The need to set explicit goals for human germline gene editing public dialogues.

Given the potentially large ethical and societal implications of human germline gene editing (HGGE) the urgent need for public and stakeholder engagement (PSE) has been repeatedly expressed. However, the explicit goals of such PSE efforts often remain poorly defined. In this program report, we outline the goals of our Dutch project called De DNA dialogen (The DNA dialogues). We believe that setting explicit goals in advance is essential to enable meaningful PSE efforts. Moreover, it enables the evaluation of our engagement efforts. The following four goals, which result from intensive consultations among the transdisciplinary projects' consortium members and based on the literature, form the foundation for how we will engage the public and stakeholders in deliberation about HGGE: 1) Enable publics and stakeholders to deliberate on "what if" questions, before considering "whether" and "how" questions regarding HGGE, 2) Investigate agreement and disagreement in values and beliefs regarding HGGE in order to agree and disagree more precisely, 3) Involve diverse publics with various perspectives, with a focus on those that are typically underrepresented in PSE, 4) Enable societally aligned policy making by providing policymakers, health care professionals and legal experts insight into how values are weighed and ascribed meaning in the context of HGGE by various publics, and how these values relate to the principles of democratic rule of law and fundamental rights. The effort to describe our goals in detail may serve as an example and can inform future initiatives striving for open science and open governance in the context of PSE.

Ethical Development of Artificial Amniotic Sac and Placenta Technology: A Roadmap.

In this paper we present an initial roadmap for the ethical development and eventual implementation of artificial amniotic sac and placenta technology in clinical practice. We consider four elements of attention: (1) framing and societal dialogue; (2) value sensitive design, (3) research ethics and (4) ethical and legal research resulting in the development of an adequate moral and legal framework. Attention to all elements is a necessary requirement for ethically responsible development of this technology. The first element concerns the importance of framing and societal dialogue. This should involve all relevant stakeholders as well as the general public. We also identify the need to consider carefully the use of terminology and how this influences the understanding of the technology. Second, we elaborate on value sensitive design: the technology should be designed based upon the principles and values that emerge in the first step: societal dialogue. Third, research ethics deserves attention: for proceeding with first-in-human research with the technology, the process of recruiting and counseling eventual study participants and assuring their informed consent deserves careful attention. Fourth, ethical and legal research should concern the status of the subject in the AAPT. An eventual robust moral and legal framework for developing and implementing the technology in a research setting should combine all previous elements. With this roadmap, we emphasize the importance of stakeholder engagement throughout the process of developing and implementing the technology; this will contribute to ethically and responsibly innovating health care.

The DNA-Dialogue: A Broad Societal Dialogue About Human Germline Genome Editing in the Netherlands.

For years, calls for public involvement in the debate concerning the acceptability of human germline genome editing (HGGE) have been made. A multidisciplinary consortium of 11 organizations in the Netherlands organized a broad societal dialogue to inquire about the views of Dutch society toward HGGE. The project aimed to reach a wide and diverse audience and to stimulate a collective process of deliberative opinion forming and reflection. To that end, several instruments and formats were developed and employed. We present the results of 27 moderated dialogues organized between October 2019 and October 2020. Overall, participants of the dialogues were capable of assessing and discussing the subject of HGGE in a nuanced way. Analysis of these dialogues shows that in general, participants had no fundamental and absolute objections toward HGGE technology. However, they only deemed HGGE to be acceptable when it is used to prevent serious heritable diseases and under strict conditions, without affecting important (societal) values. There was a small group of participants who found HGGE fundamentally unacceptable because it would cross natural, socio-ethical, or religious boundaries.

From clinical decision support to clinical reasoning support systems.

Despite the great promises that artificial intelligence (AI) holds for health care, the uptake of such technologies into medical practice is slow. In this paper, we focus on the epistemological issues arising from the development and implementation of a class of AI for clinical practice, namely clinical decision support systems (CDSS). We will first provide an overview of the epistemic tasks of medical professionals, and then analyse which of these tasks can be supported by CDSS, while also explaining why some of them should remain the territory of human experts. Clinical decision making involves a reasoning process in which clinicians combine different types of information into a coherent and adequate 'picture of the patient' that enables them to draw explainable and justifiable conclusions for which they bear epistemological responsibility. Therefore, we suggest that it is more appropriate to think of a CDSS as clinical reasoning support systems (CRSS). Developing CRSS that support clinicians' reasoning process therefore requires that: (a) CRSSs are developed on the basis of relevant and well-processed data; and (b) the system facilitates an interaction with the clinician. Therefore, medical experts must collaborate closely with AI experts developing the CRSS. In addition, responsible use of an CRSS requires that the data generated by the CRSS is empirically justified through an empirical link with the individual patient. In practice, this means that the system indicates what factors contributed to arriving at an advice, allowing the user (clinician) to evaluate whether these factors are medically plausible and applicable to the patient. Finally, we defend that proper implementation of CRSS allows combining human and artificial intelligence into hybrid intelligence, were both perform clearly delineated and complementary empirical tasks. Whereas CRSSs can assist with statistical reasoning and finding patterns in complex data, it is the clinicians' task to interpret, integrate and contextualize.

