Chemiluminescent 1,2-Dioxetane Iridium Complexes for Near-Infrared Oxygen Sensing.

Chemiluminescent iridium-based sensors which demonstrate oxygen dependent responses have been developed. The molecular probes, named IrCL-1, IrCL-2 and IrCL-3 consist of oxygen-sensitive iridium complexes attached to a spiroadamantane 1,2 dioxetane and operate via energy transfer from the chemiexcited benzoate to the corresponding iridium(III) complex. Complexing the iridium(III) center with π-extended ligands results in emission in the biologically relevant, near-infrared (NIR) region. All probes demonstrate varying oxygen tolerance, with IrCL-1 being the most oxygen sensitive. These probes have been further utilized for in vitro ratiometric imaging of oxygen, as well as for intraperitoneal, intramuscular and intratumoral imaging in live mice. To our knowledge, these are the first iridium-based chemiluminescent probes that have been employed for in vitro ratiometric oxygen sensing, and for in vivo tumor imaging.

Cost-effectiveness of acarbose for the management of impaired glucose tolerance in Sweden.

We assessed the cost-effectiveness of acarbose in the management of patients with impaired glucose tolerance (IGT) in Sweden, based on progression to type 2 diabetes (T2D) and cardiovascular (CV) events reported in the STOP-NIDDM trial population, including high-risk subgroups. The cost per patient free from T2D was SEK28,000 or SEK1260 per diabetes free month prior to progression to T2D. The cost per patient free from CV events was SEK101,000 or SEK5000 per CV event free month. For the high CV risk subgroups, acarbose treatment dominated placebo (i.e. acarbose was more effective, less costly). Acarbose significantly reduces the incidence of diabetes and CV events in IGT patients. We predict this may translate into healthcare cost savings that partially or, in patients at high CV risk, fully offset the cost of acarbose. We conclude that acarbose is likely to be cost-effective in the management of impaired glucose tolerance.

Patients' preferences for characteristics associated with treatments for osteoarthritis.

OBJECTIVE: The purpose of this study was to investigate patient preferences for attributes associated with the efficacy and side-effects of treatment for osteoarthritis. METHODS: A stated preference design questionnaire was administered to a sample of 412 individuals diagnosed with osteoarthritis (OA). RESULTS: Statistically significant attributes in influencing treatment preferences were the level of joint aches, the level of physical mobility and the risk of experiencing serious side-effects from treatment. Respondents were relatively more concerned about the risk of serious side-effects (even with a very low probability) than mild to moderate side-effects (at a much higher probability). Data segmentation revealed some variations in preferences according to respondent characteristics. The importance of joint aches increased according to the severity of the symptoms of osteoarthritis, indicating that this attribute is more troublesome to those respondents with more severe symptoms. Older respondents were more willing than younger respondents to accept an increased risk of experiencing serious side-effects for an improvement in the symptoms of OA. Individuals in lower income brackets appeared to attach greater importance to joint aches and the level of mobility experienced than those in higher income brackets. Respondents who had previously experienced gastrointestinal side-effects from treatment were, as expected, more tolerant of them than those who had not. CONCLUSION: The use of conjoint analysis to assess patient preferences provides a useful insight to the likely attitudes of patients to novel treatments for osteoarthritis.

Utility of the in situ detection of HPV in Pap smears diagnosed as within normal limits.

OBJECTIVE: To determine the clinical significance in normal Pap smears of HPV detection as determined by Hybrid Capture (HC) and in situ hybridization analyses. STUDY DESIGN: We studied 135 consecutive Pap smears as well as 46 other smears from high-risk patients each initially diagnosed as within normal limits. RESULTS: The 135 "normal" Pap smears were rescreened, and 6 (4%) where found to be either ASCUS or SIL. In the remaining 129 cases, HPV DNA was detected in 0% and 9%, respectively, using in situ hybridization and HC I. Upon rescreening the high-risk patients, nine (20%) were reclassified as having SIL/ASCUS; each was in situ hybridization positive, and eight were HC positive; six (67%) of these women developed SIL on follow-up. In the 37 Pap smears in high-risk women still within normal limits after manual rescreening, HPV was detected in 2% by in situ hybridization and 46% by HC; 6% of the HC-positive women developed SIL on follow-up. CONCLUSION: In situ hybridization rarely detects HPV in Pap smears diagnosed as within normal limits after manual rescreening. In situ hybridization is very effective in detecting rare, atypical cells in Pap smears diagnosed as within normal limits and, in a high-risk population, is predictive of SIL on clinical follow-up.

