Current concepts for quality assured long-distance transport of temperature-sensitive red blood cell concentrates.

BACKGROUND AND OBJECTIVES: The German Armed Forces Blood Service in Koblenz supplies red blood cell concentrates (RBCs) to military and civilian institutions at home and to field hospitals during peacekeeping operations abroad. During long-distance transport, blood products can be exposed to extreme environmental conditions or inappropriate handling, which may compromise product quality. MATERIALS AND METHODS: Different active and passive cooling systems, cooling elements, packaging material and data loggers were examined in a climate chamber. A number of techniques for measuring temperature were investigated in order to preserve the blood products' quality during transport, including some field tests with multiparametric data recording. RESULTS: Any kind of active cooling systems, conventional cooling elements and customary packaging material, as well as temperature-sensitive labels, minimum-maximum thermometers and intra-product measurement were found to be unsuitable for military requirement. The best results were obtained when the passively cooling RCB 25 transport box (Dometic) was used together with latent heat/cold storage elements (deltaT) and Junior data loggers (Escort). CONCLUSION: The elaborated protocol allows temperatures to be maintained between 2 and 6 degrees C as required by European guidelines for at least 36 h each and between 1 and 10 degrees C as required by German guidelines for at least 48 or 64 h at ambient temperatures between -10 and 40 degrees C. Preliminary results indicate that care must be taken concerning additional factors such as air pressure variation or vibration.

Overview of economic evaluation of positron-emission tomography.

Since the 1990s positron-emission tomography (PET) in Germany has been used increasingly in clinical diagnostics in the areas of oncology, cardiology, and neurology/ psychiatry. As the use of PET requires a complex and expensive infrastructure, analysis of the cost-effectiveness of PET compared to common diagnostic methods is becoming increasingly important. This contribution summarizes and discusses the results of a health technology assessment report on the cost-effectiveness of PET.

Health values and prospect theory: a comment.

In a recent volume of Medical Decision Making, Treadwell and Lenert stated that under prospect theory, community members compared with patients underestimate the utility of health improvements. In this comment, the authors show that this statement holds only for a subset of possible preference functions. Furthermore, the authors provide arguments that, in general, the rater's current health state is not the appropriate reference level if applying prospect theory to health valuations.

[Not Available]. / Eine Übersicht über die ökonomische Evaluation der Positronen-Emissions-Tomographie.

Since the nineties positron emission tomography (PET) has been increasingly used in clinical diagnostics in the area of oncology, cardiology, and neurology/psychiatry in Germany. As the use of PET requires a complex and expensive infrastructure, analysis of the cost-effectiveness of PET compared to common diagnostic methods is becoming increasingly important. This article summarizes and discusses the results of a report on cost-effectiveness studies on PET.

Primary staging of lymphomas: cost-effectiveness of FDG-PET versus computed tomography.

The objective of this study was to measure the incremental cost-effectiveness of 2-(fluorine-18) fluorodeoxyglucose positron emission tomography (FDG-PET) versus computed tomography (CT) as diagnostic procedures in the primary staging of malignant lymphomas. The study was based on 22 patients of a clinical study who underwent the diagnostic procedures at Ulm University Hospital between April 1997 and May 1998. Direct costs of FDG-PET and CT, including staff, materials, investment, maintenance and overheads, were valued using a micro-costing approach. The effectiveness of both diagnostic procedures was measured as the percentage of correctly staged patients, given a gold standard for staging. The incremental cost-effectiveness ratio was the main outcome measure. Costs per patient of FDG-PET were 257 euros for FDG production and 704 euros for the FGD-PET scan, thus totalling 961 euros (in 1999 prices). The cost per patient of CT scans was found to be 391 euros. Verified PET findings induced an upstaging in four patients such that the effectiveness was 81.8% (18/22) for CT and 100% (22/22) for PET. Incremental cost-effectiveness ratios (interpreted as the additional costs of a more effective diagnostic strategy per additional unit of effectiveness, i.e. additionally correctly staged patient, achieved) were 478 euros per correctly staged patient for CT versus "no diagnostics" and 3133 euros for FDG-PET versus CT. Great potential for cost saving was identified in sensitivity analyses for FDG-PET. It is concluded that diagnostic accuracy and the costs of the diagnostic procedures could be measured precisely. FDG-PET was more accurate than CT. Decision-makers who consider savings in treatment costs significant may find the cost-effectiveness ratio of PET to lie within an acceptable range. However, more research is needed to assess the long-term treatment and cost effects of more accurate staging. There is significant potential to improve the technical efficiency of PET.

