Anidulafungin Pharmacokinetics in Ascites Fluid and Pleural Effusion of Critically Ill Patients.

Anidulafungin concentrations were quantified with high-pressure liquid chromatography (HPLC) and UV detection of the ascites fluid and pleural effusion of 10 adult critically ill patients. Samples were collected from ascites fluid and from pleural drains or during paracentesis and thoracentesis, respectively. Anidulafungin levels in ascites fluid (0.12 to 0.99 µg/ml) and in pleural effusion (0.32 to 2.02 µg/ml) were below the simultaneous levels in plasma (1.04 to 7.70 and 2.48 to 13.36 µg/ml, respectively) and below the MIC values for several pathogenic Candida strains.

Cost impact of prospective HLA-B*5701-screening prior to abacavir/lamivudine fixed dose combination use in Germany.

OBJECTIVE: Avoiding abacavir in HIV-infected patients tested positive for HLA-B*5701 reduces the risk of abacavir hypersensitivity reaction (ABC-HSR). Our aim was to assess the costs of clinically suspected HSR and to estimate potential cost savings of implementing prospective HLA-B*5701-screening for HIV-infected patients initiating abacavir/lamivudine fixed-dose combination (ABC/3TC FDC) compared to initiating respective treatment without screening. METHODS: Employing a decision tree model the expected HSR-related costs of screening vs. no screening were estimated from the societal and healthcare payer perspective (reference year 2007). A retrospective standardized assessment of all clinically suspected ABC-HSR cases without screening at 5 German HIV-centres was performed to measure resource consumption. In- and outpatient care, discarded ABC/3TC FDC and concomitant medication were considered. Direct resource utilization was valued using German fees (EBM, G-DRGs). Indirect costs were measured with the human capital approach. Estimates for the HLA-B*5701-prevalence, HSR-incidence, and hospitalization rate were based on clinical trials and cohorts and it was assumed that screening reduces the incidence of clinically suspected ABC-HSR from 10% to 0.5%. RESULTS: Thirty-two ABC-HSR cases were identified from 1998 to 2007. Mean direct and total costs per clinically suspected HSR case were Euro 1,362 and Euro 2,235, respectively. Hospital costs contributed 63.3% to direct costs. Potential cost savings when implementing genetic screening were estimated at Euro 44 and Euro 127 per screened patient, from a healthcare payer or societal perspective. CONCLUSION: HLA-B*5701 screening prior to ABC/3TC FDC initiation prevents significant HSR-related costs per screened patient and is likely to lead to overall net savings.

Health economic methodology illustrated with recent work on Chlamydia screening: the concept of extended dominance.

The health economic concepts of dominance were reviewed on the basis of two recently published cost-effectiveness analyses on screening for asymptomatic Chlamydia trachomatis, one in this journal. On the basis of dominance, some strategies may be deleted from the set options from which to choose. The two investigated studies were from the United Kingdom and The Netherlands. Both studies nicely illustrate situations of so-called extended dominance in practical decision making. Extended dominance is a theoretical topic in many health-economic text books but is only scarcely encountered in daily practice. Although the concept of extended dominance is theoretical in nature, a formal analysis and explanation may help show which options under consideration are not optimal from a strictly health-economic perspective; however, these options might still be attractive policy options for other reasons.

Economic evaluation of meningococcal serogroup C conjugate vaccination programmes in The Netherlands and its impact on decision-making.

The cost-effectiveness of one time vaccination of all persons aged 14 months to 18 years (catch-up programme) and of routine childhood immunisation at either ages 2 + 3 + 4 months, 5 + 6 months, or 14 months with a meningococcal C conjugate vaccine was estimated for The Netherlands, from a societal and a health care payer perspective. A decision analysis cohort model was employed (time horizon 77 years), direct and indirect costs (friction cost method) were considered and future costs and effects were discounted at 4%. The results showed that all vaccination options yield a substantial health gain and that the catch-up programme and routine vaccination at 14 months render favourable cost-effectiveness ratios: between about 13,200 and 17,700 per life year gained for the catch-up programme and between about 2200 and 2400 per life year gained for routine childhood vaccination at 14 months, depending on the perspective. In comparison to vaccination at 14 months, routine childhood vaccination during the first year of life is much less cost-effective: each additional life year gained costs approximately 147,000 (2 + 3 + 4 months) or 102,000 (5 + 6 months), from both perspectives. Additionally, inclusion of the likely herd immunity effect of the catch-up programme increases these incremental cost-effectiveness ratios. These results played a major role in the decision to add meningococcal C vaccination to the routine childhood immunisation schedule at 14 months and to implement a catch-up vaccination programme in The Netherlands in 2002.