Epistemology for interdisciplinary research - shifting philosophical paradigms of science.

In science policy, it is generally acknowledged that science-based problem-solving requires interdisciplinary research. For example, policy makers invest in funding programs such as Horizon 2020 that aim to stimulate interdisciplinary research. Yet the epistemological processes that lead to effective interdisciplinary research are poorly understood. This article aims at an epistemology for interdisciplinary research (IDR), in particular, IDR for solving 'real-world' problems. Focus is on the question why researchers experience cognitive and epistemic difficulties in conducting IDR. Based on a study of educational literature it is concluded that higher-education is missing clear ideas on the epistemology of IDR, and as a consequence, on how to teach it. It is conjectured that the lack of philosophical interest in the epistemology of IDR is due to a philosophical paradigm of science (called a physics paradigm of science), which prevents recognizing severe epistemological challenges of IDR, both in the philosophy of science as well as in science education and research. The proposed alternative philosophical paradigm (called an engineering paradigm of science) entails alternative philosophical presuppositions regarding aspects such as the aim of science, the character of knowledge, the epistemic and pragmatic criteria for accepting knowledge, and the role of technological instruments. This alternative philosophical paradigm assume the production of knowledge for epistemic functions as the aim of science, and interprets 'knowledge' (such as theories, models, laws, and concepts) as epistemic tools that must allow for conducting epistemic tasks by epistemic agents, rather than interpreting knowledge as representations that objectively represent aspects of the world independent of the way in which it was constructed. The engineering paradigm of science involves that knowledge is indelibly shaped by how it is constructed. Additionally, the way in which scientific disciplines (or fields) construct knowledge is guided by the specificities of the discipline, which can be analyzed in terms of disciplinary perspectives. This implies that knowledge and the epistemic uses of knowledge cannot be understood without at least some understanding of how the knowledge is constructed. Accordingly, scientific researchers need so-called metacognitive scaffolds to assist in analyzing and reconstructing how 'knowledge' is constructed and how different disciplines do this differently. In an engineering paradigm of science, these metacognitive scaffolds can also be interpreted as epistemic tools, but in this case as tools that guide, enable and constrain analyzing and articulating how knowledge is produced (i.e., explaining epistemological aspects of doing research). In interdisciplinary research, metacognitive scaffolds assist interdisciplinary communication aiming to analyze and articulate how the discipline constructs knowledge.

Interdisciplinary expertise in medical practice: Challenges of using and producing knowledge in complex problem-solving.

Purpose: Clarification of interdisciplinary expertise as the ability to deal with the cognitive and epistemological challenges of multi- and interdisciplinary problem-solving-such as in developing and implementing medical technology for diagnoses and treatment of patients in collaborations between clinicians, technicians, and engineers-and of the higher-order cognitive skills needed as part of this expertise. Method: Clarify the epistemological difficulties of combining scientific knowledge, methodologies and technologies from different disciplines in problem-solving, by drawing on recent developments in the philosophy of science. Conclusion: We argue that interdisciplinary expertise involves the cognitive ability to connect, translate and establish links between disciplinary knowledge, as well as the metacognitive ability to understand and explain the role of the disciplinary perspective-consisting of, e.g. basic concepts, theories, models, methodologies, technologies, and specific ways of measuring, reasoning and modeling in a discipline-in how knowledge is used and produced.

Mono, bi- and tri-exponential diffusion MRI modelling for renal solid masses and comparison with histopathological findings.

