Circulating maternal and umbilical cord steroid hormone and insulin-like growth factor concentrations in twin and singleton pregnancies.

In addition to being associated with a higher risk of complications during pregnancy, twinning may also be a proxy for altered hormonal exposure for mothers and twin offspring, with implications for their health later in life. We compared maternal and fetal steroid hormone and insulin-like growth factor concentrations between singleton (n=62) and twin (n=41) pregnancies. Maternal concentrations of androgens, estrogens, insulin-like growth factor (IGF)-1, IGF-binding protein (BP)-3 and prolactin were quantified during the third trimester and at delivery, as well as in the fetal circulation at birth. Geometric means accounting for gestational age were calculated for hormone concentrations and compared between matched twin and singleton pregnancies. Most maternal hormone concentrations were modestly higher in twin than in singleton pregnancies in the third trimester (ranging from 8.3% for IGF-1 to 17.1% for estradiol) and at delivery (ranging from 11.1% for IGFBP-3 to 15.2% for estriol). Cord serum hormones were generally similar in twin and singleton pregnancies, except for IGFBP-3, which was 200% lower in twins. The modest differences in maternal hormones in late gestation seem unlikely to explain alterations in hormonally related disease risk in mothers of twins compared with singletons. The large deficit of IGFBP-3 in the fetal circulation of twins at birth may allow for sufficient concentrations of IGF-2 for growth and development in an environment of shared nutritional resources.

Physicians' labelling of end-of-life practices: a hypothetical case study.

OBJECTIVES: To investigate why physicians label end-of-life acts as either 'euthanasia/ending of life' or 'alleviation of symptoms/palliative or terminal sedation', and to study the association of such labelling with intended reporting of these acts. METHODS: Questionnaires were sent to a random, stratified sample of 2100 Dutch physicians (response: 55%). They were asked to label six hypothetical end-of-life cases: three 'standard' cases and three cases randomly selected (out of 47), that varied according to (1) type of medication, (2) physician's intention, (3) type of patient request, (4) patient's life expectancy and (5) time until death. We identified the extent to which characteristics of cases are associated with physician's labelling, with multilevel multivariable logistic regression. RESULTS: The characteristics that contributed most to labelling cases as 'euthanasia/ending of life' were the administration of muscle relaxants (99% of these cases were labelled as 'euthanasia/ending of life') or disproportional morphine (63% of these cases were labelled accordingly). Other important factors were an intention to hasten death (54%) and a life expectancy of several months (46%). Physicians were much more willing to report cases labelled as 'euthanasia' (87%) or 'ending of life' (56%) than other cases. CONCLUSIONS: Similar cases are not uniformly labelled. However, a physicians' label is strongly associated with their willingness to report their acts. Differences in how physicians label similar acts impede complete societal control. Further education and debate could enhance the level of agreement about what is physician-assisted dying, and thus should be reported, and what not.

Deciding about continuous deep sedation: physicians' perspectives: a focus group study.

Although guidelines restrict the use of continuous deep sedation to patients with refractory physical symptoms and a short life-expectancy, its use is not always restricted to these conditions. A focus group study of physicians was conducted to gain more insight in the arguments for and against the use of continuous deep sedation in several clinical situations. Arguments in favour of continuous deep sedation for patients with a longer life-expectancy were that the overall clinical situation is more relevant than life-expectancy alone, and that patients' wishes should be followed. Continuous deep sedation for patients with predominantly emotional/existential suffering was considered appropriate when physicians empathize with the suffering. Further, some physicians indicated that they may consider the use of sedation in the context of a euthanasia request. Arguments were that the option of continuous deep sedation is a better alternative; it may comfort some patients when their thoughts about potential future suffering become unbearable. Further, some considered continuous deep sedation as less burdening or a bother to perform. We conclude that physicians' decision-making about continuous deep sedation is characterized by balancing the interests of patients with their own feelings. Accordingly, the reasons for its use are not unambiguous and need further debate.

Dutch criteria of due care for physician-assisted dying in medical practice: a physician perspective.