Economic evaluation of celecoxib, a new cyclo-oxygenase 2 specific inhibitor, in Switzerland.

OBJECTIVE: The aim of this study was to predict the cost effectiveness of celecoxib, a cyclo-oxygenase 2 (COX-2) specific inhibitor, in the treatment of arthritis patients in Switzerland. METHODS: We applied a decision analytical model to compare the effects of 6 months' treatment with the following: (i) celecoxib; (ii) nonsteroidal anti-inflammatory drug (NSAID) alone; NSAID protected with (iii) proton pump inhibitor (PPI), (iv) histamine H2 receptor antagonist (H2RA), or (v) misoprostol; and (vi) diclofenac/misoprostol. Treatment costs included drug acquisition and the management of gastrointestinal (GI) adverse effects, classified as GI discomfort, symptomatic ulcer, anaemia and serious GI events (requiring hospitalisation). Probabilities were derived from celecoxib clinical trials and the literature. Drug utilisation patterns and treatment costs reflecting Swiss practice were obtained from local sources. Analysis was from the public health insurers' perspective. A range of sensitivity analyses was performed. RESULTS: For the base case of patients at typical risk (0.56% per 6 months) of serious GI events, the total expected costs of 6 months' treatment were as follows: celecoxib 435 Swiss francs (SwF); NSAID alone SwF510; diclofenac/misoprostol SwF522; and other protected NSAID regimens between SwF1034 and SwF1415. Celecoxib remained the lowest costing treatment over all categories of GI risk. Celecoxib generated 115 expected adverse events per 1000 patients per 6 months, followed by NSAID + PPI (119), NSAID + H2RA (154), NSAID + misoprostol (202), diclofenac/misoprostol (203), and NSAID alone (220), again for the base case. The cost per adverse event averted for celecoxib compared with NSAIDs alone was estimated in a stochastic version of the model using Monte Carlo simulation. In 95% of 500 iterations, celecoxib was predicted to save both costs and adverse events, thus dominating NSAIDs alone; the maximum cost per adverse event averted was SwF440. CONCLUSIONS: Celecoxib is predicted to be the most cost effective of the treatments considered for managing arthritis patients in Switzerland. A policy of switching patients from NSAIDs to celecoxib is predicted to be cost saving for public health insurers, while reducing the burden of iatrogenic GI side effects. Greater cost savings would be realised when patients are switched from NSAIDs used with gastroprotective agents. Models such as this can provide a useful but simplified view of treatment outcomes and predicted results require prospective validation in clinical practice.

The burden of arthritis and nonsteroidal anti-inflammatory treatment. A European literature review.

The purpose of this literature review is to summarise data available from publications describing the burden of osteoarthritis and rheumatoid arthritis in Europe, and to highlight gaps in the literature. On the basis of extensive literature research, the epidemiology of arthritis, its treatment costs, and iatrogenic costs related to nonsteroidal anti-inflammatory drug (NSAID) treatments are described, differentiating results by country. The review shows that, as well as having a significant impact on healthcare budgets, arthritis also affects patients and caregivers. For those countries where data were available, indirect costs were found to be of comparable magnitude to direct costs. Additionally, it was found that the iatrogenic costs related to the treatment of NSAID-induced adverse events are a significant component of the total costs of arthritis. The number of publications on the burden of arthritis in Europe is rather small in comparison with what is available for the US. Comparison of national results shows wide variations between countries, which may be partly due to discrepancies in the methodology applied to estimate the burden of arthritis, the cost items included in the analysis, and the data sources used to gather cost information. Additionally, comparing the burden of arthritis by country across Europe is difficult because of the variety of ways in which results are presented, e.g. on a per-patient basis, or for the whole population. To better understand the burden of illness of arthritis in Europe, not only is more research required, but the methodology to be applied in burden-of-illness analyses must also be standardised.

An economic model for determining the costs and consequences of using various treatment alternatives for the management of arthritis in Canada.

