Evaluation of two vaginal, uterus sparing operations for pelvic organ prolapse: modified Manchester operation (MM) and sacrospinous hysteropexy (SSH), a study protocol for a multicentre randomized non-inferiority trial (the SAM study).

BACKGROUND: Pelvic organ prolapse (POP) affects up to 40% of parous women which adversely affects the quality of life. During a life time, 20% of all women will undergo an operation. In general the guidelines advise a vaginal operation in case of uterine descent: hysterectomy with uterosacral ligament plication (VH), sacrospinous hysteropexy (SSH) or a modified Manchester operation (MM). In the last decade, renewed interest in uterus sparing techniques has been observed. Previous studies have shown non-inferiority between SSH and VH. Whether or not SSH and MM are comparable concerning anatomical and functional outcome is still unknown. The practical application of both operations is at least in The Netherlands a known cause of practice pattern variation (PPV). To reveal any difference between both techniques the SAM-study was designed. METHODS: The SAM-study is a randomized controlled multicentre non-inferiority study which compares SSH and MM. Women with symptomatic POP in any stage, uterine descent and POP-Quantification (POP-Q) point D at ≤ minus 1 cm are eligible. The primary outcome is the composite outcome at two years of absence of prolapse beyond the hymen in any compartment, the absence of bulge symptoms and absence of reoperation for pelvic organ prolapse. Secondary outcomes are hospital parameters, surgery related morbidity/complications, pain perception, further treatments for prolapse or urinary incontinence, POP-Q anatomy in all compartments, quality-of-life, sexual function, and cost-effectiveness. Follow-up takes place at 6 weeks, 12 and 24 months. Additionally at 12 weeks, 6 and 9 months cost-effectiveness will be assessed. Validated questionnaires will be used and gynaecological examination will be performed. Analysis will be performed following the intention-to-treat and per protocol principle. With a non-inferiority margin of 9% and an expected loss to follow-up of 10%, 424 women will be needed to prove non-inferiority with a confidence interval of 95%. DISCUSSION: This study will evaluate the effectiveness and costs of SSH versus MM in women with primary POP. The evidence will show whether the existing PPV is detrimental and a de-implementation process regarding one of the operations is needed. TRIAL REGISTRATION: Dutch Trial Register (NTR 6978, http://www.trialregister.nl ). Date of registration: 29 January 2018. Prospectively registered.

A randomized clinical trial indicates that levamisole increases the time to relapse in children with steroid-sensitive idiopathic nephrotic syndrome.

Levamisole has been considered the least toxic and least expensive steroid-sparing drug for preventing relapses of steroid-sensitive idiopathic nephrotic syndrome (SSINS). However, evidence for this is limited as previous randomized clinical trials were found to have methodological limitations. Therefore, we conducted an international multicenter, placebo-controlled, double-blind, randomized clinical trial to reassess its usefulness in prevention of relapses in children with SSINS. The efficacy and safety of one year of levamisole treatment in children with SSINS and frequent relapses were evaluated. The primary analysis cohort consisted of 99 patients from 6 countries. Between 100 days and 12 months after the start of study medication, the time to relapse (primary endpoint) was significantly increased in the levamisole compared to the placebo group (hazard ratio 0.22 [95% confidence interval 0.11-0.43]). Significantly, after 12 months of treatment, six percent of placebo patients versus 26 percent of levamisole patients were still in remission. During this period, the most frequent serious adverse event (four of 50 patients) possibly related to levamisole was asymptomatic moderate neutropenia, which was reversible spontaneously or after treatment discontinuation. Thus, in children with SSINS and frequent relapses, levamisole prolonged the time to relapse and also prevented recurrence during one year of treatment compared to prednisone alone. However, regular blood controls are necessary for safety issues.

Comparison of nuisance parameters in pediatric versus adult randomized trials: a meta-epidemiologic empirical evaluation.