INTRODUCTION: The Dutch Euthanasia Act (2002) states that euthanasia is not punishable if the attending physician acts in accordance with the statutory due care criteria. These criteria hold that: there should be a voluntary and well-considered request, the patient's suffering should be unbearable and hopeless, the patient should be informed about their situation, there are no reasonable alternatives, an independent physician should be consulted, and the method should be medically and technically appropriate. This study investigates whether physicians experience problems with these criteria in medical practice. METHODS: In 2006, questionnaires were sent to a random, stratified sample of 2100 Dutch physicians (response rate: 56%). Physicians were asked about problems in their decision-making related to requests for euthanasia or assisted suicide after enforcement of the 2002 Euthanasia Act. RESULTS: Of all physicians who had received a request for euthanasia or assisted suicide (75%), 25% had experienced problems in the decision-making with regard to at least one of the criteria of due care. Physicians who had experienced problems mostly indicated to have had problems related to evaluating whether or not the patient's suffering was unbearable and hopeless (79%) and whether or not the patient's request was voluntary or well considered (58%). DISCUSSION: Physicians in The Netherlands most frequently reported problems related to aspects in which they have to evaluate the patient's subjective perspective(s). However, it can be questioned whether placing emphasis on these subjective aspects is an adequate fulfilment of the duties imposed on physicians, as laid down in the Dutch Euthanasia Act.

[Trends in the agents used for euthanasia and the relationship with the number of notifications]. / Trends in gebruikte middelen bij euthanasie en samenhang met het aantal meldingen.

OBJECTIVE: To provide insight into the relationship between the drugs used for euthanasia and its notification. DESIGN: Retrospective and descriptive. METHODS: By comparing the drugs used for euthanasia according to different components of studies carried out in 1990, 1995 and 2000, insight was obtained into the drugs used in all cases of euthanasia satisfying the definition thereof (death-certificate studies), those cases of euthanasia that, in addition, were defined as such by the physician (physician interviews), and the cases of euthanasia that, in addition, had been reported (reported case studies). RESULTS: In 2001, standard drugs for euthanasia were used in 76% of cases and opioids in 23%. Euthanasia with standard drugs was reported in 73% of cases in 1995, and in 71% of cases in 2000, while euthanasia with opioids was reported in 2% and 1% of cases, respectively. The total percentage of euthanasia reported was higher in 2001 than in 1995 (54% versus 44%), since in 2001 euthanasia was apparently performed more often with standard drugs and less with opioids. CONCLUSION: An increasing proportion of cases of euthanasia is being carried out with the drugs recommended for this purpose. Euthanasia with opioids was rarely reported. Possibly, physicians did not always consider these cases to be euthanasia.

[Fourth evaluation of the law on the review of termination of life on request and assisted suicide (Euthanasia Act)]. / Vierde evaluatie van de Wet Toetsing Levensbeëindiging op Verzoek en Hulp bij Zelfdoding (Euthanasiewet).

This fall, an extensive study will start to evaluate the Dutch Euthanasia Act. This law was enacted in 2002. According to this law, physicians must report cases of euthanasia and physician-assisted suicide. The cases are then judged by regional euthanasia review committees consisting of a lawyer, a physician and an ethicist. Only if they conclude that the case does not meet the requirements for prudent practice, it will be sent to the public prosecutor. The study will be focused on the practice of medical end-of-life decision-making, the functioning and effects of the Euthanasia Act, and opinions of physicians about the scope of the law and the demarcation between different end-of-life decisions. The study will comprise 4 sub-studies: a judicial evaluation, a death certificate study, a survey among physicians and a panel study among physicians, nurses, members of euthanasia review committees, lawyers and ethicists. This study is the fourth in a row of nationwide studies into end-of-life practices that have been performed since 1990. The previous studies contributed to the public debate about medical care at the end of life and to the development of policy in this field. It is expected that this study, by providing up-to-date information on and insight into end-of-life care in the Netherlands, will do the same.

[No conspicuous changes in the practice of medical end-of-life decision-making for neonates and infants in the Netherlands in 2001 as compared to 1995]. / Geen opvallende wijziging in de praktijk van medische beslissingen rond het levenseinde bij pasgeborenen en zuigelingen in Nederland in 2001 vergeleken met 1995.