Epidemiologic impact and cost-effectiveness of universal infant vaccination with a 7-valent conjugated pneumococcal vaccine in the Netherlands.

BACKGROUND: Streptococcus pneumoniae is one of the main causes of bacterial meningitis, bacteremia, pneumonia, and otitis media in the Netherlands. These diseases lead to substantial mortality, morbidity, and costs. The societal impact is especially severe because most cases occur in very young infants. OBJECTIVE: The aim of this study was to estimate the epidemiological impact and cost-effectiveness of universal infant vaccination with a 7-valent conjugated pneumococcal vaccine in the Netherlands. METHODS: Decision analysis was performed using epidemiological data and data on health care resource use from 1996 to 2001. A model was used to project the impact of pneumococcal vaccination on the incidence of pneumococcal infections in infants and children from birth to age 10 years. Costs, benefits, and health gains were estimated, and cost-effectiveness was calculated. All analyses were performed from a societal perspective. RESULTS: On average, 339 cases per year of invasive pneumococcal infection occurred in infants and children from birth to age 10 years in the Netherlands from 1996 to 2001. The model predicted that introduction of the 7-valent conjugated pneumococcal vaccine would prevent 48 cases of bacterial meningitis and 88 cases of pneumococcal bacteremia per year, as well as 42,695 cases of pneumococcal otitis media and 3411 cases of invasive pneumococcal pneumonia. The model also predicted that vaccination would save 13 lives per year and prevent 31 cases of lifelong sequelae, rendering 382 discounted quality-adjusted life-years (QALYs) gained or 329 discounted life-years gained per year. Considering these health gains, vaccination would prevent Euro 9,453,600 of direct and indirect medical costs of meningococcal and pneumococcal infections in the Netherlands, including acute medical care, management of sequelae, and lost time at work. With a vaccine price of Euro 40 per dose, the base-case cost-effectiveness ratio would be Euro 71,250 per QALY. The model was sensitive to changes in incidence of infections, vaccine effectiveness, and vaccine price. CONCLUSIONS: Our analytic model predicted that universal pneumococcal vaccination of infants in the Netherlands could prevent a large number of pneumococcal infections and considerably reduce related mortality and morbidity. However, the baseline cost-effectiveness ratio of such a vaccination program would be relatively unfavorable compared with other interventions implemented in the Netherlands.

Cost-effectiveness of partner pharmacotherapy in screening women for asymptomatic infection with Chlamydia Trachomatis.

OBJECTIVE: To assess the cost-effectiveness of pharmacotherapy for male partners in screening women for asymptomatic infection with Chlamydia trachomatis (CT). METHODS AND DATA: A pharmacoeconomic decision analysis model was constructed for the health outcomes of a CT screening program, such as averted cases of pelvic inflammatory disease and infertility (major outcomes). Reinfection in the absence of partner pharmacotherapy was included in the model. Cost-effectiveness from a societal perspective was estimated for prevalence data from a selective opportunistic screening program in Amsterdam. For diagnosis of asymptomatic CT infection a Ligase Chain Reaction (LCR) test on urine was used; for pharmacotherapy of women and partners azithromycin was used. By linking health outcomes with health care costs and productivity losses, averted costs were estimated. Cost-effectiveness was expressed as net costs per major outcome averted. RESULTS: Partner pharmacotherapy reduces net costs per major outcome averted of the screening program by approximately 50%. Sensitivity analysis indicates significant improvements in cost-effectiveness of the screening program, even when relevant assumptions are varied. Within the broader framework of the screening program, partner pharmacotherapy is a cost-saving activity. CONCLUSIONS: Inclusion of partner pharmacotherpy provides significant improvements in overall cost-effectiveness of the CT screening program among women aged 15 to 29. Partner pharmacotherapy lowers net costs per major outcome averted to the realm where implementation of the screening program should be considered. Considering the cost-saving potential, male partner pharmacotherapy should be pursued within the broader framework of a CT screening program for women. Reinfection should be included in any future pharmacoeconomic model of CT screening. Further work on this type of model should also be directed to linking cost-effectiveness to epidemiological models for the long-term spread of infectious diseases in populations.