BACKGROUND: We wished to compare the nuisance parameters of pediatric vs. adult randomized-trials (RCTs) and determine if the latter can be used in sample size computations of the former. METHODS: In this meta-epidemiologic empirical evaluation we examined meta-analyses from the Cochrane Database of Systematic-Reviews, with at least one pediatric-RCT and at least one adult-RCT. Within each meta-analysis of binary efficacy-outcomes, we calculated the pooled-control-group event-rate (CER) across separately all pediatric and adult-trials, using random-effect models and subsequently calculated the control-group event-rate risk-ratio (CER-RR) of the pooled-pediatric-CERs vs. adult-CERs. Within each meta-analysis with continuous outcomes we calculated the pooled-control-group effect standard deviation (CE-SD) across separately all pediatric and adult-trials and subsequently calculated the CE-SD-ratio of the pooled-pediatric-CE-SDs vs. adult-CE-SDs. We then calculated across all meta-analyses the pooled-CER-RRs and pooled-CE-SD-ratios (primary endpoints) and the pooled-magnitude of effect-sizes of CER-RRs and CE-SD-ratios using REMs. A ratio < 1 indicates that pediatric trials have smaller nuisance parameters than adult trials. RESULTS: We analyzed 208 meta-analyses (135 for binary-outcomes, 73 for continuous-outcomes). For binary outcomes, pediatric-RCTs had on average 10% smaller CERs than adult-RCTs (summary-CE-RR: 0.90; 95% CI: 0.83, 0.98). For mortality outcomes the summary-CE-RR was 0.48 (95% CIs: 0.31, 0.74). For continuous outcomes, pediatric-RCTs had on average 26% smaller CE-SDs than adult-RCTs (summary-CE-SD-ratio: 0.74). CONCLUSIONS: Clinically relevant differences in nuisance parameters between pediatric and adult trials were detected. These differences have implications for design of future studies. Extrapolation of nuisance parameters for sample-sizes calculations from adult-trials to pediatric-trials should be cautiously done.

The Effect of Maternal Milk on Tolerance and Growth in Premature Infants: A Hypothesis-generating Study.

OBJECTIVE: Early growth rates and feeding advancement rates of preterm infants are thought to influence later health. Feeding advancement is often difficult because of feeding intolerance. Exclusive human milk feeding improves tolerance, but can result in a lower weight gain rate. The addition of human milk fortifier has advantages for growth, but there are concerns that it may nullify the beneficial effect of human milk on tolerance. Therefore, the objective of the present study was to evaluate the relation between the amount of fortified human milk or formula and feeding tolerance and growth in preterm infants. METHODS: Patients (n = 174) participating in the TOL trial and born with a gestational age 30 weeks or younger were divided into tertiles according to the amount of human milk received during feeding advancement. Data on feeding tolerance during the advancement phase of enteral nutrition and anthropometrics were analysed. RESULTS: The infants (n = 59) receiving the lowest percentage of their enteral intake as human milk (0%-57%) had the lowest amount of gastric residuals (P = 0.034) compared with the other 2 tertiles. Time to reach full enteral feeding and other tolerance parameters were not different among the groups. There was no dose response effect of the amount of human milk consumed on growth. CONCLUSIONS: In preterm infants, an association between type of feeding (human milk vs infant formula) and time to achieve full enteral feeding or short-term growth was not found. Future prospective trials are needed to verify our results and focus on means to improve tolerance further.

A systematic review to investigate the measurement properties of goal attainment scaling, towards use in drug trials.

