Study protocol for POSITIF, a randomised multicentre feasibility trial of a brief cognitive-behavioural intervention plus information versus information alone for the treatment of post-stroke fatigue

© 2020 The Author(s). Background: Approximately, half of stroke survivors experience fatigue. Fatigue may persist for many months and interferes with participation in everyday activities and has a negative impact on social and family relationships, return to work, and quality of life. Fatigue is among the top 10 priorities for 'Life after Stroke' research for stroke survivors, carers, and clinicians. We previously developed and tested in a small uncontrolled pilot study a manualised, clinical psychologist-delivered, face-to-face intervention, informed by cognitive behavioural therapy (CBT). We then adapted it for delivery by trained therapists via telephone. We now aim to test the feasibility of this approach in a parallel group, randomised controlled feasibility trial (Post Stroke Intervention Trial In Fatigue, POSITIF). Methods/design: POSITIF aims to recruit 75 stroke survivors between 3 months and 2 years post-stroke who would like treatment for their fatigue. Eligible consenting stroke survivors will be randomised to either a 7-session manualised telephone-delivered intervention based on CBT principles plus information about fatigue, or information only. The aims of the intervention are to (i) provide an explanation for post-stroke fatigue, in particular that it is potentially reversible (an educational approach), (ii) encourage participants to overcome the fear of taking physical activity and challenge negative thinking (a cognitive approach) and (iii) promote a balance between daily activities, rest and sleep and then gradually increase levels of physical activity (a behavioural approach). Fatigue, mood, quality of life, return to work and putative mediators will be assessed at baseline (just before randomisation), at the end of treatment and 6 months after randomisation. POSITIF will determine the feasibility of recruitment, adherence to the intervention and the resources required to deliver the intervention in a larger trial. Discussion: The POSITIF feasibility trial will recruit until 31 January 2020. Data will inform the utility and design of a future adequately powered randomised controlled trial. Trial registration: ClinicalTrials.gov, NCT03551327. Registered on 11 June 2018

Establishing a colorectal cancer research database from routinely collected health data: the process and potential from a pilot study.

OBJECTIVE: Colorectal cancer is a common cause of death and morbidity. A significant amount of data are routinely collected during patient treatment, but they are not generally available for research. The National Institute for Health Research Health Informatics Collaborative in the UK is developing infrastructure to enable routinely collected data to be used for collaborative, cross-centre research. This paper presents an overview of the process for collating colorectal cancer data and explores the potential of using this data source. METHODS: Clinical data were collected from three pilot Trusts, standardised and collated. Not all data were collected in a readily extractable format for research. Natural language processing (NLP) was used to extract relevant information from pseudonymised imaging and histopathology reports. Combining data from many sources allowed reconstruction of longitudinal histories for each patient that could be presented graphically. RESULTS: Three pilot Trusts submitted data, covering 12 903 patients with a diagnosis of colorectal cancer since 2012, with NLP implemented for 4150 patients. Timelines showing individual patient longitudinal history can be grouped into common treatment patterns, visually presenting clusters and outliers for analysis. Difficulties and gaps in data sources have been identified and addressed. DISCUSSION: Algorithms for analysing routinely collected data from a wide range of sites and sources have been developed and refined to provide a rich data set that will be used to better understand the natural history, treatment variation and optimal management of colorectal cancer. CONCLUSION: The data set has great potential to facilitate research into colorectal cancer

TLR9 polymorphisms in African populations: no association with severe malaria, but evidence of cis-variants acting on gene expression

