Preschool children have been proven to possess nonsymbolic approximate arithmetic skills before learning how to manipulate symbolic math and thus before any formal math instruction. It has been assumed that nonsymbolic approximate math tasks necessitate the allocation of Working Memory (WM) resources. WM has been consistently shown to be an important predictor of children's math development and achievement. The aim of our study was to uncover the specific role of WM in nonsymbolic approximate math. For this purpose, we conducted a (...) dual-task study with preschoolers with active phonological, visual, spatial, and central executive interference during the completion of a nonsymbolic approximate addition dot task. With regard to the role of WM, we found a clear performance breakdown in the central executive interference condition. Our findings provide insight into the underlying cognitive processes involved in storing and manipulating nonsymbolic approximate numerosities during early arithmetic. (shrink)

About one third of patients with epilepsy have seizures refractory to the medical treatment. Electrical stimulation mapping is the gold standard for the identification of “eloquent” areas prior to resection of epileptogenic tissue. However, it is time-consuming and may cause undesired side effects. Broadband gamma activity recorded with extraoperative electrocorticography during cognitive tasks may be an alternative to ESM but until now has not proven of definitive clinical value. Considering their role in cognition, the alpha and beta bands could further (...) improve the identification of eloquent cortex. We compared gamma, alpha and beta activity, and their combinations for the identification of eloquent cortical areas defined by ESM. Ten patients with intractable focal epilepsy participated in a delayed-match-to-sample task, where syllable sounds were compared to visually presented letters. We used a generalized linear model approach to find the optimal weighting of each band for predicting ESM-defined categories and estimated the diagnostic ability by calculating the area under the receiver operating characteristic curve. Gamma activity increased more in eloquent than in non-eloquent areas, whereas alpha and beta power decreased more in eloquent areas. Diagnostic ability of each band was close to 0.7 for all bands but depended on multiple factors including the time period of the cognitive task, the location of the electrodes and the patient’s degree of attention to the stimulus. We show that diagnostic ability can be increased by 3–5% by combining gamma and alpha and by 7.5–11% when gamma and beta were combined. We then show how ECoG power modulation from cognitive testing can be used to map the probability of eloquence in individual patients and how this probability map can be used in clinical settings to optimize ESM planning. We conclude that the combination of gamma and beta power modulation during cognitive testing can contribute to the identification of eloquent areas prior to ESM in patients with refractory focal epilepsy. (shrink)

Introduction: In The Netherlands, physicians have to be convinced that the patient suffers unbearably and hopelessly before granting a request for euthanasia. The extent to which general practitioners (GPs), consulted physicians and members of the euthanasia review committees judge this criterion similarly was evaluated. Methods: 300 GPs, 150 consultants and 27 members of review committees were sent a questionnaire with patient descriptions. Besides a “standard case” of a patient with physical suffering and limited life expectancy, the descriptions included cases in (...) which the request was mainly rooted in psychosocial or existential suffering, such as fear of future suffering or dependency. For each case, respondents were asked whether they recognised the case from their own practice and whether they considered the suffering to be unbearable. Results: The cases were recognisable for almost all respondents. For the “standard case” nearly all respondents were convinced that the patient suffered unbearably. For the other cases, GPs thought the suffering was unbearable less often (2–49%) than consultants (25–79%) and members of the euthanasia review committees (24–88%). In each group, the suffering of patients with early dementia and patients who were “tired of living” was least often considered to be unbearable. Conclusions: When non-physical aspects of suffering are central in a euthanasia request, there is variance between and within GPs, consultants and members of the euthanasia committees in their judgement of the patient’s suffering. Possible explanations could be differences in their roles in the decision-making process, differences in experience with evaluating a euthanasia request, or differences in views regarding the permissibility of euthanasia. (shrink)

