Correlations between stochastic endemic infection in multiple interacting subpopulations.

Heterogeneity plays an important role in the emergence, persistence and control of infectious diseases. Metapopulation models are often used to describe spatial heterogeneity, and the transition from random- to heterogeneous-mixing is made by incorporating the interaction, or coupling, within and between subpopulations. However, such couplings are difficult to measure explicitly; instead, their action through the correlations between subpopulations is often all that can be observed. We use moment-closure methods to investigate how the coupling and resulting correlation are related, considering systems of multiple identical interacting populations on highly symmetric complex networks: the complete network, the k-regular tree network, and the star network. We show that the correlation between the prevalence of infection takes a relatively simple form and can be written in terms of the coupling, network parameters and epidemiological parameters only. These results provide insight into the effect of metapopulation network structure on endemic disease dynamics, and suggest that detailed case-reporting data alone may be sufficient to infer the strength of between population interaction and hence lead to more accurate mathematical descriptions of infectious disease behaviour

Believing for a Reason is (at least) Nearly Self-Intimating

This paper concerns a specific epistemic feature of believing for a reason (e.g., believing that it will rain on the basis of the grey clouds outside). It has commonly been assumed that our access to such facts about ourselves is akin in all relevant respects to our access to why other people hold their beliefs. Further, discussion of self-intimation - that we are necessarily in a position to know when we are in certain conditions - has centred largely around mental states. In contrast to both assumptions, this paper argues that believing for a reason is (at least) very nearly self-intimating: necessarily, if a subject believes that q for the reason that p, then, provided relevant conceptual and rational capacities, she is in a position to form a justified true belief that she believes that q for the reason that p. We should think this on the basis of the role that believing for a reason plays from the subjects’ perspective, and in particular, the way in which it intellegises one’s belief

Standpoints, knowledge, and power: Introducing standpoint epistocracy

Should citizens have equal say regarding the running of society? Following the principles of democracy, and most of political philosophy: yes (at least at a fundamental level, thus allowing for representatives and the like). Indeed, comparing the main alternative seemingly supports this intuition. Epistocracy would instead give power just to the most epistemically competent. Yet testing citizens’ political and economic knowledge looks apt to disproportionately disempower marginalised groups, making the position seem like a nonstarter and democracy the clear winner. Nevertheless, this paper argues against giving citizens equal say, or at least, it offers the strongest possible motivation for this position. In particular, I introduce the progressive case for epistocracy, and what I term standpoint epistocracy. This account refigures the relevant notion of political competence such that it is not the most privileged classes who would most likely constitute our epistocracy, but rather, the least. The resulting picture considerably improves on traditional versions of epistocracy and also democracy

Extensive Plasmid Library to Prepare Tau Protein Variants and Study Their Functional Biochemistry

Tau neurofibrillary tangles are key pathological features of Alzheimer’s disease and other tauopathies. Recombinant protein technology is vital for studying the structure and function of tau in physiology and aggregation in pathophysiology. However, open-source and well-characterized plasmids for efficiently expressing and purifying different tau variants are lacking. We generated 44 sequence-verified plasmids including those encoding full length (FL) tau-441, its four-repeat microtubule-binding (K18) fragment, and their respective selected familial pathological variants (N279K, V337M, P301L, C291R, and S356T). Moreover, plasmids for expressing single (C291A), double (C291A/C322A), and triple (C291A/C322A/I260C) cysteine-modified variants were generated to study alterations in cysteine content and locations. Furthermore, protocols for producing representative tau forms were developed. We produced and characterized the aggregation behavior of the triple cysteine-modified tau-K18, often used in real-time cell internalization and aggregation studies because it can be fluorescently labeled on a cysteine outside the microtubule-binding core. Similar to the wild type (WT), triple cysteine-modified tau-K18 aggregated by progressive β-sheet enrichment, albeit at a slower rate. On prolonged incubation, cysteine-modified K18 formed paired helical filaments similar to those in Alzheimer’s disease, sharing morphological phenotypes with WT tau-K18 filaments. Nonetheless, cysteine-modified tau-K18 filaments were significantly shorter (p = 0.002) and mostly wider than WT filaments, explainable by their different principal filament elongation pathways: vertical (end-to-end) and lateral growth for WT and cysteine-modified, respectively. Cysteine rearrangement may therefore induce filament polymorphism. Together, the plasmid library, the protein production methods, and the new insights into cysteine-dependent aggregation should facilitate further studies and the design of antiaggregation agents

Assessing the cost-effectiveness of HPV vaccination strategies for adolescent girls and boys in the UK.

