How much disease risk is due to old age and established risk factors?

Improved healthcare is leading to older populations and increasing numbers of individuals experiencing multiple diseases, possibly concurrently (multimorbidity). This article asks whether the observed number of new diseases is more than expected based on age and established risk factors alone, assuming that disease risk is unchanged by prior or pre-existing disease. This is accomplished by designing a new epidemiological approach, where the expected number of disease types are estimated for individuals without prior disease, by combining individual risk predictions with a "Poisson-Binomial" model to estimate the expected number of new diseases and its confidence interval. For 123 diseases in men and 99 diseases in women, the expected number of new diseases based on age and established risk factors was approximately 2/3 of that observed, with the observed number of new diseases approximately 1.5 times that predicted. The differences could not be explained by natural statistical variation, and provide a rigorous statistical demonstration of lower disease risk for individuals without any previous disease. The multiple of 1.5 was sufficiently consistent across different diseases to prevent its use for classification of disease types, but there were differences for subgroups such as smokers with high body mass index, and for some classes of disease (as defined by the International Classification of Diseases, version 10). The results suggest that empirical modeling might allow reliable predictions of future hospital admissions, and confirm the value of conventional epidemiological approaches that study disease risk in healthy individuals. The implications and future possibilities of this new approach are discussed.

Characterisation, identification, clustering, and classification of disease.

The importance of quantifying the distribution and determinants of multimorbidity has prompted novel data-driven classifications of disease. Applications have included improved statistical power and refined prognoses for a range of respiratory, infectious, autoimmune, and neurological diseases, with studies using molecular information, age of disease incidence, and sequences of disease onset ("disease trajectories") to classify disease clusters. Here we consider whether easily measured risk factors such as height and BMI can effectively characterise diseases in UK Biobank data, combining established statistical methods in new but rigorous ways to provide clinically relevant comparisons and clusters of disease. Over 400 common diseases were selected for analysis using clinical and epidemiological criteria, and conventional proportional hazards models were used to estimate associations with 12 established risk factors. Several diseases had strongly sex-dependent associations of disease risk with BMI. Importantly, a large proportion of diseases affecting both sexes could be identified by their risk factors, and equivalent diseases tended to cluster adjacently. These included 10 diseases presently classified as "Symptoms, signs, and abnormal clinical and laboratory findings, not elsewhere classified". Many clusters are associated with a shared, known pathogenesis, others suggest likely but presently unconfirmed causes. The specificity of associations and shared pathogenesis of many clustered diseases provide a new perspective on the interactions between biological pathways, risk factors, and patterns of disease such as multimorbidity.

Statistical characterization and classification of edge-localized plasma instabilities.

The statistics of edge-localized plasma instabilities (ELMs) in toroidal magnetically confined fusion plasmas are considered. From first principles, standard experimentally motivated assumptions are shown to determine a specific probability distribution for the waiting times between ELMs: the Weibull distribution. This is confirmed empirically by a statistically rigorous comparison with a large data set from the Joint European Torus. The successful characterization of ELM waiting times enables future work to progress in various ways. Here we present a quantitative classification of ELM types, complementary to phenomenological approaches. It also informs us about the nature of ELM processes, such as whether they are random or deterministic. The methods are extremely general and can be applied to numerous other quasiperiodic intermittent phenomena.

Reducing dissolved inorganic nitrogen in surface runoff water from sugarcane production systems.

Nitrogen (N) lost from farms, especially as the highly bioavailable dissolved inorganic form, may be damaging Australia's Great Barrier Reef (GBR). As sugarcane is the dominant cropping system in GBR catchments, its N management practises are coming under increasing scrutiny. This study measured dissolved inorganic N lost in surface runoff water and sugarcane productivity over 3 years. The experiment compared the conventional fertiliser N application rate to sugarcane (average 180kg N/ha/year) and a rate based on replacing N exported in the previous crop (average 94kg N/ha/year). Dissolved inorganic N losses in surface water were 72%, 48% and 66% lower in the three monitored years in the reduced N fertiliser treatment. There was no significant difference in sugarcane yield between the two fertiliser N treatments, nor any treatment difference in soil mineral N - both of these results are indicators of the sustainability of the lower fertiliser N applications.

Magnetohydrodynamic stability of a toroidal plasma's separatrix.

Large tokamaks capable of fusion power production such as ITER, should avoid large edge localized modes (ELMs), thought to be triggered by an ideal magnetohydrodynamic instability due to current at the plasma's separatrix boundary. Unlike analytical work in a cylindrical approximation, numerical work finds the modes are stable. The plasma's separatrix might stabilize modes, but makes analytical and numerical work difficult. We generalize a cylindrical model to toroidal separatrix geometry, finding one parameter Delta' determines stability. The conformal transformation method is generalized to allow nonzero derivatives of a function on a boundary, and calculation of the equilibrium vacuum field allows Delta' to be found analytically. As a boundary more closely approximates a separatrix, we find the energy principle indicates instability, but the growth rate asymptotes to zero.