BACKGROUND: During malaria infection the Toll-like receptor 9 (TLR9) is activated through induction with plasmodium DNA or another malaria motif not yet identified. Although TLR9 activation by malaria parasites is well reported, the implication to the susceptibility to severe malaria is not clear. The aim of this study was to assess the contribution of genetic variation at TLR9 to severe malaria. METHODS: This study explores the contribution of TLR9 genetic variants to severe malaria using two approaches. First, an association study of four common single nucleotide polymorphisms was performed on both family- and population-based studies from Malawian and Gambian populations (n>6000 individual). Subsequently, it was assessed whether TLR9 expression is affected by cis-acting variants and if these variants could be mapped. For this work, an allele specific expression (ASE) assay on a panel of HapMap cell lines was carried out. RESULTS: No convincing association was found with polymorphisms in TLR9 for malaria severity, in either Gambian or Malawian populations, using both case-control and family based study designs. Using an allele specific expression assay it was observed that TLR9 expression is affected by cis-acting variants, these results were replicated in a second experiment using biological replicates. CONCLUSION: By using the largest cohorts analysed to date, as well as a standardized phenotype definition and study design, no association of TLR9 genetic variants with severe malaria was found. This analysis considered all common variants in the region, but it is remains possible that there are rare variants with association signals. This report also shows that TLR9 expression is potentially modulated through cis-regulatory variants, which may lead to differential inflammatory responses to infection between individuals

Pleiotropy of genetic variants on obesity and smoking phenotypes: Results from the Oncoarray Project of The International Lung Cancer Consortium

Obesity and cigarette smoking are correlated through complex relationships. Common genetic causes may contribute to these correlations. In this study, we selected 241 loci potentially associated with body mass index (BMI) based on the Genetic Investigation of ANthropometric Traits (GIANT) consortium data and calculated a BMI genetic risk score (BMI-GRS) for 17,037 individuals of European descent from the Oncoarray Project of the International Lung Cancer Consortium (ILCCO). Smokers had a significantly higher BMI-GRS than never-smokers (p = 0.016 and 0.010 before and after adjustment for BMI, respectively). The BMI-GRS was also positively correlated with pack-years of smoking (p<0.001) in smokers. Based on causal network inference analyses, seven and five of 241 SNPs were classified to pleiotropic models for BMI/smoking status and BMI/pack-years, respectively. Among them, three and four SNPs associated with smoking status and pack-years (p<0.05), respectively, were followed up in the ever-smoking data of the Tobacco, Alcohol and Genetics (TAG) consortium. Among these seven candidate SNPs, one SNP (rs11030104, BDNF) achieved statistical significance after Bonferroni correction for multiple testing, and three suggestive SNPs (rs13021737, TMEM18; rs11583200, ELAVL4; and rs6990042, SGCZ) achieved a nominal statistical significance. Our results suggest that there is a common genetic component between BMI and smoking, and pleiotropy analysis can be useful to identify novel genetic loci of complex phenotypes

Association between the BRCA2 N372H variant and male breast cancer risk: a population-based case-control study in Tuscany, Central Italy

Background: Male breast cancer (MBC) is a rare disease and little is known about its aetiology. Germline mutations of BRCA2 and, at lower frequency, of BRCA1 are implicated in a relatively small proportion of MBC cases. Common polymorphic variants in BRCA1 and BRCA2 genes may represent breast cancer (BC) susceptibility alleles and could be associated with a modestly increased risk of MBC at population level. Considering the relevant role of BRCA2 in MBC, we investigated whether the BRCA2 N372H variant, representing the only common non-synonymous polymorphism in BRCA2, might modulate the risk of BC in male populations.Methods: A case-control study was performed comparing a population-based series of 99 MBC cases, characterized for BRCA1 and BRCA2 mutations, with 261 male population controls, all residing in Tuscany, Central Italy. All MBC cases and controls were genotyped for the BRCA2 N372H allele by TaqMan allelic discrimination assays. To evaluate the genotype specific risk of the BRCA2 N372H variant, MBC carriers of germ-line BRCA1/2 mutations were excluded from the analyses.Results: No association emerged in univariate and age-adjusted analyses. Age-specific analyses suggested an increased risk for the HH homozygous genotype in subjects younger than 60 years. A statistically significant interaction emerged between this genotype and age (p = 0.032). When analyses were restricted to MBC cases enrolled in the first 4 years following diagnosis, a recessive model showed a significantly increased risk of MBC in HH subjects younger than 60 years (OR = 5.63; 95% CI = 1.70; 18.61).Conclusion: Overall, our findings, although based on a relatively small series, suggest that the BRCA2 HH homozygous genotype might be positively associated with an increased risk of MBC in men younger than 60 years

