Emergence and spread of drug resistant influenza: A two-population game theoretical model

Background The potential for emergence of antiviral drug resistance during influenza pandemics has raised great concern for public health. Widespread use of antiviral drugs is a significant factor in producing resistant strains. Recent studies show that some influenza viruses may gain antiviral drug resistance without a fitness penalty. This creates the possibility of strategic interaction between populations considering antiviral drug use strategies. Methods To explain why, we develop and analyze a classical 2-player game theoretical model where each player chooses from a range of possible rates of antiviral drug use, and payoffs are derived as a function of final size of epidemic with the regular and mutant strain. Final sizes are derived from a stochastic compartmental epidemic model that captures transmission within each population and between populations, and the stochastic emergence of antiviral drug resistance. High treatment levels not only increase the spread of the resistant strain in the subject population but also affect the other population by increasing the density of the resistant strain infectious individuals due to travel between populations. Results We found two Nash equilibria where both populations treat at a high rate, or both treat at a low rate. Hence the game theoretical analysis predicts that populations will not choose different treatment strategies than other populations, under these assumptions. The populations may choose to cooperate by maintaining a low treatment rate that does not increase the incidence of mutant strain infections or cause case importations to the other population. Alternatively, if one population is treating at a high rate, this will generate a large number of mutant infections that spread to the other population, in turn incentivizing that population to also treat at a high rate. The prediction of two separate Nash equilibria is robust to the mutation rate and the effectiveness of the drug in preventing transmission, but it is sensitive to the volume of travel between the two populations. Conclusions Model-based evaluations of antiviral influenza drug use during a pandemic usually consider populations in isolation from one another, but our results show that strategic interactions could strongly influence a population's choice of antiviral drug use policy. Furthermore, the high treatment rate Nash equilibrium has the potential to become socially suboptimal (i.e. non-Pareto optimal) under model assumptions that might apply under other conditions. Because of the need for players to coordinate their actions, we conclude that communication and coordination between jurisdictions during influenza pandemics is a priority, especially for influenza strains that do not evolve a fitness penalty under antiviral drug resistance.Game theoryStochastic compartmental modelAntiviral drugsDrug resistanceH1N1Fitness penalt

Complete analysis of the B-cell response to a protein antigen, from in vivo germinal centre formation to 3-D modelling of affinity maturation

Somatic hypermutation of immunoglobulin variable region genes occurs within germinal centres (GCs) and is the process responsible for affinity maturation of antibodies during an immune response. Previous studies have focused almost exclusively on the immune response to haptens, which may be unrepresentative of epitopes on protein antigens. In this study, we have exploited a model system that uses transgenic B and CD4<sup>+</sup> T cells specific for hen egg lysozyme (HEL) and a chicken ovalbumin peptide, respectively, to investigate a tightly synchronized immune response to protein antigens of widely differing affinities, thus allowing us to track many facets of the development of an antibody response at the antigen-specific B cell level in an integrated system <i>in</i> <i>vivo</i>. Somatic hypermutation of immunoglobulin variable genes was analysed in clones of transgenic B cells proliferating in individual GCs in response to HEL or the cross-reactive low-affinity antigen, duck egg lysozyme (DEL). Molecular modelling of the antibody–antigen interface demonstrates that recurring mutations in the antigen-binding site, selected in GCs, enhance interactions of the antibody with DEL. The effects of these mutations on affinity maturation are demonstrated by a shift of transgenic serum antibodies towards higher affinity for DEL in DEL-cOVA immunized mice. The results show that B cells with high affinity antigen receptors can revise their specificity by somatic hypermutation and antigen selection in response to a low-affinity, cross-reactive antigen. These observations shed further light on the nature of the immune response to pathogens and autoimmunity and demonstrate the utility of this novel model for studies of the mechanisms of somatic hypermutation

Treatment adherence among sputum smear-positive pulmonary tuberculosis patients in mountainous areas in China

