Investigating the Relationship Between Midazolam Serum Concentrations and Paediatric Delirium in Critically Ill Children

OBJECTIVES: Intravenous midazolam is widely used for sedation in critically ill children. Sometimes, these children develop a paediatric delirium (PD). Our aim was to determine the relationship between midazolam serum concentration and the development of new PD in critically ill children.DESIGN: Prospective observational pilot study.SETTING: Paediatric Intensive Care Unit (PICU), Groningen, the Netherlands.PATIENTS: All children admitted to the PICU from October-December 2019 who received continuous midazolam administration.INTERVENTIONS: None.MEASUREMENTS AND MAIN RESULTS: Twenty-five percent (n = 7) of the included patients (n = 28) developed new PD. In most patients, PD occurred following midazolam dose reduction. The median cumulative midazolam dose was higher in patients who developed PD compared to those without PD. We analysed 104 blood samples to determine the midazolam concentrations. To determine whether patients had PD, the Sophia Observation withdrawal Symptoms-Paediatric Delirium (SOS-PD) score was used. Patients suffering PD (n = 7) had a lower median midazolam concentration on that day compared with the day prior to PD detection. Analysis of the active metabolites, 1-hydroxymidazolam and 1-hydroxymidazolam glucuronide, showed similar results.CONCLUSIONS: PD may be linked to a sudden and significant reduction in the midazolam concentration in critically ill children. Further investigation in larger patient populations is necessary to validate our findings.</p

Leven, leren en dromen na 2 jaar Campus Eemsdelta:Jongeren, leefbaarheid en toekomstperspectief

Onderzoeksrapport fase 4, september 2023-juli 202

Small Continental Mammoths and the Phenomenon of Dwarfism

Abstract: In the evolution of proboscideans, the emergence of dwarf and semi-dwarf forms occurred repeatedly, on various territories and at various times, due to a lack of resources caused by geographic isolation on the islands and landscape isolation on the mainland. Despite a significant amount of information on the island forms of mammoths and elephants, the question of the association between a decrease in the body size and morphological changes in the dental system remains controversial. According to some data, the formation of dwarf forms was accompanied by a unidirectional decrease in the number of dental plates (NDP) of the tooth and thickening of the enamel. According to other data, changes in the dental system on the islands were mosaic in nature; that is, the NDP could decrease, remain unchanged, or even increase. Taking into account the importance of the NDP as a diagnostic tool for species identification of proboscidean taxa and the absence of a consensus on the stability of a trend towards a decrease in the NDP from tall continental ancestors to island dwarf descendants, we (1) summarize data on the finds of small teeth of mammoths from the Mammuthus genus with a reduced NDP in the localities in northern Eurasia, (2) present new radiocarbon dates, and (3) consider the NDP as a characteristic of developing dwarfism in continental mammoths. The study of small teeth of the last generation of M. primigenius from the coastal part of northeastern Siberia and a comparison with data from other regions demonstrated that the posterior sections of cheek teeth in mammoths are the most variable and represent a reduction complex. For woolly mammoth, the reduction primarily affects that part of the crown that became more complex by the gradual addition of the plates during phyletic evolution in the Middle–Late Pleistocene. A rapid loss of evolutionary achievements of the ancestral forms due to reduction is not a unique peculiarity of the woolly mammoth teeth, and was also traced in other mammals. The similarity of the reduction complexes of cheek teeth in proboscideans and rodents of the Arvicolinae subfamily was demonstrated; it can be traced by a decrease in the number of serially homologous elements of the crown: plates in proboscideans and pairs of prisms in arvicolines. A comparison of the NDP with the size of the M. primigenius teeth allowed us to make the assumption that a decrease in the NDP while maintaining other species-specific peculiarities of the tooth can be used as a criterion for separating semi-dwarf and small individuals of the woolly mammoth. The size of continental mammoths decreased most intensively during warmer intervals, when significant transformation of landscapes and a reduction in resource space occurred.</p

Trajectories of intrinsic connectivity one year post pediatric mild traumatic brain injury:Neural injury superimposed on neurodevelopment

The developing brain undergoes rapid changes throughout middle childhood and adolescence. The disambiguation of long-term changes in intrinsic activity following pediatric mild traumatic brain injury (pmTBI) from typical development can therefore only be ascertained in longitudinal studies with large sample size and at least three serial assessments. A comprehensive clinical battery and resting-state fMRI data were collected approximately 1-week (N = 263; 8-18 years old), 4-months (N = 192) and 1-year (N = 153) post-injury, with identical visits in a large cohort (N = 228) of age- and sex-matched healthy controls (HC). Results indicated persistent frontocerebellar and thalamic connectivity changes up to 1-year post-injury in pmTBI relative to controls (P's &lt; .001), with similar longitudinal connectivity trajectories (i.e., typical neurodevelopment). Alterations in precuneal midline connectivity (p's &lt; .05) and occupancy of a default mode/limbic dynamic brain state were present only up to 4-months (p's &lt; .001) rather than 1-year (p's &gt; .44) post-injury. However, absent group differences at 1-year post-injury may be explained as pseudo-normalization due to altered longitudinal connectivity trajectories in pmTBI associated with neurodevelopment. Persistent alterations of precuneal connectivity were also associated with lower executive function and long-term memory scores. In conclusion, pmTBI may result in chronic changes to both static and dynamic intrinsic connectivity which further interact with typical neurodevelopment. Longer follow-up studies may be needed to unravel this interaction.</p

