Timing of dialysis in acute kidney injury using routinely collected data and dynamic treatment regimes.

BACKGROUND AND OBJECTIVES: Defining the optimal moment to start renal replacement therapy (RRT) in acute kidney injury (AKI) remains challenging. Multiple randomized controlled trials (RCTs) addressed this question whilst using absolute criteria such as pH or serum potassium. However, there is a need for identification of the most optimal cut-offs of these criteria. We conducted a causal analysis on routinely collected data (RCD) to compare the impact of different pre-specified dynamic treatment regimes (DTRs) for RRT initiation based on time-updated levels of potassium, pH, and urinary output on 30-day ICU mortality. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: Patients in the ICU of Ghent University Hospital were included at the time they met KDIGO-AKI-stage ≥ 2. We applied inverse-probability-of-censoring-weighted Aalen-Johansen estimators to evaluate 30-day survival under 81 DTRs prescribing RRT initiation under different thresholds of potassium, pH, or persisting oliguria. RESULTS: Out of 13,403 eligible patients (60.8 ± 16.8 years, SOFA 7.0 ± 4.1), 5622 (63.4 ± 15.3 years, SOFA 8.2 ± 4.2) met KDIGO-AKI-stage ≥ 2. The DTR that delayed RRT until potassium ≥ 7 mmol/l, persisting oliguria for 24-36 h, and/or pH < 7.0 (non-oliguric) or < 7.2 (oliguric) despite maximal conservative treatment resulted in a reduced 30-day ICU mortality (from 12.7% [95% CI 11.9-13.6%] under current standard of care to 10.5% [95% CI 9.5-11.7%]; risk difference 2.2% [95% CI 1.3-3.8%]) with no increase in patients starting RRT (from 471 [95% CI 430-511] to 475 [95% CI 342-572]). The fivefold cross-validation benchmark for the optimal DTR resulted in 30-day ICU mortality of 10.7%. CONCLUSIONS: Our causal analysis of RCD to compare RRT initiation at different thresholds of refractory low pH, high potassium, and persisting oliguria identified a DTR that resulted in a decrease in 30-day ICU mortality without increase in number of RRTs. Our results suggest that the current criteria to start RRT as implemented in most RCTs may be suboptimal. However, as our analysis is hypothesis generating, this optimal DTR should ideally be validated in a multicentric RCT.

A riddle, wrapped in a mystery, inside an enigma: How semantic black boxes and opaque artificial intelligence confuse medical decision-making.

The use of artificial intelligence (AI) in healthcare comes with opportunities but also numerous challenges. A specific challenge that remains underexplored is the lack of clear and distinct definitions of the concepts used in and/or produced by these algorithms, and how their real world meaning is translated into machine language and vice versa, how their output is understood by the end user. This "semantic" black box adds to the "mathematical" black box present in many AI systems in which the underlying "reasoning" process is often opaque. In this way, whereas it is often claimed that the use of AI in medical applications will deliver "objective" information, the true relevance or meaning to the end-user is frequently obscured. This is highly problematic as AI devices are used not only for diagnostic and decision support by healthcare professionals, but also can be used to deliver information to patients, for example to create visual aids for use in shared decision-making. This paper provides an examination of the range and extent of this problem and its implications, on the basis of cases from the field of intensive care nephrology. We explore how the problematic terminology used in human communication about the detection, diagnosis, treatment, and prognosis of concepts of intensive care nephrology becomes a much more complicated affair when deployed in the form of algorithmic automation, with implications extending throughout clinical care, affecting norms and practices long considered fundamental to good clinical care.

"Many roads lead to Rome and the Artificial Intelligence only shows me one road": an interview study on physician attitudes regarding the implementation of computerised clinical decision support systems.

