Individualised Estimation of Quality-adjusted Survival Benefit and Cost-effectiveness of Proton Beam Therapy in Intermediate-stage Hodgkin Lymphoma.

AIMS: Radiotherapy for Hodgkin lymphoma leads to the irradiation of organs at risk (OAR), which may confer excess risks of late effects. Comparative dosimetry studies show that proton beam therapy (PBT) may reduce OAR irradiation compared with photon radiotherapy, but PBT is more expensive and treatment capacity is limited. The purpose of this study is to inform the appropriateness of PBT for intermediate-stage Hodgkin lymphoma (ISHL). MATERIALS AND METHODS: A microsimulation model simulating the course of ISHL, background mortality and late effects was used to estimate comparative quality-adjusted life years (QALYs) lived and healthcare costs after consolidative pencil beam scanning PBT or volumetric modulated arc therapy (VMAT), both in deep-inspiration breath-hold. Outcomes were compared for 606 illustrative patients covering a spectrum of clinical presentations, varying by two age strata (20 and 40 years), both sexes, three smoking statuses (never, former and current) and 61 pairs of OAR radiation doses from a comparative planning study. Both undiscounted and discounted outcomes at 3.5% yearly discount were estimated. The maximum excess cost of PBT that might be considered cost-effective by the UK's National Institute for Health and Care Excellence was calculated. RESULTS: OAR doses, smoking status and discount rate had large impacts on QALYs gained with PBT. Current smokers benefited the most, averaging 0.605 undiscounted QALYs (range -0.341 to 2.171) and 0.146 discounted QALYs (range -0.067 to 0.686), whereas never smokers benefited the least, averaging 0.074 undiscounted QALYs (range -0.196 to 0.491) and 0.017 discounted QALYs (range -0.030 to 0.086). For the gain in discounted QALYs to be considered cost-effective, PBT would have to cost at most £4812 more than VMAT for current smokers and £645 more for never smokers. This is below preliminary National Health Service cost estimates of PBT over photon radiotherapy. CONCLUSION: In a UK setting, PBT for ISHL may not be considered cost-effective. However, the degree of unquantifiable uncertainty is substantial.

Cost-effectiveness analysis of a placebo-controlled randomized trial evaluating the effectiveness of arthroscopic subacromial decompression in patients with subacromial shoulder pain.

AIMS: The aims of this study were to compare the use of resources, costs, and quality of life outcomes associated with subacromial decompression, arthroscopy only (placebo surgery), and no treatment for subacromial pain in the United Kingdom National Health Service (NHS), and to estimate their cost-effectiveness. PATIENTS AND METHODS: The use of resources, costs, and quality-adjusted life-years (QALYs) were assessed in the trial at six months and one year. Results were extrapolated to two years after randomization. Differences between treatment arms, based on the intention-to-treat principle, were adjusted for covariates and missing data were handled using multiple imputation. Incremental cost-effectiveness ratios were calculated, with uncertainty around the values estimated using bootstrapping. RESULTS: Cumulative mean QALYs/mean costs of health care service use and surgery per patient from baseline to 12 months were estimated as 0.640 (standard error (se) 0.024)/£3147 (se 166) in the decompression arm, 0.656 (se 0.020)/£2830 (se 183) in the arthroscopy only arm and 0.522 (se 0.029)/£1451 (se 151) in the no treatment arm. Statistically significant differences in cumulative QALYs and costs were found at six and 12 months for the decompression versus no treatment comparison only. The probabilities of decompression being cost-effective compared with no treatment at a willingness-to-pay threshold of £20 000 per QALY were close to 0% at six months and approximately 50% at one year, with this probability potentially increasing for the extrapolation to two years. DISCUSSION: The evidence for cost-effectiveness at 12 months was inconclusive. Decompression could be cost-effective in the longer-term, but results of this analysis are sensitive to the assumptions made about how costs and QALYs are extrapolated beyond the follow-up of the trial.

Modelling incremental benefits on complications rates when targeting lower HbA1c levels in people with Type 2 diabetes and cardiovascular disease.

