Search

BACKGROUND: SARS-CoV-2 binding to ACE2 is potentially associated with severe pneumonia due to COVID-19. The aim of the study was to test whether Mas-receptor activation by 20-hydroxyecdysone (BIO101) could restore the Renin-Angiotensin System equilibrium and limit the frequency of respiratory failure and mortality in adults hospitalized with severe COVID-19. METHODS: Double-blind, randomized, placebo-controlled phase 2/3 trial. Randomization: 1:1 oral BIO101 (350 mg BID) or placebo, up to 28 days or until an endpoint was reached. Primary endpoint: mortality or respiratory failure requiring high-flow oxygen, mechanical ventilation, or extra-corporeal membrane oxygenation. Key secondary endpoint: hospital discharge following recovery (ClinicalTrials.gov Number, NCT04472728). FINDINGS: Due to low recruitment the planned sample size of 310 was not reached and 238 patients were randomized between August 26, 2020 and March 8, 2022. In the modified ITT population (233 patients; 126 BIO101 and 107 placebo), respiratory failure or early death by day 28 was 11.4% lower in the BIO101 (13.5%) than in the placebo (24.3%) group, (p = 0.0426). At day 28, proportions of patients discharged following recovery were 80.1%, and 70.9% in the BIO101 and placebo group respectively, (adjusted difference 11.0%, 95% CI [-0.4%, 22.4%], p = 0.0586). Hazard Ratio for time to death over 90 days: 0.554 (95% CI [0.285, 1.077]), a 44.6% mortality reduction in the BIO101 group (not statistically significant). Treatment emergent adverse events of respiratory failure were more frequent in the placebo group. INTERPRETATION: BIO101 significantly reduced the risk of death or respiratory failure supporting its use in adults hospitalized with severe respiratory symptoms due to COVID-19. FUNDING: Biophytis.

Experimental studies show that the tendency to derive Scalar Implicatures (SIs) varies considerably between individuals: some individuals accept sentences that are literally true but carry a false SI, while others systematically reject them. The question of what factors drive these differences is crucial to understanding the mechanisms involved in SIs and currently at the center of numerous discussions. To date, there is no agreement on how to quantify individual differences in SI rates. In this article, we show how a hierarchical Bayesian modelling approach can be used to quantify subjects' preferences observed in the results of a truth value judgement task that investigated intra-individual and inter-individual variability in the rates of upper-bounding and lower-bounding SIs associated with the -scale. The results provide further evidence that the robustness of an SI is modulated within individuals by certain linguistic features, such as the presence of negation.

The Interface Transparency Thesis (ITT) proposes that people tend to use a canonical interpretation of linguistic expressions, even when this interpretation is sub-optimal for the task at hand. The current paper sought to investigate this claim further by adding a time-pressure manipulation to a quantified sentence verification task and analyzing the results through a computational model of decision-making. The results indicate that time pressure -while effectively changing behavioral responses- does not alter cognitive processes associated with quantifier verification, thus supporting the ITT.

According to logical theories of meaning, a meaning of an expression can be formalized and encoded in truth conditions. Vagueness of the language and individual differences between people are a challenge to incorporate into the meaning representations. In this paper, we propose a new approach to study truth-conditional representations of vague concepts. For a case study, we selected two natural language quantifiers "most" and "more than half." We conducted two online experiments, each with 90 native English speakers. In the first experiment, we tested between-subjects variability in meaning representations. In the second experiment, we tested the stability of meaning representations over time by testing the same group of participants in two experimental sessions. In both experiments, participants performed the verification task. They verified a sentence with a quantifier (e.g., "'Most' of the gleerbs are feezda.") based on the numerical information provided in the second sentence, (e.g., "60% of the gleerbs are feezda"). To investigate between-subject and within-subject differences in meaning representations, we proposed an extended version of the Diffusion Decision Model with two parameters capturing truth conditions and vagueness. We fit the model to responses and reaction times data. In the first experiment, we found substantial between-subject differences in representations of "most" as reflected by the variability in the truth conditions. Moreover, we found that the verification of "most" is proportion-dependent as reflected in the reaction time effect and model parameter. In the second experiment, we showed that quantifier representations are stable over time as reflected in stable model parameters across two experimental sessions. These findings challenge semantic theories that assume the truth-conditional equivalence of "most" and "more than half" and contribute to the representational theory of vague concepts. The current study presents a promising approach to study semantic representations, which can have a wide application in experimental linguistics.

