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Background: Screening men for prostate cancer using prostate-specific antigen (PSA) testing remains controversial. We aimed to estimate the likely budgetary impact on secondary care in England and Wales to inform screening decision makers. Methods: The Cluster randomised triAl of PSA testing for Prostate cancer study (CAP) compared a single invitation to men aged 50–69 for a PSA test with usual care (no screening). Routinely collected hospital care data were obtained for all men in CAP, and NHS reference costs were mapped to each event via Healthcare Resource Group (HRG) codes. Secondary-care costs per man per year were calculated, and cost differences (and population-level estimates) between arms were derived annually for the first five years following randomisation. Results: In the first year post-randomisation, secondary-care costs averaged across all men (irrespective of a prostate cancer diagnosis) in the intervention arm (n = 189279) were £44.80 (95% confidence interval: £18.30-£71.30) higher than for men in the control arm (n = 219357). Extrapolated to a population level, the introduction of a single PSA screening invitation could lead to additional secondary care costs of £314 million. Conclusions: Introducing a single PSA screening test for men aged 50–69 across England and Wales could lead to very high initial secondary-care costs. [ABSTRACT FROM AUTHOR]

Background: There is limited evidence about the effectiveness of varenicline and nicotine replacement therapy (NRT) for long-term smoking cessation in primary care, or whether the treatment effectiveness differs by socioeconomic position (SEP). Therefore, we estimated the long-term effectiveness of varenicline versus NRT (> 2 years) on smoking cessation, and investigated whether effectiveness differs by SEP.Methods: This is a prospective cohort study of electronic medical records from 654 general practices in England, within the Clinical Practice Research Datalink, using three different analytical methods: multivariable logistic regression, propensity score matching and instrumental variable analyses. Exposure was prescription of varenicline versus NRT, and the primary outcome was smoking cessation at 2 years' follow-up; outcome was also assessed at 3, 6, and 9 months, and at 1 and 4 years after exposure. SEP was defined using the Index of Multiple Deprivation.Results: At 2 years, 28.8% (N = 20 362/70 610) of participants prescribed varenicline and 24.3% (N = 36 268/149 526) of those prescribed NRT quit; adjusted odds ratio was 1.26 [95% confidence interval (CI): 1.23 to 1.29], P < 0.0001. The association persisted for up to 4 years and was consistent across all analyses. We found little evidence that the effectiveness of varenicline differed greatly by SEP. However, patients from areas of higher deprivation were less likely to be prescribed varenicline; adjusted odds ratio was 0.91 (95% CI: 0.90 to 0.92), P < 0.0001.Conclusions: Patients prescribed varenicline were more likely to be abstinent up to 4 years after first prescription than those prescribed NRT. In combination with other evidence, the results from this study may be used to update clinical guidelines on the use of varenicline for smoking cessation. [ABSTRACT FROM AUTHOR]

Objectives: The Hospital Episode Statistics (HES) dataset is a source of administrative 'big data' with potential for costing purposes in economic evaluations alongside clinical trials. This study assesses the validity of coverage in the HES outpatient dataset.Methods: Men who died of, or with, prostate cancer were selected from a prostate-cancer screening trial (CAP, Cluster randomised triAl of PSA testing for Prostate cancer). Details of visits that took place after 1/4/2003 to hospital outpatient departments for conditions related to prostate cancer were extracted from medical records (MR); these appointments were sought in the HES outpatient dataset based on date. The matching procedure was repeated for periods before and after 1/4/2008, when the HES outpatient dataset was accredited as a national statistic.Results: 4922 outpatient appointments were extracted from MR for 370 men. 4088 appointments recorded in MR were identified in the HES outpatient dataset (83.1%; 95% confidence interval [CI] 82.0-84.1). For appointments occurring prior to 1/4/2008, 2195/2755 (79.7%; 95% CI 78.2-81.2) matches were observed, while 1893/2167 (87.4%; 95% CI 86.0-88.9) appointments occurring after 1/4/2008 were identified (p for difference <0.001). 215/370 men (58.1%) had at least one appointment in the MR review that was unmatched in HES, 155 men (41.9%) had all their appointments identified, and 20 men (5.4%) had no appointments identified in HES.Conclusions: The HES outpatient dataset appears reasonably valid for research, particularly following accreditation. The dataset may be a suitable alternative to collecting MR data from hospital notes within a trial, although caution should be exercised with data collected prior to accreditation. [ABSTRACT FROM AUTHOR]

