270 research outputs found
Should all medical research be published? the moral responsibility of medical journal editors
This article reinvigorates a key question in publication ethics: Is there research that it is permissible to conduct but that ought not to be published? The article raises the question in relation to two recent medical studies. It is argued (1) that the publication of these studies may cause significant harm to individuals, (2) that editors of medical journals have a moral responsibility for such harm, (3) that denial of publication is inadequate as an instrument to fulfil this moral responsibility and (4) that internationally acknowledged publication ethics codes should incorporate this aspect of editorsâ moral responsibility.</jats:p
The four dimensions of contestable AI diagnostics - A patient-centric approach to explainable AI
The impact of telephone crisis services on suicidal users: A systematic review of the past 45 years
Purpose
â Telephone crisis services are increasingly subject to a requirement to âprove their worthâ as a suicide prevention strategy. The purpose of this paper is to: first, provide a detailed overview of the evidence on the impact of telephone crisis services on suicidal users; second, determine the limitations of the outcome measures used in this evidence; and third, suggest directions for future research.
Design/methodology/approach
â MEDLINE via Pubmed (from 1966), PsycINFO APA (from 1967) and ProQuest Dissertation and Theses (all to 4 June 2015) were searched. Papers were systematically extracted by title then abstract according to predefined inclusion and exclusion criteria.
Findings
â In total, 18 articles met inclusion criteria representing a range of outcome measures: changes during calls, reutilization of service, compliance with advice, caller satisfaction and counsellor satisfaction. The majority of studies showed beneficial impact on an immediate and intermediate degree of suicidal urgency, depressive mental states as well as positive feedback from users and counsellors.
Research limitations/implications
â A major limitation pertains to differences in the use of the term âsuicidalâ. Other limitations include the lack of long-term follow-up and of controlled research designs. Future research should include a focus on long-term follow-up designs, involving strict data protection. Furthermore, more qualitative research is needed in order to capture the essential nature of the intervention.
Originality/value
â This paper attempts to broaden the study and the concept of âeffectivenessâ as hitherto used in the literature about telephone crisis services and offers suggestions for future research.
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The impact of influences in a medical screening programme invitation:a randomized controlled trial
The acidic domain of the endothelial membrane protein GPIHBP1 stabilizes lipoprotein lipase activity by preventing unfolding of its catalytic domain.
GPIHBP1 is a glycolipid-anchored membrane protein of capillary endothelial cells that binds lipoprotein lipase (LPL) within the interstitial space and shuttles it to the capillary lumen. The LPLâ˘GPIHBP1 complex is responsible for margination of triglyceride-rich lipoproteins along capillaries and their lipolytic processing. The current work conceptualizes a model for the GPIHBP1â˘LPL interaction based on biophysical measurements with hydrogen-deuterium exchange/mass spectrometry, surface plasmon resonance, and zero-length cross-linking. According to this model, GPIHBP1 comprises two functionally distinct domains: (1) an intrinsically disordered acidic N-terminal domain; and (2) a folded C-terminal domain that tethers GPIHBP1 to the cell membrane by glycosylphosphatidylinositol. We demonstrate that these domains serve different roles in regulating the kinetics of LPL binding. Importantly, the acidic domain stabilizes LPL catalytic activity by mitigating the global unfolding of LPL's catalytic domain. This study provides a conceptual framework for understanding intravascular lipolysis and GPIHBP1 and LPL mutations causing familial chylomicronemia
Improved PET imaging of uPAR expression using new (64)Cu-labeled cross-bridged peptide ligands:comparative in vitro and in vivo studies
The correlation between uPAR expression, cancer cell invasion and metastases is now well-established and has prompted the development of a number of uPAR PET imaging agents, which could potentially identify cancer patients with invasive and metastatic lesions. In the present study, we synthesized and characterized two new cross-bridged (64)Cu-labeled peptide conjugates for PET imaging of uPAR and performed a head-to-head comparison with the corresponding and more conventionally used DOTA conjugate. Based on in-source laser-induced reduction of chelated Cu(II) to Cu(I), we now demonstrate the following ranking with respect to the chemical inertness of their complexed Cu ions: DOTA-AE105 << CB-TE2A-AE105 < CB-TE2A-PA-AE105, which is correlated to their corresponding demetallation rate. No penalty in the uPAR receptor binding affinity of the targeting peptide was encountered by conjugation to either of the macrobicyclic chelators (IC(50) ~ 5-10 nM) and high yields and radiochemical purities (>95%) were achieved in all cases by incubation at 95ÂşC. In vivo, they display identical tumor uptake after 1h, but differ significantly after 22 hrs, where the DOTA-AE105 uptake remains surprisingly high. Importantly, the more stable of the new uPAR PET tracers, (64)Cu-CB-TE2A-PA-AE105, exhibits a significantly reduced liver uptake compared to (64)Cu-DOTA-AE105 as well as (64)Cu-CB-TE2A-AE105, (p<0.0001), emphasizing that our new in vitro stability measurements by mass spectrometry predicts in vivo stability in mice. Specificity of the best performing ligand, (64)Cu-CB-TE2A-PA-AE105 was finally confirmed in vivo using a non-binding (64)Cu-labeled peptide as control ((64)Cu-CB-TE2A-PA-AE105(mut)). This control PET-tracer revealed significantly reduced tumor uptake (p<0.0001), but identical hepatic uptake compared to its active counterpart ((64)Cu-CB-TE2A-PA-AE105) after 1h. In conclusion, our new approach using in-source laser-induced reduction of Cu(II)-chelated PET-ligands provides useful information, which are predictive for the tracer stability in vivo in mice. Furthermore, the increased stability of our new macrobicyclic (64)Cu-CB-TE2A-PA-AE105 PET ligand is paralleled by an excellent imaging contrast during non-invasive PET scanning of uPAR expression in preclinical mouse cancer models. The translational promises displayed by this PET-tracer for future clinical cancer patient management remains, however, to be investigated
Did evolution create a flexible ligand-binding cavity in the urokinase receptor through deletion of a plesiotypic disulfide bond?
The urokinase receptor (uPAR) is a founding member of a small protein family with multiple Ly6/uPAR (LU) domains. The motif defining these LU domains contains five plesiotypic disulfide bonds stabilizing its prototypical three-fingered fold having three protruding loops. Notwithstanding the detailed knowledge on structure-function relationships in uPAR, one puzzling enigma remains unexplored. Why does the first LU domain in uPAR (DI) lack one of its consensus disulfide bonds, when the absence of this particular disulfide bond impairs the correct folding of other single LU domain-containing proteins? Here, using a variety of contemporary biophysical methods, we found that reintroducing the two missing half-cystines in uPAR DI caused the spontaneous formation of the corresponding consensus 7â8 LU domain disulfide bond. Importantly, constraints due to this cross-link impaired (i) the binding of uPAR to its primary ligand urokinase and (ii) the flexible interdomain assembly of the three LU domains in uPAR. We conclude that the evolutionary deletion of this particular disulfide bond in uPAR DI may have enabled the assembly of a high-affinity urokinase-binding cavity involving all three LU domains in uPAR. Of note, an analogous neofunctionalization occurred in snake venom Îą-neurotoxins upon loss of another pair of the plesiotypic LU domain half-cystines. In summary, elimination of the 7â8 consensus disulfide bond in the first LU domain of uPAR did have significant functional and structural consequences
Lipid-Induced Insulin Resistance Affects Women Less Than Men and Is Not Accompanied by Inflammation or Impaired Proximal Insulin Signaling
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