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1.  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.
Purpose
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1007/s10552-014-0500-5
PMCID: PMC4298668  PMID: 25488826
Prostate cancer; Vitamin D; Vitamin D pathway genes; 25 hydroxyvitamin-D; 1,25-dihydroxyvitamin-D
2.  Men’s knowledge and attitudes towards dietary prevention of a prostate cancer diagnosis: a qualitative study 
BMC Cancer  2014;14(1):812.
Background
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1186/1471-2407-14-812
PMCID: PMC4232627  PMID: 25374269
Diet; Green Tea; Lycopene; Prostatic neoplasms; Qualitative research
3.  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.
Highlights
•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.
doi:10.1016/j.socscimed.2014.07.024
PMCID: PMC4151136  PMID: 25054280
Suicide rates; suicide trends; Economic recession; England and Wales; Risk; Joinpoint regression
4.  Suicide in Sri Lanka 1975–2012: age, period and cohort analysis of police and hospital data 
BMC Public Health  2014;14(1):839.
Background
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.
Methods
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).
Results
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.
Conclusions
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.
doi:10.1186/1471-2458-14-839
PMCID: PMC4148962  PMID: 25118074
Sri Lanka; Pesticide poisoning; Suicide; Period effects; Birth-cohort effects
5.  Challenges and opportunities of a paperless baseline survey in Sri Lanka 
BMC Research Notes  2014;7:452.
Background
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.
Findings
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.
Discussion
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.
doi:10.1186/1756-0500-7-452
PMCID: PMC4118630  PMID: 25027231
Sri Lanka; Computer; Handheld; Data collection; Randomised control trial; Epidemiology
6.  Validation of suicide and self-harm records in the Clinical Practice Research Datalink 
Aims
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1111/bcp.12059
PMCID: PMC3703237  PMID: 23216533
Clinical Practice Research Datalink; General Practice Research Database; nonfatal self-harm; suicide; validation
7.  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.
Background
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.
Methods/Design
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.
Discussion
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 http://www.controlled-trials.com; the ROMIO trial record at that site gives a link to the original version of the study protocol.
doi:10.1186/1745-6215-15-200
PMCID: PMC4084574  PMID: 24888266
Feasibility studies; Upper gastrointestinal neoplasms; Pilot study; Surgical procedures; Minimally invasive; Randomized controlled trial
8.  Hospital Presenting Self-Harm and Risk of Fatal and Non-Fatal Repetition: Systematic Review and Meta-Analysis 
PLoS ONE  2014;9(2):e89944.
Background
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.
Conclusions
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.
doi:10.1371/journal.pone.0089944
PMCID: PMC3938547  PMID: 24587141
9.  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.
doi:10.1093/ije/dys191
PMCID: PMC3535746  PMID: 23179303
Circadian rhythm; self-injurious behaviour; toxicology; poisoning; Cascabela thevetia; pesticides; Sri Lanka
10.  Physicians' prescribing preferences were a potential instrument for patients' actual prescriptions of antidepressants☆ 
Journal of Clinical Epidemiology  2013;66(12):1386-1396.
Objectives
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.
Results
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).
Conclusion
The main instrumental variable assumptions held, suggesting that physicians' prescribing preferences are valid instruments for evaluating the short-term effects of antidepressants.
doi:10.1016/j.jclinepi.2013.06.008
PMCID: PMC3824069  PMID: 24075596
Instrumental variables; Clinical Practice Research Datalink (CPRD); Physicians' prescribing preferences; Confounding by indication; Causality; Translational epidemiology
13.  Mediated effect of cognitive behavioural therapy on depression outcomes 
Trials  2013;14(Suppl 1):P112.
doi:10.1186/1745-6215-14-S1-P112
PMCID: PMC3981652
14.  Circulating folate, vitamin B12, homocysteine, vitamin B12 transport proteins and risk of prostate cancer: a case-control study, systematic review and meta-analysis 
Background
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.
Methods
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.
Results
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).
Conclusion
Vitamin B12 and (in cohort studies) folate were associated with increased prostate cancer risk.
