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Cost-effectiveness of α<sub>2</sub> agonists for intravenous sedation in patients with critical Illness
No full textIMPORTANCE Propofol and the α2 agonists dexmedetomidine and clonidine are used for sedation in patients with critical illness receiving mechanical ventilation. Evidence about thecosteffectiveness of intravenous (IV) sedation with these medications is lacking.OBJECTIVE To investigate the cost-effectiveness of dexmedetomidine-, clonidine-, and propofolbased IV sedation in patients with critical illness receiving mechanical ventilation.DESIGN, SETTING, AND PARTICIPANTS This economic evaluation used within-trial cost-utility analysis with a 6-month time horizon comparing dexmedetomidine-, clonidine-, and propofol-basedIV sedation from a UK National Health Service and Personal Social Services perspective, with individual-level data collected from the Alpha 2 Agonists for Sedation to Produce Better OutcomesFrom Critical Illness (A2B) trial. Adults with critical illness receiving mechanical ventilation, with ananticipated total requirement for mechanical ventilation of at least 2 days, from 41 intensive careunits in the UK were included. Recruitment ran from December 2018 through October 2023; the lastvdate of follow-up was December 10, 2023.INTERVENTIONS Dexmedetomidine, clonidine, or propofol IV sedation. Patients receiving α2agonists were permitted to receive supplemental propofol to achieve the target sedation score ifrequired.MAIN OUTCOMES AND MEASURES Incremental costs and quality-adjusted life years (QALYs)gained between dexmedetomidine-based vs propofol-based and clonidine-based vs propofol-basedIV sedation were assessed. Mean net monetary benefits with each medication were assessed.RESULTS Among 1404 adults with critical illness receiving mechanical ventilation (mean [SD] age,59.2 [14.9] years; 901 male [64.2%]), the mean (SD) Acute Physiology and Chronic Health Evaluation(APACHE) II score was 20.3 (8.2). The incremental cost for dexmedetomidine vs propofol was 5000 to 1328 (−4459). Fordexmedetomidine vs propofol, there were 0.0008 QALYs (95% CI, −0.0198 to 0.0214 QALYs)gained, and for clonidine vs propofol, there were −0.0019 QALYs (95% CI, −0.0221 to 0.0181 QALYs)gained. Mean net monetary benefits for dexmedetomidine, clonidine, and propofol were −58 063 to −50 882 (95% CI, −46 762), and −56 230 to −16 250.CONCLUSIONS AND RELEVANCE In this study, dexmedetomidine-, clonidine-, and propofol-basedIV sedation in patients with critical illness receiving mechanical ventilation had similar costs andQALYs. These findings suggest that economic considerations should not affect which sedative thesepatients receive
Novel method for realistically simulating the deposition of thin films from the gas phase and its application to study the growth of thin gold film on crystalline silicon
No full textWe present a novel approach for simulating thin film (TF) deposition from the gas phase at the atomistic scale, combining molecular dynamics (MD) and time-stamped force-bias Monte Carlo (tfMC). In this approach, MD, with its fine temporal resolution, captures fast events, such as incident atom-substrate collisions, while tfMC simulates slow relaxation processes, enhancing temporal scale coverage. The proposed approach also adequately models deposition conditions, for example, by accounting for realistic energy and angle distributions in the description of the incident flux. To demonstrate its efficacy, we apply it to simulate the physical vapor deposition of a 3 nm Au TF on crystalline Si. We find that the entire deposition process consisted of four distinct stages: (i) the initial degradation of the Si substrate, (ii) formation of a mixed Au-Si interface layer, (iii) nucleation and growth of a polycrystalline Au layer, proceeding in a fashion close to the Frank-van der Merwe mode (layer-by-layer growth), and (iv) postdeposition relaxation of microstructure. The produced TF was comprehensively characterized, revealing that the deposited polycrystalline Au layer contained a considerable number of defects, including dislocations, stacking faults, grain boundaries, and Si impurities. The analysis also showed that in the simulated high-energy deposition the Si substrate was considerably degraded and that the disordered Au-Si layer which formed at the interface resembled the melt-quenched Au82Si18 eutectic. A comparison with an analogous MD simulation revealed that the MD + tfMC approach extended the accessible time scale 5-fold, allowing us to reach the microsecond scale, and yielding a TF with higher crystallinity and better-developed microstructure. The deposition rate used in the MD + tfMC simulation was two to 3 orders of magnitude lower than in other recent, but purely MD, simulations, being significantly closer to experiment.</p
Subnational variations in the quality of household survey data in sub-Saharan Africa
No full textNationally representative household surveys collect geocoded data that are vital to tackling health and other development challenges in sub-Saharan Africa. Scholars and practitioners generally assume uniform data quality but subnational variation of errors in household data has never been investigated at high spatial resolution. Here, we explore within-country variation in the quality of most recent household surveys for 35 African countries at 5 × 5 km resolution and district levels. Findings show a striking heterogeneity in the subnational distribution of sampling and measurement errors. Data quality degrades with greater distance from settlements, and missing data as well as imprecision of estimates add to quality problems that can result in vulnerable remote populations receiving less than optimal services and needed resources. Our easy-to-access geospatial estimates of survey data quality highlight the need to invest in better targeting of household surveys in remote areas.</p
Structure-guided disulfide engineering restricts antibody conformation to elicit TNFR agonism
No full textA promising strategy in cancer immunotherapy is activation of immune signalling pathways through antibodies that target co-stimulatory receptors. hIgG2, one of four human antibody isotypes, is known to deliver strong agonistic activity, and modification of hIgG2 hinge disulfides can influence immune-stimulating activity. This was shown for antibodies directed against the hCD40 receptor, where cysteine-to-serine exchange mutations caused changes in antibody conformational flexibility. Here we demonstrate that the principles of increasing agonism by restricting antibody conformation through disulfide modification can be translated to the co-stimulatory receptor h4-1BB, another member of the tumour necrosis factor receptor superfamily. Furthermore, we explore structure-guided design of the anti-hCD40 antibody ChiLob7/4 and show that engineering additional disulfides between opposing F(ab’) arms can elicit conformational restriction, concomitant with enhanced agonism. These results support a mode where subtle increases in rigidity can deliver significant improvements in immunostimulatory activity, thus providing a strategy for the rational design of more powerful antibody therapeutics.</p
