Unacceptable failures: the final report of the <em>Lancet</em> Commission into liver disease in the UK

This final report of the Lancet Commission into liver disease in the UK stresses the continuing increase in burden of liver disease from excess alcohol consumption and obesity, with high levels of hospital admissions which are worsening in deprived areas. Only with comprehensive food and alcohol strategies based on fiscal and regulatory measures (including a minimum unit price for alcohol, the alcohol duty escalator, and an extension of the sugar levy on food content) can the disease burden be curtailed. Following introduction of minimum unit pricing in Scotland, alcohol sales fell by 3%, with the greatest effect on heavy drinkers of low-cost alcohol products. We also discuss the major contribution of obesity and alcohol to the ten most common cancers as well as measures outlined by the departing Chief Medical Officer to combat rising levels of obesity—the highest of any country in the west. Mortality of severely ill patients with liver disease in district general hospitals is unacceptably high, indicating the need to develop a masterplan for improving hospital care. We propose a plan based around specialist hospital centres that are linked to district general hospitals by operational delivery networks. This plan has received strong backing from the British Association for Study of the Liver and British Society of Gastroenterology, but is held up at NHS England. The value of so-called day-case care bundles to reduce high hospital readmission rates with greater care in the community is described, along with examples of locally derived schemes for the early detection of disease and, in particular, schemes to allow general practitioners to refer patients directly for elastography assessment. New funding arrangements for general practitioners will be required if these proposals are to be taken up more widely around the country. Understanding of the harm to health from lifestyle causes among the general population is low, with a poor knowledge of alcohol consumption and dietary guidelines. The Lancet Commission has serious doubts about whether the initiatives described in the Prevention Green Paper, with the onus placed on the individual based on the use of information technology and the latest in behavioural science, will be effective. We call for greater coordination between official and non-official bodies that have highlighted the unacceptable disease burden from liver disease in England in order to present a single, strong voice to the higher echelons of government

Management of Interests & External Interactions: A SPECTRUM Policy Document

The SPECTRUM Management of Interests and External Interactions document aims to make clear the official position of the Consortium with respect to engagement with external partners particularly where they may constitute, or give rise to, a conflict of interest or present a reputational or other risk to the Consortium. Additionally, it: - clarifies what interests and interactions are covered by the policy, - explains what is meant by conflict of interest, - provides guidance to members on the processes for proactively identifying risks and conflicts in order to prevent them, and how to mitigate and manage them if and when they do arise

Genetic predisposition to in situ and invasive lobular carcinoma of the breast.

Invasive lobular breast cancer (ILC) accounts for 10-15% of all invasive breast carcinomas. It is generally ER positive (ER+) and often associated with lobular carcinoma in situ (LCIS). Genome-wide association studies have identified more than 70 common polymorphisms that predispose to breast cancer, but these studies included predominantly ductal (IDC) carcinomas. To identify novel common polymorphisms that predispose to ILC and LCIS, we pooled data from 6,023 cases (5,622 ILC, 401 pure LCIS) and 34,271 controls from 36 studies genotyped using the iCOGS chip. Six novel SNPs most strongly associated with ILC/LCIS in the pooled analysis were genotyped in a further 516 lobular cases (482 ILC, 36 LCIS) and 1,467 controls. These analyses identified a lobular-specific SNP at 7q34 (rs11977670, OR (95%CI) for ILC = 1.13 (1.09-1.18), P = 6.0 × 10(-10); P-het for ILC vs IDC ER+ tumors = 1.8 × 10(-4)). Of the 75 known breast cancer polymorphisms that were genotyped, 56 were associated with ILC and 15 with LCIS at P<0.05. Two SNPs showed significantly stronger associations for ILC than LCIS (rs2981579/10q26/FGFR2, P-het = 0.04 and rs889312/5q11/MAP3K1, P-het = 0.03); and two showed stronger associations for LCIS than ILC (rs6678914/1q32/LGR6, P-het = 0.001 and rs1752911/6q14, P-het = 0.04). In addition, seven of the 75 known loci showed significant differences between ER+ tumors with IDC and ILC histology, three of these showing stronger associations for ILC (rs11249433/1p11, rs2981579/10q26/FGFR2 and rs10995190/10q21/ZNF365) and four associated only with IDC (5p12/rs10941679; rs2588809/14q24/RAD51L1, rs6472903/8q21 and rs1550623/2q31/CDCA7). In conclusion, we have identified one novel lobular breast cancer specific predisposition polymorphism at 7q34, and shown for the first time that common breast cancer polymorphisms predispose to LCIS. We have shown that many of the ER+ breast cancer predisposition loci also predispose to ILC, although there is some heterogeneity between ER+ lobular and ER+ IDC tumors. These data provide evidence for overlapping, but distinct etiological pathways within ER+ breast cancer between morphological subtypes

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer.