BACKGROUND: One of the main challenges for drug evaluation in rare diseases is the often heterogeneous course of these diseases. Traditional outcome measures may not be applicable for all patients, when they are in different stages of their disease. For instance, in Duchenne Muscular Dystrophy, the Six Minute Walk Test is often used to evaluate potential new treatments, whereas this outcome is irrelevant for patients who are already in a wheelchair. A measurement instrument such as Goal Attainment Scaling (GAS) can evaluate the effect of an intervention on an individual basis, and may be able to include patients even when they are in different stages of their disease. It allows patients to set individual goals, together with their treating professional. However, the validity of GAS as a measurement instrument in drug studies has never been systematically reviewed. Therefore, we have performed a systematic review to answer two questions: 1. Has GAS been used as a measurement instrument in drug studies? 2: What is known of the validity, responsiveness and inter- and intra-rater reliability of GAS, particularly in drug trials? METHODS: We set up a sensitive search that yielded 3818 abstracts. After careful screening, data-extraction was executed for 58 selected articles. RESULTS: Of the 58 selected articles, 38 articles described drug studies where GAS was used as an outcome measure, and 20 articles described measurement properties of GAS in other settings. The results show that validity, responsiveness and reliability of GAS in drug studies have hardly been investigated. The quality of the reporting of validity in studies in which GAS was used to evaluate a non-drug intervention also leaves much room for improvement. CONCLUSIONS: We conclude that there is insufficient information to assess the validity of GAS, due to the poor quality of the validity studies. Therefore, we think that GAS needs further validation in drug studies, especially since GAS can be a potential solution when a small heterogeneous patient group is all there is to test a promising new drug. TRIAL REGISTRATION: The protocol has been registered in the PROSPERO international prospective register for systematic reviews, with registration number CRD42014010619. http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42014010619 .

Intermittent Bolus or Semicontinuous Feeding for Preterm Infants?

OBJECTIVES: The aim of the present study was to assess the clinical benefits and risks of semicontinuous (CON) versus intermittent nasogastric tube feeding in low-birth-weight infants. METHODS: Infants with a birth weight <1750 g and gestational age <32 weeks were stratified according to birth weight and assigned to either CON or intermittent bolus (BOL) feeding. The primary endpoint was days to full enteral feeding (defined as 120 mL(-1) · kg(-1) · day(-1)). We also collected data on feeding tolerance, weight gain, respiratory support, and complications (sepsis, necrotising enterocolitis, and death). RESULTS: There was no difference between the 2 groups (CON n = 121, BOL n = 125) in days to reach full enteral feeding--7 (5-10) versus 6 (5-8) days, respectively, with a difference 1 (-0.05 to 2.1). Mean daily gastric residual volumes, however, were significantly lower in the BOL group (4.8 vs 3.9 mL/day, difference 0.9 mL/day [0.1-1.7]), as was the total number of patients with feeding interruptions (76 vs 59, difference 16% [3%-28%]). CONCLUSIONS: Bolus and continuous feeding are equally suitable feeding strategies for preterm neonates. BOL feeding, however, may be preferable.

Remaining symptoms in half the children treated for milk allergy.

UNLABELLED: The aim of this study was to investigate the cumulative incidence and predictive variables of treatment failure with a whey-based extensively hydrolyzed formula (w-eHF) in children with cow's milk allergy (CMA). All children were diagnosed with CMA, using double-blind placebo-controlled food challenge (DBPCFC) with amino acid-based formula as placebo, and receive w-eHF treatment after diagnosis. Forty-nine children with CMA were included. w-eHF treatment failure was defined as incomplete resolution of original CMA symptoms upon w-eHF treatment and disappearance of these symptoms upon replacement of w-eHF with amino acid-based formula. A multiple logistic regression model was used to investigate which variables could predict treatment failure. Twenty-five (51%; 95% confidence interval (CI) 38-64%) of the children with CMA failed on w-eHF. Only "gastrointestinal discomfort" was found to contribute independently to the probability of failing w-eHF, odds ratio (95% CI) 8.994 (1.007-79.457). CONCLUSIONS: In half of the children with proven CMA, there is incomplete resolution of symptoms upon w-eHF treatment. This study needs to be repeated including DBPCFC with w-eHF to provide more definitive diagnosis, especially since gastrointestinal discomfort seems to be the sole predictive variable for treatment failure. In the meantime, a change in formula should be considered in children with incomplete symptom resolution upon w-eHF treatment.

