Prevention of colorectal cancer in Scotland: strategies for those at increased genetic risk

The identification of people at increased genetic risk of colorectal cancer and the provision of appropriate clinical screening represents one approach to the prevention of colorectal cancer in the Scottish population. This thesis aims to contribute to current knowledge regarding the available tools for identifying those at increased genetic risk in a population, namely genetic testing and family history assessment.Key issues relating to the use of family history in this context were addressed through the analysis of a unique data set, comprising family history information reported by a colorectal cancer case or control subject at interview and the results of record linkage of this data to the Scottish Cancer Registry. Retrospective family history case-control analysis showed that individuals with an affected first-degree relative were at an increased risk of developing colorectal cancer (ORimh 2.14, 95% CI = 1.11, 4.14). Prevalence of such a family history in control subjects was 9.4% (95% CI = 4.9, 13.9). Substantial under-reporting of family history was evident, with sensitivity of interview as a means of determining a history of colorectal cancer in a first-degree relative being approximately 0.55 for both cases and controls. These studies illustrate the potential advantages of targeting people with a family history, but also highlight some of the limitations of such an approach.The genetic epidemiology of the mismatch repair genes hMLH 1 and hMSH2 and their association with colorectal cancer was considered in a systematic literature review. Although conventional epidemiological studies are lacking, there is compelling evidence to implicate mutations in these genes in the aetiology of a sub-set of colorectal cancers, with penetrance of approximately 80% in males and 40% in females. A total of 550 different published gene variants were identified, and this high degree of heterogeneity was illustrated in a unique database. This review indicates that carriers of mismatch repair gene mutations merit particular consideration in the context of colorectal cancer prevention through targeting people at increased genetic risk.Accordingly, the challenge of identifying asymptomatic mismatch repair gene mutation carriers in Scotland was addressed through the development of a computer model of cascade genetic testing, a strategy in which a mutation is identified in one family member and systematically traced through a pedigree. The model predicts that application of cascade genetic testing to colorectal cancer cases < 55 years of age over a twenty- year period would involve testing 7142 patients and 849 relatives of known carriers, and would identify 321.2 (95%CI = 305.3, 337.1) asymptomatic mutation carriers, representing approximately 27% of the estimated 1209 carriers in Scotland. Model outcomes were highly sensitive to the prevalence and penetrance of mutations, and the participation rates of those offered testing. Overall, outcomes from this computer model suggest that cascade genetic testing is potentially a useful means of identifying asymptomatic mismatch repair gene mutation carriers in Scotland. Followup work should ensure that it is also of practical importance as a tool for planning research and health policy.Identification and screening of mismatch repair gene mutation carriers is an important approach to colorectal cancer prevention, but is only relevant to a minority of people at increased genetic risk. Hence, despite inherent limitations, family history remains a crucial tool for genetic risk assessment in a population. An integrated approach to the prevention of colorectal cancer through targeting people at increased genetic risk can potentially provide substantial health benefits to a sub-group of the population, and thus contribute to the overall prevention of colorectal cancer in Scotland

Dataset for the Incorporation of Climate Change into a Multiple Stressor Risk Assessment for the Chinook Salmon (Oncorhynchus tshawytscha) Population in the Yakima River, Washington USA

Data files available below This data set is in support of Landis et al (in press 2024). A key question in understanding the implications of climate change is how to integrate ecological risk assessments that focus on contaminants with the environmental alterations from climate projections. This article summarizes the results of integrating selected direct and indirect effects of climate change into an existing Bayesian network previously used for ecological risk assessment. The existing Bayesian network Relative Risk Model (BN-RRM) integrated the effects of organophosphate pesticides concentrations, water temperature, and dissolved oxygen levels on the Chinook salmon population in the Yakima River Basin, Washington, USA, with the endpoint being no net loss to the population described by a three patch metapopulation age structured model. Climate change-induced changes in water quality parameters (temperature and dissolved oxygen levels) were incorporated into the model based on projected climatic conditions in the 2050s and 2080s. Pesticide concentrations in the original model were modified assuming different bounding scenarios of pest control strategies in the future, as climate change may alter pest numbers and species and thus the required emission of pesticides. Our results suggest that future direct and indirect changes to the Yakima River Basin result in a high probability (62%) that the salmon population will drop below the management goal of no net loss. The key driver in salmon population risk was found to be increases in temperature levels, with pesticide concentrations playing little to no role, as indicated by the sensitivity analysis. However, indirect effects to community structure and dynamics, such as changes in the food web, were not considered. Our study demonstrates the feasibility of incorporating the direct effects of climate change and its indirect effects on chemical emissions into an integrated Bayesian network relative risk framework. It also highlights the value of using Bayesian networks for identifying key drivers of ecological risk and elucidating possible mitigation measures to avoid unacceptable changes in risk. Future research needs are also described for incorporating climate change projections into exposure-driven ecological risk assessments. The Netica file can be opened and read with the free download version of Netica available at https://www.norsys.com/netica.html. The structure of the model and the notes for each node and the conditional probability tables can then be accessed. A licensed version of Netica can run and modify the file