AIM: Glucose-lowering interventions in Type 2 diabetes mellitus have demonstrated reductions in microvascular complications and modest reductions in macrovascular complications. However, the degree to which targeting different HbA1c reductions might reduce risk is unclear. METHODS: Participant-level data for Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) participants with established cardiovascular disease were used in a Type 2 diabetes-specific simulation model to quantify the likely impact of different HbA1c decrements on complication rates. Ten-year micro- and macrovascular rates were estimated with HbA1c levels fixed at 86, 75, 64, 53 and 42 mmol/mol (10%, 9%, 8%, 7% and 6%) while holding other risk factors constant at their baseline levels. Cumulative relative risk reductions for each outcome were derived for each HbA1c decrement. RESULTS: Of 5717 participants studied, 72.0% were men and 74.2% White European, with a mean (sd) age of 66.2 (7.9) years, systolic blood pressure 134 (16.9) mmHg, LDL-cholesterol 2.3 (0.9) mmol/l, HDL-cholesterol 1.13 (0.3) mmol/l and median Type 2 diabetes duration 9.6 (5.1-15.6) years. Ten-year cumulative relative risk reductions for modelled HbA1c values of 75, 64, 53 and 42 mmol/mol, relative to 86 mmol/mol, were 4.6%, 9.3%, 15.1% and 20.2% for myocardial infarction; 6.0%, 12.8%, 19.6% and 25.8% for stroke; 14.4%, 26.6%, 37.1% and 46.4% for diabetes-related ulcer; 21.5%, 39.0%, 52.3% and 63.1% for amputation; and 13.6%, 25.4%, 36.0% and 44.7 for single-eye blindness. CONCLUSIONS: These simulated complication rates might help inform the degree to which complications might be reduced by targeting particular HbA1c reductions in Type 2 diabetes.

Cost-effectiveness of a pragmatic structured education intervention for the prevention of type 2 diabetes: economic evaluation of data from the Let's Prevent Diabetes cluster-randomised controlled trial.

OBJECTIVES: Prevention of type 2 diabetes mellitus (TD2M) is a priority for healthcare systems. We estimated the cost-effectiveness compared with standard care of a structured education programme (Let's Prevent) targeting lifestyle and behaviour change to prevent progression to T2DM in people with prediabetes. DESIGN: Cost-effectiveness analysis alongside randomised controlled trial. SETTING: 44 general practices in Leicestershire, England. PARTICIPANTS: 880 participants with prediabetes randomised to receive either standard care or a 6-hour group structured education programme with follow-up sessions in a primary care setting. MAIN OUTCOME MEASURE: Incremental cost utility from the UK National Health Service (NHS) perspective. Quality of life and resource use measured from baseline and during the 36 months follow-up using the EuroQoL EQ-5D and 15D instruments and an economic questionnaire. Outcomes measured using quality-adjusted life years (QALYs) and healthcare costs calculated in 2012-2013 prices. RESULTS: After accounting for clustering and missing data, the intervention group was found to have a net gain of 0.046 (95% CI -0.0171 to 0.109) QALYs over 3 years, adjusted for baseline utility, at an additional cost of £168 (95% CI -395 to 732) per patient compared with the standard care group. The incremental cost-effectiveness ratio is £3643/QALY with an 86% probability of being cost-effective at a willingness to pay threshold of £20 000/QALY. CONCLUSIONS: The education programme had higher costs and higher quality of life compared with the standard care group. The Let's Prevent programme is very likely to be cost-effective at a willingness to pay threshold of £20 000/QALY gained. TRIAL REGISTRATION NUMBER: ISRCTN80605705.

Impact of hip fracture on hospital care costs: a population-based study.

