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1.  Choice of Moisturiser for Eczema Treatment (COMET): study protocol for a randomized controlled trial 
Trials  2015;16:304.
Eczema is common in children and in the UK most cases are managed in primary care. The foundation of all treatment is the regular use of leave-on emollients to preserve and restore moisture to the skin. This not only improves comfort but may also reduce the need for rescue treatment for ‘flares’, such as topical corticosteroids. However, clinicians can prescribe many different types of emollient and there is a paucity of evidence to guide this choice. One reason for this may be the challenges of conducting a clinical trial: are parents or carers of young children willing to be randomly allocated an emollient and followed up for a meaningful amount of time?
This is a single-centre feasibility study of a pragmatic, four-arm, single-masked, randomized trial. Children with eczema who are eligible (from 1 month to less than 5 years of age, not known to be sensitive or allergic to any of study emollients or their constituents) are recruited via their general practices. Participants are allocated Aveeno® lotion, Diprobase® cream, Doublebase® gel or Hydromol® ointment via a web-based system, using a simple randomization process in a 1:1:1:1 fashion. Researchers are masked to the study emollient. Participants are assessed at baseline and followed up for 3 months. Data are collected by daily diaries, monthly researcher visits and review of electronic medical records. Because this is a feasibility study, a formal sample size calculation for the estimation of treatment effectiveness has not be made but we aim to recruit 160 participants.
Recruitment is on-going. At the end of the study, as well as being able to answer the question, ‘Is it is possible to recruit and retain children with eczema from primary care into a four-arm randomized trial of emollients?’, we will also have collected important data on the acceptability and effectiveness of four commonly used emollients.
Trial registration
Current Controlled Trials ISRCTN21828118 and Clinical Trials Register EudraCT2013-003001-26.
Electronic supplementary material
The online version of this article (doi:10.1186/s13063-015-0830-y) contains supplementary material, which is available to authorized users.
PMCID: PMC4501045  PMID: 26170126
children; eczema; emollients; feasibility; primary care; RCT
2.  Role of information in preparing men for transrectal ultrasound guided prostate biopsy: a qualitative study embedded in the ProtecT trial 
The histological diagnosis of prostate cancer requires a prostate needle biopsy. Little is known about the relationship between information provided to prepare men for transrectal ultrasound guided biopsy (TRUS-Bx) and how men experience biopsy. The objectives were a) to understand men’s experiences of biopsy as compared to their expectations; and b) to propose current evidence-based information for men undergoing TRUS-Bx.
Between February 2006 and May 2008, 1,147 men undergoing a standardised 10-core transrectal ultrasound guided biopsy protocol under antibiotic cover following a PSA 3.0-19.9 ng/ml in the Prostate Testing for Cancer and Treatment (ProtecT) trial, completed questionnaires about biopsy symptoms. In this embedded qualitative study, in-depth interviews were undertaken with 85 men (mean age 63.6 yrs, mean PSA 4.5 ng/ml) to explore men’s experiences of prostate biopsy and how the experience might be improved. Interview data were analysed thematically using qualitative research methods. Findings from the qualitative study were used to guide selection of key findings from the questionnaire study in developing a patient information leaflet preparing men for biopsy.
Although most men tolerated TRUS-Bx, a quarter reported problematic side-effects and anxiety. Side effects were perceived as problematic and anxiety arose most commonly when experiences deviated from information provided. Men who were unprepared for elements of TRUS-Bx procedure or its sequelae responded by contacting health professionals for reassurance and voiced frustration that pre-biopsy information had understated the possible severity or duration of pain/discomfort and bleeding. Findings from questionnaire and interview data were combined to propose a comprehensive, evidence-based patient information leaflet for TRUS-Bx.
Men reported anxiety associated with TRUS-Bx or its side-effects most commonly if they felt inadequately prepared for the procedure. Data from this qualitative study and the previous questionnaire study have been used to propose an updated, comprehensive evidence-based set of information for men undergoing TRUS-Bx.
Electronic supplementary material
The online version of this article (doi:10.1186/s12913-015-0729-z) contains supplementary material, which is available to authorized users.
PMCID: PMC4350900  PMID: 25889315
Biopsy; Cancer; Patient information; Prostate; Qualitative methods
3.  Study protocol: the effectiveness and cost effectiveness of an employer-led intervention to increase walking during the daily commute: the Travel to Work randomised controlled trial 
BMC Public Health  2015;15:154.
Physical inactivity increases the risk of many chronic diseases including coronary heart disease, type 2 diabetes and some cancers. It is recommended that adults should undertake at least 150 minutes of moderate intensity physical activity throughout the week but many adults do not achieve this. An opportunity for working adults to accumulate the recommended activity levels is through the daily commute.
