Causal attribution fractions, and the attribution of smoking and BMI to the landscape of disease incidence in UK Biobank.

Unlike conventional epidemiological studies that use observational data to estimate "associations" between risk factors and disease, the science of causal inference has identified situations where causal estimates can be made from observational data, using results such as the "backdoor criteria". Here these results are combined with established epidemiological methods, to calculate simple population attribution fractions that estimate the causal influence of risk factors on disease incidence, and can be estimated using conventional proportional hazards methods. A counterfactual argument gives an attribution fraction for individuals. Causally meaningful attribution fractions cannot be constructed for all risk factors or confounders, but they can for the important established risk factors of smoking and body mass index (BMI). Using the new results, the causal attribution of smoking and BMI to the incidence of 226 diseases in the UK Biobank are estimated, and summarised in terms of disease chapters from the International Classification of Diseases (ICD-10). The diseases most strongly attributed to smoking and BMI are identified, finding 11 with attribution fractions greater than 0.5, and a small number with protective associations. The results provide new tools to quantify the causal influence of risk factors such as smoking and BMI on disease, and survey the causal influence of smoking and BMI on the landscape of disease incidence in the UK Biobank population.

The Relationships Between Childhood Abuse and Neglect, Sub-clinical Symptoms of Psychosis and Self-harm in a Non-clinical Community Sample.

There is now substantial evidence that childhood adverse events are a significant risk factor for symptoms of psychosis in both clinical and community samples. Both childhood trauma and positive symptoms of psychosis are associated with an increased risk of self-harming behaviours. Therefore the current study aimed to consider the relationship between retrospective reports of childhood adversity, sub-clinical positive symptoms of psychosis and self-harm in a non-clinical community sample. The study employed a cross-sectional survey design, distributed online. Participants were asked to complete psychometric assessments relating to: demographic characteristics including past-year substance misuse; childhood adversity; sub-clinical symptoms of psychosis (delusions and hallucinations) and self-harming behaviours. The results found that, after controlling for substance misuse, childhood adversity predicted significant variance in sub-clinical delusions and hallucinations in the general population. Both symptoms of psychosis and childhood adversity increased the risk of self-harming behaviours. Positive symptoms partially mediated the relationship between early adversity and self-harming behaviours. For some people, the sequelae of early adversity including sub-clinical delusions and hallucinations may increase the risk of self-harming behaviours. Future research would benefit from considering the role of dissociation in these relationships and the affective impact of pseudo-psychotic experiences. Practitioners should consider the impact of childhood adversity, unusual perceptual experiences and distorted beliefs when working with people who self-harm. The current research was limited by the cross-sectional survey design and non-random sampling methodology.

Sporadic, late-onset, and multistage diseases.

Multistage disease processes are often characterized by a linear relationship between the log of incidence rates and the log of age. Examples include sequences of somatic mutations, that can cause cancer, and have recently been linked with a range of non-malignant diseases. Using a Weibull distribution to model diseases that occur through an ordered sequence of stages, and another model where stages can occur in any order, we characterized the age-related onset of disease in UK Biobank data. Despite their different underlying assumptions, both models accurately described the incidence of over 450 diseases, demonstrating that multistage disease processes cannot be inferred from this data alone. The parametric models provided unique insights into age-related disease, that conventional studies of relative risks cannot. The rate at which disease risk increases with age was used to distinguish between "sporadic" diseases, with an initially low and slowly increasing risk, and "late-onset" diseases whose negligible risk when young rapidly increases with age. "Relative aging rates" were introduced to quantify how risk factors modify age-related risk, finding the effective age-at-risk of sporadic diseases is strongly modified by common risk factors. Relative aging rates are ideal for risk-stratification, allowing the identification of ages with equivalent-risk in groups with different exposures. Most importantly, our results suggest that a substantial burden of sporadic diseases can be substantially delayed or avoided by early lifestyle interventions.

The changing face of science communication, technology, extension and improved decision-making at the farm-water quality interface.

