192815 research outputs found
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Exercise treadmill testing for efficacy evaluation in randomized, controlled trials
Get PDFExercise treadmill testing measures functional capacity and inducible myocardial ischemia and has historically served as an endpoint in phase 2 trials. The Precision Medicine with Zibotentan in Microvascular Angina trial evaluated the selective endothelin-A receptor antagonist zibotentan as a potential disease-modifying therapy for microvascular angina. The trial had a randomized, double-blind, cross-over design and the primary outcome was exercise duration. Compared with placebo, zibotentan at a dose of 10-mg daily for 12-weeks did not improve exercise duration or angina symptoms. In this prespecified analysis, exercise duration was compared across four sequential study visits and the factors associated with within-trial changes were evaluated. Exercise test duration increased progressively in all participants during sequential trial phases, independent of treatment with either zibotentan or placebo. This improvement in exercise duration was associated with female sex (interaction p-value = .0213; effect estimate [95% confidence interval]) 34.95 [13.99, 55.78] seconds, P = .002). In conclusion, the exercise test has limitations as an objective endpoint of efficacy in randomized trials
Corrigendum to Exploring the effects of pharmacological treatments on suicidality in children and adolescents: a structured review of the literature and narrative synthesis eClinicalMedicine Vol 91 January 2026, 103748
Get PDFNo abstract available
Hearts of fire, bodies on the line: impressions of work and labour in The Red Shoes
Get PDFThis article is concerned with representations of artistic work and labour in Michael Powell and Emeric Pressburger’s The Red Shoes (1948). In contrast to previous readings, which have tended to emphasise the film’s variously inauthentic, impressionistic or ‘magical’ depictions of labour, I suggest the film offers us two much more earthly lessons about the nature of artmaking. Firstly, the film quite consistently reveals that the performance of art is not so much a supernatural or transcendent labour but one that is derived from (and visibly demonstrates) some of the material conditions and the personal and social relations necessary for its production. Secondly, the film’s seemingly archaic and stylised representations of workplace politics offer some instructive insights that resonate with more recent debates on the unequal social organisation of artistic labour – or as I prefer to term it, ‘cultural work’
The pragmatics and the normativity of ignorance attributions
No full textThe way we attribute ignorance to each other is often connected to normative considerations. Intuitively, attributions such as ‘S is ignorant that p’ sound odd when S is under no obligation to know that p. These linguistic intuitions about attributions of ignorance have been used to motivate the increasingly popular Normative Account of the nature of ignorance (Pritchard 2021a, https://doi.org/10.5840/philtopics202149223 2021b; https://doi.org/10.1007/s10670-022-00529-7 2024) according to which ignorance is a lack of a positive epistemic standing which manifests a failure of inquiry. Here, I will argue that champions of the Normative Account who want to draw metaphysical and conceptual conclusions about ignorance from linguistic intuitions may be too quick to do so. In fact, the normative weigh of ignorance attributions can be explained on a pragmatic basis
Participatory systems mapping: a review of population health research practice
Get PDFBackground:
Participatory systems mapping (PSM) methods are increasingly applied in population health research to understand and address complex challenges. Despite their growing use, there remains limited understanding of how these approaches are implemented in practice. This systematic scoping review aimed to explore the application of PSM in population health research, identify methodological gaps and highlight opportunities for advancing methods development and reporting standards, with particular attention to participatory approaches.
Methods:
A systematic search of OVID MEDLINE and Scopus identified peer-reviewed papers published in English between January 2000 and September 2023 that: (1) applied and presented the results of PSM related to population health or health improvement questions and (2) incorporated a participatory design. Two reviewers screened and assessed papers, extracting data on study characteristics, participatory approaches, map features and integration of conceptual frameworks and methods not directly related to PSM.
Results:
In the 123 included studies, involving stakeholders in building causal loop diagrams was the most commonly used approach. Variability was evident in geographical focus, study design, application and reporting. Participant involvement was mostly limited to map building, with less engagement in map validation. Significant gaps in reporting study samples and procedures were identified. A small number of studies involved end users or people with lived experiences in mapping processes. Only a few studies evaluated stakeholders’ experience with participatory processes. Lessons learnt on participatory processes include: PSM in population health benefits from cross-disciplinary, inclusive collaboration and capacity-building efforts that support meaningful involvement, shared ownership and trust among diverse stakeholders. Adaptability in the design of PSM approaches, continuous reflection and long-term partnerships are essential to maintaining relevance, enhancing impact and fostering systemic change over time.
