Cost-effectiveness analysis of a first-trimester screening test for preterm preeclampsia in the Netherlands

Objectives: The risk of preterm preeclampsia (PT PE) can significantly be reduced by starting acetylsalicylic acid ≤ 16 weeks of gestational age. First trimester predictive models based on maternal risk factors to effectively start this therapy lacked sufficient power, but recent studies showed that these models can be improved by including test results of biochemical and/or -physical markers. To investigate whether testing a biochemical marker in the first trimester is cost-effective in the Netherlands, a cost-effectiveness analysis was performed in this study. Study design: The outcome of this study was expressed as an incremental cost-effectiveness ratio (ICER) with as effect prevented PT PE cases. To evaluate the impact of each model parameter and to determine model uncertainties, both univariate and probabilistic sensitivity analyses were performed. Results: When compared to the baseline strategy, the test strategy is estimated to save almost 4 million euros per year on a national scale and at the same time this would prevent an additional 228 PT PE cases. The sensitivity analyses showed that the major drivers of the result are the costs to monitor a high-risk pregnancy and the specificity and that most of the model simulations were in the southeast quadrant: cost saving and more prevented complications. Conclusions: This study showed that a first-trimester test strategy to screen for PT PE in the first trimester is potentially cost-effective in the Dutch healthcare setting. The fact that the specificity is a major driver of the ICER indicates the importance for a (new) screening model to correctly classify low-risk pregnancies.</p

Healthy and preeclamptic pregnancies show differences in Guanylate-Binding Protein-1 plasma levels

The large interferon-inducible anti-angiogenic pro-inflammatory GTPase Guanylate Binding Protein-1 (GBP-1) is produced and secreted by activated endothelial cells and is highly induced by inflammatory cytokines and inhibited by angiogenic growth factors. During pregnancy a generalized mild inflammatory response is observed. During preeclampsia this generalized inflammatory response is even further activated and activation of the endothelium occurs. We hypothesized that GBP-1 is increased in healthy pregnancy and will be even further increased during preeclampsia. In the first experiment, plasma and placentas were collected from healthy and preeclamptic pregnancies. Plasma was also collected from non-pregnant women. For the second experiment longitudinal blood samples from women with a healthy or preeclamptic pregnancy were collected from the end of the first trimester until birth and one sample postpartum. The plasma GBP-1 levels were measured by ELISA and GBP-1 mRNA and protein levels in the placenta were tested by qPCR and immunohistochemistry. During pregnancy higher plasma concentrations of GBP-1 compared with non-pregnant women were observed. Surprisingly, during preeclampsia, plasma GBP-1 levels were lower than in control pregnancies and similar to the level of non-pregnant controls. Placental GBP-1 mRNA levels were not different between healthy and preeclamptic pregnancies and GBP-1 protein was virtually undetectable in the trophoblast by immunohistochemistry in placental tissue. Evaluation of longitudinal samples showed that plasma GBP-1 concentrations increased towards the end of pregnancy in healthy pregnancies, but not in preeclampsia. In line with our hypothesis, we found higher GBP-1 plasma levels during healthy pregnancy. However, plasma GBP-1 did not further increase during preeclampsia, but was stable. Further studies are needed to evaluate why GBP-1 does not increase during preeclampsia

Oxazepam and temazepam attenuate paroxetine-induced elevation of serotonin levels in guinea-pig hippocampus

Selective serotonin (5-HT) reuptake inhibitors (SSRIs) are used as a first-line treatment in depression. However, many depressed patients are also treated with benzodiazepines to alleviate increased anxiety and sleep disturbances normally associated with depression. Since benzodiazepines inhibit 5-HT neuronal firing activity, they might attenuate SSRI-induced increase in extracellular 5-HT levels. This study aimed to assess, using in-vivo microdialysis, the effects of the benzodiazepines oxazepam or temazepan on the SSRI paroxetine-induced 5-HT increase in the hippocampus of freely moving guinea-pigs. It was found that the acute systemic administration of paroxetine increased extracellular 5-HT levels. Pre-administration of oxazepam or temazepam significantly diminished the paroxetine-induced elevation of extracellular 5-HT levels (from 350% to 200% of baseline). It was concluded that benzodiazepines attenuate the ability of SSRIs to elevate hippocampal 5-HT levels. Thus, co-administration of benzodiazepines might affect the therapeutic efficacy of SSRI treatment