The development, implementation and testing of a lameness control programme based on HACCP principles and designed for heifers on dairy farms.

This paper describes the development and testing of a lameness control programme (LCP) for heifers on dairy farms. The LCP, which is based on the analysis of hazards and critical control points (HACCP), was tested via a randomised intervention study on 60 farms. Tangible hazards for each farm were identified, allotted to 11 categories of proximate hazard and scored on each farm to quantify the risks presented by each hazard. Feet were inspected for signs of claw horn disease and infection, such as digital dermatitis. Intervention was generally ineffective, primarily through failure to implement the LCP. However, retrospective analysis was able to demonstrate highly significant associations between risks attached to proximate hazards and probabilities of lameness and foot lesions, allowing the severity of these hazards to be ranked. The most significant proximate hazards of environmental origin were prolonged standing on concrete, standing in wet slurry and factors that cause claw trauma. The most severe proximate hazards however were those associated with failures of management, especially poor claw condition and inadequate foot care. Overall farm risks (OFR) were estimated by summing the products of the generic severity for proximate hazards with on-farm risks. Changes in OFR were significantly related to changes in outcome (lameness and lesions).

Assessment of the behaviour and welfare of laying hens on free-range units.

The aims of this study were twofold: to develop and test an animal-based protocol for the assessment of the physical and emotional elements of the welfare of laying hens on free-range units and to investigate the effects of different approaches to housing and management on the welfare of the birds. The protocol was tested on 25 free-range units for laying hens, each of which was visited on four occasions by one of five trained observers; further information about husbandry, health and productivity was gathered from interviews with the farmers. Measures of the birds' attitude included arousal, noise, flight distance and response to a novel object, measures of their activity included feather pecking, aggression and use of range, and measures of their physical welfare included mortality, body condition and egg quality. Increased arousal was associated with increased flight distance, greater reluctance to approach a novel object and higher levels of feather pecking and feather loss, but the correlation between pecking and feather loss was low. The birds maintained body condition throughout the period of lay. Neither body condition, feather pecking nor feather loss was affected by the extent of beak trimming. Estimated losses (deaths and culls) ranged from 1.8 to 21.4 per cent (median 6.95 per cent). Few birds showed signs of ill health, limb lesions or red mite infestation. No feature of building design had a significant effect on mortality, but there were consistent differences in the birds' attitude, behaviour and performance attributable to the type of floor and the presence or absence of perches, which suggested that the welfare of the hens was inferior when they were housed on plastic floors with no perches.

Effects of housing, parturition and diet change on the biochemistry and biomechanics of the support structures of the hoof of dairy heifers.

This study investigated effects of housing, diet and parturition on the biochemistry, biomechanics and pathology of feet of maiden, pregnant and lactating dairy heifers. Strength/laxity, laminar morphology, connective tissue (CT) biochemistry and sole lesions were assessed. Although no animals became clinically lame, severity of sole lesions was significantly greater in heifers housed in cubicles vs. straw yards, and in lactating/pregnant heifers vs. maidens. These effects were additive. Cubicle housing and parturition each increased CT metabolism (and were additive), and altered CT composition. Similarly, both impaired the biomechanical resilience of the hoof. There were no effects for diet. The results indicate that parturition/lactation causes non-inflammatory changes in CT that impair resilience of the feet to external stresses associated with poor housing. This "parturition effect" appears to be unrelated to change in diet and relatively brief, unless exacerbated by additional stresses of housing. Thus heifer lameness may be significantly reduced through short-term, low-cost improvements in husbandry around the time of calving.

Herd health planning: farmers' perceptions in relation to lameness and mastitis.

Between December 2002 and December 2003, the herd health planning activities on 61 dairy farms in the uk were compared with several measures of lameness and mastitis. Lameness had been reported as a problem in 53 of the herds directly by the farm and in the other eight by the nominating local veterinary practice; 54 of the farms also reported having a mastitis problem. Fifty-three (87 per cent) of the farms had some form of written herd health plan, of which 21 (40 per cent) had been in place for 12 months or less. All the farms were recording mastitis in some way, although 38 (62 per cent) of the farmers did not review these records and only four retained the results of a comprehensive record review. Farms defined as having a high incidence of mastitis were more likely to be reviewing their health records, but farms defined as having a high prevalence of lameness in a sentinel group of early lactation heifers were less likely to be reviewing their health records.

Role of ketoprofen in the modulation of hyperalgesia associated with lameness in dairy cattle.