To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC

Detectable clonal mosaicism and its relationship to aging and cancer

In an analysis of 31,717 cancer cases and 26,136 cancer-free controls from 13 genome-wide association studies, we observed large chromosomal abnormalities in a subset of clones in DNA obtained from blood or buccal samples. We observed mosaic abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of >2 Mb in size in autosomes of 517 individuals (0.89%), with abnormal cell proportions of between 7% and 95%. In cancer-free individuals, frequency increased with age, from 0.23% under 50 years to 1.91% between 75 and 79 years (P = 4.8 × 10(-8)). Mosaic abnormalities were more frequent in individuals with solid tumors (0.97% versus 0.74% in cancer-free individuals; odds ratio (OR) = 1.25; P = 0.016), with stronger association with cases who had DNA collected before diagnosis or treatment (OR = 1.45; P = 0.0005). Detectable mosaicism was also more common in individuals for whom DNA was collected at least 1 year before diagnosis with leukemia compared to cancer-free individuals (OR = 35.4; P = 3.8 × 10(-11)). These findings underscore the time-dependent nature of somatic events in the etiology of cancer and potentially other late-onset diseases

Policy Actors' Perceptions of Conflicts of Interest and Alcohol Industry Engagement in UK Policy Processes.

BACKGROUND: Alcohol industry organisations occupy a prominent position in UK alcohol policy, but their involvement has been contested by public health bodies on the basis that a conflict of interest (COI) exists between their economic objectives and those of public health. There are ongoing debates in the research literature about how to conceptualise COI and mitigate this in health research and practise. However, less attention has been paid to these issues in relation to the alcohol industry specifically. This article explores similarities and differences in beliefs among alcohol policy actors regarding COI and the implications of engagement with the alcohol industry in the context of UK public health policy. METHODS: Semi-structured interviews with a range of policy actors (n=26) including medical professionals, parliamentarians, civil servants, academic researchers, health campaigners, and alcohol industry representatives. Interviews with alcohol industry representatives were supplemented with an analysis of industry responses to a public consultation. All data was thematically coded using NVivo software. RESULTS: Two competing "coalitions" were identified, expressing beliefs about COI linked to alcohol industry engagement. Both divergent and convergent beliefs were expressed by the two coalitions in relation to the type of industry actor, form of engagement, the policy issue under discussion and the stage of policy process. CONCLUSION: Alcohol policy is a complex and contested space in which policy actors have differing, nuanced and contingent understandings of COI and identify varying risks associated with alcohol industry engagement. In identifying the areas of convergence and diversion in both understanding and evaluation of COI in alcohol-specific settings, these findings will assist both decision-makers and non-governmental actors in developing policies and guidelines to manage potential COI in future

A comparative study of industry responses to government consultations about alcohol and gambling in the UK

Background: There is growing evidence that common strategies are used across unhealthy commodity industries (UCIs) to influence policy decisions in line with their commercial interests. To date, there have been relatively few studies comparing corporate political activity (CPA) across UCIs, especially comparing the alcohol and gambling industries. Methods: A comparative and inductive thematic analysis of alcohol and gambling industry submissions to two House of Lords (HoL) inquiries in the United Kingdom (UK) was conducted. Themes in the framing, arguments and strategies used by the alcohol and gambling industries in CPA were compared. Results: Alcohol and gambling industry responses largely used the same framings, both in terms of the problems and solutions. This included arguing that harms are only experienced by a ‘minority’ of people, emphasising individual responsibility, and shifting blame for harms to other industry actors. They promoted targeted or localized solutions to these harms, in place of more effective population level solutions, and emphasised the perceived harms of introducing regulation not in the industries’ interests. Conclusions: These findings are consistent with previous literature suggesting that UCIs use the same framing and arguments to shape the narrative around their harms and solutions to those harms. This study also identified novel strategies such as shifting blame of harms to other industry actors. Policy makers should be aware of these strategies to avoid undue industry influence on policy decisions and understanding commonalities in strategies may help to inform more effective public health responses across all UCIs

UK alcohol marketing regulation is failing: a new approach is needed to prioritise protection for all

This commentary about alcohol marketing regulation in the UK draws on a conference held by the Institute of Alcohol Studies, highlighting a need for policy interventions to prevent harm and improve public health. Hazardous and harmful alcohol use is associated with many health conditions, wider social consequences, and harms to others. Following no improvement in alcohol mortality rates in the past decade, 2020 saw alcohol-specific deaths rise to record levels in the UK. Bans or comprehensive restrictions on alcohol advertising across multiple types of media are listed by the World Health Organization (WHO) as one of the ‘best buy’ policies to reduce alcohol harm. The UK’s current complaints-led self-regulatory approach fails to protect consumers and vulnerable groups from being exposed to influential alcohol marketing. There are few meaningful sanctions to deter brands and companies from violating existing codes, processes are retrospective, reactive and slow, and the codes fail in their stated aim of protecting young people. Other important impacts on heavier drinkers and those in recovery, as well as on gender and health equity, are also inadequately addressed. Innovation is also urgently needed to effectively regulate ever-evolving digital alcohol marketing. Addressing these issues through a combination of comprehensive restrictions, content controls, labelling, and replacing self-regulation with an independent body will benefit public health as well as protecting the vulnerable, including heavier drinkers, people in recovery, and children and young people.Output Status: Forthcoming/Available Onlin