UNLABELLED: Using a large cohort of hip fracture patients, we estimated hospital costs to be £14,163 and £2139 in the first and second year following fracture, respectively. Second hip and non-hip fractures were major cost drivers. There is a strong economic incentive to identify cost-effective approaches for hip fracture prevention. INTRODUCTION: The purpose of this study was to estimate hospital costs of hip fracture up to 2 years post-fracture and compare costs before and after the index fracture. METHODS: A cohort of patients aged over 60 years admitted with a hip fracture in a UK region between 2003 and 2013 were identified from hospital records and followed until death or administrative censoring. All hospital records were valued using 2012/2013 unit costs, and non-parametric censoring methods were used to adjust for censoring when estimating average annual costs. A generalised linear model examined the main predictors of hospital costs. RESULTS: A cohort of 33,152 patients with a hip fracture was identified (mean age 83 years (SD 8.2). The mean censor-adjusted 1- and 2-year hospital costs after index hip fracture were £14,163 (95 % confidence interval (CI) £14,008 to £14,317) and £16,302 (95 % CI £16,097 to £16,515), respectively. Index admission accounted for 61 % (£8613; 95 % CI £8565 to £8661) of total 1-year hospital costs which were £10,964 higher compared to the year pre-event (p < 0.001). The main predictors of 1-year hospital costs were second hip fracture, other non-hip fragility fractures requiring hospitalisation and hip fracture-related complications. Total UK annual hospital costs associated with incident hip fractures were estimated at £1.1 billion. CONCLUSIONS: Hospital costs following hip fracture are high and mostly occur in the first year after the index hip fracture. Experiencing a second hip fracture after the index fracture accounted for much of the increase in costs. There is a strong economic incentive to prioritise research funds towards identifying the best approaches to prevent both index and subsequent hip fractures.

The impact of social isolation on delayed hospital discharges of older hip fracture patients and associated costs.

UNLABELLED: Delayed discharges represent an inefficient use of acute hospital beds. Social isolation and referral to a public-funded rehabilitation unit were significant predictors of delayed discharges while admission from an institution was a protective factor for older hip fracture patients. Preventing delays could save between 11.2 and 30.7 % of total hospital costs for this patient group. INTRODUCTION: Delayed discharges of older patients from acute care hospitals are a major challenge for administrative, humanitarian, and economic reasons. At the same time, older people are particularly vulnerable to social isolation which has a detrimental effect on their health and well-being with cost implications for health and social care services. The purpose of the present study was to determine the impact and costs of social isolation on delayed hospital discharge. METHODS: A prospective study of 278 consecutive patients aged 75 or older with hip fracture admitted, as an emergency, to the Orthopaedics Department of Hospital Universitário de Santa Maria, Portugal, was conducted. A logistic regression model was used to examine the impact of relevant covariates on delayed discharges, and a negative binomial regression model was used to examine the main drivers of days of delayed discharges. Costs of delayed discharges were estimated using unit costs from national databases. RESULTS: Mean age at admission was 85.5 years and mean length of stay was 13.1 days per patient. Sixty-two (22.3 %) patients had delayed discharges, resulting in 419 bed days lost (11.5 % of the total length of stay). Being isolated or at a high risk of social isolation, measured with the Lubben social network scale, was significantly associated with delayed discharges (odds ratio (OR) 3.5) as was being referred to a public-funded rehabilitation unit (OR 7.6). These two variables also increased the number of days of delayed discharges (2.6 and 4.9 extra days, respectively, holding all else constant). Patients who were admitted from an institution were less likely to have delayed discharges (OR 0.2) with 5.5 fewer days of delay. Total costs of delayed discharges were between 11.2 and 30.7 % of total costs (€2352 and €9317 per patient with delayed discharge) conditional on whether waiting costs for placement in public-funded rehabilitation unit were included. CONCLUSION: High risk of social isolation, social isolation and referral to public-funded rehabilitation units increase delays in patients' discharges from acute care hospitals.

UKPDS outcomes model 2: a new version of a model to simulate lifetime health outcomes of patients with type 2 diabetes mellitus using data from the 30 year United Kingdom Prospective Diabetes Study: UKPDS 82.