Determination of choline concentration in breast lesions: quantitative multivoxel proton MR spectroscopy as a promising noninvasive assessment tool to exclude benign lesions.

PURPOSE: To determine the optimal cutoff of choline (Cho) concentration in quantitative multivoxel magnetic resonance (MR) spectroscopic data to safely prove benignancy in breast lesions. MATERIALS AND METHODS: The study was institutional review board approved, and informed consent was obtained from each patient. Between July 2009 and July 2010, multivoxel MR spectroscopy was performed in 24 consecutive patients with 25 breast lesions assessed as Breast Imaging Reporting and Data System 3 or 4 and larger than 1 cm in diameter at mammography. Two-dimensional point-resolved spatially localized spectroscopy chemical shift imaging was first performed without signal suppression (repetition time msec/echo time msec, 1500/30) as reference measurement and was performed subsequently with suppression of water and fat signals (1500/135) to detect Cho. Differences in mean and highest Cho concentration in the breast lesions were tested for significance by using the independent sample t test. The final diagnosis was confirmed with pathologic findings. RESULTS: Fourteen of 25 breast lesions were malignant. The mean Cho concentration varied between 0.3 and 1.3 mmol/L (0.84 mmol/L ± 0.32 [standard deviation]) in benign lesions and between 1.3 and 9.5 mmol/L (3.10 mmol/L ± 2.21) in malignant lesions. The highest Cho concentrations in benign and malignant lesions were 0.4-1.5 mmol/L (1.19 mmol/L ± 0.33) and 1.7-11.8 mmol/L (4.08 mmol/L ± 2.81), respectively. Mean and highest Cho concentrations in benign and malignant breast lesions differed significantly (P = .02 for both). CONCLUSION: The study, in a relatively small patient population, shows that quantitative multivoxel MR spectroscopy can be applied to exclude benign breast lesions from further invasive diagnostic work-up with the implementation of a Cho concentration of 1.5 mmol/L or lower as a cutoff. Further larger studies will be needed to confirm these results.

Intracranial aneurysms in patients with subarachnoid hemorrhage: CT angiography as a primary examination tool for diagnosis--systematic review and meta-analysis.

PURPOSE: To calculate the sensitivity and specificity of computed tomographic (CT) angiography in the diagnosis of cerebral aneurysms in patients with acute subarachnoid hemorrhage (SAH) at presentation. MATERIALS AND METHODS: A systematic search for relevant studies was performed of the PubMed/MEDLINE and EMBASE databases. Two reviewers independently assessed the methodologic quality of each study by using the Quality Assessment of Diagnostic Accuracy Studies tool. The inclusion criteria were met by 50 studies. Heterogeneity was tested, and the presence of publication bias was visually assessed (by using a funnel plot). A meta-analysis of the reported sensitivity and specificity of each study with 95% confidence intervals (CIs) was performed on a per-patient level. RESULTS: Concerning sensitivity, the selected studies showed moderate heterogeneity. For specificity, low heterogeneity was observed. Moderate-heterogeneity studies that investigated only sensitivity or specificity were excluded from the pooled analyses by using a bivariate random effects model. The majority of the studies (n = 30) used a four-detector row CT scanner. The studies had good methodologic quality. Pooled sensitivity was 98% (95% CI: 97%, 99%), and pooled specificity was 100% (95% CI: 97%, 100%). Potential sources of variability among the studies were variations in the methodologic features (quality score), CT examination procedure (number of rows on the multidetector CT scanner), the standard of reference used, and the prevalence of ruptured intracranial aneurysms. There was evidence for publication bias, which may have led to overestimation of the diagnostic accuracy of CT angiography. CONCLUSION: Multidetector CT angiography can be used as a primary examination tool in the diagnostic work-up of patients with SAH.

Computer-aided detection in breast MRI: a systematic review and meta-analysis.

