Ethics in medicine: Challenges in the 21st century

The article provides an overview of important topics in contemporary medical ethics. Methodologically, it is a literature review. The article addresses only a limited selection of the problematic areas, which are, however, related to each other: digitisation of medicine, genome editing, personalised medicine as well as ethical problems and dilemmas of allocation in healthcare. The global COVID-19 pandemic has emerged as a focus and trigger. Reflections on human rights and justice in medicine are fundamental not only on the individual and social level but also on a global scale. The fundamental question is how society as a whole can be involved in the complex biopolitical and bioethical debate. The social and cultural consequences of life increasingly being understood as a technical product rather than a gift are serious. Contribution: The article also reflects on the specific contribution that Christian theology, and in particular the reformed heritage, can make to bioethical debates in modern society. The distinction between instrumental knowledge [ Verfügungswissen ] and orientational knowledge [ Orientierungswissen ] is helpful for its better understanding. A crucial result of this article is that medical treatment is repeatedly faced with ethical dilemmas. Moreover, medical progress not only creates new and better solutions to medical problems, it also raises new ethical questions that did not exist before. The purpose of medical ethics lies in identifying such dilemmas and developing ethical decision-making processes that help us to deal with such dilemmas to some extent.

Microbiome in the Framework of Predictive, Preventive and Personalised Medicine

The human body is inhabited by trillions of diverse microorganisms collectively called "microbiome" or "microbiota". Microbiota consists of bacteria, viruses, fungi, protozoa, and archaea. Microbiome demonstrates multi-faceted effects on human physical and mental health. Per evidence there is a multi-functional interplay between the whole-body microbiome composition on the epithelial surfaces including skin, nasal and oral cavities, airway, gastro-intestinal and urogenital tracts on one hand and on the other hand, the individual health status. Microbiota composition as well as an option to modulate it - together create a highly attractive operation area for the translational bio/medical research with multi-professional expertise and healthcare-relevant output in the framework of predictive, preventive and personalised medicine (PPPM/3 PM). Advanced PPPM strategies implemented in the microbiome area are expected to significantly improve individual outcomes and overall cost-efficacy of healthcare. According to the accumulated research data, corresponding diagnostic and treatment approaches are applicable to primary care (health risk assessment in individuals with sub-optimal health conditions and prevention of a disease development), secondary care (personalised treatment of clinically manifested disorders preventing a disease progression) and tertiary care (making palliation to an optimal management of non-curable diseases). In the current book, we do highlight the implementation potential of the microbiome-relevant research in the framework of predictive diagnostics, targeted prevention and treatments tailored to the individualised patient profile.Copyright © 2023, The Author(s), under exclusive license to Springer Nature Switzerland AG.

‘The plural of silo is not ecosystem': Qualitative study on the role of innovation ecosystems in supporting ‘Internet of Things' applications in health and care

Background: Internet of Things (IoT) innovations such as wearables and sensors promise improved health outcomes and service efficiencies. Yet, most applications remain experimental with little routine use in health and care settings. We sought to examine the multiple interacting influences on IoT implementation, spread and scale-up, including the role of regional innovation ‘ecosystems' and the impact of the COVID-19 context. Methods: Qualitative study involving 20 participants with clinical, entrepreneurial and broader innovation experience in 18 in-depth interviews, focusing primarily on heart monitoring and assistive technology applications. Data analysis was informed by the NASSS (non-adoption, abandonment, scale-up, spread, sustainability) framework. Results: Interviewees discussed multiple tensions and trade-offs, including lack of organisational capacity for routine IoT use, limited ability to receive and interpret data, complex procurement and governance processes, and risk of health disparities and inequalities without system support and funding. Although the pandemic highlighted opportunities for IoT use, it was unclear whether these would be sustained, with framings of innovation as ‘disruption' coming at odds with immediate needs in healthcare settings. Even in an ‘ecosystem' with strong presence of academic and research institutions, support was viewed as limited, with impressions of siloed working, conflicting agendas, fragmentation and lack of collaboration opportunities. Conclusions: IoT development, implementation and roll-out require support from multiple ecosystem actors to be able to articulate a value proposition beyond experimental or small-scale applications. In contexts where clinical, academic and commercial worlds collide, sustained effort is needed to align needs, priorities and motives, and to strengthen potential for good value IoT innovation. © The Author(s) 2023.

