To summarize and compare qualitative studies which explored attitudes of patients, families and healthcare providers towards medical futility.
A systematic search of qualitative studies via the ...PubMed database was conducted. Data were extracted in terms of two aspects: 1) Group of people, which were interviewed about futility; 2) Definitions of medical futility given by these participants. Data were analyzed and synthesized using the method of qualitative content analysis.
The initial search identified 737 articles. 71 studies were reviewed in detail and 10 were finally selected. As a result, three groups of people (physicians, caregiver and patients) and six core categories could be identified: patient treatment, quantitative aspects, resources, professional aspects, reference to balance, definition challenges.
This review describes existing opinions about medical futility and demonstrates the multifaceted understanding of medical futility by physicians, caregivers and patients. The difficulties in defining medical futility demonstrate the need for resources to help healthcare providers and patients to deal with decision-making in such situations.
•Qualitative review study of understandings of medical futility according to physicians, nursing staff and patients•No shared meaning of medical futility in clinical practice and no specific differences between physicians, nurses and patients detected•Provides basis to reflect one's own practice and the communication with nursing staff, patients and families
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Unterschiede in der finanziellen Leistungsfähigkeit von Gebietskörperschaften nachgelagerter Ebenen können über horizontale oder vertikale Ausgleichszahlungen abgebaut werden. Während der ...bundesdeutsche Finanzausgleich beide Komponenten kennt, praktizieren andere große Föderationen wie die USA oder Kanada ausschließlich das vertikale Verfahren. Eine zentrale Rolle in der internationalen Diskussion spielt dabei die finanzpolitische Autonomie nachgelagerter Gebietskörperschaften. Da sich nach diesem Kriterium keine eindeutigen Prioritäten zugunsten der einen oder anderen Ausgleichsmethode gewinnen lassen, konzentriert sich die weitere Analyse auf mögliche Verteilungs- und Allokationswirkungen.
PML nuclear bodies (PML-NBs) are enigmatic structures of the cell nucleus that act as key mediators of intrinsic immunity against viral pathogens. PML itself is a member of the E3-ligase TRIM family ...of proteins that regulates a variety of innate immune signaling pathways. Consequently, viruses have evolved effector proteins to modify PML-NBs; however, little is known concerning structure-function relationships of viral antagonists. The herpesvirus human cytomegalovirus (HCMV) expresses the abundant immediate-early protein IE1 that colocalizes with PML-NBs and induces their dispersal, which correlates with the antagonization of NB-mediated intrinsic immunity. Here, we delineate the molecular basis for this antagonization by presenting the first crystal structure for the evolutionary conserved primate cytomegalovirus IE1 proteins. We show that IE1 consists of a globular core (IE1CORE) flanked by intrinsically disordered regions. The 2.3 Å crystal structure of IE1CORE displays an all α-helical, femur-shaped fold, which lacks overall fold similarity with known protein structures, but shares secondary structure features recently observed in the coiled-coil domain of TRIM proteins. Yeast two-hybrid and coimmunoprecipitation experiments demonstrate that IE1CORE binds efficiently to the TRIM family member PML, and is able to induce PML deSUMOylation. Intriguingly, this results in the release of NB-associated proteins into the nucleoplasm, but not of PML itself. Importantly, we show that PML deSUMOylation by IE1CORE is sufficient to antagonize PML-NB-instituted intrinsic immunity. Moreover, co-immunoprecipitation experiments demonstrate that IE1CORE binds via the coiled-coil domain to PML and also interacts with TRIM5α We propose that IE1CORE sequesters PML and possibly other TRIM family members via structural mimicry using an extended binding surface formed by the coiled-coil region. This mode of interaction might render the antagonizing activity less susceptible to mutational escape.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The West African Ebola virus epidemic from 2014 to 2016 is unprecedented in its scale, surpassing all previous and subsequent Ebola outbreaks since 1976. This epidemic provoked a humanitarian ...emergency that extended to different spheres of life, making visible ethical challenges in addition to medical, economic, and social ones. The present article aims to identify and differentiate the scope of ethical issues associated with the Ebola epidemic.
An online media analysis was performed on articles published from March 2014 to September 2015 in ten preselected academic journals (scientific press) and two online newspapers (lay press). Two methodological approaches were combined: a systematic literature search and a qualitative content analysis. An additional keyword search was conducted on the PubMed database for the period after the end of the Ebola epidemic (2016-2020) to obtain an overview of research dealing with medical ethics due to the epidemic and to compare these results with the identified ethical challenges.
A total of 389 articles dealing with the subject fields "Ebola epidemic" and "ethics" were researched. For qualitative content analysis, the time span with the highest article density was selected and a total of 64 articles were included (15 scientific articles, 49 popular articles). Five core ethical challenges of the Ebola epidemic emerged: 1. Responsibility and Accountability, 2. Spillover Effects, 3. Research and Development, 4. Health Communication, and 5. Resource Allocation. Articles in academic journals were dominated by the discussion of normative aspects in the area of "research and development", while newspaper articles focused on aspects of "responsibility and accountability".