Forty lame dairy cows were randomly assigned to receive a course of either the non-steroidal anti-inflammatory drug ketoprofen, or sterile saline, together with conventional treatment for lameness. The effect of the ketoprofen was measured by using locomotion scoring and by testing the cows' nociceptive threshold over a period of 28 days. The locomotion score of all the cows improved but ketoprofen had no significant effect on this change. However, in the cows that received ketoprofen the hyperalgesia associated with lameness, recorded using a nociceptive threshold test, was significantly modulated on days 3, 8 and 28 after their initial examination, drug administration and treatment of lesions.

Role of flow shear in the ballooning stability of tokamak transport barriers.

A tokamak's confinement time is greatly increased by a transport barrier (TB), a region having a high pressure gradient and usually also a strongly sheared plasma flow. The pressure gradient in a TB can be limited by ideal magnetohydrodynamic instabilities with a high toroidal mode number n ("ballooning modes"). Previous studies in the limit n--> infinity showed that arbitrarily small (but nonzero) flow shears have a large stabilizing influence. In contrast, the more realistic finite n ballooning modes studied here are found to be insensitive to sub-Alfvénic flow shears, provided the magnetic shear s approximately 1 (typical for TBs near the plasma's edge). However, for the lower magnetic shears that are associated with internal transport barriers, significantly lower flow shears will influence ballooning mode stability, and flow shear should be retained in the analysis of their stability.

The life history legacy of evolutionary body size change in carnivores.

We estimate the body sizes of direct ancestors of extant carnivores, and examine selected aspects of life history as a function not only of species' current size, but also of recent changes in size. Carnivore species that have undergone marked recent evolutionary size change show life history characteristics typically associated with species closer to the ancestral body size. Thus, phyletic giants tend to mature earlier and have larger litters of smaller offspring at shorter intervals than do species of the same body size that are not phyletic giants. Phyletic dwarfs, by contrast, have slower life histories than nondwarf species of the same body size. We discuss two possible mechanisms for the legacy of recent size change: lag (in which life history variables cannot evolve as quickly as body size, leading to species having the 'wrong' life history for their body size) and body size optimization (in which life history and hence body size evolve in response to changes in energy availability); at present, we cannot distinguish between these alternatives. Our finding that recent body size changes help explain residual variation around life history allometries shows that a more dynamic view of character change enables comparative studies to make more precise predictions about species traits in the context of their evolutionary background.

Assessment of the welfare of dairy cattle using animal-based measurements: direct observations and investigation of farm records.

A protocol was developed by consultation with experts on the welfare of cattle to use direct observations of cattle and an examination of farm records to assess welfare. Fifty-three dairy farms in England were visited and assessed during the winter of 2000/01. The findings were compiled and the results of the welfare measurements were examined by 50 experts who indicated at what level they considered that improvement was required. More than 75 per cent of them considered that 32 of the 53 farms needed to take action to reduce the incidence of mastitis, and that at least 42 of the farms needed to take action to reduce the prevalence of lameness, overgrown claws, swollen and ulcerated hocks, and injuries from the environment.

Effect of the RSPCA Freedom Food Scheme on the welfare of dairy cattle.

To evaluate the effect of the Royal Society for the Prevention of Cruelty to Animals Freedom Food (FF) scheme on the welfare of dairy cattle in England, 28 FF and 25 non-FF farms were assessed during the winter of 2000 to 2001. The assessments were based on a protocol which included the examination of the farms' records, the farmers' estimates of the incidence of disease, and independent observations of the behaviour and physical condition of the cows. The data were analysed to identify which measures of welfare were affected by FF membership and to assess the number of farms on which intervention would be required, as defined by a panel of 50 experts. The FF farms had better results for 12 of the welfare indicators, including those for mastitis, non-hock injuries, cow cleanliness and body condition, and poorer welfare indicators for eight of the measures, including hock injuries, lameness and restrictions in rising behaviour. Except for the prevalence of dull coats (which was lower on the FF farms) there were no significant differences in the proportions of FF and non-FF farms on which intervention was required according to the experts' assessment.

Effects of housing practices on the development of foot lesions in dairy heifers in early lactation.