Employees will be recruited from workplaces in south-west England and south Wales. In the intervention arm, workplace Walk-to-Work promoters will be recruited and trained. Participating employees will receive Walk-to-Work materials and support will be provided through four contacts from the promoters over 10 weeks. Workplaces in the control arm will continue with their usual practice. The intervention will be evaluated by a cluster randomized controlled trial including economic and process evaluations. The primary outcome is daily minutes of moderate to vigorous physical activity (MVPA). Secondary outcomes are: overall physical activity; sedentary time; modal shift away from private car use during the commute; and physical activity/MVPA during the commute. Accelerometers, GPS receivers and travel diaries will be used at baseline and one year follow-up. Questionnaires will be used at baseline, immediately post intervention, and one year follow-up. The process evaluation will examine the context, delivery and response to the intervention from the perspectives of employers, Walk-to-Work promoters and employees using questionnaires, descriptive statistics, fieldnotes and interviews. A cost-consequence study will include employer, employee and health service costs and outcomes. Time and consumables used in implementing the intervention will be measured. Journey time, household commuting costs and expenses will be recorded using travel diaries to estimate costs to employees. Presenteeism, absenteeism, employee wellbeing and health service use will be recorded.
Compared with other forms of physical activity, walking is a popular, familiar and convenient, and the main option for increasing physical activity in sedentary populations. To our knowledge, this is the first full-scale randomised controlled trial to objectively measure (using accelerometers and GPS receivers) the effectiveness of a workplace intervention to promote walking during the commute to and from work.
Trial registration
ISRCTN15009100 (10 December 2014).
PMCID: PMC4339476  PMID: 25884986
Active travel; Walking; Workplace; Physical activity measurement; Randomised controlled trial
4.  Standardisation of information submitted to an endpoint committee for cause of death assignment in a cancer screening trial – lessons learnt from CAP (Cluster randomised triAl of PSA testing for Prostate cancer) 
In cancer screening trials where the primary outcome is target cancer-specific mortality, the unbiased determination of underlying cause of death (UCD) is crucial. To minimise bias, the UCD should be independently verified by expert reviewers, blinded to death certificate data and trial arm. We investigated whether standardising the information submitted for UCD assignment in a population-based randomised controlled trial of prostate-specific antigen (PSA) testing for prostate cancer reduced the reviewers’ ability to correctly guess the trial arm.
Over 550 General Practitioner (GP) practices (>415,000 men aged 50–69 years) were cluster-randomised to PSA testing (intervention arm) or the National Health Service (NHS) prostate cancer risk management programme (control arm) between 2001 and 2007. Assignment of UCD was by independent reviews of researcher-written clinical vignettes that masked trial arm and death certificate information. A period of time after the process began (the initial phase), we analysed whether the reviewers could correctly identify trial arm from the vignettes, and the reasons for their choice. This feedback led to further standardisation of information (second phase), after which we re-assessed the extent of correct identification of trial arm.
1099 assessments of 509 vignettes were completed by January 2014. In the initial phase (n = 510 assessments), reviewers were unsure of trial arm in 33% of intervention and 30% of control arm assessments and were influenced by symptoms at diagnosis, PSA test result and study-specific criteria. In the second phase (n = 589), the respective proportions of uncertainty were 45% and 48%. The percentage of cases whereby reviewers were unable to determine the trial arm was greater following the standardisation of information provided in the vignettes. The chances of a correct guess and an incorrect guess were equalised in each arm, following further standardisation.
It is possible to mask trial arm from cause of death reviewers, by using their feedback to standardise the information submitted to them.
Trial registration
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2288-15-6) contains supplementary material, which is available to authorized users.
PMCID: PMC4429825  PMID: 25613468
Underlying cause of death; Verification; Bias; Prostate cancer; Blinding; Standardisation of information; Trial arm; Endpoint review; Outcome assessors
5.  Associations of vitamin D pathway genes with circulating 25-hydroxyvitamin-D, 1,25-dihydroxyvitamin-D, and prostate cancer: a nested case–control study 
Cancer Causes & Control  2014;26:205-218.
Vitamin D pathway single nucleotide polymorphisms (SNPs) are potentially useful proxies for investigating whether circulating vitamin D metabolites [total 25-hydroxyvitamin-D, 25(OH)D; 1,25-dihydroxyvitamin, 1,25(OH)2D] are causally related to prostate cancer. We investigated associations of sixteen SNPs across seven genes with prostate-specific antigen-detected prostate cancer.
