Association between socioeconomic factors and cancer risk: a population cohort study in Scotland (1991-2006).

BACKGROUND: Lung and upper aero-digestive tract (UADT) cancer risk are associated with low socioeconomic circumstances and routinely measured using area socioeconomic indices. We investigated effect of country of birth, marital status, one area deprivation measure and individual socioeconomic variables (economic activity, education, occupational social class, car ownership, household tenure) on risk associated with lung, UADT and all cancer combined (excluding non melanoma skin cancer). METHODS: We linked Scottish Longitudinal Study and Scottish Cancer Registry to follow 203,658 cohort members aged 15+ years from 1991-2006. Relative risks (RR) were calculated using Poisson regression models by sex offset for person-years of follow-up. RESULTS: 21,832 first primary tumours (including 3,505 lung, 1,206 UADT) were diagnosed. Regardless of cancer, economically inactivity (versus activity) was associated with increased risk (male: RR 1.14, 95% CI 1.10-1.18; female: RR 1.06, 95% CI 1.02-1.11). For lung cancer, area deprivation remained significant after full adjustment suggesting the area deprivation cannot be fully explained by individual variables. No or non degree qualification (versus degree) was associated with increased lung risk; likewise for UADT risk (females only). Occupational social class associations were most pronounced and elevated for UADT risk. No car access (versus ownership) was associated with increased risk (excluding all cancer risk, males). Renting (versus home ownership) was associated with increased lung cancer risk, UADT cancer risk (males only) and all cancer risk (females only). Regardless of cancer group, elevated risk was associated with no education and living in deprived areas. CONCLUSIONS: Different and independent socioeconomic variables are inversely associated with different cancer risks in both sexes; no one socioeconomic variable captures all aspects of socioeconomic circumstances or life course. Association of multiple socioeconomic variables is likely to reflect the complexity and multifaceted nature of deprivation as well as the various roles of these dimensions over the life course.

Does widowhood increase mortality risk?: testing for selection effects by comparing causes of spousal death.

BACKGROUND: We consider whether widowhood increases mortality risk. Although commonly observed, this "widowhood effect" could be due to selection effects, as married couples share various characteristics related to the risk of death. We therefore consider the widowhood effect by various causes of spousal death; some causes of death are correlated with shared characteristics in couples, while others are not. METHODS: Using data from the Scottish Longitudinal Study, we compare outcomes for men and women by the causes of death of their spouse, controlling for a range of individual- and household-level characteristics. RESULTS: The widowhood effect in these data is greater than has been found in other recent studies, with adjusted hazard ratios of 1.40 (95% confidence interval = 1.33-1.47) for men and 1.36 (1.30-1.44) for women. The risk is highest shortly after widowhood, but remains raised for at least 10 years. There was little evidence that these hazard ratios differed by any classification of the cause of death of the spouse, but interactions were found for those with pre-existing illness or other risk factors. The hazard ratios for widowhood were lower for persons with preexisting risks. CONCLUSIONS: Our analysis of the widowhood effect uses 3 methods of classifying the causes of spousal death in an attempt to control for potential selection effects. Our results are highly consistent and suggest that this is a causal effect, rather than a result of selection.

Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL) trial: An intention-to-treat analysis of amputation-free and overall survival in patients randomized to a bypass surgery-first or a balloon angioplasty-first revascularization strategy.