PURPOSE: To compare diffusion tensor imaging (DTI), intravoxel incoherent motion (IVIM), and tri-exponential models of the diffusion magnetic resonance imaging (MRI) signal for the characterization of renal lesions in relationship to histopathological findings. METHODS: Sixteen patients planned to undergo nephrectomy for kidney tumour were scanned before surgery at 3 T magnetic resonance imaging (MRI), with T2-weighted imaging, DTI and diffusion weighted imaging (DWI) using ten b-values. DTI parameters (mean diffusivity [MD] and fractional anisotropy [FA]) were obtained by iterative weighted linear least squared fitting of the DTI data and bi-, and tri-exponential fit parameters (Dbi, fstar,and Dtri, ffast,finterm) using a nonlinear fit of the multiple b-value DWI data. Average parameters were calculated for regions of interest, selecting the lesions and healthy kidney tissue. Tumour type and specificities were determined after surgery by histological examination. Mean parameter values of healthy tissue and solid lesions were compared using a Wilcoxon-signed ranked test and MANOVA. RESULTS: Thirteen solid lesions (nine clear cell carcinomas, two papillary renal cell carcinoma, one haemangioma and one oncocytoma) and four cysts were included. The mean MD of solid lesions are significantly (p < 0.05) lower than healthy cortex and medulla, (1.94 ± 0.32*10- 3 mm2/s versus 2.16 ± 0.12*10- 3 mm2/s and 2.21 ± 0.14*10- 3 mm2/s, respectively) whereas ffast is significantly higher (7.30 ± 3.29% versus 4.14 ± 1.92% and 4.57 ± 1.74%) and finterm is significantly lower (18.7 ± 5.02% versus 28.8 ± 5.09% and 26.4 ± 6.65%). Diffusion coefficients were high (≥2.0*10- 3 mm2/s for MD, 1.90*10- 3 mm2/s for Dbi and 1.6*10- 3 mm2/s for Dtri) in cc-RCCs with cystic structures and/or haemorrhaging and low (≤1.80*10- 3 mm2/s for MD, 1.40*10- 3 mm2/s for Dbi and 1.05*10- 3 mm2/s for Dtri) in tumours with necrosis or sarcomatoid differentiation. CONCLUSION: Parameters derived from a two- or three-component fit of the diffusion signal are sensitive to histopathological features of kidney lesions.

A social-technological epistemology of clinical decision-making as mediated by imaging.

In recent years there has been growing attention to the epistemology of clinical decision-making, but most studies have taken the individual physicians as the central object of analysis. In this paper we argue that knowing in current medical practice has an inherently social character and that imaging plays a mediating role in these practices. We have analyzed clinical decision-making within a medical expert team involved in diagnosis and treatment of patients with pulmonary hypertension (PH), a rare disease requiring multidisciplinary team involvement in diagnosis and management. Within our field study, we conducted observations, interviews, video tasks, and a panel discussion. Decision-making in the PH clinic involves combining evidence from heterogeneous sources into a cohesive framing of a patient, in which interpretations of the different sources can be made consistent with each other. Because pieces of evidence are generated by people with different expertise and interpretation and adjustments take place in interaction between different experts, we argue that this process is socially distributed. Multidisciplinary team meetings are an important place where information is shared, discussed, interpreted, and adjusted, allowing for a collective way of seeing and a shared language to be developed. We demonstrate this with an example of image processing in the PH service, an instance in which knowledge is distributed over multiple people who play a crucial role in generating an evaluation of right heart function. Finally, we argue that images fulfill a mediating role in distributed knowing in 3 ways: first, as enablers or tools in acquiring information; second, as communication facilitators; and third, as pervasively framing the epistemic domain. With this study of clinical decision-making in diagnosis and treatment of PH, we have shown that clinical decision-making is highly social and mediated by technologies. The epistemology of clinical decision-making needs to take social and technological mediation into account.

Intravoxel incoherent motion modeling in the kidneys: Comparison of mono-, bi-, and triexponential fit.

PURPOSE: To evaluate if a three-component model correctly describes the diffusion signal in the kidney and whether it can provide complementary anatomical or physiological information about the underlying tissue. MATERIALS AND METHODS: Ten healthy volunteers were examined at 3T, with T2 -weighted imaging, diffusion tensor imaging (DTI), and intravoxel incoherent motion (IVIM). Diffusion tensor parameters (mean diffusivity [MD] and fractional anisotropy [FA]) were obtained by iterative weighted linear least squares fitting of the DTI data and mono-, bi-, and triexponential fit parameters (D1 , D2 , D3 , ffast2 , ffast3 , and finterm ) using a nonlinear fit of the IVIM data. Average parameters were calculated for three regions of interest (ROIs) (cortex, medulla, and rest) and from fiber tractography. Goodness of fit was assessed with adjusted R2 ( Radj2) and the Shapiro-Wilk test was used to test residuals for normality. Maps of diffusion parameters were also visually compared. RESULTS: Fitting the diffusion signal was feasible for all models. The three-component model was best able to describe fast signal decay at low b values (b < 50), which was most apparent in Radj2 of the ROI containing high diffusion signals (ROIrest ), which was 0.42 ± 0.14, 0.61 ± 0.11, 0.77 ± 0.09, and 0.81 ± 0.08 for DTI, one-, two-, and three-component models, respectively, and in visual comparison of the fitted and measured S0 . None of the models showed significant differences (P > 0.05) between the diffusion constant of the medulla and cortex, whereas the ffast component of the two and three-component models were significantly different (P < 0.001). CONCLUSION: Triexponential fitting is feasible for the diffusion signal in the kidney, and provides additional information. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 1 J. MAGN. RESON. IMAGING 2017;46:228-239.