OBJECTIVES: To evaluate the additional value of computer-aided detection (CAD) in breast MRI by assessing radiologists' accuracy in discriminating benign from malignant breast lesions. METHODS: A literature search was performed with inclusion of relevant studies using a commercially available CAD system with automatic colour mapping. Two independent researchers assessed the quality of the studies. The accuracy of the radiologists' performance with and without CAD was presented as pooled sensitivity and specificity. RESULTS: Of 587 articles, 10 met the inclusion criteria, all of good methodological quality. Experienced radiologists reached comparable pooled sensitivity and specificity before and after using CAD (sensitivity: without CAD: 89%; 95% CI: 78-94%, with CAD: 89%; 95%CI: 81-94%) (specificity: without CAD: 86%; 95% CI: 79-91%, with CAD: 82%; 95% CI: 76-87%). For residents the pooled sensitivity increased from 72% (95% CI: 62-81%) without CAD to 89% (95% CI: 80-94%) with CAD, however, not significantly. Concerning specificity, the results were similar (without CAD: 79%; 95% CI: 69-86%, with CAD: 78%; 95% CI: 69-84%). CONCLUSIONS: CAD in breast MRI has little influence on the sensitivity and specificity of experienced radiologists and therefore their interpretation remains essential. However, residents or inexperienced radiologists seem to benefit from CAD concerning breast MRI evaluation.

Exposure to low-dose radiation and the risk of breast cancer among women with a familial or genetic predisposition: a meta-analysis.

BACKGROUND: Women with familial or genetic aggregation of breast cancer are offered screening outside the population screening programme. However, the possible benefit of mammography screening could be reduced due to the risk of radiation-induced tumours. A systematic search was conducted addressing the question of how low-dose radiation exposure affects breast cancer risk among high-risk women. METHODS: A systematic search was conducted for articles addressing breast cancer, mammography screening, radiation and high-risk women. Effects of low-dose radiation on breast cancer risk were presented in terms of pooled odds ratios (OR). RESULTS: Of 127 articles found, 7 were selected for the meta-analysis. Pooled OR revealed an increased risk of breast cancer among high-risk women due to low-dose radiation exposure (OR = 1.3, 95% CI: 0.9- 1.8). Exposure before age 20 (OR = 2.0, 95% CI: 1.3-3.1) or a mean of ≥5 exposures (OR = 1.8, 95% CI: 1.1-3.0) was significantly associated with a higher radiation-induced breast cancer risk. CONCLUSION: Low-dose radiation increases breast cancer risk among high-risk women. When using low-dose radiation among high-risk women, a careful approach is needed, by means of reducing repeated exposure, avoidance of exposure at a younger age and using non-ionising screening techniques.

Rare disease registries: potential applications towards impact on development of new drug treatments.

BACKGROUND: Low prevalence, lack of knowledge about the disease course, and phenotype heterogeneity hamper the development of drugs for rare diseases. Rare disease registries (RDRs) can be helpful by playing a role in understanding the course of the disease, and providing information necessary for clinical trial design, if designed and maintained properly. We describe the potential applications of a RDR and what type of information should be incorporated to support the design of clinical trials in the process of drug development, based on a broad inventory of registry experience. We evaluated two existing RDRs in more detail to check the completeness of these RDRs for trial design. RESULTS: Before and during the application for regulatory approval a RDR can improve the efficiency and quality in clinical trial design by informing the sample size calculation and expected disease course. In exceptional circumstances information from RDRs has been used as historical controls for a one-armed clinical trial, and high quality RDRs may be used for registry-based randomized controlled trials. In the post marketing phase of (conditional) drug approval a disease-specific RDR is likely to provide more relevant information than a product-specific registry. CONCLUSIONS: A RDR can be very helpful to improve the efficiency and quality of clinical trial design in several ways. To enable the applicability and optimal use of a RDR longitudinal data collection is indispensable, and specific data collection, prepared for repeated measurement, is needed. The developed checklist can help to define the appropriate variables to include. Attention should be paid to the inclusion of patient-relevant outcome measures in the RDR from the start. More research and experience is needed on the possibilities and limitations of combining RDR information with clinical trial data to maximize the availability of relevant evidence for regulatory decisions in rare diseases.

