Opinion Models, Election Data, and Political Theory.

A unifying setup for opinion models originating in statistical physics and stochastic opinion dynamics are developed and used to analyze election data. The results are interpreted in the light of political theory. We investigate the connection between Potts (Curie-Weiss) models and stochastic opinion models in the view of the Boltzmann distribution and stochastic Glauber dynamics. We particularly find that the q-voter model can be considered as a natural extension of the Zealot model, which is adapted by Lagrangian parameters. We also discuss weak and strong effects (also called extensive and nonextensive) continuum limits for the models. The results are used to compare the Curie-Weiss model, two q-voter models (weak and strong effects), and a reinforcement model (weak effects) in explaining electoral outcomes in four western democracies (United States, Great Britain, France, and Germany). We find that particularly the weak effects models are able to fit the data (Kolmogorov-Smirnov test) where the weak effects reinforcement model performs best (AIC). Additionally, we show how the institutional structure shapes the process of opinion formation. By focusing on the dynamics of opinion formation preceding the act of voting, the models discussed in this paper give insights both into the empirical explanation of elections as such, as well as important aspects of the theory of democracy. Therefore, this paper shows the usefulness of an interdisciplinary approach in studying real world political outcomes by using mathematical models.

Contact tracing & super-spreaders in the branching-process model.

In recent years, it became clear that super-spreader events play an important role, particularly in the spread of airborne infections. We investigate a novel model for super-spreader events, not based on a heterogeneous contact graph but on a random contact rate: Many individuals become infected synchronously in single contact events. We use the branching-process approach for contact tracing to analyze the impact of super-spreader events on the effect of contact tracing. Here we neglect a tracing delay. Roughly speaking, we find that contact tracing is more efficient in the presence of super-spreaders if the fraction of symptomatics is small, the tracing probability is high, or the latency period is distinctively larger than the incubation period. In other cases, the effect of contact tracing can be decreased by super-spreaders. Numerical analysis with parameters suited for SARS-CoV-2 indicates that super-spreaders do not decrease the effect of contact tracing crucially in case of that infection.

Are the better cooperators dormant or quiescent?

Despite the wealth of empirical and theoretical studies, the origin and maintenance of cooperation is still an evolutionary riddle. In this context, ecological life-history traits which affect the efficiency of selection may play a role despite being often ignored. We consider here species such as bacteria, fungi, invertebrates and plants which exhibit resting stages in the form of a quiescent state or a seed bank. When quiescent, individuals are inactive and reproduce upon activation, while under seed bank parents produce offspring remaining dormant for different amount of time. We assume weak frequency-dependent selection modeled using game-theory and the prisoner's dilemma (cooperation/defect) as payoff matrix. The cooperators and defectors are allowed to evolve different quiescence or dormancy times. By means of singular perturbation theory we reduce the model to a one-dimensional equation resembling the well known replicator equation, in which the gain functions are scaled with lumped parameters reflecting the time scale of the resting state of the cooperators and defectors. If both time scales are identical cooperation cannot persist in a homogeneous population. If, however, the time scale of the cooperator is distinctively different from that of the defector, cooperation may become a locally asymptotically stable strategy. Interestingly enough, in the seed bank case the cooperator needs to become active faster than the defector, while in the quiescent case the cooperator has to be slower. We use adaptive dynamics to identify situations where cooperation may evolve and form a convergent stable ESS. We conclude by highlighting the relevance of these results for many non-model species and the maintenance of cooperation in microbial, invertebrate or plant populations.

Characterization and clinical enrichment of HLA-C*07:02-restricted Cytomegalovirus-specific CD8+ T cells.