In a nested case–control study (within the ProtecT trial), we estimated odds ratios and 95 % confidence intervals (CIs) quantifying associations between SNPs and prostate cancer. Subgroup analyses investigated whether associations were stronger in men who had high/low sun exposure [a proxy for 25(OH)D]. We quantified associations of SNPs with stage (T1–T2/T3–T4) and grade (<7/≥7). Multiple variant scores included SNPs encoding proteins involved in 25(OH)D synthesis and metabolism.
We included 1,275 prostate cancer cases (141 locally advanced, 385 high grades) and 2,062 healthy controls. Vitamin D-binding protein SNPs were associated with prostate cancer (rs4588-A: OR 1.20, CI 1.01, 1.41, p = 0.04; rs7041-T: OR 1.19, CI 1.02, 1.38, p = 0.03). Low 25(OH)D metabolism score was associated with high (vs low) grade (OR 0.76, CI 0.63, 0.93, p = 0.01); there was a similar association of its component variants: rs6013897-A in CYP24A1 (OR 0.78, CI 0.60, 1.01, p = 0.06) and rs10877012-T in CYP27B1 (OR 0.80, CI 0.63, 1.02, p = 0.07). There was no evidence that associations differed by level of sun exposure.
We found some evidence that vitamin D pathway SNPs were associated with prostate cancer risk and grade, but not stage. There was no evidence of an association in men with deficient vitamin D (measured by having low sun exposure).
Electronic supplementary material
The online version of this article (doi:10.1007/s10552-014-0500-5) contains supplementary material, which is available to authorized users.
PMCID: PMC4298668  PMID: 25488826
Prostate cancer; Vitamin D; Vitamin D pathway genes; 25 hydroxyvitamin-D; 1,25-dihydroxyvitamin-D
6.  Men’s knowledge and attitudes towards dietary prevention of a prostate cancer diagnosis: a qualitative study 
BMC Cancer  2014;14:812.
Prostate cancer (PC) incidence and progression may be influenced by dietary factors, but little is known about the acceptability of dietary modification to men at increased risk of PC. Qualitative interviews with men participating in the ProDiet study were undertaken to explore the feasibility of implementing dietary interventions for the prevention of prostate cancer.
An interview study nested within the ProDiet randomised feasibility trial of dietary interventions to prevent a PC diagnosis. Men (n = 133) who previously participated in community based prostate specific antigen (PSA) testing without PC but who were at increased risk of the disease were randomly allocation to both lycopene (lycopene or placebo capsules or lycopene rich diet) and green tea (green tea or placebo capsules or green tea drink) for 6 months. Semi-structured interviews were conducted with participants shortly after randomisation, to investigate attitudes towards dietary modification for PC prevention and dietary information. Interviews were audio-recorded, transcribed and analysed to identify common themes.
Interviews were conducted with 21 participants aged 52-72 years with PSA levels between 2.5 and 2.95 ng/ml, or a negative prostate biopsy result. Most men identified the major causes of cancer in general to include diet, environment, ageing and genetic factors. This contrasted sharply with men’s uncertainty about PC aetiology, and the function of the prostate. Men were confused by conflicting messages in the media about dietary practices to promote health overall, but were positive about the potential of lycopene and green tea in relation to PC prevention, valuing their natural components. Furthermore these men wanted tailored dietary advice for PC prevention from their clinicians, whom they considered a trusted source of information.
Men at elevated risk of PC reported uncertainty about PC aetiology and the role of diet in PC prevention, but enthusiasm for dietary modifications that were perceived as ‘simple’ and ‘natural’. The men looked to clinicians to provide consistent disease specific dietary advice. These factors should be taken into consideration by clinicians discussing elevated PSA results with patients and those planning to embark on future trials investigating dietary modification interventions for the prevention of a PC diagnosis.
PMCID: PMC4232627  PMID: 25374269
Diet; Green Tea; Lycopene; Prostatic neoplasms; Qualitative research
7.  Suicide and the 2008 economic recession: Who is most at risk? Trends in suicide rates in England and Wales 2001–2011 
Social Science & Medicine (1982)  2014;117(100):76-85.
