Background Dose-finding studies in anaesthesiology aim to target the effective dose (ED) of an anaesthetic agent in a specific population. The common dose-finding designs used are the up and down method (UDM), the biased-coin up and down (BCD), and the continual reassessment method (CRM). Although the advantages of CRM over the UDM and BCD methods have been described in the statistical literature in terms of precision and direct estimation of ED, CRM may also offer attractive properties from an ethical point of view. Methods Based on Monte Carlo simulations, this article aims to compare the three methods with regard to 1) their ability to find as close an estimate as possible for the ED95 or ED90 and 2) the total number of patients needed to treat and the number of failures. Results In contrast to BCD and UDM, CRM does find an estimate for ED95 and ED90. UDM underestimates both ED95 and ED90. BCD is close to the targeted EDs when the starting dose does not exceed the ED of interest, otherwise it overestimates it. CRM with cohorts of two patients is closest to the ED of interest independently of the starting doses. CRM requires between 20 and 50 observations, UDM should include 90 patients, and BCD 100 or 60 observations. Lastly, CRM is associated with fewer failures, compared with BCD and UDM. Conclusions Based on Monte Carlo simulations, our work suggests that the UDM is not an adequate dose-finding method because it underestimates the ED of interest. Compared with BCD, CRM offers the advantages of being more efficient, requires fewer patients to be included, and is associated with fewer failures.
This paper presents a novel human-robot interaction setup for robot and human learning of symbolic language for identifying robot homeostatic needs. The robot and human learn to use and respond to the same language symbols that convey homeostatic needs and the stimuli that satisfy the homeostatic needs, respectively. We adopted a differential outcomes training (DOT) protocol whereby the robot provides feedback specific (differential) to its internal needs (e.g. ‘hunger’) when satisfied by the correct stimulus (e.g. cookie). We found evidence that DOT can enhance the human’s learning efficiency, which in turn enables more efficient robot language acquisition. The robot used in the study has a vocabulary similar to that of a human infant in the linguistic “babbling” phase. The robot software architecture is built upon a model for affect-grounded language acquisition where the robot associates vocabulary with internal needs (hunger, thirst, curiosity) through interactions with the human. The paper presents the results of an initial pilot study conducted with the interactive setup, which reveal that the robot’s language acquisition achieves higher convergence rate in the DOT condition compared to the non-DOT control condition. Additionally, participants reported positive affective experiences, feeling of being in control, and an empathetic connection with the robot. This mutual learning (teacher-student learning) approach offers a potential contribution of facilitating cognitive interventions with DOT (e.g. for people with dementia) through increased therapy adherence as a result of engaging humans more in training tasks by taking an active teaching-learning role. The homeostatic motivational grounding of the robot’s language acquisition has potential to contribute to more ecologically valid and social (collaborative/nurturing) interactions with robots.
How does a great power ally's demonstration of toughness toward a common adversary influence the sense of security among its weaker ally's citizens? The literature on the effects of standing firm against adversaries has significantly evolved in recent years, but empirical evidence is scarce, especially at the mass level. By taking advantage of the unique opportunity of the 2019 North Korea–US Hanoi summit, we examine the conditions under which a powerful alliance partner's firm and uncompromising posture toward a common adversary reassures the citizens of a junior ally. Based on alliance literature, we hypothesize that a patron's hawkish policy reassures its protégé when the protégé fears abandonment more than entrapment and that the more a citizen of the protégé fears abandonment, the more reassuring the patron's hawkish policy is to the individual. Our analysis of online surveys conducted before and after the summit using a quota sample of the Japanese electorate shows that the level of threat perception is significantly lower in the post-summit sample than in the pre-summit one, especially among the respondents who fear abandonment by the US. We thus conclude that President Trump's decision not to compromise with North Korea on its nuclear programs alleviated Japanese citizens’ concerns about US alliance commitments to Japan, improving their security perception. This study is significant in showing that a patron state's policy toward a common adversary can greatly influence the perception of its ally's citizens as well as its government.
This paper presents an authentication and key agreement protocol for users who want to have access to constrained sensor nodes deployed in the field, e.g. doctor with healthcare nodes of patient. Both sensor and user device provide direct multi-factor authentication relying on physical unclonable functions and biometrics respectively. In addition, our scheme offers protection against the presence of a semi-trusted third party, perfect forward secrecy, anonymity, untraceability and protection against session specific data loss attacks. The combination of all these security features is unique. Moreover, it is shown that the resulting scheme outperforms most state-of-the art schemes with respect to computation and communication costs.
