Is a single item stress measure independently associated with subsequent severe injury: a prospective cohort study of 16,385 forest industry employees

Background: A previous review showed that high stress increases the risk of occupational injury by three- to five-fold. However, most of the prior studies have relied on short follow-ups. In this prospective cohort study we examined the effect of stress on recorded hospitalised injuries in an 8-year follow-up.
Methods: A total of 16,385 employees of a Finnish forest company responded to the questionnaire. Perceived stress was measured with a validated single-item measure, and analysed in relation recorded hospitalised injuries from 1986 to 2008. We used Cox proportional hazard regression models to examine the prospective associations between work stress, injuries and confounding factors.
Results: Highly stressed participants were approximately 40% more likely to be hospitalised due to injury over the follow-up period than participants with low stress. This association remained significant after adjustment for age, gender, marital status, occupational status, educational level, and physical work environment.
Conclusions: High stress is associated with an increased risk of severe injury.

Post-diagnostic prescriptions for low-dose aspirin and breast cancer-specific survival: a nested case-control study in a breast cancer cohort from the UK Clinical Practice Research Datalink

INTRODUCTION: Recent observational studies indicate that post-diagnostic use of aspirin in breast cancer patients may protect against cancer progression perhaps by inhibiting cyclooxygenase-2 dependent mechanisms. Evidence also supports a crucial role for interactions between tumour cells and circulating platelets in cancer growth and dissemination, therefore, use of low-dose aspirin may reduce the risk of death from cancer in breast cancer patients.

METHODS: A cohort of newly diagnosed breast cancer patients (1998 to 2006) were identified in the UK Clinical Practice Research Datalink (and confirmed by cancer registry linkage). Cancer-specific deaths were identified up to 2011 from Office for National Statistics mortality data. A nested case-control analysis was conducted using conditional logistic regression to compare post-diagnostic aspirin exposure using General Practice prescription data in 1,435 cases (breast cancer deaths) with 5,697 controls (matched by age and year of diagnosis).

RESULTS: After breast cancer diagnosis, 18.3% of cancer-specific deaths and 18.5% of matched controls received at least one prescription for low-dose aspirin, corresponding to an odds ratio (OR) of 0.98 (95% CI 0.83, 1.15). Adjustment for potential confounders (including stage and grade) had little impact on this estimate. No dose response relationship was observed when the number of tablets was investigated and no associations were seen when analyses were stratified by receipt of prescriptions for aspirin in the pre-diagnostic period, by stage at diagnosis or by receipt of prescriptions for hormone therapy.

CONCLUSIONS: Overall, in this large population-based cohort of breast cancer patients, there was little evidence of an association between receipt of post-diagnostic prescriptions for low-dose aspirin and breast cancer-specific death. However, information was not available on medication compliance or over-the-counter use of aspirin, which may have contributed to the null findings.

The DietCompLyf study: A prospective cohort study of breast cancer survival and phytoestrogen consumption

DietCompLyf is a multi-centre prospective study designed to investigate associations between phytoestrogens - naturally occurring plant compounds with oestrogenic properties - and other diet and lifestyle factors with breast cancer recurrence and survival. 3159 women with grades I-III breast cancer were recruited 9-15 months post-diagnosis from 56 UK hospitals. Detailed information on clinico-pathological, diet, lifestyle and quality of life is collected annually up to 5 years. Biological samples have also been collected as a resource for subsequent evaluation. The characteristics of the patients and associations between pre-diagnosis intake of phytoestrogens (isoflavones and lignans; assessed using the EPIC-Norfolk UK 130 question food frequency questionnaire) and breast cancer (i) risk factors and (ii) prognostic factors are described for 1797 women who had complete data for all covariates and phytoestrogens of interest. Isoflavone intakes were higher in the patients who were younger at diagnosis, in the non-smokers, those who had breast-fed and those who took supplements. Lignan intakes were higher in patients with a higher age at diagnosis, in ex-smokers, those who had breast-fed, who took supplements, had a lower BMI at diagnosis, lower age at menarche and were nulliparous. No significant associations between pre-diagnosis phytoestrogen intake and factors associated with improved breast cancer prognosis were observed. The potential for further exploration of the relationship between phytoestrogens and breast cancer recurrence and survival, and for the establishment of evidence to improve dietary and lifestyle advice offered to patients following breast cancer diagnosis using DietCompLyf data is discussed.