Two decades of research on euthanasia in the Netherlands have resulted into clear insights in the frequency and characteristics of euthanasia and other medical end-of-life decisions in the Netherlands. These empirical studies have contributed to the quality of the public debate, and to the regulating and public control of euthanasia and physician-assisted suicide. No slippery slope seems to have occurred. Physicians seem to adhere to the criteria for due care in the large majority of cases. Further, it has been shown (...) that the majority of physicians think that the euthanasia Act has improved their legal certainty and contributes to the carefulness of life-terminating acts. In 2005, eighty percent of the euthanasia cases were reported to the review committees. Thus, the transparency envisaged by the Act still does not extend to all cases. Unreported cases almost all involve the use of opioids, and are not considered to be euthanasia by physicians. More education and debate is needed to disentangle in these situations which acts should be regarded as euthanasia and which should not. Medical end-of-life decision-making is a crucial part of end-of-life care. It should therefore be given continuous attention in health care policy and medical training. Systematic periodic research is crucial for enhancing our understanding of end-of-life care in modern medicine, in which the pursuit of a good quality of dying is nowadays widely recognized as an important goal, in addition to the traditional goals such as curing diseases and prolonging life. (shrink)

© 2015 Elsevier Inc.Postnatal organogenesis occurs in an immune competent environment and is tightly controlled by interplay between positive and negative regulators. Innate immune cells have beneficial roles in postnatal tissue remodeling, but roles for the adaptive immune system are currently unexplored. Here we show that adaptive immune responses participate in the normal postnatal development of a non-lymphoid epithelial tissue. Since the mammary gland is the only organ developing predominantly after birth, we utilized it as a powerful system to study (...) adaptive immune regulation of organogenesis. We found that antigen-mediated interactions between mammary antigen-presenting cells and interferon-γ -producing CD4+ T helper 1 cells participate in MG postnatal organogenesis as negative regulators, locally orchestrating epithelial rearrangement. IFNγ then affects luminal lineage differentiation. This function of adaptive immune responses, regulating normal development, changes the paradigm for studying players of postnatal organogenesis and provides insights into immune surveillance and cancer transformation. Plaks et al. (shrink)

We apply an online optimization process based on machine learning to the production of Bose-Einstein condensates. BEC is typically created with an exponential evaporation ramp that is optimal for ergodic dynamics with two-body s-wave interactions and no other loss rates, but likely sub-optimal for real experiments. Through repeated machine-controlled scientific experimentation and observations our ’learner’ discovers an optimal evaporation ramp for BEC production. In contrast to previous work, our learner uses a Gaussian process to develop a statistical model of the (...) relationship between the parameters it controls and the quality of the BEC produced. We demonstrate that the Gaussian process machine learner is able to discover a ramp that produces high quality BECs in 10 times fewer iterations than a previously used online optimization technique. Furthermore, we show the internal model developed can be used to determine which parameters are essential in BEC creation and which are unimportant, providing insight into the optimization process of the system. (shrink)

BackgroundThe Netherlands is one of the few countries where euthanasia is legal under strict conditions. This study investigates whether Dutch newspaper articles use the term ‘euthanasia’ according to the legal definition and determines what arguments for and against euthanasia they contain.MethodsWe did an electronic search of seven Dutch national newspapers between January 2009 and May 2010 and conducted a content analysis.ResultsOf the 284 articles containing the term ‘euthanasia’, 24% referred to practices outside the scope of the law, mostly relating to (...) the forgoing of life-prolonging treatments and assistance in suicide by others than physicians. Of the articles with euthanasia as the main topic, 36% described euthanasia in the context of a terminally ill patient, 24% for older persons, 16% for persons with dementia, and 9% for persons with a psychiatric disorder. The most frequent arguments for euthanasia included the importance of self-determination and the fact that euthanasia contributes to a good death. The most frequent arguments opposing euthanasia were that suffering should instead be alleviated by better care, that providing euthanasia can be disturbing, and that society should protect the vulnerable.ConclusionsOf the newspaper articles, 24% uses the term ‘euthanasia’ for practices that are outside the scope of the euthanasia law. Typically, the more unusual cases are discussed. This might lead to misunderstandings between citizens and physicians. Despite the Dutch legalisation of euthanasia, the debate about its acceptability and boundaries is ongoing and both sides of the debate are clearly represented. (shrink)

