Variable Clinical Courses of Varicella Zoster Virus Infection-related or Vaccination-related Bone Marrow Failure.

We report 5 children with bone marrow failure (BMF) after primary varicella zoster virus (VZV) infection or VZV vaccination, highlighting the highly variable course. Two patients were treated with intravenous immunoglobulins; one had a slow hematologic recovery, and the other was rescued by allogeneic hematopoietic stem cell transplantation (HSCT). Of the 2 patients treated with immunosuppressive therapy with antithymocyte globulin and cyclosporine, one had a complete response, and the other was transplanted for nonresponse. One patient underwent a primary allograft. All patients are alive. This study demonstrated that VZV-associated BMF is a life-threatening disorder that often requires HSCT.

A Personalized Patient Preference Predictor for Substituted Judgments in Healthcare: Technically Feasible and Ethically Desirable.

When making substituted judgments for incapacitated patients, surrogates often struggle to guess what the patient would want if they had capacity. Surrogates may also agonize over having the (sole) responsibility of making such a determination. To address such concerns, a Patient Preference Predictor (PPP) has been proposed that would use an algorithm to infer the treatment preferences of individual patients from population-level data about the known preferences of people with similar demographic characteristics. However, critics have suggested that even if such a PPP were more accurate, on average, than human surrogates in identifying patient preferences, the proposed algorithm would nevertheless fail to respect the patient's (former) autonomy since it draws on the 'wrong' kind of data: namely, data that are not specific to the individual patient and which therefore may not reflect their actual values, or their reasons for having the preferences they do. Taking such criticisms on board, we here propose a new approach: the Personalized Patient Preference Predictor (P4). The P4 is based on recent advances in machine learning, which allow technologies including large language models to be more cheaply and efficiently 'fine-tuned' on person-specific data. The P4, unlike the PPP, would be able to infer an individual patient's preferences from material (e.g., prior treatment decisions) that is in fact specific to them. Thus, we argue, in addition to being potentially more accurate at the individual level than the previously proposed PPP, the predictions of a P4 would also more directly reflect each patient's own reasons and values. In this article, we review recent discoveries in artificial intelligence research that suggest a P4 is technically feasible, and argue that, if it is developed and appropriately deployed, it should assuage some of the main autonomy-based concerns of critics of the original PPP. We then consider various objections to our proposal and offer some tentative replies.

Meaningful Human Control over AI for Health? A Review.

Artificial intelligence is currently changing many areas of society. Especially in health, where critical decisions are made, questions of control must be renegotiated: who is in control when an automated system makes clinically relevant decisions? Increasingly, the concept of meaningful human control (MHC) is being invoked for this purpose. However, it is unclear exactly how this concept is to be understood in health. Through a systematic review, we present the current state of the concept of MHC in health. The results show that there is not yet a robust MHC concept for health. We propose a broader understanding of MHC along three strands of action: enabling, exercising and evaluating control. Taking into account these strands of action and the established rules and processes in the different health sectors, the MHC concept needs to be further developed to avoid falling into two gaps, which we have described as theoretical and labelling gaps.

Atelectasis in obese patients undergoing laparoscopic bariatric surgery are not increased upon discharge from Post Anesthesia Care Unit.

Background: Obese patients frequently develop pulmonary atelectasis upon general anesthesia. The risk is increased during laparoscopic surgery. This prospective, observational single-center study evaluated atelectasis dynamics using Electric Impedance Tomography (EIT) in patients undergoing laparoscopic bariatric surgery. Methods: We included adult patients with ASA physical status I-IV and a BMI of ≥40. Exclusion criteria were known severe pulmonary hypertension, home oxygen therapy, heart failure, and recent pulmonary infections. The primary outcome was the proportion of poorly ventilated lung regions (low tidal variation areas) and the global inhomogeneity (GI) index assessed by EIT before discharge from the Post Anesthesia Care Unit compared to these same measures prior to initiation of anesthesia. Results: The median (IQR) proportion of low tidal variation areas at the different analysis points were T1 10.8% [3.6-15.1%] and T5 10.3% [2.6-18.9%], and the mean difference was -0.7% (95% CI: -5.8% -4.5%), i.e., lower than the predefined non-inferiority margin of 5% (p = 0.022). There were no changes at the four additional time points compared to T1 or postoperative pulmonary complications during the 14 days following the procedure. Conclusion: We found that obese patients undergoing laparoscopic bariatric surgery do not leave the Post Anesthesia Care Unit with increased low tidal variation areas compared to the preoperative period.

Reflections on Putting AI Ethics into Practice: How Three AI Ethics Approaches Conceptualize Theory and Practice.