AIMS/HYPOTHESIS: The aim of this project was to build a new version of the United Kingdom Prospective Diabetes Study (UKPDS) Outcomes Model (UKPDS-OM1), a patient-level simulation tool for predicting lifetime health outcomes of people with type 2 diabetes mellitus. METHODS: Data from 5,102 UKPDS patients from the 20 year trial and the 4,031 survivors entering the 10 year post-trial monitoring period were used to derive parametric proportional hazards models predicting absolute risk of diabetes complications and death. We re-estimated the seven original event equations and estimated new equations for diabetic ulcer and some second events. The additional data permitted inclusion of new risk factor predictors such as estimated GFR. We also developed four new equations for all-cause mortality. Internal validation of model predictions of cumulative incidence of all events and death was carried out and a contemporary patient-level dataset was used to compare 10 year predictions from the original and the new models. RESULTS: Model equations were based on a median 17.6 years of follow-up and up to 89,760 patient-years of data, providing double the number of events, greater precision and a larger number of significant covariates. The new model, UKPDS-OM2, is internally valid over 25 years and predicts event rates for complications, which are lower than those from the existing model. CONCLUSIONS/INTERPRETATION: The new UKPDS-OM2 has significant advantages over the existing model, as it captures more outcomes, is based on longer follow-up data, and more comprehensively captures the progression of diabetes. Its use will permit detailed and reliable lifetime simulations of key health outcomes in people with type 2 diabetes mellitus.

UK research expenditure on dementia, heart disease, stroke and cancer: are levels of spending related to disease burden?

BACKGROUND AND PURPOSE: A UK government review recommended that the impact of disease on the population and economy should be assessed to inform health research priorities. This study aims to quantify UK governmental and charity research funding for dementia, cancer, coronary heart disease (CHD) and stroke in 2007/08 and assess whether the levels of research expenditure are aligned with disease and economic burden. METHODS: We identified UK governmental agencies and charities providing health research funding and determined their levels of funding for dementia, cancer, CHD and stroke. Research funding levels were compared to the number of cases, disability-adjusted life years (DALYs) and economic burden. Economic costs were estimated using data on morbidity, mortality, health and social care use, private costs and other related indicators. RESULTS: Research funding to the four diseases was £833 million, of which £590 million (71%) was devoted to cancer, £169 million (20%) to CHD, £50 million (6%) to dementia and £23 million (4%) to stroke. Cancer received £482 in research funding per 1000 DALYs lost, CHD received £266, dementia received £166, with stroke receiving £71. In terms of economic burden, for every £1 million of health and social care costs attributable to each disease, cancer received £129 269 in research funding, CHD received £73 153, stroke received £8745 and dementia received £4882. CONCLUSIONS: Most health research funding in the UK is currently directed towards cancer. When compared to their burden, our analysis suggests that research spending on dementia and stroke is severely underfunded in comparison with cancer and CHD.

The cost-effectiveness of adjuvant chemotherapy for early breast cancer: A comparison of no chemotherapy and first, second, and third generation regimens for patients with differing prognoses.

BACKGROUND: The risk of recurrence following surgery in women with early breast cancer varies, depending upon prognostic factors. Adjuvant chemotherapy reduces this risk; however, increasingly effective regimens are associated with higher costs and toxicity profiles, making it likely that different regimens may be cost-effective for women with differing prognoses. To investigate this we performed a cost-effectiveness analysis of four treatment strategies: (1) no chemotherapy, (2) chemotherapy using cyclophosphamide, methotrexate, and fluorouracil (CMF) (a first generation regimen), (3) chemotherapy using Epirubicin-CMF (E-CMF) or fluorouracil, epirubicin, and cyclophosphamide (FEC60) (a second generation regimens), and (4) chemotherapy with FEC60 followed by docetaxel (FEC-D) (a third generation regimen). These adjuvant chemotherapy regimens were used in three large UK-led randomised controlled trials (RCTs). METHODS: A Markov model was used to simulate the natural progression of early breast cancer and the impact of chemotherapy on modifying this process. The probability of a first recurrent event within the model was estimated for women with different prognostic risk profiles using a parametric regression-based survival model incorporating established prognostic factors. Other probabilities, treatment effects, costs and quality of life weights were estimated primarily using data from the three UK-led RCTs, a meta-analysis of all relevant RCTs, and other published literature. The model predicted the lifetime costs, quality adjusted life years (QALYs) and cost-effectiveness of the four strategies for women with differing prognoses. Sensitivity analyses investigated the impact of uncertain parameters and model assumptions. FINDINGS: For women with an average to high risk of recurrence (based upon prognostic factors and any other adjuvant therapies received), FEC-D appeared most cost-effective assuming a threshold of £20,000 per QALY for the National Health Service (NHS). For younger low risk women, E-CMF/FEC60 tended to be the optimal strategy and, for some older low risk women, the model suggested a policy of no chemotherapy was cost-effective. For no patient group was CMF chemotherapy the preferred option. Sensitivity analyses demonstrated cost-effectiveness results to be particularly sensitive to the treatment effect estimate for FEC-D and the future price of docetaxel. INTERPRETATION: To our knowledge, this analysis is the first cost-effectiveness comparison of no chemotherapy, and first, second, and third generation adjuvant chemotherapy regimens for early breast cancer patients with differing prognoses. The results demonstrate the potential for different treatment strategies to be cost-effective for different types of patients. These findings may prove useful for policy makers attempting to formulate cost-effective treatment guidelines in the field of early breast cancer.