Terminally differentiated cells are commonly regarded as the most stable cell state in adult organisms, characterized by growth arrest while fulfilling their specialized functions. A better understanding of the mechanisms involved in promoting cell cycle exit will improve the ability to differentiate pluripotent cells into mature tissues for both pharmacological and therapeutic use. Here, it demonstrates that a hyperosmolar environment enforces a protective p53‐independent quiescent state in immature hepatoma cells and in pluripotent stem cell‐derived models of human hepatocytes and endothelial cells. Prolonged culture in hyperosmolar conditions stimulates changes in gene expression promoting functional cell maturation. Interestingly, hyperosmolar conditions do not only trigger growth arrest and cellular maturation but are also necessary to maintain this maturated state, as switching back to plasma osmolarity reverses the changes in expression of maturation and proliferative markers. Transcriptome analysis revealed sequential stages of osmolarity‐regulated growth arrest followed by cell maturation, mediated by activation of NF‐κВ, and repression of WNT signaling, respectively. This study reveals that a modulated increase in osmolarity serves as a biochemical signal to promote long‐term growth arrest and cellular maturation into different lineages, providing a practical method to generate differentiated hiPSCs that resemble their mature counterpart more closely.
The dynamic nature of multilingual families and their language policies has been touched upon by numerous studies. Adding to the field, the present study assesses the stability of family language policy in a standardised and quantitative manner. To this end, a linguistically heterogenous sample consisting of 488 multilingual families raising young children in Belgium’s Flemish Community was surveyed twice, eighteen months apart. Based on the collected longitudinal survey data, the present study offers statistically verifiable evidence for the (partially) dynamic character of family language policy. Firstly, parental beliefs in a multilingual advantage were strengthened and a change was found in language-specific beliefs regarding children’s language acquisition. Secondly, the families’ practices demonstrate a shift towards the Dutch institutional language, particularly in parental language use when communicating with each other and with their child, and in the child’s overall exposure. The observed shift in practices and beliefs underscores not only parents’ continuous assessment of their children’s linguistic needs and development, but also the societal environment influencing this assessment and adjustment. However, while significant changes in language beliefs and practices were uncovered, the more conscious and explicit component of language management proved stable across time, corroborating the independent character of the three family language policy components.
Premature ovarian insufficiency (POI) is a rare cause of primary amenorrhea in adolescents. For young women with uncertain etiology of POI, genetic and autoimmune testing may be recommended to assist in treatment and management decisions. This report presents a case of POI in a 16-year-old adolescent with both poly-autoimmune disease and a heterozygous missense variant in the bone morphogenic factor 15 (BMP15) gene, both potentially involved in the pathogenesis of POI. Accurately distinguishing between autoimmune and genetic causes is crucial for effective treatment and counseling. In addition, given the significant psychological impact and the need for reproductive options counseling, a multidisciplinary approach that includes psychological support is highly recommended.
Background: Studies across the globe generally reported increased mortality risks associated with particulate matter with aerodynamic diameter ≤2.5μm (PM2.5) exposure with large heterogeneity in the magnitude of reported associations and the shape of concentration-response functions (CRFs). We aimed to evaluate the impact of key study design factors (including confounders, applied exposure model, population age, and outcome definition) on PM2.5 effect estimates by harmonizing analyses on three previously published large studies in Canada [Mortality-Air Pollution Associations in Low Exposure Environments (MAPLE), 1991-2016], the United States (Medicare, 2000-2016), and Europe [Effects of Low-Level Air Pollution: A Study in Europe (ELAPSE), 2000-2016] as much as possible. Methods: We harmonized the study populations to individuals 65+ years of age, applied the same satellite-derived PM2.5 exposure estimates, and selected the same sets of potential confounders and the same outcome. We evaluated whether differences in previously published effect estimates across cohorts were reduced after harmonization among these factors. Additional analyses were conducted to assess the influence of key design features on estimated risks, including adjusted covariates and exposure assessment method. A combined CRF was assessed with meta-analysis based on the extended shape-constrained health impact function (eSCHIF). Results: More than 81 million participants were included, contributing 692 million person-years of follow-up. Hazard ratios and 95% confidence intervals (CIs) for all-cause mortality associated with a 5-μg/m3 increase in PM2.5 were 1.039 (1.032, 1.046) in MAPLE, 1.025 (1.021, 1.029) in Medicare, and 1.041 (1.014, 1.069) in ELAPSE. Applying a harmonized analytical approach marginally reduced difference in the observed associations across the three studies. Magnitude of the association was affected by the adjusted covariates, exposure assessment methodology, age of the population, and marginally by outcome definition. Shape of the CRFs differed across cohorts but generally showed associations down to the lowest observed PM2.5 levels. A common CRF suggested a monotonically increased risk down to the lowest exposure level. https://doi.org/10.1289/EHP12141.
