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Arterial effects of anthracycline: structural and inflammatory assessments in non-human primates and lymphoma patients
Get PDFBackground: Anthracyclines, such as doxorubicin, are important anti-cancer therapies but are associated with arterial injury. Histopathological insights have been limited to small animal models and the role of inflammation in the arterial toxic effects of anthracycline is unclear in humans. Our aims were: 1) To evaluate aortic media fibrosis and injury in non-human primates treated with anthracyclines; 2) To assess the effect of anthracycline on aortic inflammation in patients treated for lymphoma. Methods1) African Green monkeys (AGM) received doxorubicin (30–60 mg/m2/biweekly intravenously, cumulative dose: 240 mg/m2). Blinded histopathologic analyses of the ascending aorta were performed 15 weeks after the last doxorubicin dose and compared to 5 age- and gender-matched healthy, untreated AGMs. 2) Analysis of the thoracic aorta of patients with diffuse large B-cell lymphoma (DLBCL), at baseline and after doxorubicin exposure, was performed using 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) in this observational study by maximal tissue-to-background ratio (TBRmax).</p> Results: In AGMs, doxorubicin exposure was associated with greater aortic fibrosis (collagen deposition: doxorubicin 6.23±0.88% vs. controls 4.67±0.54%; p=0.01) and intracellular vacuolization (doxorubicin 66.3±10.1 vs controls 11.5±4.2 vacuoles/field, p<0.0001) than untreated controls. In 101 patients with DLBCL, there was no change in aortic TBRmax after anthracycline exposure (TBRmax 1.46 ± 0.16 vs 1.44 ± 0.14 respectively, p=0.14). Univariate analyses yielded similar results.</p> Conclusions: In a large animal model, anthracycline exposure was associated with aortic fibrosis. In patients with lymphoma, anthracycline exposure was not associated with aortic inflammation. Further research is required to elucidate the mechanisms of anthracycline-related vascular harm
Urinary proteomics and systems biology link eight proteins to the higher risk of hypertension and related complications in blacks versus whites
Get PDFBlacks are more prone to salt‐sensitive hypertension than Whites. This cross‐sectional analysis of a multi‐ethnic cohort aimed to search for proteins potentially involved in the susceptibility to salt sensitivity, hypertension, and hypertension‐related complications. The study included individuals enrolled in African Prospective Study on the Early Detection and Identification of Cardiovascular Disease and Hypertension (African‐PREDICT), Flemish Study of the Environment, Genes and Health Outcomes (FLEMENGHO), Prospective Cohort Study in Patients with Type 2 Diabetes Mellitus for Validation of Biomarkers (PROVALID)‐Austria, and Urinary Proteomics Combined with Home Blood Pressure Telemonitoring for Health Care Reform Trial (UPRIGHT‐HTM). Sequenced urinary peptides detectable in 70% of participants allowed the identification of parental proteins and were compared between Blacks and Whites. Of 513 urinary peptides, 300 had significantly different levels among healthy Black (n = 476) and White (n = 483) South Africans sharing the same environment. Analyses contrasting 582 Blacks versus 1731 Whites, and Sub‐Saharan Blacks versus European Whites replicated the findings. COL4A1, COL4A2, FGA, PROC, MGP, MYOCD, FYXD2, and UMOD were identified as the most likely candidates underlying the racially different susceptibility to salt sensitivity, hypertension, and related complications. Enriched pathways included hemostasis, platelet activity, collagens, biology of the extracellular matrix, and protein digestion and absorption. Our study suggests that MGP and MYOCD being involved in cardiovascular function, FGA and PROC in coagulation, FYXD2 and UMOD in salt homeostasis, and COL4A1 and COL4A2 as major components of the glomerular basement membrane are among the many proteins potentially incriminated in the higher susceptibility of Blacks compared to Whites to salt sensitivity, hypertension, and its complication. Nevertheless, these eight proteins and their associated pathways deserve further exploration in molecular and human studies as potential targets for intervention to reduce the excess risk of hypertension and cardiovascular complications in Blacks versus Whites
The moral grounding of changing educational assessment and accountability: a theoretically informed analysis of moral assemblages in Denmark
Get PDFThis paper examines, via the concept of moral assemblage, the function of assessment as a tool for moral accountability and legitimation. Moral assemblages consist of disciplinary institutions, technologies, and practices, intertwined with elements of moral relationality, such as blame and shame, trust and risk, recognition and misrecognition, and care and safeguarding. The focus of this analysis is the Danish education system, which has undergone significant upheavals and changes in terms of assessment and accountability, including the moral foundations underlying these shifts in recent years. Empirically, the paper draws on policy documents, radio interviews, debate papers, and interviews with key actors at school, local, and national levels in Denmark. By drawing conclusions about the evolving moral foundations surrounding accountability-driven assessment policies, this paper enhances our understanding of how changes in accountability and assessment systems – even within a liberal and decentralised education system – reflect moral considerations in the context of increased demands for legitimation and system control