<p>Abstract</p> <p>Background</p> <p>We carried out an investigation in five provinces in China to assess treatment adherence and identify factors associated with insufficient treatment adherence in tuberculosis (TB) patients in mountainous, rural areas of China.</p> <p>Methods</p> <p>In each of the five provinces, all counties with > 80% mountainous area were stratified into three groups according to their gross domestic product. In each stratum, one county was randomly sampled. Study subjects were sampled from all smear positive TB cases registered in 2007 in the target counties. TB patients, village doctors, county doctors and directors of the TB prevention and control institutes were interviewed. Insufficient medication adherence was defined as taking less than 90% of anti-TB drug doses prescribed. Insufficient re-examination adherence was defined as having less than the recommended three sputum smear examinations during the treatment course.</p> <p>Results</p> <p>A minority of patients took drugs under direct observation: on average 29% during the intensive phase of treatment. In total, 524 TB patients were included, of whom 49 (9.4%) took less than 90% of all doses prescribed and 92 (17.6%) did not have all sputum smear examinations, with substantial variations between the provinces. In multivariable analysis, no direct observation of treatment during the intensive phase and the presence of adverse events were associated both with insufficient medication adherence and insufficient re-examination adherence. Overall, 79% of patients were adherent both to treatment and re-examinations.</p> <p>Conclusions</p> <p>In these remote and poor areas of China, the TB control program is not fully functioning according to the guidelines. The majority of patients are not treated under direct observation, while direct observation by health care staff was associated with better adherence, both to drug therapy and re-examinations. Insufficient adherence increases the risk of unsuccessful treatment outcomes and development of drug resistance. Measures should be taken urgently in these areas to strengthen implementation of the international Stop TB strategy.</p

Edoxaban versus warfarin in patients with atrial fibrillation

Contains fulltext : 125374.pdf (publisher's version ) (Open Access)BACKGROUND: Edoxaban is a direct oral factor Xa inhibitor with proven antithrombotic effects. The long-term efficacy and safety of edoxaban as compared with warfarin in patients with atrial fibrillation is not known. METHODS: We conducted a randomized, double-blind, double-dummy trial comparing two once-daily regimens of edoxaban with warfarin in 21,105 patients with moderate-to-high-risk atrial fibrillation (median follow-up, 2.8 years). The primary efficacy end point was stroke or systemic embolism. Each edoxaban regimen was tested for noninferiority to warfarin during the treatment period. The principal safety end point was major bleeding. RESULTS: The annualized rate of the primary end point during treatment was 1.50% with warfarin (median time in the therapeutic range, 68.4%), as compared with 1.18% with high-dose edoxaban (hazard ratio, 0.79; 97.5% confidence interval [CI], 0.63 to 0.99; P<0.001 for noninferiority) and 1.61% with low-dose edoxaban (hazard ratio, 1.07; 97.5% CI, 0.87 to 1.31; P=0.005 for noninferiority). In the intention-to-treat analysis, there was a trend favoring high-dose edoxaban versus warfarin (hazard ratio, 0.87; 97.5% CI, 0.73 to 1.04; P=0.08) and an unfavorable trend with low-dose edoxaban versus warfarin (hazard ratio, 1.13; 97.5% CI, 0.96 to 1.34; P=0.10). The annualized rate of major bleeding was 3.43% with warfarin versus 2.75% with high-dose edoxaban (hazard ratio, 0.80; 95% CI, 0.71 to 0.91; P<0.001) and 1.61% with low-dose edoxaban (hazard ratio, 0.47; 95% CI, 0.41 to 0.55; P<0.001). The corresponding annualized rates of death from cardiovascular causes were 3.17% versus 2.74% (hazard ratio, 0.86; 95% CI, 0.77 to 0.97; P=0.01), and 2.71% (hazard ratio, 0.85; 95% CI, 0.76 to 0.96; P=0.008), and the corresponding rates of the key secondary end point (a composite of stroke, systemic embolism, or death from cardiovascular causes) were 4.43% versus 3.85% (hazard ratio, 0.87; 95% CI, 0.78 to 0.96; P=0.005), and 4.23% (hazard ratio, 0.95; 95% CI, 0.86 to 1.05; P=0.32). CONCLUSIONS: Both once-daily regimens of edoxaban were noninferior to warfarin with respect to the prevention of stroke or systemic embolism and were associated with significantly lower rates of bleeding and death from cardiovascular causes. (Funded by Daiichi Sankyo Pharma Development; ENGAGE AF-TIMI 48 ClinicalTrials.gov number, NCT00781391.)