Palliative care, double effect and the law in Australia

Care and decision-making at the end of life that promotes comfort and dignity is widely endorsed by public policy and the law. In ethical analysis of palliative care interventions that are argued potentially to hasten death, these may be deemed to be ethically permissible by the application of the doctrine of double effect, if the doctor’s intention is to relieve pain and not cause death. In part because of the significance of ethics in the development of law in the medical sphere, this doctrine is also likely to be recognized as part of Australia’s common law, although hitherto there have been no cases concerning palliative care brought before a court in Australia to test this. Three Australian States have, nonetheless, created legislative defences that are different from the common law with the intent of clarifying the law, promoting palliative care, and distinguishing it from euthanasia. However, these defences have the potential to provide less protection for doctors administering palliative care. In addition to requiring a doctor to have an appropriate intent, the defences insist on adherence to particular medical practice standards and perhaps require patient consent. Doctors providing end-of-life care in these States need to be aware of these legislative changes. Acting in accordance with the common law doctrine of double effect may not provide legal protection. Similar changes are likely to occur in other States and Territories as there is a trend towards enacting legislative defences that deal with the provision of palliative care

Antigenic evolution of SARS-CoV-2 in immunocompromised hosts

Prolonged infections of immunocompromised individuals have been proposed as a crucial source of new variants of SARS-CoV-2 during the COVID-19 pandemic. In principle, sustained within-host antigenic evolution in immunocompromised hosts could allow novel immune escape variants to emerge more rapidly, but little is known about how and when immunocompromised hosts play a critical role in pathogen evolution. Here, we use a simple mathematical model to understand the effects of immunocompromised hosts on the emergence of immune escape variants in the presence and absence of epistasis. We show that when the pathogen does not have to cross a fitness valley for immune escape to occur (no epistasis), immunocompromised individuals have no qualitative effect on antigenic evolution (although they may accelerate immune escape if within-host evolutionary dynamics are faster in immunocompromised individuals). But if a fitness valley exists between immune escape variants at the between-host level (epistasis), then persistent infections of immunocompromised individuals allow mutations to accumulate, therefore facilitating rather than simply speeding up antigenic evolution. Our results suggest that better genomic surveillance of infected immunocompromised individuals and better global health equality, including improving access to vaccines and treatments for individuals who are immunocompromised (especially in lower- and middle-income countries), may be crucial to preventing the emergence of future immune escape variants of SARS-CoV-2

Tolerance-conferring defensive symbionts and the evolution of parasite virulence

Defensive symbionts in the host microbiome can confer protection from infection or reduce the harms of being infected by a parasite. Defensive symbionts are therefore promising agents of biocontrol that could be used to control or ameliorate the impact of infectious diseases. Previous theory has shown how symbionts can evolve along the parasitism–mutualism continuum to confer greater or lesser protection to their hosts and in turn how hosts may coevolve with their symbionts to potentially form a mutualistic relationship. However, the consequences of introducing a defensive symbiont for parasite evolution and how the symbiont may coevolve with the parasite have received relatively little theoretical attention. Here, we investigate the ecological and evolutionary implications of introducing a tolerance-conferring defensive symbiont into an established host–parasite system. We show that while the defensive symbiont may initially have a positive impact on the host population, parasite and symbiont evolution tend to have a net negative effect on the host population in the long term. This is because the introduction of the defensive symbiont always selects for an increase in parasite virulence and may cause diversification into high- and low-virulence strains. Even if the symbiont experiences selection for greater host protection, this simply increases selection for virulence in the parasite, resulting in a net negative effect on the host population. Our results therefore suggest that tolerance-conferring defensive symbionts may be poor biocontrol agents for population-level infectious disease control

Herd immunity

Herd immunity is an important yet often misunderstood concept in epidemiology. As immunity accumulates in a population — naturally during the course of an epidemic or through vaccination — the spread of an infectious disease is limited by the depletion of susceptible hosts. If a sufficient proportion of the population is immune — above the ‘herd immunity threshold’ — then transmission generally cannot be sustained. Maintaining herd immunity is therefore critical to long-term disease control. In this primer, we discuss the concept of herd immunity from first principles, clarify common misconceptions, and consider the implications for disease control. Much is being said about herd immunity these days. But the concept, though seemingly simple, is often misunderstood. Ben Ashby and Alex Best explain what exactly herd immunity is, how it is achieved in a population, how it is lost, and what it means for disease control.</p

Multi-mode fluctuating selection in host-parasite coevolution

Understanding fluctuating selection is important for our understanding of patterns of spatial and temporal diversity in nature. Host-parasite theory has classically assumed fluctuations either occur between highly specific genotypes (Matching Alleles: MA) or from specialism to generalism (Gene-for-Gene: GFG). However, while MA can only generate one mode of fluctuating selection, we show that GFG can in fact produce both rapid “within-range” fluctuations (among genotypes with identical levels of investment but which specialise on different subsets of the population) and slower cycling “between ranges” (different levels of investment), emphasising that MA is a subset of GFG. Our findings closely match empirical observations, although sampling rates need to be high to detect these novel dynamics empirically. Within-range cycling is an overlooked process by which fluctuating selection can occur in nature, suggesting that fluctuating selection may be a more common and important process than previously thought in generating and maintaining diversity

Efficient coupling of within- and between-host infectious disease dynamics

Mathematical models of infectious disease transmission typically neglect within-host dynamics. Yet within-host dynamics - including pathogen replication, host immune responses, and interactions with microbiota - are crucial not only for determining the progression of disease at the individual level, but also for driving within-host evolution and onwards transmission, and therefore shape dynamics at the population level. Various approaches have been proposed to model both within- and between-host dynamics, but these typically require considerable simplifying assumptions to couple processes at contrasting scales (e.g., the within-host dynamics quickly reach a steady state) or are computationally intensive. Here we propose a novel, readily adaptable and broadly applicable method for modelling both within- and between-host processes which can fully couple dynamics across scales and is both realistic and computationally efficient. By individually tracking the deterministic within-host dynamics of infected individuals, and stochastically coupling these to continuous host state variables at the population-level, we take advantage of fast numerical methods at both scales while still capturing individual transient within-host dynamics and stochasticity in transmission between hosts. Our approach closely agrees with full stochastic individual-based simulations and is especially useful when the within-host dynamics do not rapidly reach a steady state or over longer timescales to track pathogen evolution. By applying our method to different pathogen growth scenarios we show how common simplifying assumptions fundamentally change epidemiological and evolutionary dynamics.Comment: 34 pages, 5 figure

Duality based error control for the Signorini problem

In this paper we study the a posteriori bounds for a conforming piecewise linear finite element approximation of the Signorini problem. We prove new rigorous a posteriori estimates of residual type in $L^{p}$, for $p \in (4,\infty)$ in two spatial dimensions. This new analysis treats the positive and negative parts of the discretisation error separately, requiring a novel sign- and bound-preserving interpolant, which is shown to have optimal approximation properties. The estimates rely on the sharp dual stability results on the problem in $W^{2,(4 - \varepsilon)/3}$ for any $\varepsilon \ll 1$. We summarise extensive numerical experiments aimed at testing the robustness of the estimator to validate the theory