The MAGIC trial: a pragmatic, multicentre, parallel, noninferiority, randomised trial of melatonin versus midazolam in the premedication of anxious children attending for elective surgery under general anaesthesia

\ua9 2023 The Author(s)Background: Child anxiety before general anaesthesia and surgery is common. Midazolam is a commonly used premedication to address this. Melatonin is an alternative anxiolytic, however trials evaluating its efficacy in children have delivered conflicting results. Methods: This multicentre, double-blind randomised trial was performed in 20 UK NHS Trusts. A sample size of 624 was required to declare noninferiority of melatonin. Anxious children, awaiting day case elective surgery under general anaesthesia, were randomly assigned 1:1 to midazolam or melatonin premedication (0.5 mg kg−1, maximum 20 mg) 30 min before transfer to the operating room. The primary outcome was the modified Yale Preoperative Anxiety Scale-Short Form (mYPAS-SF). Secondary outcomes included safety. Results are presented as n (%) and adjusted mean differences with 95% confidence intervals. Results: The trial was stopped prematurely (n=110; 55 per group) because of recruitment futility. Participants had a median age of 7 (6–10) yr, and 57 (52%) were female. Intention-to-treat and per-protocol modified Yale Preoperative Anxiety Scale-Short Form analyses showed adjusted mean differences of 13.1 (3.7–22.4) and 12.9 (3.1–22.6), respectively, in favour of midazolam. The upper 95% confidence interval limits exceeded the predefined margin of 4.3 in both cases, whereas the lower 95% confidence interval excluded zero, indicating that melatonin was inferior to midazolam, with a difference considered to be clinically relevant. No serious adverse events were seen in either arm. Conclusion: Melatonin was less effective than midazolam at reducing preoperative anxiety in children, although the early termination of the trial increases the likelihood of bias. Clinical trial registration: ISRCTN registry: ISRCTN18296119

The computational and energy cost of simulation and storage for climate science: lessons from CMIP6

The Coupled Model Intercomparison Project (CMIP) is one of the biggest international efforts aimed at better understanding the past, present, and future of climate changes in a multi-model context. A total of 21 model intercomparison projects (MIPs) were endorsed in its sixth phase (CMIP6), which included 190 different experiments that were used to simulate 40 000 years and produced around 40 PB of data in total. This paper presents the main findings obtained from the CPMIP (the Computational Performance Model Intercomparison Project), a collection of a common set of metrics, specifically designed for assessing climate model performance. These metrics were exclusively collected from the production runs of experiments used in CMIP6 and primarily from institutions within the IS-ENES3 consortium. The document presents the full set of CPMIP metrics per institution and experiment, including a detailed analysis and discussion of each of the measurements. During the analysis, we found a positive correlation between the core hours needed, the complexity of the models, and the resolution used. Likewise, we show that between 5 %–15 % of the execution cost is spent in the coupling between independent components, and it only gets worse by increasing the number of resources. From the data, it is clear that queue times have a great impact on the actual speed achieved and have a huge variability across different institutions, ranging from none to up to 78 % execution overhead. Furthermore, our evaluation shows that the estimated carbon footprint of running such big simulations within the IS-ENES3 consortium is 1692 t of CO2 equivalent. As a result of the collection, we contribute to the creation of a comprehensive database for future community reference, establishing a benchmark for evaluation and facilitating the multi-model, multi-platform comparisons crucial for understanding climate modelling performance. Given the diverse range of applications, configurations, and hardware utilised, further work is required for the standardisation and formulation of general rules. The paper concludes with recommendations for future exercises aimed at addressing the encountered challenges which will facilitate more collections of a similar nature

The MAGIC trial: a pragmatic, multicentre, parallel, noninferiority, randomised trial of melatonin versus midazolam in the premedication of anxious children attending for elective surgery under general anaesthesia

BACKGROUND: Child anxiety before general anaesthesia and surgery is common. Midazolam is a commonly used premedication to address this. Melatonin is an alternative anxiolytic, however trials evaluating its efficacy in children have delivered conflicting results. METHODS: This multicentre, double-blind randomised trial was performed in 20 UK NHS Trusts. A sample size of 624 was required to declare noninferiority of melatonin. Anxious children, awaiting day case elective surgery under general anaesthesia, were randomly assigned 1:1 to midazolam or melatonin premedication (0.5 mg kg-1, maximum 20 mg) 30 min before transfer to the operating room. The primary outcome was the modified Yale Preoperative Anxiety Scale-Short Form (mYPAS-SF). Secondary outcomes included safety. Results are presented as n (%) and adjusted mean differences with 95% confidence intervals. RESULTS: The trial was stopped prematurely (n=110; 55 per group) because of recruitment futility. Participants had a median age of 7 (6-10) yr, and 57 (52%) were female. Intention-to-treat and per-protocol modified Yale Preoperative Anxiety Scale-Short Form analyses showed adjusted mean differences of 13.1 (3.7-22.4) and 12.9 (3.1-22.6), respectively, in favour of midazolam. The upper 95% confidence interval limits exceeded the predefined margin of 4.3 in both cases, whereas the lower 95% confidence interval excluded zero, indicating that melatonin was inferior to midazolam, with a difference considered to be clinically relevant. No serious adverse events were seen in either arm. CONCLUSION: Melatonin was less effective than midazolam at reducing preoperative anxiety in children, although the early termination of the trial increases the likelihood of bias. CLINICAL TRIAL REGISTRATION: ISRCTN registry: ISRCTN18296119