[Expanded criteria for assessment of legal competence and testifying capacity in borderline cases of organic brain syndromes--an important field for cooperation between medicine and law]. / Erweiterte Beurteilungsmöglichkeiten in den Grenzgebieten der Testier- und Geschäftsfähigkeit bei organischen Psychosyndromen--ein wichtiges Zusammenarbeitsgebiet von Medizin und Jurisprudenz.

The three well-known criteria for legal competence and testamentary capacity, that is: consideration, awareness and the ability to express oneself in writing and speaking, ought to be extended by three further dimensions, namely: motivation, long-term intentions, gestures. This demands increased specialised competence and increased time, but seems indispensable in order to meet the postulate of human ethics: to give the patient the optimum support for a sensible realisation of will. This equally applies to medical experts and jurists (especially notaries and lawyers). The related demand to give increased time and attention to a patient, often in the form of repeated observation over several days, with detailed written documentation, shows that it is not at all a weakening, which is supported, but rather a more precise formation of concept. In this sense, we expect to meet better the demand of the best possible "objectivity" in evaluation, rather than within a merely schematic, single, short-time assessment. We substantiate this with several examples, taken from various areas, namely: in isolated aphasic/agraphic disorders, testamentary capacity and even legal competence can be retained according to the above criteria (despite the inability to write and speak). In analogy, also "last minute" decisions of the incurably sick person must be taken into account. We also show, however, that an assertion of legal competence (unrestricted ability to reach a decision) based on merely formalistic guide-lines, without taking into account long-term intentions and motivation, might seriously harm a patient. There is the case of a post-apoplexy patient who demanded immediate discharge to return home. This patient proved fully aware in classical questions of reference, but, due to homesickness, post-apoplectic syndrome and senile stubbornness, failed to take into account her inability to walk and incontinence. A consolidated discharge, however, was very well possible several weeks later. At an earlier stage this would have led to disaster. There will always remain a zone in which it is not possible to reach clear expert decisions either pro or contra but by incorporating the criteria above quoted, it will be possible to considerably narrow this zone. This corresponds to an evaluation process, which cultivates both optimum objectivity and optimum fairness.

Health economics of a hexavalent meningococcal outer-membrane vesicle vaccine in children: potential impact of introduction in the Dutch vaccination program.

The cost-effectiveness of universal vaccination of infants with a new hexavalent meningococcal B outer-membrane vesicle vaccine is projected for The Netherlands by applying decision analysis. The societal perspective is taken and direct and productivity costs (friction costs method) are considered. Future costs and effects are discounted at 4% (base year 1998). In this simulation model, vaccination would prevent 19 deaths and eight cases with severe long-term sequelae per year, rendering 526 additional quality adjusted life years (QALYs) per year. Yearly costs of acute phase of illness due to meningococcal infections in children are estimated at 1,426,634, while the future costs due to sequelae are estimated at 3,801,121 per year. Of all these costs, the vaccination program could prevent 3,334,052 per year. The program costs of meningococcal vaccination are estimated at 11,601,356, resulting in a cost-effectiveness ratio (CER) of 15,721 per QALY. These results are sensitive to the vaccine dose price (conservatively estimated at 10), efficacy, and coverage of meningococcal sero-subtypes.

Comparative model-based analysis of screening programs for Chlamydia trachomatis infections.

The design of a screening program for asymptomatic genital infections with Chlamydia trachomatis, requires decisions about which sex or age group should be targeted and whether partner referral should be included in the program. To investigate the effects of various screening programs on the prevalence and incidence of asymptomatic C. trachomatis infections in women, in May 1996 to April 1997 in Bilthoven, the Netherlands, the authors used a stochastic simulation model for C. trachomatis transmission in an age-structured, heterosexual population with a sexually highly active core group. Different screening scenarios were implemented over a time period of 10 years. Prevalence, incidence, and the fraction of infected persons found by partner referral were computed. Through screening of men and women between ages 15 and 24 years (baseline scenario), the prevalence of asymptomatic infections in women could be reduced from 4.2% to 1.4% in 10 years. Increasing the age range of screening up to ages 29 or 34 years led to prevalences of 0.4% and 0.06%, respectively, after 10 years. About 28% of all infected persons were found via partner referral. There are considerable indirect positive effects of screening on those population groups that are not included in the screening because of the reduced risk of becoming infected. Partner referral contributes substantially to prevalence reduction.

