Project description:ObjectivesIn 2005, England and Wales switched from universal BCG vaccination against tuberculosis (TB) disease for school-age children to targeted vaccination of neonates. We aimed to recreate and re-evaluate a previously published model, the results of which informed this policy change.DesignWe recreated an approach for estimating the impact of ending the BCG schools scheme, correcting a methodological flaw in the model, updating the model with parameter uncertainty and improving parameter estimates where possible. We investigated scenarios for the assumed annual decrease in TB incidence rates considered by the UK's Joint Committee on Vaccination and Immunisation and explored alternative scenarios using notification data.SettingEngland and Wales.Outcome measuresThe number of vaccines needed to prevent a single notification and the average annual additional notifications caused by ending the policy change.ResultsThe previously published model was found to contain a methodological flaw and to be spuriously precise. It greatly underestimated the impact of ending school-age vaccination compared with our updated, corrected model. The updated model produced predictions with wide CIs when parameter uncertainty was included. Model estimates based on an assumption of an annual decrease in TB incidence rates of 1.9% were closest to those estimated using notification data. Using this assumption, we estimate that 1600 (2.5; 97.5% quantiles: 1300, 2000) vaccines would have been required to prevent a single notification in 2004.ConclusionsThe impact of ending the BCG schools scheme was found to be greater than previously thought when notification data were used. Our results highlight the importance of independent evaluations of modelling evidence, including uncertainty, and evaluating multiple scenarios when forecasting the impact of changes in vaccination policy.
Project description:ObjectiveTo use mathematical and economic models to predict the epidemiological and economic impact of vaccination with Bexsero, designed to protect against group B meningococcal disease, to help inform vaccine policy in the United Kingdom.DesignModelling study.SettingEngland.PopulationPeople aged 0-99.InterventionsIncremental impact of introductory vaccine strategies simulated with a transmission dynamic model of meningococcal infection and vaccination including potential herd effects. Model parameters included recent evidence on the vaccine characteristics, disease burden, costs of care, litigation costs, and loss of quality of life from disease, including impacts on family and network members. The health impact of vaccination was assessed through cases averted and quality adjusted life years (QALYs) gained.Main outcome measuresCases averted and cost per QALY gained through vaccination; programmes were deemed cost effective against a willingness to pay of £20,000 (€25,420, $32,677) per QALY gained from an NHS and personal and social services perspective.ResultsIn the short term, case reduction is greatest with routine infant immunisation (26.3% of cases averted in the first five years). This strategy could be cost effective at £3 (€3.8, $4.9) a vaccine dose, given several favourable assumptions and the use of a quality of life adjustment factor. If the vaccine can disrupt meningococcal transmission more cases are prevented in the long term with an infant and adolescent combined programme (51.8% after 30 years), which could be cost effective at £4 a vaccine dose. Assuming the vaccine reduces acquisition by 30%, adolescent vaccination alone is the most favourable strategy economically, but takes more than 20 years to substantially reduce the number of cases.ConclusionsRoutine infant vaccination is the most effective short term strategy and could be cost effective with a low vaccine price. Critically, if the vaccine reduces carriage acquisition in teenagers, the combination of infant and adolescent vaccination could result in substantial long term reductions in cases and be cost effective with competitive vaccine pricing.
Project description:How and when a newborn is first colonized by microbes continues to be of great interest due to its broad implications on human health and disease. Payne et al. express their opinion about our recent study in which we characterized the virome and bacterial microbiota of amniotic fluid from 24 uncomplicated term pregnancies. We conducted additional validation studies and respond to their comments. We conclude that in amniotic fluid from healthy term pregnancies, the bacterial microbiota is indistinguishable from contamination controls, and there is no evidence of a core virome.
Project description:Dollo's law of irreversibility states that once a complex structure is lost, it cannot be regained in the same form. Several putative exceptions to Dollo's law have been identified using phylogenetic comparative methods, but the anatomy and development of these traits are often poorly understood. Gastrotheca guentheri is renowned as the only frog with teeth on the lower jaw. Mandibular teeth were lost in the ancestor of frogs more than 200 million years ago and subsequently regained in G. guentheri. Little is known about the teeth in this species despite being a frequent example of trait "re-evolution," leaving open the possibility that it may have mandibular pseudoteeth. We assessed the dental anatomy of G. guentheri using micro-computed tomography and histology and confirmed the longstanding assumption that true mandibular teeth are present. Remarkably, the mandibular teeth of G. guentheri are nearly identical in gross morphology and development to upper jaw teeth in closely related species. The developmental genetics of tooth formation are unknown in this possibly extinct species. Our results suggest that an ancestral odontogenic pathway has been conserved but suppressed in the lower jaw since the origin of frogs, providing a possible mechanism underlying the re-evolution of lost mandibular teeth.
