[Ethics of (big) data applications in psychiatric practice]. / Ethiek van (big)datatoepassingen in de psychiatrische praktijk.

BACKGROUND: Due to rapid digitalization, an increasing amount of data is available in healthcare settings; big data and artificial intelligence (AI) have also made their appearance. AIM: To provide insight into various ethical dilemmas that need to be considered when applying big data in clinical practice. METHOD: Description and analyses of the ethical aspects associated with the use of clinical data in the context of psychiatric care. RESULTS: Various ethical aspects play a role in four phases; data collection, analysis, dissemination and application of results. In order to use clinical data and AI in a responsible manner, these aspects must be taken into account. CONCLUSION: The use of big data and AI in healthcare should aim to stimulate learning and improving care together with patients and professionals. Big data and AI should not be seen as the holy grail, but as a supporting tool in healthcare - a field in which many of the aspects that play a role in clinical care cannot be converted into measurable data.

Responsible data sharing in a big data-driven translational research platform: lessons learned.

BACKGROUND: To foster responsible data sharing in health research, ethical governance complementary to the EU General Data Protection Regulation is necessary. A governance framework for Big Data-driven research platforms will at least need to consider the conditions as specified a priori for individual datasets. We aim to identify and analyze these conditions for the Innovative Medicines Initiative's (IMI) BigData@Heart platform. METHODS: We performed a unique descriptive case study into the conditions for data sharing as specified for datasets participating in BigData@Heart. Principle investigators of 56 participating databases were contacted via e-mail with the request to send any kind of documentation that possibly specified the conditions for data sharing. Documents were qualitatively reviewed for conditions pertaining to data sharing and data access. RESULTS: Qualitative content analysis of 55 relevant documents revealed overlap on the conditions: (1) only to share health data for scientific research, (2) in anonymized/coded form, (3) after approval from a designated review committee, and while (4) observing all appropriate measures for data security and in compliance with the applicable laws and regulations. CONCLUSIONS: Despite considerable overlap, prespecified conditions give rise to challenges for data sharing. At the same time, these challenges inform our thinking about the design of an ethical governance framework for data sharing platforms. We urge current data sharing initiatives to concentrate on: (1) the scope of the research questions that may be addressed, (2) how to deal with varying levels of de-identification, (3) determining when and how review committees should come into play, (4) align what policies and regulations mean by "data sharing" and (5) how to deal with datasets that have no system in place for data sharing.

Narrative medicine as a medical education tool: A systematic review.

Aim: Narrative medicine has been promoted as an innovative and effective means of stimulating medical students' professional development by teaching them to approach their patients' experiences of illness with more understanding and compassion. This systematic literature review aims to answer the following question: what evidence of effect is available in the literature about models for teaching narrative medicine? Methods: We conducted a narrative review of 36 articles and used the Best Evidence in Medical Education (BEME) Global Scale and Kirkpatrick Scale for strength and importance of evidence to categorize reported assessment strategies and to evaluate the effectiveness of their narrative medicine programs. Results: We found evidence that narrative medicine is an effective pedagogic tool with a clear and replicable structure and methodology. We also determined that a positive impact could be measured when pertaining to participation and modification of attitudes, knowledge, and skills. However, unequivocal evidence of the effect of narrative medicine on students' behavior or ongoing interaction with colleagues and patients is still lacking. Conclusion: While many recent publications describe the goals and virtues of a narrative-based approach, more research is needed to determine whether or not there is an ideological consensus undergirding this approach. In addition, it is still unclear whether the long-term impact of narrative medicine classroom interventions are felt by patients, or whether such interventions positively impact patient care.

Directional K+ channel insertion in a single phospholipid bilayer: Neutron reflectometry and electrophysiology in the joint exploration of a model membrane functional platform.

We investigated the insertion of small potassium (K+) channel proteins (KcvMA-1D and KcvNTS) into model membranes and the lipid-protein structural interference, combining neutron reflectometry and electrophysiology. Neutron reflectometry experiments showed how the transverse structure and mechanical properties of the bilayer were modified, upon insertion of the proteins in single model-membranes, either supported on solid substrate or floating. Parallel electrophysiology experiments were performed on the same channels reconstituted in free-standing planar lipid bilayers, of both typical composition and matched to the neutron reflectometry experiment, assessing their electrical features. Functional and structural results converge in detecting that the proteins, conical in shape, insert with a directionality, cytosolic side first. Our work addresses the powerful combination of the two experimental approaches. We show here that membrane structure spectroscopy and ion channel electrophysiology can become synergistic tools in the analysis of structural-functional properties of biomimetic complex environment.

