The Use of Autologous Subcutaneous Fat Tissue to Embolize an Infected Iliac Artery Pseudoaneurysm.

We describe a patient with a fistula between small bowel and a polyester patch of the common iliac artery. After emergency treatment with an endograft, the patch was replaced by a venous patch. Within 3-week a symptomatic pseudoaneurysm developed. It was decided to embolize the pseudoaneurysm using autologous subcutaneous fat, followed by a femoro-femoral crossover bypass using an allograft. Using this technique, the pseudoaneurysm was successfully excluded. This case shows that subcutaneous fat tissue can be used as an autologous embolic material, also in larger vessel pathology and in cases of ongoing infection, where regular embolization material cannot be used.

Cell death associated release of volatile organic sulphur compounds with antioxidant properties in chemical-challenged tobacco BY-2 suspension cultured cells.

The production of volatile organic compounds (VOCs) during programmed cell death (PCD) is still insufficiently studied and their implication in the process is not well understood. The present study demonstrates that the release of VOSCs with presumed antioxidant capacity (methanethiol, dimethylsulfide and dimethyldisulfide) accompanies the cell death in chemical-stressed tobacco BY-2 suspension cultured cells. The cells were exposed to cell death inducers of biotic nature mastoparan (MP, wasp venom) and camptothecin (CPT, alkaloid), and to the abiotic stress agent CdSO4. The VOCs emission was monitored by proton-transfer reaction mass spectrometry (PTR-MS). The three chemicals induced PCD expressing apoptotic-like phenotype. The identified VOSCs were emitted in response to MP and CPT but not in presence of Cd. The VOSCs production occurred within few hours after the administration of the elicitors, peaked up when 20-50 % of the cells were dead and further levelled off with cell death advancement. This suggests that VOSCs with antioxidant activity may contribute to alleviation of cell death-associated oxidative stress at medium severity of cell death in response to the stress factors of biotic origin. The findings provide novel information about cell death defence mechanisms in chemical-challenged BY-2 cells and show that PCD related VOSCs synthesis depends on the type of inducer.

Non-invasive Biomarkers of Acute Rejection in Kidney Transplantation: Novel Targets and Strategies.

Kidney transplantation is considered the favored treatment for patients suffering from end-stage renal disease, since successful transplantation is associated with longer survival and improved quality of life compared to dialysis. Alloreactive immune responses against the donor kidney may lead to acute rejection of the transplant. The current diagnosis of renal allograft rejection mainly relies on clinical monitoring, including serum creatinine, proteinuria, and confirmation by histopathologic assessment in the kidney transplant biopsy. These parameters have their limitations. Identification and validation of biomarkers, which correlate with or predict the presence of acute rejection, and which could improve therapeutic decision making, are priorities for the transplantation community. There is a need for alternative, less invasive but sensitive markers to diagnose acute graft rejection. Here, we provide an overview of the current status on research of biomarkers of acute kidney transplant rejection in blood and urine. We specifically discuss relatively novel research strategies in biomarker research, including transcriptomics and proteomics, and elaborate on donor-derived cell-free DNA as a potential biomarker.

Cost-effectiveness of breast cancer control strategies in Central America: the cases of Costa Rica and Mexico.

This paper reports the most cost-effective policy options to support and improve breast cancer control in Costa Rica and Mexico. Total costs and effects of breast cancer interventions were estimated using the health care perspective and WHO-CHOICE methodology. Effects were measured in disability-adjusted life years (DALYs) averted. Costs were assessed in 2009 United States Dollars (US$). To the extent available, analyses were based on locally obtained data. In Costa Rica, the current strategy of treating breast cancer in stages I to IV at a 80% coverage level seems to be the most cost-effective with an incremental cost-effectiveness ratio (ICER) of US$4,739 per DALY averted. At a coverage level of 95%, biennial clinical breast examination (CBE) screening could improve Costa Rica's population health twofold, and can still be considered very cost-effective (ICER US$5,964/DALY). For Mexico, our results indicate that at 95% coverage a mass-media awareness raising program (MAR) could be the most cost-effective (ICER US$5,021/DALY). If more resources are available in Mexico, biennial mammography screening for women 50-70 yrs (ICER US$12,718/DALY), adding trastuzumab (ICER US$13,994/DALY) or screening women 40-70 yrs biennially plus trastuzumab (ICER US$17,115/DALY) are less cost-effective options. We recommend both Costa Rica and Mexico to engage in MAR, CBE or mammography screening programs, depending on their budget. The results of this study should be interpreted with caution however, as the evidence on the intervention effectiveness is uncertain. Also, these programs require several organizational, budgetary and human resources, and the accessibility of breast cancer diagnostic, referral, treatment and palliative care facilities should be improved simultaneously. A gradual implementation of early detection programs should give the respective Ministries of Health the time to negotiate the required budget, train the required human resources and understand possible socioeconomic barriers.