Building neutron stars with the MUSES calculation engine
No full textExploring the equation of state of dense matter is an essential part of interpreting the observable properties of neutron stars. We present here the first results for dense matter in the zero-temperature limit generated by the MUSES Calculation Engine, a composable workflow management system that orchestrates calculation and data processing stages comprising a collection of software modules designed within the MUSES framework. The modules presented in this work calculate equations of state using algorithms spanning three different theories/models: (1) Crust Density Functional Theory, valid starting at low densities, (2) Chiral Effective Field Theory, valid around saturation density, and (3) the Chiral Mean Field model, valid beyond saturation density. Lepton contributions are added through the Lepton module to each equation of state, ensuring charge neutrality and the possibility of -equilibrium. Using the Synthesis module, we match the three equations of state using different thermodynamic variables and different methods. We then couple the complete equation of state to a novel full-general-relativity solver (QLIMR) module that calculates neutron star properties. We find that the matching performed using different thermodynamic variables affects differently the range obtained for neutron star masses and radii (although never beyond a few percent difference). We also investigate the universality of equation of state-independent relations for our matched stars. Finally, for the first time, we use the Flavor Equilibration module to estimate bulk viscosity and flavor relaxation charge fraction and rates (at low temperature) for Chiral Effective Field Theory and the Chiral Mean Field model
Challenges and opportunities in uncertainty quantification for healthcare and biological systems
No full textUncertainty quantification (UQ) is an essential aspect of computational modelling and statistical prediction. Multiple applications, including geophysics, climate science and aerospace engineering, incorporate UQ in the development and translation of new technologies. In contrast, the application of UQ to biological and healthcare models is understudied and suffers from several critical knowledge gaps. In an era of personalized medicine, patient-specific modelling, and digital twins, a lack of UQ understanding and appropriate implementation of UQ methodology limits the success of modelling and simulation in a clinical setting. The main contribution of our review article is to emphasize the importance and current deficiencies of UQ in the development of computational frameworks for healthcare and biological systems. As the introduction to the special issue on this topic, we provide an overview of UQ methodologies, their applications in non-biological and biological systems and the current gaps and opportunities for UQ development, as later highlighted by authors publishing in the special issue.This article is part of the theme issue ‘Uncertainty quantification for healthcare and biological systems (Part 1)’
Response of downstream moving European eel (<i>Anguilla anguilla</i>) to hydrodynamic conditions created by channel constrictions
No full textThe efficacy of bypass channels that provide safe routes of passage for downstream moving fish at river infrastructure can be compromised if fish avoid the hydrodynamics encountered at the entrance. Using an open-channel flume, avoidance exhibited by European eel (Anguilla anguilla) was investigated in response to: (1) hydrodynamics created by a smooth tapered constriction under three discharge regimes (low, medium, high); and (2) a smooth tapered and sharp angled constriction under the low discharge. Although eel exhibited avoidance on encountering the smooth tapered constriction, prevalence and magnitude of response was not influenced by flow acceleration, the hydrodynamic factor often considered responsible for deterring fish. Eel more frequently rejected the sharp angled compared to the smooth tapered channel by retreating upstream, delaying downstream progress. This was likely due to flow recirculation (i.e. the occurrence of flow reversal upstream and downstream of the constriction) that was generated only at the sharp angled entrance. Flow accelerated at both constriction geometries, suggesting that recirculation had a greater influence on behaviour and subsequent rate of downstream movement. Minimising areas of flow recirculation, a seldom considered factor, as well as rates of acceleration at bypass entrances is likely to enhance their efficiency
Data report: age-depth model of the Corinth synrift sequence, Site M0079, IODP Expedition 381
No full textWe present a high-resolution age-depth model for Site M0079, drilled in the Corinth rift, central Greece, during International Ocean Discovery Program Expedition 381. To establish the model, we use available age constrains derived from postcruise research, including ages from 14C analysis and visible tephra layers, together with published ages from U/Th analysis, magnetostratigraphy, and relative paleointensity data. The age-depth model is built for the entire length of the Site M0079 drill hole using a probabilistic modeling approach in OxCal software. The resulting age-depth model provides a robust chronological framework for sediment accumulation within the Gulf of Corinth, constraining the most recent phase of synrift deposition over the past 800,000 y
Neighbourhood Insight Engine 1.0
No full textThe Neighbourhood Insight Engine is a multi-user, hypertextual, offline, browser-based tool for exploring qualitative data that enables users to generate reports. This is a conceptual and practical move from an observatory, which holds or connects data, to a platform that enables users to supply and share qualitative data and which supports discussion, debate and decision-making. It creates a shared and level floor to transparently connect diverse types of data. It provides the flexibility to work with diverse types of data. It creates the framework for conversations and decision-making using citizen-generated qualitative data
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