Methods for think-aloud interviews in health-related resource-use research: the PECUNIA RUM instrument.

BACKGROUND: The think-aloud (TA) approach is a qualitative research method that allows for gaining insight into thoughts and cognitive processes. It can be used to incorporate a respondent's perspective when developing resource-use measurement (RUM) instruments. Currently, the application of TA methods in RUM research is limited, and so is the guidance on how to use them. Transparent publication of TA methods for RUM in health economics studies, which is the aim of this paper, can contribute to reducing the aforementioned gap. METHODS: Methods for conducting TA interviews were iteratively developed by a multi-national working group of health economists and additional qualitative research expertise was sought. TA interviews were conducted in four countries to support this process. A ten-step process was outlined in three parts: Part A 'before the interview' (including translation, recruitment, training), Part B 'during the interview' (including setting, opening, completing the instrument, open-ended questions, closing), and part C 'after the interview' (including transcription and data analysis, trustworthiness). CONCLUSIONS: This manuscript describes the step-by-step approach for conducting multi-national TA interviews with potential respondents of the PECUNIA RUM instrument. It increases the methodological transparency in RUM development and reduces the knowledge gap of using qualitative research methods in health economics.

International comparability of reference unit costs of education services: when harmonizing methodology is not enough (PECUNIA project).

BACKGROUND: Health problems can lead to costs in the education sector. However, these costs are rarely incorporated in health economic evaluations due to the lack of reference unit costs (RUCs), cost per unit of service, of education services and of validated methods to obtain them. In this study, a standardized unit cost calculation tool developed in the PECUNIA project, the PECUNIA RUC Template for services, was applied to calculate the RUCs of selected education services in five European countries. METHODS: The RUCs of special education services and of educational therapy were calculated using the information collected via an exploratory gray literature search and contact with service providers. RESULTS: The RUCs of special education services ranged from €55 to €189 per school day. The RUCs of educational therapy ranged from €6 to €25 per contact and from €5 to €35 per day. Variation was observed in the type of input data and measurement unit, among other. DISCUSSION: The tool helped reduce variability in the RUCs related to costing methodology and gain insights into other aspects that contribute to the variability (e.g. data availability). Further research and efforts to generate high quality input data are required to reduce the variability of the RUCs.

[Inter-sectoral costs and benefits arising from mental health (disorders)]. / Intersectorale kosten en baten van geestelijke (on)gezondheid.

BACKGROUND: Mental health disorders may bring costs and benefits to areas and sectors lying outside the health care system. However, little is known about these inter-sectoral costs and benefits (ICBs) in spite of the increasing interest in societal cost-benefit analyses (SCBA) that attempt to quantify all costs and benefits involved.
AIM: To present a first inventory of ICBs relating to mental health care and to describe the relation between ICBs and SCBA.
METHOD: We reviewed the literature and conducted a secondary analysis of the results of a previous study.
RESULTS: We found that at least eight mental health disorders were reported to have a (financial) impact on at least three sectors outside the health care system.
CONCLUSION: Further research into ICBs is needed so that future inter-sectoral policy can be better directed and targeted more efficiently.

FOXA1 repression is associated with loss of BRCA1 and increased promoter methylation and chromatin silencing in breast cancer.