The negative impacts of previous economic recessions on suicide rates have largely been attributed to rapid rises in unemployment in the context of inadequate social and work protection programmes. We have investigated trends in indicators of the 2008 economic recession and trends in suicide rates in England and Wales in men and women of working age (16–64 years old) for the period 2001–2011, before, during and after the economic recession, our aim was to identify demographic groups whose suicide rates were most affected. We found no clear evidence of an association between trends in female suicide rates and indicators of economic recession. Evidence of a halt in the previous downward trend in suicide rates occurred for men aged 16–34 years in 2006 (95% CI Quarter 3 (Q3) 2004, Q3 2007 for 16–24 year olds & Q1 2005, Q4 2006 for 25–34 year olds), whilst suicide rates in 35–44 year old men reversed from a downward to upward trend in early 2010 (95% CI Q4 2008, Q2 2011). For the younger men (16–34 years) this change preceded the sharp increases in redundancy and unemployment rates of early 2008 and lagged behind rising trends in house repossessions and bankruptcy that began around 2003. An exception were the 35–44 year old men for whom a change in suicide rate trends from downwards to upwards coincided with peaks in redundancies, unemployment and rises in long-term unemployment. Suicide rates across the decade rose monotonically in men aged 45–64 years. Male suicide in the most-to-medium deprived areas showed evidence of decreasing rates across the decade, whilst in the least-deprived areas suicide rates were fairly static but remained much lower than those in the most-deprived areas. There were small post-recession increases in the proportion of suicides in men in higher management/professional, small employer/self-employed occupations and fulltime education. A halt in the downward trend in suicide rates amongst men aged 16–34 years, may have begun before the 2008 economic recession whilst for men aged 35–44 years old increased suicide rates mirrored recession related unemployment. This evidence suggests indicators of economic strain other than unemployment and redundancies, such as personal debt and house repossessions may contribute to increased suicide rates in younger-age men whilst for men aged 35–44 years old job loss and long-term unemployment is a key risk factor.
•Indicators showed economic hardship was increasing 5 years prior to the 2008 economic recession.•The downward trends in younger male suicide rates (16–34 year olds) halted around 2006.•Economic strain and unemployment may contribute to rises in suicide rates in men aged 35–44 years old.•There was no clear evidence of an impact of the 2008 economic recession on suicide rates in females.
PMCID: PMC4151136  PMID: 25054280
Suicide rates; suicide trends; Economic recession; England and Wales; Risk; Joinpoint regression
8.  Suicide in Sri Lanka 1975–2012: age, period and cohort analysis of police and hospital data 
BMC Public Health  2014;14:839.
Sri Lanka has experienced major changes in its suicide rates since the 1970s, and in 1995 it had one of the highest rates in the world. Subsequent reductions in Sri Lanka’s suicide rates have been attributed to the introduction of restrictions on the availability of highly toxic pesticides. We investigate these changes in suicide rates in relation to age, gender, method specific trends and birth-cohort and period effects, with the aim of informing preventative strategies.
Secular trends of suicide in relation to age, sex, method, birth-cohort and period effects were investigated graphically using police data (1975–2012). Poisoning case-fatality was investigated using national hospital admission data (2004–2010).
There were marked changes to the age-, gender- and method-specific incidence of suicide over the study period. Year on year declines in rates began in 17–25 year olds in the early 1980s. Reduction in older age groups followed and falls in all age groups occurred after all class I (the most toxic) pesticides were banned. Distinct changes in the age/gender pattern of suicide are observed: in the 1980s suicide rates were highest in 21–35 year old men; by the 2000s, this pattern had reversed with a stepwise increase in male rates with increasing age. Throughout the study period female rates were highest in 17–25 year olds. There has been a rise in suicide by hanging, though this rise is relatively small in relation to the marked decline in self-poisoning deaths. The patterns of suicides are more consistent with a period rather than birth-cohort effect.
The epidemiology of suicide in Sri Lanka has changed noticeably in the last 30 years. The introduction of pesticide regulations in Sri Lanka coincides with a reduction in suicide rates, with evidence of limited method substitution.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2458-14-839) contains supplementary material, which is available to authorized users.
PMCID: PMC4148962  PMID: 25118074
Sri Lanka; Pesticide poisoning; Suicide; Period effects; Birth-cohort effects
9.  Challenges and opportunities of a paperless baseline survey in Sri Lanka 
BMC Research Notes  2014;7:452.
Personal digital assistants (PDAs) have been shown to reduce costs associated with survey implementation and digitisation, and to improve data quality when compared to traditional paper based data collection. Few studies, however, have shared their experiences of the use of these devices in rural settings in Asia. This paper reports on our experiences of using a PDA device for data collection in Sri Lanka as part of a large cluster randomised control trial.
We found that PDAs were useful for collecting data for a baseline survey of a large randomised control trial (54,000 households). We found that the PDA device and survey format was easy to use by inexperienced field staff, even though the survey was programmed in English. The device enabled the rapid digitisation of survey data, providing a good basis for continuous data quality assurance, supervision of staff and survey implementation. An unexpected advantage was the improved community opinion of the research project as a result of the device, because the use of the technology gave data collectors an elevated status amongst the community. In addition the global positioning system (GPS) functionality of the device allowed precise mapping of households, and hence distinct settlements to be identified as randomisation clusters. Future users should be mindful that to save costs the piloting should be completed before programming. In addition consideration of a local after-care service is important to avoid costs and time delays associated with sending devices back to overseas providers.