Human Cytomegalovirus (CMV) reactivation remains a major source of morbidity in patients after solid organ and hematopoietic stem cell transplantation (HSCT). Adoptive T cell therapy (ACT) with CMV-specific T cells is a promising therapeutic approach for HSCT recipients, but might be counteracted by CMV's immune evasion strategies. HLA-C*07:02 is less susceptible to viral immune evasion suggesting HLA-C*07:02-restricted viral epitopes as promising targets for ACT. For a better understanding of HLA-C*07:02-restricted CMV-specific T cells we used recently generated reversible HLA-C*07:02/IE-1 multimers (Streptamers) recognizing a CMV-derived Immediate-Early-1 (IE-1) epitope and analyzed phenotypic and functional T cell characteristics. Initially, we detected very high frequencies of HLA-C*07:02/IE-1 multimer+ T cells (median = 11.35%), as well as robust functional responses after stimulation with IE-1 peptide (IFNγ+; median = 5.02%) in healthy individuals. However, MHC-multimer+ and IFNγ-secreting T cell frequencies showed a relatively weak correlation (r2 = 0.77), which could be attributed to an unexpected contribution of CMV-epitope-independent KIR2DL2/3-binding of HLA-C*07:02/IE-1 multimers. Therefore, we developed a MHC-multimer double-staining approach against a cancer epitope-specific HLA-C*07:02 multimer to identify truly HLA-C*07:02/IE-1 epitope-specific T cells. The frequencies of these truly HLA-C*07:02/IE-1 multimer+ T cells were still high (median = 6.86%) and correlated now strongly (r2 = 0.96) with IFNγ-secretion. Interestingly, HLA-C*07:02/IE-1-restricted T cells contain substantial numbers with a central memory T cell phenotype, indicating high expansion potential e.g. for ACT. In line with that, we developed a clinical enrichment protocol avoiding epitope-independent KIR-binding to make HLA-C*07:02/IE-1-restricted T cells available for ACT. Initial depletion of KIR-expressing CD8+ T cells followed by HLA-C*07:02/IE-1 Streptamer positive selection using paramagnetic labeling techniques allowed to enrich successfully HLA-C*07:02/IE-1-restricted T cells. Such specifically enriched populations of functional HLA-C*07:02/IE-1-restricted T cells with significant central memory T cell content could become a potent source for ACT.

Primary Cytomegalovirus Infection in Seronegative Kidney Transplant Patients Is Associated with Protracted Cold Ischemic Time of Seropositive Donor Organs.

Human Cytomegalovirus (CMV) can lead to primary infection or reactivation in CMV-seronegative or -seropositive kidney transplant recipients, respectively. Complications comprise severe end-organ diseases and acute or chronic transplant rejection. Risk for CMV manifestation is stratified according to the CMV-IgG-serostatus, with donor+/recipient- (D+/R-) patients carrying the highest risk for CMV-replication. However, risk factors predisposing for primary infection in CMV-seronegative recipients are still not fully elucidated. Therefore, we monitored D+/R- high-risk patients undergoing kidney transplantation in combination with antiviral prophylaxis for the incidence of CMV-viremia for a median follow-up time of 784 days (156-1155 days). In this period, we analyzed the functional CMV-specific T cell response by intracellular cytokine staining and CMV-serology by ELISA. Only four of eight D+/R- patients developed clinically relevant CMV-viremia followed by seroconversion. Viremia triggered expansion of functional CMV-specific T cells correlating with protection against secondary CMV-reactivations. In contrast, all other patients remained permanently aviremic and showed no immunological correlate of infection after discontinuation of antiviral prophylaxis for up to three years. Comparing cold ischemic times (CIT) of viremic (median = 1020 min; 720-1080 min) and aviremic patients (median = 335 min; 120-660 min) revealed significantly (p = 0.0286) protracted CIT in patients with primary CMV-infection. Taken together, primary CMV-infection affects only a subgroup of D+/R- patients correlating with length of CIT. Therefore, patients with extended CIT should be thoroughly monitored for CMV-replication well beyond discontinuation of antiviral prophylaxis. In contrast, patients with short CIT remained permanently uninfected and might benefit from shorter prophylactic treatment.

Prediction of bleeding events in patients with venous thromboembolism on stable anticoagulation treatment.

Attempts at identifying patients with an elevated risk of bleeding while on anticoagulation following acute venous thromboembolism (VTE) have largely been unsuccessful thus far. We sought to develop a clinical prediction score for bleeding during stable anticoagulation treatment after acute VTE.We performed a post hoc analysis of the pooled RE-COVER studies, two double-blind randomised "sister" trials evaluating dabigatran versus standard treatment in 5107 VTE patients.A score was derived from patients randomised to dabigatran using logistic regression analysis covering the complete follow-up period. The final model, named VTE-BLEED, included six variables and yielded a c-statistic of 0.72 (95% CI 0.67-0.76). Patients from the derivation cohort in the low-risk group (<2 points; 74% of the derivation population) had a bleeding incidence of 2.8% compared to 12.6% in the elevated-risk group (OR 5.0; 95% CI 3.5-7.1). The score proved accurate for our primary end-point, i.e. prediction of major bleeding after day 30 ("stable" anticoagulation), both in patients on dabigatran (c-statistic 0.75, 95% CI 0.61-0.89) and those on warfarin (0.78, 95% CI 0.68-0.86; p=0.77 for difference).The new VTE-BLEED score accurately predicted major bleeding events in VTE patients on stable anticoagulation with both dabigatran and warfarin.