BACKGROUND: A 2005 interim analysis of the Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL) trial showed that in patients with severe lower limb ischemia (SLI; rest pain, ulceration, gangrene) due to infrainguinal disease, bypass surgery (BSX)-first and balloon angioplasty (BAP)-first revascularization strategies led to similar short-term clinical outcomes, although BSX was about one-third more expensive and morbidity was higher. We have monitored patients for a further 2.5 years and now report a final intention-to-treat (ITT) analysis of amputation-free survival (AFS) and overall survival (OS). METHODS: Of 452 enrolled patients in 27 United Kingdom hospitals, 228 were randomized to a BSX-first and 224 to a BAP-first revascularization strategy. All patients were monitored for 3 years and more than half for >5 years. RESULTS: At the end of follow-up, 250 patients were dead (56%), 168 (38%) were alive without amputation, and 30 (7%) were alive with amputation. Four were lost to follow-up. AFS and OS did not differ between randomized treatments during the follow-up. For those patients surviving 2 years from randomization, however, BSX-first revascularization was associated with a reduced hazard ratio (HR) for subsequent AFS of 0.85 (95% confidence interval [CI], 0.5-1.07; P = .108) and for subsequent OS of 0.61 (95% CI, 0.50-0.75; P = .009) in an adjusted, time-dependent Cox proportional hazards model. For those patients who survived for 2 years after randomization, initial randomization to a BSX-first revascularization strategy was associated with an increase in subsequent restricted mean overall survival of 7.3 months (95% CI, 1.2-13.4 months, P = .02) and an increase in restricted mean AFS of 5.9 months (95% CI, 0.2-12.0 months, P = .06) during the subsequent mean follow-up of 3.1 years (range, 1-5.7 years). CONCLUSIONS: Overall, there was no significant difference in AFS or OS between the two strategies. However, for those patients who survived for at least 2 years after randomization, a BSX-first revascularization strategy was associated with a significant increase in subsequent OS and a trend towards improved AFS.

Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL) trial: Health-related quality of life outcomes, resource utilization, and cost-effectiveness analysis.

BACKGROUND: The Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL) trial showed that survival in patients with severe lower limb ischemia (rest pain, tissue loss) who survived postintervention for >2 years after initial randomization to bypass surgery (BSX) vs balloon angioplasty (BAP) was associated with an improvement in subsequent amputation-free and overall survival of about 6 and 7 months, respectively. We now compare the effect on hospital costs and health-related quality of life (HRQOL) of the BSX-first and BAP-first revascularization strategies using a within-trial cost-effectiveness analysis. METHODS: We measured HRQOL using the Vascular Quality of Life Questionnaire (VascuQol), the Short Form 36 (SF-36), and the EuroQol (EQ-5D) health outcome measure up to 3 years from randomization. Hospital use was measured and valued using United Kingdom National Health Service hospital costs over 3 years. Analysis was by intention-to-treat. Incremental cost-effectiveness ratios were estimated for cost per quality-adjusted life-year (QALY) gained. Uncertainty was assessed using nonparametric bootstrapping of incremental costs and incremental effects. RESULTS: No significant differences in HRQOL emerged when the two treatment strategies were compared. During the first year from randomization, the mean cost of inpatient hospital treatment in patients allocated to BSX ($34,378) was estimated to be about $8469 (95% confidence interval, $2,417-$14,522) greater than that of patients allocated to BAP ($25,909). Owing to increased costs subsequently incurred by the BAP patients, this difference decreased at the end of follow-up to $5521 ($45,322 for BSX vs $39,801 for BAP) and was no longer significant. The incremental cost-effectiveness ratio of a BSX-first strategy was $184,492 per QALY gained. The probability that BSX was more cost-effective than BAP was relatively low given the similar distributions in HRQOL, survival, and hospital costs. CONCLUSIONS: Adopting a BSX-first strategy for patients with severe limb ischemia does result in a modest increase in hospital costs, with a small positive but insignificant gain in disease-specific and generic HRQOL. However, the real-world choice between BSX-first and BAP-first revascularization strategies for severe limb ischemia due to infrainguinal disease cannot depend on costs alone and will require a more comprehensive consideration of individual patient preferences conditioned by expectations of survival and other health outcomes.

Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL) trial: Analysis of amputation free and overall survival by treatment received.