OBJECTIVE: To establish whether the practice of end-of-life decision-making for neonates and infants under the age of 1 in the Netherlands in 2000 was different from that in 1995. DESIGN: Retrospective descriptive and comparative study. METHODS: In both years, all deaths of children under the age of one year that took place in August-November (1995: n = 338; 2001: n = 347) were studied. The response rate was 96% in 1995 and 84% in 2001. The questionnaires which were sent to the physicians who reported the deaths, included structured questions about whether or not death had been preceded by end-of-life decisions, i.e. decisions to withhold or withdraw potentially life-prolonging treatment or to administer (potentially) life-shortening drugs, and questions about the decision-making process. RESULTS: The proportion of end-of-life decisions increased slightly from 62% to 68% of all deaths in the first year of life, but the difference was not statistically significant. The large majority of these decisions involved withholding or withdrawing life-sustaining treatment. The frequency of decisions to actively terminate the life of an infant who was not dependent on life-sustaining treatment remained stable at 1%. The proportion of decisions that had been discussed with the parents increased slightly, from 91% in 1995 to 97% in 2001; similar percentages of the decisions had been discussed with other physicians. The percentage of decisions that had been discussed with the nursing staff decreased from 40 in 1995 to 28 in 2001. CONCLUSION: The findings suggest that the practice of end-of-life decision-making in neonatology was rather stable between 1995 and 2001. The frequency of the active termination of life had not increased, despite the new euthanasia regulation in the Netherlands.

Positive and negative affect after diagnosis of advanced cancer.

Anxiety and depression are studied thoroughly in patients with advanced cancer. However, little is known about the nature of mood disorders in this stage of the disease. We studied positive and negative affect in patients who have had a diagnosis of advanced cancer, and examined how these are related to anxiety and depression, and to other patient and care factors. One hundred and five patients filled out a written questionnaire and were interviewed personally. The PANAS positive affect scores were lower than those in the general population, but the negative affect scores were fairly similar. We found a rather low prevalence of depression (13%) and anxiety (8%) as measured by the HADS. The emotional problems patients mentioned most frequently were anxiety about metastases (26%), the unpredictability of the future (18%) and anxiety about physical suffering (15%). Both positive and negative affect were most strongly related to patient's sense of meaning and peace. We conclude that distinguishing positive and negative affect enhances the understanding of psychological distress of patients with advanced cancer, that seems to be mainly caused by low levels of positive affect. Several theories are discussed to explain this finding, that may contribute to efforts to improve care for these patients.

A cluster-randomised trial of screening for language disorders in toddlers.

OBJECTIVE: To assess the screening performance of a specific language-screening instrument at 18 and 24 months of age and to assess its effect on the early detection and prognosis of language delay. DESIGN: Child health care physicians were randomised to the intervention group, in which specific language screening was conducted twice (at age 18 months and 24 months), or to the control group (usual care). The specific screening instrument consisted of a uniform set of questions for the parents and test elements for the child, with scaled scores to assess responses. SETTING: Child health care in the Netherlands and referral of screen-positive children. SUBJECTS: 5734 children in the intervention group and 4621 in the control group. MAIN OUTCOME MEASURES: Test characteristics and disorders at 24 months, and confirmed diagnoses of a language disorder before 36 months in both groups. Gold standard based on reports of parents, specialists and expert panel. Prognosis estimated from two diagnostic language development performance scores at 36 months (in questionnaire). RESULTS: In the intervention group, 3147 of the 5734 children (55%) were screened with the specific screening instrument and 73 of the screened children (2.3%) were screen-positive. Of the screen-positive children, 41 (55%) had confirmed language delay (diagnostic assessment and/or reported treatment). The estimated sensitivity of the test ranged between 24-52% depending on the severity of language disorders. The prevalence of language disorders in three-year olds was estimated to be 2.4-5.3%. In the intervention group, 1.25-2 times more children with language delay had been diagnosed before 36 months. The assessment of language development at 36 months showed no statistically significant differences between the intervention and the control groups. CONCLUSIONS: The inclusion of a specific language-screening instrument in child health centre activities resulted in the earlier detection of children with language delay. Short-term health benefits could not be demonstrated. Large-scale introduction cannot be recommended on the basis of this information alone.

Medical decision making in scarcity situations.