In recent decades, significant advances have been made in understanding the generation, fates and consequences of water quality pollutants in the Great Barrier Reef ecosystem. However, skepticism and lack of trust in water quality science by farming stakeholders has emerged as a significant challenge. The ongoing failures of both compulsory and particularly voluntary practices to improve land management and reduce diffuse agricultural pollution from the Great Barrier Reef catchment underlines the need for more effective communication of water quality issues at appropriate decision-making scales to landholders. Using recent Great Barrier Reef catchment experiences as examples, we highlight several emerging themes and opportunities in using technology to better communicate land use-water quality impacts and delivery of actionable knowledge to farmers, specifically supporting decision-making, behavior change, and the spatial identification of nutrient generation 'hotspots' in intensive agriculture catchments. We also make recommendations for co-designed monitoring-extension platforms involving farmers, governments, researchers, and related agencies, to cut across stakeholder skepticism, and achieve desired water quality and ecosystem outcomes.

Grasping at digitalisation: turning imagination into fact in the sugarcane farming community.

Nutrient runoff from catchments that drain into the Great Barrier Reef (GBR) is a significant source of stress for this World Heritage Area. An alliance of collaborative on-ground water quality monitoring (Project 25) and technologically driven digital application development (Digiscape GBR) projects were formulated to provide data that highlighted the contribution of a network of Australian sugar cane farmers, amongst other sources, to nutrient runoff. This environmental data and subsequent information were extended to the farming community through scientist-led feedback sessions and the development of specialised digital technology (1622™WQ) that help build an understanding of the nutrient movements, in this case nitrogen, such that farmers might think about and eventually act to alter their fertilizer application practices. This paper reflects on a socio-environmental sustainability challenge that emerged during this case study, by utilising the nascent concept of digi-grasping. We highlight the importance of the entire agricultural knowledge and advice network being part of an innovation journey to increase the utility of digital agricultural technologies developed to increase overall sustainability. We develop the digi-MAST analytical framework, which explores modes of being and doing in the digital world, ranging from 'the everyday mystery of the digital world (M)', through digital 'awareness (A)', digitally 'sparked' being/s (S), and finally the ability of individuals and/or groups to 'transform (T)' utilising digital technologies and human imaginations. Our digi-MAST framework allows us to compare agricultural actors, in this case, to understand present modes of digi-grasping to help determine the resources and actions likely to be required to achieve impact from the development of various forms of digital technological research outputs.

Multi-stage models for the failure of complex systems, cascading disasters, and the onset of disease.

Complex systems can fail through different routes, often progressing through a series of (rate-limiting) steps and modified by environmental exposures. The onset of disease, cancer in particular, is no different. Multi-stage models provide a simple but very general mathematical framework for studying the failure of complex systems, or equivalently, the onset of disease. They include the Armitage-Doll multi-stage cancer model as a particular case, and have potential to provide new insights into how failures and disease, arise and progress. A method described by E.T. Jaynes is developed to provide an analytical solution for a large class of these models, and highlights connections between the convolution of Laplace transforms, sums of random variables, and Schwinger/Feynman parameterisations. Examples include: exact solutions to the Armitage-Doll model, the sum of Gamma-distributed variables with integer-valued shape parameters, a clonal-growth cancer model, and a model for cascading disasters. Applications and limitations of the approach are discussed in the context of recent cancer research. The model is sufficiently general to be used in many contexts, such as engineering, project management, disease progression, and disaster risk for example, allowing the estimation of failure rates in complex systems and projects. The intended result is a mathematical toolkit for applying multi-stage models to the study of failure rates in complex systems and to the onset of disease, cancer in particular.

Hereditary angioedema: a survey of UK emergency departments and recommendations for management.