Statistical or clinical improvement? Determining the minimally important difference for the vascular quality of life questionnaire in patients with critical limb ischemia.

OBJECTIVE: Interpreting whether changes in quality of life (Qol) in patients with peripheral arterial disease (PAD) are not only statistically significant but also clinically relevant, may be difficult. This study introduces the concept of the minimally important difference (MID) to vascular surgeons using Qol outcomes of patients treated for chronic critical limb ischemia (CLI). METHODS: The Vascular Quality of Life (VascuQol) questionnaire was recorded at baseline before treatment and after 6 months follow-up in consecutive patients with CLI treated between May 2007 and May 2010. Statistical significance of change in VascuQol score was tested with the Wilcoxon Signed Rank test. The MID for the VascuQol score was determined using a clinical anchor-based method and a distribution-based method. RESULTS: A total of 127 patients with CLI completed the VascuQol after 6 months. The VascuQol sum scores improved from 3.0 (range 1.1-5.9) at baseline to 4.0 (range 1.2-6.7) at 6 months (p < .001). The MID on the VascuQol sumscore indicating a clinically important change determined with the anchor-based method was 0.36, and with the distribution-based method was 0.48. On an individual level, depending on the method of determining the MID, this resulted in 60% to 68% of the patients with an important benefit. CONCLUSIONS: Expression of changes in Qol by means of the MID provides better insight into clinically important changes than statistical significance.

The value of a QALY: individual willingness to pay for health gains under risk.

BACKGROUND: There is an increased interest in the monetary value of a quality-adjusted life-year (QALY). Past studies commonly derived willingness to pay (WTP) for certain future QALY gains. However, obtaining valid WTP per QALY estimates proved to be difficult. OBJECTIVE: We conducted a contingent valuation study and estimated the individual WTP per QALY under risk. We demonstrate the impact of probability weighting on WTP per QALY estimates in the Netherlands. RESULTS: Our estimates of the value of a QALY are in the range of €80,000-110,000 when the weighting correction was applied, and €250,500 without correction. The validity of these estimates, applying probability weighting, appears to be good. CONCLUSIONS: Given the reasonable support for their validity and practical meaningfulness, the estimates derived while correcting for probability weighting may provide valuable input for the debate on the consumption value of health. While decision makers should not apply these estimates without further consideration, since strictly individual valuations may not carry all relevant information and values for societal decision-making, the current estimates may provide a good and informed basis for further discussion and study of this important topic.

Cytoreductive surgery and intraperitoneal chemotherapy for colorectal peritoneal and hepatic metastases: a case-control study.

BACKGROUND: Concomitant treatment of colorectal peritoneal metastases (PM) and hepatic metastases (HM) remains controversial. This study compares the cytoreductive surgery (CRS) and intraperitoneal chemotherapy (IPC) treatment of colorectal peritoneal metastases (PM) with the CRS/IPC/hepatic resection treatment of colorectal PM and HM. METHODS: All patients from a prospective PM registry at the Uppsala institution treated concomitantly for PM/HM with CRS/IPC/hepatic resections were included in a PM/HM-group, n=11. They were matched 1(:)2 with patients from the registry being treated only for PM with CRS/IPC, n=22. Overall survival (OS), disease-free survival (DFS), morbidity, mortality, and recurrences were compared. RESULTS: The PM/HM-group had median OS of 15 months (95% CI: 6-46 months) and the PM-group had a median OS of 34 months (95% CI: 19-37 months), P=0.2. The DFS was 10 months (95% CI: 3-14 months) and 24 months (95% CI: 10-32 months) respectively, P=0.1. Morbidity was 27% in both groups and one postoperative death in the PM/HM-group. Currently, 1/10 (10%) patients with an R1 resection are disease-free in the PM/HM group while 9/20 (45%) are disease-free in the PM group (P=0.05). CONCLUSIONS: Concomitant treatment of PM and HM with CRS/IPC/hepatic resections is feasible with no significant increase in morbidity compared to CRS/IPC. The risk of recurrences is higher in the PM/HM group with a tendency towards worse DFS.

Valuing QALY gains by applying a societal perspective.