Estimation and external validation of a new prognostic model for predicting recurrence-free survival for early breast cancer patients in the UK.

BACKGROUND: We aimed to estimate and externally validate a new UK-specific prognostic model for predicting the long-term risk of a first recurrent event (local recurrence, metastatic recurrence, or second primary breast cancer) in women diagnosed with early breast cancer. METHODS: Using data on the prognostic characteristics and outcomes of 1844 women treated for early breast cancer at the Churchill Hospital in Oxford, parametric regression-based survival analysis was used to estimate a prognostic model for recurrence-free survival. The model, which incorporated established prognostic factors, was externally validated using independent data. Its performance was compared with that of the Nottingham Prognostic Index (NPI) and Adjuvant! Online. RESULTS: The number of positive axillary lymph nodes, tumour grade, tumour size and patient age were strong predictors of recurrence. Oestrogen receptor (ER) positivity was shown to afford a moderate protective effect. The model was able to separate patients into distinct prognostic groups, and predicted well at the patient level, mean Brier Accuracy Score=0.17 (s.e.=0.004) and overall C=0.745 (95% CI, 0.717-0.773). Its performance diminished only slightly when applied to a second independent data set. When compared with the NPI, the model was able to better discriminate between women with excellent and good prognoses, and it did not overestimate 10-year recurrence-free survival to the extent observed for Adjuvant! Online. CONCLUSION: The model estimated here predicts well at both the individual patient and group levels, and appears transportable to patients treated at other UK hospitals. Its parametric form permits long-term extrapolation giving it an advantage over other prognostic tools currently in use. A simple point scoring system and reference table allow 5-, 10-, and 15-year predictions from the model to be quickly and easily estimated. The model is also available to download as an interactive computer program.

Anti-CD22-MCC-DM1: an antibody-drug conjugate with a stable linker for the treatment of non-Hodgkin's lymphoma.

Antibody-drug conjugates (ADCs) are potent cytotoxic drugs linked to antibodies through chemical linkers, and allow specific targeting of drugs to neoplastic cells. The expression of CD22 is limited to B-cells, and we show that CD22 is expressed on the vast majority of non-Hodgkin's lymphomas (NHLs). An ideal target for an ADC for the treatment of NHL would have limited expression outside the B-cell compartment and be highly effective against NHL. We generated an ADC consisting of a humanized anti-CD22 antibody conjugated to the anti-mitotic agent maytansine with a stable linker (anti-CD22-MCC-DM1). Anti-CD22-MCC-DM1 was broadly effective in in vitro killing assays on NHL B-cell lines. We did not find a strong correlation between in vitro potency and CD22 surface expression, internalization of ADC or sensitivity to free drug. We show that anti-CD22-MCC-DM1 was capable of inducing complete tumor regression in NHL xenograft mouse models. Further, anti-CD22-MCC-DM1 was well tolerated in cynomolgus monkeys and substantially decreased circulating B-cells as well as follicle size and germinal center formation in lymphoid organs. These results suggest that anti-CD22-MCC-DM1 has an efficacy, safety and pharmacodynamic profile that support its use as a treatment for NHL.

An investigation into the performance of the Adjuvant! Online prognostic programme in early breast cancer for a cohort of patients in the United Kingdom.