Impact
Given current controversies over mandatory fortification, further research is needed to determine whether these are causal associations.
doi:10.1158/1055-9965.EPI-10-0180
PMCID: PMC3759018  PMID: 20501771
folate; vitamin B12; cobalamin; transcobalamin; haptocorrin; homocysteine; folate-mediated one-carbon metabolism; prostate cancer
15.  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.
doi:10.1098/rsbl.2013.0492
PMCID: PMC3730660  PMID: 23804293
wildlife; endocrine-disrupting chemicals; non-steroidal anti-inflammatory drugs; vultures; risk prediction; bioindicators
16.  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.
doi:10.1100/2012/828343
PMCID: PMC3549342  PMID: 23346024
17.  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.
doi:10.1002/ijc.27327
PMCID: PMC3378478  PMID: 22033893
Prostate cancer; vitamin D; 25-hydroxyvitamn D
21.  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
22.  A community-based cluster randomised trial of safe storage to reduce pesticide self-poisoning in rural Sri Lanka: study protocol 
BMC Public Health  2011;11:879.
Background
The WHO recognises pesticide poisoning to be the single most important means of suicide globally. Pesticide self-poisoning is a major public health and clinical problem in rural Asia, where it has led to case fatality ratios 20-30 times higher than self-poisoning in the developed world. One approach to reducing access to pesticides is for households to store pesticides in lockable "safe-storage" containers. However, before this approach can be promoted, evidence is required on its effectiveness and safety.
Methods/Design
A community-based cluster randomised controlled trial has been set up in 44,000 households in the North Central Province, Sri Lanka. A census is being performed, collecting baseline demographic data, socio-economic status, pesticide usage, self-harm and alcohol. Participating villages are then randomised and eligible households in the intervention arm given a lockable safe storage container for agrochemicals.
The primary outcome will be incidence of pesticide self-poisoning over three years amongst individuals aged 14 years and over. 217,944 person years of follow-up are required in each arm to detect a 33% reduction in pesticide self-poisoning with 80% power at the 5% significance level. Secondary outcomes will include the incidence of all pesticide poisoning and total self-harm.
Discussion
This paper describes a large effectiveness study of a community intervention to reduce the burden of intentional poisoning in rural Sri Lanka. The study builds on a strong partnership between provincial health services, local and international researchers, and local communities. We discuss issues in relation to randomisation and contamination, engaging control villages, the intervention, and strategies to improve adherence.
Trial Registritation
The trial is registered on ClinicalTrials.gov ref: NCT1146496 (http://clinicaltrialsfeeds.org/clinical-trials/show/NCT01146496).
doi:10.1186/1471-2458-11-879
PMCID: PMC3227631  PMID: 22104027
23.  Development of a New Method for Monitoring Prostate-Specific Antigen Changes in Men with Localised Prostate Cancer: A Comparison of Observational Cohorts 
European urology  2009;57(3):446-452.
Background
Prostate-specific antigen (PSA) measurements are increasingly used to monitor men with localised prostate cancer (PCa), but there is little consensus about the method to use.
Objective
To apply age-specific predictions of PSA level (developed in men without cancer) to one cohort of men with clinically identified PCa and one cohort of men with PSA-detected PCa. We hypothesise that among men with clinically identified cancer, the annual increase in PSA level would be steeper than in men with PSA-detected cancer.
Design, setting, and participants
The Scandinavian Prostatic Cancer Group 4 (SPCG-4) cohort consisted of 321 men assigned to the watchful waiting arm of the SPCG-4 trial. The UK cohort consisted of 320 men with PSA-detected PCa in the Prostate Testing for Cancer and Treatment (ProtecT) study in nine UK centres between 1999 and 2007 who opted for monitoring rather than treatment. Multilevel models describing changes in PSA level were fitted to the two cohorts, and average PSA level at age 50, change in PSA level with age, and predicted PSA values were derived.
Measurements
PSA level.