A Prospective Cohort Study of Body Size and Risk of Head and Neck Cancers in the NIH-AARP Diet and Health Study

Background: The association between body size and head and neck cancers (HNCA) is unclear, partly because of the biases in case–control studies. Methods: In the prospective NIH–AARP cohort study, 218,854 participants (132,288 men and 86,566 women), aged 50 to 71 years, were cancer free at baseline (1995 and 1996), and had valid anthropometric data. Cox proportional hazards regression was used to examine the associations between body size and HNCA, adjusted for current and past smoking habits, alcohol intake, education, race, and fruit and vegetable consumption, and reported as HR and 95% confidence intervals (CI). Results: Until December 31, 2006, 779 incident HNCAs occurred: 342 in the oral cavity, 120 in the oro- and hypopharynx, 265 in the larynx, 12 in the nasopharynx, and 40 at overlapping sites. There was an inverse association between HNCA and body mass index, which was almost exclusively among current smokers (HR = 0.76 per each 5 U increase; 95% CI, 0.63–0.93), and diminished as initial years of follow-up were excluded. We observed a direct association with waist-to-hip ratio (HR = 1.16 per 0.1 U increase; 95% CI, 1.03–1.31), particularly for cancers of the oral cavity (HR, 1.40; 95% CI, 1.17–1.67). Height was also directly associated with total HNCAs (P = 0.02), and oro- and hypopharyngeal cancers (P < 0.01). Conclusions: The risk of HNCAs was associated inversely with leanness among current smokers, and directly with abdominal obesity and height. Impact: Our study provides evidence that the association between leanness and risk of HNCAs may be due to effect modification by smoking. Cancer Epidemiol Biomarkers Prev; 23(11); 2422–9. ©2014 AACR.

Regional variation in five indicators of health in early childhood: a cohort study

Background Persistent and marked differences in adult morbidity and mortality between regions in the United Kingdom (UK) are often referred to as the north-south gradient (or divide) and the Scottish effect, and are only partly explained by adult levels of socioeconomic status (SES) or risk factors which suggests variation arising earlier in life. The aim of the current study was to examine regional variations in five health indicators in children in England and Scotland at birth and three years of age.
Methods Respondents were 10,500 biological Caucasian mothers of singleton children recruited to the Millennium Cohort Study (MCS). Outcome variables were: gestational age and weight at birth, and height, body mass index (BMI), and externalising behaviour at age three. Region/Country was categorised as: South (reference), Midlands, North, and Scotland. Respondents provided information on child, maternal, household, and socioeconomic characteristics when the cohort infant/child was aged nine months and again when aged three years. 
Results There were no significant regional variations for gestational age or birthweight. However, at age three there was a north-south gradient for externalising behaviour and a north-south divide in BMI which attenuated on adjustment. However, a north-south divide in height was not fully explained by the adjusted model. There was also evidence of a ‘Midlands effect’, with increased likelihoods of shorter stature and behaviour problems. Results showed a Scottish effect for height and BMI in the unadjusted models, and height in the adjusted model. However, Scottish children were less likely to show behaviour problems in crude and adjusted models. 
Conclusions Findings indicated no marked regional differences in children at birth, but by age three some regional health differences were evident, and though not distinct north-south gradients or Scottish effects, are evidence of health inequalities appearing at an early age and dependent on geographic location.

The effect of warfarin therapy on breast, colorectal, lung, and prostate cancer survival: a population-based cohort study using the Clinical Practice Research Datalink

PURPOSE: Pre-clinical studies suggest that oral anticoagulant agents, such as warfarin, may inhibit metastases and potentially prolong survival in cancer patients. However, few population-based studies have examined the association between warfarin use and cancer-specific mortality.

METHODS: Using prescribing, cause of death, and cancer registration data from the UK Clinical Practice Research Datalink, four population-based cohorts were constructed, comprising breast, colorectal, lung, and prostate cancer patients diagnosed between 1 January 1998, and the 31 December 2010. Comparing pre-diagnostic warfarin users to non-users, multivariable Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95 % confidence intervals (CIs) for cancer-specific mortality.

RESULTS: Overall, 16,525 breast, 12,902 colorectal, 12,296 lung, and 12,772 prostate cancers were included. Pre-diagnostic warfarin use ranged from 2.4 to 4.7 %. There was little evidence of any strong association between warfarin use pre-diagnosis and cancer-specific mortality in prostate (adjusted HR 1.03, 95 % CI 0.84-1.26), lung (adjusted HR 1.06, 95 % CI 0.96-1.16), breast (adjusted HR 0.81, 95 % CI 0.62-1.07), or colorectal (adjusted HR 0.88, 95 % CI 0.77-1.01) cancer patients. Dose-response analyses did not reveal consistent evidence of reductions in users of warfarin defined by the number of prescriptions used and daily defined doses.

