Physician-assisted deaths under the euthanasia law in Belgium: a population-based survey

Background

Legalization of euthanasia and physician-assisted suicide has been heavily debated in many countries. To help inform this debate, we describe the practices of euthanasia and assisted suicide, and the use of life-ending drugs without an explicit request from the patient, in Flanders, Belgium, where euthanasia is legal.

Methods

We mailed a questionnaire regarding the use of life-ending drugs with or without explicit patient request to physicians who certified a representative sample (n = 6927) of death certificates of patients who died in Flanders between June and November 2007.

Results

The response rate was 58.4%. Overall, 208 deaths involving the use of life-ending drugs were reported: 142 (weighted prevalence 2.0%) were with an explicit patient request (euthanasia or assisted suicide) and 66 (weighted prevalence 1.8%) were without an explicit request. Euthanasia and assisted suicide mostly involved patients less than 80 years of age, those with cancer and those dying at home. Use of life-ending drugs without an explicit request mostly involved patients 80 years of older, those with a disease other than cancer and those in hospital. Of the deaths without an explicit request, the decision was not discussed with the patient in 77.9% of cases. Compared with assisted deaths with the patient’s explicit request, those without an explicit request were more likely to have a shorter length of treatment of the terminal illness, to have cure as a goal of treatment in the last week, to have a shorter estimated time by which life was shortened and to involve the administration of opioids.

Interpretation

Physician-assisted deaths with an explicit patient request (euthanasia and assisted suicide) and without an explicit request occurred in different patient groups and under different circumstances. Cases without an explicit request often involved patients whose diseases had unpredictable end-of-life trajectories. Although opioids were used in most of these cases, misconceptions seem to persist about their actual life-shortening effects.Euthanasia and physician-assisted suicide are heavily debated issues in medical practice. In recent years, three European countries (Belgium and the Netherlands in 2002, and Luxemburg in 2009) and two US states (Oregon in 1997 and Washington State in 2009) decriminalized euthanasia and physician-assisted suicide under formal conditions.^1–5 Canada is among a number of countries where the debate over legalization has flared up, with a proposed bill reaching Parliament and a pro-euthanasia proposal by the Quebec College of Physicians.⁶Understandably, the issue of euthanasia triggers much emotion and can be fraught with speculative arguments. Opponents of euthanasia often argue that legalizing the procedure will lead to a rise in the use of life-ending drugs without a patient’s explicit request, especially in vulnerable patient groups.^7–10 Thus far, however, no indications of this have been found in studies of physician-assisted deaths before and after legalization in Belgium and the Netherlands.^9,11,12 In Belgium, the percentage of deaths in which life-ending drugs were used remained stable, and the proportion without an explicit request from the patient decreased.¹² Other studies have shown that euthanasia, physician-assisted suicide and the use of life-ending drugs without explicit patient request are not confined to countries where physician-assisted death is legal.^13–16In addition to knowing the overall occurrence of physician-assisted death, it is equally important for an adequately informed, empirically based debate to know its performance in vulnerable patient groups and the care put into the decision and performance. In light of legalization and its alleged effects on the use of life-ending drugs without patient request, it is also important to map similarities and differences between euthanasia and the use of life-ending drugs without explicit patient request. In this article, we report our investigation of demographic and clinical characteristics associated with physician-assisted deaths in Flanders, Belgium; the involvement of the patient, relatives and other caregivers in the decision-making process; reasons for the decisions; aspects of the treatment trajectory; and details of the performance in terms of drug use and the people administering the life-ending drugs.     

The postsynaptic density 95/disc-large/zona occludens protein syntenin directly interacts with frizzled 7 and supports noncanonical Wnt signaling

Wnt signaling pathways are essential for embryonic patterning, and they are disturbed in a wide spectrum of diseases, including cancer. An unresolved question is how the different Wnt pathways are supported and regulated. We previously established that the postsynaptic density 95/disc-large/zona occludens (PDZ) protein syntenin binds to syndecans, Wnt coreceptors, and known stimulators of protein kinase C (PKC)alpha and CDC42 activity. Here, we show that syntenin also interacts with the C-terminal PDZ binding motif of several Frizzled Wnt receptors, without compromising the recruitment of Dishevelled, a key downstream Wnt-signaling component. Syntenin is coexpressed with cognate Frizzled during early development in Xenopus. Overexpression and down-regulation of syntenin disrupt convergent extension movements, supporting a role for syntenin in noncanonical Wnt signaling. Syntenin stimulates c-jun phosphorylation and modulates Frizzled 7 signaling, in particular the PKCalpha/CDC42 noncanonical Wnt signaling cascade. The syntenin-Frizzled 7 binding mode indicates syntenin can accommodate Frizzled 7-syndecan complexes. We propose that syntenin is a novel component of the Wnt signal transduction cascade and that it might function as a direct intracellular link between Frizzled and syndecans.     

