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Choreographing triage: making patient requests ‘flow’ through digitally enabled systems of access and decision-making in NHS primary care
No full textThis paper explores the altered landscape of primary care following the accelerated process of implementing digitally enabled triage across UK General Practice in response to Covid-19. Traditional understandings of triage are based on a static ‘pile sorting’ logic, which suggests that triage outcomes depend upon a single decision in time and space. With the introduction of remote, asynchronous and distributed decision-making, triage needs a more dynamic conceptualisation. Drawing on a team ethnography in three GP practices in England, we develop the concept of ‘triage choreography’ to explore the (often hidden) work involved in achieving the ‘flow’ of patient requests through triage systems. We ask who participates in this work, who might be excluded, and the consequences for triage outcomes. Our findings extend the literature on digital in/exclusion in primary care, providing a critical analysis of ‘flow’ in digitally enabled triage and what it means for patients. We show how, as patient requests enter digital systems, triaging work becomes distributed, often in uneven ways. And whilst digitally enabled routes through systems afford faster and smoother movement, they can also limit patients’ ability to influence how they access care and the modality in which it is delivered
Comparison of Carotid Plaque Ultrasound and Computed Tomography in Patients and Ex Vivo Specimens-Agreement of Composition Analysis
Get PDFBackground: Carotid plaque composition is central to stroke risk, but some aspects of plaque characterization are derived from ex vivo imaging, while clinical decision-making relies on in vivo ultrasound (US) and computed tomography (CT). High correlation of clinical in vivo and ex vivo imaging is necessary when including ex vivo plaque features in artificial intelligence (AI) models, but the extent of this correlation between CT and US remains poorly understood. Methods: Patients undergoing carotid endarterectomy (n = 188) were enrolled. Preoperative carotid US (n = 182) and CT (n = 156) were performed. Plaque specimens from 187 patients were imaged on ex vivo CT and US. Quantitative metrics included plaque volumes, relative calcified/non-calcified volumes, HU and grayscale distributions, Agatston and calcification scores, and heterogeneity indices (coefficient of variation). Qualitative US parameters (echogenicity, juxtaluminal echolucency, discrete white areas) were visually graded. Correlation between in vivo and ex vivo imaging was assessed, and agreement was quantified for parameters with the highest correlation with Bland-Altman analysis. Results: CT of patients and ex vivo CT showed moderate to strong correlation for total, calcified, and non-calcified plaque volumes and whole-plaque mean HU (r = 0.55-0.79; CCC = 0.43-0.74). Agatston and calcification scores correlated strongly (r = 0.78-0.80; CCC = 0.63-0.76). In contrast, most non-calcified and heterogeneity metrics showed negligible-to-weak correlation. Correlations between in vivo and ex vivo US were substantially weaker (maximum correlation: 75th grayscale percentile r = 0.35). In vivo CT overestimated calcified volume (bias: 8.7%) and in vivo US underestimated the 75th grayscale quantile (bias: -25.5 grayscale). Conclusions: Quantitative CT metrics-particularly relative calcified plaque volume and calcium scores-translate reasonably well from ex vivo to in vivo imaging and represent robust candidates for radiomics and AI-based stroke risk models, even ex vivo. Ultrasound parameters show limited translational validity, underscoring the need for volumetric clinical US and discouraging the inclusion of ex vivo ultrasound features for machine learning applications
Revising the ABIDE MCI to dementia prediction model for automated cerebrospinal fluid assays
Get PDFINTRODUCTION: Automated cerebrospinal fluid (CSF) biomarker assays have largely replaced manual immunoassays for measuring amyloid pathology in CSF. We refitted and validated the ABIDE model, predicting progression from mild cognitive impairment (MCI) to dementia, with CSF measurements from the automated Elecsys platform. METHODS: We included 2413 MCI participants (998 [41%] amyloid‐positive) from seven observational cohorts. Elecsys was used in 958 (40%) participants. The parameters of the previous ABIDE Cox model were re‐estimated. Model discrimination and calibration were evaluated with leave‐one‐cohort‐out cross‐validation. RESULTS: During follow‐up, 1034 (42%; 585 [58%] amyloid‐positive) participants developed dementia. Discrimination was good with Harrell's C of 0.70 (95% confidence interval [CI]: 0.66–0.73). Calibration was good in the total population and amyloid‐positive subgroup, with substantial predicted progression risks for all amyloid‐positive participants. DISCUSSION: We refitted the ABIDE model, predicting MCI to dementia progression, with automated CSF measurements. The model was well calibrated in amyloid‐positive patients and may support clinical discussions regarding ATTs
Presencing Echoes in the Archive: Material Voices Through Space and Time