CONCLUSIONS: There was little evidence of associations between pre-diagnostic use of warfarin and cancer-specific mortality in lung, prostate, breast, or colorectal cancer patients.

Genetic studies of body mass index yield new insights for obesity biology

Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.

Statin Use and Survival from Lung Cancer: A Population-Based Cohort Study

Background: Preclinical evidence from lung cancer cell lines and animal models suggest that statins could have anticancer properties. We investigated whether statin users had reduced risk of cancer-specific mortality in a population based cohort of lung cancer patients.
Methods: Newly diagnosed lung cancer patients, from 1998 to 2009, were identified from English cancer registry data and linked to the UK Clinical Practice Research Datalink, providing prescription records, and to Office of National Statistics mortality data up to 2012. Cox regression models were used to calculate hazard ratios (HR) for cancer-specific mortality and 95% confidence intervals (CIs) by statin use before and after diagnosis and to adjust these HRs for potential confounders.
Results: In 3,638 lung cancer patients, there was some evidence that statin use after diagnosis was associated with reduced lung cancer-specific mortality (adjusted HR=0.89, 95% CI 0.78, 1.02; P=0.09). Associations were more marked after 12 prescriptions (adjusted HR=0.81, 95% CI 0.67, 0.98; P=0.03) and when lipophilic statins were investigated (adjusted HR=0.81, 95% CI 0.70, 0.94; P=0.01) but were attenuated in some sensitivity analyses. Furthermore, in 11,051 lung cancer patients, statin use before diagnosis was associated with reduced lung cancer-specific mortality (adjusted HR=0.88, 95% CI, 0.83, 0.93; P<0.001).
Conclusions: There was some evidence that lung cancer patients who used statins, and particularly simvastatin, had reduced rates of cancer-specific mortality.
 Impact: These findings should first be confirmed in observational studies, but provide some support for conducting randomized controlled trials of simvastatin as adjuvant cancer therapy in lung cancer patients.

Core Outcomes in Ventilation Trials (COVenT): protocol for a core outcome set using a Delphi survey with a nested randomised trial and observational cohort study

Background
Among clinical trials of interventions that aim to modify time spent on mechanical ventilation for critically ill patients there is considerable inconsistency in chosen outcomes and how they are measured. The Core Outcomes in Ventilation Trials (COVenT) study aims to develop a set of core outcomes for use in future ventilation trials in mechanically ventilated adults and children.

Methods/design
We will use a mixed methods approach that incorporates a randomised trial nested within a Delphi study and a consensus meeting. Additionally, we will conduct an observational cohort study to evaluate uptake of the core outcome set in published studies at 5 and 10 years following core outcome set publication. The three-round online Delphi study will use a list of outcomes that have been reported previously in a review of ventilation trials. The Delphi panel will include a range of stakeholder groups including patient support groups. The panel will be randomised to one of three feedback methods to assess the impact of the feedback mechanism on subsequent ranking of outcomes. A final consensus meeting will be held with stakeholder representatives to review outcomes.

Discussion
The COVenT study aims to develop a core outcome set for ventilation trials in critical care, explore the best Delphi feedback mechanism for achieving consensus and determine if participation increases use of the core outcome set in the long term.

β-Blocker usage and colorectal cancer mortality:a nested case-control study in the UK Clinical Practice Research Datalink cohort

BACKGROUND: Epidemiological and laboratory studies suggest that β-blockers may reduce cancer progression in various cancer sites. The aim of this study was to conduct the first epidemiological investigation of the effect of post-diagnostic β-blocker usage on colorectal cancer-specific mortality in a large population-based colorectal cancer patient cohort.

PATIENTS AND METHODS: A nested case-control analysis was conducted within a cohort of 4794 colorectal cancer patients diagnosed between 1998 and 2007. Patients were identified from the UK Clinical Practice Research Datalink and confirmed using cancer registry data. Patients with a colorectal cancer- specific death (data from the Office of National Statistics death registration system) were matched to five controls. Conditional logistic regression was applied to calculate odds ratios (OR) and 95% confidence intervals (95% CIs) according to β-blocker usage (data from GP-prescribing records).