Research regarding the drivers of acceptance of clinical decision support systems (CDSS) by physicians is still rather limited. The literature that does exist, however, tends to focus on problems regarding the user-friendliness of CDSS. We have performed a thematic analysis of 24 interviews with physicians concerning specific clinical case vignettes, in order to explore their underlying opinions and attitudes regarding the introduction of CDSS in clinical practice, to allow a more in-depth analysis of factors underlying (non-)acceptance of CDSS. We identified three general themes from the results. First, 'the perceived role of the AI', including items referring to the tasks that may properly be assigned to the CDSS according to the respondents. Second, 'the perceived role of the physician', referring to the aspects of clinical practice that were seen as being fundamentally 'human' or non-automatable. Third, 'concerns regarding AI', including items referring to more general issues that were raised by the respondents regarding the introduction of CDSS in general and/or in clinical medicine in particular. Apart from the overall concerns expressed by the respondents regarding user-friendliness, we will explain how our results indicate that our respondents were primarily occupied by distinguishing between parts of their job that should be automated and aspects that should be kept in human hands. We refer to this distinction as 'the division of clinical labor.' This division is not based on knowledge regarding AI or medicine, but rather on which parts of a physician's job were seen by the respondents as being central to who they are as physicians and as human beings. Often the respondents' view that certain core parts of their job ought to be shielded from automation was closely linked to claims concerning the uniqueness of medicine as a domain. Finally, although almost all respondents claimed that they highly value their final responsibility, a closer investigation of this concept suggests that their view of 'final responsibility' was not that demanding after all.

An exploration of expectations and perceptions of practicing physicians on the implementation of computerized clinical decision support systems using a Qsort approach.

BACKGROUND: There is increasing interest in incorporating clinical decision support (CDS) into electronic healthcare records (EHR). Successful implementation of CDS systems depends on acceptance of them by healthcare workers. We used a mix of quantitative and qualitative methods starting from Qsort methodology to explore expectations and perceptions of practicing physicians on the use of CDS incorporated in EHR. METHODS: The study was performed in a large tertiary care academic hospital. We used a mixed approach with a Q-sort based classification of pre-defined reactions to clinical case vignettes combined with a thinking-aloud approach, taking into account COREQ recommendations The open source software of Ken-Q Analysis version 1.0.6. was used for the quantitative analysis, using principal components and a Varimax rotation. For the qualitative analysis, a thematic analysis based on the four main themes was performed based on the audiotapes and field notes. RESULTS: Thirty physicians were interviewed (7 in training, 8 junior staff and 15 senior staff; 16 females). Nearly all respondents were strongly averse towards interruptive messages, especially when these also were obstructive. Obstructive interruption was considered to be acceptable only when it increases safety, is adjustable to user expertise level and/or allows deviations when the end-user explains why a deviation is desirable in the case at issue. Transparency was deemed an essential feature, which seems to boil down to providing sufficient clarification on the factors underlying the recommendations of the CDS, so that these can be compared against the physicians' existing knowledge, beliefs and convictions. CONCLUSION: Avoidance of disruptive workflows and transparency of the underlying decision processes are important points to consider when developing CDS systems incorporated in EHR.

The concept of justifiable healthcare and how big data can help us to achieve it.

Over the last decades, the face of health care has changed dramatically, with big improvements in what is technically feasible. However, there are indicators that the current approach to evaluating evidence in health care is not holistic and hence in the long run, health care will not be sustainable. New conceptual and normative frameworks for the evaluation of health care need to be developed and investigated. The current paper presents a novel framework of justifiable health care and explores how the use of artificial intelligence and big data can contribute to achieving the goals of this framework.

Euthanasia in Belgium: Shortcomings of the Law and Its Application and of the Monitoring of Practice.

In 2002 with the passing of the Euthanasia Law, Belgium became one of the few countries worldwide to legalize euthanasia. In the 18 years since the passing of the law, much has changed. We argue that in Belgium a widening of the use of euthanasia is occurring and that this can be ethically and legally problematic. This is in part related to the fact that several legal requirements intended to operate as safeguards and procedural guarantees in reality often fail to operate as such. We focus on three kinds of safeguards or procedural guarantees: (1) the legally defined due care criteria for eligibility for euthanasia; (2) the consultation of a second (and sometimes third) physician; and (3) the reporting of euthanasia cases to the Federal Control and Evaluation Commission for Euthanasia. We will show how each of these three safeguards can exhibit shortcomings in theory and practice.

'Capacity for Discernment' and Euthanasia on Minors in Belgium.

In 2014, the Belgian Euthanasia Law was amended so as to extend the possibility of obtaining euthanasia to minors who have the capacity for discernment. The amendment led to considerable debate among Belgian legal experts, health care professionals and ethicists, in large part due to concerns about the scope and assessment of the minor's 'capacity for discernment', a concept first introduced in Belgian medical law by the amendment. This article offers a critical legal analysis of the concept of 'capacity for discernment' and its implications for euthanasia practice in Belgium. We do so by focusing on a ruling of the Belgian Constitutional Court of 29 October 2015, where the concept figured prominently in the examination of the constitutionality of the amendment. This approach also allows us to shed light on the interpretation of several core aspects of the original 2002 Euthanasia Law and its 2014 amendment.