Background: A diagnosis of prostate cancer leads to emotional distress and anxiety, prompting calls for rapid diagnostic pathways. Nevertheless, it remains unclear what impact time between diagnosis and surgery has upon prostate cancer survival.Methods: Using national databases for England (cancer registries, Hospital Episode Statistics and Office of National Statistics), we identified 17,043 men with prostate cancer, aged 15 years and older, diagnosed in 1996-2009, and who had surgical resection with curative intent within 6 months of diagnosis. We used relative survival to investigate associations between waiting times and five- and ten-year survival.Results: Five- and ten-year relative survival estimates for the total study sample were 1.04 (95% CI: 1.04 to 1.05) and 1.08 (95% CI: 1.06-1.09), respectively. There were no notable differences in survival between patients who had surgery at 0-3 and 4-6 months after diagnosis. Relative survival was higher among the elderly (>65) and those with well and moderately differentiated tumours.Conclusion: The high relative survival in our cohort probably reflects adherence to selection criteria for surgery among men with localised prostate cancer. Among men treated with surgery within 6 months of diagnosis, we found little evidence of an association between time from diagnosis to surgery and survival. [ABSTRACT FROM AUTHOR]

Background The publication in 2002 of the women's health initiative (WHI) trial revealed long-term risks and benefits of hormone replacement therapy (HRT). Increased cardiovascular disease, venous thromboembolism and breast cancer risks outweighed benefits on hip fracture, colorectal and endometrial cancer. We investigated whether the subsequent 50% fall in HRT use in England impacted on population rates of these outcomes. Methods Time-series analysis of hospital admissions, incidence and mortality amongst women aged 50–69, England 1997–2006. Results There was no relationship between reduced HRT prescribing after 2002 and trends in breast cancer, colorectal cancer or hip fracture. Amongst 50–59 year olds, the annual percentage change in venous thromboembolism hospitalizations fell from 0.0% [95% confidence interval (CI): −2.3 to 2.3%] between 1997 and 2000 to −5.7% (−7.7 to −3.6%) between 2000 and 2006 (P-value = 0.001); the annual change in endometrial cancer mortality increased from 0.7% (−3.2 to 4.8%) between 1997 and 2003 to 11.0% (0.2 to 22.9%) after 2003 (P-value = 0.07); and previously falling acute myocardial infarction hospitalizations (annual change: −6.8%) and stroke (−3.0%) stabilized (−0.4%) or increased (+0.8%), respectively, around 2001 (P < 0.0001). Conclusion Although rates of venous thromboembolism (decline) and endometrial cancer mortality (increase) changed in line with WHI findings, the decline in venous thromboembolism may have started before 2002 and increased fatal endometrial cancers could be a chance finding. [ABSTRACT FROM PUBLISHER]

Objective: To assess the association of having been breast fed with social class mobility between childhood and adulthood. Design: Historical cohort study with a 60-year follow-up from childhood into adulthood. Setting: 16 urban and rural centres in England and Scotland. Participants: 3182 original participants in the Boyd Orr Survey of Diet and Health in Pre-War Britain (1937–39) were sent follow-up questionnaires between 1997 and 1998. Analyses are based on 1414 (44%) responders with data on breast feeding measured in childhood and occupational social class in both childhood and adulthood. Main outcome: Odds of moving from a lower to a higher social class between childhood and adulthood in those who were ever breast fed versus those who were bottle fed. Results: The prevalence of breast feeding varied by survey district (range 45-86%) but not with household income (p=0.7), expenditure on food (p=0.3), number of siblings (p=0.7), birth order (p=0.5) or social class (p=0.4) in childhood. Participants who had been breast fed were 41% (95% CI 10% to 82%) more likely to move up a social class in adulthood (p=0.007) than bottle-fed infants. Longer breastfeeding duration was associated with greater odds of upward social mobility in fully adjusted models (p for trend=0.003). Additionally controlling for survey district, household income and food expenditure in childhood, childhood height, birth order or number of siblings did not attenuate these associations. In an analysis comparing social mobility among children within families with discordant breastfeeding histories, the association was somewhat attenuated (OR 1.16; 95% CI 0.74 to 1.8). Conclusions: Breast feeding was associated with upward social mobility. Confounding by other measured childhood predictors of social class in adulthood did not explain this effect, but we cannot exclude the possibility of residual or unmeasured confounding. [ABSTRACT FROM AUTHOR]