Data commons is an often-used but also ambiguous notion, and aspires to connect the complex notion of ‘data’ with that of the ‘commons’ — a concept with an equally variable and contested meaning. This entry collects and connects several recent contributions to discussions on data commons as a means to foreground several important community-related themes. We take this discursive move to be important because the adjective ‘data’ has the tendency to transform social, communal, and political problems into technological ones that result in confusions between means and ends that endanger the viability of the commons. We discuss four themes that help to re-prioritise community-related interests and problems over their technological solutions. We discuss a data commons relationship to itself (1), its relationship to other commons (2), to capitalism (3), and sustainability (4). We structure the literature on data commons to contextualise, historicise, and politicise data commons, and ultimately understand them as ways of living together (with data) rather than as instruments to manage data.

Abstract Changes in upstream land-use have significantly transformed downstream coastal ecosystems around the globe. Restoration of coastal ecosystems often focuses on local-scale processes, thereby overlooking landscape-scale interactions that can ultimately determine restoration outcomes. Here we use an idealized bio-morphodynamic model, based on estuaries in New Zealand, to investigate the effects of both increased sediment inputs caused by upstream deforestation following European settlement and mangrove removal on estuarine morphology. Our results show that coastal mangrove removal initiatives, guided by knowledge on local-scale bio-morphodynamic feedbacks, cannot mitigate estuarine mud-infilling and restore antecedent sandy ecosystems. Unexpectedly, removal of mangroves enhances estuary-scale sediment trapping due to altered sedimentation patterns. Only reductions in upstream sediment supply can limit estuarine muddification. Our study demonstrates that bio-morphodynamic feedbacks can have contrasting effects at local and estuary scales. Consequently, human interventions like vegetation removal can lead to counterintuitive responses in estuarine landscape behavior that impede restoration efforts, highlighting that more holistic management approaches are needed.

Abstract Climate change adaptation is paramount, but increasing evidence suggests that adaptation action is subject to a range of constraints. For a realistic assessment of future adaptation prospects, it is crucial to understand the timescales needed to overcome these constraints. Here, we combine data on documented adaptation from the Global Adaptation Mapping Initiative with national macro indicators and assess future changes in adaptation constraints alongside the Shared Socioeconomic Pathways, spanning a wide range of future socio-economic development scenarios. We find that even in the most optimistic scenario, it will take until well after 2050 to overcome key constraints, which will limit adaptation for decades to come particularly in vulnerable countries. The persistence of adaptation constraints calls for stringent mitigation, improved adaptation along with dedicated finance and increasing efforts to address loss and damage. Our approach allows to ground truth indicators that can be further used in climate modelling efforts, improving the representation of adaptation and its risk reduction potential.

A recent sampling-based model of causal cognition, the Mutation Sampler, can explain the average responses of participants on a wide variety of tasks (Davis & Rehder, 2020). Careful analysis, however, shows that the predicted response distributions do not match empirical data. As an explanation for the observed response distributions, we propose that people engage in mutation sampling when confronted with a causal query and subsequently integrate this information with a prior. Several theoretical arguments can be made for the notion that people use priors in causal judgements; it is rational and matches the phenomenology of making such judgements. We have modelled this process with a new model called the Bayesian Mutation Sampler (BMS). We fit the BMS to experimental data and find that, in addition to average responses, the BMS explains multiple ‘distributional phenomena’, such as the moderate conservatism of the bulk of responses and the lack of extreme responses.

In skill acquisition, instructing individuals the stimulus-response mappings indicating how to perform and act, yields better performance. Additionally, performance is helped by repeated practice. Whether providing instructions and repeated practice interact to achieve optimal performance remains debated. This paper addresses that question by analyzing the learning curves of individuals learning stimulus-response mappings of varying complexity. We particularly focus on the question whether instructions lead to improved performance in the longer run. Via evidence accumulation modeling, we find no evidence for this assertion. Instructions seem to provide individuals with a head start, leading to better initial performance in the early stages of learning, without long-lasting effects on behavior. We discuss the results in light of related studies that do report long-lasting effects of instructions, and propose that the complexity of a skill determines whether long-lasting benefits of initial instructions exist.