Critics currently argue that applied ethics approaches to artificial intelligence (AI) are too principles-oriented and entail a theory-practice gap. Several applied ethical approaches try to prevent such a gap by conceptually translating ethical theory into practice. In this article, we explore how the currently most prominent approaches of AI ethics translate ethics into practice. Therefore, we examine three approaches to applied AI ethics: the embedded ethics approach, the ethically aligned approach, and the Value Sensitive Design (VSD) approach. We analyze each of these three approaches by asking how they understand and conceptualize theory and practice. We outline the conceptual strengths as well as their shortcomings: an embedded ethics approach is context-oriented but risks being biased by it; ethically aligned approaches are principles-oriented but lack justification theories to deal with trade-offs between competing principles; and the interdisciplinary Value Sensitive Design approach is based on stakeholder values but needs linkage to political, legal, or social governance aspects. Against this background, we develop a meta-framework for applied AI ethics conceptions with three dimensions. Based on critical theory, we suggest these dimensions as starting points to critically reflect on the conceptualization of theory and practice. We claim, first, that the inclusion of the dimension of affects and emotions in the ethical decision-making process stimulates reflections on vulnerabilities, experiences of disregard, and marginalization already within the AI development process. Second, we derive from our analysis that considering the dimension of justifying normative background theories provides both standards and criteria as well as guidance for prioritizing or evaluating competing principles in cases of conflict. Third, we argue that reflecting the governance dimension in ethical decision-making is an important factor to reveal power structures as well as to realize ethical AI and its application because this dimension seeks to combine social, legal, technical, and political concerns. This meta-framework can thus serve as a reflective tool for understanding, mapping, and assessing the theory-practice conceptualizations within AI ethics approaches to address and overcome their blind spots.

Oncogenic drivers dictate immune control of acute myeloid leukemia.

Acute myeloid leukemia (AML) is a genetically heterogeneous, aggressive hematological malignancy induced by distinct oncogenic driver mutations. The effect of specific AML oncogenes on immune activation or suppression is unclear. Here, we examine immune responses in genetically distinct models of AML and demonstrate that specific AML oncogenes dictate immunogenicity, the quality of immune response and immune escape through immunoediting. Specifically, expression of NrasG12D alone is sufficient to drive a potent anti-leukemia response through increased MHC Class II expression that can be overcome with increased expression of Myc. These data have important implications for the design and implementation of personalized immunotherapies for patients with AML.

Data justice and data solidarity.

Datafication shapes and gradually transforms societies. Given this impact, issues of justice around data-driven practices have received more and more attention in recent years as shown, for example, by various reports and guidelines on artificial intelligence and data ethics. In this article, we elaborate on and defend two claims. First, these discourses on justice tend to center primarily around conceptions of fairness. We argue that justice in connection with datafication relates to, but ultimately encompasses more than, solely fairness. Second, although it is an important project to clarify what justice in connection with datafication encompasses, we argue that attention toward attitudes and practices of data solidarity have so far been largely overlooked. They are, however, indispensable as a catalytic element to advance toward data justice in practice.

Digital twins and the ethics of health decision-making concerning children.

In this review, we explore from an ethical perspective the opportunities and challenges for decision-making concerning children if digital twins (DTs) were to be used to provide better information about their health status as a basis for proxy decision-making. We note a sense of urgency due to the speed of progress and implementation of this advancing technology and argue that bringing a solid conceptual basis into the development process is of utmost importance for the effective protection of children's rights and interests.

Calibration and Validation of a Linear-Elastic Numerical Model for Timber Step Joints Based on the Results of Experimental Investigations.

The paper is dedicated to the numerical analysis of a single-step joint, enabling the prediction of stiffness and failure modes of both single- and double-step joints. An experimental analysis of the geometrically simplest version, the single-step joint, serves as a reference for the calibration of the subsequent finite element model. The inhomogeneous and anisotropic properties of solid timber make detailed modelling computationally intensive and strongly dependent on the respective specimen. Therefore, the authors present a strategy for simplified but still appropriate modelling for the prediction of local failure at certain load levels. The used mathematical approach is based on the linear elasticity theory and orthotropic material properties. The finite element calculations are performed in the environment of the software Abaqus FEA. The calibrated numerical model shows a good conformity until first failures occur. It allows for a satisfactory quantification of the stiffness of the connection and estimation of the force when local failure begins and is, therefore, recommended for future, non-destructive research of timber connections of various shapes.

Shut-Down of Type IX Protein Secretion Alters the Host Immune Response to Tannerella forsythia and Porphyromonas gingivalis.