Aims To estimate the rates of common adverse events in patients treated with the proton pump inhibitors omeprazole, lansoprazole and pantoprazole in general practice in England. Methods In prescription‐event monitoring cohort studies, data on dispensed prescriptions prescribed by general practitioners in England soon after each drug was launched were linked to subsequent clinical events recorded by the prescriber. 16 205 patients prescribed omeprazole between June 1989 and June 1990, 17 329 patients prescribed lansoprazole between May and November 1994, and 11 541 patients prescribed pantoprazole between December 1996 and June 1997 were studied. Results The commonest adverse events in the omeprazole, lansoprazole and pantoprazole cohorts were diarrhoea (incidence: 0.18, 0.39 and 0.23 per 1000 days of exposure, respectively); nausea/vomiting (incidence: 0.16, 0.22 and 0.18 per 1000 days of exposure, respectively); abdominal pain (incidence: 0.17, 0.21 and 0.17 per 1000 days of exposure, respectively); and headache (incidence rates: 0.10, 0.17 and 0.15 per 1000 days of exposure, respectively). The remaining adverse events occurred at rates of less than 0.11 per 1000 days of exposure. There were little absolute differences in the rates of most events between the three proton pump inhibitors. However, diarrhoea was more commonly associated with lansoprazole compared with omeprazole (rate difference: 0.21 per 1000 days of exposure; 95% CI 0.17, 0.25; rate ratio: 2.11; 1.78, 2.51), and there was a clear age‐response relationship. Conclusions Adverse events occurred relatively infrequently in all three cohorts. There were only small absolute differences in event rates between the three drugs, although these data suggest the hypothesis that lansoprazole is associated with more frequent occurrence of diarrhoea, particularly in the elderly. [ABSTRACT FROM AUTHOR]

Aims Meloxicam is a novel nonsteroidal anti‐inflammatory drug (NSAID) which may be associated with fewer adverse upper gastrointestinal events than other NSAIDs because it preferentially inhibits the inducible enzyme cyclo‐oxygenase‐2 relative to the constitutive isoform, cyclo‐oxygenase‐1. The aims of the study were to: determine the rate of adverse events associated with meloxicam in general practice, stratify these rates by selected risk factors, and to identify signals of previously unsuspected adverse events associated with meloxicam. Methods As part of the national prescription‐event monitoring pharmacovigilance system for newly launched drugs in general practice, all patients prescribed meloxicam in England between December 1996 and March 1997 were identified by the central Prescription Pricing Authority. We sent short questionnaires to all prescribers asking about adverse events experienced within 6 months of the first prescription. Results There were 19 087 patients in the study. The rate of dyspepsia during the first month of exposure was 28.3 per 1000 patient‐months. There were 33 reports of upper gastrointestinal haemorrhage during treatment (rate: 0.4 per 1000 months). A history of gastrointestinal disorder in the previous year was associated with an increased rate of dyspepsia (rate ratio: 3.0; 95% confidence interval: 2.6, 3.4), abdominal pain (2.1; 1.6, 2.6), and peptic ulcer (4.0; 1.4, 13.2). Prior NSAID use was associated with a 20–30% decrease in the rate of dyspepsia and abdominal pain in patients starting meloxicam, while patients prescribed concomitant gastroprotective agents had a two to three‐fold increased rate of dyspepsia, abdominal pain and peptic ulceration. Other rare events were thrombocytopenia (n = 2); interstitial nephritis (n = 1) and idiosyncratic liver abnormalities (n = 1). Conclusions In the absence of gastro‐intestinal risk factors the incidence of gastro‐intestinal disturbance was low. Such risk factors should be carefully reviewed prior to prescribing meloxicam. [ABSTRACT FROM AUTHOR]

