This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.Page 1 of 27A c c e p t e d M a n u s c r i p t A previously isolated contagious ovine digital dermatitis spirochete was located within 34 one of the three phylogroups, group 3, and could also be identified within this group on 35 the basis of phenotype testing, suggesting BDD and contagious ovine digital dermatitis 36 may share the same aetiological agent. A strain isolated from a bovine interdigital 37 dermatitis lesion, could be identified as part of BDD isolate group 2, suggesting bovine 38 interdigital dermatitis and BDD may have the same causative agent. Two common 39 enzyme activities, C4 esterase and C8 esterase lipase, were identified in all BDD 40 associated treponemes suggesting common metabolic pathways for sharing this novel 41 niche or even common virulence traits. Further studies are required to determine whether 42 the three groups of novel treponemes are representative of new treponeme taxa and to 43 delineate how they interact with bovine tissues to cause disease. 44

This study used a PCR-based approach targeting 16S rRNA gene fragments to determine the occurrence and association of the three bovine digital dermatitis (BDD) treponeme phylogroups within lesions found in cattle from the United Kingdom. Examination of 51 BDD lesions collected from infected cattle across the United Kingdom revealed that BDD treponeme group 1 (Treponema medium/Treponema vincentii-like), group 2 (Treponema phagedenis-like), and group 3 (Treponema putidum/Treponema denticola-like) were present in 96.1%, 98%, and 76.5% of BDD lesions, respectively. The three phylogroups were present together in 74.5% of lesions. The PCR assays enabled the isolation of further treponeme strains from previously mixed primary BDD lesion cultures. Here a representative from each of the three distinct treponeme phylogroups was isolated from a single BDD lesion for the first time. These data highlight the extent to which this disease is polytreponemal. Immunohistochemistry and electron microscopy were used to investigate lesional hoof tissues, resulting in treponemes being identified copiously in hair follicles and sebaceous glands, suggesting a potential route of exit and/or entry for these pathogens. This study gives further evidence for the importance of the three treponeme groups in BDD pathogenesis and reiterates the value of molecular genetic approaches for isolating and identifying fastidious anaerobes.

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The three databases broadly agreed with each other, but important differences existed in both species composition and spatial coverage which raises concern over their accuracy. Importantly, they cannot be reliably linked together to provide a single picture of New Zealand's livestock industry, limiting the ability to use advanced quantitative techniques to provide effective decision support during disease outbreaks. We recommend that a single integrated database be developed, with alignment of resources and legislation for its upkeep.

For many diseases the infection status of individuals cannot be observed directly, but can only be inferred from biomarkers that are subject to measurement error. Diagnosis of infection based on observed symptoms can itself be regarded as an imperfect test of infection status. The temporal relationship between infection and marker outcomes may be complex, especially for recurrent diseases where individuals can experience multiple bouts of infection. We propose an approach that first models the unobserved longitudinal infection status of individuals conditional on relevant covariates, and then jointly models the longitudinal sequence of biomarker outcomes conditional on infection status and covariate information through time, thus resulting in a joint model for longitudinal infection and biomarker sequences. This model can be used to investigate the temporal dynamics of infection, and to evaluate the usefulness of biomarkers for monitoring purposes. Our work is motivated and illustrated by a longitudinal study of bovine digital dermatitis (BDD) on commercial dairy farms in North West England and North Wales, in which the infection of interest is Treponeme spp., and the biomarkers of interest are a continuous enzyme-linked immunosorbent assay test outcome and a dichotomous outcome, foot lesion status. BDD is known to be one of the possible causes of foot lesions in cows.

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SUMMARYUsing data from a cohort study conducted by the Veterinary Laboratories Agency (VLA), evidence of spatial clustering at distances up to 30 km was found for S. Agama and S. Dublin (P values of 0 . 001) and borderline evidence was found for spatial clustering of S. Typhimurium (P=0 . 077). The evolution of infection status of study farms over time was modelled using a Markov Chain model with transition probabilities describing changes in status at each of four visits, allowing for the effect of sampling visit. The degree of geographical clustering of infection, having allowed for temporal effects, was assessed by comparing the residual deviance from a model including a measure of recent neighbourhood infection levels with one excluding this variable. The number of cases arising within a defined distance and time period of an index case was higher than expected. This provides evidence for spatial and spatio-temporal clustering, which suggests either a contagious process (e.g. through direct or indirect farm-to-farm transmission) or geographically localized environmental and/or farm factors which increase the risk of infection. The results emphasize the different epidemiology of the three Salmonella serovars investigated.