BackgroundResearch ethics committees (RECs) are tasked to assess the risks and the benefits of a trial. Currently, two procedure-level approaches are predominant, the Net Risk Test and the Component Analysis.DiscussionBy looking at decision studies, we see that both procedure-level approaches conflate the various risk-benefit tasks, i.e., risk-benefit assessment, risk-benefit evaluation, risk treatment, and decision making. This conflation makes the RECs’ risk-benefit task confusing, if not impossible. We further realize that RECs are not meant to do all the risk-benefit tasks; instead, (...) RECs are meant to evaluate risks and benefits, appraise risk treatment suggestions, and make the final decision.ConclusionAs such, research ethics would benefit from looking beyond the procedure-level approaches and allowing disciplines like decision studies to be involved in the discourse on RECs’ risk-benefit task. (shrink)

This article provides ethical guidance on using race in health research as a variable or in defining the study population. To this end, a plain, non-exhaustive checklist is provided for researchers and research ethics committees, preceded by a brief introduction on the need for justification when using race as a variable or in defining a study population, the problem of exoticism, that distinctions pertain between race, ethnicity and ancestry, the problematic naming of races, and that race does not serve well (...) as a presumed biological construct in genetic research. (shrink)

Argumentation as the public exchange of reasons is widely thought to enhance deliberative interactions that generate and justify reasonable public policies. Adopting an argumentation-theoretic perspective, we survey the norms that should govern public argumentation and address some of the complexities that scholarly treatments have identified. Our focus is on norms associated with the ideals of correctness and participation as sources of a politically legitimate deliberative outcome. In principle, both ideals are mutually coherent. If the information needed for a correct deliberative (...) outcome is distributed among agents, then maximising participation increases information diversity. But both ideals can also be in tension. If participants lack competence or are prone to biases, a correct deliberative outcome requires limiting participation. The central question for public argumentation, therefore, is how to strike a balance between both ideals. Rather than advocating a preferred normative framework, our main purpose is to illustrate the complexity of this theme. (shrink)

SummaryIntense, sustained nursing lengthens inter-birth intervals and is causally linked with low natural fertility. However, in traditional settings, the effects of such nursing on fertility are difficult to disentangle from those of nutrition. Results from an prospective, direct observational study of reproductive function in well-nourished Amele women who nurse intensively and persistently but who also have high fertility are here presented. Endocrine measures show that ovarian activity resumes by median 11·0 months postpartum. Median duration of postpartum amenorrhoea is 11·3 months, (...) time to next conception is 19·0 months, and the inter-birth interval is 28·0 months. Average life time fertility is 6·8. High fertility in Amele women is due both to refractoriness of reproductive function to suckling stimuli, and to maintenance of equivalent age-specific fertility rates across the reproductive life span. (shrink)

This interview study investigates the short- and long-term implications of incidental findings detected through brain imaging on research participants’ lives and their surroundings. For this study, nine participants of the Rotterdam Scan Study with an incidental finding were approached and interviewed. When examining research participants’ narratives on the impact of the disclosure of incidental findings, the authors identified five sets of tensions with regard to motivations for and expectations of research participation, preferences regarding disclosure, short- and long-term impacts and impacts (...) on self and others. The paper shows: that the impact of incidental findings may be greater than participants at first let on; incidental findings can have significant effects on participants’ social environment; and participants may not feel prepared for disclosure even if incidental findings have been discussed during the informed consent process. The authors call for investigators to be aware of research participants’ experiences and these short- and long-term impacts when designing suitable courses of action for the detection and management of incidental findings in research settings. (shrink)

Introduction In 2007, a national review committee was instituted in The Netherlands to review cases of active ending of life for newborns. It was expected that 15–20 cases would be reported. To date, however, only one case has been reported to this committee. Reporting is essential to obtain societal control and transparency; the possible explanations for this lack of reporting were therefore explored. Methods Data on end-of-life decision-making were scrutinised from Dutch nation-wide studies (1995, 2001 and 2005), before institution of (...) the committee. Physicians received a questionnaire about their medical decision-making for stratified samples of deceased infants up to 1 year, drawn from the central death registry. Results In 2005, 58% of all deaths were preceded by an end-of-life decision, compared with 68% in 2001 and 62% in 1995. The use of drugs with a possible life-shortening effect tended to be lower. In 2005, all four cases in the study in which an infants' life was actively ended were preceded by a decision to forego life-prolonging treatment. In three cases, the infant's life expectancy was short; one case involved a longer life expectancy. Discussion The expected number of cases is probably an overestimation due to changes in medical practice such as the tendency to attribute less life-shortening effects to opioids. The lack of reports is probably also associated with requirements in the regulation; it may be difficult to fulfil them due either to time constraints or the nature of the suffering that is addressed. If societal control of active ending of life is considered useful, changes in the regulation may be needed. (shrink)