Importance: The Cluster Randomized Trial of PSA Testing for Prostate Cancer (CAP) reported no effect of prostate-specific antigen (PSA) screening on prostate cancer mortality at a median 10-year follow-up (primary outcome), but the long-term effects of PSA screening on prostate cancer mortality remain unclear., Objective: To evaluate the effect of a single invitation for PSA screening on prostate cancer-specific mortality at a median 15-year follow-up compared with no invitation for screening., Design, Setting, and Participants: This secondary analysis of the CAP randomized clinical trial included men aged 50 to 69 years identified at 573 primary care practices in England and Wales. Primary care practices were randomized between September 25, 2001, and August 24, 2007, and men were enrolled between January 8, 2002, and January 20, 2009. Follow-up was completed on March 31, 2021., Intervention: Men received a single invitation for a PSA screening test with subsequent diagnostic tests if the PSA level was 3.0 ng/mL or higher. The control group received standard practice (no invitation)., Main Outcomes and Measures: The primary outcome was reported previously. Of 8 prespecified secondary outcomes, results of 4 were reported previously. The 4 remaining prespecified secondary outcomes at 15-year follow-up were prostate cancer-specific mortality, all-cause mortality, and prostate cancer stage and Gleason grade at diagnosis., Results: Of 415 357 eligible men (mean [SD] age, 59.0 [5.6] years), 98% were included in these analyses. Overall, 12 013 and 12 958 men with a prostate cancer diagnosis were in the intervention and control groups, respectively (15-year cumulative risk, 7.08% [95% CI, 6.95%-7.21%] and 6.94% [95% CI, 6.82%-7.06%], respectively). At a median 15-year follow-up, 1199 men in the intervention group (0.69% [95% CI, 0.65%-0.73%]) and 1451 men in the control group (0.78% [95% CI, 0.73%-0.82%]) died of prostate cancer (rate ratio [RR], 0.92 [95% CI, 0.85-0.99]; P = .03). Compared with the control, the PSA screening intervention increased detection of low-grade (Gleason score [GS] ≤6: 2.2% vs 1.6%; P < .001) and localized (T1/T2: 3.6% vs 3.1%; P < .001) disease but not intermediate (GS of 7), high-grade (GS ≥8), locally advanced (T3), or distally advanced (T4/N1/M1) tumors. There were 45 084 all-cause deaths in the intervention group (23.2% [95% CI, 23.0%-23.4%]) and 50 336 deaths in the control group (23.3% [95% CI, 23.1%-23.5%]) (RR, 0.97 [95% CI, 0.94-1.01]; P = .11). Eight of the prostate cancer deaths in the intervention group (0.7%) and 7 deaths in the control group (0.5%) were related to a diagnostic biopsy or prostate cancer treatment., Conclusions and Relevance: In this secondary analysis of a randomized clinical trial, a single invitation for PSA screening compared with standard practice without routine screening reduced prostate cancer deaths at a median follow-up of 15 years. However, the absolute reduction in deaths was small., Trial Registration: isrctn.org Identifier: ISRCTN92187251.

The scientific question of whether protracted low-dose or low-dose-rate exposure to external radiation is causally related to the risk of circulatory disease continues to be an important issue for radiation protection. Previous analyses of a matched case-control dataset nested in a large cohort of UK nuclear fuel cycle workers indicated that there was little evidence that observed associations between external radiation dose and ischemic heart disease (IHD) mortality risk [OR = 1.35 (95% CI: 0.99-1.84) for 15-year-lagged exposure] could alternatively be explained by confounding from pre-employment tobacco smoking, BMI or blood pressure, or from socioeconomic status or occupational exposure to excessive noise or shiftwork. To improve causal inference about the observed external radiation dose and IHD mortality association, we estimated the potential magnitude and direction of non-random errors, incorporated sensitivity analyses and simulated bias effects under plausible scenarios. We conducted quantitative bias analyses of plausible scenarios based on 1,000 Monte Carlo samples to explore the impact of exposure measurement error, missing information on tobacco smoking, and unmeasured confounding, and assessed whether observed associations were reliant on the inclusion of specific matched pairs using bootstrapping with 10% of matched pairs randomly excluded in 1,000 samples. We further explored the plausibility that having been monitored for internal exposure, which was an important confounding factor in the case-control analysis for which models were adjusted, was indeed a confounding factor or whether it might have been the result of some form of selection bias. Consistent with the broader epidemiological evidence-base, these analyses provide further evidence that the dose-response association between cumulative external radiation exposure and IHD mortality is non-linear in that it has a linear shape plateauing at an excess risk of 43% (95% CI: 7-92%) on reaching 390 mSv. Analyses of plausible scenarios of patterns of missing data for tobacco smoking at start of employment indicated that this resulted in relatively little bias towards the null in the original analysis. An unmeasured confounder would have had to have been highly correlated (rp > 0.60) with cumulative external radiation dose to importantly bias observed associations. The confounding effect of "having been monitored for internal dose" was unlikely to have been a true confounder in a biological sense, but instead may have been some unknown factor related to differences over time and between sites in selection criteria for internal monitoring, possibly resulting in collider bias. Plausible patterns of exposure measurement error negatively biased associations regardless of the modeled scenario, but did not importantly change the shape of the observed dose-response associations. These analyses provide additional support for the hypothesis that the observed association between external radiation exposure and IHD mortality may be causal., (©2021 by Radiation Research Society. All rights of reproduction in any form reserved.)

