• Relationship of alcohol intake and sex steroid concentrations in blood in pre- and post-menopausal women: the European Prospective Investigation into Cancer and Nutrition.

    30 March 2018

    OBJECTIVE: Women with a moderate intake of alcohol have higher concentrations of sex steroids in serum, and higher risk of developing breast cancer, compared to non-drinkers. In the present study, we investigate the relationships between alcohol consumption and serum levels of sex steroids and sex-hormone binding globulin (SHBG) in 790 pre- and 1,291 post-menopausal women, who were part of the European Prospective Investigation into Cancer and Nutrition (EPIC). METHODS: Serum levels of testosterone (T), androstenedione (Delta4), dehydroepiandrosterone sulphate (DHEAS), estrone (E1), estradiol (E2) and SHBG were measured by direct immunoassays. Free T (fT) and free E2 (fE2) were calculated according to mass action laws. Current alcohol intake exposure to alcohol was assessed from dietary questionnaires. RESULTS: Pre-menopausal women who consumed more than 25 g/day of alcohol had about 30% higher DHEAS, T and fT, 20% higher Delta4 and about 40% higher E1, concentrations compared to women who were non-consumers. E2, fE2 and SHBG concentrations showed no association with current alcohol intake. In post-menopausal women, DHEAS, fT, T, Delta4, and E1 concentrations were between 10% and 20% higher in women who consumed more than 25 g/day of alcohol compared to non-consumers. E2 or fE2 were not associated with alcohol intake at all. SHBG levels were about 15% lower in alcohol consumers compared to non-consumers. CONCLUSION: This study supports the hypothesis of an influence of alcohol intake on sex hormone concentrations in blood.

  • Diabetes and the risk of non-Hodgkin's lymphoma and multiple myeloma in the European Prospective Investigation into Cancer and Nutrition.

    6 March 2018

    BACKGROUND: Non-Hodgkin's lymphomas are a heterogeneous group of neoplasms arising from the lymphopoietic system including a wide range of subtypes of either B-cell or T-cell lymphomas. The few established risk factors for the development of these neoplasms include viral infections and immunological abnormalities, but their etiology remains largely unknown. Evidence suggests that certain medical conditions may be linked, through immunosuppression, to the risk of non-Hodgkin's lymphoma. Multiple myeloma is a neoplasm of plasma cells that accounts for approximately 15% of lymphopoietic cancers. Increases in the incidence of non-Hodgkin's lymphoma and multiple myeloma in the past implicate environmental factors as potential causal agents. DESIGN AND METHODS: In the European Prospective Investigation into Cancer and Nutrition (EPIC), 1,213 histologically confirmed incident cases of non-Hodgkin's lymphoma and multiple myeloma (594 men; 619 women) were identified during a follow-up of 8.5 years. Cox proportional hazard models were used to explore the association between self-reported diabetes, diagnosed after 30 years of age, and the risk of non-Hodgkin's lymphoma overall and multiple myeloma and various lymphoma subtypes. RESULTS: We found no association between a personal history of diabetes and the risk of non-Hodgkin's lymphoma overall in men (HR: 1.28, 95% CI: 0.89-1.84), in women (HR: 0.71, 95% CI: 0.41- 1.24), or in men and women combined (HR: 1.09, 95% CI: 0.80-1.47). Among the B-non-Hodgkin's lymphoma subtypes, we observed a statistically significant increased risk of B-cell chronic lymphocytic leukemia (HR: 2.0, 95% CI: 1.04-3.86) in men, but not in women (HR: 1.07, 95% CI: 0.33-3.43). CONCLUSIONS: This prospective study did not provide evidence for a role of self-reported diabetes in the etiology of non-Hodgkin's lymphoma overall or multiple myeloma. We found an increased risk of B-cell chronic lymphocytic leukemia among men with diabetes, but not among women. We hypothesize that diabetes may not play a causal role in the etiology of B-cell chronic lymphocytic leukemia, though the underlying pathogenic mechanisms of both disorders may include shared genetic, host and/or environmental susceptibility factors.

  • Fruit and vegetable consumption and lymphoma risk in the European Prospective Investigation into Cancer and Nutrition (EPIC).

    16 March 2018

    INTRODUCTION: Lymphomas are a heterogeneous group of malignant diseases of cells of the immune system. The best-established risk factors are related to dys-regulation of immune function, and evidence suggests that factors such as dietary or lifestyle habits may be involved in the etiology. MATERIAL AND METHODS: In the European Prospective Investigation into Cancer and Nutrition (EPIC), 849 lymphoma cases were identified in a median follow-up period of 6.4 years. Fruit and vegetable consumption was estimated from validated dietary questionnaires. Cox proportional hazard models were used to examine the association between fruit and vegetable intake with the risk of lymphomas overall and subentities. RESULTS: There was no overall association between total fruit and vegetable consumption and risk of lymphoma [hazard ratio (HR)=0.95, 95% confidence interval (CI) 0.78-1.15 comparing highest with lowest quartile]. However, the risk of diffuse large B-cell lymphomas (DLBCL) tended to be lower in participants with a high intake of total vegetables (HR=0.49, 95% CI 0.23-1.02). CONCLUSION: In this large prospective study, an inverse associations between fruit and vegetable consumption and risk of lymphomas overall could not be confirmed. Associations with lymphoma subentities such as DLBCL warrant further investigation.