Roadmap for the development of desalination powered by renewable energy: Promotion for renewable energy for water production through desalination

The world water crisis is one of the largest public health issues of our time. One in eight people (884 million people) lack access to safe drinking water. The lack of clean, safe drinking water is estimated to kill almost 4,000 children per day. Many regions of the world are increasingly turning to desalination of brackish and sea water in their effort to match the increasing demand with the available natural resources. The trend is intensified by climate change, which seems to be already affecting the water cycle resulting in long periods of drought. The desalination industry has responded well to the increasing demand and is constantly evolving by reducing the costs and reliably producing water of very high quality. Most innovations focus on reducing the energy demand, since this is associated with high operating costs. However, desalination processes will always require considerable amounts of energy. If conventional energy sources are used, they contribute to climate change, which, in turn, affects the water cycle and intensifies the original problem that desalination was intending to solve. For desalination to remain a viable option in a world with a changing climate, renewable energy sources have to be used to meet at least part of its power requirements. The scientific community has been working for decades on optimising technological combinations where the desalination process is powered directly by renewable sources; thermal energy, electricity or shaft power. The industry is also recognising the potential and various companies are active in this field. The Roadmap ist the main outcome of the ProDes -Promotion of Renewable Energy for water production through desalination. It has been developed with input from various key actors from the industry and academia. This roadmap is intended to assist in coordinating and guiding the renewable energy-desalination community in overcoming the barriers they are currently facing

Desmosomal localization of beta-catenin in the skin of plakoglobin null-mutant mice

Plakoglobin, a protein belonging to the Armadillo-repeat gene family, is the only component that adherens junctions and desmosomes have in common. Plakoglobin null-mutant mouse embryos die because of severe heart defects and may exhibit an additional skin phenotype, depending on the genetic background. Lack of plakoglobin affects the number and structure of desmosomes, resulting in visible defects when cells are subjected to increasing mechanical stress, e.g. when embryonic blood starts circulating or during skin differentiation. By analysing plakoglobin-negative embryonic skin differentiation in more detail, we show here that, in the absence of plakoglobin, its closest homologue, beta-catenin, becomes localized to desmosomes and associated with desmoglein. This substitution may account for the relatively late appearance of the developmental defects seen in plakoglobin null-mutant embryos. beta-catenin cannot, however, fully compensate a lack of plakoglobin. In the absence of plakoglobin, there was reduced cell-cell adhesion, resulting in large intercellular spaces between keratinocytes, subcorneal acantholysis and necrosis in the granular layer of the skin. Electron microscopic analysis documented a reduced number of desmosomes, and those present lacked the inner dense plaque and had fewer keratin filaments anchored. Our analysis underlines the central role of plakoglobin for desmosomal assembly and function during embryogenesis

The added value of large-eddy and storm-resolving models for simulating clouds and precipitation

This study investigates, if atmospheric models with horizontal resolutions of 100 m to 2 km are able to better simulate key features, like clouds and precipitation, of the climate system than currently used models employing much coarser resolution and parameterized convection. Precipitation characteristics are much more realistic in the simulations with explicitly convection, already at kilometer resolutions. Increasing resolution to hectometer scales improves the simulation of precipitation only modestly, but substantially improves the simulation of clouds. The results suggest that new climate models, which explicitly resolve convection and the interaction with its environment, offer exciting opportunities to learn about the climate system

ICON-Sapphire: simulating the components of the Earth System and their interactions at kilometer and subkilometer scales. In open review for Geoscientific Model Development

State-of-the-art Earth System models typically employ grid spacings of O(100 km), too coarse to explicitly resolve main drivers of the flow of energy and matter across the Earth System. In this paper, we present the new ICON-Sapphire model configuration, which targets a representation of the components of the Earth System and their interactions with a grid spacing of 10 km and finer. Through the use of selected simulation examples, we demonstrate that ICON-Sapphire can already now (i) be run coupled globally on seasonal time scales with a grid spacing of 5 km and on monthly time scales with a grid spacing of 2.5 km, (ii) resolve large eddies in the atmosphere using hectometer grid spacings on limited-area domains in atmosphere-only simulations, (iii) resolve submesoscale ocean eddies by using a global uniform grid of 1.25 km or a telescoping grid with a finest grid spacing of 530 m, the latter coupled to a uniform atmosphere and (iv) simulate biogeochemistry in an ocean-only simulation integrated for 4 years at 10 km. Comparison to observations of these various configurations reveals no obvious pitfall. The throughput of the coupled 5-km global simulation is 126 simulated days per day employing 21 % of the latest machine of the German Climate Computing Center. Extrapolating from these results, multi-decadal global simulations including interactive carbon are now possible and short global simulations resolving large eddies in the atmosphere and submesoscale eddies in the ocean are within reac

