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Understanding user trust and expectations in answerable sociotechnical systems
Get PDFToday, we see an increase in the number of systems where Artificial intelligence and Autonomous systems (AI/AS) are included in decision-making processes even in high-stake domains such as healthcare. It is often not clear how to take responsibility appropriately and provide restitution when significant harms happen, especially when organizations use opaque AI/AS to make decisions. We focus on the notion of responsibility as answerability, which demands that individuals have a duty to supply their “reasons and justifications” for an action, or respond to inquiries about why they acted in a particular manner. We investigate the trust towards organizations that use mediator agents, people’s expectations from such agents, perceived benefits and risks of using this new intervention to enable answerability in organizations. Our findings indicate that providing explanations and offering remedies for harm through mediator agents does not affect the level of trust individuals have in organizations.</p
Characterisation of lmx1b paralogues in zebrafish reveals divergent roles in skeletal, kidney and muscle development
Get PDFLMX1B, a LIM-homeodomain family transcription factor, plays critical roles in the development of multiple tissues, including limbs, eyes, kidneys, brain, and spinal cord. Mutations in the human LMX1B gene cause the rare autosomal-dominant disorder Nail-patella syndrome, which affects development of limbs, eyes, brain, and kidneys. In zebrafish, lmx1b has two paralogues: lmx1ba and lmx1bb. While lmx1b morpholino data exists, stable mutants were previously lacking. Here, we describe the characterisation of lmx1b stable mutant lines, with a focus on development of tissues that are affected in Nail-patella syndrome. We demonstrate that the lmx1b paralogues have divergent developmental roles in zebrafish, with lmx1ba affecting skeletal and neuronal development, and lmx1bb affecting renal development. The double mutant, representing loss of both paralogues (lmx1b dKO) showed a stronger phenotype, which included additional defects to trunk muscle patterning, and a failure to fully inflate the notochord leading to a dramatic reduction in body length. Overall, these mutant lines demonstrate the utility of zebrafish for modelling Nail-patella syndrome and describe a previously undescribed role for lmx1b in notochord cell inflation
A novel cause of type 1 von Willebrand disease:impaired exocytosis of Weibel-Palade bodies due to biallelic MADD variants
Get PDFThe regulated secretion of von Willebrand factor (VWF) from Weibel-Palade bodies (WPBs) in endothelial cells is fundamental to hemostasis. This process relies on recruiting Rab GTPases and their effectors to the WPB membrane, with the guanine nucleotide exchange factor MAPK-activating death domain (MADD) playing a central role. Biallelic variants in MADD lead to a pleiotropic neurological and developmental disorder that can include bleeding abnormalities. This study investigates the impact of pathogenic MADD variants on VWF secretion using patient-derived endothelial cells. We isolated endothelial colony-forming cells (ECFCs) from 3 pediatric patients with biallelic MADD variants and unaffected heterozygous family members. All patients exhibited low VWF plasma levels (22-30 IU/dL). Proteomic analysis of patient-derived ECFCs revealed an absence of MADD peptides, reduced VWF, and downregulation of proteins involved in the exocytotic machinery, including Rab3D and the Rab3/27 effector Slp4-a. Functional assays demonstrated diminished Rab27A and Rab3D activity and their failure to localize to WPBs in patient cells. Biochemical and live-imaging studies showed that histamine-induced VWF and VWF propeptide secretion were significantly reduced in patient cells due to delayed and reduced degranulation of WPBs. Our findings demonstrate the critical role of MADD in maintaining the secretion competence of WPBs and the magnitude of VWF secretion by regulating the recruitment of the endothelial exocytotic machinery. This study highlights the in vivo significance of WPB exocytosis in maintaining plasma VWF levels and establishes MADD as the first causal gene for quantitative von Willebrand disease in patients without pathogenic VWF variants.</p
Bacteria in RSV-infected children: a systematic review and meta-analysis in the context of recent microbiome research