Interpreting the outcomes of cost utility analyses requires an appropriately defined threshold for costs per quality-adjusted life year (QALY). A common view is that the threshold should represent the (consumption) value a society attaches to a QALY. So far, individual valuations of personal health gains have mainly been studied rather than potentially relevant social values. In this study, we present the first direct empirical estimates of the willingness to pay for a QALY from a societal perspective. We used the contingent valuation approach, valuing QALYs under uncertainty and correcting for probability weighting. The estimates obtained in a representative sample of the Dutch population (n = 1004) range from €52,000 to €83,000, depending on the specification of the societal perspective. The scale sensitivity was weak, however.

Inquiry into the relationship between equity weights and the value of the QALY.

BACKGROUND: A commonly held view of the decision rule in economic evaluations in health care is that the final incremental cost-effectiveness ratio needs to be judged against some threshold, which is equal for all quality-adjusted life-year (QALY) gains. This reflects the assumption that "a QALY is a QALY" no matter who receives it, or the equity notion that all QALY gains are equally valuable, regardless of the context in which they are realized. If such an assumption does not adequately reflect the distributional concerns in society, however, different thresholds could be used for different QALY gains, whose relative values can be seen as "equity weights." AIM: Our aim was to explore the relationship between equity or distributional concerns and the social value of QALYs within the health economics literature. In light of the empirical interest in equity-related concerns as well as the nature and height of the incremental cost-effectiveness ratio threshold, this study investigates the "common ground" between the two streams of literature and considers how the empirical literature estimating the incremental cost-effectiveness ratio threshold treats existing distributional considerations.

Update of the Dutch Manual for Costing in Economic Evaluations.

OBJECTIVES: In 2000, the first "Dutch Manual for Costing: METHODS and Reference Prices for Economic Evaluations in Healthcare" was published, followed by an updated version in 2004. The purpose of the Manual is to facilitate the implementation and assessment of costing studies in economic evaluations. New developments necessitated the publication of a thoroughly updated version of the Manual in 2010. The present study aims to describe the main changes of the 2010 Manual compared with earlier editions of the Manual. METHODS: New and updated topics of the Manual were identified. The recommendations of the Manual were compared with the health economic guidelines of other countries, eliciting strengths and limitations of alternative methods. RESULTS: New topics in the Manual concern medical costs in life-years gained, the database of the Diagnosis Treatment Combination (DBC) casemix System, reference prices for the mental healthcare sector and the costs borne by informal care-givers. Updated topics relate to the friction cost method, discounting future effects and options for transferring cost results from international studies to the Dutch situation. CONCLUSIONS: The Action Plan is quite similar to many health economic guidelines in healthcare. However, the recommendations on particular aspects may differ between national guidelines in some respects. Although the Manual may serve as an example to countries intending to develop a manual of this kind, it should always be kept in mind that preferred methods predominantly depend on a country's specific context.

SUPERvised exercise therapy or immediate PTA for intermittent claudication in patients with an iliac artery obstruction--a multicentre randomised controlled trial; SUPER study design and rationale.

INTRODUCTION: Treatment of intermittent claudication (IC) due to peripheral arterial disease (PAD) is aimed at improving walking distance and includes secondary prevention of cardiovascular disease. Both supervised exercise therapy (SET) and percutaneous transluminal angioplasty (PTA) have proven to be effective in increasing maximum and pain-free walking distance in IC. However, the optimal treatment strategy in patients with IC due to iliac artery stenosis or occlusion remains unclear. OBJECTIVE: To compare the (cost-) effectiveness of initial PTA versus initial SET in patients with disabling IC due to an iliac artery obstruction. DESIGN: In a multicentre randomised controlled trial 400 consecutive patients with IC will be randomly assigned to PTA (with additional stent placement on indication) or SET. Primary outcomes are maximum walking distance and health-related quality of life measured using the disease-specific VascuQol instrument after 1 year. Secondary outcomes are pain-free walking distance, functional status, generic quality of life, complications related to each of the interventions, additional interventions, treatment failures and costs (cost-effectiveness and cost-utility) after 1 year. CONCLUSION AND IMPLICATIONS: Based on the results of this proposed large study well-founded adjustments of existing guidelines on the treatment of iliac artery occlusive disease can be implemented (Clinical Trials.gov NCT01385774; Nederlands Trial Register NTR2776).

Systematic review of exercise training or percutaneous transluminal angioplasty for intermittent claudication.