Cost-effectiveness of screening for genital Chlamydia trachomatis.

Chlamydia trachomatis is the most common, curable, sexually transmitted disease in many Western countries, leading to severe sequelae, such as infertility and ectopic pregnancy. As most chlamydial infections are asymptomatic, screening programs seem to be an attractive public health measure. MEDLINE, EMBASE, the Health Economic Evaluation Database and the National Health Service Economic Evaluation Database were searched for economic evaluations of Chlamydia trachomatis screening programs. Key factors influencing the cost-effectiveness are identified and assessed, such as screening strategy, test system and treatment regimen. Standard and new methodological approaches for assessing the cost-effectiveness are presented and future developments in the field are predicted. The most cost-effective screening approaches are compared with the recommendations of international guidelines.

[Screening for asymptomatic Chlamydia trachomatis infection in pregnancy; cost-effectiveness favorable at a minimum prevalence rate of 3% or more]. / Screening op asymptomatische infectie met Chlamydia trachomatis in de zwangerschap; gunstige kosteneffectiviteit bij een prevalentie van tenminste 3%.

OBJECTIVE: To estimate the cost-effectiveness of antenatal screening for Chlamydia trachomatis. DESIGN: Pharmaco-economic model analysis. METHOD: The risks of C. trachomatis infection during pregnancy and of complications of the infection as well as the cost of screening for complications (pelvic inflammatory disease, chronic pelvic pain, ectopic pregnancy, infertility and neonatal pneumonia) and of treatment were estimated. Assumed were a ligase chain reaction on urine and treatment of identified infected cases with erythromycin or amoxicillin (second choice). Cost-effectiveness was calculated and presented in net direct and indirect costs per major complication averted. RESULTS: For C. trachomatis prevalences in pregnancy above 4% benefits exceed the costs. For prevalences between 2.82% and 4.00% net costs are positive, but a major complication averted costs less than f 1000.-. Considering sensitivity analysis as well, screening for C. trachomatis at prevalences above 3% costs less than f 1000.-per major complication averted and might even save costs. No recent Dutch data on C. trachomatis prevalence in pregnancy are published however. CONCLUSION: Given the current information, antenatal C. trachomatis screening can be recommended from a pharmaco-economic perspective if C. trachomatis prevalence in pregnancy is 3% or more.

Cost-effectiveness of screening programs for Chlamydia trachomatis: a population-based dynamic approach.

BACKGROUND: Models commonly used for the economic assessment of chlamydial screening programs do not consider population effects. GOAL: To develop a novel dynamic approach for the economic evaluation of chlamydial prevention measures and to determine the cost-effectiveness of a general practitioner-based screening program. STUDY DESIGN: The dynamic approach was used to estimate the cost-effectiveness of a screening program for the first 10 years of screening in The Netherlands. Screening involved a ligase chain reaction test on urine followed by standardized therapies and partner referral. Eligible persons were sexually active, 15 to 24 years, visited a general practitioner, and had no symptoms of sexually transmitted diseases. The heterosexual model population, which consisted of persons 15 to 64 years, had a total chlamydial prevalence of 4.1% before screening. Screening effects on chlamydial incidence were computed by using a population-based stochastic simulation model. Incidence data were connected with a decision analysis model to determine the health effects of the program. The net costs of the program were calculated (investment costs minus averted costs, in 1997 US$) from a societal perspective and expressed per major outcome averted (symptomatic pelvic inflammatory disease, chronic pelvic pain, ectopic pregnancy, infertility, neonatal pneumonia). RESULTS: Unlike the standard static approach, our model adequately addresses dynamic processes such as chlamydial transmission and the impact of screening programs on chlamydial incidence in the population. During the first 10 years of screening, the investigated program yields savings of US $492 or US $1,086 per major outcome averted, excluding or including indirect costs, respectively. These results depend on chlamydial prevalence and partner referral. CONCLUSIONS: The cost-effectiveness of chlamydial screening programs seems best to be determined by using dynamic modeling on a population basis. In addition to preventing negative health outcomes, the investigated screening program may save costs.