FOXA1 expression correlates with the breast cancer luminal subtype and patient survival. RNA and protein analysis of a panel of breast cancer cell lines revealed that BRCA1 deficiency is associated with the downregulation of FOXA1 expression. Knockdown of BRCA1 resulted in the downregulation of FOXA1 expression and enhancement of FOXA1 promoter methylation in MCF-7 breast cancer cells, whereas the reconstitution of BRCA1 in Brca1-deficent mouse mammary epithelial cells (MMECs) promoted Foxa1 expression and methylation. These data suggest that BRCA1 suppresses FOXA1 hypermethylation and silencing. Consistently, the treatment of MMECs with the DNA methylation inhibitor 5-aza-2'-deoxycitydine induced Foxa1 mRNA expression. Furthermore, treatment with GSK126, an inhibitor of EZH2 methyltransferase activity, induced FOXA1 expression in BRCA1-deficient but not in BRCA1-reconstituted MMECs. Likewise, the depletion of EZH2 by small interfering RNA enhanced FOXA1 mRNA expression. Chromatin immunoprecipitation (ChIP) analysis demonstrated that BRCA1, EZH2, DNA methyltransferases (DNMT)1/3a/3b and H3K27me3 are recruited to the endogenous FOXA1 promoter, further supporting the hypothesis that these proteins interact to modulate FOXA1 methylation and repression. Further co-immunoprecipitation and ChIP analysis showed that both BRCA1 and DNMT3b form complexes with EZH2 but not with each other, consistent with the notion that BRCA1 binds to EZH2 and negatively regulates its methyltransferase activity. We also found that EZH2 promotes and BRCA1 impairs the deposit of the gene silencing histone mark H3K27me3 on the FOXA1 promoter. These associations were validated in a familial breast cancer patient cohort. Integrated analysis of the global gene methylation and expression profiles of a set of 33 familial breast tumours revealed that FOXA1 promoter methylation is inversely correlated with the transcriptional expression of FOXA1 and that BRCA1 mutation breast cancer is significantly associated with FOXA1 methylation and downregulation of FOXA1 expression, providing physiological evidence to our findings that FOXA1 expression is regulated by methylation and chromatin silencing and that BRCA1 maintains FOXA1 expression through suppressing FOXA1 gene methylation in breast cancer.

Opportunities and hurdles in the treatment of BRCA1-related breast cancer.

BRCA1 functions as a classical tumor suppressor in breast and ovarian cancer. While the role of BRCA1 in homology-directed repair of DNA double-strand breaks contributes to its tumor suppressive activity, it also renders BRCA1-deficient cells highly sensitive to DNA-damaging agents. Although BRCA1 deficiency is therefore considered to be an attractive therapeutic target, re-activation of BRCA1 by secondary mutations has been shown to cause therapy resistance. In this review, we will assess the role of BRCA1 in both hereditary and sporadic breast cancer and discuss how different functionalities of the BRCA1 protein can contribute to its tumor suppressor function. In addition, we will discuss how this knowledge on BRCA1 function can help to overcome the hurdles encountered in the clinic and improve current treatment strategies for patients with BRCA1-related breast cancer.

Site-Dependent Coordination Bonding in Self-Assembled Metal-Organic Networks.

The combination of organic linkers with metal atoms on top of inorganic substrates offers promising perspectives for functional electronic and magnetic nanoscale devices. Typically, coordination bonds between electron-rich end groups and transition-metal atoms lead to the self-assembly of metal-organic nanostructures, whose shape and electronic and magnetic properties crucially depend on the type of ligand. Here, we report on the site-selective bonding properties of Co atoms to the dichotomic dicyanoazobenzene molecule with its carbonitrile and diazo N-based moieties as possible ligands. Using low-temperature scanning tunneling microscopy (STM) and spectroscopy measurements, we resolve the formation of self-assembled metal-organic motifs. Cobalt atoms exhibit a clear spectroscopic fingerprint dependent on the different coordination site, which is further used to map their position, otherwise not clearly visible in the topographic STM images. Density functional theory corroborates the observed bonding patterns and evidences their coordinative nature.

Preclinical mouse models for BRCA1-associated breast cancer.

A substantial part of all hereditary breast cancer cases is caused by BRCA1 germline mutations. In this review, we will discuss the insights into BRCA1 functions that we obtained from mouse models with conventional and conditional mutations in Brca1. The most advanced models closely resemble human BRCA1-related breast cancer and may therefore be useful for addressing clinically relevant questions.

DSM-IV internal construct validity: when a taxonomy meets data.

The use of DSM-IV based questionnaires in child psychopathology is on the increase. The internal construct validity of a DSM-IV based model of ADHD, CD, ODD, Generalised Anxiety, and Depression was investigated in 11 samples by confirmatory factor analysis. The factorial structure of these syndrome dimensions was supported by the data. However, the model did not meet absolute standards of good model fit. Two sources of error are discussed in detail: multidimensionality of syndrome scales, and the presence of many symptoms that are diagnostically ambiguous with regard to the targeted syndrome dimension. It is argued that measurement precision may be increased by more careful operationalisation of the symptoms in the questionnaire. Additional approaches towards improved conceptualisation of DSM-IV are briefly discussed. A sharper DSM-IV model may improve the accuracy of inferences based on scale scores and provide more precise research findings with regard to relations with variables external to the taxonomy.

Visualization of flow patterns from stents and stent-grafts in an in vitro flow-model.