Objectives: To confirm the association of previously reported prognostic factors with future progression of localised prostate cancer using primary care data and identify new potential prognostic factors for further assessment in prognostic model development and validation., Design: Retrospective cohort study, employing Cox proportional hazards regression controlling for age, prostate specific antigen (PSA), and Gleason score, was stratified by diagnostic stage., Setting: Primary care in England., Participants: Males with localised prostate cancer diagnosedbetween 01/01/1987 and 31/12/2016 within the Clinical Practice ResearchDatalink database, with linked data from the National Cancer Registration andAnalysis Service and Office for National Statistics., Primary and Secondary Outcomes: Primary outcome measure was prostate cancer mortality. Secondary outcome measures were all-cause mortality and commencing systemic therapy. Up-staging after diagnosis was not used as a secondary outcome owing to significant missing data., Results: 10 901 men (mean age 74.38±9.03 years) with localised prostate cancer were followed up for a mean of 14.12 (±6.36) years. 2331 (21.38%) men underwent systemic therapy and 3450 (31.65%) died, including 1250 (11.47%) from prostate cancer. Factors associated with an increased risk of prostate cancer mortality included age; high PSA; current or ex-smoker; ischaemic heart disease; high C reactive protein; high ferritin; low haemoglobin; high blood glucose and low albumin., Conclusions: This study identified several new potential prognostic factors for prostate cancer progression, as well as confirming some known prognostic factors, in an independent primary care data set. Further research is needed to develop and validate a prognostic model for prostate cancer progression., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Epidemiological studies have suggested a link between low-level radiation exposure and an increased risk of cardiovascular disease, but the possibility of bias or confounding must be considered. We analyzed data from a matched case-control study nested in a cohort of British male industrial (i.e., blue-collar) nuclear fuel cycle workers using paired conditional logistic regression. The cases were comprised of workers from two nuclear sites who had died from ischemic heart disease (IHD) and were matched to controls on nuclear site, date of birth and first year of employment (1,220 pairs). Radiation doses from external sources and to the liver from internally deposited plutonium and uranium were obtained. Models were adjusted for age at start of employment at either site, decade of start, age at exit from study (death or censoring), process/other worker and socio-economic status. Included potential confounding factors of interest were occupational noise, shift work, pre-employment blood pressure, body mass index and tobacco smoking. Cumulative external doses ranged from 0-1,656 mSv and cumulative internal doses for those monitored for radioactive intakes ranged from 0.004-5,732 mSv. In a categorical analysis, additionally adjusted for whether or not a worker was monitored for internal exposure, IHD mortality risk was associated with cumulative external unlagged dose with a 42% excess risk (95% CI: 4%, 95%) at >103 mSv (highest quartile relative to lowest quartile), and 35% (95% CI: -1%, 84%) at >109 mSv 15-year lagged dose. The log-linear increase in risk per 100 mSv was 2% (95% CI: -4%, 8%) for unlagged external dose and 5% (95% CI: -2%, 11%) for 15-year lagged dose. Associations with external dose for workers monitored only for exposure to external radiation reflected those previously reported for the cohort from which the cases and controls were drawn. There was little evidence of excess risk associated with cumulative doses from internal sources, which had not been assessed in the cohort study. The impact of the included potential confounding variables was minimal, with the possible exception of occupational noise exposure. Subgroup analyses indicated evidence of heterogeneity between sites, occupational groups and employment duration, and an important factor was whether workers were monitored for the potential presence of internal emitters, which was not explained by other factors included in the study. In summary, we found evidence for an increased IHD mortality risk associated with external radiation dose, but little evidence of an association with internal dose. External dose associations were minimally affected by important confounders. However, the considerable heterogeneity in the associations with external doses observed between subgroups of workers is difficult to explain and requires further work., (©2020 by Radiation Research Society. All rights of reproduction in any form reserved.)

Objective: Dietary factors and physical activity may alter prostate cancer progression. We explored the feasibility of lifestyle interventions following radical prostatectomy for localised prostate cancer., Design: Patients were recruited into a presurgical observational cohort; following radical prostatectomy, they were offered randomisation into a 2×3 factorial randomised controlled trial (RCT)., Setting: A single National Health Service trust in the South West of England, UK., Participants: Those with localised prostate cancer and listed for radical prostatectomy were invited to participate., Randomisation: Random allocation was performed by the Bristol Randomised Trial Collaboration via an online system., Interventions: Men were randomised into both a modified nutrition group (either increased vegetable and fruit, and reduced dairy milk; or lycopene supplementation; or control) and a physical activity group (brisk walking or control) for 6 months., Blinding: Only the trial statistician was blind to allocations., Primary Outcome Measures: Primary outcomes were measures of feasibility: randomisation rates and intervention adherence at 6 months. Collected at trial baseline, three and six months, with daily adherence reported throughout. Our intended adherence rate was 75% or above, the threshold for acceptable adherence was 90%., Results: 108 men entered the presurgical cohort, and 81 were randomised into the postsurgical RCT (randomisation rate: 93.1%) and 75 completed the trial. Of 25 men in the nutrition intervention, 10 (40.0%; 95% CI 23.4% to 59.3%) adhered to the fruit and vegetable recommendations and 18 (72.0%; 95% CI 52.4% to 85.7%) to reduced dairy intake. Adherence to lycopene (n=28), was 78.6% (95% CI 60.5% to 89.8%), while 21/39 adhered to the walking intervention (53.8%; 95% CI 38.6% to 68.4%). Most men were followed up at 6 months (75/81; 92.6%). Three 'possibly related' adverse events were indigestion, abdominal bloating and knee pain., Conclusions: Interventions were deemed feasible, with high randomisation rates and generally good adherence. A definitive RCT is proposed., Trial Registration Number: ISRCTN 99048944., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.)