An ethical discussion of the Ebola epidemic requires an examination of as many of the ethical dimensions involved as possible. The presented investigation of the two types of media with regard to the Ebola epidemic offers this possibility of a more comprehensive insight into this diversity as a basis for ethical discussions.
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Patient advocacy organizations (PAOs) have an increasing influence on health policy and biomedical research, therefore, questions about the specific character of their responsibility arise: Can PAOs ...bear moral responsibility and, if so, to whom are they responsible, for what and on which normative basis? Although the concept of responsibility in healthcare is strongly discussed, PAOs particularly have rarely been systematically analyzed as morally responsible agents. The aim of the current paper is to analyze the character of PAOs' responsibility to provide guidance to themselves and to other stakeholders in healthcare. Responsibility is presented as a concept with four reference points: (1) The subject, (2) the object, (3) the addressee and (4) the underlying normative standard. This four-point relationship is applied to PAOs and the dimensions of collectivity and prospectivity are analyzed in each reference point. Understood as collectives, PAOs are, in principle, capable of intentionality and able to act and, thus, fulfill one prerequisite for the attribution of moral responsibility. Given their common mission to represent those affected, PAOs can be seen as responsible for patients' representation and advocacy, primarily towards a certain group but secondarily in a broader social context. Various legal and political statements and the bioethical principles of justice, beneficence and empowerment can be used as a normative basis for attributing responsibility to PAOs. The understanding of responsibility as a four-point relation incorporating collective and forward-looking dimensions helps one to understand the PAOs' roles and responsibilities better. The analysis, thus, provides a basis for the debate about PAOs' contribution and cooperation in the healthcare sector.
The provisioning of compound libraries with a high degree of diversity and attractive pharmacological properties is a limiting step in drug development. This study reports the production of highly ...bioactive sulfated polysaccharides, originally present in a nonsulfated, dormant state in natural sources, and demonstrates their antiviral activity (human cytomegalovirus EC50 values of 2.34–7.77 μg/mL) at a low degree of cytotoxicity. Furthermore, data strongly suggested the inhibition of virus entry as the main mode of antiviral action. Remarkably, the utilized oleum-DMF reagent was able to generate a range of sulfated polysaccharides from various natural sources, possessing varying saccharide compositions, degrees of sulfation (0.4–1.7) and molecular masses (38–94,000 g/mol). Typically, in a matter of minutes, this reagent not only solubilized polysaccharides but also chemically converted their hydroxyl functionality into sulfates. The most active sulfated polysaccharide (EC50 of 2.62 μg/mL) proved to be a 94,000 g/mol branched glucan with sulfates at C-6/C-3,6/C-2,3,6 positions. In conclusion, the important determinants of such compounds' antiviral activity are: (i) degree of sulfation, (ii) molecular mass and (iii) structural features. Thus, our approach offers a huge prospect for the improvement of natural source-derived libraries based on biologically active polysaccharides with diversified chemical profiles.
•Polysaccharides with varied structures were produced and activated from natural sources.•Concurrent extraction and sulfation of polysaccharides was achieved by one-pot strategy.•Produced compounds exhibited strong antiviral activity and low degree of cytotoxicity.•Huge prospect for the generation of bioactive polysaccharides from other natural sources
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Symptom checker applications (SCAs) may help laypeople classify their symptoms and receive recommendations on medically appropriate actions. Further research is necessary to estimate the influence of ...user characteristics, attitudes and (e)health-related competencies.
The objective of this study is to identify meaningful predictors for SCA use considering user characteristics.
An explorative cross-sectional survey was conducted to investigate German citizens' demographics, eHealth literacy, hypochondria, self-efficacy, and affinity for technology using German language-validated questionnaires. A total of 869 participants were eligible for inclusion in the study. As n = 67 SCA users were assessed and matched 1:1 with non-users, a sample of n = 134 participants were assessed in the main analysis. A four-step analysis was conducted involving explorative predictor selection, model comparisons, and parameter estimates for selected predictors, including sensitivity and post hoc analyses.
Hypochondria and self-efficacy were identified as meaningful predictors of SCA use. Hypochondria showed a consistent and significant effect across all analyses OR: 1.24-1.26 (95% CI: 1.1-1.4). Self-efficacy OR: 0.64-0.93 (95% CI: 0.3-1.4) showed inconsistent and nonsignificant results, leaving its role in SCA use unclear. Over half of the SCA users in our sample met the classification for hypochondria (cut-off on the WI of 5).
Hypochondria has emerged as a significant predictor of SCA use with a consistently stable effect, yet according to the literature, individuals with this trait may be less likely to benefit from SCA despite their greater likelihood of using it. These users could be further unsettled by risk-averse triage and unlikely but serious diagnosis suggestions.
