Defining disease severity in atopic dermatitis and psoriasis for the application to biomarker research: an interdisciplinary perspective.

More severe atopic dermatitis and psoriasis are associated with a higher cumulative impact on quality of life, multimorbidity and healthcare costs. Proactive, early intervention in those most at risk of severe disease may reduce this cumulative burden and modify the disease trajectory to limit progression. The lack of reliable biomarkers for this at-risk group represents a barrier to such a paradigm shift in practice. To expedite discovery and validation, the BIOMarkers in Atopic Dermatitis and Psoriasis (BIOMAP) consortium (a large-scale European, interdisciplinary research initiative) has curated clinical and molecular data across diverse study designs and sources including cross-sectional and cohort studies (small-scale studies through to large multicentre registries), clinical trials, electronic health records and large-scale population-based biobanks. We map all dataset disease severity instruments and measures to three key domains (symptoms, inflammatory activity and disease course), and describe important codependencies and relationships across variables and domains. We prioritize definitions for more severe disease with reference to international consensus, reference standards and/or expert opinion. Key factors to consider when analysing datasets across these diverse study types include explicit early consideration of biomarker purpose and clinical context, candidate biomarkers associated with disease severity at a particular point in time and over time and how they are related, taking the stage of biomarker development into account when selecting disease severity measures for analyses, and validating biomarker associations with disease severity outcomes using both physician- and patient-reported measures and across domains. The outputs from this exercise will ensure coherence and focus across the BIOMAP consortium so that mechanistic insights and biomarkers are clinically relevant, patient-centric and more generalizable to current and future research efforts.

Atopic dermatitis (AD), and psoriasis are long-term skin conditions that can significantly affect people's lives, especially when symptoms are severe. Approximately 10% of adults and 20% of children are affected by AD, while psoriasis affects around 5% of people in the UK. Both conditions are associated with debilitating physical symptoms (such as itch) and have been linked to depression and anxiety. Biomarkers are naturally occurring chemicals in the human body and have potential to enhance the longer-term management of AD and psoriasis. Currently, there are no routinely used biomarkers that can identify people who experience or will go on to develop severe AD and psoriasis. For this reason, research is under way to understand which biomarkers are linked to severity. In this study, a multidisciplinary team of skin researchers from across Europe, along with patient groups, discussed the complexities of studying severity-related biomarkers. We identified a number of severity measurement approaches and there were recommendations for future biomarker research, including (i) considering multiple measures as no single measure can encompass all aspects of severity, (ii) exploring severity measures recorded by both healthcare professionals and patients, as each may capture different aspects, and (iii) accounting for influencing factors, such as different treatment approaches, that may impact AD and psoriasis severity, which make it challenging to compare findings across studies. Overall, we anticipate that the insights gained from these discussions will increase the likelihood of biomarkers being effectively applied in real-world settings, to ultimately improve outcomes for people with AD and psoriasis.

Ethical layering in AI-driven polygenic risk scores-New complexities, new challenges.

Researchers aim to develop polygenic risk scores as a tool to prevent and more effectively treat serious diseases, disorders and conditions such as breast cancer, type 2 diabetes mellitus and coronary heart disease. Recently, machine learning techniques, in particular deep neural networks, have been increasingly developed to create polygenic risk scores using electronic health records as well as genomic and other health data. While the use of artificial intelligence for polygenic risk scores may enable greater accuracy, performance and prediction, it also presents a range of increasingly complex ethical challenges. The ethical and social issues of many polygenic risk score applications in medicine have been widely discussed. However, in the literature and in practice, the ethical implications of their confluence with the use of artificial intelligence have not yet been sufficiently considered. Based on a comprehensive review of the existing literature, we argue that this stands in need of urgent consideration for research and subsequent translation into the clinical setting. Considering the many ethical layers involved, we will first give a brief overview of the development of artificial intelligence-driven polygenic risk scores, associated ethical and social implications, challenges in artificial intelligence ethics, and finally, explore potential complexities of polygenic risk scores driven by artificial intelligence. We point out emerging complexity regarding fairness, challenges in building trust, explaining and understanding artificial intelligence and polygenic risk scores as well as regulatory uncertainties and further challenges. We strongly advocate taking a proactive approach to embedding ethics in research and implementation processes for polygenic risk scores driven by artificial intelligence.