Background: Drugs for dementia have been available in England since 1997. Since their launch, there have been several changes to national guidelines and initiatives that may have influenced prescribing. These include changes in National Institute for Health and Care Excellence (NICE) guidance, several government dementia strategies, the addition of dementia to the Quality and Outcomes Framework (QOF), and the expiry of drug patents. Despite this, there has been little research into the effect of these events on prescribing. This paper examines prescribing trends in England using data from the U.K. Clinical Practice Research Datalink since the launch of drugs for dementia up to 1st January 2016., Methods: We considered the monthly proportion of patients eligible for treatment, with a diagnosis of probable Alzheimer's disease, receiving their first prescription for each drug class-namely, acetylcholinesterase (AChE) inhibitors (donepezil, rivastigmine, galantamine) and N-methyl-D-aspartate (NMDA) receptor antagonists (memantine). Trend analysis using joinpoint models was then applied to identify up to two trend changes per treatment of interest., Results: The overall trend was for increasing prescriptions in each drug class over the period in which they were studied. This was indicated by the average monthly percentage change, which was 6.0% (95% CI, - 6.4 to 19.9; June 1997 to December 2015) for AChE inhibitors and 15.4% (95% CI, - 77.1 to 480.9; January 2003 to December 2015) for NMDA receptor antagonists. Prescriptions of AChE inhibitors increased at the end of 2012, probably in response to the patent expiry of these drugs earlier that year. The Prime Minister's Dementia Challenge launched in May 2012 may also have contributed to the observed increase. However, neither this strategy nor patent expiry appeared to influence prescriptions of NMDA receptor antagonists. Instead trend changes in this drug class were driven by NICE guidance released in 2011 that allowed access to these drugs outside of clinical trials., Conclusions: Dementia drug prescribing does not always respond to factors such as regulatory guidance, recommendations, or patent expiry, and when it does, not necessarily in a predictable way. This suggests that communication with clinicians may need to be improved to use drugs for dementia more cost-effectively.

Objectives: To ascertain the challenges associated with implementation of the 2-week wait referral criteria and waiting time targets for colorectal cancer and to identify recommendations for improvements to the pathway., Design: Qualitative research using semistructured interviews and applying thematic analysis using the method of constant comparison., Setting: 10 primary care surgeries and 6 secondary care centres from 3 geographical areas in the England., Participants: Purposive sample of 24 clinicians (10 general practitioners (GPs), 7 oncologists and 7 colorectal surgeons)., Results: GPs and specialists highlighted delays in patient help-seeking, difficulties applying the colorectal cancer referral criteria due to their low predictive value, and concerns about the stringent application of targets because of potential impact on individual care and associated penalties for breaching. Promoting patient awareness and early presentation, clarifying predictive symptoms, allowing flexibility, optimising resources and maximising care coordination were suggested as improvements., Conclusions: Challenges during diagnosis and treatment persist, with guidelines and waiting time targets producing the perception of unintended harms at individual and organisational levels. This has led to variations in how guidelines are implemented. These require urgent evaluation, so that effective practices can be adopted more widely., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Rapid diagnostic pathways for cancer have been implemented, but evidence whether shorter diagnostic intervals (time from primary care presentation to diagnosis) improves survival is lacking. Using the Clinical Practice Research Datalink, we identified patients diagnosed with female breast (8,639), colorectal (5,912), lung (5,737) and prostate (1,763) cancers between 1998 and 2009, and aged >15 years. Presenting symptoms were classified as alert or non-alert, according to National Institute for Health and Care Excellence guidance. We used relative survival and excess risk modeling to determine associations between diagnostic intervals and five-year survival. The survival of patients with colorectal, lung and prostate cancer was greater in those with alert, compared with non-alert, symptoms, but findings were opposite for breast cancer. Longer diagnostic intervals were associated with lower mortality for colorectal and lung cancer patients with non-alert symptoms, (colorectal cancer: Excess Hazards Ratio, EHR >6 months vs <1 month: 0.85; 95% CI: 0.72-1.00; Lung cancer: EHR 3-6 months vs <1 month: 0.87; 95% CI: 0.80-0.95; EHR >6 months vs <1 month: 0.81; 95% CI: 0.74-0.89). Prostate cancer mortality was lower in patients with longer diagnostic intervals, regardless of type of presenting symptom. The association between diagnostic intervals and cancer survival is complex, and should take into account cancer site, tumour biology and clinical practice. Nevertheless, unnecessary delay causes patient anxiety and general practitioners should continue to refer patients with alert symptoms via the cancer pathways, and actively follow-up patients with non-alert symptoms in the community.