Systemic Hydrocortisone To Prevent Bronchopulmonary Dysplasia in preterm infants (the SToP-BPD study): statistical analysis plan.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is the most common complication of preterm birth with short-term and long-term adverse consequences. Although the glucocorticoid dexamethasone has been proven to be beneficial for the prevention of BPD, there are concerns about an increased risk of adverse neurodevelopmental outcome. Hydrocortisone has been suggested as an alternative therapy. The aim of the Systemic Hydrocortisone To Prevent Bronchopulmonary Dysplasia in preterm infants (SToP-BPD) trial is to assess the efficacy and safety of postnatal hydrocortisone administration for the reduction of death or BPD in ventilator-dependent preterm infants. METHODS/DESIGN: The SToP-BPD study is a multicentre, double-blind, placebo-controlled hydrocortisone trial in preterm infants at risk for BPD. After parental informed consent is obtained, ventilator-dependent infants are randomly allocated to hydrocortisone or placebo treatment during a 22-day period. The primary outcome measure is the composite outcome of death or BPD at 36 weeks postmenstrual age. Secondary outcomes are short-term effects on pulmonary condition and long-term neurodevelopmental sequelae assessed at 2 years corrected age. Complications of treatment, other serious adverse events and suspected unexpected serious adverse reactions are reported as safety outcomes. This pre-specified statistical analysis plan was written and submitted without knowledge of the unblinded data. TRIAL REGISTRATION: Netherlands Trial Register, NTR2768 . Registered on 17 February 2011. EudraCT, 2010-023777-19. Registered on 2 November 2010.

Granted, undecided, withdrawn, and refused requests for euthanasia and physician-assisted suicide.

BACKGROUND: The aims of this study were to obtain information about the characteristics of requests for euthanasia and physician-assisted suicide (EAS) and to distinguish among different types of situations that can arise between the request and the physician's decision. METHODS: All general practitioners in 18 of the 23 Dutch general practitioner districts received a written questionnaire in which they were asked to describe the most recent request for EAS they received. RESULTS: A total of 3614 general practitioners responded to the questionnaire (response rate, 60%). Of all explicit requests for EAS, 44% resulted in EAS. In the other cases the patient died before the performance (13%) or finalization of the decision making (13%), the patient withdrew the request (13%), or the physician refused the request (12%). Patients' most prominent symptoms were "feeling bad," "tiredness," and "lack of appetite." The most frequently mentioned reasons for requesting EAS were "pointless suffering," "loss of dignity," and "weakness." The patients' situation met the official requirements for accepted practice best in requests that resulted in EAS and least in refused requests. A lesser degree of competence and less unbearable and hopeless suffering had the strongest associations with the refusal of a request. CONCLUSIONS: The complexity of EAS decision making is reflected in the fact that besides granting and refusing a request, 3 other situations could be distinguished. The decisions physicians make, the reasons they have for their decisions, and the way they arrived at their decisions seem to be based on patient evaluations. Physicians report compliance with the official requirements for accepted practice.

Effect of Donor Milk on Severe Infections and Mortality in Very Low-Birth-Weight Infants: The Early Nutrition Study Randomized Clinical Trial.