Conclusions:
To advance participatory systems mapping in population health, there is a need for further methodological innovation, stronger stakeholder engagement and more transparent, reflexive reporting practices. Building capacity through training, practical guidance and cross-disciplinary communities of practice will also be essential to support rigorous and inclusive application of these methods
Parasocial relationship: reconceptualization, scale development and validation
No full textParasocial relationship (PSR) plays a key role in consumer behavior, yet its conceptualization has been muddled. Existing PSR measurements, developed primarily for offline contexts, fail to address the need for valid and reliable scales applicable to online environments. This research reconceptualizes PSR in the modern marketplace and develops a new, valid, and reliable measurement instrument to assess it. By integrating multidisciplinary literature and consumer insights, this paper proposes a refined definition of PSR that captures its multidimensional nature. Based on a systematic literature review and five empirical studies, it introduces a new online PSR scale comprising three dimensions, including intimacy, maintenance, and real-life relationship intention, which demonstrates high reliability and validity. The new definition and scale significantly contribute to consumer behavior literature and offer practical implications
Advancing oncology nursing science and practice in hereditary cancer care
No full textNo abstract available
From single-sequences to evolutionary trajectories: protein language models capture the evolutionary potential of SARS-CoV-2
Get PDFProtein language models (PLMs) capture features of protein three-dimensional structure from amino acid sequences alone, without requiring multiple sequence alignments (MSA). The concepts of grammar and semantics from natural language have been suggested to have the potential to capture functional properties of proteins. Here, we investigate how these representations enable assessment of variation due to mutation. Applied to the SARS-CoV-2 spike protein via in silico deep mutational scanning (DMS), the PLM ESM-2 captures evolutionary constraints directly from sequence context, recapitulating what normally requires MSA data. Unlike other state-of-the-art methods which require protein structures or multiple sequences for training, we show what can be accomplished using an unmodified pretrained PLM. Applied to SARS-CoV-2 variants across the pandemic, we demonstrate that ESM-2 representations encode the evolutionary history between variants, as well as the distinct nature of variants of concern upon their emergence, associated with shifts in receptor binding and antigenicity. ESM-2 likelihoods can also identify epistatic interactions among sites in the protein. Our results here affirm that PLMs like ESM-2 are broadly useful for variant-effect prediction, including unobserved changes, and can be applied to understand novel viral pathogens with the potential to be applied to any protein sequence, pathogen or otherwise
Long-read sequencing reveals increased isoform diversity in key transcription factor effectors of intercellular signalling at the invertebrate-vertebrate transition
Get PDFBackground: Several intercellular signalling pathways (including wingless (Wnt), hedgehog (Hh), and bone morphogenetic protein (BMP)) are used repeatedly in animals throughout development and evolution and are also frequent targets for disease-associated disruptions. We have previously shown that the major transcriptional effectors of β-catenin-dependent Wnt signalling, the TCF/LEF proteins, in contrast to other pathway components, have a higher gene number and isoform diversity in vertebrates versus invertebrates, but this increased diversity has only been poorly quantified. Considering that isoform diversity correlates with organism complexity, any increase in major signalling effectors is likely to have made a significant contribution to vertebrate evolution. Results: Using de novo long-read transcriptomes, we compared isoform number per gene for the chordates Ciona intestinalis, Lampetra planeri and Xenopus tropicalis, thus encompassing the invertebrate sister group to vertebrates, as well as a cyclostome and a gnathostome vertebrate. We find a significant increase in the number of transcript isoforms per gene expressed during embryo development and organogenesis at the invertebrate-to-vertebrate transition, specifically for the main transcription factor effectors of the Wnt/β-catenin, Hh and BMP pathways, i.e. TCF/LEF, GLI and SMAD. Conclusions: Our results implicate an increase in isoform diversity of the transcription factors of major intercellular signalling pathways as having a disproportionate role in the evolutionary origin and diversification of vertebrates
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