HDAC inhibitors increase NRF2-signaling in tumour cells and blunt the efficacy of co-adminstered cytotoxic agents

The NRF2 signalling cascade provides a primary response against electrophilic chemicals and oxidative stress. The activation of NRF2-signaling is anticipated to have adverse clinical consequences; NRF2 is activated in a number of cancers and, additionally, its pharmacological activation by one compound can reduce the toxicity or efficiency of a second agent administered concomitantly. In this work, we have analysed systematically the ability of 152 research, pre-clinical or clinically used drugs to induce an NRF2 response using the MCF7-AREc32 NRF2 reporter. Ten percent of the tested drugs induced an NRF2 response. The NRF2 activators were not restricted to classical cytotoxic alkylating agents but also included a number of emerging anticancer drugs, including an IGF1-R inhibitor (NVP-AEW541), a PIM-1 kinase inhibitor (Pim1 inhibitor 2), a PLK1 inhibitor (BI 2536) and most strikingly seven of nine tested HDAC inhibitors. These findings were further confirmed by demonstrating NRF2-dependent induction of endogenous AKR genes, biomarkers of NRF2 activity. The ability of HDAC inhibitors to stimulate NRF2-signalling did not diminish their own potency as antitumour agents. However, when used to pre-treat cells, they did reduce the efficacy of acrolein. Taken together, our data suggest that the ability of drugs to stimulate NRF2 activity is common and should be investigated as part of the drug-development process

Factors contributing to the time taken to consult with symptoms of lung cancer: a cross-sectional study

<b>Objectives</b>: To determine what factors are associated with the time people take to consult with symptoms of lung cancer, with a focus on those from rural and socially deprived areas. <b>Methods</b>: A cross-sectional quantitative interview survey was performed of 360 patients with newly diagnosed primary lung cancer in three Scottish hospitals (two in Glasgow, one in NE Scotland). Supplementary data were obtained from medical case notes. The main outcome measures were the number of days from (1) the date participant defined first symptom until date of presentation to a medical practitioner; and (2) the date of earliest symptom from a symptom checklist (derived from clinical guidelines) until date of presentation to a medical practitioner. <b>Results</b>: 179 participants (50%) had symptoms for more than 14 weeks before presenting to a medical practitioner (median 99 days; interquartile range 31–381). 270 participants (75%) had unrecognised symptoms of lung cancer. There were no significant differences in time taken to consult with symptoms of lung cancer between rural and/or deprived participants compared with urban and/or affluent participants. Factors independently associated with increased time before consulting about symptoms were living alone, a history of chronic obstructive pulmonary disease (COPD) and longer pack years of smoking. Haemoptysis, new onset of shortness of breath, cough and loss of appetite were significantly associated with earlier consulting, as were a history of chest infection and renal failure. <b>Conclusion</b>: For many people with lung cancer, regardless of location and socioeconomic status, the time between symptom onset and consultation was long enough to plausibly affect prognosis. Long-term smokers, those with COPD and/or those living alone are at particular risk of taking longer to consult with symptoms of lung cancer and practitioners should be alert to this

Young people's views about the purpose and composition of research ethics committees:findings from the PEARL qualitative study

BACKGROUND: Avon Longitudinal Study of Parents and Children (ALSPAC) is a birth cohort study within which the Project to Enhance ALSPAC through Record Linkage (PEARL) was established to enrich the ALSPAC resource through linkage between ALSPAC participants and routine sources of health and social data. PEARL incorporated qualitative research to seek the views of young people about data linkage, including their opinions about appropriate safeguards and research governance. In this paper we focus on views expressed about the purpose and composition of research ethics committees. METHODS: Digitally recorded interviews were conducted with 48 participants aged 17–19 years. Participants were asked about whether medical research should be monitored and controlled, their knowledge of research ethics committees, who should sit on these committees and what their role should be. Interview recordings were fully transcribed and anonymised. Thematic analysis was undertaken, assisted by the Framework approach to data management. RESULTS: The majority of interviewees had little or no specific knowledge of ethics committees. Once given basic information about research ethics committees, only three respondents suggested there was no need for such bodies to scrutinise research. The key tasks of ethics committees were identified as monitoring the research process and protecting research participants. The difficulty of balancing the potential to inhibit research against the need to protect research participants was acknowledged. The importance of relevant research and professional expertise was identified but it was also considered important to represent wider public opinion, and to counter the bias potentially associated with self-selection possibly through a selection process similar to ‘jury duty’. CONCLUSIONS: There is a need for more education and public awareness about the role and composition of research ethics committees. Despite an initial lack of knowledge, interviewees were able to contribute their ideas and balance the rights of individuals with the wider benefits from research. The suggestion that public opinion should be represented through random selection similar to jury duty may be worth pursuing in the light of the need to ensure diversity of opinion and establish trust amongst the general public about the use of ‘big data’ for the wider public good

Associations between patient factors and successful colon capsule endoscopy – a prospective cohort study

Funding statement This study was funded by an NHS Highland Research Development and Innovation grant. Acknowledgements We would like to thank all patients and staff involved in the ScotCap evaluation. We would also like to thank The Data Lab for their contribution to the project.Peer reviewedPostprin

Socioeconomic factors and other sources of variation in the prevalence of genital chlamydia infections: A systematic review and meta-analysis