Tectonics of a K⁺ channel: The importance of the N-terminus for channel gating.

The small K⁺ channel Kcv represents the pore module of complex potassium channels. It was found that its gating can be modified by sensor domains, which are N-terminally coupled to the pore. This implies that the short N-terminus of the channel can transmit conformational changes from upstream sensors to the channel gates. To understand the functional role of the N-terminus in the context of the entire channel protein, we apply combinatorial screening of the mechanical coupling and long-range interactions in the Kcv potassium channel by reduced molecular models. The dynamics and mechanical connections in the channel complex show that the N-terminus is indeed mechanically connected to the pore domain. This includes a long rang coupling to the pore and the inner and outer transmembrane domains. Since the latter domains host the two gates of the channel, the data support the hypothesis that mechanical perturbation of the N-terminus can be transmitted to the channel gates. This effect is solely determined by the topology of the channel; sequence details only have an implicit effect on the coarse-grained dynamics via the fold and not through biochemical details at a smaller scale. This observation has important implications for engineering of synthetic channels on the basis of a K⁺ channel pore.

Phospholamban spontaneously reconstitutes into giant unilamellar vesicles where it generates a cation selective channel.

Phospholamban (PLN) is a small integral membrane protein, which modulates the activity of the Sarcoplasmic Reticulum Ca(2+)-ATPase (SERCA) of cardiac myocytes. PLN, as a monomer, can directly interact and tune SERCA activity, but the physiological function of the pentameric form is not yet fully understood and still debated. In this work, we reconstituted PLN in Giant Unilamellar Vesicles (GUVs), a simple and reliable experimental model system to monitor the activity of proteins in membranes. By Laser Scanning Confocal Microscopy (LSCM) and Fluorescence Correlation Spectroscopy (FCS) we verified a spontaneous reconstitution of PLN into the phospholipid bilayer. In parallel experiments, we measured with the patch clamp technique canonical ion channel fluctuations, which highlight a preference for Cs(+) over K(+) and do not conduct Ca(2+). The results prove that PLN forms, presumably in its pentameric form, a cation selective ion channel.

Thymic-thoracic ratio in fetuses with trisomy 21, 18 or 13.

OBJECTIVES: To assess thymic size expressed as the thymic-thoracic ratio (TT-ratio) in fetuses with trisomy 21, 18 or 13. METHODS: The TT-ratio, the quotient of the anteroposterior thymic and the intrathoracic mediastinal diameter, was measured in 65 trisomic fetuses between 15 and 36 weeks' gestation, including 30 cases with trisomy 21, 19 with trisomy 18 and 16 with trisomy 13. In addition these 65 fetuses were divided into two groups, according to whether they showed growth that was appropriate-for-gestational age (AGA) (n = 39) or intrauterine growth restriction (IUGR) (n = 26). Measurements were compared with reference ranges from 302 normal fetuses. RESULTS: The TT-ratio was low in 27.7% (n = 18) of the 65 fetuses with aneuploidy. In comparison to normal fetuses (mean TT-ratio, 0.44), those with trisomy 18 or 21 had a significantly smaller TT-ratio (mean, 0.38 (P < 0.001) and 0.40 (P < 0.05), respectively), while those with trisomy 13 did not (mean, 0.43). These values were not as low as those observed previously in fetuses with del.22q11, suggesting a mechanism involving accelerated thymic involution rather than primary thymic hypoplasia. Furthermore, the TT-ratio was significantly lower than normal in both AGA (P < 0.05) and IUGR (P < 0.001) fetuses. CONCLUSION: Fetuses with trisomy 18 or 21, but not trisomy 13, have a small thymus, suggesting accelerated thymic involution in utero. IUGR may contribute to the reduced thymic size in trisomy 18 fetuses. Trisomy 21 fetuses seem to have additional factors leading to a small thymus which could be a possible confirmation of the reduced immune response observed in fetuses and neonates with Down syndrome.

The thymic-thoracic ratio in fetal heart defects: a simple way to identify fetuses at high risk for microdeletion 22q11.