Project description:Amoebae are generally assumed to be asexual. We argue that this view is a relict of early classification schemes that lumped all amoebae together inside the 'lower' protozoa, separated from the 'higher' plants, animals and fungi. This artificial classification allowed microbial eukaryotes, including amoebae, to be dismissed as primitive, and implied that the biological rules and theories developed for macro-organisms need not apply to microbes. Eukaryotic diversity is made up of 70+ lineages, most of which are microbial. Plants, animals and fungi are nested among these microbial lineages. Thus, theories on the prevalence and maintenance of sex developed for macro-organisms should in fact apply to microbial eukaryotes, though the theories may need to be refined and generalized (e.g. to account for the variation in sexual strategies and prevalence of facultative sex in natural populations of many microbial eukaryotes). We use a revised phylogenetic framework to assess evidence for sex in several amoeboid lineages that are traditionally considered asexual, and we interpret this evidence in light of theories on the evolution of sex developed for macro-organisms. We emphasize that the limited data available for many lineages coupled with natural variation in microbial life cycles overestimate the extent of asexuality. Mapping sexuality onto the eukaryotic tree of life demonstrates that the majority of amoeboid lineages are, contrary to popular belief, anciently sexual, and that most asexual groups have probably arisen recently and independently. Additionally, several unusual genomic traits are prevalent in amoeboid lineages, including cyclic polyploidy, which may serve as alternative mechanisms to minimize the deleterious effects of asexuality.
Project description:Speciation as the result of barriers to genetic exchange is the foundation for the general biological species concept. However, the relevance of genetic exchange for defining microbial species is uncertain. In fact, the extent to which microbial populations comprise discrete clusters of evolutionarily related organisms is generally unclear. Metagenomic data from an acidophilic microbial community enabled a genomewide, comprehensive investigation of variation in individuals from two coexisting natural archaeal populations. Individuals are clustered into species-like groups in which cohesion appears to be maintained by homologous recombination. We quantified the dependence of recombination frequency on sequence similarity genomewide and found a decline in recombination with increasing evolutionary distance. Both inter- and intralineage recombination frequencies have a log-linear dependence on sequence divergence. In the declining phase of interspecies genetic exchange, recombination events cluster near the origin of replication and are localized by tRNAs and short regions of unusually high sequence similarity. The breakdown of genetic exchange with increasing sequence divergence could contribute to, or explain, the establishment and preservation of the observed population clusters in a manner consistent with the biological species concept.
Project description:Gene introgression and hybrid barriers have long been a major focus of studies of geographically overlapping species. Two pine species, Pinus massoniana and P. hwangshanensis, are frequently observed growing adjacent to each other, where they overlap in a narrow hybrid zone. As a consequence, these species constitute an ideal system for studying genetic introgression and reproductive barriers between naturally hybridizing, adjacently distributed species. In this study, we sampled 270 pine trees along an elevation gradient in Anhui Province, China and analyzed these samples using EST-SSR markers. The molecular data revealed that direct gene flow between the two species was fairly low, and that the majority of gene introgression was intermediated by backcrossing. On the basis of empirical observation, the on-site distribution of pines was divided into a P. massoniana zone, a hybrid zone, and a P. hwangshanensis zone. STRUCTURE analysis revealed the existence of a distinct species boundary between the two pine species. The genetic boundary of the hybrid zone, on the other hand, was indistinct owing to intensive backcrossing with parental species. Compared with P. massoniana, P. hwangshanensis was found to backcross with the hybrids more intensively, consistent with the observation that morphological and anatomical characteristics of trees in the contact zone were biased towards P. hwangshanensis. The introgression ability of amplified alleles varied across species, with some being completely blocked from interspecific introgression. Our study has provided a living example to help explain the persistence of adjacently distributed species coexisting with their interfertile hybrids.
Project description:Causal processes can give rise to distinctive distributions in the linguistic variables that they affect. Consequently, a secure understanding of a variable's distribution can hold a key to understanding the forces that have causally shaped it. A storied distribution in linguistics has been Zipf's law, a kind of power law. In the wake of a major debate in the sciences around power-law hypotheses and the unreliability of earlier methods of evaluating them, here we re-evaluate the distributions claimed to characterize phoneme frequencies. We infer the fit of power laws and three alternative distributions to 166 Australian languages, using a maximum likelihood framework. We find evidence supporting earlier results, but also nuancing them and increasing our understanding of them. Most notably, phonemic inventories appear to have a Zipfian-like frequency structure among their most-frequent members (though perhaps also a lognormal structure) but a geometric (or exponential) structure among the least-frequent. We compare these new insights the kinds of causal processes that affect the evolution of phonemic inventories over time, and identify a potential account for why, despite there being an important role for phonetic substance in phonemic change, we could still expect inventories with highly diverse phonetic content to share similar distributions of phoneme frequencies. We conclude with priorities for future work in this promising program of research.