Since the start of this study, PDA devices have rapidly developed and are increasingly used. The use of PDA or similar devices for research is not without its problems; however we believe that the universal lessons learnt as part of this study are even more important for the effective utilisation of these rapidly developing technologies in resource poor settings.
PMCID: PMC4118630  PMID: 25027231
Sri Lanka; Computer; Handheld; Data collection; Randomised control trial; Epidemiology
10.  Validation of suicide and self-harm records in the Clinical Practice Research Datalink 
The UK Clinical Practice Research Datalink (CPRD) is increasingly being used to investigate suicide-related adverse drug reactions. No studies have comprehensively validated the recording of suicide and nonfatal self-harm in the CPRD. We validated general practitioners' recording of these outcomes using linked Office for National Statistics (ONS) mortality and Hospital Episode Statistics (HES) admission data.
We identified cases of suicide and self-harm recorded using appropriate Read codes in the CPRD between 1998 and 2010 in patients aged ≥15 years. Suicides were defined as patients with Read codes for suicide recorded within 95 days of their death. International Classification of Diseases codes were used to identify suicides/hospital admissions for self-harm in the linked ONS and HES data sets. We compared CPRD-derived cases/incidence of suicide and self-harm with those identified from linked ONS mortality and HES data, national suicide incidence rates and published self-harm incidence data.
Only 26.1% (n = 590) of the ‘true’ (ONS-confirmed) suicides were identified using Read codes. Furthermore, only 55.5% of Read code-identified suicides were confirmed as suicide by the ONS data. Of the HES-identified cases of self-harm, 68.4% were identified in the CPRD using Read codes. The CPRD self-harm rates based on Read codes had similar age and sex distributions to rates observed in self-harm hospital registers, although rates were underestimated in all age groups.
The CPRD recording of suicide using Read codes is unreliable, with significant inaccuracy (over- and under-reporting). Future CPRD suicide studies should use linked ONS mortality data. The under-reporting of self-harm appears to be less marked.
PMCID: PMC3703237  PMID: 23216533
Clinical Practice Research Datalink; General Practice Research Database; nonfatal self-harm; suicide; validation
11.  The feasibility of a randomized controlled trial of esophagectomy for esophageal cancer - the ROMIO (Randomized Oesophagectomy: Minimally Invasive or Open) study: protocol for a randomized controlled trial 
Trials  2014;15:200.
There is a need for evidence of the clinical effectiveness of minimally invasive surgery for the treatment of esophageal cancer, but randomized controlled trials in surgery are often difficult to conduct. The ROMIO (Randomized Open or Minimally Invasive Oesophagectomy) study will establish the feasibility of a main trial which will examine the clinical and cost-effectiveness of minimally invasive and open surgical procedures for the treatment of esophageal cancer.
A pilot randomized controlled trial (RCT), in two centers (University Hospitals Bristol NHS Foundation Trust and Plymouth Hospitals NHS Trust) will examine numbers of incident and eligible patients who consent to participate in the ROMIO study. Interventions will include esophagectomy by: (1) open gastric mobilization and right thoracotomy, (2) laparoscopic gastric mobilization and right thoracotomy, and (3) totally minimally invasive surgery (in the Bristol center only). The primary outcomes of the feasibility study will be measures of recruitment, successful development of methods to monitor quality of surgery and fidelity to a surgical protocol, and development of a core outcome set to evaluate esophageal cancer surgery. The study will test patient-reported outcomes measures to assess recovery, methods to blind participants, assessments of surgical morbidity, and methods to capture cost and resource use. ROMIO will integrate methods to monitor and improve recruitment using audio recordings of consultations between recruiting surgeons, nurses, and patients to provide feedback for recruiting staff.
The ROMIO study aims to establish efficient methods to undertake a main trial of minimally invasive surgery versus open surgery for esophageal cancer.
Trial registration
The pilot trial has Current Controlled Trials registration number ISRCTN59036820(25/02/2013) at; the ROMIO trial record at that site gives a link to the original version of the study protocol.
PMCID: PMC4084574  PMID: 24888266
Feasibility studies; Upper gastrointestinal neoplasms; Pilot study; Surgical procedures; Minimally invasive; Randomized controlled trial
12.  Hospital Presenting Self-Harm and Risk of Fatal and Non-Fatal Repetition: Systematic Review and Meta-Analysis 
PLoS ONE  2014;9(2):e89944.