Patenting Foundational Technologies: Lessons From CRISPR and Other Core Biotechnologies.

In 2012, a new and promising gene manipulation technique, CRISPR-Cas9, was announced that seems likely to be a foundational technique in health care and agriculture. However, patents have been granted. As with other technological developments, there are concerns of social justice regarding inequalities in access. Given the technologies' "foundational" nature and societal impact, it is vital for such concerns to be translated into workable recommendations for policymakers and legislators. Colin Farrelly has proposed a moral justification for the use of patents to speed up the arrival of technology by encouraging innovation and investment. While sympathetic to his argument, this article highlights a number of problems. By examining the role of patents in CRISPR and in two previous foundational technologies, we make some recommendations for realistic and workable guidelines for patenting and licensing.

Time-lapse microscopy patent upheld in Europe: response to Pearce.

In this piece, we comment on the article by Pearce earlier in this journal. As Pearce correctly points out, what is fundamentally at issue in ESHRE et al's opposition to Stanford University's European patent on time-lapse microscopy is whether an exclusion from patentability, here of methods of medical diagnosis, should be interpreted narrowly or not. In the present case, the dominant piece of case law from the European Patent Office (EPO) gives a narrow interpretation of what a method of diagnosis must be in order not to be patentable. In their submissions to the EPO, ESHRE et al. have argued that this narrow interpretation is unfounded and incorrect.

Patenting medical diagnosis methods in Europe: Stanford University and time-lapse microscopy.

In 2013, a European Patent for the technique of time-lapse microscopy was granted by the European Patent Office (EPO) to Stanford University and was subsequently opposed by Unisense FertiliTech A/S and by the European Society for Human Reproduction and Embryology (ESHRE), Sigrid Sterckx, Julian Cockbain and Guido Pennings. ESHRE et al.'s opposition was based on the argument that Stanford's patent was directed to a method of medical diagnosis, methods that are excluded from patentability by Article 53(c) of the European Patent Convention. The Opposition Division of the EPO rejected the oppositions in November 2015, and both opponents have now filed their appeals. In this paper, we comment on the Opposition Division decision and the grounds of appeal put forward by ESHRE et al.

Raising the Barriers to Access to Medicines in the Developing World - The Relentless Push for Data Exclusivity.

Since the adoption of the WTO-TRIPS Agreement in 1994, there has been significant controversy over the impact of pharmaceutical patent protection on the access to medicines in the developing world. In addition to the market exclusivity provided by patents, the pharmaceutical industry has also sought to further extend their monopolies by advocating the need for additional 'regulatory' protection for new medicines, known as data exclusivity. Data exclusivity limits the use of clinical trial data that need to be submitted to the regulatory authorities before a new drug can enter the market. For a specified period, generic competitors cannot apply for regulatory approval for equivalent drugs relying on the originator's data. As a consequence, data exclusivity lengthens the monopoly for the original drug, impairing the availability of generic drugs. This article illustrates how the pharmaceutical industry has convinced the US and the EU to impose data exclusivity on their trade partners, many of them developing countries. The key arguments formulated by the pharmaceutical industry in favor of adopting data exclusivity and their underlying ethical assumptions are described in this article, analyzed, and found to be unconvincing. Contrary to industry's arguments, it is unlikely that data exclusivity will promote innovation, especially in developing countries. Moreover, the industry's appeal to a property rights claim over clinical test data and the idea that data exclusivity can prevent the generic competitors from 'free-riding' encounters some important problems: Neither legitimize excluding all others.

Controversies surrounding continuous deep sedation at the end of life: the parliamentary and societal debates in France.