OBJECTIVE: To construct a decision analytical model to compare the costs and clinical consequences of treating patients with celecoxib or various nonsteroidal anti-inflammatory drug (NSAID)/gastrointestinal (GI) co-therapy regimens for the management of osteoarthritis and rheumatoid arthritis. The model quantified the number of patients expected to experience any GI complication commonly associated with NSAID therapy. DESIGN: Resource use for the treatment of each GI complication in the model was estimated after consulting Canadian experts. Standard unit costs from Ontario were applied to resources to calculate the cost of each complication. MAIN OUTCOME MEASURES AND RESULTS: The model revealed that the NSAID-alone regimen was associated with the lowest cost [$262 Canadian dollars ($Can) per patient per 6 months] followed by the celecoxib regimen ($Can273), diclofenac/misoprostol ($Can365), NSAID + histamine H2 receptor antagonist ($Can413), NSAID + misoprostol ($Can421), and NSAID + proton pump inhibitor ($Can731). A break-even analysis showed that up to 80% of the study cohort could be treated with celecoxib instead of the NSAID-alone regimen without increasing the health system's overall budget. Celecoxib was associated with the fewest GI-related deaths, hospitalised events; symptomatic ulcers, and cases of anaemia. The celecoxib regimen was also associated with the fewest cases of upper GI distress. Sensitivity analyses revealed that the model was most sensitive to the distribution of GI risk in the population and to the ingredient costs of the treatment alternatives. CONCLUSIONS: This model indicates that the use of celecoxib could lead to the avoidance of a significant number of NSAID-attributable GI adverse events, and the incremental cost of using celecoxib for arthritis patients > or = 65 years of age in place of current treatment alternatives would not impose an excessive incremental impact on a Canadian provincial healthcare budget.

Nitric oxide synthase type 2 promoter polymorphisms, nitric oxide production, and disease severity in Tanzanian children with malaria.

Nitric oxide (NO) plays an important role in host resistance to infection with a variety of organisms. Two recent reports from Gabon and Gambia identified associations of malaria disease severity with the inducible NO synthase (NOS2) promoter G-954C and short allele (<11 repeats) pentanucleotide microsatellite polymorphisms, respectively. It was postulated that there would be a correlation of these polymorphisms with malaria disease severity and with measures of NO production in our cohort of Tanzanian children with malaria. In Tanzanian children, 15% were heterozygous or homozygous for the G-954C polymorphism, and 13% had the short-allele microsatellite polymorphism. There was no significant correlation of either polymorphism with disease severity or with measures of NO production and NOS2 expression. Black and white Americans differed significantly in the frequencies of these polymorphisms. The various association of these gene polymorphisms with malaria severity in different populations underscores the complexity of host resistance to malaria.

Anesthesia for restorative dentistry.

The use of parenteral conscious sedation and general anesthesia for restorative dentistry has increased markedly over the past 20 years. Yet even this increased availability for patients to receive selected dental services under sedation and general anesthesia has not kept pace with the well-documented public demand. This article details the use of anesthesia in restorative dentistry, with particular focus on airway management.

Research into the use of health economics in decision making in the United Kingdom--Phase II. Is health economics 'for good or evil'?

The purpose of this phased research project is to better understand the role of health economic arguments in the decision making process of healthcare providers and purchasers in the United Kingdom. Phase I of the research was directed at General Practitioners (GPs); in phase II we broadened the scope of the research to include different agents who influence resource allocation and the wider health care environment. The objective of phase II was to determine the relevance and appeal of diverse health economic measures to different decision makers. This phase of qualitative research involved 34 decision makers in 17 duo interviews. The study has provided a rich source of qualitative evidence on the role of health economics in decision making. The main conclusions to emerge are; different individuals seek different outcomes; health economic studies should report actionable conclusions; and any cost savings must be applicable. To succeed, economists need to demonstrate a better understanding of the contracting and budgetary processes of the National Health Service. Opinions of the value of health economic evaluations varied widely, however most respondents believed it would become increasingly influential in the prioritisation process in the National Health Service of the future.

Modelling the cost effectiveness of lamivudine/zidovudine combination therapy in HIV infection.