Clinical Priority Setting and Decision-Making in Sweden: A Cross-sectional Survey Among Physicians.

BACKGROUND: Priority setting in healthcare that aims to achieve a fair and efficient allocation of limited resources is a worldwide challenge. Sweden has developed a sophisticated approach. Still, there is a need for a more detailed insight on how measures permeate clinical life. This study aimed to assess physicians' views regarding (1) impact of scarce resources on patient care, (2) clinical decision-making, and (3) the ethical platform and national guidelines for healthcare by the National Board of Health and Welfare (NBHW). METHODS: An online cross-sectional questionnaire was sent to two groups in Sweden, 2016 and 2017. Group 1 represented 331 physicians from different departments at one University hospital and group 2 consisted of 923 members of the Society of Cardiology. RESULTS: Overall, a 26% (328/1254) response rate was achieved, 49% in group 1 (162/331), 18% in group 2 (166/923). Scarcity of resources was perceived by 59% more often than 'at least once per month,' whilst 60% felt less than 'well-prepared' to address this issue. Guidelines in general had a lot of influence and 19% perceived them as limiting decision-making. 86% professed to be mostly independent in decision-making. 36% knew the ethical platform 'well' and 'very well' and 64% NBHW's national guidelines. 57% expressed a wish for further knowledge and training regarding the ethical platform and 51% for support in applying NBHW's national guidelines. CONCLUSION: There was a need for more support to deal with scarcity of resources and for increased knowledge about the ethical platform and NBHW's national guidelines. Independence in clinical decision-making was perceived as high and guidelines in general as important. Priority setting as one potential pathway to fair and transparent decision-making should be highlighted more in Swedish clinical settings, with special emphasis on the ethical platform.

Rescue of STAT3 Function in Hyper-IgE Syndrome Using Adenine Base Editing.

STAT3-hyper IgE syndrome (STAT3-HIES) is a primary immunodeficiency presenting with destructive lung disease along with other symptoms. CRISPR-Cas9-mediated adenine base editors (ABEs) have the potential to correct one of the most common STAT3-HIES causing heterozygous STAT3 mutations (c.1144C>T/p.R382W). As a proof-of-concept, we successfully applied ABEs to correct STAT3 p.R382W in patient fibroblasts and induced pluripotent stem cells (iPSCs). Treated primary STAT3-HIES patient fibroblasts showed a correction efficiency of 29% ± 7% without detectable off-target effects evaluated through whole-genome and high-throughput sequencing. Compared with untreated patient fibroblasts, corrected single-cell clones showed functional rescue of STAT3 signaling with significantly increased STAT3 DNA-binding activity and target gene expression of CCL2 and SOCS3. Patient-derived iPSCs were corrected with an efficiency of 30% ± 6% and differentiated to alveolar organoids showing preserved plasticity in treated cells. In conclusion, our results are supportive for ABE-based gene correction as a potential causative treatment of STAT3-HIES.

[Ethical issues raised by direct-to-consumer personal genome analysis and whole body scans: discussion and contextualisation of a report by the Nuffield Council on Bioethics]. / Zur Ethik einer Vorsorge durch (direct-to-consumer) individuelle Genanalysen und Ganzkörper-MRTs. Erläuterung und Diskussion der Empfehlungen des Nuffield Council on Bioethics.

The paradigm of personalised medicine has many different facets, further to the application of pharmacogenetics. We examine here (direct-to-consumer) personal genome analysis and whole body scans and summarise findings from the Nuffield Council's on Bioethics recent report "Medical profiling and online medicine: the ethics of 'personalised healthcare' in a consumer age". We describe the current situation in Germany with regard to access to such services, and contextualise the Nuffield Council's report with summaries of position statements by German professional bodies. We conclude with three points that merit examination further to the analyses of the Nuffield Council's report and the German professional bodies. These concern the role of indirect evidence in considering restrictive policies, the question of whether regulations should require commercial providers to contribute to the generation of better evidence, and the option of using data from evaluations in combination with indirect evidence in justifying restrictive policies.