Prediction of brain clozapine and norclozapine concentrations in humans from a scaled pharmacokinetic model for rat brain and plasma pharmacokinetics

BACKGROUND: Clozapine is highly effective in treatment-resistant schizophrenia, although, there remains significant variability in the response to this drug. To better understand this variability, the objective of this study was to predict brain extracellular fluid (ECF) concentrations and receptor occupancy of clozapine and norclozapine in human central nervous system by translating plasma and brain ECF pharmacokinetic (PK) relationships in the rat and coupling these with known human disposition of clozapine in the plasma. METHODS: Unbound concentrations of clozapine and norclozapine were measured in rat brain ECF using quantitative microdialysis after subcutaneous administration of a 10 mg/kg single dose of clozapine or norclozapine. These data were linked with plasma concentrations obtained in the same rats to develop a plasma-brain ECF compartmental model. Parameters describing brain ECF disposition were then allometrically scaled and linked with published human plasma PK to predict human ECF concentrations. Subsequently, prediction of human receptor occupancy at several CNS receptors was based on an effect model that related the predicted ECF concentrations to published concentration-driven receptor occupancy parameters. RESULTS: A one compartment model with first order absorption and elimination best described clozapine and norclozapine plasma concentrations in rats. A delay in the transfer of clozapine and norclozapine from plasma to the brain ECF compartment was captured using a transit compartment model approach. Human clozapine and norclozapine concentrations in brain ECF were simulated, and from these the median percentage of receptor occupancy of dopamine-2, serotonin-2A, muscarinic-1, alpha-1 adrenergic, alpha-2 adrenergic and histamine-1 for clozapine, and dopamine-2 for norclozapine were consistent with values reported in the literature. CONCLUSIONS: A PK model that relates clozapine and norclozapine disposition in rat plasma and brain, including blood-brain barrier transport, was developed. Using allometry and published human plasma PK, the model was successfully translated to predict clozapine and norclozapine concentrations and accordant receptor occupancy of both agents in human brain. These predicted exposure and occupancy measures at several receptors that bind clozapine may be employed to extend our understanding of clozapine's complex behavioral effects in humans

First trimester secreted Frizzled-Related Protein 4 and other adipokine serum concentrations in women developing gestational diabetes mellitus

BACKGROUND: The aim of this study was to evaluate whether soluble frizzled-related protein 4 (sFRP4) concentration in the first trimester of pregnancy is individually, or in combination with Leptin, Chemerin and/or Adiponectin, associated with the development of gestational diabetes (GDM). METHODS: In a nested case-control study, 50 women with GDM who spontaneously conceived and delivered a live-born infant were matched with a total of 100 uncomplicated singleton control pregnancies based on body mass index (± 2 kg/m2), gestational age at sampling (exact day) and maternal age (± 2 years). In serum samples, obtained between 70-90 days gestational age, sFRP4, Chemerin, Leptin and Adiponectin concentrations were determined by ELISA. Statistical comparisons were performed using univariate and multi-variate logistic regression analysis after logarithmic transformation of the concentrations. Discrimination of the models was assessed by the area under the curve (AUC). RESULTS: First trimester sFRP4 concentrations were significantly increased in GDM cases (2.04 vs 1.93 ng/ml; p<0.05), just as Chemerin (3.19 vs 3.15 ng/ml; p<0.05) and Leptin (1.44 vs 1.32 ng/ml; p<0.01). Adiponectin concentrations were significantly decreased (2.83 vs 2.94 ng/ml; p<0.01) in GDM cases. Further analysis only showed a weak, though significant, correlation of sFRP4 with Chemerin (R2 = 0.124; p<0.001) and Leptin (R2 = 0.145; p<0.001), and Chemerin with Leptin (R2 = 0.282; p<0.001) in the control group. In a multivariate logistic regression model of these four markers, only Adiponectin showed to be significantly associated with GDM (odds ratio 0.12, 95%CI 0.02-0.68). The AUC of this model was 0.699 (95%CI 0.605-0.793). CONCLUSION: In the first trimester of pregnancy, a multi-marker model with sFRP4, Leptin, Chemerin and Adiponectin is associated with the development of GDM. Therefore, this panel seems to be an interesting candidate to further evaluate for prediction of GDM in a prospective study