BACKGROUND: The aim was to summarize the results of all randomized clinical trials (RCTs) comparing percutaneous transluminal angioplasty (PTA) with (supervised) exercise therapy ((S)ET) in patients with intermittent claudication (IC) to obtain the best estimates of their relative effectiveness. METHODS: A systematic review was performed of relevant RCTs identified from the MEDLINE, Embase and Cochrane Library databases. Eligible RCTs compared PTA with (S)ET, included patients with IC due to suspected or known aortoiliac and/or femoropopliteal artery disease, and compared their effectiveness in terms of functional outcome and/or quality of life (QoL). RESULTS: Eleven of 258 articles identified (reporting data on eight randomized clinical trials) met the inclusion criteria. One trial included patients with isolated aortoiliac artery obstruction, three trials studied those with femoropopliteal artery obstruction and five included those with combined lesions. Two trials compared PTA with advice on ET, four PTA with SET, two PTA plus SET with SET and two PTA plus SET with PTA. Although the endpoints in most trials comprised walking distances and QoL, pooling of data was impossible owing to heterogeneity. Generally, the effectiveness of PTA and (S)ET was equivalent, although PTA plus (S)ET improved walking distance and some domains of QoL scales compared with (S)ET or PTA alone. CONCLUSION: As IC is a common healthcare problem, defining the optimal treatment strategy is important. A combination of PTA and exercise (SET or ET advice) may be superior to exercise or PTA alone, but this needs to be confirmed.

GET MORE, PAY MORE? An elaborate test of construct validity of willingness to pay per QALY estimates obtained through contingent valuation.

Estimates of WTP per QALY can be taken as an indication of the monetary value of health gains, which may carry information regarding the appropriate height of the cost-effectiveness threshold. Given the far-reaching consequences choosing a particular threshold, and thus the potential relevance of WTP per QALY estimates, it is important to address the validity of these estimates. This study addresses this issue. Our findings offer little support to the validity of WTP per QALY estimates obtained in this study. Implications for general WTP per QALY estimates and further research are discussed.

Burden of illness of Pompe disease in patients only receiving supportive care.

BACKGROUND: Pompe disease is an orphan disease for which enzyme replacement therapy (ERT) recently became available. This study aims to estimate all relevant aspects of burden of illness--societal costs, use of home care and informal care, productivity losses, and losses in health-related quality of life (HRQoL)--for adult Pompe patients only receiving supportive care. METHODS: We collected data on all relevant aspects of burden of illness via a questionnaire. We applied a societal perspective in calculating costs. The EQ-5D was used to estimate HRQoL. RESULTS: Eighty adult patients (87% of the total Dutch adult Pompe population) completed a questionnaire. Disease severity ranged from mild to severe. Total annual costs were estimated at 22,475 (range 0-169,539) per adult Pompe patient. Patients on average received 8 h of home care and 19 h of informal care per week. Eighty-five percent of the patients received informal care from one or more caregivers; 40% had stopped working due to their disease; another 20% had reduced their working hours. HRQoL for Pompe patients who only received supportive care was estimated at 0.72, 17% lower than the Dutch population at large. CONCLUSIONS: Adult Pompe disease is associated with a considerable burden of illness at both the societal and patient levels. The disease leads to substantial costs and dependency on medical devices, home care, and informal care, and has a high impact on the patient's social network. In addition, patients are limited in their ability to work and have significantly reduced HRQoL.

Secondary "thin-DSEK" after long-term graft failure in DLEK: a double transplanted cornea.

PURPOSE: To describe a case of secondary "thin Descemet stripping endothelial keratoplasty" ("Thin-DSEK"), for borderline decompensation 6 years after an initial deep lamellar endothelial keratoplasty (DLEK). METHODS: In a 31-year-old man, who initially underwent a DLEK for bullous keratopathy in the presence of a phakic intraocular lens, a secondary Thin-DSEK was performed, while leaving the entire DLEK graft (including the donor Descemet membrane and the endothelium) in situ. RESULTS: After the initial DLEK, the best-corrected visual acuity (BCVA) improved from 20/200 (0.1) to 20/25 (0.8). Six years later, the transplanted cornea showed intermittent decompensation with a decrease in BCVA again to 20/200 (0.1). After the secondary Thin-DSEK, the BCVA improved again to 20/25 (0.8) at 1 month postoperatively and remained stable thereafter. CONCLUSIONS: Our case may show that a secondary DSEK may be a simple and effective treatment to manage secondary graft failure after DLEK. Despite the presence of a "double" stromal interface in the visual axis, secondary Thin-DSEK may provide visual rehabilitation similar to that after primary Thin-DSEK.

[New drugs: money-back guarantee?]. / Nieuwe geneesmiddelen: niet goed, geld terug?