Incidence of severe critical events in paediatric anaesthesia (APRICOT): a prospective multicentre observational study in 261 hospitals in Europe

Background Little is known about the incidence of severe critical events in children undergoing general anaesthesia in Europe. We aimed to identify the incidence, nature, and outcome of severe critical events in children undergoing anaesthesia, and the associated potential risk factors. Methods The APRICOT study was a prospective observational multicentre cohort study of children from birth to 15 years of age undergoing elective or urgent anaesthesia for diagnostic or surgical procedures. Children were eligible for inclusion during a 2-week period determined prospectively by each centre. There were 261 participating centres across 33 European countries. The primary endpoint was the occurence of perioperative severe critical events requiring immediate intervention. A severe critical event was defined as the occurrence of respiratory, cardiac, allergic, or neurological complications requiring immediate intervention and that led (or could have led) to major disability or death. This study is registered with ClinicalTrials.gov, number NCT01878760. Findings Between April 1, 2014, and Jan 31, 2015, 31â127 anaesthetic procedures in 30â874 children with a mean age of 6·35 years (SD 4·50) were included. The incidence of perioperative severe critical events was 5·2% (95% CI 5·0â5·5) with an incidence of respiratory critical events of 3·1% (2·9â3·3). Cardiovascular instability occurred in 1·9% (1·7â2·1), with an immediate poor outcome in 5·4% (3·7â7·5) of these cases. The all-cause 30-day in-hospital mortality rate was 10 in 10â000. This was independent of type of anaesthesia. Age (relative risk 0·88, 95% CI 0·86â0·90; p<0·0001), medical history, and physical condition (1·60, 1·40â1·82; p<0·0001) were the major risk factors for a serious critical event. Multivariate analysis revealed evidence for the beneficial effect of years of experience of the most senior anaesthesia team member (0·99, 0·981â0·997; p<0·0048 for respiratory critical events, and 0·98, 0·97â0·99; p=0·0039 for cardiovascular critical events), rather than the type of health institution or providers. Interpretation This study highlights a relatively high rate of severe critical events during the anaesthesia management of children for surgical or diagnostic procedures in Europe, and a large variability in the practice of paediatric anaesthesia. These findings are substantial enough to warrant attention from national, regional, and specialist societies to target education of anaesthesiologists and their teams and implement strategies for quality improvement in paediatric anaesthesia. Funding European Society of Anaesthesiology

Incidence of severe critical events in paediatric anaesthesia (APRICOT): a prospective multicentre observational study in 261 hospitals in Europe

Background Little is known about the incidence of severe critical events in children undergoing general anaesthesia in Europe. We aimed to identify the incidence, nature, and outcome of severe critical events in children undergoing anaesthesia, and the associated potential risk factors. Methods The APRICOT study was a prospective observational multicentre cohort study of children from birth to 15 years of age undergoing elective or urgent anaesthesia for diagnostic or surgical procedures. Children were eligible for inclusion during a 2-week period determined prospectively by each centre. There were 261 participating centres across 33 European countries. The primary endpoint was the occurence of perioperative severe critical events requiring immediate intervention. A severe critical event was defined as the occurrence of respiratory, cardiac, allergic, or neurological complications requiring immediate intervention and that led (or could have led) to major disability or death. This study is registered with ClinicalTrials.gov, number NCT01878760. Findings Between April 1, 2014, and Jan 31, 2015, 31 127 anaesthetic procedures in 30 874 children with a mean age of 6.35 years (SD 4.50) were included. The incidence of perioperative severe critical events was 5.2% (95% CI 5.0-5.5) with an incidence of respiratory critical events of 3.1% (2.9-3.3). Cardiovascular instability occurred in 1.9% (1.7-2.1), with an immediate poor outcome in 5.4% (3.7-7.5) of these cases. The all-cause 30-day in-hospital mortality rate was 10 in 10 000. This was independent of type of anaesthesia. Age (relative risk 0.88, 95% CI 0.86-0.90; p<0.0001), medical history, and physical condition (1.60, 1.40-1.82; p<0.0001) were the major risk factors for a serious critical event. Multivariate analysis revealed evidence for the beneficial effect of years of experience of the most senior anaesthesia team member (0.99, 0.981-0.997; p<0.0048 for respiratory critical events, and 0.98, 0.97-0.99; p=0.0039 for cardiovascular critical events), rather than the type of health institution or providers. Interpretation This study highlights a relatively high rate of severe critical events during the anaesthesia management of children for surgical or diagnostic procedures in Europe, and a large variability in the practice of paediatric anaesthesia. These findings are substantial enough to warrant attention from national, regional, and specialist societies to target education of anaesthesiologists and their teams and implement strategies for quality improvement in paediatric anaesthesia