OBJECTIVES: To establish reference ranges for the fetal thymic-thoracic ratio (TT-ratio) and to compare results with those from fetuses with congenital heart defects (CHD) with and without microdeletion 22q11 (del.22q11), a condition known to be associated with a hypoplastic thymus. METHODS: TT-ratio was defined as the quotient of the anteroposterior thymic to the intrathoracic mediastinal diameters measured in the three vessels and trachea view. This ratio was measured in a prospective cross-sectional study of 302 normal healthy fetuses between 15 and 39 weeks' gestation. The study group comprised two groups: one group (CHDn) consisted of 90 fetuses with CHD and a normal karyotype with no del.22q11 and the other group (CHD(22)) included 20 fetuses with CHD and a normal karyotype but with proven del.22q11. RESULTS: The TT-ratio of the normal fetuses did not show any statistically significant change during gestation, with a mean value of 0.44. The values of all 90 fetuses of the CHDn group were within the normal range and no different from normal fetuses. However, 19 of the 20 (95%) fetuses in the CHD(22) group had a significantly smaller TT-ratio (P < 0.001) compared with both the CHDn group and the normal fetuses, having a mean value of 0.25. CONCLUSIONS: The TT-ratio is reliable and easy to obtain during fetal echocardiography. Fetuses with CHD and a low TT-ratio can be considered at high risk of having microdeletion del.22q11.

Identification of a protein that binds to the SH3 region of Abl and is similar to Bcr and GAP-rho.

A Src homology 3 (SH3) region is a sequence of approximately 50 amino acids found in many nonreceptor tyrosine kinases and other proteins. Deletion of the SH3 region from the protein encoded by the c-abl proto-oncogene activates the protein's transforming capacity, thereby suggesting the participation of the SH3 region in the negative regulation of transformation. A complementary DNA was isolated that encoded a protein, 3BP-1, to which the SH3 region of Abl bound with high specificity and to which SH3 regions from other proteins bound differentially. The sequence of the 3BP-1 protein is similar to that of a COOH-terminal segment of Bcr and to guanosine triphosphatase-activating protein (GAP)-rho, which suggests that it might have GAP activity for Ras-related proteins. The 3BP-1 protein may therefore be a mediator of SH3 function in transformation inhibition and may link tyrosine kinases to Ras-related proteins.

A potassium channel protein encoded by chlorella virus PBCV-1.

The large chlorella virus PBCV-1, which contains double-stranded DNA (dsDNA), encodes a 94-codon open reading frame (ORF) that contains a motif resembling the signature sequence of the pore domain of potassium channel proteins. Phylogenetic analyses of the encoded protein, Kcv, indicate a previously unidentified type of potassium channel. The messenger RNA encoded by the ORF leads to functional expression of a potassium-selective conductance in Xenopus laevis oocytes. The channel blockers amantadine and barium, but not cesium, inhibit this conductance, in addition to virus plaque formation. Thus, PBCV-1 encodes the first known viral protein that functions as a potassium-selective channel and is essential in the virus life cycle.

Intracellular localisation of PPI1 (proton pump interactor, isoform 1), a regulatory protein of the plasma membrane H(+)-ATPase of Arabidopsis thaliana.

PPI1 (proton pump interactor isoform 1) is a novel protein able to interact with the C-terminal autoinhibitory domain of the Arabidopsis thaliana plasma membrane (PM) H(+)-ATPase. In vitro, PPI1 binds the PM H(+)-ATPase in a site different from the known 14-3-3 binding site and stimulates its activity. In this study, we analysed the intracellular localisation of PPI1. The intracellular distribution was monitored in A. thaliana cultured cells by immunolocalisation using an antiserum against the PPI1 N-terminus and in Vicia faba guard cells and epidermal cells by transient expression of a GFP::PPI1 fusion. The results indicate that the bulk of PPI1 is localised at the endoplasmic reticulum, from which it might be recruited to the PM for interaction with the H(+)-ATPase in response to as yet unidentified signals.

The justificatory power of moral experience.

A recurrent issue in the vast amount of literature on reasoning models in ethics is the role and nature of moral intuitions. In this paper, we start from the view that people who work and live in a certain moral practice usually possess specific moral wisdom. If we manage to incorporate their moral intuitions in ethical reasoning, we can arrive at judgements and (modest) theories that grasp a moral experience that generally cannot be found outside the practice. Reflective equilibrium (RE) provides a framework for balancing moral intuitions, ethical principles and general theories. Nevertheless, persisting problems associated with the use of intuitions need to be addressed. One is the objection that moral intuitions lack the credibility necessary to guide moral reasoning. Ethicists have tried to solve this problem by formulating criteria to separate the "bad" intuitions from the "good" ones at the beginning of the reasoning process. We call this the credible input-justified outcome strategy. An example is the appeal to the common morality by Beauchamp and Childress. We think this approach is unsuccessful. As an alternative, we outline the good reasoning-justified outcome strategy. It connects to a variant of RE in which intuitions from different sources are incorporated. We argue that the elements of RE have different levels of justificatory power at the start of reasoning. In our strategy, each element can gain or lose justificatory power when it is tested in a reasoning process that meets several criteria.

Ethics in clinical trial regulation: ethically relevant issues from EMA inspection reports.

