Spatial clusters of gonorrhoea in England with particular reference to the outcome of partner notification: 2012 and 2013

Background: This study explored spatial-temporal variation in diagnoses of gonorrhoea to identify and quantify endemic areas and clusters in relation to patient characteristics and outcomes of partner notification (PN) across England, UK. Methods: Endemic areas and clusters were identified using a two-stage analysis with Kulldorff’s scan statistics (SaTScan). Results Of 2,571,838 tests, 53,547 diagnoses were gonorrhoea positive (positivity = 2.08%). The proportion of diagnoses in heterosexual males was 1.5 times that in heterosexual females. Among index cases, men who have sex with men (MSM) were 8 times more likely to be diagnosed with gonorrhoea than heterosexual males (p<0.0001). After controlling for age, gender, ethnicity and deprivation rank, 4 endemic areas were identified including 11,047 diagnoses, 86% of which occurred in London. 33 clusters included 17,629 diagnoses (34% of total diagnoses in 2012 and 2013) and spanned 21 locations, some of which were dominated by heterosexually acquired infection, whilst others were MSM focused. Of the 53,547 diagnoses, 14.5% (7,775) were the result of PN. The proportion of patients who attended services as a result of PN varied from 0% to 61% within different age, gender and sexual orientation cohorts. A third of tests resulting from PN were positive for gonorrhoea. 25% of Local Authorities (n = 81, 95% CI: 20.2, 29.5) had a higher than expected proportion for female PN diagnoses as compared to 16% for males (n = 52, 95% CI: 12.0, 19.9). Conclusions: The English gonorrhoea epidemic is characterised by spatial-temporal variation. PN success varied between endemic areas and clusters. Greater emphasis should be placed on the role of PN in the control of gonorrhoea to reduce the risk of onward transmission, re-infection, and complications of infection

Macroparasites of the Eurasian otter: distributions, life-cycles and population dynamics

Potential alterations of host and parasite ranges are likely with climate change so an understanding of the host traits and ecological factors that can influence host-parasite interactions is vital for the effective protection of ecosystems. Accidental introductions of non-native species can place elevated stress on native ecosystems so that the examination of key species can act as early warning systems. The Eurasian otter, Lutra lutra¸ is a top predator and sentinel species for the health of European freshwater ecosystems and is therefore a suitable model for exploring parasite fauna introductions. In this PhD, the patterns and processes that define macro-parasitic infections were explored using evidence from post-mortems of 587 otters. Specifically, the invasive status of two helminths (Pseudamphistomum truncatum and Metorchis albidus: Trematoda; Opisthorchiidae) was investigated, both species having been identified in the UK otter populations for the first time within the last 10 years. Genetic variation, however, was similar across Europe indicating neither helminth is likely to have been a recent introduction to the UK., The distribution of both helminths as well as the only ectoparasite, Ixodes hexagonus (Arthropoda; Ixodidae), recovered from UK otters, were associated with abiotic factors, particularly temperature. The complexity of the parasite life cycles was investigated; otters act as a definitive host for both helminth species considered in this thesis and early stage intermediate hosts were identified for P. truncatum as the snail Radix balthica and the roach Rutilus rutilus. Metacercariae of M. ablidus were detected on chub (Leuciscus cephalus), rudd (Scardinius erythrophthalmus) and roach. Parasite aggregation and parasite fecundity of the P. truncatum populations were influenced by abiotic factors, region and season, whilst P. truncatum abundance was defined better by the biotic factors host age-class and condition demonstrating how multiple factors combine to produce parasite population dynamics in wild fauna. Ultimately, the data collated throughout this PhD was used to parameterise a susceptible-infected Susceptible-Infected (SI) model describing the host population dynamics of opisthorchiid trematodes. This model is applied to the P. truncatum system to examine which factors might determine the proportion of hosts that become infected