Get PDFIntroductionRecent evidence highlights the role of respiratory microbial community imbalances as a potential driver of acute respiratory infections (ARIs). This paradigm shift emphasizes the need to investigate the etiology of ARIs within the broader context of respiratory microbial ecosystems. This systematic review examines bacterial species detected in children <5 years with respiratory syncytial virus (RSV) infection, evaluates factors influencing their proportions, and assesses their impact on clinical features, including symptoms, radiological findings, biomarkers, pathogenesis, immune responses, infection severity, and healthcare resource utilization.MethodsThis study followed a registered protocol in the PROSPERO database (CRD42024545522). Eligible studies included those investigating children <5 years with RSV-associated ARIs that assessed bacterial presence using any diagnostic method in any setting. A comprehensive search was conducted across eight databases for studies published between January 1, 1996, and April 4, 2025. Two independent reviewers assessed the quality of the included studies using a standardized evaluation form. Study-level and pooled proportions were estimated using random-effects models. Meta-regression analysis was performed based on demographic and clinical factors. We compared clinical outcomes between RSV-monoinfected children and those with RSV-bacterial co-detection using study-level estimates (odds ratios, standardized mean differences, or median differences). ResultsA total of 125 studies conducted across all six WHO regions met the eligibility criteria and were included in the analysis. The review identified over 60 bacterial species associated with RSV infections, with three dominant pathogens, Moraxella catarrhalis (21.7% [11.2-34.3]), Haemophilus influenzae (17.5% [10.6-25.6]), and Streptococcus pneumoniae (18.0% [12.3-24.4]). The aggregated proportion of detecting at least one bacterium in RSV-infected children was 28.9% [24.7-33.3].Bacterial prevalence was significantly higher in low- and middle-income countries and varied by sample type, with the highest proportions observed in upper and lower respiratory tract samples. Bordetella pertussis showed the highest prevalence in children aged 0-11 months compared to older age groups. Bacterial co-detection in RSV-infected children was associated with significantly increased risks of specific symptoms, e.g. fever; elevated levels of biomarkers e.g. C-reactive protein (CRP); and poor outcomes including higher mortality rates, pediatric intensive care unit admissions, prolonged hospital stays, increased severity scores, greater antibiotic use, and heightened respiratory support requirements, including oxygen, invasive and non-invasive ventilation, and prolonged mechanical ventilation. ConclusionThe findings of this review highlight the substantial diversity of respiratory bacteria in RSV-infected children, with M. catarrhalis, H. influenzae, and S. pneumoniae being the most frequently detected species. Respiratory bacterial co-detection in RSV-infected children is associated with distinct clinical symptoms, radiological findings, specific biomarkers, increased disease severity, and higher healthcare resource use. These findings collectively emphasize the importance of integrating microbiome-preserving strategies, precision diagnostics, and innovative prevention and therapeutic measures to optimize care and outcomes for children with RSV-associated ARIs.<br/
Keeping up with the neighbours: local synchronisation of cell fate decisions during development
Get PDFEven before the advent of multicellular life, unicellular creatures would communicate with their neighbours to coordinate their behaviours. Multicellular organisms have the particular challenge of orchestrating the differentiation of stem and progenitor cells to generate and maintain coherent functional tissues. However, stem and progenitor cells face a problem: their differentiation response can be buffeted by oscillations or stochastic fluctuations in intrinsic regulators. This generates cell-to-cell variability, which can be further compounded when extrinsic cues don't provide clear unambiguous instructions. So, left to their own devices, cells may differentiate at different rates or different directions even in response to the same cues. Fortunately, cells in multicellular organisms are not left to their own devices: they continually sense and respond to the behaviours of their neighbours. Here we discuss when, where, and how stem and progenitor cells communicate to synchronise their response to differentiation cues. We highlight technical challenges in identifying such synchronisation mechanisms, and survey emerging technologies that may help overcome these challenges
Validation and cost-effectiveness of an mHealth tool for cognitive impairment detection in Peru:protocol for the IMPACT Salud observational study