Assessing global progress on human adaptation to climate change is an urgent priority. Although the literature on adaptation to climate change is rapidly expanding, little is known about the actual extent of implementation. We systematically screened >48,000 articles using machine learning methods and a global network of 126 researchers. Our synthesis of the resulting 1,682 articles presents a systematic and comprehensive global stocktake of implemented human adaptation to climate change. Documented adaptations were largely fragmented, local and incremental, with limited evidence of transformational adaptation and negligible evidence of risk reduction outcomes. We identify eight priorities for global adaptation research: assess the effectiveness of adaptation responses, enhance the understanding of limits to adaptation, enable individuals and civil society to adapt, include missing places, scholars and scholarship, understand private sector responses, improve methods for synthesizing different forms of evidence, assess the adaptation at different temperature thresholds, and improve the inclusion of timescale and the dynamics of responses.

Abstract Tamoxifen may lead to bothersome side effects contributing to non-compliance and decreased quality of life. Patients searching for relief are increasingly turning to cannabinoids such as CBD-oil. However, CBD-oil might affect tamoxifen pharmacokinetics (PK) through CYP2D6 inhibition. The aims of this open-label, single-arm study were (1) to determine the PK profile of tamoxifen when using CBD-oil, and (2) to subsequently investigate whether CBD-oil has a beneficial influence on side effects. Study patients had to have steady-state endoxifen concentrations ≥16 nM (conservative threshold). PK sampling and side effect assessment was done at initiation of CBD-oil and 28 days thereafter. Bio-equivalence could be concluded if the 90% confidence interval (CI) for the difference in endoxifen AUC fell within the [−20%; +25%] interval. The effect of CBD-oil on side effects was evaluated using the FACT-ES questionnaire. Endoxifen AUC decreased after CBD-oil by 12.6% (n = 15, 90% CI −18.7%, −6.1%) but remained within bio-equivalence boundaries. The endocrine sub-scale of the FACT-ES improved clinically relevant with 6.7 points (n = 26, p

While causal reasoning is a core facet of our cognitive abilities, its time-course has not received proper attention. As the duration of reasoning might prove crucial in understanding the underlying cognitive processes, we asked participants in two experiments to make probabilistic causal inferences while manipulating time pressure. We found that participants are less accurate under time pressure, a speed-accuracy-tradeoff, and that they respond more conservatively. Surprisingly, two other persistent reasoning errors-Markov violations and failures to explain away-appeared insensitive to time pressure. These observations seem related to confidence: Conservative inferences were associated with low confidence, whereas Markov violations and failures to explain were not. These findings challenge existing theories that predict an association between time pressure and all causal reasoning errors including conservatism. Our findings suggest that these errors should not be attributed to a single cognitive mechanism and emphasize that causal judgements are the result of multiple processes.

In countries endemic for foot-and-mouth disease (FMD), routine or emergency vaccinations are strategic tools to control the infection. According to the WOAH/FAO guidelines, a prior estimation of vaccine effectiveness is recommendable to optimize control programs. This study reports the results of a small-scale immunogenicity study performed in Transcaucasian Countries. Polyvalent vaccines, including FMDV serotypes O, A (two topotypes) and Asia1 from two different manufacturers, were evaluated in Georgia, Azerbaijan and Armenia. Naïve large and small ruminants were vaccinated once and a subgroup received a second booster dose. The titers of neutralizing antibodies in sera collected sequentially up to 180 DPV were determined through the Virus Neutralization Test versus homologous strains. This study led to the estimate that both the vaccines evaluated will not induce a protective and long-lasting population immunity, even after a second vaccination, stressing that consecutive administrations of both vaccines every three months are mandatory if one aspires to achieve protective herd immunity.

Background Diagnostic delay in patients with pulmonary embolism (PE) is typical, yet the proportion of patients with PE that experienced delay and for how many days is less well described, nor are determinants for such delay.Objectives This study aimed to assess the prevalence and extent of delay in diagnosing PE.Methods A systematic literature search was performed to identify articles reporting delays in diagnosing PE. The primary outcome was mean delay (in days) or a percentage of patients with diagnostic delay (defined as PE diagnosis more than seven days after symptom onset). The secondary outcome was determinants of delay. Random-effect meta-analyses were applied to calculate a pooled estimate for mean delay and to explore heterogeneity in subgroups.Results The literature search yielded 10,933 studies, of which 24 were included in the final analysis. The pooled estimate of the mean diagnostic delay based on 12 studies was 6.3 days (95% prediction interval 2.5 to 15.8). The percentage of patients having more than seven days of delay varied between 18% and 38%. All studies assessing the determinants of coughing (n = 3), chronic lung disease (n = 6) and heart failure (n = 8) found a positive association with diagnostic delay. Similarly, all studies assessing recent surgery (n = 7) and hypotension (n = 6), as well as most studies assessing chest pain (n = 8), found a negative association with diagnostic delay of PE.Conclusion Patients may have symptoms for almost one week before PE is diagnosed and in about a quarter of patients, the diagnostic delay is even longer.