We present two deep unfolding neural networks for the simultaneous tasks of background subtraction and foreground detection in video. Unlike conventional neural networks based on deep feature extraction, we incorporate domain-knowledge models by considering a masked variation of the robust principal component analysis problem (RPCA). With this approach, we separate video clips into low-rank and sparse components, respectively corresponding to the backgrounds and foreground masks indicating the presence of moving objects. Our models, coined ROMAN-S and ROMAN-R, map the iterations of two alternating direction of multipliers methods (ADMM) to trainable convolutional layers, and the proximal operators are mapped to non-linear activation functions with trainable thresholds. This approach leads to lightweight networks with enhanced interpretability that can be trained on limited data. In ROMAN-S, the correlation in time of successive binary masks is controlled with side-information based on ℓ1-ℓ1 minimization. ROMAN-R enhances the foreground detection by learning a dictionary of atoms to represent the moving foreground in a high-dimensional feature space and by using reweighted-ℓ1-ℓ1 minimization. Experiments are conducted on both synthetic and real video datasets, for which we also include an analysis of the generalization to unseen clips. Comparisons are made with existing deep unfolding RPCA neural networks, which do not use a mask formulation for the foreground, and with a 3D U-Net baseline. Results show that our proposed models outperform other deep unfolding networks, as well as the untrained optimization algorithms. ROMAN-R, in particular, is competitive with the U-Net baseline for foreground detection, with the additional advantage of providing video backgrounds and requiring substantially fewer training parameters and smaller training sets.
Food waste is a challenge to the sustainability of global food systems and to the environment and demonstrates a dire need for solutions in which the food produced for human consumption actually feeds people. Food rescue practices respond to this challenge through the redistribution of food waste materials, working towards a circular economic system. Through analysis of two food rescue organisations, this article maps the food waste network and the actors engaged in practices of transforming discarded food waste materials back into an edible food resource. Despite their best intentions to uphold the fundamental goal of saving food, 'food heroes' face logistical, financial, and ethical hurdles as they implement their food rescue practices. Operating within the globalised food system, which prioritises profit and productivity, is a major challenge to food rescue organisations. This article demonstrates the fragile intricacies of the food waste network and compares how food rescue operates within different levels of the food supply chain.
Modified cardiac sympathetic denervation (CSD) with stellate ganglion (SG) sparing is a novel technique for cardiac neuromodulation in patients with refractory ventricular tachycardia (VT). Our aim is to describe the mid- to long-term clinical outcome of the modified CSD with SG sparing in a series of patients with structural heart disease (SHD) and refractory VT. All consecutive patients with SHD and refractory VT undergoing modified CSD were enrolled. Baseline clinical characteristics and periprocedural data were collected for all patients. The primary outcome was any recurrence of sustained VT. We enrolled 15 patients (age: 69.2 ± 7.9 years; male 100%) undergoing modified CSD. Left ventricular ejection fraction was 37 ± 11% and all patients had an implantable cardiac defibrillator (ICD); the underlying cardiomyopathy was non-ischemic in 73.3% of them. At least one previous ablation had been attempted in 66.6% of cases. The 73.3% of patients underwent bilateral CSD and the mean effective surgical time was 10.8 ± 2.4 min per side; no major periprocedural complication occurred. After a median follow-up time of 15 months (IQR: 8.5–24.5 months), the primary outcome occurred in 47.6% of cases. All patients experienced a reduction of ICD shocks after CSD (3.1 ICD shocks/patient before vs. 0.3 ICD shocks/patient after CSD; p-value: 0.001). Bilateral CSD and a VT cycle length < 340 ms were associated with better outcomes. A modified CSD approach with stellate ganglion sparing appears to be safe, fast, and effective in the treatment of patients with SHD and refractory VTs.
In this chapter, fluid management in both acute and acute-on chronic liver failure is discussed. For each pathology, the specific hemodynamic alterations are first described and followed by some general and specific considerations during hemodynamic optimization and evidence-based guidance in the choice of fluids.
The death literacy index (DLI) was developed in Australia to measure death literacy, a set of experience-based knowledge needed to understand and act on end-of-life (EOL) care options but has not yet been validated outside its original context. The aim of this study was to develop a culturally adapted Swedish-language version of the DLI, the DLI-S, and assess sources of evidence for its validity in a Swedish context. The study involved a multi-step process of translation and cultural adaptation and two validation phases: examining first content and response process validity through expert review ( n = 10) and cognitive interviews ( n = 10); and second, internal structure validity of DLI-S data collected from an online cross-sectional survey ( n = 503). The psychometric evaluation involved analysis of descriptive statistics on item and scale-level, internal consistency and test-retest reliability, and confirmatory factor analysis. During translation and adaptation, changes were made to adjust items to the Swedish context. Additional adjustments were made following findings from the expert review and cognitive interviews. The content validity index exceeded recommended thresholds (S-CVI Ave = 0.926). The psychometric evaluation provided support for DLI-S’ validity. The hypothesized six-factor model showed good fit (χ ² = 1107.631 p <0.001, CFI = 0.993, TLI = 0.993, RMSEA = 0.064, SRMR = 0.054). High internal consistency reliability was demonstrated for the overall scale (Cronbach’s α = 0.94) and each sub-scale ( α 0.81–0.92). Test-retest reliability was acceptable, ICC ranging between 0.66–0.85. Through a comprehensive assessment of several sources of evidence, we show that the DLI-S demonstrates satisfactory validity and acceptability to measure death literacy in the Swedish context. There are, however, indications that the sub-scales measuring community capacity perform worse in comparison to other sca and may function differently in Sweden than in the original context. The DLI-S has potential to contribute to research on community-based EOL interventions.
