Reassortment of two tripartite genomes producing a novel reassortant.

<p>A) Diagrammatic representation of the emergence of a novel reassortant strain with genes derived from two parents. B) Phylogenetic discordance between segments 1 and 3 (left) and segment 2 (right) for three tripartite strains. Branches in bolder colors represent parental strains, whereas lighter colors represent the acquisition of gene segments from different parents to form a novel reassortant strain.</p

Epidemiological trends in notified influenza cases in Australia’s Northern Territory, 2007-2016

Background: The Northern Territory (NT) of Australia has a mix of climates, sparsely distributed population and a large proportion of the populace are Indigenous Australians, and influenza is known to have a disproportionate impact upon this group. Understanding the epidemiology of influenza in this region would inform public health strategies. Objectives: To assess if there are consistent patterns in characteristics of influenza outbreaks in the NT. Methods: Laboratory confirmed influenza cases in the NT are notified to the NT Centre for Disease Control. We conducted analyses on notified cases from 2007-2016 to determine incidence rates (by age group, Indigenous status and area), seasonality of cases and spatial distribution of influenza types. Notified cases were linked to laboratory datasets to update information on influenza type or subtype. Results: The disparity in Indigenous and non-Indigenous notification rates varied by age group, with rate ratios for Indigenous versus non-Indigenous ranging from 1.58 (95% CI:1.39, 1.80) for ages 15-24 to 5.56 (95% CI: 4.71, 6.57) for ages 55-64. The disparity between Indigenous and non-Indigenous notification rates appeared higher in the Central Australia region. Indigenous versus non-Indigenous hospitalisation and mortality rate ratios were 6.51 (95% CI: 5.91, 7.18) and 5.46 (95% CI: 2.40, 12.71) respectively. Inter-seasonal peaks during February and March occurred in 2011, 2013 and 2014, and were due to influenza activity in the tropical north of the NT. Conclusions: Our results highlight the importance of influenza vaccination across all age groups for Indigenous Australians. An early vaccination campaign targeted against outbreaks in February-March would be best focused on the tropical north

Preexisting CD8⁺ T-cell immunity to the H7N9 influenza A virus varies across ethnicities

The absence of preexisting neutralizing antibodies specific for the novel A (H7N9) influenza virus indicates a lack of prior human exposure. As influenza A virus-specific CD8+ T lymphocytes (CTLs) can be broadly cross-reactive, we tested whether immunogenic peptides derived from H7N9 might be recognized by memory CTLs established following infection with other influenza strains. Probing across multiple ethnicities, we identified 32 conserved epitopes derived from the nucleoprotein (NP) and matrix-1 (M1) proteins. These NP and M1 peptides are presented by HLAs prevalent in 16-57% of individuals. Remarkably, some HLA alleles (A*0201, A *0301, B*5701, B*1801, and B*0801) elicit robust CTL responses against any human influenza A virus, including H7N9, whereas ethnicities where HLA-A*0101, A*6801, B*1501, and A*2402 are prominent, show limited CTL response profiles. By this criterion, some groups, especially the Alaskan and Australian Indigenous peoples, would be particularly vulnerable to H7N9 infection. This dissection of CTL-mediated immunity to H7N9 thus suggests strategies for both vaccine delivery and development

Subject disposition for CELADEN study [17].

<p>Subject disposition for CELADEN study [<a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0004851#pntd.0004851.ref017" target="_blank">17</a>].</p

PK profile of castanospermine (semi-log plot).

<p>Solid brown line is the predicted concentration of castanospermine based on the mean PK parameters and the dosing regimen studied in the trial. Gray open circles are the observed peak and trough concentrations of castanospermine. Symbols and error bars are the mean and SEM, respectively. Black dotted line is the target trough concentration (400 ng/mL) predicted based on animal efficacy studies.</p

Correlation between viremia by qPCR and plaque assay.

<p>Red filled circles–patients who received celgosivir; blue open squares–patients who received placebo; lines–linear regression to all data. Pearson correlation coefficient for all data (A)Day 1 0.79 (95% CI: 0.64 to 0.87); (B) Day 2 0.79 (95% CI: 0.65 to 0.87); (C) Day 3 0.83 (95% CI: 0.72 to 0.90); (D) Day 4 (95% CI: 0.55 to 0.83); (E) Day 5 0.36 (95% CI: 0.08 to 0.58).</p

Evolutionary relationship of the whole genome of dengue samples isolated from celgosivir treatment and placebo in relation to representative samples collected from Asia.

<p>Maximum likelihood trees were generated using the nucleotide alignment from start to stop codon of the coding region. Tip labels are coloured based on sample type, and genotypes are labelled adjacent to tip labels for DENV 2, and along branches for DENV 1 and 3. Scale bar represents nucleotide substitutions per site.</p

Predicted exposure for different dosing regimens.

<p>The Box-25th to 75^th percentile, whiskers-minimum and maximum values for the various dosing regimens is shown. (A) C_min range for the various dosing regimens shows that 150 mg every 6 hr is predicted to yield a 4.5-fold increase in median Cmin used in CELADEN trial (B) C_max, range do not vary significantly for the various dosing regimens and (C) AUC only shows a modest 1.33-fold increase over the dosing regimen used in the CELADEN trial.</p

Dependence of pharmacokinetic parameters on covariates.

<p>Body Weight (A and B); Age (C and D); Creatinine Clearance (E); and Sex (F). Clearance or volume of distribution were not significantly affected by patients’ body weight, age or sex. Drug clearance was significantly correlated with creatinine clearance, indicating a significant role of the kidneys for elimination of celgosvir. Solid line-linear regression, dashed line- 95% CI. The slope of the linear regression line of creatinine clearance versus drug clearance was 0.86 (95% CI: 0.376, 1.351).</p

Changes in platelets and hematocrit for celgosivir (red filled circles) or placebo (blue open squares) treated patients.

<p>Mean ± SEM changes in platelets count (A) and hematocrit (B) at different study days in all patients. (C) and (D) are Mean ± SEM changes in platelets count (C) and hematocrit (D) at different study days for secondary dengue patients only. Platelet nadir values (E) and difference between maximum and minimum hematocrit values (F) for secondary dengue patients treated with celgosivir or placebo, solid line–median, bars—interquartile range.</p