A multicentre, patient- and assessor-blinded, non-inferiority, randomised and controlled phase II trial to compare standard and torque teno virus-guided immunosuppression in kidney transplant recipients in the first year after transplantation: TTVguideIT.

BACKGROUND: Immunosuppression after kidney transplantation is mainly guided via plasma tacrolimus trough level, which cannot sufficiently predict allograft rejection and infection. The plasma load of the non-pathogenic and highly prevalent torque teno virus (TTV) is associated with the immunosuppression of its host. Non-interventional studies suggest the use of TTV load to predict allograft rejection and infection. The primary objective of the current trial is to demonstrate the safety, tolerability and preliminary efficacy of TTV-guided immunosuppression. METHODS: For this purpose, a randomised, controlled, interventional, two-arm, non-inferiority, patient- and assessor-blinded, investigator-driven phase II trial was designed. A total of 260 stable, low-immunological-risk adult recipients of a kidney graft with tacrolimus-based immunosuppression and TTV infection after month 3 post-transplantation will be recruited in 13 academic centres in six European countries. Subjects will be randomised in a 1:1 ratio (allocation concealment) to receive tacrolimus either guided by TTV load or according to the local centre standard for 9 months. The primary composite endpoint includes the occurrence of infections, biopsy-proven allograft rejection, graft loss, or death. The main secondary endpoints include estimated glomerular filtration rate, graft rejection detected by protocol biopsy at month 12 post-transplantation (including molecular microscopy), development of de novo donor-specific antibodies, health-related quality of life, and drug adherence. In parallel, a comprehensive biobank will be established including plasma, serum, urine and whole blood. The date of the first enrolment was August 2022 and the planned end is April 2025. DISCUSSION: The assessment of individual kidney transplant recipient immune function might enable clinicians to personalise immunosuppression, thereby reducing infection and rejection. Moreover, the trial might act as a proof of principle for TTV-guided immunosuppression and thus pave the way for broader clinical applications, including as guidance for immune modulators or disease-modifying agents. TRIAL REGISTRATION: EU CT-Number: 2022-500024-30-00.

Point-of-care diagnosis and monitoring of fibrinolysis resistance in the critically ill: results from a feasibility study.

BACKGROUND: Fibrinolysisis is essential for vascular blood flow maintenance and is triggered by endothelial and platelet release of tissue plasminogen activator (t-PA). In certain critical conditions, e.g. sepsis, acute respiratory failure (ARF) and trauma, the fibrinolytic response is reduced and may lead to widespread thrombosis and multi-organ failure. The mechanisms underpinning fibrinolysis resistance include reduced t-PA expression and/or release, reduced t-PA and/or plasmin effect due to elevated inhibitor levels, increased consumption and/or clearance. This study in critically ill patients with fibrinolysis resistance aimed to evaluate the ability of t-PA and plasminogen supplementation to restore fibrinolysis with assessment using point-of-care ClotPro viscoelastic testing (VET). METHODS: In prospective, observational studies, whole-blood ClotPro VET evaluation was carried out in 105 critically ill patients. In 32 of 58 patients identified as fibrinolysis-resistant (clot lysis time > 300 s on the TPA-test: tissue factor activated coagulation with t-PA accelerated fibrinolysis), consecutive experimental whole-blood VET was carried out with repeat TPA-tests spiked with additional t-PA and/or plasminogen and the effect on lysis time determined. In an interventional study in a patient with ARF and fibrinolysis resistance, the impact of a 24 h intravenous low-dose alteplase infusion on coagulation and fibrinolysis was prospectively monitored using standard ClotPro VET. RESULTS: Distinct response groups emerged in the ex vivo experimental VET, with increased fibrinolysis observed following supplementation with (i) t-PA only or (ii) plasminogen and t-PA. A baseline TPA-test lysis time of > 1000 s was associated with the latter group. In the interventional study, a gradual reduction (25%) in serial TPA-test lysis times was observed during the 24 h low-dose alteplase infusion. CONCLUSIONS: ClotPro viscoelastic testing, the associated TPA-test and the novel experimental assays may be utilised to (i) investigate the potential mechanisms of fibrinolysis resistance, (ii) guide corrective treatment and (iii) monitor in real-time the treatment effect. Such a precision medicine and personalised treatment approach to the management of fibrinolysis resistance has the potential to increase treatment benefit, while minimising adverse events in critically ill patients. TRIAL REGISTRATION: VETtiPAT-ARF, a clinical trial evaluating ClotPro-guided t-PA (alteplase) administration in fibrinolysis-resistant patients with ARF, is ongoing (ClinicalTrials.gov NCT05540834 ; retrospectively registered September 15th 2022).