BACKGROUND: Adjuvant! Online is an internet-based computer programme providing 10-year prognosis predictions for early breast cancer patients. It was developed in the United States, has been successfully validated in Canada, and is used in the United Kingdom and elsewhere. This study investigates the performance of Adjuvant! in a cohort of patients from the United Kingdom. METHODS: Data on the prognostic factors and management of 1065 women with early breast cancer diagnosed consecutively at the Churchill Hospital in Oxford between 1986 and 1996 were entered into Adjuvant! to generate predictions of overall survival (OS), breast cancer-specific survival (BCSS), and event-free survival (EFS) at 10 years. Such predictions were compared with the observed 10-year outcomes of these patients. RESULTS: For the whole cohort, Adjuvant! significantly overestimated OS (by 5.54%, P<0.001), BCSS (by 4.53%, P<0.001), and EFS (by 3.51%, P=0.001). For OS and BCSS, overestimation persisted across most demographic, pathologic, and treatment subgroups investigated. Differences between Adjuvant! predicted and observed EFS appeared smaller, and were significant for far fewer subgroups, only 5 out of the 28. The likely explanation for such discordance is that US breast cancer mortality rates (upon which Adjuvant! is based) appear to be systematically lower than breast cancer mortality rates in the United Kingdom. Differences in survival after recurrence would seem to be one contributory factor, with data suggesting that prognosis after relapse appears poorer in the United Kingdom. This may reflect the fact that new and more effective cancer drugs are often only approved for use in the United Kingdom many years after their adoption in the United States. CONCLUSION: The use of Adjuvant! by clinicians within the UK National Health Service is increasing, under the assumption that the programme is transferrable to the United Kingdom. At least for women treated for breast cancer at the Churchill Hospital in Oxford, however, Adjuvant!'s predictions were on the whole overoptimistic. If the findings reported here could be shown to be generalisable to other areas of the United Kingdom, then thought should perhaps be given to the development of a UK-specific version of the programme.

The economic analyses of the UK prospective diabetes study.

An economic analysis was not initially included in the study design of the UK Prospective Diabetes Study (UKPDS). However, data were collected throughout the study on hospital drugs and medications used and these were supplemented near the end of the study by cross-sectional surveys of non-inpatient healthcare use and quality of life. Evaluations of tight vs. less tight blood pressure control, intensive vs. less conventional blood glucose control and metformin showed that each was highly cost-effective and that all could be provided at modest total cost. Further analyses showed that amputations and stroke had particularly severe consequences for quality of life, and that amputations and non-fatal MI had high cost consequences. Finally, patient-level data were used to construct a diabetes outcomes model, which estimates the probability of longer-term complications from patient-specific risk factors and can be used in populations at different stages of diabetes progression. The economic analyses arising from the UKPDS have provided new evidence to clinicians, policymakers and researchers on the consequences of diabetes and the cost-effectiveness of interventions, thereby assisting the development of treatment guidelines and improved standards of care. The analyses also illustrated a number of methodological innovations. Finally, the UKPDS Outcomes Model is gaining widespread acceptance as a validated tool for long-term economic and clinical prediction in diabetes.

Cost-utility analyses of intensive blood glucose and tight blood pressure control in type 2 diabetes (UKPDS 72).

AIMS/HYPOTHESIS: This study estimated the economic efficiency (1) of intensive blood glucose control and tight blood pressure control in patients with type 2 diabetes who also had hypertension, and (2) of metformin therapy in type 2 diabetic patients who were overweight. METHODS: We conducted cost-utility analysis based on patient-level data from a randomised clinical controlled trial involving 4,209 patients with newly diagnosed type 2 diabetes conducted in 23 hospital-based clinics in England, Scotland and Northern Ireland as part of the UK Prospective Diabetes Study (UKPDS). Three different policies were evaluated: intensive blood glucose control with sulphonylurea/insulin; intensive blood glucose control with metformin for overweight patients; and tight blood pressure control of hypertensive patients. Incremental cost : effectiveness ratios were calculated based on the net cost of healthcare resources associated with these policies and on effectiveness in terms of quality-adjusted life years gained, estimated over a lifetime from within-trial effects using the UKPDS Outcomes Model. RESULTS: The incremental cost per quality-adjusted life years gained (in year 2004 UK prices) for intensive blood glucose control was 6,028 UK pounds, and for blood pressure control was 369 UK pounds. Metformin therapy was cost-saving and increased quality-adjusted life expectancy. CONCLUSIONS/INTERPRETATION: Each of the three policies evaluated has a lower cost per quality-adjusted life year gained than that of many other accepted uses of healthcare resources. The results provide an economic rationale for ensuring that care of patients with type 2 diabetes corresponds at least to the levels of these interventions.

