We discuss here a series of testable hypotheses concerning the role of chromosome folding into topologically associating domains (TADs). Several lines of evidence suggest that segmental packaging of chromosomal neighborhoods may underlie features of chromatin that span large domains, such as heterochromatin blocks, association with the nuclear lamina and replication timing. By defining which DNA elements preferentially contact each other, the segmentation of chromosomes into TADs may also underlie many properties of long‐range transcriptional regulation. Several observations suggest that TADs can (...) indeed provide a structural basis to regulatory landscapes, by controlling enhancer sharing and allocation. We also discuss how TADs may shape the evolution of chromosomes, by causing maintenance of synteny over large chromosomal segments. Finally we suggest a series of experiments to challenge these ideas and provide concrete examples illustrating how they could be practically applied. (shrink)

Objectives Access to healthcare in most western societies is based on equality. Rapidly rising costs have fuelled debates about differentiation in access to healthcare. We assessed the public's perceptions and attitudes about differentiation in healthcare according to lifestyle behaviour. Methods A vignette study was undertaken in participants in a colorectal cancer screening pilot programme in the Netherlands. Screenees with a negative test result received a questionnaire in which nine hypothetical situations were described: three different healthcare settings (screening, lung cancer, chronic (...) obstructive pulmonary disease) combined with three forms of differentiation each: a difference in premium, waiting list ordering or copayment according to lifestyle. We evaluated the responses using a general hierarchical linear model. Results The percentage of participants in agreement with differentiation varied from 20% to 58% (overall mean of 40%). Significantly more participants were in favour of giving a premium discount to those who do not engage in unhealthy behaviour compared with supporters for higher payments for those who do. More differentiation was supported for non-smoking versus smoking cessation than for participation versus non-participation in screening. We observed in-group favouritism in smokers, but no significant effects of age or disease. There was no support for waiting list ordering based on lifestyle. Conclusions Results of this study show that Dutch citizens eligible for colorectal cancer screening are in favour of some form of financial differentiation in the distribution of healthcare, but that significant differences exist between type of setting and the type of behaviour. Our study can be used in the ongoing discussion about solidarity and behaviour in healthcare. (shrink)

Background: Although genetic research into Alzheimer disease (AD) is increasing, the ethical aspects of this kind of research and the differences between ethical issues related to genetic and non-genetic research into AD have not yet received much attention. Objectives: (1) To identify and compare the five ethical issues considered most important by surveyed expert panellists in non-genetic and genetic AD research and (2) to compare our empirical findings with ethical issues in genetic research in general as described in the literature. (...) Method: A modified Delphi study in two rounds Results: Genetic and non-genetic research into AD generated an approximately equal number of topics with a considerable overlap. Different priorities in the ethics of both types of research were found. Genetic research raised new topics such as “confidentiality of genetic information” and “implications of research for relatives” which changes the impact and application of existing ethical topics such as “informed consent” and is judged to have more impact on both individuals and society. A difference with the results of more theoretical approaches on ethical aspects related to AD research was also found. Conclusions: Different priorities are given to ethical issues in genetic and non-genetic research. These arise partly because genetic research causes unique and new questions, mostly related to the position of family members and the status of and access to genetic information. Differences found between the results of our empirical study and the more theoretical literature, suggest an additional value for empirical research in medical ethics. (shrink)

PurposeAlthough an increasing body of literature suggests a relationship between brain irradiation and deterioration of neurocognitive function, it remains as the standard therapeutic and prophylactic modality in patients with brain tumors. This review was aimed to abstract and evaluate the prediction models for radiation-induced neurocognitive decline in patients with primary or secondary brain tumors.MethodsMEDLINE was searched on October 31, 2021 for publications containing relevant truncation and MeSH terms related to “radiotherapy,” “brain,” “prediction model,” and “neurocognitive impairments.” Risk of bias was (...) assessed using the Prediction model Risk Of Bias ASsessment Tool.ResultsOf 3,580 studies reviewed, 23 prediction models were identified. Age, tumor location, education level, baseline neurocognitive score, and radiation dose to the hippocampus were the most common predictors in the models. The Hopkins verbal learning and the trail making tests were the most frequent outcome assessment tools. All studies used regression as machine learning method. All models were judged to have a high risk of bias mainly due to issues in the analysis.ConclusionExisting models have limited quality and are at high risk of bias. Following recommendations are outlined in this review to improve future models: developing cognitive assessment instruments taking into account the peculiar traits of the different brain tumors and radiation modalities; adherence to model development and validation guidelines; careful choice of candidate predictors according to the literature and domain expert consensus; and considering radiation dose to brain substructures as they can provide important information on specific neurocognitive impairments. (shrink)