When a new medical technology, for example a new drug, is introduced onto the market there should be a discussion of the balance between "uncertainty versus value to society and demand". The new technology is sometimes given the benefit of the doubt due to a lack of information. Follow-up investigation is actually essential but is seldom mandatory and hardly ever spontaneously initiated. Specific measures, based on stimulation or penalization, could reduce the degree of uncertainty concerning the efficacy, safety and efficiency of a new technology. A serious option when a new drug produces disappointing results is to pay the manufacturer less.

Incorporation of economic evidence in the Dutch guideline 'cardiovascular risk management'.

RATIONALE, AIMS AND OBJECTIVES: The consideration of economic evidence in guideline development may be particularly important in health care management when different (drug) therapies show similar efficacy on clinical endpoints, such as in cardiovascular diseases. This article investigates to what extent the Dutch guideline 'cardiovascular risk management' (2006) considers cost-effectiveness and budget impact according to the most recent economic evidence. METHOD: We carried out a systematic review of economic evaluations on cholesterol-lowering drugs and antihypertensives followed by an assessment of guideline recommendations. RESULTS: The guideline does not consider the most recent economic evidence but does consider cost-effectiveness based on economic evaluations performed in conjunction with clinical trials. Their conclusions are largely in agreement with the most recent economic evidence. An innovative aspect in the guideline is the application of a budget impact analysis to take accessibility and affordability constraints into account when considering cost-effectiveness. CONCLUSIONS: Based on the most recent economic evidence, the guideline could be improved by more firmly formulating recommendations in favour of cost-effective drug therapies (simvastatin, pravastatin and low-dose diuretics) to stimulate compliance to the guideline in clinical practice.

Health effects in significant others: separating family and care-giving effects.

BACKGROUND: Changes in the health of patients may affect the health of so-called "significant others" in 2 distinct ways. First, an individual may provide informal care to the patient and be burdened by the process of care giving. We label this indirect effect of a patient's health on the health of the care giver the "care-giving effect." Second, a person may suffer from health losses because someone in his or her social environment is ill, regardless of his or her care-giving status. The health of the patient then directly affects the health of this significant other, which we label the "family effect." METHODS: We investigate the occurrence of the family and care-giving effect in a convenience sample of Dutch care givers (n = 751). The family effect was approximated by the health status of the patient (measured on EuroQol-VAS), and the care-giving effect by the number of the care-giving tasks was provided. It was assumed that care givers' health is positively associated with patients' health, that is, the family effect, and negatively associated with care-giving burden, that is, the care-giving effect. Relationships are studied using multivariate regressions. RESULTS: Our results support the existence of both types of health effects. The analysis shows that the 2 effects are separable and independently associated with the health of care givers. Not accounting for the family effect conflates the care-giving effect. CONCLUSIONS: If the goal of health care policy is to optimize health, all important effects should be captured. The scope of economic evaluations should also include health effects in significant others. This study suggests that significant others include both care givers and broader groups of affected individuals, such as family members.

Willingness to pay for a quality-adjusted life-year: the individual perspective.

OBJECTIVE: The aim of this study was to elicit the individual willingness to pay (WTP) for a quality-adjusted life-year (QALY). METHODS: In a Web-based questionnaire containing contingent valuation exercises, respondents valued health changes in five scenarios. In each scenario, the respondents first valued two health states on a visual analog scale (VAS) and expressed their WTP for avoiding a decline in health from the better health state to the worse, using a payment scale followed by a bounded open contingent valuation question. ANALYSIS: WTP per QALY was calculated for QALY gains calculated using VAS valuations, as well as the Dutch EQ-5D tariffs, the two steps in the WTP estimations and each scenario. Heterogeneity in WTP per QALY ratios was examined from the perspective of: 1) household income; and 2) the level of certainty in WTP indicated by respondents. Theoretical validity was analyzed using clustered multivariate regressions. RESULTS: A total of 1091 respondents, representative of the Dutch population, participated in the survey. Mean WTP per QALY was € 12,900 based on VAS valuations, and € 24,500 based on the Dutch EuroQoL tariffs. WTP per QALY was strongly associated with income, varying from € 5000 in the lowest to € 75,400 in the highest income group. Respondents indicating higher certainty exhibited marginally higher WTP. Regression analyses confirmed expected relations between WTP per QALY, income, and other personal characteristics. CONCLUSION: Individual WTP per QALY values elicited in this study are similar to those found in comparable studies. The use of individual valuations in social decision-making deserves attention, however.