A model to estimate the lifetime health outcomes of patients with type 2 diabetes: the United Kingdom Prospective Diabetes Study (UKPDS) Outcomes Model (UKPDS no. 68).

AIMS/HYPOTHESIS: The aim of this study was to develop a simulation model for type 2 diabetes that can be used to estimate the likely occurrence of major diabetes-related complications over a lifetime, in order to calculate health economic outcomes such as quality-adjusted life expectancy. METHODS: Equations for forecasting the occurrence of seven diabetes-related complications and death were estimated using data on 3642 patients from the United Kingdom Prospective Diabetes Study (UKPDS). After examining the internal validity, the UKPDS Outcomes Model was used to simulate the mean difference in expected quality-adjusted life years between the UKPDS regimens of intensive and conventional blood glucose control. RESULTS: The model's forecasts fell within the 95% confidence interval for the occurrence of observed events during the UKPDS follow-up period. When the model was used to simulate event history over patients' lifetimes, those treated with a regimen of conventional glucose control could expect 16.35 undiscounted quality-adjusted life years, and those receiving treatment with intensive glucose control could expect 16.62 quality-adjusted life years, a difference of 0.27 (95% CI: -0.48 to 1.03). CONCLUSIONS/INTERPRETATIONS: The UKPDS Outcomes Model is able to simulate event histories that closely match observed outcomes in the UKPDS and that can be extrapolated over patients' lifetimes. Its validity in estimating outcomes in other groups of patients, however, remains to be evaluated. The model allows simulation of a range of long-term outcomes, which should assist in informing future economic evaluations of interventions in type 2 diabetes.

L-NAME (N omega-nitro-L-arginine methyl ester), a nitric-oxide synthase inhibitor, and WIN 55212-2 [4,5-dihydro-2-methyl-4(4-morpholinylmethyl)-1-(1-naphthalenyl-carbonyl)-6H-pyrrolo[3,2,1ij]quinolin-6-one], a cannabinoid agonist, interact to evoke synergistic hypothermia.

Cannabinoids evoke profound hypothermia in rats by activating central CB(1) receptors. Nitric oxide (NO), a prominent second messenger in central and peripheral neurons, also plays a crucial role in thermoregulation, with previous studies suggesting pyretic and antipyretic functions. Dense nitric-oxide synthase (NOS) staining and CB(1) receptor immunoreactivity have been detected in regions of the hypothalamus that regulate body temperature, suggesting that intimate NO-cannabinoid associations may exist in the central nervous system. The present study investigated the effect of N(omega)-nitro-L-arginine methyl ester (L-NAME), a NO synthase inhibitor, on the hypothermic response to WIN 55212-2 [4,5-dihydro-2-methyl-4(4-morpholinylmethyl)-1-(1-naphthalenylcarbonyl)-6H-pyrrolo[3,2,1ij]quinolin-6-one], a selective cannabinoid agonist, in rats. WIN 55212-2 (1-5 mg/kg, i.m.) produced dose-dependent hypothermia that peaked 45 to 90 min post-injection. L-NAME (10-100 mg/kg, i.m.) by itself did not significantly alter body temperature. However, a nonhypothermic dose of L-NAME (50 mg/kg) potentiated the hypothermia caused by WIN 55212-2 (0.5-5 mg/kg). The augmentation was strongly synergistic, indicated by a 2.5-fold increase in the relative potency of WIN 55212-2. The inactive enantiomer of WIN 55212-2, WIN 55212-3 [S-(-)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-napthanlenyl) methanone mesylate] (5 mg/kg, i.m.), did not produce hypothermia in the absence or presence of L-NAME (50 mg/kg), confirming that cannabinoid receptors mediated the synergy. The present data are the first evidence that drug combinations of NOS blockers and cannabinoid agonists produce synergistic hypothermia. Thus, NO and cannabinoid systems may interact to induce superadditive hypothermia.