Patients with hereditary angioedema may present to the emergency department (ED) with subcutaneous and submucosal swellings, the most important being the development of laryngeal oedema, which can rapidly obstruct the airways and cause death. The aim of this study was to establish whether local guidelines exist for the management of such patients and to determine where the C1 inhibitor concentrate (C1 INHC) was kept in the trusts. A questionnaire survey of the availability and use of C1 INHC was sent to 35 EDs across the UK with established immunology services within their trusts. A hundred percent response was received. Thirty-three trusts had a supply of the drug C1 INHC in varying quantities. Nineteen trusts had it in their ED. Only 17 departments had any guidance with regard to their use. There is a significant lack of guidance for C1 INHC use in the EDs surveyed. A guideline was developed as a result that can be used by EDs across Europe.

Nutritional adequacy of different menu settings in elite Spanish adolescent soccer players.

The article describes a study that evaluated the adequacy of 2 different menu settings in a group of elite adolescent Spanish soccer players. Five-day food intake was assessed on 2 occasions, while athletes were consuming a flexible "buffet-style" diet (B; n = 33) and a fixed "menu-style" diet (M; n = 29). For all principal meals of the day food weighing was performed, and snacks were recorded by self-report. M provided significantly higher total energy and carbohydrate intakes than B. Breakfast and snacks both provided more energy in M. Calories obtained from fat were excessive in both settings. Calcium and vitamin D were below recommendations in B but not in M. Fiber, magnesium, folate, vitamin A, and vitamin E intake fell below recommended values in both settings. M provided significantly greater quantities of magnesium and vitamins D and E. Both feeding options were far from optimal in satisfying current scientifically based recommendations for active adolescents.

Physical activity during treatment in children with leukemia: a pilot study.

The purpose of this pilot study was to measure physical activity (PA) levels in children undergoing treatment for acute lymphoblastic leukemia (ALL) and to compare the results with those from age-matched healthy children. We used the MTI Actigraph accelerometer to determine PA (during a 1 week period) in children (n = 7; age = 4-7 y) undergoing maintenance treatment for ALL and in age-matched controls (n = 7). The number of children accumulating at least 60 min of moderate-to-vigorous physical activity (MVPA) for 5 or more days of the week was 3 for the control group, whereas no children with ALL met this criterion. Significantly lower levels of total weekly time of MVPA were seen in children being treated for ALL (328 +/- 107 min) than in controls (506 +/- 175 min) (p < 0.05). When weekday data was analyzed, the ALL patients also had significantly lower mean daily times of MVPA (49 +/- 23 min vs. 79 +/- 25 min). It is thus important that young ALL sufferers are encouraged to participate in appropriate sports, games, and physical activities both in the family and school environments that will prime them with positive attitudes to PA during the critical early years of life.

Clinical and Immunological Spectrum of Common Variable Immunodeficiency (CVID).

We have analysed data from 150 patients initially classified as having CVID. About 10% had laboratory abnormalities suggesting known single gene disorders (eg: hyper-IgM syndrome), and in a few a genetic defect has been confirmed. We have attempted to sub-classify the remaining patients by analysis of their circulating lymphocytes. B lymphocyte markers have been used to estimate the numbers of circulating immature and class switched B cells; there is an association between the presence of high relative numbers of immature circulating B cells, splenomegaly and autoimmune disease. About 25% of CVID patients have a moderate CD4+ T lymphopenia, sometimes with a relative expansion of CD8+ T cells. About 30% of CVID patients have persistent relatively high levels of circulating CD8+ T cells binding immunogenic peptides from EBV or CMV. Many of these patients also have high relative numbers of circulating CD8+ perforin positive T cells, and there is evidence that these cells may be responsible for neutropenia or inflammatory bowel disease in some patients. The clinical spectrum of CVID is diverse, with some patients suffering from few infections, and over 50% have evidence of structural lung damage. About 25% of UK patients have chronic inflammation in various organs, particularly the lungs, liver and spleen, often with granulomatous changes. Steroids are used to treat many of the patients with chronic inflammatory complications, although trials are in progress with anti-TNF agents. The incidence of these inflammatory complications is different between countries, being rare in Sweden. Attempts to correlate clinical phenotypes with the laboratory abnormalities described above have been disappointing, suggesting that unknown genetic factors unrelated to the cause of the immunodeficiency determine the complications; attempts to identify some of these factors will be discussed. Finally a provisional scheme to sub classify CVID patients according to lymphocyte abnormalities will be presented, the purpose being to focus the screening of candidate genes causing CVID to specific subsets of patients.