Case note: ECLI:NL:HR:2024:1797

De Hoge Raad oordeelt dat het naar maatstaven van redelijkheid en billijkheid onaanvaardbaar is dat de man die zijn vrouw opzettelijk om het leven heeft gebracht maar door de strafrechter volledig ontoerekeningsvatbaar is verklaard aanspraak kan maken op haar nalatenschap. Aan de toepassing van art. 6:2 BW moeten dezelfde rechtsgevolgen worden toegekend als aan onwaardigheid in de zin van art. 4:3 BW

A novel approach to rapidly tracking whole-farm methane emissions

Enteric fermentation and manure from livestock farming are major sources of methane (CH4) emissions and have a large potential for emissions reduction. However, there is a lack of effective methods for evaluating future emissions reduction efforts, especially at the farm scale. We developed a rapid analysis method to evaluate CH4 emissions from a large number of dairy cow farms in the Netherlands based on single-transect mobile van measurements of CH4 concentrations downwind of farms located between 80 and 750 m from the road. Methane emissions from 51 dairy cow farms were determined on four campaign days within a total of 7 measurement hours between November 2017 and November 2018 using an inverse Gaussian approach combined with two different wind datasets and their composite. We found a range of moderate to high correlation (R2: minimum 0.42, maximum 0.86) between the estimated CH4 emission rates for 11-16 farms on each measurement day and the number of animal units (AUs, 1 AU equals 500 kg of animal weight) across four individual days. The whole-farm CH4 emission factors (including both enteric fermentation and manure) for the four separate campaign days were estimated using the slope between the CH4 emission rates derived from the composite of two distinct wind datasets and the number of AUs. Daily emission factors for the four campaign days were estimated to be in the range of 0.18-0.50 kgCH4/d/AU. From the dataset, averaged over each of the four campaign days, we derived an estimate of the whole-farm CH4 emission factor, with a 95% confidence interval of 0.47 [0.13-0.81] kgCH4/d/AU. Our results demonstrate that CH4 emissions from a large number of dairy cow farms can be rapidly estimated, providing an independent way to evaluate country-specific emission factors and a potential way to monitor future emission reductions.</p

Intrapericardial injection of hydrogels with ASC and their secretome to treat dilated cardiomyopathies

Doxorubicin-induced cardiomyopathy (DOX-IC) is a significant and common complication in patients undergoing chemotherapy, leading to cardiac remodeling and reduced heart function. We hypothesized that the intrapericardial injection of hydrogels derived from the cardiac decellularized extracellular matrix (dECM) loaded with adipose tissue-derived stromal cells (ASC) and their secretome dampens or reverses the progression of DOX-IC. DOX-IC was induced in Wistar male rats through ten weekly intra-peritoneal injections of doxorubicin (cumulative dose: 18 mg/kg). We performed intrapericardial treatment in week five with dECM hydrogel loaded with ASC and their conditioned medium (CMed). The volume of intrapericardial injection was 2 ml/kg, the ASC density was 20 million/mL, while the hydrogel contained 100-fold concentrated CMed. Interstitial myocardial fibrosis was assessed by PicroSirius Red staining and hemodynamics parameters in pressure-volume loops. Compared to saline controls, interstitial myocardial fibrosis was reduced in ASC/CMed-loaded hydrogels treated animals (p = 0.0139). Ejection fraction and cardiac work efficiency improved in the ASC/CMed-treated rats compared to saline treatment (p = 0.0151 and p = 0.0655, respectively). The intrapericardial injection of dECM hydrogels loaded with ASC and their secretome warrants a novel therapeutic modality to improve ventricular hemodynamics and reduce cardiac remodeling in DOX-IC.</p

Evaluation of a comprehensive set of normal tissue complication probability models for patients with head and neck cancer in an international cohort

BACKGROUND/PURPOSE: Normal tissue complication probability (NTCP) models can be used to guide radiation therapy (RT) decisions by estimating side-effect risks pretreatment to minimize (late) side-effects. Recently, a comprehensive individual toxicity risk (CITOR) profile of NTCP models addressing common side-effects in head and neck cancer (HNC) patients was developed. This study investigates the generalizability of these models in an international setting, with different treatment approaches and side-effect assessments, promoting their integration into more widespread clinical practice.MATERIALS/METHODS: From a prospective registry study, 407 HNC patients were included who were treated with definitive RT with or without systemic therapy between 2015 and 2022. NTCP models predicting dysphagia, aspiration, xerostomia, sticky saliva, taste loss, speech problems, oral pain, and fatigue at 6 and 12 months after RT were evaluated. All side-effects were patient-rated using the MDASI-HN, except dysphagia which was reported by clinicians using the PSS-HN diet normalcy score. Model performance was appraised by discrimination (area under the curve [AUC]) and calibration.RESULTS: CITOR models showed moderate-to-high performance in this cohort (mean AUC = 0.67[range = 0.55-0.80], moderate-to-good calibration). NTCP models for dysphagia, xerostomia, sticky saliva, and fatigue were the top performing models. Models for aspiration, taste loss and speech problems performed moderately well, which was partly explained by lower incidences.CONCLUSION: Despite differences between the CITOR development and this evaluation cohort, including use of different side-effect scoring systems, most models exhibited moderate-to-high performance. This demonstrated that the dose-effect relations were generalizable. Therefore, this study supports further integration of these NTCP models in clinical practice.</p

The Regulation, Governance and Ethics of Smart Robotic Systems in Manufacturing:UK and EU Insights

This White Paper—intended for policymakers, regulators, and other key stakeholders, such as employers, trade unions—outlines key regulatory, governance, and ethics considerations surrounding smart robotic systems aimed at the manufacturing sector. Drawing on the interdisciplinary research conducted within the UKRI Made Smarter Innovation-Research Centre for Smart, Collaborative Industrial Robotics, this White Paper outlines existing frameworks for collaborative robots and smart robotic systems and provides recommendations for their reform to support safer and more effective adoption in manufacturing