BACKGROUND: Within the EU, regulators are obliged to take ethical issues into consideration during marketing authorization deliberation. The goal of this manuscript is to identify what kinds of ethical issues regulators encounter during marketing authorization application deliberations, and the incidence of these ethical issues. METHODS: This study used an EMA-provided Excel file that contains all the GCP non-compliance findings from all inspection reports from 2008-2012. There were 112 medicinal products and a total of 288 clinical trial sites. There were a total of 4014 GCP non-compliance findings. The findings that were ethically relevant were extracted using NVivo 10.0 and categories for the ethically relevant findings (ERFs) were created. Note was taken of the incidence of ERFs for each category and the inspectors' gradings of these findings were extracted. This study also looked at the mean and the maximum number of ERFs per grading per medicinal product application, as well as the number of medicinal products with at least one ERF and those with at least major ERFs. RESULTS: With multiple coding, there were 1685 ERFs. ERFs were present in almost all of the medicinal products (97.3%). The majority of ERFs were graded as major. At least major ERFs were present in almost all medicinal products with ERFs. The categories with the highest number of ERFs were protocol issues, patient safety, and professionalism issues. In terms of the density of combined critical and major findings, monitoring and oversight, protocol issues, and respect for persons top the list. This study also showed that, on average, there were 7.54 major and 2.95 critical ERFs per medicinal product application, although ERFs can increase to 30 major and 12 critical. CONCLUSION: Regulators regularly encounter ERFs that at least "might adversely affect the rights, safety or well-being of the subjects". It remains to be explored how regulators respond to these ethical issues.

A comprehensive genetic and histopathologic analysis identifies two subgroups of B-cell malignancies carrying a t(14;19)(q32;q13) or variant BCL3-translocation.

The biologic and pathologic features of B-cell malignancies bearing a translocation t(14;19)(q32;q13) leading to a fusion of IGH and BCL3 are still poorly described. Herein we report the results of a comprehensive cytogenetic, fluorescence in situ hybridization (FISH), molecular and histopathological survey of a large series of B-cell malignancies with t(14;19) or variant translocations. A total of 56 B-cell malignancies with a FISH-proven BCL3 involvement were identified with the translocation partners being IGH (n=51), IGL (n=2), IGK (n=2) and a non-IG locus (n=1). Hierarchical clustering of chromosomal changes associated with the t(14;19) indicated the presence of two different groups of IG/BCL3-positive lymphatic neoplasias. The first group included 26 B-cell malignancies of various histologic subtypes containing a relatively high number of chromosomal changes and mostly mutated IgVH genes. This cluster displayed three cytogenetic branches, one with rearrangements in 7q, another with deletions in 17p and a third one with rearrangements in 1q and deletions in 6q and 13q. The second group included 19 cases, mostly diagnosed as B-cell chronic lymphocytic leukemia (B-CLL), and characterized by few additional chromosomal changes (e.g. trisomy 12) and unmutated IgVH genes. In conclusion, our study indicates that BCL3 translocations are not restricted to B-CLL but present in a heterogeneous group of B-cell malignancies.

14-3-3 proteins regulate the potassium channel KAT1 by dual modes.

KAT1 is a cloned plant potassium channel belonging to the superfamily of Shaker-like Kv channels. Previous studies have shown that 14-3-3 proteins significantly increase KAT1 current by modifying the channel open probability. Employing a 14-3-3 scavenger construct to lower the long-term availability of endogenous 14-3-3 proteins, we found that 14-3-3 proteins not only control the voltage dependency of the channel but also the number of channels in the plasma membrane.

Site-specific ion occupation in the selectivity filter causes voltage-dependent gating in a viral K+ channel.

Many potassium channels show voltage-dependent gating without a dedicated voltage sensor domain. This is not fully understood yet, but often explained by voltage-induced changes of ion occupation in the five distinct K+ binding sites in the selectivity filter. To better understand this mechanism of filter gating we measured the single-channel current and the rate constant of sub-millisecond channel closure of the viral K+ channel KcvNTS for a wide range of voltages and symmetric and asymmetric K+ concentrations in planar lipid membranes. A model-based analysis employed a global fit of all experimental data, i.e., using a common set of parameters for current and channel closure under all conditions. Three different established models of ion permeation and various relationships between ion occupation and gating were tested. Only one of the models described the data adequately. It revealed that the most extracellular binding site (S0) in the selectivity filter functions as the voltage sensor for the rate constant of channel closure. The ion occupation outside of S0 modulates its dependence on K+ concentration. The analysis uncovers an important role of changes in protein flexibility in mediating the effect from the sensor to the gate.