How Can the EU Beating Cancer Plan Help in Tackling Lung Cancer, Colorectal Cancer, Breast Cancer and Melanoma?

Cancer is the second leading cause of mortality in EU countries, and the needs to tackle cancer are obvious. New scientific understanding, techniques and methodologies are opening up horizons for significant improvements in diagnosis and care. However, take-up is uneven, research needs and potential outstrip currently available resources, manifestly beneficial practices-such as population-level screening for lung cancer-are still not generalised, and the quality of life of patients and survivors is only beginning to be given attention it merits. This paper, mainly based on a series of multistakeholder expert workshops organised by the European Alliance for Personalised Medicine (EAPM), looks at some of those specifics in the interest of planning a way forward. Part of this exercise also involves taking account of the specific nature of Europe and its constituent countries, where the complexities of planning a way forward are redoubled by the wide variations in national and regional approaches to cancer, local epidemiology and the wide disparities in health systems. Despite all the differences between cancers and national and regional resources and approaches to cancer care, there is a common objective in pursuing broader and more equal access to the best available care for all European citizens.

Overview of recent advancements in asthma management.

Asthma is a common but complex heterogenous inflammatory airway disorder. Despite significant developments in our understanding of the pathophysiology and treatment of asthma, it remains a major cause of mortality and morbidity. Optimal management involves addressing modifiable risk factors, titration of inhaled pharmacotherapy in a stepwise approach and, in severe disease, consideration of biologic agents. Appreciation of the clinical characteristics of asthma and recognition of the immune pathways involved has allowed the development of phenotypic and endotypic subtypes of asthma to be better defined. This has revolutionised asthma management, allowing risk stratification of patients, targeted use of biologic agents to modify cytokine responses that drive asthma and improved patient outcomes. Patient education and engagement are critical to the management of this disease in an era of personalised medicine and a rapidly changing global environment.

SARS-CoV-2 infection in cardiovascular disease: Unmet need of stem cell models.

This review aims to summarise new approaches in SARS-CoV-2-related research in cardiology. We provide a head-to-head comparison of models, such as animal research and human pluripotent stem cells, to investigate the pathomechanisms of COVID-19 and find an efficient therapy. In vivo methods were useful for studying systemic processes of the disease; however, due to differences in animal and human biology, the clinical translation of the results remains a complex task. In vitro stem cell research makes cellular events more observable and effective for finding new drugs and therapies for COVID-19, including the use of stem cells. Furthermore, multicellular 3D organoids even make it possible to observe the effects of drugs to treat SARS-CoV-2 infection in human organ models.

Meeting the Need for a Discussion of Unmet Medical Need.