The study was registered in the German Clinical Trials Register (DRKS) DRKS00022465, DERR1- https://doi.org/10.2196/34026 .
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Promyelocytic leukemia nuclear bodies, also termed nuclear domain 10 (ND10), have emerged as nuclear protein accumulations mediating an intrinsic cellular defense against viral infections via ...chromatin-based mechanisms, however, their contribution to the control of herpesviral latency is still controversial. In this study, we utilized the monocytic cell line THP-1 as an in vitro latency model for human cytomegalovirus infection (HCMV). Characterization of THP-1 cells by immunofluorescence andWestern blot analysis confirmed the expression of all major ND10 components. THP-1 cells with a stable, individual knockdown of PML, hDaxx or Sp100 were generated. Importantly, depletion of the major ND10 proteins did not prevent the terminal cellular differentiation of THP-1 monocytes. After construction of a recombinant, endotheliotropic human cytomegalovirus expressing IE2-EYFP, we investigated whether the depletion of ND10 proteins affects the onset of viral IE gene expression. While after infection of differentiated, THP-1-derived macrophages as well as during differentiation-induced reactivation from latency an increase in the number of IE-expressing cells was readily detectable in the absence of the major ND10 proteins, no effect was observed in non-differentiated monocytes. We conclude that PML, hDaxx and Sp100 primarily act as cellular restriction factors during lytic HCMV replication and during the dynamic process of reactivation but do not serve as key determinants for the establishment of HCMV latency.
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Herpesviral nuclear egress is a regulated process shared by all family members, ensuring the efficient cytoplasmic release of viral capsids. In the case of human cytomegalovirus (HCMV), the core of ...the nuclear egress complex (NEC) consists of the pUL50-pUL53 heterodimer that builds hexameric lattices for capsid binding and multicomponent interaction, including NEC-associated host factors. A characteristic feature of NEC interaction is the N-terminal hook structure of pUL53 that binds to an alpha-helical groove of pUL50, thus termed as hook-into-groove interaction. This central regulatory element is essential for viral replication and shows structural-functional conservation, which has been postulated as a next-generation target of antiviral strategies. However, a solid validation of this concept has been missing. In the present study, we focused on the properties of oligomeric HCMV core NEC interaction and the antiviral activity of specifically targeted prototype inhibitors. Our data suggest the following: (i) transiently expressed, variably tagged versions of HCMV NEC proteins exert hook-into-groove complexes, putatively in oligomeric assemblies that are distinguishable from heterodimers, as shown by in vitro assembly and coimmunoprecipitation approaches; (ii) this postulated oligomeric binding pattern was further supported by the use of a pUL50::pUL53 fusion construct also showing a pronounced multi-interaction potency; (iii) using confocal imaging cellular NEC-associated proteins were found partly colocalized with the tagged core NECs; (iv) a small inhibitory molecule, recently identified by an in vitro binding inhibition assay, was likewise active in blocking pUL50-pUL53 oligomeric assembly and in exerting antiviral activity in HCMV-infected fibroblasts. In summary, the findings refine the previous concept of HCMV core NEC formation and nominate this drug-accessible complex as a validated antiviral drug target.
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The complex host interaction network of human cytomegalovirus (HCMV) involves the regulatory protein kinase pUL97, which represents a viral cyclin-dependent kinase (CDK) ortholog. pUL97 interacts ...with the three human cyclin types T1, H, and B1, whereby the binding region of cyclin T1 and the pUL97 oligomerization region were both assigned to amino acids 231-280. We further addressed the question of whether HCMVs harboring mutations in ORF-UL97, i.e., short deletions or resistance-conferring point mutations, are affected in the interaction with human cyclins and viral replication. To this end, clinically relevant UL97 drug-resistance-conferring mutants were analyzed by whole-genome sequencing and used for genetic marker transfer experiments. The recombinant HCMVs indicated conservation of pUL97–cyclin interaction, since all viral UL97 point mutants continued to interact with the analyzed cyclin types and exerted wild-type-like replication fitness. In comparison, recombinant HCMVs UL97 Δ231-280 and also the smaller deletion Δ236-275, but not Δ241-270, lost interaction with cyclins T1 and H, showed impaired replication efficiency, and also exhibited reduced kinase activity. Moreover, a cellular knock-out of cyclins B1 or T1 did not alter HCMV replication phenotypes or pUL97 kinase activity, possibly indicating alternative, compensatory pUL97–cyclin interactions. In contrast, however, cyclin H knock-out, similar to virus deletion mutants in the pUL97–cyclin H binding region, exhibited strong defective phenotypes of HCMV replication, as supported by reduced pUL97 kinase activity in a cyclin H-dependent coexpression setting. Thus, cyclin H proved to be a very relevant determinant of pUL97 kinase activity and viral replication efficiency. As a conclusion, the results provide evidence for the functional importance of pUL97–cyclin interaction. High selective pressure on the formation of pUL97–cyclin complexes was identified by the use of clinically relevant mutants.
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