A data-driven approach to multiple-stressor impact assessment for a marine protected area.

The coastal environment is not managed in a way that considers the impact of cumulative threats, despite being subject to threats from all realms (marine, land, and atmosphere). Relationships between threats and species are often nonlinear; thus, current (linear) approaches to estimating the impact of threats may be misleading. We developed a data-driven approach to assessing cumulative impacts on ecosystems and applied it to explore nonlinear relationships between threats and a temperate reef fish community. We used data on water quality, commercial fishing, climate change, and indicators of recreational fishing and urbanization to build a cumulative threat map of the northern region in New South Wales, Australia. We used statistical models of fish abundance to quantify associations among threats and biophysical covariates and predicted where cumulative impacts are likely to have the greatest impact on fish. We also assessed the performance of no-take zones (NTZs), to protect fish from cumulative threats across 2 marine protected area networks (marine parks). Fishing had a greater impact on fish than water quality threats (i.e., percent increase above the mean for invertivores was 337% when fishing was removed and was 11% above the mean when water quality was removed inside NTZs), and fishing outside NTZs affected fish abundances inside NTZs. Quantifying the spatial influence of multiple threats enables managers to understand the multitude of management actions required to address threats.

Una estrategia basada en datos para la evaluación de impacto de múltiples estresores en un área marina protegida Resumen Los ambientes costeros no se manejan de manera que se considere el impacto de las amenazas acumulativas, a pesar de que se enfrentan a amenazas de todos los entornos (marinas, terrestres y atmosféricas). Las relaciones entre las amenazas y las especies casi siempre son no lineales; por lo tanto, las estrategias actuales (lineales) para estimar el impacto de las amenazas pueden ser engañosas. Desarrollamos una estrategia basada en datos para evaluar el impacto acumulativo sobre los ecosistemas y la aplicamos para explorar las relaciones no lineales entre las amenazas y la comunidad de peces de arrecifes templados. Usamos datos de la calidad del agua, pesca comercial, cambio climático e indicadores de pesca recreativa y urbanización para construir un mapa acumulativo de amenazas de la región norte de Nueva Gales del Sur, Australia. Usamos modelos estadísticos de la abundancia de peces para cuantificar las asociaciones entre las amenazas y las covarianzas biofísicas y pronosticamos en dónde es probable que los impactos acumulativos sean mayores sobre los peces. También evaluamos el desempeño de las zonas de veda para así proteger a los peces de las amenazas acumulativas en dos redes de áreas marinas protegidas (parques marinos). La pesca tuvo un mayor impacto que la calidad del agua sobre los peces (es decir, el incremento del porcentaje por encima de la media de depredadores de invertebrados fue de 337% cuando se eliminó la pesca y fue de 11% por encima de la media cuando se eliminó la calidad del agua dentro de las zonas de veda) y la pesca fuera de las zonas de veda afectó la abundancia de los peces dentro de ellas. La cuantificación de la influencia espacial de las múltiples amenazas permite que los gestores entiendan la multitud de acciones de manejo que se requieren para abordar las amenazas.

The UK-PBC risk scores: Derivation and validation of a scoring system for long-term prediction of end-stage liver disease in primary biliary cholangitis.

UNLABELLED: The biochemical response to ursodeoxycholic acid (UDCA)--so-called "treatment response"--strongly predicts long-term outcome in primary biliary cholangitis (PBC). Several long-term prognostic models based solely on the treatment response have been developed that are widely used to risk stratify PBC patients and guide their management. However, they do not take other prognostic variables into account, such as the stage of the liver disease. We sought to improve existing long-term prognostic models of PBC using data from the UK-PBC Research Cohort. We performed Cox's proportional hazards regression analysis of diverse explanatory variables in a derivation cohort of 1,916 UDCA-treated participants. We used nonautomatic backward selection to derive the best-fitting Cox model, from which we derived a multivariable fractional polynomial model. We combined linear predictors and baseline survivor functions in equations to score the risk of a liver transplant or liver-related death occurring within 5, 10, or 15 years. We validated these risk scores in an independent cohort of 1,249 UDCA-treated participants. The best-fitting model consisted of the baseline albumin and platelet count, as well as the bilirubin, transaminases, and alkaline phosphatase, after 12 months of UDCA. In the validation cohort, the 5-, 10-, and 15-year risk scores were highly accurate (areas under the curve: >0.90). CONCLUSIONS: The prognosis of PBC patients can be accurately evaluated using the UK-PBC risk scores. They may be used to identify high-risk patients for closer monitoring and second-line therapies, as well as low-risk patients who could potentially be followed up in primary care.

The new epidemiology of primary biliary cirrhosis.

Primary biliary cirrhosis (PBC) is an autoimmune cholestatic liver disease. Susceptibility to PBC probably arises from a combination of genetic and environmental factors. The prevalence of PBC varies both on an international and a regional level. This can be explained, in part, by differences in clinical practice and case-finding activity. It is likely, however, that substantive geographical differences exist both in terms of genetic susceptibility and environmental factors that potentially trigger the disease in genetically susceptible individuals. The study of the epidemiology of PBC has strongly supported the concept of an environmental triggering factor, but as yet no specific agent has been identified. Ongoing work to discover the environmental agent, as well as the mechanism that causes the disease will answer key questions as to the epidemiology of this complex autoimmune disease as well as providing useful information for other autoimmune conditions.

Pathogenesis of primary biliary cirrhosis and its fatigue.