Reproducibility of haemodynamical simulations in a subject-specific stented aneurysm model--a report on the Virtual Intracranial Stenting Challenge 2007

This paper presents the results of the Virtual Intracranial Stenting Challenge (VISC) 2007, an international initiative whose aim was to establish the reproducibility of state-of-the-art haemodynamical simulation techniques in subject-specific stented models of intracranial aneurysms (IAs). IAs are pathological dilatations of the cerebral artery walls, which are associated with high mortality and morbidity rates due to subarachnoid haemorrhage following rupture. The deployment of a stent as flow diverter has recently been indicated as a promising treatment option, which has the potential to protect the aneurysm by reducing the action of haemodynamical forces and facilitating aneurysm thrombosis. The direct assessment of changes in aneurysm haemodynamics after stent deployment is hampered by limitations in existing imaging techniques and currently requires resorting to numerical simulations. Numerical simulations also have the potential to assist in the personalized selection of an optimal stent design prior to intervention. However, from the current literature it is difficult to assess the level of technological advancement and the reproducibility of haemodynamical predictions in stented patient-specific models. The VISC 2007 initiative engaged in the development of a multicentre-controlled benchmark to analyse differences induced by diverse grid generation and computational fluid dynamics (CFD) technologies. The challenge also represented an opportunity to provide a survey of available technologies currently adopted by international teams from both academic and industrial institutions for constructing computational models of stented aneurysms. The results demonstrate the ability of current strategies in consistently quantifying the performance of three commercial intracranial stents, and contribute to reinforce the confidence in haemodynamical simulation, thus taking a step forward towards the introduction of simulation tools to support diagnostics and interventional planning.     

Flocculation onset in Saccharomyces cerevisiae: the role of nutrients

AIMS: To examine the role of the nutrients on the onset of flocculation in an ale-brewing strain, Saccharomyces cerevisiae NCYC 1195. METHODS AND RESULTS: Flocculation was evaluated using the method of Soares, E.V. and Vroman, A. [Journal of Applied Microbiology (2003) 95, 325]. For cells grown in chemically defined medium (yeast nitrogen base with glucose) or in rich medium (containing yeast extract, peptone and fermentable sugars: fructose or maltose), the onset of flocculation occurred after the end of exponential respiro-fermentative phase of growth being coincident with the attainment of the lower level of carbon source in the culture medium. Cells, in exponential respiro-fermentative phase of growth, transferred to a glucose-containing medium without nitrogen source, developed a flocculent phenotype, while these carbon source starved cells, in the presence of all other nutrients that support growth, did not flocculate. In addition, cells in exponential phase of growth, under catabolite repression, when transferred to a medium containing 0.2% (w/v) of fermentable sugar (fructose or maltose) or 2% (v/v) ethanol, showed a rapid triggering of flocculation, while when incubated in 2% (v/v) glycerol did not develop a flocculent phenotype. CONCLUSIONS: The onset of flocculation occurs when a low sugar and/or nitrogen concentration is reached in culture media. The triggering of flocculation is an energetic dependent process influenced by the carbon source metabolism. The presence of external nitrogen source is not necessary for developing a flocculent phenotype. SIGNIFICANCE AND IMPACT OF THE STUDY: This work contributes to the elucidation of the role of nutrients on the onset of flocculation in NewFlo phenotype yeast strains. This information might be useful to the brewing industry, in the control of yeast flocculation, as the time when the onset of flocculation occurs can determine the fermentation performance and the beer quality.     

A new dendritic cell vaccine generated with interleukin-3 and interferon-β induces CD8+ T cell responses against NA17-A2 tumor peptide in melanoma patients

Dendritic cells derived from monocytes cultured in the presence of type I interferon were found to induce efficient T cell responses against tumor antigens in vitro. We vaccinated eight stage III or IV melanoma patients with dendritic cells generated with interferon-β and interleukin-3, activated by poly I: C, and pulsed with the tumor-specific antigen NA17.A2. This dendritic cell vaccine was well-tolerated with only minor and transient flu-like symptoms and inflammatory reactions at the injection sites. In most patients, isotopic imaging documented dendritic cells (DC) migration from the intradermal injection site to the draining lymph nodes. Finally, mixed lymphocyte-peptide culture under limiting dilution conditions followed by tetramer labeling indicated that three out of eight patients mounted a CD8 T cell response against the NA17.A2 antigenic peptide. We conclude that DC generated in type I-IFN represent an interesting alternative to DC generated in IL-4 and GM-CSF for cancer immunotherapy.     