RESULTS: Post-diagnostic β-blocker use was identified in 21.4% of 1559 colorectal cancer-specific deaths and 23.7% of their 7531 matched controls, with little evidence of an association (OR = 0.89 95% CI 0.78-1.02). Similar associations were found when analysing drug frequency, β-blocker type or specific drugs such as propranolol. There was some evidence of a weak reduction in all-cause mortality in β-blocker users (adjusted OR = 0.88; 95% CI 0.77-1.00; P = 0.04) which was in part due to the marked effect of atenolol on cardiovascular mortality (adjusted OR = 0.62; 95% CI 0.40-0.97; P = 0.04).

CONCLUSIONS: In this novel, large UK population-based cohort of colorectal cancer patients, there was no evidence of an association between post-diagnostic β-blocker use and colorectal cancer-specific mortality.

CLINICAL TRIALS NUMBER: NCT00888797.

Long-Term Follow-Up of a Large Active Surveillance Cohort of Patients With Prostate Cancer

PURPOSE: Active surveillance is increasingly accepted as a treatment option for favorable-risk prostate cancer. Long-term follow-up has been lacking. In this study, we report the long-term outcome of a large active surveillance protocol in men with favorable-risk prostate cancer.

PATIENTS AND METHODS: In a prospective single-arm cohort study carried out at a single academic health sciences center, 993 men with favorable- or intermediate-risk prostate cancer were managed with an initial expectant approach. Intervention was offered for a prostate-specific antigen (PSA) doubling time of less than 3 years, Gleason score progression, or unequivocal clinical progression. Main outcome measures were overall and disease-specific survival, rate of treatment, and PSA failure rate in the treated patients.

RESULTS: Among the 819 survivors, the median follow-up time from the first biopsy is 6.4 years (range, 0.2 to 19.8 years). One hundred forty-nine (15%) of 993 patients died, and 844 patients are alive (censored rate, 85.0%). There were 15 deaths (1.5%) from prostate cancer. The 10- and 15-year actuarial cause-specific survival rates were 98.1% and 94.3%, respectively. An additional 13 patients (1.3%) developed metastatic disease and are alive with confirmed metastases (n = 9) or have died of other causes (n = 4). At 5, 10, and 15 years, 75.7%, 63.5%, and 55.0% of patients remained untreated and on surveillance. The cumulative hazard ratio for nonprostate-to-prostate cancer mortality was 9.2:1.

CONCLUSION: Active surveillance for favorable-risk prostate cancer is feasible and seems safe in the 15-year time frame. In our cohort, 2.8% of patients have developed metastatic disease, and 1.5% have died of prostate cancer. This mortality rate is consistent with expected mortality in favorable-risk patients managed with initial definitive intervention.

Metformin use and survival after colorectal cancer: A population-based cohort study.

Preclinical evidence suggests that metformin could delay cancer progression. Previous epidemiological studies however have been limited by small sample sizes and certain time-related biases. This study aimed to investigate whether colorectal cancer patients with type 2 diabetes who were exposed to metformin had reduced cancer-specific mortality. We conducted a retrospective cohort study of 1,197 colorectal cancer patients newly diagnosed from 1998 to 2009 (identified from English cancer registries) with type 2 diabetes (based upon Clinical Practice Research Datalink, CPRD, prescription and diagnosis records). In this cohort 382 colorectal cancer-specific deaths occurred up to 2012 from the Office of National Statistics (ONS) mortality data. Metformin use was identified from CPRD prescription records. Using time-dependent Cox regression models, unadjusted and adjusted hazard ratios (HR) and 95% CIs were calculated for the association between post-diagnostic exposure to metformin and colorectal cancer-specific mortality. Overall, there was no evidence of an association between metformin use and cancer-specific death before or after adjustment for potential confounders (adjusted HR 1.06, 95% CI 0.80, 1.40). In addition, after adjustment for confounders, there was also no evidence of associations between other diabetic medications and cancer-specific mortality including sulfonylureas (HR 1.14, 95% CI 0.86, 1.51), insulin use (HR 1.35, 95% CI 0.95, 1.93) or other anti-diabetic medications including thiazolidinediones (HR 0.73, 95% CI 0.46, 1.14). Similar associations were observed by duration of use and for all-cause mortality. This population-based study, the largest to date, does not support a protective association between metformin and survival in colorectal cancer patients.