Primary biliary cirrhosis (PBC) is an autoimmune cholestatic liver disease characterised by a breakdown of immune tolerance to mitochondrial and nuclear antigens, causing injury to the biliary epithelial cells (BEC) lining the small intrahepatic bile ducts. This leads to bile duct injury and the retention of hydrophobic bile acids which cause further BEC injury leading to a self-sustaining cycle of bile duct injury. Initially the BEC respond to injury via a homeostatic response including through proliferation. Ultimately they become senescent; an active process with accompanying release of inflammatory cytokines ('the senescent secretome') which contributes to the process of interface hepatitis which is a feature of high-risk and treatment-unresponsive disease. This model for pathogenesis of PBC has implications for potential therapy approaches in targeting both the 'upstream' immune injury and 'downstream' BEC response to the immune injury. Fatigue is the commonest reported symptom in PBC and has a negative impact on patients' perceived quality of life, often through social isolation. It is unrelated to the severity of liver disease and appears unresponsive to current therapies, including ursodeoxycholic acid and transplantation. Fatigue in PBC is complex, with numerous associated peripheral and CNS features. Initially, cholestasis causes degenerative CNS change affecting areas of the brain regulating autonomic dysfunction and sleep, and these changes lead directly to some manifestations of fatigue and the associated cognitive impairment. In addition to this, the anti-mitochondrial antibody has direct muscle level metabolic effects leading to over-utilisation of anaerobic metabolism. Autonomic dysfunction contributes to the impact of this metabolic change by limiting the capacity of the muscle to respond through increased proton/lactate efflux from cells and outflow from tissues. The model has a number of implications for potential therapy approaches.

The effect of liver transplantation on fatigue in patients with primary biliary cirrhosis: a prospective study.

BACKGROUND & AIMS: The role of liver transplantation (LT) for the relief of fatigue in patients with primary biliary cirrhosis (PBC) is unclear, and while many centers exclude fatigue as an indication for transplantation, there have been no studies to prospectively evaluate the impact of LT on fatigue. We aimed at assessing the severity of fatigue in LT candidates with PBC and the impact of LT on fatigue. METHODS: In a prospective, longitudinal study, we used the PBC-40 questionnaire in 49 adult patients with PBC at listing and at 6, 12, and 24 months after LT and in two sex- and age-matched cohorts of community controls and non-transplanted PBC patients. Correlation analysis was used to assess the relationship between liver function and fatigue. ANOVA was used to compare the variation of fatigue score before and after LT. RESULTS: There was no correlation between MELD and fatigue before LT (r(2)=0.01). Overall, the fatigue score after LT was substantially lower than before LT, falling from 40.7 ± 11.4 pre-transplant to 27.7 ± 9.5, 28.7 ± 10.1, 26.2 ± 10.1 (p<0.0001) at 6, 12, and 24 months after LT, respectively. The same improvement of fatigue was observed in both low-MELD (<17) and high-MELD (≥ 17) patients. Improvement in fatigue was also evident in the comparison with a "non-transplant PBC" control group (31.1 ± 11.6, p=0.03). However, 44% of the total cohort, and 47% of those with low-MELD, for whom the probability of dying of LT may be higher than that of dying without LT, had moderate to severe fatigue (defined as a fatigue score ≥ 29) at two years after LT. Moreover, fatigue scores at two years were higher in the transplant PBC cohort compared to a cohort of community controls (17.8 ± 5.9, p<0.0001). CONCLUSIONS: Liver transplantation is associated with improvement in fatigue in patients with PBC. However, a substantial proportion of patients continue to suffer from significant fatigue after two years. Whether the improvement is enough to justify organ allocation in patients with fatigue alone, without liver failure, is still an open issue. Certainly, in the era of organ shortage, with many patients dying waiting for a graft, this may not represent the optimal use of donated deceased organs.

The effect of time spent in treatment and dropout status on rates of convictions, cautions and imprisonment over 5 years in a primary care-led methadone maintenance service.

BACKGROUND: Methadone maintenance treatment (MMT) in primary care settings is used increasingly as a standard method of delivering treatment for heroin users. It has been shown to reduce criminal activity and incarceration over periods of periods of 12 months or less; however, little is known about the effect of this treatment over longer durations. AIMS: To examine the association between treatment status and rates of convictions and cautions (judicial disposals) over a 5-year period in a cohort of heroin users treated in a general practitioner (GP)-led MMT service. DESIGN: Cohort study. SETTING: The primary care clinic for drug dependence, Sheffield, 1999-2005. PARTICIPANTS: The cohort comprised 108 consecutive patients who were eligible and entered treatment. Ninety were followed-up for the full 5 years. INTERVENTION: The intervention consisted of MMT provided by GPs in a primary care clinic setting. MEASUREMENTS: Criminal conviction and caution rates and time spent in prison, derived from Police National Computer (PNC) criminal records. FINDINGS: The overall reduction in the number of convictions and cautions expected for patients entering MMT in similar primary care settings is 10% for each 6 months retained in treatment. Patients in continuous treatment had the greatest reduction in judicial disposal rates, similar to those who were discharged for positive reasons (e.g. drug free). Patients who had more than one treatment episode over the observation period did no better than those who dropped out of treatment. CONCLUSIONS: MMT delivered in a primary care clinic setting is effective in reducing convictions and cautions and incarceration over an extended period. Continuous treatment is associated with the greatest reductions.

First-perspective spatial alignment effects from real-world exploration.

When spatial knowledge is acquired from secondary-learning media, such as text, people sometimes remember a route in alignment with the first perspective or first direction of travel. However, this first-perspective alignment (FPA) effect has been found only under special circumstances from primary real-world exploration. In Experiment 1, recall of an enclosed small-scale, U-shaped route was compared following learning from a verbal description, a video recording, or real-world exploration; an FPA effect was found in all cases. In Experiments 2 and 3, exploration of physically larger real routes led to statistically significant evidence of an FPA effect when the route was enclosed, but not when cues external to the route were available. The data are discussed in relation to current theories of spatial reference frames.