BACKGROUND: The success of chlamydia screening programmes relies on their ability to effectively target those with greatest need. Young people from disadvantaged backgrounds may be at greater need for chlamydia screening, but existing evidence on the variation of prevalence with social position is inconclusive. We carried out a systematic review to examine variation in chlamydia prevalence in populations and possible sources of this variation. METHODS: Studies were eligible if they reported chlamydia prevalence derived from population-based samples that included young people aged 15–24 years from Europe, North America or Australia. Systematic searches of the following databases were undertaken from their inception to November 2014: MEDLINE, Embase, Web of Science and PsychINFO. There were no restrictions by language or publication date. Independent screening for eligibility and data extraction were carried out by two reviewers. Where possible, data were pooled in a meta-analysis using a random effects model. Heterogeneity was further investigated using meta-regression techniques. RESULTS: Of 1248 unique titles and abstracts and 263 potentially relevant full texts, 29 studies were eligible for inclusion. There was relatively strong evidence that disadvantaged young people had an increased risk of having a chlamydia infection across multiple measures of disadvantage, including lower educational attainment (OR 1.94, 95 % CI: 1.52 to 2.47), lower occupational class (OR 1.49, 95 % CI: 1.07 to 2.08) and residence in deprived areas (OR 1.76, 95 % CI: 1.15 to 2.71) with an overall OR of 1.66 (95 % CI: 1.37 to 2.02). Socioeconomic disadvantage was associated with chlamydia infection in both men and women. There was weaker evidence that prevalence estimates also varied by gender and age. CONCLUSIONS: This review provides evidence of a consistent association between socioeconomic disadvantage and higher risk of Chlamydia infection. This association may reflect a number of factors including social variation in engagement with Chlamydia control programmes. Chlamydia screening could therefore reduce or increase health inequalities, depending on service provision and uptake by different socioeconomic groups. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12889-015-2069-7) contains supplementary material, which is available to authorized users

Colon capsule endoscopy investigation based on faecal haemoglobin concentration in symptomatic patients to detect bowel disease

We would like to thank the biochemistry laboratory staff at Raigmore and Ninewells Hospital for processing and analysing FIT samples, and all the patients who participated in the ScotCap evaluation.Peer reviewe

Should I stay or should I go?: consistency and switching of delivery locations among new mothers in 39 Sub-Saharan African and South/Southeast Asian countries.

The objective of this article is to assess the extent and determinants of switching delivery location between women's first and second deliveries. We used Demographic and Health Survey data from 39 low- and middle-income countries on delivery locations from >30 000 women who had their first two deliveries in the 5-year survey recall period. Each delivery was characterized as occurring at home or in a health facility, facilities were classified as public- or private-sector. The extent of switching was estimated for each country, region and overall. Multivariable logistic regression models assessed determinants of switching (home to facility or facility to home), using four dimensions (perceived/biological need, socioeconomic characteristics, utilization of care and availability of care). Overall, 49.0% of first and 44.5% of second deliveries occurred in health facilities. Among women who had their first delivery at home, 11.8% used a facility for their second (7.0% public-sector and 4.8% private-sector). Among women who had their first delivery in a facility, 21.6% switched to a home location for their second. The extent of switching varied by country; but the overall net effect was either non-existent (n = 20) or away from facilities (n = 17) in all but two countries-Cambodia and Burkina Faso. Four factors were associated with switching to a facility after a home delivery: higher education, urban residence, non-poor household status and multiple gestation. Majority of women consistently used the same delivery location for their first two deliveries. We found some evidence that where switching occurred, women were being lost from facility care during this important transition, and that all four included dimensions were important determinants of women's pattern of delivery care use. The relative importance of these factors should be understood in each specific context to improve retention in and provision of quality intrapartum care for women and their newborns

Early breastfeeding practices: Descriptive analysis of recent Demographic and Health Surveys.

The aim of this study was to describe early breastfeeding practices (initiation within 1 hr of birth, no prelacteal feeding, and a combination of both-"optimal" early breastfeeding) according to childbirth location in low- and middle-income countries. Using data from the most recent Demographic and Health Survey (2000-2013) for 57 countries, we extracted information on the most recent birth for women aged 15-49 with a live birth in the preceding 24 months. Childbirth setting was self-reported by location (home or facility) and subtype (home delivery with or without a skilled birth attendant; public or private facility). We produced overall world and four region-level summary statistics by applying national population adjusted survey weights. Overall, 39% of children were breastfed within 1 hr of birth (region range 31-60%), 49% received no prelacteal feeding (41-65%), and 28% benefited from optimal early breastfeeding (21-46%). In South/Southeast Asia and Sub-Saharan Africa, early breastfeeding outcomes were more favourable for facility births compared to home births; trends were less consistent in Latin America and Middle East/Europe. Among home deliveries, there was a higher prevalence of positive breastfeeding practices for births with a skilled birth attendant across all regions other than Latin America. For facility births, breastfeeding practices were more favourable among those taking place in the public sector. This study is the most comprehensive assessment to date of early breastfeeding practices by childbirth location. Our results suggest that skilled delivery care-particularly care delivered in public sector facilities-appears positively correlated with favourable breastfeeding practices

Colon capsule endoscopy investigation based on faecal haemoglobin concentration in symptomatic patients to detect bowel disease

We would like to thank the biochemistry laboratory staff at Raigmore and Ninewells Hospital for processing and analysing FIT samples, and all the patients who participated in the ScotCap evaluation.Peer reviewe