The issue of the allocation of resources in health care is here to stay. The goal of this study was to explore the views of physicians on several topics that have arisen in the debate on the allocation of scarce resources and to compare these with the views of policy makers. We asked physicians (oncologists, cardiologists, and nursing home physicians) and policy makers to participate in an interview about their practices and opinions concerning factors playing a role in decision making for patients in different age groups. Both physicians and policy makers recognised allocation decisions as part of their reality. One of the strong general opinions of both physicians and policy makers was the rejection of age discrimination. Making allocation decisions as such seemed to be regarded as a foreign entity to the practice of medicine. In spite of the reluctance to make allocation decisions, physicians sometimes do. This would seem to be only acceptable if it is justified in terms of the best interests of the patient from whom treatment is withheld.

[Centenary of the Health Council of the Netherlands. II 'Public health']. / Honderd jaar Gezondheidsraad. II. 'Public health'.

In its 100-year existence (1902/2002), the Health Council has played an important role in the introduction of effective measures in the area of public health and in doing so has made a significant contribution to improving health in the Netherlands. Successes have been achieved in vaccinations (from before 1900 to about 1985), infectious-diseases control (since about 1900), safety at work (since about 1900), healthier mothers and babies (since about 1900) and safer and healthier food (since 1920). Success factors in implementing an advisory report are the extent to which political support is forthcoming, the evidence on which the advisory report is based, the economic consequences of implementing the advisory report, the ethical implications and the extent to which social and/or scientific developments provide a basis for the advisory report.

[Idiopathic scoliosis in adolescents; an inventory into the possibilities of studying the efficacy of screening and treatment]. / Idiopathische scoliose bij adolescenten; inventarisatie van mogelijkheden van onderzoek naar de effectiviteit van screening en behandeling.

OBJECTIVE: To collect information for the purpose of establishing starting points and possibilities for a cost-effectiveness analysis of screening for adolescent idiopathic scoliosis (AIS). DESIGN: Interviews, literature review, questionnaires, an estimation of costs and discussions with experts and involved parties. METHOD: Following an initial interview with 16 orthopaedic surgeons and school doctors a literature study into the efficacy of treatment was carried out regarding the years 1989-1999. The variation in current practice was delineated by means of a questionnaire sent to all 51 municipal health services in the Netherlands. The costs of screening and treatment were estimated on the basis of health insurance premiums and a municipal health service cost model. All of the results were presented to five methodological experts and finally the study results and the recommendations of the five methodological experts were evaluated during a meeting of persons especially invited for this purpose. RESULTS: Screening for AIS was established to realise early diagnosis and treatment with a brace, so as to reduce unsatisfactory cosmetic outcomes and the need for surgery. Screening was performed using the bending test and was performed in 40/48 (83%) of the participating municipal health services. The overall costs of screening and treatment amount to 6 million euros per year. There was no convincing evidence that the screening programme was sufficiently sensitive and bracing sufficiently effective. Neither was there proof of the opposite. The following was recommended: obtain reliable data by carrying out a randomised controlled trial on the effectiveness of treating AIS with bracing in an early stage; carry out a case-control study combined with a retrospective patient follow-up study to evaluate the current screening practice; draw up a national standard for the screening of postural disorders in youth healthcare to ensure effective practice.

[The scientific basis for population screening for breast cancer in the Netherlands]. / De wetenschappelijke basis van het bevolkingsonderzoek naar borstkanker in Nederland.

A recent Cochrane review stated that there was a lack of evidence for a decrease in mortality as a result of population breast-cancer screening. The principal data were drawn from five Swedish randomized controlled trials and one Canadian trial. However, the studies cannot be so easily combined because there were important differences in the attendance rate, detection rate, technical quality, referral rate, clinical baseline situation and screening interval. For example, in one of the studies the women from the control arm underwent an annual clinical palpation carried out by a trained nurse or physician, which could have led to an underestimation of the screening effect. Further breast-cancer mortality might not be a good outcome measure because this was not reliably determined; only total mortality was to be observed. This is clinically and methodologically incorrect because breast-cancer mortality was meticulously studied, documented and validated. In the Cochrane review it is suggested that the randomisation was inadequate, but evidence for this was not supplied. The discussion about age differences as a marker for incorrect randomisation is out of date and has been revealed to be unjust. It seems likely that an important part of the decreasing trend in breast-cancer mortality in several countries (including the Netherlands) is due to screening programmes. However, the evaluation of breast-cancer mortality over the next five years is crucial, if greater certainty is to be gained about this.