BackgroundIn research ethics, the most basic question would always be, “which is an ethical issue, which is not?” Interestingly, depending on which ethics guideline we consult, we may have various answers to this question. Though we already have several international ethics guidelines for biomedical research involving human participants, ironically, we do not have a harmonized document which tells us what these various guidelines say and shows us the areas of consensus. In this manuscript, we attempted to do just that.MethodsWe extracted (...) the imperatives from five internationally-known ethics guidelines and took note where the imperatives came from. In doing so, we gathered data on how many guidelines support a specific imperative.ResultsWe found that there is no consensus on the majority of the imperatives and that in only 8.2 % of the imperatives were there at least moderate consensus. Of the 12 clusters, Informed Consent has the highest level of consensus and Research Collaboration and Regulatory Sanctions have the least.ConclusionThere was a lack of consensus in the majority of imperatives from the five internationally-known ethics guidelines. This may be partly explained by the differences among the guidelines in terms of their levels of specification as well as conceptual/ideological differences. (shrink)

Given its non-invasive nature, there is increasing interest in the use of transcutaneous vagus nerve stimulation across basic, translational and clinical research. Contemporaneously, tVNS can be achieved by stimulating either the auricular branch or the cervical bundle of the vagus nerve, referred to as transcutaneous auricular vagus nerve stimulation and transcutaneous cervical VNS, respectively. In order to advance the field in a systematic manner, studies using these technologies need to adequately report sufficient methodological detail to enable comparison of results between (...) studies, replication of studies, as well as enhancing study participant safety. We systematically reviewed the existing tVNS literature to evaluate current reporting practices. Based on this review, and consensus among participating authors, we propose a set of minimal reporting items to guide future tVNS studies. The suggested items address specific technical aspects of the device and stimulation parameters. We also cover general recommendations including inclusion and exclusion criteria for participants, outcome parameters and the detailed reporting of side effects. Furthermore, we review strategies used to identify the optimal stimulation parameters for a given research setting and summarize ongoing developments in animal research with potential implications for the application of tVNS in humans. Finally, we discuss the potential of tVNS in future research as well as the associated challenges across several disciplines in research and clinical practice. (shrink)

Background In the EU, clinical assessors, rapporteurs and the Committee for Medicinal Products for Human Use are obliged to assess the ethical aspects of a clinical development program and include major ethical flaws in the marketing authorization deliberation processes. To this date, we know very little about the manner that these regulators put this obligation into action. In this paper, we intend to look into the manner and the extent that ethical issues discovered during inspection have reached the deliberation processes. (...) Methods To gather data, we used the Dutch Medicines Evaluation Board database and first searched for the inspections, and their accompanying site inspection reports and integrated inspection reports, related to central marketing authorization applications of drugs submitted to the European Medicines Agency from 2011 to 2015. We then extracted inspection findings that were purely of ethical nature, i.e., those that did not affect the benefit/risk balance of the study. Only findings graded at least major by the inspectorate were included. Lastly, to identify how many of the ethically relevant findings reach the application deliberation processes, we extracted the relevant joint response assessment reports and reviewed the sections that discussed inspection findings. Results From 2011 to 2015, there were 390 processed applications, of which 65 had inspection reports and integrated inspection reports accessible via the database of the Dutch Medicines Evaluation Board. Of the 65, we found ERFs in 37. The majority of the ERFs were graded as major and half of the time it was informed-consent related. A third of these findings were related to research ethics committee processes and requirements. Of the 37 inspections with ERFs, 30 were endorsed in the integrated inspection reports as generally GCP compliant. Day 150 joint response assessment reports and Day 180 list of outstanding issues were reviewed for all 37 inspections, and none of the ERFs were carried over in any of the assessment reports or list of outstanding issues. Conclusion None of the ethically relevant findings, all of which were graded as major or critical in integrated inspection reports, were explicitly carried over to the joint assessment reports. This calls for more transparency in EMA application deliberations on how ERFs are considered, if at all, in the decision-making processes. (shrink)