The use of combination antiretroviral therapy is supported by clinical evidence for its superiority over monotherapy. Lamivudine (3TC) has been studied in combination with zidovudine (ZDV) and is recommended for use specifically in combination therapy. With the associated increase in drug acquisition cost, the economics of combination therapy versus monotherapy warrant study. An economic evaluation was undertaken to compare 3TC/ZDV combination therapy with ZDV monotherapy, taking a UK public finance perspective. The cost effectiveness of each of the 2 treatments was estimated using a Markov model of progression through 3 HIV-positive disease states: (i) CD4 cells > 200 and < 500 cells/mm3; (ii) CD4 < 200 cells/mm3, non-AIDS; and (iii) AIDS to eventual death. Progression probabilities and life expectancy were derived from a cohort treated at Chelsea and Westminster Hospital in London, using data for 1987 to 1995, along with cost data for a ZDV intent-to-treat population for 1994 and 1995. The relative risk of progression for 3TC/ZDV compared with ZDV monotherapy was estimated from meta-analysis of 4 completed comparative trials. To predict the effect of 3TC/ZDV on life expectancy and lifetime costs, progression probabilities were adjusted by the relative risk statistic for the duration of treatment with 3TC/ZDV. On the basis of an estimated relative risk of progression of 0.509 (95% CI 0.365 to 0.710), treatment with 3TC/ZDV is predicted to yield an incremental cost-effectiveness ratio of Pounds 6276 (95% CI Pounds 5337 to Pounds 9075) per life year saved (discounted at 6% per year). Extensive sensitivity analyses were performed to test the effects of varying values of input parameters on the model results. Under reasonable assumptions, the predicted cost effectiveness of 3TC/ZDV combination therapy compares favourably with previously reported economic analyses of various HIV treatments.

Constructing health state preference values from descriptive quality of life outcomes: mission impossible?

Descriptive quality of life questionnaires are commonly administered in clinical trials, to evaluate outcomes from the patient's perspective alongside conventional clinical measures. When expressed in single index form as health state preference values (HSPVs), quality of life information is also relevant to economic evaluations. By combining HSPVs with survival information, quality adjusted life years (QALYs) may be derived for cost-utility analysis. Although HSPVs are rarely measured prospectively in cancer clinical trials, the UK Medical Research Council Cancer Therapy Committee recommends the routine administration of two specific quality of life questionnaires: the Rotterdam Symptom Checklist and the Hospital Anxiety Depression Scale. This study explores two potential methods for secondary derivation of HSPVs from these instruments, using data gathered in a clinical trial of two forms of radiotherapy for non-small cell cancer of the bronchus. The first method, secondary mapping to existing utility scales, was found to be infeasible from the above questionnaires. The second method used factor analysis to summarize the descriptive quality of life data collected through the questionnaires. This revealed five distinct factors prevalent in the trial population. Using these factors, simplified health state scenarios were developed from which direct measurement of HSPVs was feasible. As the resulting HSPVs and any QALYs that may be derived from them are cancer specific, their potential value in informing resource allocation would be limited to decisions within oncology services.

Adenosine potentiates flow-induced dilation of coronary arterioles by activating KATP channels in endothelium.

Coronary microvascular diameter is significantly influenced by adenosine and flow. However, the interaction between these two regulatory mechanisms in the control of coronary microvascular tone remains unknown. Because adenosine can activate ATP-sensitive K+ (KATP) channels and these channels are located on the endothelium in addition to vascular smooth muscle, we hypothesized that adenosine can potentiate flow-induced vasodilation by activating endothelial KATP channels in the coronary microcirculation. To test this hypothesis, experiments were performed in porcine subepicardial coronary arterioles (50-150 microns) using isolated, cannulated vessel techniques to allow intraluminal pressure and flow to be independently controlled. All vessels developed active tone, approximately 67-73% of maximum diameter, at 60 cmH2O intraluminal pressure and showed graded dilation to stepwise increases in flow. The magnitude of flow-induced dilation was potentiated by a threshold dose of adenosine (10(-10) M) but not by nitroprusside (10(-10) M). Luminal application of a high K+ concentration ([K+]) (40 mM) completely blocked flow-induced arteriolar dilation. In addition, luminal glibenclamide (10(-6) M) abolished the adenosine-potentiated component of flow-induced response. Indomethacin (10(-5) M) did not alter the dose-dependent dilation to adenosine. However, endothelial denudation, NG-monomethyl-L-arginine (10(-5) M), and luminal administration of a high [K+] or glibenclamide each produced identical inhibition of adenosine-induced vasodilation by shifting the 50% effective dose to the right by an order of magnitude. In contrast, vasodilation in response to nitroprusside was not altered by these pharmacological interventions.(ABSTRACT TRUNCATED AT 250 WORDS)