[Opportunistic screening for genital infections with Chlamydia trachomatis among the sexually active population in Amsterdam. III. Cost-effectiveness analysis of screening women and the role of reinfection and partner treatment]. / Opportunistische screening op genitale infecties met Chlamydia trachomatis onder de seksueel actieve bevolking in Amsterdam. III. Kosteneffectiviteitsanalyse van screening bij vrouwen uitgebreid met de rol van herinfectie en partnermeebehandeling.

The role of reinfection and the importance of partner treatment were added to a pharmacoeconomic model for the analysis of a GP-based opportunistic screening programme for Chlamydia trachomatis (CT) in sexually active women in Amsterdam. A favourable cost-effectiveness was found for partner treatment. Partner treatment was cost saving and overall net costs per major outcome averted by the screening programme were reduced by 40% or more due to partner treatment. From a pharmacoeconomic point of view partner treatment should be routinely provided in the framework of a CT screening programme for Amsterdam women.

[Opportunistic screening for genital infections with Chlamydia trachomatis in sexually active population of Amsterdam. II. Cost-effectiveness analysis of screening women]. / Opportunistische screening op genitale infecties met Chlamydia trachomatis onder de seksueel actieve bevolking in Amsterdam. II. Kosteneffectiviteitsanalyse van screening bij vrouwen.

OBJECTIVE: To estimate the cost effectiveness of Chlamydia trachomatis (CT) screening of young women visiting general practitioners. DESIGN: Economic model analysis. METHODS: Data on the health care needs for CT complications were derived from various sources; costing was done using estimated cost prices, charges and the friction cost method; epidemiological data were derived from a pilot study among 22 general practices in Amsterdam, the Netherlands. The analyses were carried out assuming screening with ligase chain reaction test of a urine sample and treatment of identified cases of infection with single-dose azitromycin. The model intervention consisted of screening all heterosexually active women aged 15-19, 15-24, 15-29, or 15-34 years (strategies 1, 2, 3 and 4, respectively). Cost effectiveness was presented in net direct and indirect costs per woman cured and per major outcome averted (pelvic inflammatory disease (PID), chronic pelvic pain, ectopic pregnancy, infertility and pneumonia of newborns). RESULTS: The first two strategies were cost saving. For the third strategy net costs per woman cured and per major outcome averted were almost 110.- Dutch guilders (DFL) and over DFL 300, respectively. The last strategy costs over DFL 320 per woman cured and over DFL 910 per major outcome averted. The cost effectiveness was sensitive to the assumed probability of progression of CT infection to PID. CONCLUSION: Universal implementation of the screening programme investigated in Amsterdam for women aged 15-24 years would result in approximately equal savings and costs. Screening of all 15-29-year-old women would require a net investment of DFL 350,000.

Altered P53 conformation.

The p53 protein is a transcription factor that is frequently mutated in human malignancies. Using the MCF10AT model for early human breast cancer we show that P53 protein is unmutated indicating that mutations are not necessary for alterations in growth and morphology that accompany preneoplastic stages of breast tumor progression. Although p53 protein is wild-type in cells of the MCF10AT model system, it exists predominantly in a conformationally altered state that is defective in its ability both to bind DNA in a sequence-specific manner and to induce transcriptional activation from the WAF-1 promoter. This contrasts with P53 from the non-tumorigenic parental MCF10A cells which is predominantly conformationally normal and functionally active. The possibility that stabilized wild-type but conformationally altered P53 plays a role in the neoplastic progression of preneoplastic MCF10AT system cells is discussed.

[Determination of the time of dealth after dismemberment. Muscle electrophoretic criteria for estimating the early postmortal period in cadaver parts (author's transl)]. / Todeszeitbestimmung nach Leichenzerstckelung. Muskelelektrophoretische Kriterien zur frühpostmortalen Liegezeitabschätzung an Leichentielen.

Proteolytic fission products that allow estimation of the time of death can be demonstrated by electrofocussing of cadaver muscles already within the first 5 days postmortem. The fractionation rate, which progressively increases the later the tissue is examined, is based on the number of fractions resulting from protein decomposition. Some fractions appear relatively late, while others occur with increasing frequency and can be used as criteria to determine the time of death. This examination procedure can be used as a method for estimating the time of death in cadaver parts.