BACKGROUND: Human papillomavirus (HPV) is the most widespread sexually transmitted infection worldwide. It causes several health consequences, in particular accounting for the majority of cervical cancer cases in women. In the United Kingdom, a vaccination campaign targeting 12-year-old girls started in 2008; this campaign has been successful, with high uptake and reduced HPV prevalence observed in vaccinated cohorts. Recently, attention has focused on vaccinating both sexes, due to HPV-related diseases in males (particularly for high-risk men who have sex with men) and an equity argument over equalising levels of protection. METHODS: We constructed an epidemiological model for HPV transmission in the UK, accounting for nine of the most common HPV strains. We complemented this with an economic model to determine the likely health outcomes (healthcare costs and quality-adjusted life years) for individuals from the epidemiological model. We then tested vaccination with the three HPV vaccines currently available, vaccinating either girls alone or both sexes. For each strategy we calculated the threshold price per vaccine dose, i.e. the maximum amount paid for the added health benefits of vaccination to be worth the cost of each vaccine dose. We calculated results at 3.5% discounting, and also 1.5%, to consider the long-term health effects of HPV infection. RESULTS: At 3.5% discounting, continuing to vaccinate girls remains highly cost-effective compared to halting vaccination, with threshold dose prices of £56-£108. Vaccination of girls and boys is less cost-effective (£25-£53). Compared to vaccinating girls only, adding boys to the programme is not cost-effective, with negative threshold prices (-£6 to -£3) due to the costs of administration. All threshold prices increase when using 1.5% discounting, and adding boys becomes cost-effective (£36-£47). These results are contingent on the UK's high vaccine uptake; for lower uptake rates, adding boys (at the same uptake rate) becomes more cost effective. CONCLUSIONS: Vaccinating girls is extremely cost-effective compared with no vaccination, vaccinating both sexes is less so. Adding boys to an already successful girls-only programme has a low cost-effectiveness, as males have high protection through herd immunity. If future health effects are weighted more heavily, threshold prices increase and vaccination becomes cost-effective

Functional Locomotor Consequences of Uneven Forefeet for Trot Symmetry in Individual Riding Horses

ABSTRACT: Left-right symmetrical distal limb conformation can be an important prerequisite for a successful performance, and it is often hypothesized that asymmetric or uneven feet are important enhancing factors for the development of lameness. On a population level, it has been demonstrated that uneven footed horses are retiring earlier from elite level competition, but the biomechanical consequences are not yet known. The objectives of this study were to compare the functional locomotor asymmetries of horses with uneven to those with even feet. Hoof kinetics and distal limb kinematics were collected from horses (n = 34) at trot. Dorsal hoof wall angle was used to classify horses as even or uneven (1.5° difference between forefeet respectively) and individual feet as flat (55°). Functional kinetic parameters were compared between even and uneven forefeet using MANOVA followed by ANOVA. The relative influences of differences in hoof angle between the forefeet and of absolute hoof angle on functional parameters were analysed using multiple regression analysis (P<0.05). In horses with uneven feet, the side with the flatter foot showed a significantly larger maximal horizontal braking and vertical ground reaction force, a larger vertical fetlock displacement and a suppler fetlock spring. The foot with a steeper hoof angle was linearly correlated with an earlier braking-propulsion transition. The conformational differences between both forefeet were more important for loading characteristics than the individual foot conformation of each individual horse. The differences in vertical force and braking force between uneven forefeet could imply either an asymmetrical loading pattern without a pathological component or a subclinical lameness as a result of a pathological development in the steeper foot

Developing a framework for public involvement in mathematical and economic modelling : bringing new dynamism to vaccination policy recommendations

