NIDCD NIH HHS; R03 DC014045 - NIDCD NIH HHS; T32 DC000038 - NIDCD NIH HHSPublished versio

Epidemiology of nasopharyngeal carriage of respiratory bacterial pathogens in children and adults: cross-sectional surveys in a population with high rates of pneumococcal disease

<p>Abstract</p> <p>Background</p> <p>To determine the prevalence of carriage of respiratory bacterial pathogens, and the risk factors for and serotype distribution of pneumococcal carriage in an Australian Aboriginal population.</p> <p>Methods</p> <p>Surveys of nasopharyngeal carriage of <it>Streptococcus pneumoniae</it>, non-typeable <it>Haemophilus influenzae</it>, and <it>Moraxella catarrhalis </it>were conducted among adults (≥16 years) and children (2 to 15 years) in four rural communities in 2002 and 2004. Infant seven-valent pneumococcal conjugate vaccine (7PCV) with booster 23-valent pneumococcal polysaccharide vaccine was introduced in 2001. Standard microbiological methods were used.</p> <p>Results</p> <p>At the time of the 2002 survey, 94% of eligible children had received catch-up pneumococcal vaccination. 324 adults (538 examinations) and 218 children (350 examinations) were enrolled. Pneumococcal carriage prevalence was 26% (95% CI, 22-30) among adults and 67% (95% CI, 62-72) among children. Carriage of non-typeable <it>H. influenzae </it>among adults and children was 23% (95% CI, 19-27) and 57% (95% CI, 52-63) respectively and for <it>M. catarrhalis</it>, 17% (95% CI, 14-21) and 74% (95% CI, 69-78) respectively. Adult pneumococcal carriage was associated with increasing age (p = 0.0005 test of trend), concurrent carriage of non-typeable <it>H. influenzae </it>(Odds ratio [OR] 6.74; 95% CI, 4.06-11.2) or <it>M. catarrhalis </it>(OR 3.27; 95% CI, 1.97-5.45), male sex (OR 2.21; 95% CI, 1.31-3.73), rhinorrhoea (OR 1.66; 95% CI, 1.05-2.64), and frequent exposure to outside fires (OR 6.89; 95% CI, 1.87-25.4). Among children, pneumococcal carriage was associated with decreasing age (p < 0.0001 test of trend), and carriage of non-typeable <it>H. influenzae </it>(OR 9.34; 95% CI, 4.71-18.5) or <it>M. catarrhalis </it>(OR 2.67; 95% CI, 1.34-5.33). Excluding an outbreak of serotype 1 in children, the percentages of serotypes included in 7, 10, and 13PCV were 23%, 23%, and 29% (adults) and 22%, 24%, and 40% (2-15 years). Dominance of serotype 16F, and persistent 19F and 6B carriage three years after initiation of 7PCV is noteworthy.</p> <p>Conclusions</p> <p>Population-based carriage of <it>S. pneumoniae</it>, non-typeable <it>H. influenzae</it>, and <it>M. catarrhalis </it>was high in this Australian Aboriginal population. Reducing smoke exposure may reduce pneumococcal carriage. The indirect effects of 10 or 13PCV, above those of 7PCV, among adults in this population may be limited.</p

Variation in the Ovine Abomasal Lymph Node Transcriptome between Breeds Known to Differ in Resistance to the Gastrointestinal Nematode

Texel lambs are known to be more resistant to gastrointestinal nematode (GIN) infection than Suffolk lambs, with a greater ability to limit infection. The objectives of this study were to: 1) profile the whole transcriptome of abomasal lymph node tissue of GIN-free Texel and Suffolk lambs; 2) identify differentially expressed genes and characterize the immune-related biological pathways and networks associated with these genes. Abomasal lymph nodes were collected from Texel (n = 6) and Suffolk (n = 4) lambs aged 19 weeks that had been GIN-free since 6 weeks of age. Whole transcriptome profiling was performed using RNA-seq on the Illumina platform. At the time of conducting this study, a well annotated Ovine genome was not available and hence the sequence reads were aligned with the Bovine (UMD3.1) genome. Identification of differentially expressed genes was followed by pathway and network analysis. The Suffolk breed accounted for significantly more of the differentially expressed genes, (276 more highly expressed in Suffolk v 162 in Texel; P < 0.001). The four most significant differentially expressed pathways were all related to immunity and were classified as: Role of Pattern Recognition Receptors in Recognition of Bacteria and Viruses, Activation of IRF by Cytosolic Pattern Recognition Receptors, Role of RIG-I-like Receptors in Antiviral Innate Immunity, and Interferon Signaling. Of significance is the fact that all of these four pathways were more highly expressed in the Suffolk. These data suggest that in a GIN-free environment, Suffolk lambs have a more active immune profile relative to the Texel: this immune profile may contribute to the poorer efficiency of response to a GIN challenge in the Suffolk breed compared to the Texel breed

Development of a novel monoclonal antibody with reactivity to a wide range of Venezuelan equine encephalitis virus strains

<p>Abstract</p> <p>Background</p> <p>There is currently a requirement for antiviral therapies capable of protecting against infection with Venezuelan equine encephalitis virus (VEEV), as a licensed vaccine is not available for general human use. Monoclonal antibodies are increasingly being developed as therapeutics and are potential treatments for VEEV as they have been shown to be protective in the mouse model of disease. However, to be truly effective, the antibody should recognise multiple strains of VEEV and broadly reactive monoclonal antibodies are rarely and only coincidentally isolated using classical hybridoma technology.</p> <p>Results</p> <p>In this work, methods were developed to reliably derive broadly reactive murine antibodies. A phage library was created that expressed single chain variable fragments (scFv) isolated from mice immunised with multiple strains of VEEV. A broadly reactive scFv was identified and incorporated into a murine IgG2a framework. This novel antibody retained the broad reactivity exhibited by the scFv but did not possess virus neutralising activity. However, the antibody was still able to protect mice against VEEV disease induced by strain TrD when administered 24 h prior to challenge.</p> <p>Conclusion</p> <p>A monoclonal antibody possessing reactivity to a wide range of VEEV strains may be of benefit as a generic antiviral therapy. However, humanisation of the murine antibody will be required before it can be tested in humans.</p> <p>Crown Copyright © 2009</p

Toward estimating the impact of changes in immigrants' insurance eligibility on hospital expenditures for uncompensated care

BACKGROUND: The Personal Responsibility and Work Opportunity Reconciliation Act (PRWORA) of 1996 gave states the option to withdraw Medicaid coverage of nonemergency care from most legal immigrants. Our goal was to assess the effect of PRWORA on hospital uncompensated care in the United States. METHODS: We collected the following state-level data for the period from 1994 through 1999: foreign-born, noncitizen population and health uninsurance rates (US Census Current Population Survey); percentage of teaching hospitals (American Hospital Association Annual Survey of Hospitals); and each state's decision whether to implement the PRWORA Medicaid bar for legal permanent residents or to continue offering nonemergency Medicaid coverage using state-only funds (Urban Institute). We modeled uncompensated care expenditures by state (also from the Annual Survey of Hospitals) in both univariate and multivariable regression analyses. RESULTS: When measured at the state level, there was no significant relationship between uncompensated care expenditures and states' percentage of noncitizen immigrants. Uninsurance rates were the only significant factor in predicting uncompensated hospital care expenditures by state. CONCLUSIONS: Reducing the number of uninsured patients would most surely reduce hospital expenditures for uncompensated care. However, data limitations hampered our efforts to obtain a monetary estimate of hospitals' financial losses due specifically to the immigrant eligibility changes in PRWORA. Quantifying the impact of these provisions on hospitals will require better data sources