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A generalisable pixel classifier for cellular phenotyping in multiplex immunofluorescence images
No full textObjectives: This study aimed to evaluate the cost-effectiveness (CE) of four hepatocellular carcinoma (HCC) in the UK, the GAAD algorithm, which combines patient gender and age with Elecsys® alpha-fetoprotein (AFP) and Elecsys protein induced by vitamin K absence-II (PIVKA-II) biomarker assays, ultrasound (US), US+AFP and GAAD+US.Methods: A de novo micro-simulation model was developed in Microsoft Excel® from the perspective of the UK National Health Service to calculate life years, quality-adjusted life-years (QALYs), costs, incremental CE ratios, and net monetary benefits. Parameters were sourced from peer-reviewed published literature, national guidelines, and public cost databases. Sensitivity and scenario analyses were performed to evaluate the impact of parameter and structural uncertainty on the results. Results: In a simulated cohort of 100,000 patients, discounted costs and QALYs per patient were £8,663 and 6·066 for US, £9,095 and 6·076 for US+AFP, £8,719 and 6·078 for GAAD alone, and £9,114 and 6·086 for GAAD+US. At a CE threshold of £20,000/QALY, GAAD was the most cost-effective strategy; however, although most costly, GAAD+US was the most clinically effective. Sensitivity and scenario analyses indicated that HCC incidence, along with the costs associated with diagnostic performance influence CE.Conclusion: Considering the cost of US and the low incidence of HCC in the UK, this study suggests that GAAD alone or in combination with US are cost-effective surveillance strategies compared with US and US+AFP. Whilst GAAD+US showed the highest QALY increase, GAAD alone is considered preferable with regard to CE; however, better performance estimates for GAAD+US are needed to confirm.<br/
Trialling the Hailie® smart inhaler with Children and Young People for asthma management in the United Kingdom: A Nested Qualitative Evaluation
No full textBackground Monitoring of inhaler use in high-risk children has the potential to reduce asthma attacks and asthma-related deaths. We, therefore, undertook the first UK primary care study to identify high-risk children and young people by searching primary care health records and provided the Hailie® smart inhaler to monitor their asthma medication usage. In this paper, we present data from the nested qualitative study, conducted with key stakeholders. Methods This qualitative interview-based study explored a range of topics relating to the experiences of paediatric asthma care and management, including the use of the Hailie® smart inhaler, from the perspectives of the children, their parents/carers and healthcare professionals. Interview transcripts were generated and thematically analysed. Results Six parent-child dyads and one parent were interviewed, either online or face-to-face. Additionally, three healthcare professionals (1 Nurse, 1 Pharmacist and 1 Practice Manager) involved in paediatric asthma care and/or management were also interviewed. Two specific themes were identified: Firstly, app-based monitoring was generally viewed positively and was reassuring to parents. Children also appreciated learning about using their inhalers. Secondly, challenges with synching were identified and users had some practical suggestions for improvement. Healthcare professionals also observed that monitoring should not replace clinical support for self-management. Conclusion Our findings support the acceptability and usefulness of the Hailie® smart inhaler amongst children with high-risk asthma, although some technical difficulties need to be addressed. Further research is needed to assess effectiveness in clinical care management
Parasite responses to resource provisioning can be altered by within-host co-infection interactions
No full textAnthropogenic changes to the environment significantly impact wildlife infectious diseases by modifying food resources and impacting host-parasite interactions through changes in host demography, behaviour, and immune defences. Supplemental resource provisioning has been found to both enhance and mitigate parasite transmission; however, the role of co-infecting parasites in mediating these effects remains understudied. We developed a mathematical model to explore these dynamics, motivated by the empirical system of wood mice (Apodemus sylvaticus) infected with the nematode Heligmosomoides polygyrus, which suppresses co-infections by the apicomplexan microparasite Eimeria hungaryensis. Our model shows that the effects of resource provisioning on parasite epidemiology can be mediated, and potentially reversed, by within-host co-infection interactions, through effects on host-parasite contact rates and host susceptibility. Provisioning may elevate microparasite prevalence by reducing nematode burdens, thereby releasing the microparasite from the negative effects of co-infection. However, if provisioning increases host contact rates with parasite infective stages in the environment, the associated increase in nematode burdens can result in concomitant reductions in the microparasite, due to the negative within-host co-infection interaction. Our study highlights the need for experimental designs that decouple the complex factors of provisioning on co-infecting parasite dynamics and provides a framework for interpreting outcomes in multi-parasite systems
