Methods for population size estimation of problem drug users using a single registration

BackgroundThe number of problem drug users is used as a key indicator to monitor the drug situation in the European Union. An alternative approach to estimate the number of problem drug users is given by ‘the one-source capture–recapture analysis’ that uses a single registration.MethodsTwo variants of the one-source capture–recapture analysis were applied to a single registration: the truncated Poisson regression model (TPR) and the Zelterman regression model. These models were applied to data about clinical drug-related hospital admissions derived from the Dutch Hospital Registration (LMR). The TPR accounts for heterogeneity in capture probabilities by allowing for covariates and the Zelterman regression model relies on the problem drug users that were seen only once or twice in the hospital; the latter model is known to be robust against unobserved heterogeneity.ResultsThe TPR model was found to have a bad fit due to unobserved heterogeneity. The Zelterman regression model estimated the population size at 10,415 problem drug users (95% CI is 8400–12,429). This figure is an estimate of the number of problem drug users who are at risk of a clinical hospital admission due to the medical consequences of their drug use. The model can also provide estimates of different subgroups of problematic drug users.ConclusionThe method presented here offers a promising alternative for estimating the number of problem drug users, including different subgroups of drug users. In addition, observed and unobserved heterogeneity can be accounted for in these estimates.     

Analysis of breast cancer related gene expression using natural splines and the Cox proportional hazard model to identify prognostic associations

Many studies correlating gene expression data to clinical parameters assume a linear increase or decrease of the clinical parameter under investigation with the expression of a gene. We have studied genes encoding important breast cancer-related proteins using a model for survival-type data that is based on natural splines and the Cox proportional hazard model, thereby removing the linearity assumption. Expression data of 16 genes were studied in relation to metastasis-free probability in a cohort of 295 consecutive breast cancer patients treated at The Netherlands Cancer Institute. The independent predictive power for disease outcome of the 16 individual genes was tested in a multivariable model with known clinical and pathological risk factors. There is a linear relationship between increasing expression and a higher or lower hazard for distant metastasis for ESR1, ERBB4, VEGF, CCNE2, EZH2, and UPA; for ERBB2, ERBB3, CCND1, CCNE1, EED, CXCR4, CCR7, SDF1, and PAI1 there is no clear increase or decrease; and for EGFR there seems to be a non-linear relation. Multivariable analysis showed that the 70-gene prognosis profile outperforms all the other variables in the model (hazard-rate 5.4, 95% CI 2.5–11.7; P = 0.000018). EGFR-expression seems to have a non-linear relation with disease outcome, indicating that lower but also higher expression of EGFR are associated with worse outcome compared to intermediate expression levels; the other genes show no or a linear relation.     

89Zr-trastuzumab PET visualises HER2 downregulation by the HSP90 inhibitor NVP-AUY922 in a human tumour xenograft

NVP-AUY922, a potent heat shock protein (HSP) 90 inhibitor, downregulates the expression of many oncogenic proteins, including the human epidermal growth factor receptor-2 (HER2). Because HER2 downregulation is a potential biomarker for early response to HSP90-targeted therapies, we used the ⁸⁹Zr-labelled HER2 antibody trastuzumab to quantify the alterations in HER2 expression after NVP-AUY922 treatment with HER2 positron emission tomography (PET) imaging.The HER2 overexpressing human SKOV-3 ovarian tumour cell line was used for in vitro experiments and as xenograft model in nude athymic mice. In vitro HER2 membrane expression was assessed by flow cytometry and a radio-immuno assay with ⁸⁹Zr-trastuzumab. For in vivo evaluation, mice received 50 mg/kg NVP-AUY922 intraperitoneally every other day. ⁸⁹Zr-trastuzumab was injected intravenously 6 d before NVP-AUY922 treatment and after 3 NVP-AUY922 doses. MicroPET imaging was performed at 24, 72 and 144 h post tracer injection followed by ex-vivo biodistribution and immunohistochemical staining.After 24 h NVP-AUY922 treatment HER2 membrane expression showed profound reduction with flow cytometry (80%) and radio-immuno assay (75%). PET tumour quantification, showed a mean reduction of 41% (p = 0.0001) in ⁸⁹Zr-trastuzumab uptake at 144 h post tracer injection after NVP-AUY922 treatment. PET results were confirmed by ex-vivo ⁸⁹Zr-trastuzumab biodistribution and HER2 immunohistochemical staining.NVP-AUY922 effectively downregulates HER2, which can be monitored and quantified in vivo non-invasively with ⁸⁹Zr-trastuzumab PET. This technique is currently under clinical evaluation and might serve as an early biomarker for HSP90 inhibition in HER2 positive metastatic breast cancer patients.     

Relations between negative affect, coping, and emotional eating

The study was designed to examine the relations between negative affect, coping, and emotional eating. It was tested whether emotion-oriented coping and avoidance distraction, alone or in interaction with negative affect, were related to increased levels of emotional eating. Participants were 125 eating-disordered women and 132 women representing a community population. Measures included the Positive and Negative Affectivity Schedule (PANAS), the Coping Inventory for Stressful Situations (CISS), and the Dutch Eating Behavior Questionnaire (DEBQ). Both emotion-oriented coping and avoidance distraction were related to emotional eating, while controlling for levels of negative affect. Negative affect did not have a unique contribution to emotional eating over and above emotion-oriented coping or avoidance distraction. The findings suggest that emotional eating is related to reliance on emotion-oriented coping and avoidance distraction in eating-disordered women as well as in relatively healthy women.     

Effects of various amounts of dietary plant sterol esters on plasma and hepatic sterol concentration and aortic foam cell formation of cholesterol-fed hamsters

Dietary intake of plant sterol esters (PSE) lowers plasma LDL-cholesterol (LDL-C), but can modestly increase plasma plant sterol concentrations. The objective of the present study was to investigate the impact of increasing doses of dietary PSE on plasma and liver sterol concentrations as well as on aortic foam cell development as a marker of atherogenesis. One-hundred and twenty F(1)B hybrid Syrian golden hamsters (20 per group) were fed a basal atherogenic diet containing 30% of energy as fat and 0.12% (w/w) cholesterol and supplemented with 0, 0.24, 0.48, 0.96, 1.92 and 2.84% (w/w) PSE. After 12 weeks, plasma total cholesterol (TC) and LDL-C were significantly lower in the groups fed PSE compared with control. Plasma plant sterol concentrations increased with increasing dietary PSE intake up to the dietary level of 1.92% and then reached a plateau. On the other hand, hepatic campesterol and sitosterol concentrations plateaued at 0.24% PSE. Foam cell presence in the aortic arch showed an inverse relationship with dietary PSE intake (P<0.0001). Lipid-filled foam cell areas of hamsters receiving 0.24, 0.48 or 2.84% PSE were approximately 70, 90 and 100% smaller than in control hamsters fed no PSE. In summary, dietary PSE lowered plasma TC and LDL-C. Despite an increase in plasma plant sterol concentrations they did not contribute to aortic foam cell development. In fact dietary PSE significantly inhibited aortic foam cell formation. This study supports the concept that PSE through their cholesterol-lowering action prevent development of atherogenesis in this animal model.     

In search of good care: the methodology of phenomenological,theory-oriented ‘N=N case studies’ in empirically grounded ethics of care

Medicine, Health Care and Philosophy - This paper proposes a new perspective on the methodology of qualitative inquiry in (care) ethics, especially the interaction between empirical work and theory...