IMPORTANCE: Infections and necrotizing enterocolitis, major causes of mortality and morbidity in preterm infants, are reduced in infants fed their own mother's milk when compared with formula. When own mother's milk is not available, human donor milk is considered a good alternative, albeit an expensive one. However, most infants at modern neonatal intensive care units are predominantly fed with own mother's milk. The benefits of add-on donor milk over formula are not clear. OBJECTIVE: To determine whether providing donor milk instead of formula as supplemental feeding whenever own mother's milk is insufficiently available during the first 10 days of life reduces the incidence of serious infection, necrotizing enterocolitis, and mortality. DESIGN, SETTINGS, AND PARTICIPANTS: The Early Nutrition Study was a multicenter, double-blind randomized clinical trial in very low-birth-weight infants (birth weight <1500 g) admitted to 1 of 6 neonatal intensive care units in the Netherlands from March 30, 2012, through August 17, 2014. Intent-to-treat analysis was performed. INTERVENTIONS: Infants received pasteurized donor milk or preterm formula during the first 10 days of life if own mother's milk was not (sufficiently) available. MAIN OUTCOMES AND MEASURES: The primary end point was cumulative occurrence of serious infection (sepsis or meningitis), necrotizing enterocolitis, or mortality during the first 60 days of life. RESULTS: A total of 930 infants were screened for inclusion; 557 were excluded, resulting in 373 infants (183 receiving donor milk and 190 receiving formula) who were evaluated by intent-to-treat analysis (median birth weight, 1066 g; mean gestational age, 28.4 weeks). Own mother's milk comprised 89.1% and 84.5% of total mean intake during the intervention period for the donor milk and formula groups, respectively. The incidence of the combined outcome was not different (85 [44.7%] [formula] vs 77 [42.1%] [donor milk]; mean difference, 2.6%; 95% CI, -12.7% to 7.4%). The adjusted hazard ratio was 0.87 (95% CI, 0.63-1.19; P = .37). CONCLUSIONS AND RELEVANCE: In the current study, pasteurized donor milk and preterm formula as supplemental feeding during the first 10 days of life yielded similar short-term outcomes in very low-birth-weight infants regarding safety and efficacy when own mother's milk availability was insufficient. Future studies investigating longer duration of use of human donor milk on short-term and long-term outcomes are necessary. TRIAL REGISTRATION: trialregister.nl Identifier: NTR3225.

When being 'tired of living' plays an important role in a request for euthanasia or physician-assisted suicide: patient characteristics and the physician's decision.

BACKGROUND: In the Netherlands physicians are allowed to grant requests for euthanasia or physician-assisted suicide (EAS) if they meet several requirements of due care. According to jurisprudence, a physician is not allowed to end the life of a patient whose request for EAS is based on being 'tired of living', because such a request falls outside the medical domain. Our previous studies have shown that in spite of this, such requests are made approximately 400 times a year. OBJECTIVES: To learn more about patients who request EAS because they are tired of living, and about factors that influence the decision of the physician. DESIGN: Questionnaires (n=4842) completed by general practitioners (n=3994). RESULTS: According to the physicians, 17% of patients who requested EAS were 'tired of living'. Of 139 patients in whose request for EAS being tired of living played a major role, 47% suffered from cancer, 25% suffered from another severe disease and 28% had no severe disease. In all three groups the same three symptoms occurred most frequently, 'feeling bad', 'tired', and 'not active'. Each of these symptoms occurred in more than half of the patients in each group. Most of the requests from patients with cancer were granted, but those from patients who had some other severe disease, or no severe disease at all, were refused. Factors that were related to granting a request were: the presence of unbearable and hopeless suffering, the absence of alternatives, and the absence of depressive symptoms. CONCLUSIONS: Being tired of living can play a major role in requests for EAS, both in the absence and the presence of a severe disease. The high occurrence of symptoms in the absence of a classifiable severe disease implies that physical symptoms are prevalent in this group of patients, leaving the legal requirement for EAS of 'a medical cause' open to interpretation in the more complex medical practice.

Clinical Trial Decisions in Difficult Circumstances: Parental Consent Under Time Pressure.