Atmospheric water vapor as driver of litter decomposition in Mediterranean shrubland and grassland during rainless seasons

Litter production in many drought‐affected ecosystems coincides with the beginning of an extended season of no or limited rainfall. Because of lack of moisture litter decomposition during such periods has been largely ignored so far, despite potential importance for the overall decay process in such ecosystems. To determine drivers and extent of litter decay in rainless periods, a litterbag study was conducted in Mediterranean shrublands, dwarf shrublands and grasslands. Heterogeneous local and common straw litter was left to decompose in open and shaded patches of various field sites in two study regions. Fresh local litter lost 4–18% of its initial mass over about 4 months without rainfall, which amounted to 15–50% of total annual decomposition. Lab incubations and changes in chemical composition suggested that litter was degraded by microbial activity, enabled by absorption of water vapor from the atmosphere. High mean relative humidity of 85% was measured during 8–9 h of most nights, but the possibility of fog deposition or dew formation at the soil surface was excluded. Over 95% of the variation in mass loss and changes in litter nitrogen were explained by characteristics of water‐vapor uptake by litter. Photodegradation induced by the intense solar radiation was an additional mechanism of litter decomposition as indicated by lignin dynamics. Lignin loss from litter increased with exposure to ultraviolet radiation and with initial lignin concentration, together explaining 90%–97% of the variation in lignin mass change. Our results indicate that water vapor, solar radiation and litter quality controlled decomposition and changes in litter chemistry during rainless seasons. Many regions worldwide experience transient periods without rainfall, and more land area is expected to undergo reductions in rainfall as a consequence of climate change. Therefore, absorption of water vapor might play a role in decomposition and nutrient cycling in an increasing number of ecosystems.     

Pandemic Swine-Origin H1N1 Influenza Virus Replicates to Higher Levels and Induces More Fever and Acute Inflammatory Cytokines in Cynomolgus versus Rhesus Monkeys and Can Replicate in Common Marmosets

The close immunological and physiological resemblance with humans makes non-human primates a valuable model for studying influenza virus pathogenesis and immunity and vaccine efficacy against infection. Although both cynomolgus and rhesus macaques are frequently used in influenza virus research, a direct comparison of susceptibility to infection and disease has not yet been performed. In the current study a head-to-head comparison was made between these species, by using a recently described swine-origin pandemic H1N1 strain, A/Mexico/InDRE4487/2009. In comparison to rhesus macaques, cynomolgus macaques developed significantly higher levels of virus replication in the upper airways and in the lungs, involving both peak level and duration of virus production, as well as higher increases in body temperature. In contrast, clinical symptoms, including respiratory distress, were more easily observed in rhesus macaques. Expression of sialyl-α-2,6-Gal saccharides, the main receptor for human influenza A viruses, was 50 to 73 times more abundant in trachea and bronchus of cynomolgus macaques relative to rhesus macaques. The study also shows that common marmosets, a New World non-human primate species, are susceptible to infection with pandemic H1N1. The study results favor the cynomolgus macaque as model for pandemic H1N1 influenza virus research because of the more uniform and high levels of virus replication, as well as temperature increases, which may be due to a more abundant expression of the main human influenza virus receptor in the trachea and bronchi.     

Syndecan recycling [corrected] is controlled by syntenin-PIP2 interaction and Arf6

Syndecans are heparan sulfate proteoglycans that modulate the activity of several growth factors and cell adhesion molecules. PDZ domains in the adaptor protein syntenin interact with syndecans and with the phosphoinositide PIP(2), which is involved in the regulation of the actin cytoskeleton and membrane trafficking. Here, we show that the syntenin PDZ domain-PIP(2) interaction controls Arf6-mediated syndecan recycling through endosomal compartments. FGF receptor accompanies syndecan along the syntenin-mediated recycling pathway, in a heparan sulfate- and FGF-dependent manner. Syndecans that cannot recycle via this pathway become trapped intracellularly and inhibit cell spreading. This syntenin-mediated syndecan recycling pathway may regulate the surface availability of a number of cell adhesion and signaling molecules.