Clinical decisions and outcomes after switching high-sensitivity cardiac troponin assays in suspected acute coronary syndrome: A prospective interrupted time-series study
Get PDFImportance High-sensitivity cardiac troponin T and I assays are considered equivalent for the diagnosis of myocardial infarction. However, the impact of transitioning from an assay measuring cardiac troponin I to one measuring cardiac troponin T on patient care and clinical outcomes is unknown.Objective To evaluate the impact of transitioning from a high-sensitivity assay measuring cardiac troponin I to one measuring cardiac troponin T on the care and outcomes of consecutive patients with suspected acute coronary syndrome.Design, Setting, and Participants This was a prospective, multicenter, interrupted time-series study conducted at 3 acute care centers. Consecutive patients presenting with suspected acute coronary syndrome to an acute care hospital were identified between October 2020 and October 2022.Interventions All sites changed from an assay measuring cardiac troponin I to one measuring cardiac troponin T in October 2021.Main Outcomes and Measures The primary outcome was hospital admission.Results Among 25 849 patients, 13 146 (median [IQR] age, 60 [47-73] years; 6961 male [53%]) and 12 703 (median [IQR] age, 60 [47-73] years; 6825 male [54%]) presented before and after the transition to cardiac troponin T, respectively. The proportion of patients with myocardial injury increased from 21% (2800 of 13 146 patients) to 38% (4781 of 12 703 patients), and patients were more likely to be admitted to the hospital after the transition (odds ratio [OR], 2.24; 95% CI, 1.81-2.77; both P < .001). A 6-fold increase in serial testing was observed in patients undergoing a measure of cardiac troponin T compared with cardiac troponin I (OR, 6.03; 95% CI, 4.85-7.49; P < .001). Subsequent myocardial infarction, heart failure, or cardiovascular death at 1 year was comparable before and after the transition (OR, 0.83; 95% CI, 0.48-1.41; P = .49).Conclusions and Relevance The transition from a high-sensitivity assay measuring cardiac troponin I to one measuring cardiac troponin T was associated with increased identification of myocardial injury, serial troponin measurements, and hospital admissions without evidence of improved cardiovascular outcomes at 1 year
Synthesis of quantum simulators by compilation
Get PDFQuantum simulation plays a critical role in advancing our understanding and development of quantum algorithms, quantum computing hardware, and quantum information science. Despite the availability of various quantum circuit simulators, they often face challenges in terms of maintainability and extensibility. In this paper, we introduce Lightweight Functional Quantum Simulator (LFQS), a compilation-based framework that addresses these issues by leveraging an intermediate language to synthesize efficient quantum simulators in C and CUDA. The intermediate language exploits the underlying structured sparsity behind the matrix representation of quantum gates. Our framework generates efficient code for multi-core CPUs and GPUs and outperforms state-of-the-art simulators, such as Qiskit, Catalyst, and QuEST, as well as a representative of dense tensor frameworks, NumPy, in both micro-benchmark and macro-benchmark circuits.</p
Fitting and comparison of calcium-calmodulin kinetic schemes to a common data set using non-linear mixed effects modelling
Get PDFCalmodulin is a calcium binding protein that is essential in calcium signalling in the brain. There are many computational models of calcium-calmodulin binding that capture various calmodulin features. However, existing models have generally been fit to different data sets, with some publications not reporting their training and validation performance. Moreover, there is no model comparison using a common benchmark data set as is common practice in other modeling domains. Finally, some calmodulin models have been fit as a part of a larger kinetic scheme, which may have resulted in parameters being underdetermined. We address these three limitations of previous models by fitting the published calcium-calmodulin schemes to a common calcium-calmodulin data set comprising equilibrium data from Shifman et al. and dynamical data from Faas et al. Due to technical limitations, the amount of uncaged calcium in Faas et al. data could not be predicted with certainty. To find good parameter fits, despite this uncertainty, we used non-linear mixed effects modelling as implemented in the Pumas.jl package. The Akaike information criterion values for our reaction rate constants were significantly lower than for the published parameters, indicating that the published parameters are suboptimal. Moreover, there were significant differences in calmodulin activation, both between the schemes and between our reaction rate and those previously published. A kinetic scheme with independent lobes and unique, rather than identical, binding sites fit the data best. Our results support two hypotheses: (1) partially bound calmodulin is important in cellular signalling; and (2) calcium binding sites within a calmodulin lobe are kinetically distinct rather than identical. We conclude that more attention should be given to validation and comparison of models of individual molecules.</p