  • Multimodal surface matching with higher-order smoothness constraints.

    3 April 2018

    In brain imaging, accurate alignment of cortical surfaces is fundamental to the statistical sensitivity and spatial localisation of group studies, and cortical surface-based alignment has generally been accepted to be superior to volume-based approaches at aligning cortical areas. However, human subjects have considerable variation in cortical folding, and in the location of functional areas relative to these folds. This makes alignment of cortical areas a challenging problem. The Multimodal Surface Matching (MSM) tool is a flexible, spherical registration approach that enables accurate registration of surfaces based on a variety of different features. Using MSM, we have previously shown that driving cross-subject surface alignment, using areal features, such as resting state-networks and myelin maps, improves group task fMRI statistics and map sharpness. However, the initial implementation of MSM's regularisation function did not penalize all forms of surface distortion evenly. In some cases, this allowed peak distortions to exceed neurobiologically plausible limits, unless regularisation strength was increased to a level which prevented the algorithm from fully maximizing surface alignment. Here we propose and implement a new regularisation penalty, derived from physically relevant equations of strain (deformation) energy, and demonstrate that its use leads to improved and more robust alignment of multimodal imaging data. In addition, since spherical warps incorporate projection distortions that are unavoidable when mapping from a convoluted cortical surface to the sphere, we also propose constraints that enforce smooth deformation of cortical anatomies. We test the impact of this approach for longitudinal modelling of cortical development for neonates (born between 31 and 43 weeks of post-menstrual age) and demonstrate that the proposed method increases the biological interpretability of the distortion fields and improves the statistical significance of population-based analysis relative to other spherical methods.

  • Image processing and Quality Control for the first 10,000 brain imaging datasets from UK Biobank.

    3 April 2018

    UK Biobank is a large-scale prospective epidemiological study with all data accessible to researchers worldwide. It is currently in the process of bringing back 100,000 of the original participants for brain, heart and body MRI, carotid ultrasound and low-dose bone/fat x-ray. The brain imaging component covers 6 modalities (T1, T2 FLAIR, susceptibility weighted MRI, Resting fMRI, Task fMRI and Diffusion MRI). Raw and processed data from the first 10,000 imaged subjects has recently been released for general research access. To help convert this data into useful summary information we have developed an automated processing and QC (Quality Control) pipeline that is available for use by other researchers. In this paper we describe the pipeline in detail, following a brief overview of UK Biobank brain imaging and the acquisition protocol. We also describe several quantitative investigations carried out as part of the development of both the imaging protocol and the processing pipeline.

  • Mapping land cover change over continental Africa using Landsat and Google Earth Engine cloud computing.

    3 April 2018

    Quantifying and monitoring the spatial and temporal dynamics of the global land cover is critical for better understanding many of the Earth's land surface processes. However, the lack of regularly updated, continental-scale, and high spatial resolution (30 m) land cover data limit our ability to better understand the spatial extent and the temporal dynamics of land surface changes. Despite the free availability of high spatial resolution Landsat satellite data, continental-scale land cover mapping using high resolution Landsat satellite data was not feasible until now due to the need for high-performance computing to store, process, and analyze this large volume of high resolution satellite data. In this study, we present an approach to quantify continental land cover and impervious surface changes over a long period of time (15 years) using high resolution Landsat satellite observations and Google Earth Engine cloud computing platform. The approach applied here to overcome the computational challenges of handling big earth observation data by using cloud computing can help scientists and practitioners who lack high-performance computational resources.

  • A cluster randomised trial, cost-effectiveness analysis and psychosocial evaluation of insulin pump therapy compared with multiple injections during flexible intensive insulin therapy for type 1 diabetes: the REPOSE Trial.