Heparan sulphate mimetics as a therapeutic for central nervous system repair

The central nervous system (CNS) is composed of the brain, optic nerve and spinal cord and is responsible for most of the body’s functions and processing external environmental information. Damage to the CNS can develop in different pathological conditions ranging from infection, traumatic injury of the spinal cord (SCI), traumatic brain injury (TBI), and degenerative disorders such as multiple sclerosis (MS). Neural degeneration and demyelination of axons are hallmarks of CNS injury. Demyelination in the CNS occurs due to a variety of pathophysiological conditions, therefore, any repair strategies for demyelination must consider multifactorial pathways including promotion of axonal outgrowth, and remyelination. Previously, we have demonstrated that low sulphated modified heparin mimetics (LSmHeps) enhance neurite outgrowth and myelination in vitro. Heparin mimetics (mHeps) are a class of glycomolecules with structural similarities to resident heparan sulphates (HS) and are made up of repeating disaccharide units with variable sulphation groups. They are thought to modulate cell signalling by both sequestering ligands and acting as a cofactor in the formation of ligand-receptor complexes. Thus, LS-mHeps have the capacity to represent novel candidates as therapeutics for CNS damage. However, a major hurdle for CNS therapeutics is for molecules and compounds to cross the blood brain barrier (BBB). Large molecular weight is known to prevent molecules crossing the BBB; therefore, we have developed a low molecular weight form of our lead compound LS-mHep7. This thesis aimed to validate the ability of this low molecular weight form (LS-mHep7L) to maintain the ability to enhance repair in several CNS injury models including in vitro myelinating cultures, during both myelin development (MC-Dev) and demyelination (MCDeMy), and astrocyte injury assays. Additionally, this thesis aimed to optimise an ex vivo slice culture model to further validate LS-mHeps and found that spinal cords from C57BL/6 P1 mice produced healthy myelinating axons for remyelination studies. It was found that LS-mHep7L enhanced neurite outgrowth in vitro and remyelination both in vitro and ex vivo. LS-mHep7L was found to sequester CCL5 – a negative regulator of myelination both in vitro and ex vivo, and restored CCL5 induced hypomyelination in developing cultures. LS-mHeps also reduced signs of reactive astrocytes with a decrease in nestin expression and appeared to enhance gap closure in the injury model. Finally, we investigated the use of recombinant heparin mimetics (rHS) as an alternative source for heparin derived therapeutics. Currently 80% of the world’s heparin supply is sourced from China from porcine intestines and having such a reliance on a specific animal source for any new therapeutic comes with an elevated risk. Here we demonstrated that low sulphated recombinant heparan sulphate (rHS10) enhance remyelination in MC-DeMy and SC-DeMy, while rHS09 enhance neurite outgrowth in MC-Inj. In summary, the results of this thesis demonstrated that low sulphated heparin mimetics have the potential to become novel therapeutics for remyelination and neurite outgrowth for diseases and injury of the CNS. Additionally, low molecular weight LS-mHeps show the same bioactivity as the high molecular weight form, by demonstrating neurite outgrowth in vitro, enhanced remyelination and sequestration of negative regulators of repair both in vitro and ex vivo cultures

Quantifying the direct and indirect protection provided by insecticide treated bed nets against malaria

Long lasting insecticidal nets (LLINs) provide both direct and indirect protection against malaria. As pyrethroid resistance evolves in mosquito vectors, it will be useful to understand how the specific benefits LLINs afford individuals and communities may be affected. Here we use modelling to show that there is no minimum LLIN usage needed for users and non-users to benefit from community protection. Modelling results also indicate that pyrethroid resistance in local mosquitoes will likely diminish the direct and indirect benefits from insecticides, leaving the barrier effects intact, but LLINs are still expected to provide enhanced benefit over untreated nets even at high levels of pyrethroid resistance

EpiJSON: A unified data-format for epidemiology

AbstractEpidemiology relies on data but the divergent ways data are recorded and transferred, both within and between outbreaks, and the expanding range of data-types are creating an increasingly complex problem for the discipline. There is a need for a consistent, interpretable and precise way to transfer data while maintaining its fidelity. We introduce ‘EpiJSON’, a new, flexible, and standards-compliant format for the interchange of epidemiological data using JavaScript Object Notation. This format is designed to enable the widest range of epidemiological data to be unambiguously held and transferred between people, software and institutions. In this paper, we provide a full description of the format and a discussion of the design decisions made. We introduce a schema enabling automatic checks of the validity of data stored as EpiJSON, which can serve as a basis for the development of additional tools. In addition, we also present the R package ‘repijson’ which provides conversion tools between this format, line-list data and pre-existing analysis tools. An example is given to illustrate how EpiJSON can be used to store line list data. EpiJSON, designed around modern standards for interchange of information on the internet, is simple to implement, read and check. As such, it provides an ideal new standard for epidemiological, and other, data transfer to the fast-growing open-source platform for the analysis of disease outbreaks

Abiotic and biotic factors associated with tick population dynamics on a mammalian host: Ixodes hexagonus infesting otters, lutra iutra