BACKGROUND: An intention-to-treat analysis of randomized Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL) trial data showed that initial randomization to a bypass surgery (BSX)-first strategy was associated with improvements in subsequent overall survival (OS) and amputation-free survival (AFS) of about 7 and 6 months, respectively. We describe the nature and timing of first, crossover, and reinterventions and examine AFS and OS by first treatment received. We also compare vein with prosthetic BSX and transluminal with subintimal balloon angioplasty (BAP) and examine outcomes from BSX after failed BAP. METHODS: We randomly assigned 452 patients with SLI due to infrainguinal disease in 27 United Kingdom hospitals to a BSX first (n = 228) or a BAP first (n = 224) revascularization strategy. All patients have been monitored for 3 years and more than half for >5 years. We prospectively collected data on every procedure, major amputation, and death. RESULTS: Patients randomized to BAP were more likely to have their assigned treatment first (94% vs 85%, P = .01, chi(2)test). BAP had a higher immediate technical failure rate of 20% vs 2.6% (P = .01, chi(2)test). By 12 weeks after randomization 9 BAP (4%) vs 23 BSX (10%) patients had not undergone revascularization; 3 BAP (1.3%) vs 13 BSX (5.8%) had undergone the opposite treatment first; and 35 BAP (15.6%) and 2 (0.9%) BSX had received the assigned treatment and then undergone the opposite treatment. BSX distal anastomoses were divided approximately equally between the above and below knee popliteal and crural arteries; most originated from the common femoral artery. About 25% of the grafts were prosthetic and >90% of vein BSX used ipsilateral great saphenous vein. Most (80%) BAP patients underwent treatment of the SFA alone (38%) or combined with the popliteal artery (42%) and crural arteries (20%). Outcome of vein BSX was better for AFS (P = 0.003) but not OS (P = 0.38, log-rank tests) than prosthetic BSX. There were no differences in outcome between approximately equal numbers of transluminal and subintimal BAP. AFS (P = 0.006) but not OS (P = 0.06, log rank test) survival was significantly worse after BSX after failed BAP than after BSX as a first revascularization attempt. CONCLUSIONS: BAP was associated with a significantly higher early failure rate than BSX. Most BAP patients ultimately required surgery. BSX outcomes after failed BAP are significantly worse than for BSX performed as a first revascularization attempt. BSX with vein offers the best long term AFS and OS and, overall, BAP appears superior to prosthetic BSX.

Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL) trial: A description of the severity and extent of disease using the Bollinger angiogram scoring method and the TransAtlantic Inter-Society Consensus II classification.

BACKGROUND: The Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL) trial showed in patients with severe lower limb ischemia (rest pain, tissue loss) who survive for 2 years after intervention that initial randomization to bypass surgery, compared with balloon angioplasty, was associated with an improvement in subsequent amputation-free survival and overall survival of about 6 and 7 months, respectively. The aim of this report is to describe the angiographic severity and extent of infrainguinal arterial disease in the BASIL trial cohort so that the trial outcomes can be appropriately generalized to other patient cohorts with similar anatomic (angiographic) patterns of disease. METHODS: Preintervention angiograms were scored using the Bollinger method and the TransAtlantic Inter-Society Consensus (TASC) II classification system by three consultant interventional radiologists and two consultant vascular surgeons unaware of the treatment received or patient outcomes. RESULTS: As was to be expected from the randomization process, patients in the two trial arms were well matched in terms of angiographic severity and extent of disease as documented by Bollinger and TASC II. In patients with the least overall disease, it tended to be concentrated in the superficial femoral and popliteal arteries, which were the commonest sites of disease overall. The below knee arteries became increasingly involved as the overall severity of disease increased, but the disease in the above knee arteries did not tend to worsen. The posterior tibial artery was the most diseased crural artery, whereas the peroneal appeared relatively spared. There was less interobserver disagreement with the Bollinger method than with the TASC II classification system, which also appears inherently less sensitive to clinically important differences in infrapopliteal disease among patients with severe leg ischemia. CONCLUSIONS: Anatomic (angiographic) disease description in patients with severe leg ischemia requires a reproducible scoring system that is sensitive to differences in crural artery disease. The Bollinger system appears well suited for this purpose, but the TASC II classification system less so. We hope this detailed analysis will facilitate appropriate generalization of the BASIL trial data to other groups of patients affected by similar anatomic (angiographic) patterns of disease.

Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL) trial: A survival prediction model to facilitate clinical decision making.