Serologic changes following B lymphocyte depletion therapy for rheumatoid arthritis.

OBJECTIVE: To explore the changes in serologic variables and clinical disease activity following B lymphocyte depletion in 22 patients with rheumatoid arthritis (RA). METHODS: B lymphocyte depletion was attained using combination therapy based on the monoclonal anti-CD20 antibody rituximab. Levels of a serologic indicator of inflammation, C-reactive protein (CRP), of antimicrobial antibodies, of autoantibodies including IgA-, IgM-, and IgG-class rheumatoid factors (RF), and of antibodies to cyclic citrullinated peptide (anti-CCP) were assayed. RESULTS: The majority of patients showed a marked clinical improvement after treatment with rituximab, with benefit lasting up to 33 months. Levels of total serum immunoglobulins fell, although the mean values each remained within the normal range. Whereas the IgM-RF response paralleled the changes in total serum IgM levels, the levels of IgA-RF, IgG-RF, and IgG and anti-CCP antibodies decreased significantly more than did those of their corresponding total serum immunoglobulin classes. The kinetics for the reduction in CRP levels also paralleled the decreases in autoantibody levels. In contrast, levels of antimicrobial antibodies did not change significantly. B lymphocyte return occurred up to 21 months posttreatment. The time to relapse after B lymphocyte return was often long and unpredictable (range 0-17 months). Relapse was, however, closely correlated with rises in the level of at least one autoantibody. Increased autoantibody levels were rarely observed in the absence of clinical change. CONCLUSION: Following B lymphocyte depletion in patients with RA, a positive clinical response occurred in correlation with a significant drop in the levels of CRP and autoantibodies. Antibacterial antibody levels were relatively well maintained. B lymphocyte return preceded relapse in all patients. There was also a temporal relationship between clinical relapse and rises in autoantibody levels. Although these observations are consistent with a role for B lymphocytes in the pathogenesis of RA, the precise mechanisms involved remain unclear.

Effects of hyperbaric oxygen on recovery from exercise-induced muscle damage in humans.

OBJECTIVE: To determine whether hyperbaric oxygen (HBO) therapy could accelerate recovery from exercise-induced muscle damage in humans. DESIGN: Pretest-posttest design with random assignment to either a treatment (HBO) or placebo control (sham) group. SETTING: University of Alberta and Misericordia Hospital, Edmonton. PARTICIPANTS: 12 healthy male students (24.2 +/- 3.2 years) who were unaccustomed to strenuous eccentric exercise of the calf muscles. INTERVENTIONS: All subjects performed a strenuous eccentric exercise protocol designed to elicit muscle damage within the right gastrocnemius muscle. Subjects subsequently received either HBO (100% oxygen at 253 kPa [2.5 ATA] for 60 min; n = 6) or sham (atmospheric air at 132 kPa [1.3 ATA] for 60 min; n = 6) treatment conditions. The first treatment was administered 3-4 hours after damage, with a second and third at 24 and 48 hours after the first, respectively. MAIN OUTCOME MEASURES: Dependent variables included peak torque at 0.52 radians/s, peak isometric torque, and muscular endurance using isokinetic dynamometry; muscle cross-sectional area using magnetic resonance imaging; inorganic phosphate levels and T2 relaxation time using 31P and 1H magnetic resonance spectroscopy; pain sensation and unpleasantness using the Descriptor Differential Scale. These variables were assessed at baseline and until day 5 postdamage. RESULTS: There was little evidence of a difference in recovery rate between the HBO and sham groups. Faster recovery was observed in the HBO group only for isometric peak torque and pain sensation and unpleasantness. CONCLUSIONS: HBO cannot be recommended as an effective method of treatment of this form of muscle injury.