Measurements were made of sole haemorrhages and white line lesions in two groups of heifers which were either introduced to a cubicle house four weeks before they calved (group 1) or housed in a straw yard for eight weeks after calving and then moved into the cubicle house (group 2). The overall severity of the lesions was described by a cumulative score which defined the product of the severity and the area of the overall lesions in each animal. The lesions were scored on six occasions, from four weeks before to 24 weeks after parturition. Before parturition, sole lesions were absent or very small. By four weeks after calving, most of the animals had both types of lesion, but the differences between the two groups were small and statistically insignificant. There were no significant differences in the white line lesions between the two groups at any of the observations. There were, however, progressive, highly significant differences between the two groups in the severity of sole haemorrhages. By 12 weeks after calving, the median score for group 1 was 69 and that for group 2 was 11. In group 2, the sole haemorrhage score peaked at eight weeks but declined thereafter, even though these animals were moved into cubicles eight weeks after calving. By 12 weeks after calving, six of the 17 heifers in group 1 had sole ulcers but none of the 16 in group 2 had ulcers.

Biomechanical and histopathological changes in the support structures of bovine hooves around the time of first calving.

Hooves were removed from heifers killed two weeks before calving (C-2), and four and twelve weeks post-calving (C+4 and C+12), and from age-matched maiden heifers. Segments were dissected from the anterior walls of lateral hind claws, to include horn, corium and bone, and the biomechanical properties were measured. There was reduced rigidity, both overall and at a physiologically appropriate displacement of 2 mm, and a greater displacement was required to reach initial and maximum support in the hooves of calving, compared with maiden, heifers. Histological examination revealed widened and distorted interdigitating laminae, progressing to C+12 in the hind claws, but with evidence of recovery in the front claws after C+4. Increased connective tissue strength from dorsal to ventral hoof segments was correlated with protein, proteoglycan, pro- and activated matrix metalloproteinase-2, and tissue inhibitors of metalloproteinases, and was inversely correlated with fat, water and collagen content. This implies that mechanical changes reflect alterations in the biochemistry of the connective tissue. This evidence supports the hypothesis that primary causal events associated with calving weaken the connective tissue of the hoof suspensory apparatus, leading to increased susceptibility to clinical lameness associated with sole ulcers and white line disease.

Effects of housing and two forage diets on the development of claw horn lesions in dairy cows at first calving and in first lactation.

This paper describes a systematic study of the development of lesions of the claw horn (CHL, sole and white line) in heifers calving for the first time, housed either in cubicles or a straw yard and fed either a low- or high-dry-matter forage diet. The feet of all animals were inspected on five occasions, at approximately four weeks before and four, eight, 16 and 24 weeks post calving. Haemorrhagic lesions of the sole and white line were described according to a geometric lesion score for severity and a cumulative lesion score based on the product of (severity x area) for each lesion. Geometric and cumulative lesion scores increased in all groups of cattle in the first eight weeks after calving. However, the severity and persistence of the lesions were significantly greater in cattle housed in cubicle yards. Wet feeding increased the severity of CHL in the cubicle yard only. There were no associations between lesion scores and body weight, body condition or foot conformation. The heels of the cattle in straw yards tended to be thick but many showed pitting erosions. In cubicles the heels were smooth but thin. This may have contributed to CHL by increasing concussive forces within the hoof. There was a highly significant (but relatively low) correlation between scores for sole lesions and lameness in individual animals. These observations are consistent with the hypothesis that systemic events associated with calving and the onset of lactation may set in motion the chain of events that lead to the lesions of CHL; the extent and severity of these lesions being then determined by the externally imposed conditions of housing and feeding.

Study of the behaviour, digestive efficiency and gut transit times of crib-biting horses.

The spontaneous behaviour and the apparent digestibility of dry matter and fibre and transit times of digesta were compared in four normal horses and four crib-biters. A technique was developed for measuring total gut transit times (TGTT) by using single-stool analysis of the passage of radio-opaque polyethylene markers. Longer TGTT were recorded in the crib-biters than in the normal horses but the orocaecal transit times did not differ. The crib-biters rested less than the normal horses.

Farm animal welfare: the five freedoms and the free market.

This review addresses the scientific, ethical and economic factors that impact on the welfare of farm animals. Respect for animals within the food chain is considered within the context of an ethical matrix that affords respect according to the principles of wellbeing, autonomy and justice to consumers, farm animals, farmers and the living environment. The welfare of a farm animal depends on its ability to sustain fitness and avoid suffering. The responsibility of the farmer is to make provision for good welfare through good husbandry; he cannot ensure good welfare. Improvements to farm animal welfare can only come about within the context of the forces that drive the free market. In essence, consumers need to afford a greater extrinsic value to farm animals. The costs to farmers of legislation to impose higher animal welfare standards are substantial but the cost to consumers can be very small. The responsibility is therefore on the consumer to convert an expressed desire for higher welfare standards into an effective demand. A promising route to encourage and fulfil this demand is through welfare-based quality assurance schemes with quality control ensured by independent audit. At present, audit protocols are based largely on identification of the elements of good husbandry. Ultimately we need a further independent audit to ensure that the outcome of these perceived elements of good husbandry is, in fact, good animal welfare.