Background: Colorectal cancer survival in the UK is lower than in other developed countries, but the association of time interval between diagnosis and treatment on excess mortality remains unclear., Methods: Using data from cancer registries in England, we identified 46,511 patients with localised colorectal cancer between 1996-2009, who were 15 years and older, and who underwent a major surgical resection within 62 days of diagnosis. We used relative survival and excess risk modeling to investigate the association of time between diagnosis and major resection (exposure) with survival (outcome)., Results: Compared to patients who had major resection within 25-38 days of diagnosis, patients with a shorter time interval between diagnosis and resection and those waiting longer for resection had higher excess mortality (Excess Hazards Ratio, EHR <25 vs 25-38 days: 1.50; 95% Confidence Interval, CI: 1.37 to 1.66; EHR 39-62 vs 25-38 days : 1.16; 95% CI: 1.04 to 1.29). Excess mortality was associated with age (EHR 75+ vs. 15-44 year olds: 2.62; 95% CI: 2.00 to 3.42) and deprivation (EHR most vs. least deprived: 1.27; 95% CI: 1.12 to 1.45), but time between diagnosis and resection did not explain these differences., Conclusion: Within 62 days of diagnosis, a U-shaped association of time between diagnosis and major resection with excess mortality for localised colorectal cancer was evident. This indicates a complicated treatment pathway, particularly for patients who had resection earlier than 25 days, and requires further investigation.

Background: A diagnosis of prostate cancer leads to emotional distress and anxiety, prompting calls for rapid diagnostic pathways. Nevertheless, it remains unclear what impact time between diagnosis and surgery has upon prostate cancer survival., Methods: Using national databases for England (cancer registries, Hospital Episode Statistics and Office of National Statistics), we identified 17,043 men with prostate cancer, aged 15 years and older, diagnosed in 1996-2009, and who had surgical resection with curative intent within 6 months of diagnosis. We used relative survival to investigate associations between waiting times and five- and ten-year survival., Results: Five- and ten-year relative survival estimates for the total study sample were 1.04 (95% CI: 1.04 to 1.05) and 1.08 (95% CI: 1.06-1.09), respectively. There were no notable differences in survival between patients who had surgery at 0-3 and 4-6 months after diagnosis. Relative survival was higher among the elderly (>65) and those with well and moderately differentiated tumours., Conclusion: The high relative survival in our cohort probably reflects adherence to selection criteria for surgery among men with localised prostate cancer. Among men treated with surgery within 6 months of diagnosis, we found little evidence of an association between time from diagnosis to surgery and survival.

OBJECTIVE • To estimate rates of prostate-specific antigen (PSA) testing in UK general practices by age, deprivation index and geographical location. SUBJECTS AND METHODS • Practice-based, retrospective data on PSA testing patterns in 2007 were collected from a random sample of 87 general practices using EMIS LV computer systems within the passively observed non-intervention arm of a cluster-randomized controlled trial. • Information for a total of 126 716 men aged 45-89 years with no recorded diagnosis of prostate cancer prior to 1 January 2007 was collected. RESULTS • In all, 7902 (6.2%) of 126 716 men aged 45-89 without a prior diagnosis of prostate cancer underwent at least one PSA test from their general practitioner during 2007 [95% confidence interval (CI) 5.6-7.0%; practice-based inter-quartile range 3.6-8.4%]. • PSA testing rates were 1.4% (95% CI 1.1-1.6%) in men aged 45-49, rising to 11.3% (95% CI 10.0-12.9%) at age 75-79 years (P for trend <0.001). • Testing rates were lowest in the three northern centres (3.5-5.7%) vs the three more southern centres (7.1-8.9%; P < 0.001). • For every 20 points increase in the index of multiple deprivation score, the proportion of men tested fell by 1.7% (95% CI -2.5 to -0.8%; P < 0.001). • Lower proportions of men were subsequently diagnosed with prostate cancer in practices testing more men (odds ratio for a one unit increase in the natural log of testing 0.76; 95% CI 0.60-0.97; P= 0.025). CONCLUSION • Overall levels of PSA testing in UK general practice remain low, but for those tested there are important variations by age, deprivation and geographical location that do not appear to reflect clinical need or the intention of current policy. • PSA testing in general practice is currently skewed towards older men, and current policy enabling all men to make an informed choice about PSA testing is not being effectively implemented as uptake clearly varies by socioeconomic status. • This reinforces the need for robust evidence regarding the costs and benefits of using the PSA test for the detection of localized prostate cancer in the UK, a full assessment of the health economic implications and a revision of the current policy., (© 2011 THE AUTHORS. BJU INTERNATIONAL © 2011 BJU INTERNATIONAL.)