A More-than-Moore Optical Multi-Sensing Platform
Get PDFThis work demonstrates the integration of a photoluminescent sensing film on a complementary metal– oxide–semiconductor (CMOS) sensor application-specific integrated circuit (ASIC) for time-resolved optical oxygen sensing. A phosphorescent dye, platinum octaethylporphyrin (PtOEP), embedded in a polydimethylsiloxane (PDMS) matrix, was deposited on the ASIC using spin coating and photolithographic patterning. The custom ASIC includes an array of closely spaced silicon LED (SiLED) emitters and single photon avalanche diode (SPAD) detectors with the capability of multimodal sensing. The platform benefits from the dye’s long emission lifetime, resistance to photobleaching, and the intrinsic nature of the lifetime measurement concerning the analyte and dye. A custom printed circuit board (PCB) incorporating a time-correlated single photon counting (TCSPC) module based on an ARM Cortex-M7 microcontroller was developed to drive the sensor and acquire nanosecond-resolution photon timing data. The integrated sensor system was rigorously characterized in a controlled gas chamber, showing reliable oxygen detection via luminescence quenching and strong Stern–Volmer linearity ( R 2 = 0.9771 ). It exhibited excellent repeatability (<5% variation across cycles) and fast, real-time response. In order to demonstrate the multimodal sensing, we integrated multiple oxygen-sensitive dyes—PtOEP, palladium octaethylporphine (PdOEP), and zinc octaethylporphyrin (ZnOEP)—over different CMOS regions. The system was adapted for multianalyte sensing without cross sensitivity, highlighting its potential for biomedical applications in hypoxic environments.</p
Burn after leaving? Recognition denial as strategy in the post-Brexit security relationship
Get PDFProminent examples of withdrawal from IOs raise the question of how actors seek to validate their role after exit. IOs may seek legitimation either through the exclusion of the departing state or continued engagement in their activities, while departing states may validate withdrawal through continued engagement or the denial of recognition. This article claims legitimation strategies are shaped by the policy domain, with external differentiation, institutional overlap and contingent actorness making IOs more susceptible to recognition denial and thus more likely to seek continued engagement. The article demonstrates this empirically through the UKEU security relationship post-Brexit, drawing on interviews with both sides. We show how Britain’s potential contribution to EU security underscored a desire to keep Britain involved, but that politicisation in the UK brought led the Johnson government to pursue a deliberate strategy of recognition denial. Our findings help explain why actors seek different legitimation strategies after withdrawal
Mind the gap:Formal kinship care and children’s participation in decision making
Get PDFKinship care is a historically persistent phenomenon that has been utilised as a form of alternative care across the world for centuries. It is increasingly being considered as the first choice in national and regional policies for alternative care of children. This paper will focus upon the literature surrounding the paradoxical position that formal kinship care holds in the public and private spheres of child welfare. Considering the added complexity of conceptualisations of family and familial dynamics, the potential added barriers to children and young people’s participation in kinship care decision-making will be discussed. The position of children’s participation in kinship care decision making will be compared to other types of placements for looked after children. Theoretical constructs and frameworks including adopting an ecological approach will underpin this discussion to elucidate the relationship between children’s participation and kinship care decision-making. Broader implications will be discussed for how children’s participation may be improved for kinship care decision-making, the link between children's participation in decision-making and placement outcomes and how future research may contribute to bridging the gap between policy and practice
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