Get PDFThis article presences the material entanglements of analog and digital archives through a workshop-based inquiry titled “Collaging Echoes and Resonances Across Space/Time”, which applied Annie Goh’s question of whether echoes can claim a voice of their own to objects. In this session, participants collectively collaged with imprints of meaningful objects diffracted through materials like paint, tape, etc., and with the objects themselves. Group discussions yielded key considerations that we examine in the context of archiving. These include understanding materials in relation to the structures that shape the formation of their echoes; tracing how echoes may evolve into unrecognizable forms; and how iterative threads of meaning across ongoing interactions act upon each other in non-linear time. As the digital archive becomes increasingly prominent, these questions help to frame implications across archival formats to better understand the relationships between iterations of an item and the containers in which it is held, furthering the conceptualization of a posthuman archive. This paper applies new materialist perspectives of knowledge to history and archiving through an arts-based approach, offering a novel entry point to understanding archival echoes. It will interest scholars and/or practitioners in history, curation, and museum studies, enriching criticality in how knowledge is enacted in the material
BlackTHUNDER: Shedding light on a dormant and extreme little red dot at z = 8.50
Get PDFRecent photometric surveys with James Webb Space Telescope (JWST) have revealed a significant population of mysterious objects with red colours, compact morphologies, frequent signs of active galactic nucleus (AGN) activity, and negligible X-ray emission. These ‘little red dots’ (LRDs) have been explored through spectral and photometric studies, but their nature is still under debate. As part of the BlackTHUNDER survey, we have observed UNCOVER_20466, one of the most distant LRDs known (), with the JWST/NIRSpec Integral Field Unit (IFU). Previous JWST/NIRCam and JWST/NIRSpec MSA observations of this source revealed its LRD nature, as well as the presence of an AGN. Using our NIRSpec IFU data, we confirm that UNCOVER_20466 is an LRD (based on spectral slopes and compactness) that contains an overmassive black hole. However, our observed Balmer decrements do not suggest strong dust attenuation, resulting in a lower -based bolometric luminosity and () than previously found. This source lies on local relations between and , suggesting that this could be a progenitor of the core of a lower-redshift galaxy. We explore the possible evolution of this source, finding evidence for substantial black hole accretion in the past and a likely origin as a heavy seed at high redshift (). emission is strongly detected, implying . The extremely high / ratio is indicative of not only AGN photoionization and heating, but also extremely high densities (), suggesting that this black hole at such high redshift may be forming in an ultra-dense protogalaxy
Potential Pathways and Solutions to Acute Food System Crisis in the UK
Get PDFThere is increasing concern in many advanced economies about the risks of disruption and crises in agri-food systems. Government departments and non-governmental organisations are working to identify and understand specific risks but struggle to take broad, holistic perspectives and therefore underestimate the potential for civil unrest. In the interests of helping move from understanding to action, we convened a group of experts through a Delphi process to map out potential pathways to acute UK food system crises and identify interventions that would build resilience and sustainability. To this end, we consulted 31 experts, carrying out 15 expert interviews, followed by three surveys and two workshops with a further 16 experts. The experts highlighted the many existing chronic issues creating a tinderbox for an acute risk to lead to a food crisis in the UK. These chronic issues include climate change, poor policy implementation, rising inequality, food supply chain consolidation and the risks from just-in-time supply of food. They voted to include three acute triggers—(a) cyber-attack, (b) a major extreme weather event and (c) a major new international conflict—and described how any combination of these could lead to (d) a UK food availability and/or price shock that could result in widespread fear of unsafe or inadequate food, leading to violence. A total of 7 system-wide interventions were prioritised to help address these pathway elements together and build sustainability, and a further 21 were identified to address elements individually
Synthesis and in vitro evaluation of 18F-labelled ACE2 small molecule inhibitors for PET imaging studies
Get PDFThis thesis aims to develop 18F-labelled ACE2 inhibitors as PET tracers for the non-invasive visualisation of ACE2 expression, with potential applications in COVID-19 and other ACE2-related pathologies. Chapter I provides a general introduction to ACE2, its role in disease, and the rationale for fluorine-18-labelled inhibitors as PET tracers. Chapter II details the design and synthesis of novel fluorinated analogues of MLN-4760. It starts with the in silico selection of fluorinated MLN-4760 analogues guided by molecular docking, and discusses new synthetic strategies developed to overcome limitations of the existing route. The synthesis of selected analogues is described, and their ACE2 inhibitory activity is evaluated in vitro through IC50 measurements. Chapter III examines the role of PET in imaging ACE2 expression and reviews existing tracer studies. The radiolabelling of ACE2-targeting analogues is described, including precursor synthesis, fluorine-18 incorporation, and optimisation of labelling conditions. Chapter IV provides full experimental procedures and characterisation data for the compounds discussed in this thesis