Effects of central sympathetic inhibition on heart rate variability during steady-state exercise in healthy humans.

The profound reduction in heart rate variability (HRV) that occurs during exercise is thought to be, at least in part, the result of sympathetic nervous system activation. Moxonidine is a centrally acting anti-sympathetic drug, which suppresses sympathetic nervous system outflow by stimulation of central imidazoline receptors located in the rostral ventro-lateral medulla. This study was designed to investigate the combined effects of central sympathetic inhibition with moxonidine and steady-dynamic exercise on HRV. Ten normal males participated in a double-blind cross-over study, taking either placebo or 0.4 mg of moxonidine. The subjects were studied at rest and during steady-state exercise. HRV was measured considering both time and frequency domain parameters. As a non-linear measure, the Poincaré scatter-plot was measured and analysed quantitatively. Ventilation and gas exchange were also measured during exercise. In addition, plasma catecholamines were measured at rest and during exercise. The only parameter changed, at rest, by moxonidine was the blood pressure which was reduced. During exercise, moxonidine reduced plasma noradrenaline (NA), compared with the placebo (P<0.01). The only change observed in HRV during exercise was a significant reduction of the continuous long-term standard deviation (SD2) of the Poincaré scatter-plot of the R-R interval (P<0.05). However, the potential and prognostic significance of this result needs to be further assessed.

[Arguments for offering triple test serum screening for Down's syndrome to all pregnant women]. / Argumenten voor het aanbieden van de serumscreening op downsyndroom aan alle zwangeren.

In an advisory report to the Dutch Government, the Health Council of the Netherlands has recently recommended offering triple test serum screening for Down's syndrome to all pregnant women. According to a critical review in this journal, the Council should have proposed excluding those less than 30 years of age. However, there is no age at which a logical limit can be set. Moreover, to suggest that the negative aspects of the screening will prevail for those under a specific age, denies the women involved the right to make a judgment based on their own values and preferences. Secondly, although limited resources may be a reason for limiting access to screening, doing so would be a politico-ethical decision, which raises the issue of justice. Finally, there are reasons for thinking that a new age limit would complicate the necessary counselling as opposed to making it easier.

Healthcare costs of intellectual disability in the Netherlands: a cost-of-illness perspective.

Healthcare costs are continuously increasing, and impose a strong responsibility on governments for an adequate allocation of resources among healthcare provisions and patients. The aims of the present study were to describe the healthcare costs of intellectual disability (ID) and other mental disorders in the context of the total costs of all other diseases, and to determinate the future need of healthcare resources, especially for ID and mental disorders. The present authors performed a top-down cost-of-illness study comprising all healthcare costs of the Netherlands in 1994. Data on healthcare use were obtained for all 22 healthcare sectors, and used to ascribe costs to disease groups, age and sex. Costs of mental disorders are by far the largest in the Dutch healthcare system. Some 25.8% of total disease-specific costs could be ascribed to mental disorders: psychiatric conditions, 10.6%; ID, 9.0%; and dementia, 6.2%. There are large differences between age and sex groups. The costs of ID and schizophrenia are higher among men, and the costs of dementia and depression are higher among women. The age pattern shows two peaks: the first occurs at 25-35 years of age (ID and psychiatric conditions); and the second at 75-85 years of age (dementia). Time trends between 1988 and 1994 show an average annual growth rate of 5.2% for total healthcare costs: psychiatric conditions, 4.8%; ID, 5.4%; and dementia, 9.4%. Demographic projections suggest a less-than-average cost increase for ID and psychiatric disorders (with annual growth rates of 0.2% and 0.4%, respectively) compared to the costs of dementia and total healthcare (with annual growth rates of 1.6% and 0.9%, respectively). Intellectual disability and mental disorders represent a large part of healthcare use in the Netherlands. The costs will inevitably increase because of the ageing of the population and increasing life expectancy among people with disabilities. Non-specific cost containment measures may endanger the quality of care for vulnerable people at younger and older ages.

Magnetoencephalography and stereopsis: rhythmic cortical activity in humans recorded over the parieto-occipital cortex.