The study conducts a catalogue analysis that zooms in on the small market of Flanders (Belgium), and the content strategies of the eight most popular local and US-based players in the market. Through the comparative analysis, we investigate three main directions. First, we analyse the similarities and differences in the catalogue offerings of US and local video-on-demand (VoD) services. Second, we delve into the strategies of local players as they compete with US streamers and other legacy players. Third, we analyse the share and the characteristics of the Flemish titles on offer. The data was collected in the spring of 2022 and consists of 13,500 title entries. The findings point to a set of complex market dynamics. Local services and US-based players are competing and collaborating to create a jigsaw puzzle of on-demand offerings, through various strategies of complacency, resistance, differentiation and diversification/mimicry.
Although human pluripotent stem cell (PSC)‐derived brain organoids have enabled researchers to gain insight into human brain development and disease, these organoids contain solely ectodermal cells and are not vascularized as occurs during brain development. Here it is created less complex and more homogenous large neural constructs starting from PSC‐derived neuroprogenitor cells (NPC), by fusing small NPC spheroids into so‐called concentroids. Such concentroids consisted of a pro‐angiogenic core, containing neuronal and outer radial glia cells, surrounded by an astroglia‐dense outer layer. Incorporating PSC‐derived endothelial cells (EC) around and/or in the concentroids promoted vascularization, accompanied by differential outgrowth and differentiation of neuronal and astroglia cells, as well as the development of ectodermal‐derived pericyte‐like mural cells co‐localizing with EC networks. Single nucleus transcriptomic analysis revealed an enhanced neural cell subtype maturation and diversity in EC‐containing concentroids, which better resemble the fetal human brain compared to classical organoids or NPC‐only concentroids. This PSC‐derived “vascularized” concentroid brain model will facilitate the study of neurovascular/blood‐brain barrier development, neural cell migration, and the development of effective in vitro vascularization strategies of brain mimics.
This article offers an overview of the recently rediscovered archives of the Conseils de Guerre—the military court—of colonial Congo (1885–1960). As a long-considered lost collection of court records encompassing seventy years of testimonies of colonial military crimes, these archives offer unparalleled insights on the complex relation between law, impunity, and armed violence in colonial Central Africa. The article first sheds light on the history of those records and on their ongoing digitization in the context of debates about the contested heritage of Belgian “displaced” colonial public archives. It then sketches out several promising avenues for academic research and public history projects that they could help document, notably on the controversial history of violence in the Belgian empire and on the multifaceted nature of African agency under colonial rule.
Background Legionnaires’ Disease (LD) rarely evolves into pulmonary abscesses. The current systematic review has been designed to explore therapeutical strategies in pulmonary cavitary LD. Methods A research strategy was developed and applied to the databases Embase, Pubmed, and Web of Science from the 1st of January 2000 to the 1st of November 2022. Original articles, case series, case reports, and guidelines written in English, French, German, Italian, and Dutch were considered. Furthermore, medical records of patients treated at the University Hospital UZ Brussel for LD cavitary pneumonia, between the 1st of January 2016 to the 1st of January 2022, were reviewed. Results Two patients were found by the UZ Brussel’s medical records investigation. Through the literature review, 23 reports describing 29 patients, and seven guidelines were identified. The overall evidence level was low. Result of synthesis (case reports) The median age was 48 years and 65% were male. A polymicrobial infection was detected in 11 patients (44%) with other aerobic bacteria being the most commonly found. At diagnosis, 52% of patients received combination therapy, and fluoroquinolones were the preferred antimicrobial class. Anaerobic coverage was neglected in 33% of patients. Result of synthesis (guidelines) Three guidelines favor monotherapy with fluoroquinolones or macrolides, while one suggested an antimicrobial combination in case of severe LD. Four guidelines recommended anaerobic coverage in case of lung abscesses. Conclusion To date, the evidence supporting cavitary LD treatment is low. Monotherapy lowers toxicity and might be as effective as combination therapy. Finally, anaerobes should not be neglected. Graphical Abstract
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