BACKGROUND: An intention-to-treat analysis of the Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL) trial showed that in patients with severe lower limb ischemia (SLI) due to infrainguinal disease who survived for 2 years after intervention, initial randomization to a bypass surgery (BSX)-first vs balloon angioplasty (BAP)-first revascularization strategy was associated with improvements in subsequent overall survival (OS) and amputation-free survival (AFS) of about 7 and 6 months, respectively. This study explored the value of baseline factors to estimate the likelihood of survival to 2 years for the trial cohort (Cox model) and for individual BASIL trial patients (Weibull model) as an aid to clinical decision making. METHODS: Of 452 patients presenting to 27 United Kingdom hospitals, 228 were randomly assigned to a BSX-first and 224 to a BAP-first revascularization strategy. Patients were monitored for at least 3 years. Baseline factors affecting the survival of the entire cohort were examined with a multivariate Cox model. The chances of survival at 1 and 2 years for patients with given baseline characteristics were estimated with a Weibull parametric model. RESULTS: At the end of follow-up, 172 patients (38%) were alive without major limb amputation of the trial leg, and 202 (45%) were alive. Baseline factors that were significant in the Cox model were BASIL randomization stratification group, below knee Bollinger angiogram score, body mass index, age, diabetes, creatinine level, and smoking status. Using these factors to define five equally sized groups, we identified patients with 2-year survival rates of 50% to 90%. The factors that contributed to the Weibull predictive model were age, presence of tissue loss, serum creatinine, number of ankle pressure measurements detectable, maximum ankle pressure measured, a history of myocardial infarction or angina, a history of stroke or transient ischemia attack, below knee Bollinger angiogram score, body mass index, and smoking status. CONCLUSIONS: Patients in the BASIL trial were at high risk of amputation and death regardless of revascularization strategy. However, baseline factors can be used to stratify those risks. Furthermore, within a parametric Weibull model, certain of these factors can be used to help predict outcomes for individuals. It may thus be possible to define the clinical and anatomic (angiographic) characteristics of SLI patients who are likely-and not likely-to live for >2 years after intervention. Used appropriately in the context of the BASIL trial outcomes, this may aid clinical decision making regarding a BSX- or BAP-first revascularization strategy in SLI patients like those randomized in BASIL.

Randomized comparison of dry dressings versus hydrogel in management of radiation-induced moist desquamation.

PURPOSE: We present the results of a randomized controlled clinical trial that evaluated the effect of a hydrogel or dry dressing on the time to healing of moist desquamation after radiotherapy to the head-and-neck, breast, or anorectal areas. METHODS AND MATERIALS: A total of 357 patients were randomized before radiotherapy to receive simple dry dressings (Tricotex) or a hydrogel (Intrasite), with Tricotex as a secondary dressing. Patients were instructed to use their dressings from the onset of moist desquamation, if it occurred. RESULTS: Of the 357 patients, 100 (28%) developed moist desquamation. The time to healing was significantly prolonged (hazard ratio, 0.64; 95% confidence interval, 0.42-0.99), in patients assigned to gel dressings. No evidence was found that gel dressings had a significant impact on subjectively reported skin symptoms. CONCLUSION: The results of this study have not supported the routine use of hydrogels in the care of patients with moist desquamation and suggests that the healing times are prolonged, without any improvement in patient comfort.

Addressing the efficacy of dihydrocodeine versus methadone as an alternative maintenance treatment for opiate dependence: A randomized controlled trial.

AIM: The aim of this study is to define the efficacy of dihydrocodeine as an alternative to methadone in the maintenance treatment of opiate dependence. DESIGN: A pragmatic open-label randomized controlled study of patients recommended for opiate maintenance treatment to test equivalence of the two treatment options with follow-up continuing for up to 42 months after recruitment. SETTING: Assessment at either Edinburgh's Community Drug Problem Service or at two general practitioner practices with specialist drug community psychiatric nurses, then with shared care follow-up. PARTICIPANTS: Two hundred and thirty-five subjects (168 male, 67 female) with opiate dependence syndrome were recruited. Subjects selected were suitable for opiate maintenance treatment. Routine treatment was offered throughout. INTERVENTION: Patients were randomized to receive either methadone mixture 1 mg/ml or dihydrocodeine, 30 mg or 60 mg tablets. MEASUREMENTS: The primary outcome measure was retention in treatment. Eight secondary outcomes included total illicit opiate use, reported crime, physical health, mental health, injecting drug use, overdoses, selling drugs and being in education or work. Measures were compared over 42 months follow-up. FINDINGS: There was no difference in groups for retention in treatment at follow-up and there was improvement in all secondary outcomes from baseline. No significant difference in outcomes was found between randomized groups over time. Compliance with randomized treatment differed by randomized group and was affected by experiences in custody during follow-up. Those randomized to dihydrocodeine were more likely to switch treatments. CONCLUSIONS: These results, combined with existing clinical experience, provide evidence that dihydrocodeine is a viable alternative to methadone as a maintenance treatment for opiate dependence. Indirect comparisons with other studies show dihydrocodeine (and methadone) to be superior to placebo.