RATIONALE AND OBJECTIVES: The authors determine flow characteristics and pressure gradients of different stents and stent grafts in an in vitro flow-model. METHODS: Five vascular stents (Memotherm, Cragg, two Palmaz P308, Strecker, and Wall) and one stent graft (Cragg EndoPro System 1), equal in length (60 mm) and diameter (10 mm), were deployed in a closed flow-model. The inner diameter of the tube measured 9 mm. Flow at 1.5 L/min, 6 L/min, and 10 L/min was simulated. Flow patterns were visualized by anionic particles illuminated with two Helium-Neon lasers. Laminary flow characteristics and pre-/poststent pressure gradients were determined in either expanded stent, 25% stenosis, or 50% stenosis. RESULTS: Stent implantation induced a decrease of laminary flow compared with an unstented tube with and without concentric 25% stenosis (P < 0.01) at all flow rates and an increase of pressure gradients compared with an unstented tube for flow rates greater than 1.5 L/min (P < 0.01) (except for Cragg EndoPro System 1 stent, which revealed an increase of the pressure gradient at a flow rate of 1.5 L/min [P < 0.01]). Memotherm stent permitted maximum of laminary flow at all flow rates and stenoses (expanded: 79.50% at 1.5 L/min to 69.90% at 10 L/min; P < 0.01). Memotherm and Palmaz permitted lowest pressure gradients (P < 0.01). All of the endoprostheses demonstrated laminary flow at 50% stenosis. CONCLUSIONS: The investigated stents and stent grafts showed different severity of flow disturbances and pressure gradients at different graded stenoses. Inadequate stent depolyment bears the risk of creating less laminary flow and pathologic pressure gradients. Because flow disturbances and pressure gradients may influence neointimal hyperplasia, stent design and completeness of stent unfolding are important regarding the appearance of postinterventional restenoses.

Pharmacokinetic study of extradural and intrathecal sufentanil anaesthesia for major surgery.

We have studied the plasma concentrations (Cp) and pharmacokinetics of sufentanil injected i.v. (IVS), intradurally (IS) or extradurally (ES) under general anaesthesia in 31 patients undergoing major abdominal surgery. Sufentanil appeared in plasma very rapidly and Cpmax was also attained rapidly after both extradural and intrathecal injection. Apart from the first 2 min after injection, Cp after ES and IVS were comparable until the end of the study. Cp after ES was greater than after IS up to 0.25 h. Cp after IS was significantly greater than that after ES at 1 h and 2.5 h, and was also greater than that after IVS at 3 h. At tracheal extubation there was no difference in Cp between groups. Peak Cp values were significantly different between ES and IS, but the times taken to reach Cpmax were comparable. Plasma pharmacokinetics after ES and IS were similar. The plasma mean residence time and volume of distribution of sufentanil at steady state after ES and IS were significantly different in comparison with those after IVS.

Epidural morphine anesthesia for abdominal aortic surgery--pharmacokinetics.

Plasma and CSF pharmacokinetics of morphine given epidurally in combination with general anesthesia for abdominal aortic surgery were recorded. The initial plasma and CSF concentrations of morphine appeared at two minutes. The peak plasma concentrations of morphine were recorded at 8.0 +/- 2.6 minutes after epidural injection. Plasma mean residence time was 84 +/- 25.7 minutes, Vdss 121 +/- 30 L, and C1 1.5 +/- 0.32 L/min. Free morphine was not detected in plasma 360 minutes after epidural administration. The fraction of the epidural morphine that crossed the dura was 3.15% +/- 2.4 The peak CSF morphine concentrations were recorded at 56 +/- 31 minute. MRT (200 +/- 28 minute), Vdss (65 +/- 33.8 ml), and CL (0.32 +/- 0.15 ml/min) showed that variable fractions of morphine remained many hours in the CSF. Factors that could produce the interindividual variability of plasma and CSF concentrations and pharmacokinetics of epidural morphine were discussed. Abdominal aortic surgery appears to influence both plasma and CSF pharmacokinetics.

Pharmacokinetics of morphine in cerebrospinal fluid and plasma after epidural administration in man.