Blood Donation, Payment, and Non-Cash Incentives: Classical Questions Drawing Renewed Interest.

Blood is scarce, and ensuring a sufficient blood supply remains difficult for many countries. Payment for blood as a strategy to increase donations has remained highly controversial for decades, and the debate about ethical issues in paying donors has become somewhat stuck. At least from a policy perspective, it is important to find a compromise which allows for devising and implementing acceptable and successful policies to increase the blood supply. In this paper, such a compromise is developed both from a theoretical and empirical perspective, namely implementing well-designed non-cash incentives which cut across the rigid dichotomy of altruistic donations versus payment for donations. In order for this compromise to work, more attention to donation motives, the choice architecture, and the setting in blood donation needs to be paid.

Challenges of educating for medical professionalism: who should step up to the line?

CONTEXT: The teaching of professionalism has recently become an important issue in medical education. Medical professionalism remains controversial, but several recently published institutional documents on professionalism seem to express an implicit, yet broad consensus on three points: that professionalism mainly consists of adherence to a specific set of professional attributes constitutive of medical role morality and readily identifiable as virtues of medical professionalism (VMP); that medical education needs to focus on the endowment of these attributes, and that medical ethicists should play a central role in assuming this educational responsibility. METHODS: This paper examines the assumption that the task of supporting the development of the VMP should primarily fall to medical ethicists. Considerations in favour of this position are weighted against a set of countervailing considerations. The latter include the charge that the VMP are too vague as educational guidelines, that they may not be teachable, and that the responsibility for their development must be shared across the medical faculty. CONCLUSIONS: Medical ethics educators are right to embrace the professionalism agenda on four conditions: that the limitations of addressing the formation of professional attributes in university-based teaching are recognised; that there is clinical as well as university-based evaluation of professional attributes; that the development of the VMP as a process of professional socialisation is seen as an interdisciplinary educational project, and that the examination and explanation of the cognitive grounds of the VMP are the focus of medical educators' activities.

[Medical ethics teaching]. / Medizinethik als Unterrichtsfach : Lernziele und Evaluation.

In most European countries, medical ethics has become a more or less established subject in medical school curricula. Accordingly, the need to evaluate its success has arisen. In our paper, we describe the controversial debate about the proper goals of teaching medical ethics. Secondly, we present an overview of current efforts to measure and evaluate the outcome and effect of different medical ethics teaching programmes on medical students and young physicians. We conclude that medical ethics teaching is amenable to a great variety of teaching and evaluation methods. Finally, we argue that medical ethics teaching should include: (1) the teaching of moral reasoning skills, (2) the instruction about relevant ethical knowledge, as well as (3) the development of certain character traits. Methods to evaluate ethical knowledge and moral reasoning skills are readily available, while the evaluation of the development of character traits poses important conceptual difficulties.

Be careful what you wish for? Theoretical and ethical aspects of wish-fulfilling medicine.

There is a growing tendency for medicine to be used not to prevent or heal illnesses, but to fulfil individual personal wishes such as wishes for enhanced work performance, better social skills, children with specific characteristics, stress relief, a certain appearance or a better sex life. While recognizing that the subject of wish-fulfilling medicine may vary greatly and that it may employ very different techniques, this article argues that wish-fulfilling medicine can be described as a cohesive phenomenon with distinctive features. Following a few examples of well established wish-fulfilling medical practices and a brief definition of the phenomenon, both theoretical aspects and ethical implications of such practices are discussed and the question is raised how wish-fulfilling medicine should be evaluated from an ethical point of view. It is concluded that modern medicine is currently ill equipped to provide reasons why wish-fulfilling medicine should be banned or discouraged. The phenomenon of wish-fulfilling medicine serves as a prime example of the vagueness of the descriptive and the lack of decisive orientation of the normative categories employed in modern medicine.