The prevalence of CALR mutations in a cohort of patients with myeloproliferative neoplasms

INTRODUCTION: To investigate the prevalence of calreticulin (CALR) mutations in JAK2- and MPL-non-mutated patients with suspected myeloproliferative neoplasm (MPN) from a large MPN clinic and confirm a diagnosis of MPN.

METHODS: JAK2/MPL-non-mutated patients from the Belfast City Hospital (BCH) with either of the MPNs - ET or MF - and diagnosed between 1988 and 2014 were selected for CALR screen. All cases were validated according to the WHO 2008 classification for MPNs. Statistical analysis was performed with Minitab 16 Statistical Software package. Exon 9 of CALR was amplified by PCR using genomic DNA, and mutations were detected by fragment analysis.

RESULTS: Of the 62 JAK2/MPL-non-mutated MPN patients screened, 57 had ET and 5 had MF; 34 patients (53.1%) carried CALR mutations. Three of 5 MF patients were CALR positive. Thirty-one ET patients (54.3%) harboured CALR mutation, whereas 26 (45.7%) were classified as 'triple negatives'.

CONCLUSION: Detection of CALR mutations in a cohort of JAK2/MPL-non-mutated patients with suspected MPN confirmed the diagnosis of MPN in around 53% of cases. This is lower than initially reported, but similar to subsequent studies. However, a sizable cohort of patients remains lacking a specific molecular marker.

Digoxin use after diagnosis of prostate cancer and survival: a population-based cohort study

PURPOSE:
Preclinical studies have shown that digoxin exerts anticancer effects on different cancer cell lines including prostate cancer. A recent observational study has shown that digoxin use was associated with a 25% reduction in prostate cancer risk. The aim of this study was to investigate whether digoxin use after diagnosis of prostate cancer was associated with decreased prostate cancer-specific mortality.
METHODS:
A cohort of 13 134 patients with prostate cancer newly diagnosed from 1998 to 2009 was identified from English cancer registries and linked to the UK Clinical Practice Research Datalink (to provide digoxin and other prescription records) and to the Office of National Statistics mortality data (to identify 2010 prostate cancer-specific deaths). Using time-dependent Cox regression models, unadjusted and adjusted hazard ratios (HR) and 95% confidence intervals (CIs) were calculated for the association between post-diagnostic exposure to digoxin and prostate cancer-specific mortality.
RESULTS:
Overall, 701 (5%) patients with prostate cancer used digoxin after diagnosis. Digoxin use was associated with an increase in prostate cancer-specific mortality before adjustment (HR = 1.59; 95% CI 1.32-1.91), but after adjustment for confounders, the association was attenuated (adjusted HR = 1.13; 95% CI 0.93-1.37) and there was no evidence of a dose response.
CONCLUSIONS:
In this large population-based prostate cancer cohort, there was no evidence of a reduction in prostate cancer-specific mortality with digoxin use after diagnosis.

A Validation Study of Vascular Cognitive Impairment Genetics Meta-Analysis Findings in an Independent Collaborative Cohort

Vascular cognitive impairment (VCI), including its severe form, vascular dementia (VaD), is the second most common form of dementia. The genetic etiology of sporadic VCI remains largely unknown. We previously conducted a systematic review and meta-analysis of all published genetic association studies of sporadic VCI prior to 6 July 2012, which demonstrated that APOE (ɛ4, ɛ2) and MTHFR (rs1801133) variants were associated with susceptibility for VCI. De novo genotyping was conducted in a new independent relatively large collaborative European cohort of VaD (nmax = 549) and elderly non-demented samples (nmax = 552). Where available, genotype data derived from Illumina's 610-quad array for 1210 GERAD1 control samples were also included in analyses of genes examined. Associations were tested using the Cochran-Armitage trend test: MTHFR rs1801133 (OR = 1.36, 95% CI 1.16-1.58, p = <0.0001), APOE rs7412 (OR = 0.62, 95% CI 0.42-0.90, p = 0.01), and APOE rs429358 (OR = 1.59, 95% CI 1.17-2.16, p = 0.003). Association was also observed with APOE epsilon alleles; ɛ4 (OR = 1.85, 95% CI 1.35-2.52, p = <0.0001) and ɛ2 (OR = 0.67, 95% CI 0.46-0.98, p = 0.03). Logistic Regression and Bonferroni correction in a subgroup of the cohort adjusted for gender, age, and population maintained the association of APOE rs429358 and ɛ4 allele.