BACKGROUND: Continuous deep sedation at the end of life is a practice that has been the topic of considerable ethical debate, for example surrounding its perceived similarity or dissimilarity with physician-assisted dying. The practice is generally considered to be legal as a form of symptom control, although this is mostly only assumed. France has passed an amendment to the Public Health Act that would grant certain terminally ill patients an explicit right to continuous deep sedation until they pass away. Such a framework would be unique in the world. DISCUSSION: In this paper we will highlight and reflect on four relevant aspects and shortcomings of the proposed bill. First, that the bill suggests that continuous deeps sedation should be considered as a sui generis practice. Second, that it requires that sedation should always be accompanied by the withholding of all artificial nutrition and hydration. In the most recently amended version of the legal proposal it is stated that life sustaining treatments are withheld unless the patient objects. Third, that the French bill would not require that the suffering for which continuous deep sedation is initiated is unbearable. Fourth, the question as to whether the proposal should be considered as a way to avoid having to decriminalise euthanasia and/or PAS or, on the contrary, as a veiled way to decriminalise these practices. The French proposal to amend the Public Health Act to include a right to continuous deep sedation for some patients is a unique opportunity to clarify the legality of continuous deep sedation as an end-of-life practice. Moreover, it would recognize that the practice of continuous deep sedation raises ethical and legal issues that are different from those raised by symptom control on the one hand and assisted dying on the other hand. Nevertheless, there are still various issues of significant ethical concern in the French legislative proposal.

Citizen science or scientific citizenship? Disentangling the uses of public engagement rhetoric in national research initiatives.

BACKGROUND: The language of "participant-driven research," "crowdsourcing" and "citizen science" is increasingly being used to encourage the public to become involved in research ventures as both subjects and scientists. Originally, these labels were invoked by volunteer research efforts propelled by amateurs outside of traditional research institutions and aimed at appealing to those looking for more "democratic," "patient-centric," or "lay" alternatives to the professional science establishment. As mainstream translational biomedical research requires increasingly larger participant pools, however, corporate, academic and governmental research programs are embracing this populist rhetoric to encourage wider public participation. DISCUSSION: We examine the ethical and social implications of this recruitment strategy. We begin by surveying examples of "citizen science" outside of biomedicine, as paradigmatic of the aspirations this democratizing rhetoric was originally meant to embody. Next, we discuss the ways these aspirations become articulated in the biomedical context, with a view to drawing out the multiple and potentially conflicting meanings of "public engagement" when citizens are also the subjects of the science. We then illustrate two uses of public engagement rhetoric to gain public support for national biomedical research efforts: its post-hoc use in the "care.data" project of the National Health Service in England, and its proactive uses in the "Precision Medicine Initiative" of the United States White House. These examples will serve as the basis for a normative analysis, discussing the potential ethical and social ramifications of this rhetoric. We pay particular attention to the implications of government strategies that cultivate the idea that members of the public have a civic duty to participate in government-sponsored research initiatives. We argue that such initiatives should draw from policy frameworks that support normative analysis of the role of citizenry. And, we conclude it is imperative to make visible and clear the full spectrum of meanings of "citizen science," the contexts in which it is used, and its demands with respect to participation, engagement, and governance.

"You hoped we would sleep walk into accepting the collection of our data": controversies surrounding the UK care.data scheme and their wider relevance for biomedical research.

An 'Information Centre' has recently been established by law which has the power to collect, collate and provide access to the medical information for all patients treated by the National Health Service in England, whether in hospitals or by General Practitioners. This so-called 'care.data' scheme has given rise to major and ongoing controversies. We will sketch the background of the scheme and look at the responses it has elicited from citizens and medical professionals. In Autumn 2013, NHS England set up a care.data website where citizens could record their concerns regarding the collection of health-related data by the Information Centre. We have reviewed all the comments on this website up until June 2015. We have also analysed the readers' comments on the coverage of the care.data scheme in one of the main national UK newspapers. When discussing the responses of citizens, we will make a distinction between the problems that citizens detect and the solutions they propose. The solutions that are being perceived as the most relevant ones can be summarized as follows: citizens wish to further the common good without being manipulated into doing it, while at the same time being safeguarded against various abuses. The issue of trust turns out to figure prominently. Our analysis of reactions to the scheme in no way pretends to be exhaustive, yet it provides various relevant insights into the concerns identified by citizens as well as medical professionals. These concerns, moreover, have a more general relevance in relation to other contexts of medical data-mining as well as biobank research. Our analysis also offers important pointers as to how those concerns might be addressed.

Using continuous sedation until death for cancer patients: a qualitative interview study of physicians' and nurses' practice in three European countries.