IntroductionAbscessation of equine head lymph nodes can be caused by various bacteria, but Streptococcus equi subsp. equi is mainly involved. At our laboratory, samples of three unrelated horses with submandibular abscesses were found negative for S. equi, and further testing proved the presence of another genus. This raised the question for the exact identity of this pathogen and whether these isolates were epidemiologically related and it warranted further characterization with regards of virulence and resistance factors.MethodsCulture followed by identification using MALDI-TOF MS, MIC testing and whole genome sequencing (WGS) was performed to characterize the bacteria.ResultsBacterial culture and subsequent identification with MALDI-TOF MS resulted in the reliable identification of A. denticolens in two of the three cases. Final confirmation of A. denticolens for all three isolates was achieved by analysis of the WGS data, supported by multilocus sequence typing (MLST). The three isolates showed 95% nucleotide sequence identity. The number of single nucleotide polymorphisms (10,170 to 36,058) indicated that the isolates were not clonal, suggesting that these cases were epidemiologically unrelated. Only four known virulence related genes were detected. The absence of known antibiotic resistance genes was in line with the high susceptibility, as indicated by the susceptibility patterns obtained for two of the three isolates.ConclusionWe conclude that A. denticolens should be included in the differential diagnosis of (submandibular) lymph node abscessation in horses, especially if strangles cannot be confirmed with laboratory diagnostics. Furthermore, we report the first draft genome of A. denticolens isolated from horses.

A comparison of salt marsh and mangrove channel networks around the world exhibited different network extents. This could be linked to differences in vegetation colonization strategies, with major implications on coastal development.

Abstract Background Methods The KHENERGYC trial will be a phase II, randomised, double-blinded, placebo-controlled (DBPC), parallel-group study in the paediatric population (birth up to and including 17 years). The study will be recruiting 24 patients suffering from motor symptoms due to genetically confirmed PMD. The trial will be divided into two phases. The first phase of the study will be an adaptive pharmacokinetic (PK) study with four days of treatment, while the second phase will include randomisation of the participants and evaluating the efficacy and safety of sonlicromanol over 6 months. Discussion Effective novel therapies for treating PMDs in children are an unmet need. This study will assess the pharmacokinetics, efficacy, and safety of sonlicromanol in children with genetically confirmed PMDs, suffering from motor symptoms. Trial registration clinicaltrials.gov: NCT04846036 , registered April 15, 2021. European Union Clinical Trial Register (EUDRACT number: 2020–003124-16 ), registered October 20, 2020. CCMO registration: NL75221.091.20, registered on October 7, 2020.

Objective Postmarketing observational studies report that a substantial percentage of patients with atrial fibrillation (AF) receive a reduced non-vitamin K antagonist oral anticoagulant (NOAC) dose without a clear indication. Recently, increasing evidence has become available to explore the clinical consequences of such off-label reduced dosing (OLRD). This study aims to systematically review and meta-analyse observational studies that report clinical outcomes associated with OLRD of NOACs compared with on-label non-reduced dosing (OLNRD) of NOACs in patients with AF.Methods and analysis We performed a systematic literature review and meta-analysis of observational studies reporting clinical outcomes in AF patients with OLRD of an NOAC compared with AF patients with OLNRD of an NOAC. Using random effects meta-analyses, we estimated the risk of stroke/thromboembolism, bleeding and all-cause mortality.Results We included 19 studies with a total of 170 394 NOAC users. In these studies, the percentage of OLRD among patients with an indication for an on-label non-reduced NOAC dose ranged between 9% and 53%. 7 of these 19 studies met the predefined criteria for meta-analysis (n=80 725 patients). The pooled HR associated with OLRD of NOACs was 1.04 (95% CI 0.83 to 1.29; 95% prediction interval (PI) 0.60 to 1.79) for stroke/thromboembolism, 1.10 (95% CI 0.95 to 1.29; 95% PI 0.81 to 1.50) for bleeding and 1.22 (95% CI 0.81 to 1.84; 95% PI 0.55 to 2.70) for all-cause mortality.Conclusion This meta-analysis shows no statistically significant increased risk of stroke/thromboembolism, nor a decreased bleeding risk, nor a difference in risk of all-cause mortality in patients with OLRD of NOACs. Future research may focus on differences between NOACs.