Non-fatal self-harm is one of the most frequent reasons for emergency hospital admission and the strongest risk factor for subsequent suicide. Repeat self-harm and suicide are key clinical outcomes of the hospital management of self-harm. We have undertaken a comprehensive review of the international literature on the incidence of fatal and non-fatal repeat self-harm and investigated factors influencing variation in these estimates as well as changes in the incidence of repeat self-harm and suicide over the last 30 years.
Methods and Findings
Medline, EMBASE, PsycINFO, Google Scholar, article reference lists and personal paper collections of the authors were searched for studies describing rates of fatal and non-fatal self-harm amongst people who presented to health care services for deliberate self-harm. Heterogeneity in pooled estimates of repeat self-harm incidence was investigated using stratified meta-analysis and meta-regression. The search identified 177 relevant papers. The risk of suicide in the 12 months after an index attempt was 1.6% (CI 1.2–2.4) and 3.9% (CI 3.2–4.8) after 5 years. The estimated 1 year rate of non-fatal repeat self-harm was 16.3% (CI 15.1–17.7). This proportion was considerably lower in Asian countries (10.0%, CI 7.3–13.6%) and varies between studies identifying repeat episodes using hospital admission data (13.7%, CI 12.3–15.3) and studies using patient report (21.9%, CI 14.3–32.2). There was no evidence that the incidence of repeat self-harm was lower in more recent (post 2000) studies compared to those from the 1980s and 1990s.
One in 25 patients presenting to hospital for self-harm will kill themselves in the next 5 years. The incidence of repeat self-harm and suicide in this population has not changed in over 10 years. Different methods of identifying repeat episodes of self-harm produce varying estimates of incidence and this heterogeneity should be considered when evaluating interventions aimed at reducing non-fatal repeat self-harm.
PMCID: PMC3938547  PMID: 24587141
13.  Diurnal variation in probability of death following self-poisoning in Sri Lanka—evidence for chronotoxicity in humans 
Background The absorption, distribution, metabolism and elimination of medicines are partly controlled by transporters and enzymes with diurnal variation in expression. Dose timing may be important for maximizing therapeutic and minimizing adverse effects. However, outcome data for such an effect in humans are sparse, and chronotherapeutics is consequently less practised. We examined a large prospective Sri Lankan cohort of patients with acute poisoning to seek evidence of diurnal variation in the probability of survival.
Methods In all, 14 840 patients admitted to hospital after yellow oleander (Cascabela thevetia) seed or pesticide [organophosphorus (OP), carbamate, paraquat, glyphosate] self-poisoning were investigated for variation in survival according to time of ingestion.
Results We found strong evidence that the outcome of oleander poisoning was associated with time of ingestion (P < 0.001). There was weaker evidence for OP insecticides (P = 0.041) and no evidence of diurnal variation in the outcome for carbamate, glyphosate and paraquat pesticides. Compared with ingestion in the late morning, and with confounding by age, sex, time of and delay to hospital presentation and year of admission controlled, case fatality of oleander poisoning was over 50% lower following evening ingestion (risk ratio = 0.40, 95% confidence interval 0.26–0.62). Variation in dose across the day was not responsible.
Conclusions We have shown for the first time that timing of poison ingestion affects survival in humans. This evidence for chronotoxicity suggests chronotherapeutics should be given greater attention in drug development and clinical practice.
PMCID: PMC3535746  PMID: 23179303
Circadian rhythm; self-injurious behaviour; toxicology; poisoning; Cascabela thevetia; pesticides; Sri Lanka
14.  Physicians' prescribing preferences were a potential instrument for patients' actual prescriptions of antidepressants☆ 
Journal of Clinical Epidemiology  2013;66(12):1386-1396.
To investigate whether physicians' prescribing preferences were valid instrumental variables for the antidepressant prescriptions they issued to their patients.
Study Design and Setting
We investigated whether physicians' previous prescriptions of (1) tricyclic antidepressants (TCAs) vs. selective serotonin reuptake inhibitors (SSRIs) and (2) paroxetine vs. other SSRIs were valid instruments. We investigated whether the instrumental variable assumptions are likely to hold and whether TCAs (vs. SSRIs) were associated with hospital admission for self-harm or death by suicide using both conventional and instrumental variable regressions. The setting for the study was general practices in the United Kingdom.
Prior prescriptions were strongly associated with actual prescriptions: physicians who previously prescribed TCAs were 14.9 percentage points (95% confidence interval [CI], 14.4, 15.4) more likely to prescribe TCAs, and those who previously prescribed paroxetine were 27.7 percentage points (95% CI, 26.7, 28.8) more likely to prescribe paroxetine, to their next patient. Physicians' previous prescriptions were less strongly associated with patients' baseline characteristics than actual prescriptions. We found no evidence that the estimated association of TCAs with self-harm/suicide using instrumental variable regression differed from conventional regression estimates (P-value = 0.45).