Background: If treatments are used to modify a trait, then patients with high-risk genotypes for the trait should be found at higher frequency in treatment groups than in the general population. The frequency ratio of high- to low-risk genotypes treated should reflect the mean threshold above which the treatment is given in the population. As an example, we hypothesized that because APOE (apolipoprotein E) alleles affect the LDL cholesterol (LDLc) concentration, APOE genotype frequencies in statin takers should act as a proxy for the prevailing treatment threshold of LDLc., Methods: We used LDLc, statin usage, and APOE genotype data from the British Women's Heart and Health Study (n=2289; age, 60-79 years) and calculated the genotype ratio treatment index (GRTI) by dividing the proportion of ε3/ε2 or ε3/ε4 participants prescribed a statin by the proportion of ε3/ε3 participants prescribed a statin, both overall and according to socioeconomic class, geographic region, and coronary heart disease (CHD) status. Genotype-specific LDLc distributions were used to calculate the mean LDLc treatment threshold., Results: For genotype ε3/ε2, the GRTI was 0.52 (95% CI, 0.30-0.87) for statin takers overall, 0.22 (95% CI, 0.00-0.56) for those without CHD, and 0.69 (95% CI, 0.31-1.18) for those with CHD. The GRTIs for those without and with CHD backcalculate to LDLc thresholds of 5.65 mmol/L (95% CI, 5.50-5.82 mmol/L) and 4.39 mmol/L (95% CI, 4.21-4.59 mmol/L), respectively. Scotland and North England showed dissimilar GRTIs, which backcalculated to LDLc thresholds of 5.06 mmol/L (95% CI, 4.83-5.28 mmol/L) and 5.44 mmol/L (95% CI, 5.19-5.69 mmol/L), respectively, for all women., Conclusions: The findings illustrate how genotype frequencies can be a proxy for treatment thresholds used in clinical practice. Genome-wide studies have identified>500 disease-relevant polymorphisms. GRTIs from cost-efficient genotyping, in combination with phenotypic data, may have wide potential in health services research.

Associations between childhood BMI and adult cancer risk were investigated in a historical cohort study based on the Carnegie ("Boyd Orr") Survey of Diet and Health in Pre-War Britain (1937-9). In 14 centres in England and Scotland, children had their height and weight measured. We included 2,347 individuals aged between 2 and 14 years 9 months at the time of measurement, who were traced through the National Health Service Central Register. Relative cancer risk (registration or death) was estimated in relation to age- and sex-specific BMI SD scores. We studied associations with (i) all cancers, (ii) cancer groups stratified according to their relationship to smoking and (iii) certain site-specific cancers. In the 50 years of follow-up, 188 men and 192 women developed cancer. There was a 9% increase (95% CI -3 to 22%) in risk of cancer in adulthood per SD increase in BMI measured in childhood. There was no evidence of confounding by childhood or adulthood socioeconomic position, other anthropometric variables, childhood energy intake or birth order. There was a 30% increase (95% CI 10-54%) in risk of smoking-related cancers per SD increase in childhood BMI. There was no relationship between BMI and cancers not related to smoking. Associations for all cancers and non-smoking-related cancers tended to be stronger in children who were measured at an older (>8 years) rather than a younger (< or =8 years) age. We conclude that childhood BMI is related to increased risk of cancer in later life, particularly smoking-related cancers., (Copyright 2004 Wiley-Liss, Inc.)

The prevalence of psychiatric morbidity appears to be lower in rural than urban areas. Using the Fourth National GP Morbidity Survey (1991-1992) we have compared patterns of GP consultation for mental illness by young people living in rural and urban areas to investigate whether patterns of morbidity are reflected in GP help-seeking. We investigated whether urban-rural differences were due to differences in the socio-economic characteristics of residents. The crude rate ratio for consultation for mental disorder in rural compared to urban males was 0.55 (95% Cl 0.47 to 0.65) and for females was 0.78 (0.71 to 0.86). After controlling for socioeconomic differences between rural and urban areas, consultation rates for mental illness were 30% (95% Cl 19% to 41%) lower in males and 16 per cent (8% to 24%) lower in females in rural compared to urban areas. These findings are in line with population surveys indicating that levels of mental illness are lower in rural compared to urban areas. Part of the difference economic characteristics of people living in these areas. Further studies are needed to investigate possible area effects on the prevalence of mental illness. reflects differences in the socio-