AimsTo evaluate whether parameters of post-hypoglycemic hyperglycemia (PHH) correlated with glucose homeostasis during the first year after type 1 diabetes onset and helped to distinguish pediatric patients undergoing partial remission or not.MethodsIn the GLUREDIA (GLUcagon Response to hypoglycemia in children and adolescents with new-onset type 1 DIAbetes) study, longitudinal values of clinical parameters, continuous glucose monitoring metrics and residual β-cell secretion from children with new-onset type 1 diabetes were analyzed during the first year after disease onset. PHH parameters were calculated using an in-house algorithm. Correlations between PHH parameters (i.e., PHH frequency, PHH duration, PHH area under the curve [PHHAUC]) and glycemic homeostasis markers were studied using adjusted mixed-effects models.ResultsPHH parameters were strong markers to differentiate remitters from non-remitters with PHH/Hyperglycemia duration ratio being the most sensitive (ratioConclusionPHH parameters are new minimal-invasive markers to discriminate remitters from non-remitters and evaluate glycemic homeostasis during the first year of type 1 diabetes. PHH parameters may also allow patient-targeted therapeutic management of hypoglycemic episodes.

Open government and open data are often presented as the Asterix and Obelix of modern government—one cannot discuss one, without involving the other. Modern government, in this narrative, should open itself up, be more transparent, and allow the governed to have a say in their governance. The usage of technologies, and especially the communication of governmental data, is then thought to be one of the crucial instruments helping governments achieving these goals. Much open government data research, hence, focuses on the publication of open government data, their reuse, and re-users. Recent research trends, by contrast, divert from this focus on data and emphasize the importance of studying open government data in practice, in interaction with practitioners, while simultaneously paying attention to their political character. This commentary looks more closely at the implications of emphasizing the practical and political dimensions of open government data. It argues that researchers should explicate how and in what way open government data policies present solutions to what kind of problems. Such explications should be based on a detailed empirical analysis of how different actors do or do not do open data. The key question to be continuously asked and answered when studying and implementing open government data is how the solutions openness present latch onto the problem they aim to solve.

Artificial intelligence (AI) plays an important role in modern society. AI applications are omnipresent and assist many decisions we make in daily life. A common and important feature of such AI applications are user models. These models allow an AI application to adapt to a specific user. Here, we argue that user models in AI can be optimized by modeling these user models more closely to models of human cognition. We identify three levels at which insights from human cognition can be—and have been—integrated in user models. Such integration can be very loose with user models only being inspired by general knowledge of human cognition or very tight with user models implementing specific cognitive processes. Using AI-based applications in the context of education as a case study, we demonstrate that user models that are more deeply rooted in models of cognition offer more valid and more fine-grained adaptations to an individual user. We propose that such user models can also advance the development of explainable AI.

PURPOSE:We aimed to determine whether antireflux (ARC) catheter may result in better tumor targeting in liver radioembolization using 90Y-resin microspheres.METHODS:Patients treated with resin microspheres for hepatocellular carcinoma (HCC) and secondary liver malignancies were retrospectively analyzed. All patients underwent a 99mTc-macroaggregated albumin (99mTc-MAA) single photon emission computed tomography (SPECT) following the planning arteriography with a conventional end-hole catheter. For 90Y-microspheres injection, two groups were defined depending on the type of catheter used: an ARC group (n=38) and a control group treated with a conventional end-hole catheter (n=23). 90Y positron emission tomography computed tomography (PET/CT) was performed after the therapeutic arteriography. The choice of the catheter was not randomized, but left to the choice of the interventional radiologist. 99mTc-MAA SPECT and 90Y PET/CT were co-registered with the baseline imaging to determine a tumor to normal liver ratio (T/NL[MAA or 90Y]) and tumor dose (TD[MAA or 90Y]) for the planning and therapy.RESULTS:Overall, 38 patients (115 lesions) and 23 patients (75 lesions) were analyzed in the ARC and control groups, respectively. In the ARC group, T/NL90Y and TD90Y were significantly higher than T/NLMAA and TDMAA. Median (IQR) T/NL90Y was 2.16 (2.15) versus 1.74 (1.43) for T/NLMAA (p < 0.001). Median (IQR) TD90Y was 90.96 Gy (98.31 Gy) versus 73.72 Gy (63.82 Gy) for TDMAA (p < 0.001). In this group, the differences were highly significant for neuroendocrine metastases (NEM) and HCC and less significant for colorectal metastases (CRM). In the control group, no significant differences were demonstrated.CONCLUSION:The use of an ARC significantly improves tumor deposition in liver radioembolization with resin microspheres.