Refusing deterrence
Get PDFIn this article, we offer a conceptual provocation that seeks to reframe critical engagement with migration ‘deterrence’. While scholars have illustrated how deterrence policies and practices within migration governance do not necessarily work as advertised, they have rarely interrogated deterrence as such. Responding to this gap, we mobilize the method of critical juxtaposing to examine the historical and etymological origins of deterrence as a concept and set of practices. We bring together insights from critical criminology, political geography, and critical border studies to better apprehend what deterrence is and does in the world. We argue that deterrence must be understood as a form of public terror, foundational to modern states and relations of accumulation under racial capitalism. Rather than reproduce common-sense logic, language and violence of deterrence, we call for the need to refuse deterrence. In doing so, this article contributes to broader projects of police and border abolition
Guiding Retrieval using LLM-based Listwise Rankers
No full textLarge Language Models (LLMs) have shown strong promise as rerankers, especially in “listwise” settings where an LLM is prompted to rerank several search results at once. However, this “cascading” retrieve-and-rerank approach is limited by the bounded recall problem: relevant documents not retrieved initially are permanently excluded from the final ranking. Adaptive retrieval techniques address this problem, but do not work with listwise rerankers because they assume a document’s score is computed independently from other documents. In this paper, we propose an adaptation of an existing adaptive retrieval method that supports the listwise setting and helps guide the retrieval process itself (thereby overcoming the bounded recall problem for LLM rerankers). Specifically, our proposed algorithm merges results both from the initial ranking and feedback documents provided by the most relevant documents seen up to that point. Through extensive experiments across diverse LLM rerankers, first stage retrievers, and feedback sources, we demonstrate that our method can improve nDCG@10 by up to 13.23% and recall by 28.02%–all while keeping the total number of LLM inferences constant and overheads due to the adaptive process minimal. The work opens the door to leveraging LLM-based search in settings where the initial pool of results is limited, e.g., by legacy systems, or by the cost of deploying a semantic first-stage
Optogenetic control of gene expression in the cyanobacterium synechococcus sp. PCC 7002
Get PDFPhotosynthetic cyanobacteria can be utilised in biotechnology as environmentally sustainable cell factories to convert CO2 into a diverse range of biochemicals. However, a lack of molecular tools available for precise and dynamic control of gene expression hinders metabolic engineering and contributes to low product titres. Optogenetic tools enable light-regulated control of gene expression with high tunability and reversibility. To date, their application in cyanobacteria is limited and transferability between species remains unclear. In this study, we expressed the blue light-repressible YF1/FixJ and the green/red light-responsive CcaS/CcaR systems in Synechococcus sp. PCC 7002 and characterised their performance using GFP fluorescence assays and qRT-PCR. The YF1/FixJ system of non-cyanobacterial origin showed poor performance with a maximum dynamic range of 1.5-fold despite several steps to improve this. By contrast, the CcaS/CcaR system originating from the cyanobacterium Synechocystis sp. PCC 6803 responded well to light wavelengths and intensities, with a 6-fold increased protein fluorescence output observed after 30 min of green light. Monitoring GFP transcript levels allowed us to quantify the kinetics of transcriptional activation and deactivation and to test the effect of both multiple green/red and light/dark cycles on system performance. Finally, we increased CcaS/CcaR system activity under green light through targeted genetic modifications to the pCpcG2 output promoter. This study provides a detailed characterisation of the behaviour of the CcaS/CcaR system in Synechococcus sp. PCC 7002, as well as underlining the complexity of transferring optogenetic tools across species
Updating the Scottish national cardiovascular risk score: ASSIGN version 2.0
Get PDFBackground: The Assessing cardiovascular risk using Scottish Intercollegiate Guidelines Network (ASSIGN) risk score, developed in 2006, is used in Scotland for estimating the 10-year risk of first atherosclerotic cardiovascular disease (ASCVD). Rates of ASCVD are decreasing, and an update is required. This study aimed to recalibrate ASSIGN (V.2.0) using contemporary data and to compare recalibration with other potential approaches for updating the risk score.