Cytotoxic assays for screening anticancer agents.

In the process of identifying potential anticancer agents, the ability of a new agent is tested for cytotoxic activity against a panel of standard cancer cell lines. The National Cancer Institute (NCI) present the cytotoxic profile for each agent as a set of estimates of the dose required to inhibit the growth of each cell line. The NCI estimates are obtained from a linear interpolation method applied to the dose-response curves. In this paper non-linear fits are proposed as an alternative to interpolation. This is illustrated with data from two agents recently submitted to NCI for potential anticancer activity. Fitting of individual non-linear curves proved difficult, but a non-linear mixed model applied to the full set of cell lines overcame most of the problems. Two non-linear functional forms were fitted using random effect models by both maximum likelihood and a full Bayesian approach. Model-based toxicity estimates have some advantages over those obtained from interpolation. They provide standard errors for toxicity estimates and other derived quantities, allow model comparisons. Examples of each are illustrated.

Randomization inference for balanced cluster-randomized trials.

This paper discusses the choice of randomization tests for inferences from cluster-randomized trials that have been designed to ensure a balanced allocation of clusters to treatments. Methods for covariate-adjusted randomization tests are reviewed and their application to balanced cluster-randomized trials discussed. Two cluster-randomized trials with balanced designs are used to illustrate the choices that can be made in selecting a randomization test, and methods for obtaining confidence intervals for treatment effects are illustrated. The balance imposed by the randomization in these trials makes adjustment for covariates less beneficial than for an unbalanced design. However, the adjusted analyses do not appear generally to have worse properties than the unadjusted ones, and may provide protection against any imbalance that has not been controlled for in the design. The only case when adjustment for covariates may result in worse precision is when a large number of cluster-level covariates are included in the analysis. An expression is provided that allows the size of this effect to be calculated for any given set of cluster-level covariates.

Limits of teacher delivered sex education: interim behavioural outcomes from randomised trial.

OBJECTIVE: To determine whether a theoretically based sex education programme for adolescents (SHARE) delivered by teachers reduced unsafe sexual intercourse compared with current practice. DESIGN: Cluster randomised trial with follow up two years after baseline (six months after intervention). A process evaluation investigated the delivery of sex education and broader features of each school. SETTING: Twenty five secondary schools in east Scotland. PARTICIPANTS: 8430 pupils aged 13-15 years; 7616 completed the baseline questionnaire and 5854 completed the two year follow up questionnaire. INTERVENTION: SHARE programme (intervention group) versus existing sex education (control programme). MAIN OUTCOME MEASURES: Self reported exposure to sexually transmitted disease, use of condoms and contraceptives at first and most recent sexual intercourse, and unwanted pregnancies. RESULTS: When the intervention group was compared with the conventional sex education group in an intention to treat analysis there were no differences in sexual activity or sexual risk taking by the age of 16 years. However, those in the intervention group reported less regret of first sexual intercourse with most recent partner (young men 9.9% difference, 95% confidence interval -18.7 to -1.0; young women 7.7% difference, -16.6 to 1.2). Pupils evaluated the intervention programme more positively, and their knowledge of sexual health improved. Lack of behavioural effect could not be linked to differential quality of delivery of intervention. CONCLUSIONS: Compared with conventional sex education this specially designed intervention did not reduce sexual risk taking in adolescents.