[Cost analysis of the treatment of patients with multiple trauma]. / Kostenanalyse der Behandlung polytraumatisierter Patienten.

Current clinical management after multiple trauma is expensive. The aim of the present study was to quantify the actual costs of inpatient treatment after multiple trauma in a German university hospital, to compare the actual costs with the reimbursement rates, and to identify important determinants of costs. Routine documentation of hospital costs at a patient level was not available. Therefore a method for calculating the costs of resource utilization during clinical treatment of patients was developed. The concept was based on financial and utilization data provided by the hospital administration and patient-specific data. The average costs per case in the study group (mean ISS = 37) were 73.613 DM, maximal costs were up to 292.490 DM. The most costly components were intensive care, accounting for 60%, followed by procedures in the operating room (24%). A comparison with the reimbursement rates resulted in an average loss of 23.211 DM per case. Factors significantly associated with the costs of acute care hospitalization were outcome, injury severity, pattern of injury, blood volume replacement, length of mechanical ventilation, and number of operations. Whereas patient age, CNS state, mechanism of injury, pre-hospital care, and time between accident and hospital admission revealed no effect. Given the current reimbursement rates, multiple trauma care clearly belongs to those categories of care which have to be subsidized within the hospital. Any challenge to the optimal level of care resulting from this should be avoided.

The contingent valuation method in health care.

The contingent valuation method (CVM) is a survey-based, hypothetical and direct method to determine monetary valuations of effects of health technologies. This comprehensive review of CVM in the health care literature points at methodological as well as conceptual issues of CVM and on willingness to pay as a measure of benefits compared with other measures used in medical technology assessment. Studies published before 1998 were found by searching computerised databases and former review literature. Studies were included, when performing CVM using original data and meeting qualitative criteria. Theoretical validity of CVM was sufficiently shown and there were several indications of convergent validity. No results on criterion validity and only a few on reliability were found. There was widespread use of different elicitation formats, which make comparisons of studies problematic. Direct questions were seen problematic. First bids used in bidding games influenced the monetary valuation significantly (starting point bias). There were indications that the range of bids of payment cards also affected the valuation (range bias). However, no strategic bias was found. The influence of different states of valuation (ex-ante, ex-post) and of payment methods, as well as the possible aggregation of the results of decomposed scenarios rather than more complex holistic scenarios, were rarely investigated. Further methodological analysis and testing seems to be necessary before CVM may be used in health care decision making. Important research topics are the connection of assessment of different elicitation methods and criterion validity as well as tests on reliability according to methodological issues. Concerning conceptual issues, the analysis of the influence of different states of evaluation and of the status of the respondents as diseased or non-diseased, as well as the aggregation of results of decomposed scenarios, proved to be topics of further research.

Gene structure of CYP2C8 and extrahepatic distribution of the human CYP2Cs.

Extrahepatic tissue distribution of the mRNAs for the four human CYP2Cs (2C8, 2C9, 2C18, and 2C19) was examined in kidney, testes, adrenal gland, prostate, brain, uterus, mammary gland, ovary, lung, and duodenum. CYP2C mRNAs were detected by RT-PCR using specific primers for each individual CYP2C. CYP2C8 mRNA was detected in the kidney, adrenal gland, brain, uterus, mammary gland, ovary, and duodenum. CYP2C9 mRNA was detected in the kidney, testes, adrenal gland, prostate, ovary, and duodenum. CYP2C18 mRNA was found only in the brain, uterus, mammary gland, kidney, and duodenum and CYP2C19 mRNA was found only in the duodenum. Immunoblot analysis of small intestinal microsomes detected both 2C9 and 2C19 proteins. In addition, genomic clones for CYP2C8 were sequenced, and long-distance PCR was performed to determine the complete gene structure. CYP2C8 spanned a 31 kb region. Comparative analysis of the 2.4 kb upstream region of CYP2C8 with CYP2C9 revealed two previously unidentified transcription factors sites, C/EBP and HPF-1, and the latter might be involved in hepatic expression. Although CYP2C8 has been shown to be phenobarbital inducible, neither a barbiturate-responsive regulatory sequence (a Barbie box) nor a phenobarbital-responsive enhancer module (PBREM) was found within the upstream region analyzed.