Cost effectiveness analysis of radon remediation programmes.

The economic implications of regulations governing radon gas level identification and remediation in buildings are poorly understood, and attempts to address these issues have been criticised for lack of comparability. It is imperative therefore that a general model for the economic evaluation of radon remediation programmes is adopted to ensure comparability between studies and settings and to increase the usefulness of the results to decision makers. This paper presents general guidelines for the use of cost-effectiveness analysis (CEA) as an economic appraisal tool in the evaluation of radon reduction and prevention programmes. The data requirements for a CEA of radon remediation programmes concern both costs and outcomes. These components are discussed with respect to: programme objectives, comparator choice, perspective, time horizon, discounting, uncertainty, and final ratios. Adhering to clear guidelines concerning these aspects of evaluations will facilitate meaningful evaluation of radon remediation programmes. Finally, by evaluating the radon remediation programmes using methods applied to other health interventions (such as lung cancer prevention interventions), comparisons using the same metric can be made across policy areas.

A double-blind randomized controlled trial and economic evaluation of transurethral resection vs contact laser vaporization for benign prostatic enlargement: a 3-year follow-up.

OBJECTIVE: To evaluate the effect of contact laser prostate surgery in the treatment of benign prostatic hyperplasia. PATIENTS AND METHODS: A prospective double-blind randomized controlled trial of transurethral resection of the prostate (TURP) and contact laser prostatectomy was conducted, with an economic evaluation of both procedures. The primary outcome measure was the change in the American Urologic Association symptom score, with secondary outcome measures being the peak urinary flow rate, treatment-related complications, re-operation rate and health service costs. RESULTS: The perioperative blood loss and transfusion requirements were statistically significantly lower for laser prostatectomy than for TURP. There was no clinically significant difference between TURP and contact laser prostatectomy in the mean change in symptom scores and flow rates. There were distinct perioperative advantages in favour of the contact laser treatment, but some disadvantages in terms of re-catheterization and re-operation rates. CONCLUSIONS: Contact laser prostatectomy is a valid treatment for benign prostatic hypertrophy. The performance of contact laser prostatectomy as day-case surgery would have cost advantages to the National Health Service.

The traditional plant treatment, Sambucus nigra (elder), exhibits insulin-like and insulin-releasing actions in vitro.

Sambucus nigra (elder) has been documented as a traditional treatment of diabetes. In the present study, an aqueous extract of elder (AEE, 1 g/L) significantly increased 2-deoxy-glucose transport, glucose oxidation and glycogenesis of mouse abdominal muscle in the absence of added insulin (2 x 2 factorial design). in acute 20-min tests, 0.25-1 g/L AEE evoked a stepwise stimulation of insulin secretion from clonal pancreatic beta-cells. The insulin releasing effect of AEE (0.5 g/L) was significantly potentiated by 16.7 mmol/L of glucose and significantly reduced by 0.5 mmol/L of diazoxide. AEE did not further enhance insulin secretion in cells stimulated by 10 mmol/L of L-alanine, 1 mmol/L of 3-isobutyl-1-methylxanthine or a depolarizing concentration of KCl (25 mmol/L). Prior exposure of clonal pancreatic beta-cells to AEE did not alter subsequent stimulation of insulin secretion induced by 10 mmol/L of L-alanine, thereby precluding a detrimental effect on cell viability. The insulinotropic action of AEE was partially dependent upon use of heat during extract preparation. Activity of AEE was heat-stable, acetone-insoluble and unaltered by prolonged exposure to acid/alkali (0.1 mol/L of HCl and NaOH). However, activity was significantly decreased 41% by dialysis to remove components with molecular mass <2000 Da. Sequential extraction with solvents revealed activity in both methanol and water fractions, indicating a cumulative effect of more than one extract constituent. Known constituents of elder, including lectin, rutin and the lipophilic triterpenoid (lupeol) and sterol (beta-sitosterol), did not stimulate insulin secretion. The results demonstrate the presence of insulin-releasing and insulin-like activity in the traditional antidiabetic plant, Sambucus nigra.