Tannerella forsythia and Porphyromonas gingivalis target distinct virulence factors bearing a structurally conserved C-terminal domain (CTD) to the type IX protein secretion system (T9SS). The T9SS comprises an outer membrane translocation complex which works in concert with a signal peptidase for CTD cleavage. Among prominent T9SS cargo linked to periodontal diseases are the TfsA and TfsB components of T. forsythia's cell surface (S-) layer, the bacterium's BspA surface antigen and a set of cysteine proteinases (gingipains) from P. gingivalis. To assess the overall role of the bacterial T9SS in the host response, human macrophages and human gingival fibroblasts were stimulated with T. forsythia and P. gingivalis wild-type bacteria and T9SS signal peptidase-deficient mutants defective in protein secretion, respectively. The immunostimulatory potential of these bacteria was compared by analyzing the mRNA expression levels of the pro-inflammatory mediators IL-6, IL-8, MCP-1 and TNF-α by qPCR and by measuring the production of the corresponding proteins by ELISA. Shot-gun proteomics analysis of T. forsythia and P. gingivalis outer membrane preparations confirmed that several CTD-bearing virulence factors which interact with the human immune system were depleted from the signal peptidase mutants, supportive of effective T9SS shut-down. Three and, more profoundly, 16 hours post stimulation, the T. forsythia T9SS mutant induced significantly less production of cytokines and the chemokine in human cells compared to the corresponding parent strain, while the opposite was observed for the P. gingivalis T9SS mutant. Our data indicate that T9SS shut-down translates into an altered inflammatory response in periodontal pathogens. Thus, the T9SS as a potential novel target for periodontal therapy needs further evaluation.

NKG7 Is Required for Optimal Antitumor T-cell Immunity.

Tumor antigen-specific CD8+ T cells play a critical role in antitumor immunity. Clinical trials reinvigorating the immune system via immune checkpoint blockade (ICB) have shown remarkable clinical promise. Numerous studies have identified an association between NKG7 expression and patient outcome across different malignancies. However, aside from these correlative observations, very little is known about NKG7 and its role in antitumor immunity. Herein, we utilized single-cell RNA sequencing (scRNA-seq) datasets, NKG7-deficient mice, NKG7-reporter mice, and mouse tumor models to investigate the role of NKG7 in neoantigen-mediated tumor rejection and ICB immunotherapy. scRNA-seq of tumors from patients with metastatic melanoma or head and neck squamous cell carcinoma revealed that NKG7 expression is highly associated with cytotoxicity and specifically expressed by CD8+ T cells and natural killer (NK) cells. Furthermore, we identified a key role for NKG7 in controlling intratumor T-cell accumulation and activation. NKG7 was upregulated on intratumor antigen-specific CD8+ T cells and NK cells and required for the accumulation of T cells in the tumor microenvironment. Accordingly, neoantigen-expressing mouse tumors grew faster in Nkg7-deficient mice. Strikingly, efficacy of single or combination ICB was significantly reduced in Nkg7-deficient mice.See related article by Wen et al., p. 162.

Diffused responsibility: attributions of responsibility in the use of AI-driven clinical decision support systems.

Good decision-making is a complex endeavor, and particularly so in a health context. The possibilities for day-to-day clinical practice opened up by AI-driven clinical decision support systems (AI-CDSS) give rise to fundamental questions around responsibility. In causal, moral and legal terms the application of AI-CDSS is challenging existing attributions of responsibility. In this context, responsibility gaps are often identified as main problem. Mapping out the changing dynamics and levels of attributing responsibility, we argue in this article that the application of AI-CDSS causes diffusions of responsibility with respect to a causal, moral, and legal dimension. Responsibility diffusion describes the situation where multiple options and several agents can be considered for attributing responsibility. Using the example of an AI-driven 'digital tumor board', we illustrate how clinical decision-making is changed and diffusions of responsibility take place. Not denying or attempting to bridge responsibility gaps, we argue that dynamics and ambivalences are inherent in responsibility, which is based on normative considerations such as avoiding experiences of disregard and vulnerability of human life, which are inherently accompanied by a moment of uncertainty, and is characterized by revision openness. Against this background and to avoid responsibility gaps, the article concludes with suggestions for managing responsibility diffusions in clinical decision-making with AI-CDSS.

A Combination of Structural, Genetic, Phenotypic and Enzymatic Analyses Reveals the Importance of a Predicted Fucosyltransferase to Protein O-Glycosylation in the Bacteroidetes.