Navigation forces during wrist arthroscopy: assessment of expert levels.

PURPOSE: To facilitate effective and efficient training in skills laboratory, objective metrics can be used. Forces exerted on the tissues can be a measure of safe tissue manipulation. To provide feedback during training, expert threshold levels need to be determined. The purpose of this study was to define the magnitude and the direction of navigation forces used during arthroscopic inspection of the wrist. METHODS: We developed a set-up to mount a cadaver wrist to a 3D force platform that allowed measurement of the forces exerted on the wrist. Six experts in wrist arthroscopy performed two tasks: (1) Introduction of the camera and visualization of the hook. (2) Navigation through the wrist with visualization of five anatomic structures. The magnitude (Fabs) and direction of force were recorded, with the direction defined as α being the angle in the vertical plane and ß being the angle in the horizontal plane. The 10th-90th percentile of the data were used to set threshold levels for training. RESULTS: The results show distinct force patterns for each of the anatomic landmarks. Median Fabs of the navigation task is 3.8 N (1.8-7.3), α is 3.60 (-54-44) and ß is 260 (0-72). CONCLUSION: Unique expert data on navigation forces during wrist arthroscopy were determined. The defined maximum allowable navigation force of 7.3 N (90th percentile) can be used in providing feedback on performance during skills training. The clinical value is that this study contributes to objective assessment of skills levels.

An epistemological shift: from evidence-based medicine to epistemological responsibility.

In decision making concerning the diagnosis and treatment of patients, doctors have a responsibility to do this to the best of their abilities. Yet we argue that the current paradigm for best medical practice - evidence-based medicine (EBM) - does not always support this responsibility. EBM was developed to promote a more scientific approach to the practice of medicine. This includes the use of randomized controlled trials in the testing of new treatments and prophylactics and rule-based reasoning in clinical decision making. But critics of EBM claim that such a scientific approach does not always work in the clinic. In this article, we build on this critique and argue that rule-based reasoning and the use of general guidelines as promoted by EBM does not accommodate the complex reasoning of doctors in clinical decision making. Instead, we propose that a new medical epistemology is needed that accounts for complex reasoning styles in medical practice and at the same time maintains the quality usually associated with 'scientific'. The medical epistemology we propose conforms to the epistemological responsibility of doctors, which involves a specific professional attitude and epistemological skills. Instead of deferring part of the professional responsibility to strict clinical guidelines, as EBM allows for, our alternative epistemology holds doctors accountable for epistemic considerations in clinical decision making towards the diagnosis and treatment plan of individual patients. One of the key intellectual challenges of doctors is the ability to bring together heterogeneous pieces of information to construct a coherent 'picture' of a specific patient. In the proposed epistemology, we consider this 'picture' as an epistemological tool that may then be employed in the diagnosis and treatment of a specific patient.

The use of navigation forces for assessment of wrist arthroscopy skills level.

Purpose To provide an efficient learning process, feedback on performance is crucial. In skills laboratories, it is possible to measure the skills and progression of skills of the trainees objectively. This requires metrics that represent the learning curve of the trainee, which were investigated for wrist arthroscopy. The research questions were: What are the forces used by novices during wrist arthroscopy?What aspects of these navigation forces are discriminative for the wrist arthroscopy skills level?Methods A cadaver wrist was mounted in a custom-made distraction device mounted in front of a force platform (ForceTrap). Eleven novices were invited to perform two tasks on the wrist: Insertion of the scope through the 3-4 portal and the hook through the 6R portal, and visualization of the hook in the center of the imageNavigation through the wrist from radial to ulnar with probing and visualization of five predefined landmarksThe second task was repeated 10 times. The absolute force (F abs) and the direction of force were measured. The angle α is defined in the vertical plane, and the angle ß in the horizontal plane. Results The median F abs used by novices remained below the force threshold as defined from the expert data (7.3 N). However, the direction of the applied forces by novices in both planes was not consistent with expert data and showed a wider range. Also, there was no improvement after more trials. Conclusion Our study suggests by the absence of a learning curve for the novices and a significant difference between novices and experts that novices can benefit from feedback on the magnitude and direction of forces to improve their performance.