Identification of residues 286 and 289 as critical for conferring substrate specificity of human CYP2C9 for diclofenac and ibuprofen.

Specificity of human CYP2C9 for two substrates, diclofenac and ibuprofen, was studied using chimeras and site-directed mutants of CYP2C9 and the highly related CYP2C19 expressed in Escherichia coli. Data were correlated with the presence of putative substrate recognition sites (SRS). A CYP2C19 chimera containing residues 228-340 (SRS 3 and 4) of 2C9 conferred both diclofenac hydroxylation and 2- and 3-hydroxylation of ibuprofen. The regiospecificity of this construct for metabolism of ibuprofen differed from that of CYP2C9 by favoring 2-hydroxylation over 3-hydroxylation. A CYP2C9 construct containing residues 228-340 of CYP2C19 lacked both diclofenac and ibuprofen hydroxylase activities. When residues 228-282 (containing SRS 3) of CYP2C9 were replaced by those of CYP2C19, the chimera retained appreciable activity for diclofenac and ibuprofen, and tolbutamide activity was inhibited by a specific CYP2C9 inhibitor, sulfaphenazole. This suggested that SRS 3 is not important in conferring specificity. CYP2C9 and CYP2C19 differ in five residues within the region 283-340 (within SRS 4). Mutations to analyze SRS 4 were made on a CYP2C19 chimera containing residues 228-282 of CYP2C9. A single I289N mutation conferred a dramatic increase in diclofenac hydroxylation and a small increase in ibuprofen 2-hydroxylation. A second mutation (N286S and I289N) increased diclofenac hydroxylation and conferred a dramatic increase in ibuprofen 2-hydroxylation. A V288E mutation did not increase activity toward either substrate and decreased activity toward the two substrates in combination with the I289N or the N286S, I289N mutants. Therefore residues 286 and 289 of CYP2C9 are important in conferring specificity for diclofenac and ibuprofen.

The role of the CYP2C9-Leu359 allelic variant in the tolbutamide polymorphism.

Tolbutamide undergoes hydroxylation in humans via a cytochrome P450-mediated pathway. The primary P450 isozyme responsible for this metabolism is thought to be CYP2C9. Population studies have indicated the existence of slow metabolizers of tolbutamide (approximately 1 in 500) suggesting a rare polymorphism associated with 2C9. Several allelic variants of 2C9 have been identified; however, the effect of these allelic variations on metabolism in vivo is not established. In the present study, the coding regions, intron-exon junctions, and upstream region of CYP2C9 were amplified by PCR and sequenced in two slow metabolizers. One individual was homozygous for Leu359/Leu359 and the other individual was heterozygous for Arg144/Cys144 and for Ile359/Leu359. No other genetic variations in 2C9 were detected in these individuals. PCR-RFLP tests showed that Arg144 Tyr358 Ile359 Gly417 is the principle CYP2C9 allele. Frequencies of the rarer Leu359 and Cys144 alleles were 0.06 and 0.08, respectively, in a Caucasian-American population and 0.005 and 0.01 respectively in African-Americans. The frequency of the Leu359 allele was 0.026 in Chinese-Taiwanese, but the Cys144 allele was not detected in this population. Studies in a recombinant yeast expression system showed that the Leu359 variant had the highest Km and the lowest Vmac for hydroxylation of tolbutamide of all the CYP2C9 allelic variants. This allelic variant also had the highest Km for the 7-hydroxylation of S-warfarin. The present data suggest that the incidence of the Leu359 allelic variant of CYP2C9 may account for the occurrence of poor metabolizers of tolbutamide.