Methods: Data from Scotland-resident participants from UK Biobank (2006–2010) and the Generation Scotland Scottish Family Health Study (2006–2010), aged 40–69 and without previous ASCVD, were used for the derivation of scores. External evaluation was conducted on UK Biobank participants who were not residents of Scotland. The original ASSIGN predictor variables and weights formed the basis of the new sex-specific risk equation to predict the 10-year risk of ASCVD. Different approaches for updating ASSIGN (recalibration, rederivation and regression adjustment) were tested in the evaluation cohort.
Results: The original ASSIGN score overestimated ASCVD risk in the evaluation cohort, with median predicted 10-year risks of 10.6% for females and 15.1% for males, compared with observed risks of 6% and 11.4%, respectively. The derivation cohort included 44 947 (57% females and a mean age of 55) participants. The recalibrated score, ASSIGN V.2.0, improved model fit in the evaluation cohort, predicting median 10-year risk of 4% for females and 8.9% for males. Similar improvements were achieved using the regression-adjusted model. Rederivation of ASSIGN using new beta coefficients offered only modest improvements in calibration and discrimination beyond simple recalibration. At the current risk threshold of
20% 10-year risk, the original ASSIGN equation yielded a positive predictive value (PPV) of 16.3% and a negative predictive value (NPV) of 94.4%. Recalibrated ASSIGN V.2.0 showed similar performance at a 10% threshold, with a PPV of 16.8% and an NPV of 94.6%.
Conclusions: The recalibrated ASSIGN V.2.0 will give a more accurate estimation of contemporary ASCVD risk in Scotland
Children with Sydenham chorea and psychiatric disorders had variable long-term outcomes and required multidisciplinary management
Get PDFAim:
Sydenham chorea (SC) is a globally significant, post-streptococcal, childhood neuropsychiatric condition that is rare in western Europe. This retrospective single-centre study focused on children with neuropsychiatric features of SC.
Methods:
Participants were recruited from neuropsychiatry referrals to a regional paediatric neurology department in Glasgow, Scotland, from 2009 to 2012. Interviews established the course of SC and the children's medical and family histories. Semi-structured psychiatric interviews explored current and past episodes of psychopathology.
Results:
We studied 12 children (seven girls) with a mean age of 13 (range 10–15) years, and an average of six (range 4–10) years after their SC symptoms began. Before they displayed symptoms, seven children had been suspected or diagnosed neurodevelopmental problems and four had separation anxiety. Their physical symptoms were often debilitating. Psychopathology was most severe during their first episode and SC diagnoses were sometimes delayed. Educational problems were frequent. Multiple psychiatric conditions were diagnosed in 11 children and anxiety and attention deficit hyperactivity disorder were the most common. Relapses occurred in nine cases. Additional services that were accessed included cardiology, rheumatology, physiotherapy, occupational therapy and speech therapy. Medication included prophylactic penicillin and symptomatic treatment.
Conclusion:
Children with SC and psychiatric disorders had variable long-term outcomes and required multidisciplinary management
Why we should be experientialists about suffering
Get PDFIncreased interest in suffering has given rise to different accounts of what suffering is. This paper focuses the debate between experientialists and non-experientialists about suffering. The former hold that suffering is necessarily experiential—for instance, because it is necessarily unpleasant or painful; the latter deny this—for instance, because one can suffer when and because one’s objective properties are damaged, even if one does not experience this. After surveying how the two accounts fare on a range of issues, the paper presents a decisive argument in favor of experientialism. The central claim is that non-experientialist accounts cannot accommodate cases of suffering that are virtuous and that directly contribute to some objective good
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