Treatments and interventions used to care for children in emergencies should be based on strong evidence. Well-designed clinical trials investigating these interventions for children are therefore indispensable. Parental informed consent is a key ethical requirement for the enrollment of children in such studies. However, if time is limited because of an urgent need for intervention, there are additional ethical challenges to adequately support the informed consent process. The acute situation and associated psychological impact may compromise the ability of parents to give informed consent. Little evidence exists to guide the process of consent seeking for a child's research participation when time is limited. It is also unclear in what circumstances alternatives to prospective informed consent could be applied. This article describes possible options to manage the informed consent process in an appropriate, practical, and, we believe, ethical way when time is limited.

A meta analysis and hierarchical classification of HU-based atherosclerotic plaque characterization criteria.

BACKGROUND: Many computed tomography (CT) studies have reported that lipid-rich, presumably rupture-prone atherosclerotic plaques can be characterized according to their Hounsfield Unit (HU) value. However, the published HU-based characterization criteria vary considerably. The present study aims to systematically analyze these values and empirically derive a hierarchical classification of the HU-based criteria which can be referred in clinical situation. MATERIAL AND METHODS: A systematic search in PubMed and Embase for publications with HU-criteria to characterize lipid-rich and fibrous atherosclerotic plaques resulted in 36 publications, published between 1998 and 2011. The HU-criteria were systematically analyzed based on the characteristics of the reporting study. Significant differences between HU-criteria were checked using Student's t-test. Subsequently, a hierarchical classification of HU-criteria was developed based on the respective study characteristics. RESULTS: No correlation was found between HU-criteria and the reported lumen contrast-enhancement. Significant differences were found for HU-criteria when pooled according to the respective study characteristics: examination type, vessel type, CT-vendor, detector-rows, voltage-setting, and collimation-width. The hierarchical classification resulted in 21 and 22 CT attenuation value categories, for lipid-rich and fibrous plaque, respectively. More than 50% of the hierarchically classified HU-criteria were significantly different. CONCLUSION: In conclusion, variations in the reported CT attenuation values for lipid-rich and fibrous plaque are so large that generalized values are unreliable for clinical use. The proposed hierarchical classification can be used to determine reference CT attenuation values of lipid-rich and fibrous plaques for the local setting.

The validation of a simulation model incorporating radiation risk for mammography breast cancer screening in women with a hereditary-increased breast cancer risk.

INTRODUCTION: For women with a BRCA1 or BRCA2 mutation or a strong family history of breast cancer, there is no clear estimation of the risk of tumour induction versus the beneficial effects of mammography screening available. This study aims to validate the Simulation Model on Radiation Risk and breast cancer Screening (SiMRiSc) model in these women, which can provide information on the benefits and risks of screening for breast cancer for various screening scenarios. METHODS: The simulation model for breast cancer screening was developed and the values for model parameters including cancer induction due to radiation were derived from the literature. The simulation model was validated by comparing the outcome data of the model with the data from three published screening studies of women with an increased hereditary breast cancer risk. A sensitivity analysis was used to estimate the error margins of the outcome data and to analyse the sensitivity of the simulation model to each parameter. RESULTS: The model predicted 71+/-4% of the reported tumours. When excluding the excess number of incident tumours detected in the first screening round, the model predicted 85+/-6% of the tumours reported. The model was most sensitive to changes in the parameters related to lifetime breast cancer risk and sensitivity of mammography. CONCLUSIONS: We conclude that the simulation model is suitable for the provision of accurate benefits' and risks' estimations necessary for the refinement of the screening guidelines for women at an increased risk of breast cancer.

How patients and relatives experience a visit from a consulting physician in the euthanasia procedure: a study among relatives and physicians.

This study investigated the impact of a visit from a consulting physician on the patient and the relatives during the euthanasia procedure in The Netherlands. Data on experiences with the consultant's visit were collected from 86 relatives and 3,614 general practitioners, who described their most recent request for euthanasia or physician-assisted suicide. More than three-quarters of the patients experienced the visit as they had expected, or became more positive. Although about 1 out of 5 patients had negative experiences, this study indicates that, in general, a visit from a consulting physician is not perceived to be burdensome for patients.