Bimekizumab safety and efficacy in patients with psoriatic arthritis: 3-year results from two phase 3 studies
No full textObjectives Bimekizumab, a monoclonal IgG1 antibody that selectively inhibits interleukin (IL)-17F in addition to IL-17A, has demonstrated tolerability and clinical efficacy in patients with psoriatic arthritis (PsA). Here, we report an additional year of safety and efficacy of bimekizumab to 3 years. Methods BE OPTIMAL (NCT03895203; biologic disease-modifying antirheumatic drug [bDMARD]-naïve) and BE COMPLETE (NCT03896581; prior inadequate response/intolerance to tumour necrosis factor inhibitors [TNFi-IR]) assessed subcutaneous bimekizumab 160 mg every 4 weeks in patients with PsA. Study completers could enrol in the BE VITAL open-label extension (NCT04009499). Outcomes reported as observed, or using modified non-responder or multiple imputation, to 3 years. Results Overall, 546/299 (76.7/74.8%) bDMARD-naïve/TNFi-IR patients randomised to bimekizumab or placebo at baseline (Bimekizumab Total group) completed Year 3. Treatment-emergent adverse event rates (exposure-adjusted incidence rate/100 patient-years [95% CI]) for bimekizumab-treated patients through 3 years were 164.2 (152.7−176.3) in bDMARD-naïve and 88.6 (79.1−98.9) in TNFiIR patients, consistent with those at Year 1 with no new safety signals identified. Response rates for efficacy outcomes were sustained up to 3 years; at Year 1 and Year 3 respectively, 56.1/50.4% and 53.2/55.2% of bDMARD-naïve/TNFi-IR patients achieved ACR50, 61.8/58.2% and 59.5/59.1% achieved swollen joint count resolution, and 64.7/66.2% and 61.9/67.5% had 100% improvement from baseline in Psoriasis Area and Severity Index. Responses for other efficacy measures were similarly sustained and consistent in bDMARD-naïve and TNFi-IR patients. Conclusion Bimekizumab demonstrated sustained high levels of efficacy and tolerability to 3 years, supporting its suitability for long-term treatment in bDMARD-naïve and TNFi-IR patients with PsA
A bactericidal tuberculosis drug regimen driven by inhibition of the terminal oxidases by pretomanid
Get PDFPretomanid is a unique anti-tuberculosis agent that inhibits both cell-wall synthesis and bioenergetics in Mycobacterium tuberculosis. While targeting the cell wall triggers a rapid bactericidal effect on replicating mycobacteria, the release of nitric oxide is linked to bactericidal potency against antibiotic-tolerant, non-replicating subpopulations through interference with the electron transport chain. Nonetheless, the specific molecular target(s) of the drug remain unknown. Through the utilization of genetic and chemical biology approaches, we present evidence that pretomanid inhibits both the cytochrome bcc:aa3 and bd oxidase respiratory branches. This property leads to a pronounced synergy with telacebec (Q203), a clinical-stage drug targeting the cytochrome bcc:aa3, while concurrently curtailing the emergence of resistance to pretomanid. Furthermore, the incorporation of the cytochrome bd oxidase inhibitor ND-011992 resulted in a triple drug combination highly bactericidal against antibiotic-tolerant, non-replicating as well as replicating M. tuberculosis. The combination of pretomanid and drugs targeting the terminal oxidases holds the potential to serve as the cornerstone for an efficacious sterilizing drug regimen against tuberculosis
Clumped Isotope Temperature Reconstruction Using Stalagmite Drip Cups
Get PDFRationale: Application of clumped isotope palaeothermometry to speleothems (carbonate cave deposits, e.g., stalagmites and flowstones) has been restricted largely to subaqueous samples because of kinetic fractionation processes that occur during subaerial speleothem formation, which lead to erroneously high inferred temperatures. Speleothems are spatially near‐ubiquitous terrestrial archives that can be dated accurately over million‐year timescales. Thus, wider application of the clumped isotope technique in speleothems could dramatically increase our understanding of terrestrial thermal history. In this study, we assessed the potential of speleothem drip cups (concave depressions at a stalagmite apex in which dripwater accumulates to create a subaqueous environment) to yield reliable palaeotemperature inferences. Methods: We sampled along two isochronous layers that extend across both sides of a pronounced drip cup in stalagmite MAYA 22‐7 from Cenote Ch'en Mul, Yucatán, Mexico, which was dated to 1650 ce ± 23 years. We measured bulk stable (δ18O and δ13C) and clumped (Δ47) isotope values at increasing distances from the drip cup centre to test for kinetic fractionation effects. Results: Lower δ18O, δ13C, and higher Δ47 values were obtained from the drip cup's central subaqueous zone compared with the subaerial flanks, demonstrating reduced isotope fractionation in the subaqueous zone. Average clumped isotope temperatures (TΔ47) inferred from subaqueous drip cup samples are 1°C–2°C higher than modern cave temperatures and 3°C–7°C warmer than estimated formation paleotemperatures derived from nearby regional reconstructions and TEX86 analysis of our sample. This suggests a persistent degree of clumped isotope kinetic effects. Conclusions: Despite persistent kinetic effects, lower inferred temperatures from subaqueous drip cup samples suggest closer to equilibrium precipitation compared with subaerial samples. We propose that drip cup carbonates have the potential to yield reliable palaeotemperatures and describe a widely applicable test for clumped isotope kinetic effects in speleothem drip cups by sampling across isochronous layers