Genetic modifiers of radon-induced lung cancer risk: a genome-wide interaction study in former uranium miners

PURPOSE: Radon is a risk factor for lung cancer and uranium miners are more exposed than the general population. A genome-wide interaction analysis was carried out to identify genomic loci, genes or gene sets that modify the susceptibility to lung cancer given occupational exposure to the radioactive gas radon. METHODS: Samples from 28 studies provided by the International Lung Cancer Consortium were pooled with samples of former uranium miners collected by the German Federal Office of Radiation Protection. In total, 15,077 cases and 13,522 controls, all of European ancestries, comprising 463 uranium miners were compared. The DNA of all participants was genotyped with the OncoArray. We fitted single-marker and in multi-marker models and performed an exploratory gene-set analysis to detect cumulative enrichment of significance in sets of genes. RESULTS: We discovered a genome-wide significant interaction of the marker rs12440014 within the gene CHRNB4 (OR = 0.26, 95% CI 0.11-0.60, p = 0.0386 corrected for multiple testing). At least suggestive significant interaction of linkage disequilibrium blocks was observed at the chromosomal regions 18q21.23 (p = 1.2 × 10-6), 5q23.2 (p = 2.5 × 10-6), 1q21.3 (p = 3.2 × 10-6), 10p13 (p = 1.3 × 10-5) and 12p12.1 (p = 7.1 × 10-5). Genes belonging to the Gene Ontology term "DNA dealkylation involved in DNA repair" (GO:0006307; p = 0.0139) or the gene family HGNC:476 "microRNAs" (p = 0.0159) were enriched with LD-blockwise significance. CONCLUSION: The well-established association of the genomic region 15q25 to lung cancer might be influenced by exposure to radon among uranium miners. Furthermore, lung cancer susceptibility is related to the functional capability of DNA damage signaling via ubiquitination processes and repair of radiation-induced double-strand breaks by the single-strand annealing mechanism

The genetics of myopia

Myopia is the most common eye condition worldwide and its prevalence is increasing. While changes in environment, such as time spent outdoors, have driven myopia rates, within populations myopia is highly heritable. Genes are estimated to explain up to 80% of the variance in refractive error. Initial attempts to identify myopia genes relied on family studies using linkage analysis or candidate gene approaches with limited progress. More genome-wide association study (GWAS) approaches have taken over, ultimately resulting in the identification of hundreds of genes for refractive error and myopia, providing new insights into its molecular machinery. These studies showed myopia is a complex trait, with many genetic variants of small effect influencing retinal signaling, eye growth and the normal process of emmetropization. The genetic architecture and its molecular mechanisms are still to be clarified and while genetic risk score prediction models are improving, this knowledge must be expanded to have impact on clinical practice

Towards 'Engagement 2.0': Insights from a study of dynamic consent with biobank participants

Web 2.0 technologies have enabled new methods of engagement, moving from static mono-directional sources of information to interactive user-led experiences. Use of Web 2.0 technologies for engagement is gaining momentum within the health sector however this is still in its infancy in biobanking research. This paper reports on findings from focus groups with biobank participants to gauge their views on a Web 2.0 dynamic consent interface. The findings from this study suggest that participants would welcome more interactive engagement with biobanks, and the opportunity to hear more about how their data and samples are being used in research. We propose that by adopting Web 2.0 tools for dynamic consent, we can move towards an ‘Engagement 2.0’ model whereby research participants have the opportunity for more interactive engagement with medical research, setting up a two-way communication channel between participants and researchers, for the benefit of both