The main instrumental variable assumptions held, suggesting that physicians' prescribing preferences are valid instruments for evaluating the short-term effects of antidepressants.
PMCID: PMC3824069  PMID: 24075596
Instrumental variables; Clinical Practice Research Datalink (CPRD); Physicians' prescribing preferences; Confounding by indication; Causality; Translational epidemiology
17.  Mediated effect of cognitive behavioural therapy on depression outcomes 
Trials  2013;14(Suppl 1):P112.
PMCID: PMC3981652
18.  Circulating folate, vitamin B12, homocysteine, vitamin B12 transport proteins and risk of prostate cancer: a case-control study, systematic review and meta-analysis 
Disturbed folate metabolism is associated with an increased risk of some cancers. Our objective was to determine whether blood levels of folate, vitamin B12 and related metabolites were associated with prostate cancer risk.
Matched case-control study nested within the UK population-based ProtecT study of PSA-detected prostate cancer in men aged 50–69 years. Plasma concentrations of folate, B12 (cobalamin), holo-haptocorrin, holo- and total-transcobalamin, and total homocysteine (tHcy) were measured in 1,461 cases and 1,507 controls. ProtecT study estimates for associations of folate, B12, and tHcy with prostate cancer risk were included in a meta-analysis, based on a systematic review.
In the ProtecT study, increased B12 and holo-haptocorrin concentrations showed positive associations with prostate cancer risk (highest vs lowest quartile of B12 odds ratio (OR)=1.17 (95% CI 0.95–1.43), P-for-trend=0.06; highest vs lowest quartile of holo-haptocorrin OR=1.27 (1.04–1.56), P-for-trend=0.01); folate, holo-transcobalamin and tHcy were not associated with prostate cancer risk. In the meta-analysis, circulating B12 levels were associated with an increased prostate cancer risk (pooled OR=1.10 (1.01–1.19) per 100 pmol/L increase in B12, P=0.002); the pooled OR for the association of folate with prostate cancer was positive (OR=1.11 (0.96–1.28) per 10 nmol/L, P=0.2) and conventionally statistically significant if ProtecT (the only case-control study) was excluded (OR=1.18 (1.00–1.40) per 10 nmol/L, P=0.02).
Vitamin B12 and (in cohort studies) folate were associated with increased prostate cancer risk.
Given current controversies over mandatory fortification, further research is needed to determine whether these are causal associations.
PMCID: PMC3759018  PMID: 20501771
folate; vitamin B12; cobalamin; transcobalamin; haptocorrin; homocysteine; folate-mediated one-carbon metabolism; prostate cancer
19.  Assessing the exposure risk and impacts of pharmaceuticals in the environment on individuals and ecosystems 
Biology Letters  2013;9(4):20130492.
The use of human and veterinary pharmaceuticals is increasing. Over the past decade, there has been a proliferation of research into potential environmental impacts of pharmaceuticals in the environment. A Royal Society-supported seminar brought together experts from diverse scientific fields to discuss the risks posed by pharmaceuticals to wildlife. Recent analytical advances have revealed that pharmaceuticals are entering habitats via water, sewage, manure and animal carcases, and dispersing through food chains. Pharmaceuticals are designed to alter physiology at low doses and so can be particularly potent contaminants. The near extinction of Asian vultures following exposure to diclofenac is the key example where exposure to a pharmaceutical caused a population-level impact on non-target wildlife. However, more subtle changes to behaviour and physiology are rarely studied and poorly understood. Grand challenges for the future include developing more realistic exposure assessments for wildlife, assessing the impacts of mixtures of pharmaceuticals in combination with other environmental stressors and estimating the risks from pharmaceutical manufacturing and usage in developing countries. We concluded that an integration of diverse approaches is required to predict ‘unexpected’ risks; specifically, ecologically relevant, often long-term and non-lethal, consequences of pharmaceuticals in the environment for wildlife and ecosystems.
PMCID: PMC3730660  PMID: 23804293
wildlife; endocrine-disrupting chemicals; non-steroidal anti-inflammatory drugs; vultures; risk prediction; bioindicators
20.  Fate and Transport of Polycyclic Aromatic Hydrocarbons in Upland Irish Headwater Lake Catchments 
The Scientific World Journal  2012;2012:828343.