Results and limitations
In the SPCG-4 cohort, mean PSA at age 50 was similar to the cancer-free cohort but with a steeper yearly increase in PSA level (16.4% vs 4.0%). In the UK cohort, mean PSA level was higher than that in the cancer-free cohort (due to a PSA biopsy threshold of 3.0 ng/ml) but with a similar yearly increase in PSA level (4.1%). Predictions were less accurate for the SPCG-4 cohort (median observed minus predicted PSA level: −2.0 ng/ml; interquartile range [IQR]: −7.6–0.7 ng/ml) than for the UK cohort (median observed minus predicted PSA level: −0.8 ng/ml; IQR: −2.1–0.1 ng/ml).
Conclusions
In PSA-detected men, yearly change in PSA was similar to that in cancer-free men, whereas in men with symptomatic PCa, the yearly change in PSA level was considerably higher. Our method needs further evaluation but has promise for refining active monitoring protocols.
doi:10.1016/j.eururo.2009.03.023
PMCID: PMC2910432  PMID: 19303695
active surveillance; localised prostate cancer; PSA doubling time; PSA velocity; reference ranges
24.  Does consideration of either psychological or material disadvantage improve coronary risk prediction? Prospective observational study of Scottish men 
Objective
To assess the value of psychosocial risk factors in discriminating between individuals at higher and lower risk of coronary heart disease, using risk prediction equations.
Design
Prospective observational study.
Setting
Scotland.
Participants
5191 employed men aged 35 to 64 years and free of coronary heart disease at study enrolment
Main outcome measures
Area under receiver operating characteristic (ROC) curves for risk prediction equations including different risk factors for coronary heart disease.
Results
During the first 10 years of follow up, 203 men died of coronary heart disease and a further 200 were admitted to hospital with this diagnosis. Area under the ROC curve for the standard Framingham coronary risk factors was 74.5%. Addition of “vital exhaustion” and psychological stress led to areas under the ROC curve of 74.5% and 74.6%, respectively. Addition of current social class and lifetime social class to the standard Framingham equation gave areas under the ROC curve of 74.6% and 74.9%, respectively. In no case was there strong evidence for improved discrimination of the model containing the novel risk factor over the standard model.
Conclusions
Consideration of psychosocial risk factors, including those that are strong independent predictors of heart disease, does not substantially influence the ability of risk prediction tools to discriminate between individuals at higher and lower risk of coronary heart disease.
doi:10.1136/jech.2006.055921
PMCID: PMC2660009  PMID: 17699540
cardiovascular disease; risk assessment; Framingham risk score; primary prevention; psychosocial factors
25.  Life course sun exposure and risk of prostate cancer: population-based nested case-control study (ProtecT) and meta-analysis 
There is currently no means of primary prevention for prostate cancer. Increased exposure to ultraviolet-radiation may be protective, but the literature is inconclusive. We investigated associations of life-course exposure to sunlight with prostate cancer. The study design was a UK-wide nested case-control study, based on 1,020 PSA-detected cases and 5,044 matched population controls and a systematic review with meta-analysis. Men with olive/brown skin (OR= 1.47; 95% CI: 1.00 to 2.17), men who burnt rarely/never (OR= 1.11; 0.95 to 1.29) and men with the lowest levels of intense sun exposure in the 2 years prior to diagnosis (OR = 1.24; 1.03 to 1.50) had an increased prostate cancer risk. However, amongst men with prostate cancer, spending less time outside was associated with a reduced risk of advanced cancer (OR = 0.49; 0.27 to 0.89) and high Gleason grade (OR = 0.62; 0.43 to 0.91), and men who burnt rarely/never had a reduced risk of advanced cancer (OR = 0.71; 0.47 to 1.08). The meta-analysis provided weak evidence that men with the lowest (versus highest) sunlight exposure had an increased prostate cancer risk (4 studies, random-effects pooled relative risk = 1.13; 0.98 to 1.29) and higher advanced or fatal prostate cancer risk (6 studies, random-effects pooled relative risk = 1.14; 0.98 to 1.33). Our data and meta-analyses provide limited support for the hypothesis that increased exposure to sunlight may reduce prostate cancer risk. The findings warrant further investigation because of their implications for vitamin D chemoprevention trials.
doi:10.1002/ijc.24411
PMCID: PMC2873563  PMID: 19444909
Prostate cancer; sun exposure; pigmentation

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