As Europe and the world continue to battle against COVID, the customary complacency of society over future threats is clearly on display. Just 30 months ago, such a massive disruption to global lives, livelihoods and quality of life seemed unimaginable. Some remedial European Union action is now emerging, and more is proposed, including in relation to tackling "unmet medical need" (UMN). This initiative-directing attention to the future of treating disease and contemplating incentives to stimulate research and development-is welcome in principle. But the current approach being considered by EU officials merits further discussion, because it may prove counter-productive, impeding rather than promoting innovation. This paper aims to feed into these ongoing policy discussions, and rather than presenting research in the classical sense, it discusses the key elements from a multistakeholder perspective. Its central concern is over the risk that the envisaged support will fail to generate valuable new treatments if the legislation is phrased in a rigidly linear manner that does not reflect the serpentine realities of the innovation process, or if the definition placed on unmet medical need is too restrictive. It cautions that such an approach presumes that "unmet need" can be precisely and comprehensively defined in advance on the basis of the past. It cautions that such an approach can reinforce the comfortable delusion that the future is totally predictable-the delusion that left the world as easy prey to COVID. Instead, the paper urges reflection on how the legislation that will shortly enter the pipeline can be phrased so as to allow for the flourishing of a culture capable of rapid adaptation to the unexpected.

Introduction

Introducing Information Technology (IT) tools in today’s and future medicine is being increasingly considered all over the world, especially in developed countries. Indeed, these countries are suffering the most from population aging and chronic diseases. This induces original challenges not only for healthcare but also for wellbeing. In this sense, Predictive, Preventive and Personalised Medicine (3PM) has been identified since more than a decade as a research avenue having huge potential for developed societies. © Springer Nature Switzerland AG 2020.

Endothelin-1 axes in the framework of predictive, preventive and personalised (3P) medicine.

Endothelin-1 (ET-1) is involved in the regulation of a myriad of processes highly relevant for physical and mental well-being; female and male health; in the modulation of senses, pain, stress reactions and drug sensitivity as well as healing processes, amongst others. Shifted ET-1 homeostasis may influence and predict the development and progression of suboptimal health conditions, metabolic impairments with cascading complications, ageing and related pathologies, cardiovascular diseases, neurodegenerative pathologies, aggressive malignancies, modulating, therefore, individual outcomes of both non-communicable and infectious diseases such as COVID-19. This article provides an in-depth analysis of the involvement of ET-1 and related regulatory pathways in physiological and pathophysiological processes and estimates its capacity as a predictor of ageing and related pathologies,a sensor of lifestyle quality and progression of suboptimal health conditions to diseases for their targeted preventionand as a potent target for cost-effective treatments tailored to the person.

Methods to evaluate vascular function: a crucial approach towards predictive, preventive, and personalised medicine.

Endothelium, the gatekeeper of our blood vessels, is highly heterogeneous and a crucial physical barrier with the ability to produce vasoactive and protective mediators under physiological conditions. It regulates vascular tone, haemostasis, vascular inflammation, remodelling, and angiogenesis. Several cardio-, reno-, and cerebrovascular diseases begin with the dysfunction of endothelial cells, and more recently, COVID-19 was also associated with endothelial disease highlighting the need to monitor its function towards prevention and reduction of vascular dysfunction. Endothelial cells are an important therapeutic target in predictive, preventive, and personalised (3P) medicine with upmost importance in vascular diseases. The development of novel non-invasive techniques to access endothelial dysfunction for use in combination with existing clinical imaging modalities provides a feasible opportunity to reduce the burden of vascular disease. This review summarises recent advances in the principles of endothelial function measurements. This article presents an overview of invasive and non-invasive techniques to determine vascular function and their major advantages and disadvantages. In addition, the article describes mechanisms underlying the regulation of vascular function and dysfunction and potential new biomarkers of endothelial damage. Recognising these biomarkers is fundamental towards a shift from reactive to 3P medicine in the vascular field. Identifying vascular dysfunction earlier with non-invasive or minimally invasive techniques adds value to predictive diagnostics and targeted prevention (primary, secondary, tertiary care). In addition, vascular dysfunction is a potential target for treatments tailored to the person.