Objectives The Mathematical and Economic Modelling for Vaccination and Immunisation Evaluation (MEMVIE) programme aimed to explore, capture and support the potential contribution of the public to mathematical and economic modelling, in order to identify the values that underpin public involvement (PI) in modelling and co-produce a framework that identifies the nature and type of PI in modelling and supports its implementation. Methods We established a PI Reference Group, who worked collaboratively with the academic contributors to create a deliberative knowledge space, which valued different forms of knowledge, expertise and evidence. Together, we explored the key steps of mathematical and economic methods in 21 meetings during 2015–2020. These deliberations generated rich discussion, through which we identified potential points of public contribution and the values that underpin PI in modelling. We iteratively developed a framework to guide future practice of PI in modelling. Results We present the MEMVIE Public Involvement Framework in two forms: a short form to summarise key elements, and a long form framework to provide a detailed description of each potential type of public contribution at each stage of the modelling process. At a macro level, the public can contribute to reviewing context, reviewing relevance, assessing data and justifying model choice, troubleshooting, and interpreting and reviewing outcomes and decision making. The underpinning values that drive involvement include the public contributing to the validity of the model, potentially enhancing its relevance, utility and transparency through diverse inputs, and enhancing the credibility, consistency and continuous development through scrutiny, in addition to contextualising the model within a wider societal view. Discussion and Conclusion PI in modelling is in its infancy. The MEMVIE Framework is the first attempt to identify potential points of collaborative public contribution to modelling, but it requires further evaluation and refinement that we are undertaking in a subsequent study

Modelers' Perception of Mathematical Modeling in Epidemiology: A Web-Based Survey

International audienceBackground: Mathematical modeling in epidemiology (MME) is being used increasingly. However, there are many uncertainties in terms of definitions, uses and quality features of MME. Methodology/Principal Findings: To delineate the current status of these models, a 10-item questionnaire on MME was devised. Proposed via an anonymous internet-based survey, the questionnaire was completed by 189 scientists who had published in the domain of MME. A small minority (18%) of respondents claimed to have in mind a concise definition of MME. Some techniques were identified by the researchers as characterizing MME (e.g. Markov models), while others–at the same level of sophistication in terms of mathematics–were not (e.g. Cox regression). The researchers' opinions were also contrasted about the potential applications of MME, perceived as higly relevant for providing insight into complex mechanisms and less relevant for identifying causal factors. The quality criteria were those of good science and were not related to the size and the nature of the public health problems addressed. Conclusions/Significance: This study shows that perceptions on the nature, uses and quality criteria of MME are contrasted, even among the very community of published authors in this domain. Nevertheless, MME is an emerging discipline in epidemiology and this study underlines that it is associated with specific areas of application and methods. The development of this discipline is likely to deserve a framework providing recommendations and guidance at various steps of the studies, from design to report

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Apoptotic HPV Positive Cancer Cells Exhibit Transforming Properties

Previous studies have shown that DNA can be transferred from dying engineered cells to neighboring cells through the phagocytosis of apoptotic bodies, which leads to cellular transformation. Here, we provide evidence of an uptake of apoptotic-derived cervical cancer cells by human mesenchymal cells. Interestingly, HeLa (HPV 18+) or Ca Ski (HPV16+) cells, harboring integrated high-risk HPV DNA but not C-33 A cells (HPV-), were able to transform the recipient cells. Human primary fibroblasts engulfed the apoptotic bodies effectively within 30 minutes after co-cultivation. This mechanism is active and involves the actin cytoskeleton. In situ hybridization of transformed fibroblasts revealed the presence of HPV DNA in the nucleus of a subset of phagocytosing cells. These cells expressed the HPV16/18 E6 gene, which contributes to the disruption of the p53/p21 pathway, and the cells exhibited a tumorigenic phenotype, including an increased proliferation rate, polyploidy and anchorage independence growth. Such horizontal transfer of viral oncogenes to surrounding cells that lack receptors for HPV could facilitate the persistence of the virus, the main risk factor for cervical cancer development. This process might contribute to HPV-associated disease progression in vivo