Influence of family and friend smoking on intentions to smoke and smoking-related attitudes and refusal self-efficacy among 9-10 year old children from deprived neighbourhoods: a cross-sectional study.

BACKGROUND: Smoking often starts in early adolescence and addiction can occur rapidly. For effective smoking prevention there is a need to identify at risk groups of preadolescent children and whether gender-specific intervention components are necessary. This study aimed to examine associations between mother, father, sibling and friend smoking and cognitive vulnerability to smoking among preadolescent children living in deprived neighbourhoods. METHODS: Cross-sectional data was collected from 9-10 year old children (n =1143; 50.7% girls; 85.6% White British) from 43 primary schools in Merseyside, England. Children completed a questionnaire that assessed their smoking-related behaviour, intentions, attitudes, and refusal self-efficacy, as well as parent, sibling and friend smoking. Data for boys and girls were analysed separately using multilevel linear and logistic regression models, adjusting for individual cognitions and school and deprivation level. RESULTS: Compared to girls, boys had lower non-smoking intentions (P = 0.02), refusal self-efficacy (P = 0.04) and were less likely to agree that smoking is 'definitely' bad for health (P < 0.01). Friend smoking was negatively associated with non-smoking intentions in girls (P < 0.01) and boys (P < 0.01), and with refusal self-efficacy in girls (P < 0.01). Sibling smoking was negatively associated with non-smoking intentions in girls (P < 0.01) but a positive association was found in boys (P = 0.02). Boys who had a smoking friend were less likely to 'definitely' believe that the smoke from other people's cigarettes is harmful (OR 0.57, 95% CI: 0.35 to 0.91, P = 0.02). Further, boys with a smoking friend (OR 0.38, 95% CI: 0.21 to 0.69, P < 0.01) or a smoking sibling (OR 0.45, 95% CI: 0.21 to 0.98) were less likely to 'definitely' believe that smoking is bad for health. CONCLUSION: This study indicates that sibling and friend smoking may represent important influences on 9-10 year old children's cognitive vulnerability toward smoking. Whilst some differential findings by gender were observed, these may not be sufficient to warrant separate prevention interventions. However, further research is needed

Recommended reading list of early publications on atomic layer deposition-Outcome of the "Virtual Project on the History of ALD"

Atomic layer deposition (ALD), a gas-phase thin film deposition technique based on repeated, self-terminating gas-solid reactions, has become the method of choice in semiconductor manufacturing and many other technological areas for depositing thin conformal inorganic material layers for various applications. ALD has been discovered and developed independently, at least twice, under different names: atomic layer epitaxy (ALE) and molecular layering. ALE, dating back to 1974 in Finland, has been commonly known as the origin of ALD, while work done since the 1960s in the Soviet Union under the name "molecular layering" (and sometimes other names) has remained much less known. The virtual project on the history of ALD (VPHA) is a volunteer-based effort with open participation, set up to make the early days of ALD more transparent. In VPHA, started in July 2013, the target is to list, read and comment on all early ALD academic and patent literature up to 1986. VPHA has resulted in two essays and several presentations at international conferences. This paper, based on a poster presentation at the 16th International Conference on Atomic Layer Deposition in Dublin, Ireland, 2016, presents a recommended reading list of early ALD publications, created collectively by the VPHA participants through voting. The list contains 22 publications from Finland, Japan, Soviet Union, United Kingdom, and United States. Up to now, a balanced overview regarding the early history of ALD has been missing; the current list is an attempt to remedy this deficiency. (C) 2016 Author(s).Peer reviewe