Indirect comparison and cost-utility of dabigatran etexilate and rivaroxaban in the treatment and extended anticoagulation of venous thromboembolism in a UK setting.

BACKGROUND: Acute venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), is traditionally managed with a short course of parenteral anticoagulation followed by 3-6 months of a vitamin-K antagonist. Non-vitamin K oral anticoagulants (NOACs) do not require routine monitoring and dose adjustment, thus potentially provide an alternative treatment option. METHODS AND RESULTS: Because of the lack of head-to-head clinical studies, an indirect comparison was conducted of dabigatran etexilate and rivaroxaban based on the respective phase III clinical trial. The derived relative safety and efficacy estimates were used to evaluate the cost-utility of dabigatran compared with rivaroxaban in the treatment and secondary prevention of VTE. The results of the indirect comparison showed no significant difference between dabigatran and rivaroxaban in avoiding recurrent VTE following index PE, index DVT, or DVT/PE combined, in treatment and extended anticoagulation. Dabigatran has significantly less major or clinically relevant bleeds (MCRBE) compared to rivaroxaban in treatment after index DVT and treatment after DVT or PE combined, but was not significantly different from rivaroxaban after index PE or in extended anticoagulation. In cost-utility deterministic analyses, dabigatran was projected dominant in all analyzed settings, given its marginally lower total cost and marginally higher QALYs gained compared to rivaroxaban. Probabilistic analyses results showed a high likelihood of dabigatran being considered good value for money in the UK, in treatment and in secondary prevention of VTE. CONCLUSION: The cost-effectiveness evaluations showed that dabigatran can be considered the dominant treatment strategy compared to rivaroxaban in the patients' sub-groups considered, given the projected marginally higher clinical benefits and lower treatment costs.

Cost-effectiveness of modern mTOR inhibitor based immunosuppression compared to the standard of care after renal transplantation in Germany.

OBJECTIVES: Standards of immunosuppression in renal transplantation have changed dynamically in recent years. We here provide a refined advanced pharmacoeconomic model which uses state-of-the-art methods including a mixed treatment comparison (MTC) analysis. The aim was to assess the cost-effectiveness of current immunosuppressive therapy regimens (TR): "sirolimus + early withdrawal of cyclosporine + steroids" (TR1), "sirolimus-early transition" (TR2), "everolimus-early transition" (TR3) and "tacrolimus low dose + mycophenolate mofetil (MMF) + steroids" (TR4). METHODS: An up-to-date Markov model with current source data was employed to assess the cost-effectiveness of modern immunosuppressive regimens over 12-month and 10-year time periods. Transition probabilities for the occurrence of events for the first year were based on an MTC analysis. The robustness of the model was tested in extensive sensitivity analyses. RESULTS: Within the 12-month time period TR2 yields the highest life years (0.987 LY), generating costs of 17,500 . In terms of years with functioning graft (FG), TR4 yields the best efficacy over the 12-month model duration (0.970 years with FG). For the 10-year time period, TR2 yields the lowest costs (107,246 ) and dominates both TR3 and TR1, as it is simultaneously more effective. Within the 10-year model duration, TR4 reaches slightly higher effects compared with TR2 (6.493 vs. 6.474 LY) resulting in an incremental cost-effectiveness ratio of 387,684 per LY gained. CONCLUSIONS: The early transition to sirolimus provides long-term efficiency results comparable with a tacrolimus-based regimen, which represents a common treatment standard after kidney transplantation. Both are superior to other investigated immunosuppressive regimens.

Modeling clonal expansion from M-FISH experiments.

A population genetic model is used to describe dynamical aspects of chromosomal abberations observed in M-FISH experiments. Linear differential equations model the evolution of relative frequencies of mutations. The unknown parameters involved are estimated by maximum likelihood methods. We propose a scoring system to select the most important mutations. In order to reduce the number of parameters and computation time, only the highest ranked mutations are considered. First applications to M-FISH data show rather promising results.