    16 March 2018

    BACKGROUND: Insulin is generally administered to people with type 1 diabetes mellitus (T1DM) using multiple daily injections (MDIs), but can also be delivered using infusion pumps. In the UK, pumps are recommended for patients with the greatest need and adult use is less than in comparable countries. Previous trials have been small, of short duration and have failed to control for training in insulin adjustment. OBJECTIVE: To assess the clinical effectiveness and cost-effectiveness of pump therapy compared with MDI for adults with T1DM, with both groups receiving equivalent structured training in flexible insulin therapy. DESIGN: Pragmatic, multicentre, open-label, parallel-group cluster randomised controlled trial, including economic and psychosocial evaluations. After participants were assigned a group training course, courses were randomly allocated in pairs to either pump or MDI. SETTING: Eight secondary care diabetes centres in the UK. PARTICIPANTS: Adults with T1DM for > 12 months, willing to undertake intensive insulin therapy, with no preference for pump or MDI, or a clinical indication for pumps. INTERVENTIONS: Pump or MDI structured training in flexible insulin therapy, followed up for 2 years. MDI participants used insulin analogues. Pump participants used a Medtronic Paradigm(®) Veo(TM) (Medtronic, Watford, UK) with insulin aspart (NovoRapid, Novo Nordisk, Gatwick, UK). MAIN OUTCOME MEASURES: Primary outcome - change in glycated haemoglobin (HbA1c) at 2 years in participants whose baseline HbA1c was ≥ 7.5% (58 mmol/mol). Key secondary outcome - proportion of participants with HbA1c ≤ 7.5% at 2 years. Other outcomes at 6, 12 and 24 months - moderate and severe hypoglycaemia; insulin dose; body weight; proteinuria; diabetic ketoacidosis; quality of life (QoL); fear of hypoglycaemia; treatment satisfaction; emotional well-being; qualitative interviews with participants and staff (2 weeks), and participants (6 months); and ICERs in trial and modelled estimates of cost-effectiveness. RESULTS: We randomised 46 courses comprising 317 participants: 267 attended a Dose Adjustment For Normal Eating course (132 pump; 135 MDI); 260 were included in the intention-to-treat analysis, of which 235 (119 pump; 116 MDI) had baseline HbA1c of ≥ 7.5%. HbA1c and severe hypoglycaemia improved in both groups. The drop in HbA1c% at 2 years was 0.85 on pump and 0.42 on MDI. The mean difference (MD) in HbA1c change at 2 years, at which the baseline HbA1c was ≥ 7.5%, was -0.24% [95% confidence interval (CI) -0.53% to 0.05%] in favour of the pump (p = 0.098). The per-protocol analysis showed a MD in change of -0.36% (95% CI -0.64% to -0.07%) favouring pumps (p = 0.015). Pumps were not cost-effective in the base case and all of the sensitivity analyses. The pump group had greater improvement in diabetes-specific QoL diet restrictions, daily hassle plus treatment satisfaction, statistically significant at 12 and 24 months and supported by qualitative interviews. LIMITATION: Blinding of pump therapy was not possible, although an objective primary outcome was used. CONCLUSION: Adding pump therapy to structured training in flexible insulin therapy did not significantly enhance glycaemic control or psychosocial outcomes in adults with T1DM. RESEARCH PRIORITY: To understand why few patients achieve a HbA1c of < 7.5%, particularly as glycaemic control is worse in the UK than in other European countries. TRIAL REGISTRATION: Current Controlled Trials ISRCTN61215213. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 20. See the NIHR Journals Library website for further project information.

  • Staff experiences of closing out a clinical trial involving withdrawal of treatment: qualitative study.

    3 April 2018

    BACKGROUND: The ending of a clinical trial may be challenging, particularly if staff are required to withdraw the investigated treatment(s); however, this aspect of trial work is surprisingly under-researched. To address this gap, we explored the experiences of staff involved in closing out a trial that entailed withdrawal of treatment (insulin pumps) from some patients. METHODS: Interviews were conducted with n = 22 staff, recruited from seven trial sites. Data were analysed thematically. RESULTS: Staff described a myriad of ethical and emotional challenges at closeout, many of which had been unforeseen when the trial began. A key challenge for staff was that, while patients gave their agreement to participate on the understanding that pump treatment could be withdrawn, they often found themselves benefitting from this regimen in ways they could not have foreseen. Hence, as the trial progressed, patients became increasingly anxious about withdrawal of treatment. This situation forced staff to consider whether the consent patients had given at the outset remained valid; it also presented them with a dilemma at closeout because many of those who had wanted to remain on a pump did not meet the clinical criteria required for post-trial funding. When deciding whether to withdraw treatment, staff not only had to take funding pressures and patient distress into account, but they also found themselves caught between an ethic of Hippocratic individualism and one of utilitarianism. These conflicting pressures and ethical considerations resulted in staff decision-making varying across the sites, an issue that some described as a further source of ethical unease. Staff concluded that, had there been more advanced planning and discussion, and greater accountability to an ethics committee, some of the challenges they had confronted at closeout could have been lessened or even prevented. CONCLUSIONS: The same kinds of ethical issues that may vex staff at the beginning of a trial (e.g. patients having unrealistic expectations of trial participation; staff experiencing conflicts between research and clinical roles) may re-present themselves at the end. To safeguard the wellbeing of staff and patients, greater planning, coordination and ethical oversight should go into the closeout of trials involving withdrawal of treatment(s). TRIAL REGISTRATION: International Standard Randomised Controlled Trials Number (ISRCTN) Registry, ISRCTN61215213 . Registered on 11 May 2011.