In his note [5] Hausner states a simple combinatorial principle, namely: $$(H)\left\{ {\begin{array}{*{20}c} {if f is a function a non - empty finite set \sigma into itself, p a} \\ {prime, f^p = i_\sigma and \sigma _0 the set of fixed points of f, then } \\ {\left| \sigma \right| \equiv \left| {\sigma _0 } \right|(mod p).} \\\end{array}} \right.$$ .He then shows how this principle can be used to prove:Fermat's little theorem,Cauchy's theorem for finite groups,Lucas' theorem for binomial numbers.Letε=(0,1, ...),ℱ (...) 1−1 the family of all one-to-one functions from a subset ofε intoε andℳ 1−1 the family of all p.r. (i.e., partial recursive) one-to-one functions from a subset ofε intoε. A subsetα of ε is finite, ifα is not equivalent to a proper subset under a function inℱ 1−1. The setα is calledisolated, if it is not equivalent to a proper subset under a function inℳ 1−1. An isolated set can also be defined as a subset ofε which has no infinite r.e. (i.e., recursively enumerable) subset. While every finite set is isolated, there are $c = 2^{\aleph _0 }$ infinite sets which are isolated; these sets are calledimmune. It is the purpose of this paper to generalize (H) to a principle (H*) for isolated sets and to show how (H*) can be used to prove generalizations of Fermat's little theorem and Cauchy's theorem for finite groups. We have been unable to generalize Lucas' theorem in a similar manner. (shrink)

Sentences containing pronouns and indefinite noun phrases can be said toexpress open propositions, propositions which display gaps to be filled.This paper addresses the question what is the linguistic content ofthese expressions, what information they can be said to provide to ahearer, and in what sense the information of a speaker can be said tosupport their utterance. We present and motivate first order notions ofcontent, update and support. The three notions are each defined in acompositional fashion and brought together within a (...) single and coherentframework. (shrink)

In this article some of the presuppositions that underly the current ideas about decision making capacity, autonomy and independence are critically examined. The focus is on chronic disorders, especially on chronic physical disorders. First, it is argued that the concepts of decision making competence and autonomy, as they are usually applied to the problem of legal (in)competence in the mentally ill, need to be modified and adapted to the situation of the chronically (physically) ill. Second, it is argued that autonomy (...) and dependence must not be considered as two mutually exclusive categories. It is suggested that decision making may take on the form of a more or less conscious decision not to be involved in making all kinds of explicit and deliberate decisions. Elaborating on Agich's distinction between ideal and actual autonomy, the concept of Socratic autonomy is introduced. (shrink)

For a few decades, patients with Parkinson's disease have been treated with intracerebral transplantations of fetal mesencephalic tissue. The results of open trials have been variable. Double blind, placebo-controlled studies have recently been started in order to further investigate the efficacy of this new medical technique. In this paper we challenge the need for sham surgery in neurotransplantation research on PD patients. Considerations regarding the research subjects' informed consent, therapeutic misconception, the integrity of the human body, and the assessment of (...) risks and benefits argue against sham surgery for patients with PD. Moreover, there is an alternative, less harmful mode of research that can provide the same or comparable scientific evidence. A plea is made for intrapatient research based on quantitative measurements of the patient's pre- and post-operative condition combined with similar research on a reference group of patients who have received the standard treatment. (shrink)

Medicine does not usually consider the human body from an aesthetic point of view. This article explores the notion of the lived body as aesthetic object in anthropological medicine, concentrating on the views of Buytendijk and Straus on human uprightness and gracefulness. It is argued that their insights constitute a counter-balance to the way the human body is predominantly approached in medicine and medical ethics. In particular, (1) the relationship between anthropological, aesthetic and ethical norms, (2) the possible danger of (...) a naturalistic fallacy, (3) the implications for the care of disabled people and (4) the intrinsic aesthetic quality of the human body are dealt with. (shrink)