BACKGROUND: Extensive debate surrounds the practice of continuous sedation until death to control refractory symptoms in terminal cancer care. We examined reported practice of United Kingdom, Belgian and Dutch physicians and nurses. METHODS: Qualitative case studies using interviews. SETTING: Hospitals, the domestic home and hospices or palliative care units. PARTICIPANTS: In all, 57 Physicians and 73 nurses involved in the care of 84 cancer patients. RESULTS: UK respondents reported a continuum of practice from the provision of low doses of sedatives to control terminal restlessness to rarely encountered deep sedation. In contrast, Belgian respondents predominantly described the use of deep sedation, emphasizing the importance of responding to the patient's request. Dutch respondents emphasized making an official medical decision informed by the patient's wish and establishing that a refractory symptom was present. Respondents employed rationales that showed different stances towards four key issues: the preservation of consciousness, concerns about the potential hastening of death, whether they perceived continuous sedation until death as an 'alternative' to euthanasia and whether they sought to follow guidelines or frameworks for practice. CONCLUSION: This qualitative analysis suggests that there is systematic variation in end-of-life care sedation practice and its conceptualization in the United Kingdom, Belgium and the Netherlands.

Governing the postmortem procurement of human body material for research.

Human body material removed post mortem is a particularly valuable resource for research. Considering the efforts that are currently being made to study the biochemical processes and possible genetic causes that underlie cancer and cardiovascular and neurodegenerative diseases, it is likely that this type of research will continue to gain in importance. However, post mortem procurement of human body material for research raises specific ethical concerns, more in particular with regard to the consent of the research participant. In this paper, we attempt to determine which consent regime should govern the post mortem procurement of body material for research. In order to do so, we assess the various arguments that could be put forward in support of a duty to make body material available for research purposes after death. We argue that this duty does in practice not support conscription but is sufficiently strong to defend a policy of presumed rather than explicit consent.

Patenting time-lapse microscopy: the European story.

European Patent No. 2430454 of Stanford University is open to opposition before the European Patent Office if such opposition is filed by 23 October 2013. This is the European equivalent of the US Patent that raised such controversy in this journal in August 2013 as being a patent on time. The European Patent, which is directed to a method of selecting embryos for implantation using the results of time-lapse microscopy, should, in the present authors' opinion, be revoked as being directed to a method of medical diagnosis, which is unpatentable under European patent law. The only party currently opposing Stanford's patent is a competitor, Unisense FertiliTech A/S which is itself seeking to patent similar methods in Europe; the objection that Stanford has patented a method of diagnosis has not been raised by Unisense FertiliTech. We submit that Stanford's patent should be opposed to safeguard competition and to protect the freedom to operate of clinicians. In this paper we explain how Stanford's patent should fail under European law.

Pediatric priority in kidney allocation: challenging its acceptability.

Any organ which is allocated to one individual represents a missed opportunity for someone else. Given the important repercussions which organ allocation policies inevitably have for certain people, any prioritization policy should rest on a solid argumentative basis. In this study, we analyze the widespread practice of prioritizing pediatric patients in the allocation of kidneys. While official policy documents offer no arguments in support of pediatric priority, such arguments can be found in the academic literature on pediatric renal transplantation. Our study is the first to bring together and critically analyze these. We identify five commonly cited arguments and show that none of these succeeds in justifying pediatric priority policies. We argue that the legitimacy of such policies may be further undermined by their potential adverse effects on both adults and children.

Factors that facilitate or constrain the use of continuous sedation at the end of life by physicians and nurses in Belgium: results from a focus group study.

Continuous sedation at the end of life (CS) is the practice whereby a physician uses sedatives to reduce or take away a patient's consciousness until death. Although the incidence of CS is rising, as of yet little research has been conducted on how the administration of CS is experienced by medical practitioners. Existing research shows that many differences exist between medical practitioners regarding how and how often they perform CS. We conducted a focus group study to find out which factors may facilitate or constrain the use of continuous sedation by physicians and nurses. The participants often had clear ideas on what could affect the likelihood that sedation would be used. The physicians and nurses in the focus groups testified that the use of continuous sedation was facilitated in cases where a patient has a very limited life expectancy, suffers intensely, makes an explicit request and has family members who can cope with the stress that accompanies sedation. However, this 'paradigm case' was considered to occur only rarely. Furthermore, deviations from the paradigm case were said to be sometimes due to physicians initiating the discussion on CS too late or not initiating it at all for fear of inducing the patient. Deviations from the paradigm case may also occur when sedation proves to be too difficult for family members who are said to sometimes pressure the medical practitioners to increase dosages and speed up the sedation.