The morphine concentration in serum as well as in cerebrospinal fluid (CSF) after epidural administration of 0.1 mg/kg morphine to 10 patients undergoing aortic abdominal surgery, was determined. Model independent pharmacokinetic parameters in serum and CSF i.e. mean residence time (MRT), clearance (Cl) and apparent volume of distribution were calculated from the concentration time curves using a non-linear square regression fitting programme. Peak concentration of morphine in serum (86 ng/ml) and in CSF (2610 ng/ml) was reached after 10 min respectively 40 min of epidural injection.

The pharmacokinetics of intradural morphine in major abdominal surgery.

The pharmacokinetics of intradural morphine used for major abdominal surgery were evaluated. Lumbar spinal fluid and plasma concentrations were measured at intervals after morphine 0.05 mg/kg had been injected intradurally in 21 patients scheduled for elective abdominal aortic surgery. The CSF morphine concentrations were fitted by a biexponential function. A non-compartmental model based on statistical moment theory was used for calculating the intradural morphine disposition. Mean residence time was 137 +/- 54.9 minutes, mean initial volume of distribution 15 +/- 5.49 ml, mean volume of distribution at steady-state 42 +/- 18.25 ml and mean clearance 0.34 +/- 0.18 ml/min (0.02 +/- 0.01 L/h). The moments of the morphine concentration-time curves and the pharmacokinetic parameters varied between the patients. They were not significantly different with regard to morphine dosage, or patient sex or age. Free morphine could not be detected in plasma. Morphine-3-glucuronide appeared in plasma at 5 minutes, increased to a maximum at 240 minutes and fell below the detection limit at about 16 hours after morphine administration. Possible clinical causes of interindividual variations in the CSF morphine concentrations and the pharmacokinetics of intradural morphine are discussed.

The registration of medicines in The Netherlands.

The working methods and the results of the system for registration of medicines in the Netherlands are reviewed. The new structure of the Committee for the Evaluation of Medicines is identified. The necessity for more international cooperation is emphasized. The authors propose the establishment of a European registration committee. The current system is discussed from the viewpoints of government and industry.

Long-term release of copper from two multiload IUD models: MLCu250 and MLCu375.

Decrease of mean copper content was assessed for two commercial types of Multiload IUD with different copper loads. Mean daily loss of copper amounted to about 18 mcg and 30 mcg for MLCu250 and MLCu375 devices, respectively. On the basis of these estimates, we conclude that both these IUD models can be considered long-lasting interceptive agents.

Terbutaline sustained-release treatment during one week 5 mg b.i.d. compared to one week placebo: terbutaline plasma levels, c-AMP plasma levels, lung function and tremor measurement.

In a group of ten patients with chronic asthmatic bronchitis, a good improvement of the lung function was achieved by a sustained-release terbutaline preparation (Bricanyl Retard) in a dosage of 5 mg twice daily. Tremor measurements and c-AMP plasma level showed a statistically significant increase. A good patient compliance was achieved with this dosage of terbutaline two times daily. The sustained-release preparation caused a rather constant and low terbutaline plasma level. We think that this relative low terbutaline plasma level is the most important reason for the lack of side effects.

Combination therapy of theophylline and terbutaline as sustained-release preparations in patients with asthmatic bronchitis.

In a group of ten patients with chronic asthmatic bronchitis, the effect of monotherapy with theophylline and terbutaline and the combination of both drugs, as sustained-release tablets, was compared to placebo, in a double-blind cross-over, triple dummy at random study. Lung function parameters, tremor measurements, c-AMP plasma levels, theophylline- and terbutaline-plasma levels were determinated. Monotherapy with theophylline and terbutaline in a relatively low dosage achieved a good lung function improvement without severe side effects, as compared to placebo. The combination of both drugs in the same dosage achieved a statistically significant enhancement of the lung function improvement, as compared to monotherapy, without an increase of side effects. An additional effect of theophylline and terbutaline on bronchodilation is demonstrated.

A comparative study of a monoclonal immunoassay reagent strip test and high pressure liquid chromatography for theophylline.

Our experience with the determination of theophylline in serum using a monoclonal immunoassay reagent strip test is reported. The day-to-day precision of a series of drug assay controls (n = 74) was investigated with a mean theophylline value of 15,3 +/- 1,2 mg/l. Interference and/or cross reactivity of structurally related compounds and metabolites of theophylline was tested. Serum samples from 148 asthmatic patients who were treated with theophylline were analyzed by the SERALYZER ARIS*) reagent strip test and by high pressure liquid chromatography. A correlation coefficient of 0.99 was found between these techniques using a linear regression analysis.