Periodic attacks of uncertain origin, where the clinical presentationresembles epilepsy but there is no evidence of a somatic disease, arecalled Pseudo-Epilepsy or Pseudo-Epileptic Attack Disorder (PEAD). PEADmay be called a `non-disease', i.e. a disorder on the fringes ofestablished disease patterns, because it lacks a rationalpathophysiological explanation. The first aim of this article is tocriticize the idea, common in medical science, that diseases are realentities which exist separately from the patient, waiting to bediscovered by the doctor. We argue that doctor and (...) patient construct adisease, and that the construction of the disease PEAD includes manynormative evaluations. The second aim is to provide insight into thesuffering of patients with PEAD. We focus on three aspects of thepatient, identity, autonomy and responsibility. We present somecharacteristic descriptions of (pseudo-)epileptic attacks by FjodorDostoevsky, Gustave Flaubert and Thomas Mann. We argue that diagnosingPEAD reduces a meaningful life event into an insignificant, thoughintriguing, medical phenomenon, and that the patient will not benefitfrom being diagnosed as having PEAD. (shrink)

Good nursing is more than exercising a specific set of skills. It involves the personal identity of the nurse. The aim of this article is to answer two questions: (1) what kind of person should the hospice nurse be? and (2) how should the hospice nurse engage in caring conversations? To answer these questions we analyse a nurse’s story that is intended to be a profile of an exemplary hospice nurse. This story was constructed from an analysis of five semistructured (...) interviews with hospice nurses, based on the ‘ethics of the caring conversation’, which is inspired by the ethical perspective of Paul Ricoeur. The research questions concentrate on the norms of respect, responsibility and reciprocity, which are integral parts of the ‘ethics of the caring conversation’. (shrink)

Social health disparities are increasing in most countries around the world. During the past two decades, a large amount of evidence has emerged about the health consequences of social inequalities. Despite such evidence, the concept of medical fairness, as traditionally defined by the World Medical Association, has remained unchallenged and even reinforced by some scholars who emphasize that doctors should remain neutral to the socioeconomic status of their patients when providing clinical care. The inconsistency between public health and clinical care (...) perspectives raises tension between a narrow interpretation of the ethics of justice, which stresses the importance of equality and impartiality, and the ethics of care, which highlights the importance of particularity and individuality in clinical practice. This article analyzes the concept of medical fairness using the emerging evidence that demonstrates the impact of social health disparities on clinical care. It proposes a new approach of medical fairness based on equity rather than on equality and provides a consistent ethical framework based on Paul Ricoeur’s three levels of medical judgments. This integrative framework provides a better balance between public health and clinical care in medical practice. (shrink)

In ”Skepticism,” Peter Klein distinguishes between the “Academic Skeptic” who proposes that we cannot have knowledge of a certain set of propositions and the “Pyrrhonian Skeptic” who refrains from opining about whether we can have knowledge. Klein argues that Academic Skepticism is plausibly supported by a “Closure Principle‐style” argument based on the claim that if x entails y and S has justification for x, then S has justification for y. He turns to contextualism to see if it can contribute to (...) the discussion between one who claims that we can have knowledge about some epistemically interesting class of propositions and the Academic Skeptic. He outlines the background of Pyrrhonian Skepticism, pointing out that the Pyrrhonist withholds assent concerning our knowledge‐bearing status because reason cannot provide an adequate basis for assent. He assesses three possible patterns of reasoning, and concludes that the Pyrrhonist view, that reason cannot resolve matters concerning the nonevident, is vindicated. (shrink)

During the last decade a “technical” approach has become increasingly influential in health care priority setting. The various country reports illustrate, however, that non-technical considerations cannot be avoided. As they often remain implicit in health care package decisions, this paper aims to make these normative judgements an explicit part of the procedure. More specifically, it aims to integrate different models of distributive justice as well as the principle of solidarity in four different phases of a decision-making procedure, and to identify (...) important moral choices which present themselves. First four important justice models are discussed, then a justification is given for their inclusion in a four-step decision making procedure. This is followed by a discussion of different justice and solidarity problems—with their inherent conceptual difficulties in each of these stages. The paper concludes with a summary of the major moral choices that are to be made in health care package decisions. (shrink)