Diverse members of the Bacteroidetes phylum have general protein O-glycosylation systems that are essential for processes such as host colonization and pathogenesis. Here, we analyzed the function of a putative fucosyltransferase (FucT) family that is widely encoded in Bacteroidetes protein O-glycosylation genetic loci. We studied the FucT orthologs of three Bacteroidetes species-Tannerella forsythia, Bacteroides fragilis, and Pedobacter heparinus. To identify the linkage created by the FucT of B. fragilis, we elucidated the full structure of its nine-sugar O-glycan and found that l-fucose is linked ß1,4 to glucose. Of the two fucose residues in the T. forsythia O-glycan, the fucose linked to the reducing-end galactose was shown by mutational analysis to be l-fucose. Despite the transfer of l-fucose to distinct hexose sugars in the B. fragilis and T. forsythia O-glycans, the FucT orthologs from B. fragilis, T. forsythia, and P. heparinus each cross-complement the B. fragilis ΔBF4306 and T. forsythia ΔTanf_01305 FucT mutants. In vitro enzymatic analyses showed relaxed acceptor specificity of the three enzymes, transferring l-fucose to various pNP-α-hexoses. Further, glycan structural analysis together with fucosidase assays indicated that the T. forsythia FucT links l-fucose α1,6 to galactose. Given the biological importance of fucosylated carbohydrates, these FucTs are promising candidates for synthetic glycobiology.

Clinical recommendations for in-hospital airway management during aerosol-transmitting procedures in the setting of a viral pandemic.

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can lead to severe pneumonia and multiorgan failure. While most of the infected patients develop no or only mild symptoms, some need respiratory support or even invasive ventilation. The exact route of transmission is currently under investigation. While droplet exposure and direct contact seem to be the most significant ways of transmitting the disease, aerosol transmission appears to be possible under circumstances favored by high viral load. Despite the use of personal protective equipment (PPE), this situation potentially puts healthcare workers at risk of infection, especially if they are involved in airway management. Various recommendations and international guidelines aim to protect healthcare workers, although evidence-based research confirming the benefits of these approaches is still scarce. In this article, we summarize the current literature and recommendations for airway management of COVID-19 patients.

Leadership in a time of crisis: Lessons learned from a pandemic.

The current COVID-19 pandemic is testing political leaders and healthcare systems worldwide, exposing deficits in crisis communication, leadership, preparedness and flexibility. Extraordinary situations abound, with global supply chains suddenly failing, media communicating contradictory information, and politics playing an increasingly bigger role in shaping each country's response to the crisis. The pandemic threatens not just our health but also our economy, liberty, and privacy. It challenges the speed at which we work, the quality of our research, and the effectiveness of communication within the scientific community. It can impose ethical dilemmas and emotional stress on healthcare workers. Nevertheless, the pandemic also provides an opportunity for healthcare organizations, leaders, and researchers to learn from their mistakes and to place their countries and institutions in a better position to face future challenges.

Risk-Adjusted Prevention. Perspectives on the Governance of Entitlements to Benefits in the Case of Genetic (Breast Cancer) Risks.

This article is a revised version of our proposal for the establishment of the legal concept of risk-adjusted prevention in the German healthcare system to regulate access to risk-reduction measures for persons at high and moderate genetic cancer risk (Meier et al. Risikoadaptierte Prävention'. Governance Perspective für Leistungsansprüche bei genetischen (Brustkrebs-)Risiken, Springer, Wiesbaden, 2018). The German context specifics are summarized to enable the source text to be used for other country-specific healthcare systems. Establishing such a legal concept is relevant to all universal and free healthcare systems similar to Germany's. Disease risks can be determined with increasing precision using bioinformatics and biostatistical innovations ('big data'), due to the identification of pathogenic germ line mutations in cancer risk genes as well as non-genetic factors and their interactions. These new technologies open up opportunities to adapt therapeutic and preventive measures to the individual risk profile of complex diseases in a way that was previously unknown, enabling not only adequate treatment but in the best case, prevention. Access to risk-reduction measures for carriers of genetic risks is generally not regulated in healthcare systems that guarantee universal and equal access to healthcare benefits. In many countries, including Austria, Denmark, the UK and the US, entitlement to benefits is essentially linked to the treatment of already manifest disease. Issues around claiming benefits for prophylactic measures involve not only evaluation of clinical options (genetic diagnostics, chemoprevention, risk-reduction surgery), but the financial cost and-from a social ethics perspective-the relationship between them. Section 1 of this chapter uses the specific example of hereditary breast cancer to show why from a medical, social-legal, health-economic and socio-ethical perspective, regulated entitlement to benefits is necessary for persons at high and moderate risk of cancer. Section 2 discusses the medical needs of persons with genetic cancer risks and goes on to develop the healthy sick model which is able to integrate the problems of the different disciplines into one scheme and to establish criteria for the legal acknowledgement of persons at high and moderate (breast cancer) risks. In the German context, the social-legal categories of classical therapeutic medicine do not adequately represent preventive measures as a regular service within the healthcare system. We propose risk-adjusted prevention as a new legal concept based on the heuristic healthy sick model. This category can serve as a legal framework for social law regulation in the case of persons with genetic cancer risks. Risk-adjusted prevention can be established in principle in any healthcare system. Criteria are also developed in relation to risk collectives and allocation (Sects. 3, 4, 5).