Polycyclic aromatic hydrocarbons (PAHs) are a concern due to their carcinogenicity and propensity for transboundary atmospheric transport. Ireland is located on the western periphery of Europe and assumed to receive clean Atlantic air. As such, it has been used as an atmospheric reference for comparison to other regions. Nonetheless, few studies have evaluated concentrations of PAHs within the Irish environment. In the current study, PAHs were measured at five upland (500–800 masl) headwater lake catchments in coastal regions around Ireland, remote from industrial point source emissions. Semipermeable membrane devices were deployed in lakes for a 6-month period in July 2009, and topsoils were sampled from each catchment during October 2010. The concentrations of PAHs were low at most study sites with respect to other temperate regions. Homologue groups partitioned between lake and soil compartments based on their molecular weight were: “lighter” substances, such as Phenanthrene and Fluorene, were found in higher proportions in lakes, whereas “heavier” compounds, such as Chrysene and Benz[a]anthracene, were more prominent in soils. Concentrations of PAHs were highest at the east coast sites, potentially due to contributions from historical transboundary and regional combustion sources.
PMCID: PMC3549342  PMID: 23346024
21.  Associations of Circulating 25-hydroxyvitamin D with prostate cancer diagnosis, stage and grade 
Epidemiological studies suggest that vitamin D protects against prostate cancer, although evidence is limited and inconsistent. We investigated associations of circulating total 25-hydroxyvitamin D (25(OH)D) with PSA-detected prostate cancer in a case-control study nested within the Prostate Testing for Cancer and Treatment (ProtecT) trial. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) quantifying the association between circulating total 25(OH)D and prostate cancer. In case-only analyses, we used unconditional logistic regression to quantify associations of total 25(OH)D with stage (advanced vs localized) and Gleason grade (high-grade (≥7) vs low-grade (<7)). Pre-determined categories of total 25(OH)D were defined as: high: ≥30ng/mL; adequate: 20-<30ng/mL; insufficient: 12-<20ng/mL; deficient: <12ng/mL. Fractional polynomials were used to investigate the existence of any U-shaped relationship. We included 1,447 prostate cancer cases (153 advanced, 469 high-grade) and 1,449 healthy controls. There was evidence that men deficient in vitamin D had a two-fold increased risk of advanced versus localized cancer (OR for deficient vs adequate total 25(OH)D=2.33, 95% CI: 1.26,4.28) and high-grade versus low-grade cancer (OR for deficient vs adequate total 25(OH)D=1.78, 95% CI: 1.15,2.77). There was no evidence of a linear association between total 25(OH)D and prostate cancer (p=0.44) or of an increased risk of prostate cancer with high and low vitamin D levels. Our study provides evidence that lower 25(OH)D concentrations were associated with more aggressive cancers (advanced versus localized cancers and high- versus low- Gleason grade), but there was no evidence of an association with overall prostate cancer risk.
PMCID: PMC3378478  PMID: 22033893
Prostate cancer; vitamin D; 25-hydroxyvitamn D
25.  The causal roles of vitamin B12 and transcobalamin in prostate cancer: can Mendelian randomization analysis provide definitive answers? 
Circulating vitamin B12 (cobalamin/B12) and total transcobalamin (tTC) have been associated with increased and reduced risk, respectively, of prostate cancer. Mendelian randomization has the potential to determine whether these are causal associations. We estimated associations of single nucleotide polymorphisms in B12-related genes (MTR, MTRR, FUT2, TCN2, TCN1, CUBN, and MUT) with plasma concentrations of B12, tTC, holo-transcobalamin, holo-haptocorrin, folate, and homocysteine and with prostate cancer risk in a case-control study (913 cases, 895 controls) nested within the UK-wide population-based ProtecT study of prostate cancer in men age 45-69 years. Instrumental variable (IV) analysis was used to estimate odds ratios for effects of B12 and tTC on prostate cancer. We observed that B12 was lower in men with FUT2 204G>A (rs492602), CUBN 758C>T (rs1801222) and MUT 1595G>A (rs1141321) alleles (Ptrend<0.001); tTC was lower in men with the TCN2 776C>G (rs1801198) allele (Ptrend<0.001). FUT2 204G>A and CUBN 758C>T were selected as instruments for B12; TCN2 776C>G for tTC. Conventional and IV estimates for the association of loge(B12) with prostate cancer were: OR=1.17 (95% CI 0.90-1.51), P=0.2 and OR=0.60 (0.16-2.15), P=0.4, respectively. Conventional and IV estimates for the association of loge(tTC) with prostate cancer were: OR=0.81 (0.54-1.20), P=0.3 and OR=0.41 (0.13-1.32), P=0.1, respectively. Confidence intervals around the IV estimates in our study were too wide to allow robust inference. Sample size estimates based on our data indicated that Mendelian randomization in this context requires much larger studies or multiple genetic variants that explain all of the variance in the intermediate phenotype.
PMCID: PMC3243448  PMID: 22199995
Vitamin B12/cobalamin; transcobalamin; prostate cancer; Mendelian Randomization

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