We have studied human stereopsis by analysing magnetoencephalographic signals during the presentation of stereograms using frequency analysis. The study of synchronised firing of cortical neurones is a new way of understanding information processing in the brain and it is hypothesised that frequencies greater than 35 Hz are used for higher-order processing. We report the response of cortical neurones involved in stereopsis recorded from over the occipital and parietal cortices using a single channel axial superconducting quantum interference device neuromagnetometer. Our main result was increased cortical activity in the gamma-band at frequencies apparently related to stereopsis and the perception of depth. Our results are consistent with reports in the literature that suggest that frequencies above 40 Hz are involved in attention, pattern recognition and higher order visual activity.

[New research on the practice, reporting and reviewing of euthanasia and other medical end-of-life decisions, 2001/2002]. / Nieuw onderzoek naar de praktijk, de melding en de toetsing van euthanasie en andere medische beslissingen rond het levenseinde, 2001/'02.

In the second half of 2001, an extensive study will start which will evaluate the review procedure for euthanasia in the Netherlands. Since the end of 1998, euthanasia has to be reviewed by regional review committees, which include a physician and an ethicist, in addition to a legal expert. The aim of this study is to examine whether the reporting procedure meets the aim and whether there are any points which require improvement. This study follows on from those carried out in 1990/1991 and 1995/1996, which investigated euthanasia and other medical end-of-life decisions (assisted suicide, termination of life without the patient's explicit request, treatment of pain and symptoms with a possible life-shortening effect, and forgoing potentially life-prolonging treatment). The study consists of an analysis of cases of death (in which the numbers and nature of various medical end-of-life decisions will be established), physician interviews (to gain insight into the context in which medical end-of-life decisions are made), a study of reported cases (to give an overview of doctors' experiences with the review committees), and a study carried out amongst the general public (around 1,500 Dutch adults will be given a written questionnaire about their opinions concerning medical end-of-life decisions and the reporting procedure). In addition to this Dutch study, a European study subsidized by the European Commission is being carried out which will examine attitudes and experiences regarding medical end-of-life decisions in six European countries (Belgium, Denmark, Italy, the Netherlands, Sweden and Switzerland). This will, for the first time, enable a true comparison to be made between the Netherlands and other countries in terms of euthanasia and other medical end-of-life decisions.

Elucidation of structure and location of V(IV) ions in heteropolyacid catalysts H4PVMo11O40 as studied by hyperfine sublevel correlation spectroscopy and pulsed electron nuclear double resonance at W- and X-band frequencies.

Electron spin resonance, pulsed electron nuclear double resonance (ENDOR) spectroscopy at W- and X-band frequencies, and hyperfine sublevel correlation (HYSCORE) spectroscopy have been employed to determine the location of the V(IV) ions in H4PVMo11O40 heteropolyacid catalysts. In these materials the heteropolyanions have the well-known structure of the Keggin molecule. Interactions of the unpaired electrons of the paramagnetic vanadyl ions (VO(2+)) with all relevant nuclei 1H, 31P, and 51V) could be resolved. The complete analysis of the hyperfine coupling tensor for the phosphorus nucleus in the fourth coordination sphere of the V(IV) ion allowed for the first time a detailed structural analysis of the paramagnetic ions in heteropolyacids in hydrated and dehydrated catalysts. The 31P and 1H ENDOR results show that V(IV) ions are incorporated as vanadyl pentaaqua complexes [VO(H2O)5](2+) in the void space between the heteropolyanions in the hydrated heteropolyacid. For the dehydrated H4PVMo11O40 materials the distance between the V(IV) ion and the central phosphorus atom of the Keggin molecule could be determined with high accuracy on the basis of orientation-selective 31P ENDOR experiments and HYSCORE spectroscopy. The results give a first direct experimental evidence that the paramagnetic vanadium species are not incorporated at molybdenum sites into the Keggin structure of H4PVMo11O40 and also do not act as bridges between two Keggin units after calcination of the catalyst. The vanadyl species are found to be directly attached to the Keggin molecules. The VO(2+) ions are coordinated to four or three outer oxygen atoms from one PVMo11 heteropolyanion in a trigonal-pyramidal or slightly distorted square-pyramidal coordination geometry, respectively.