Relief of neuropathic pain through epidermal growth factor receptor inhibition: a randomized proof-of concept trial

Objective. Case reports and a case series have described relief of neuropathic pain (NP) after treatment with epidermal growth factor receptor inhibitors (EGFR-Is). These observations are supported by preclinical findings. The aim of this trial was to explore a potential clinical signal supporting the therapeutic efficacy of EGFR-Is in NP. Methods. In a proof-of-concept trial using a randomized, double-blind, placebo-controlled design, 14 patients with severe, chronic, therapy-resistant NP due to compressed peripheral nerves or complex regional pain syndrome were randomized to receive a single infusion of the EGFR-I cetuximab and placebo in crossover design, followed by a single open-label cetuximab infusion. Results. The mean reduction in daily average pain scores three to seven days after single-blinded cetuximab infusion was 1.73 points (90% confidence interval [CI] = 0.80 to 2.66), conferring a 1.22-point greater reduction than placebo (90% CI = -0.10 to 2.54). Exploratory analyses suggested that pain reduction might be greater in the 14 days after treatment with blinded cetuximab than after placebo. The proportion of patients who reported &gt;= 50% reduction in average pain three to seven days after cetuximab was 36% (14% after placebo), and comparison of overall pain reduction suggests a trend in favor of cetuximab. Skin rash (grade 1-2) was the most frequent side effect (12/14, 86%). Conclusions. This small proof-of-concept evaluation of an EGFR-I against NP did not provide statistical evidence of efficacy. However, substantial reductions in pain were reported, and confidence intervals do not rule out a clinically meaningful treatment effect. Evaluation of EGFR-I against NP therefore warrants further investigation.</p

Informing investment to reduce inequalities: a modelling approach

Background: Reducing health inequalities is an important policy objective but there is limited quantitative information about the impact of specific interventions. Objectives: To provide estimates of the impact of a range of interventions on health and health inequalities. Materials and methods: Literature reviews were conducted to identify the best evidence linking interventions to mortality and hospital admissions. We examined interventions across the determinants of health: a ‘living wage’; changes to benefits, taxation and employment; active travel; tobacco taxation; smoking cessation, alcohol brief interventions, and weight management services. A model was developed to estimate mortality and years of life lost (YLL) in intervention and comparison populations over a 20-year time period following interventions delivered only in the first year. We estimated changes in inequalities using the relative index of inequality (RII). Results: Introduction of a ‘living wage’ generated the largest beneficial health impact, with modest reductions in health inequalities. Benefits increases had modest positive impacts on health and health inequalities. Income tax increases had negative impacts on population health but reduced inequalities, while council tax increases worsened both health and health inequalities. Active travel increases had minimally positive effects on population health but widened health inequalities. Increases in employment reduced inequalities only when targeted to the most deprived groups. Tobacco taxation had modestly positive impacts on health but little impact on health inequalities. Alcohol brief interventions had modestly positive impacts on health and health inequalities only when strongly socially targeted, while smoking cessation and weight-reduction programmes had minimal impacts on health and health inequalities even when socially targeted. Conclusions: Interventions have markedly different effects on mortality, hospitalisations and inequalities. The most effective (and likely cost-effective) interventions for reducing inequalities were regulatory and tax options. Interventions focused on individual agency were much less likely to impact on inequalities, even when targeted at the most deprived communities

The Bristol CMIP6 Data Hackathon

The Bristol CMIP6 Data Hackathon formed part of the Met Office Climate Data Challenge Hackathon series during 2021, bringing together around 100 UK early career researchers from a wide range of environmental disciplines. The purpose was to interrogate the under-utilised but currently most advanced climate model inter-comparison project datasets to develop new research ideas, create new networks and outreach opportunities in the lead up to COP26. Experts in different science fields, supported by a core team of scientists and data specialists at Bristol, had the unique opportunity to explore together interdisciplinary environmental topics summarised in this article