Get PDFINTRODUCTION: Dementia is a chronic and progressive neurological condition characterised by cognitive and functional impairment. It is often associated with multimorbidity and imposes a significant economic burden on healthcare systems and families, especially in low-income and middle-income countries. In Peru, where dementia cases are increasing rapidly, timely detection and referral for diagnosis is crucial. This protocol is part of the IMPACT Salud project in Peru. Here, we focus on a specific component aimed at validating an mHealth tool for the detection of cognitive and functional impairment and assessing its cost-effectiveness. We will also assess changes in cognitive and functional impairment as well as health economic outcomes over 1 year.METHODS AND ANALYSIS: This observational study will be conducted in four geographically diverse regions of Peru. Community health workers are expected to contact approximately 32 000 participants (≥60 years) to apply an mHealth-enabled tool that includes cognitive and functional instruments: Ascertain Dementia 8, Peruvian version of Rowland Universal Dementia Assessment Scale and Pfeffer Functional Activities Questionnaire. From this large sample, we aim to find 3600 participants and their study partners to enrol and interview at baseline regarding sociodemographic characteristics, lifestyles, comorbidities and health economic data including resource use, costs and health-related quality of life (HR-QoL). Psychologists, blind to previous results, will assess dementia stage of the participants using an abbreviated Clinical Dementia Rating (CDR) scale. At 6-month follow-up, participants will complete a brief health economics questionnaire on resource use, costs and HR-QoL. To validate the accuracy of the detection tool, a subsample of 600 participants who completed the baseline will undergo a gold-standard clinical neuropsychological assessment. This subsample will participate in a 12-month follow-up, including health economics, cognitive and functional impairment tests and the CDR scale. Results will be analysed and presented by cognitive status, site, sex and multimorbidity profile. Finally, data from all stages and external sources will inform a decision model to implement a cost-effectiveness analysis of the detection tool at the national level.ETHICS AND DISSEMINATION: The study received ethics approval in Peru (Universidad Peruana Cayetano Heredia: CONSTANCIA-CIEI-378-33-23) and in the UK (Imperial College London: ICREC/SETREC reference number 6647445). Informed consent will be obtained from participants and their study partners, considering the participant's capacity to consent. For illiterate participants, consent will be obtained through a witnessed procedure involving study partners, with a fingerprint obtained instead of a signature. The results will be disseminated through conferences, published articles, public presentations (particularly to those involved in dementia care) and presentations or meetings with local health authorities.</p
It’s not EU, it’s we:Ontological stress and French narration of the uprisings in Tunisia
Get PDFThe ontological security dynamics of EU foreign policy cooperation and integration have been relatively under-researched. The EU’s efforts to seek ontological security – by consolidating myths, solidifying identifications, and positioning itself on the international crisis – have been discussed by Della Sala, Mitzen, Rumelili, and others, yet one question remains: can the EU provide ontological security? International crises can be an important entry point for studying the dynamics of ontological security within the EU. In this paper, I analyse how France and the European External Action Service (EEAS) narrated the 2011 uprisings in Tunisia. I argue that the EU acts as an ontological security provider in this case by providing a stable network of meaning, narrative, and social space. In the case of Tunisia, I argue that the revelation of the mismatch between its self-perception and perception of others led to significant ontological stress for France and that leaning on the EU provided a way out of this uncertainty. By leaning on the EUs narration of events, France could move past its own stress and still feel secure as part of the EU
The Burgers-FKPP advection-reaction-diffusion equation with cut-off
Get PDFWe investigate the effect of a Heaviside cut-off on the front propagation dynamics of the so-called Burgers-Fisher-Kolmogoroff-Petrowskii-Piscounov (Burgers-FKPP) advection-reaction-diffusion equation. We prove the existence and uniqueness of a “critical” travelling front solution in the presence of a cut-off in the reaction kinetics and the advection term, and we derive the leading-order asymptotics for the speed of propagation of the front in dependence on the advection strength and the cut-off parameter. Our analysis relies on geometric techniques from dynamical systems theory and specifically, on geometric desingularisation, which is also known as “blow-up”
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