The Eurasian otter, Lutra lutra, hosts several parasites with zoonotic potential. As this semiaquatic mammal has large ranges across terrestrial, freshwater and marine habitats, it has the capacity for wide dispersion of pathogens. Despite this, parasites of otters have received relatively little attention. Here, we examine their ectoparasite load and assess whether this is influenced by abiotic or biotic variables. Climatic phenomena such as the North Atlantic Oscillation (NAO) affect weather conditions in northern Europe. Consequently parasite distributions, particularly species with life stages exposed to the external environment, can be affected. We assessed the extent to which inter-annual variations in large-scale weather patterns (specifically the NAO and Central England (CE) temperatures) and host characteristics influenced tick prevalence and intensity. Ectoparasites consisted of a single species, the nidiculous tick Ixodes hexagonus (prevalence  = 24.3%; mean intensity  = 7.2; range  = 1–122; on n  = 820 otter hosts). The prevalence, but not intensity of infestation, was associated with high CE temperatures, while both prevalence and intensity were associated with positive phases of the NAO. Such associations indicate that I. hexagonus are most abundant when weather conditions are warmer and wetter. Ticks were more prevalent on juvenile than sub-adult or adult otters, which probably reflects the length of time the hosts spend in the holt where these ticks quest. High tick number was associated with poor host condition, so either poor condition hosts are more susceptible to ticks, or tick infestations negatively impact on host condition. Otters are clearly an important and common host for I. hexagonus, which has implications for vector-borne diseases. This work is the first to consider the impacts of long-term weather patterns on I. hexagonus and uses wild-animal cadavers to illustrate the importance of abiotic and biotic pressures impacting parasitic populations

The impact of introduced hosts on parasite transmission: opisthorchiid infections in American mink (Neovison vison)

Introduced animals may be considered at an advantage over native competitors because they have escaped natural parasites. In some cases however, generalist parasites in a novel environment can use introduced species as an alternative or reservoir host. This can change the dynamics of parasite populations, with implications for epidemiology. The key factor determining the impact of an alternative host is its ability to maintain a reproductively successful parasite and contribute to the transmission potential of that parasite. The digenean Pseudamphistomum truncatum is found in native otters Lutra lutra in Britain and has been reported in introduced American mink Neovison vison. To investigate whether introduced mink are competent hosts and to ask how mink compare with otters as hosts, we compared parasite prevalence, intensity and fecundity between the two host species in a region where both are common. Although prevalence was not statistically different between otters and mink (48 %, n = 27, compared to 33 %, n = 21 respectively), mean parasite intensity was higher in mink (253 ± 145 standard error parasites/infected host, compared to 46 ± 18 in otters). Parasite fecundity was lower in mink (mean egg count/parasite/host = 622 ± 64) than in otters (1,204 ± 108), and this difference was not confounded by host or parasite size or by intraspecific competition among parasites. Assuming the parasite eggs are equally viable from otters or mink, mink are not only a competent host for P. truncatum, but because of the higher parasite intensity in mink, they can potentially spread c.3 times as many parasite eggs to intermediate hosts, than otters. The naturalisation of mink to new habitats may therefore contribute to trematode infections in native fauna

The influence of feeding behaviour and temperature on the capacity of mosquitoes to transmit malaria

Insecticide-treated bed nets reduce malaria transmission by limiting contact between mosquito vectors and human hosts when mosquitoes feed during the night. However, malaria vectors can also feed in the early evening and in the morning when people are not protected. Here, we explored how the timing of blood feeding interacts with environmental temperature to influence the capacity of Anopheles mosquitoes to transmit the human malaria parasite Plasmodium falciparum. In laboratory experiments, we found no effect of biting time itself on the proportion of mosquitoes that became infectious (vector competence) at constant temperature. However, when mosquitoes were maintained under more realistic fluctuating temperatures, there was a significant increase in competence for mosquitoes feeding in the evening (18:00), and a significant reduction in competence for those feeding in the morning (06:00), relative to those feeding at midnight (00:00). These effects appear to be due to thermal sensitivity of malaria parasites during the initial stages of parasite development within the mosquito, and the fact that mosquitoes feeding in the evening experience cooling temperatures during the night, whereas mosquitoes feeding in the morning quickly experience warming temperatures that are inhibitory to parasite establishment. A transmission dynamics model illustrates that such differences in competence could have important implications for malaria prevalence, the extent of transmission that persists in the presence of bed nets, and the epidemiological impact of behavioural resistance. These results indicate that the interaction of temperature and feeding behaviour could be a major ecological determinant of the vectorial capacity of malaria mosquitoes

East-West divide: temperature and land cover drive spatial variation of Toxoplasma gondii infection in Eurasian otters (Lutra lutra) from England and Wales

Toxoplasma gondii, a zoonotic parasite of global importance, infects all endothermic vertebrates, with extensive health implications. The prevalence of this parasite is seldom monitored in wildlife. Here, a semi-aquatic species, the Eurasian otter (Lutra lutra) was used as a model to assess the potential effect of climate, land cover and biotic factors on T. gondii seroprevalence in British wildlife. The Sabin–Feldman cytoplasm-modifying dye test identified T. gondii antibodies in 25·5% of blood samples from otters found dead, mainly as road kill, in England and Wales, between 2004 and 2010. Otters in the east of England were more likely to be infected with T. gondii than those in western regions. Land cover and temperature are key determinants of T. gondii infection risk, with more infection in arable areas and lower infection where temperatures are higher. The probability of T. gondii infection increased with host age, reflecting cumulative exposure with time, but there was no association between T. gondii seroprevalence and cause of host death