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How do speakers tailor lexical choices according to their interlocutor’s accent?
No full textWhen conveying a message to an interlocutor, speakers need to code concepts in lexical expressions, a process known as lexical retrieval. There is evidence that speakers can take into account the dialectal background of their interlocutor to tailor their lexical retrieval; for instance, our pilot experiment showed that participants, when asked to guess the defined expression according to a definition, were more likely to produce American English (AE) expressions (e.g., apartment instead of flat) when the definition was spoken by an AE interlocutor than a British English (BE) interlocutor. It is possible that such an interlocutor effect arises from a top-down interlocutor model, from bottom-up accent details, or a combination of both. This registered report aimed to address this issue with two experiments. In Experiment 1, we observed that the interlocutor effect on lexical retrieval did not differ regardless of whether a definition was presented by the interlocutor via speaking (with accent details) or writing (without accent details), suggesting that the effect arises from top-down interlocutor modeling instead of bottom-up accent details. Experiment 2 interleaved two interlocutors with different dialects, one providing a spoken filler definition and the other a written target definition. Participants used more AE expressions for target definitions given by an AE interlocutor than a BE interlocutor, suggesting they maintained concurrent models for interlocutors and used them to retrieve dialect-congruent expressions. These findings highlight top-down influences of the communicative context in language production
A precision image-guided murine model of stereotactic ablative radiotherapy for hepatocellular carcinoma
No full textLiver tumours, both primary and metastatic, are diseases of unmet clinical need. Hepatocellular carcinoma (HCC) the most common primary liver tumour, like many other cancers, may be treated by stereotactic ablative radiotherapy (SABR), reducing off-target effects of radiation on local anatomical structures. However, integrating all the necessary components for stereotactic irradiation of hepatocellular carcinoma in murine models has not yet been reported. Here we provide the development and detailed characterisation of a murine SABR model combining both MRI and CT image-guided delineation of the tumour, together with CT-guided liver tumour radiotherapy. The model enables accurate delivery of clinically relevant doses of radiotherapy with good tolerability and on-target tumour responses in models with otherwise universally progressive disease. The development of this preclinical modelling platform paves the way for its integration into multimodal therapeutic and mechanistic testing in preclinical murine models of both metastatic and primary liver tumours, including hepatocellular carcinoma.</p
Variant-specific disruption to notch signaling in PAX6 microphthalmia and aniridia patient-derived hiPSC optic cup-like organoids
No full textThe homeobox-containing transcription factor PAX6 is a key regulator of eye development. Pathogenic heterozygous PAX6 variants lead to variable ocular phenotypes, most commonly haploinsufficiency-induced aniridia. Missense variants are typically associated with milder ocular conditions, although variants in the DNA-binding paired domain which alter target binding lead to severe ocular phenotypes including bilateral microphthalmia, similar to SOX2-anophthalmia syndrome. However, the variant-specific pathway disruption resulting in phenotypic heterogeneity is not well understood. To investigate pathogenic mechanisms of PAX6 variants, transcriptomic and chromatin accessibility analysis was performed on hiPSC derived 3D optic cup-like organoids generated from patients with variants (i) PAX6 N124K displaying combined microphthalmia, aniridia and optic nerve coloboma, and (ii) PAX6 R261X exhibiting typical aniridia. Total RNA sequencing analysis revealed downregulation of SOX2 in missense PAX6 N124K cups compared to both wildtype and PAX6 R261X haploinsufficient aniridia controls, along with Notch signalling components and markers of proliferation and differentiation. Transcription factor binding motifs of Notch-related genes were also found to be differentially bound in PAX6 N124K cups through ATACseq footprinting analysis. Our analysis of PAX6-related oculopathies using in vitro models reveals disruption to DNA binding perturbs SOX2 and Notch signalling, contributing to severe ocular phenotypes in patients with missense changes in the paired domain. This work reveals a previously unestablished role for PAX6 in SOX2 and Notch signalling regulation during early oculogenesis, as well as illuminating disease mechanisms underlying variant-specific ocular phenotypes and genotype-phenotype correlations. These novel insights can influence clinical care, and provide valuable data on potential therapeutic targets, which can guide future translational research.</p
The trajectory of sedative adverse events caused by antipsychotics:a meta-analysis of individual participant data from randomised, placebo-controlled, clinical trials in acute phase schizophrenia
No full textBACKGROUND: Sedative adverse events are common in patients with schizophrenia undergoing antipsychotic treatment, which affects treatment adherence and the patients' quality of life. Although tolerance to sedation is believed to develop, robust evidence documenting the timing of sedation onset and resolution remains elusive. To address this gap, we aimed to assess the dynamics of onset and resolution of sedation across various antipsychotics in patients with schizophrenia.METHODS: In this meta-analysis, we included placebo-controlled, randomised controlled trials (RCTs) of antipsychotic monotherapy for the acute phase of schizophrenia and schizoaffective disorder. We searched PubMed for RCTs from inception until May 6, 2021 and obtained individual participant data of included trials through the Yale University Open Data Access project. We created Kaplan-Meier curves to assess the probability of onset of sedation and resolution from the incidence of sedation across time after treatment initiation. People with lived experience were not involved in this study. This study is registered with PROSPERO, CRD42022351647.FINDINGS: We included a total of 6791 participants (4549 [67·0%] men and 2242 [33·0%] women, with a mean age of 38·0 years [SD 12·4, range 13-81], 1172 [17·3%] were Asian, 1626 [23·9%] were Black, 3654 [53·8%] were White, and 339 [5·0%] were other ethnicities) from 19 RCTs. Sedative adverse events were observed in 582 (8·6%) of 6791 participants and typically occurred shortly after treatment initiation. Among participants receiving antipsychotics, 418 (83%) of 505 sedation events occurred within the first 2 weeks of treatment. Following the onset of sedation, 50% of symptoms were resolved within 1 week. After 4 weeks of treatment, 24% (95% CI 19·7-29·3) continued to have sedation with oral agents and 22·3% (15·3-32·3) with long-acting injectables.INTERPRETATION: The high incidence of sedation within the first 2 weeks of treatment with antipsychotics emphasises the importance of early monitoring. Half of the sedation resolved within 1 week and 75% within 1 month, suggesting that tolerance to sedation is acquired quickly. If sedation is sustained, contributing factors should be evaluated.FUNDING: German Federal Ministry of Education and Research.</p
Proposing a multi-method phenomenological approach in exploring the perceived daily life experiences of people with dementia in their dementia care environments and immediate outdoor settings
No full textThe environment in this study is presented primarily drawing on the theoretical definition of home, and its experience and meaning to the individual with dementia, with an interest in access to outdoors. Notions of perception, cognitive image and affordance are central to the sense of home, and in turn the sense of self that this may inform and support. This theoretical framework informs the multi-method phenomenological approach proposed, through themes of spatial legibility, cultural appropriateness, fascination, user-centredness and personalisation. The novelty of the methodological toolkit lies in the incorporation of methods that have been traditionally used in research with people with dementia as the basis of the framework, but which are supplemented by additional layers developed from conventional architectural tools to create a more visual representation of the environmental experience. Despite its apparent complexity, the methodology yields a very clear and precise image of the person's presence in her surroundings, at once providing a location in space and time, her mood and engagement, as well as a layering of the affordances that may have informed her behavior. This method was developed as part of this research, and remains unique to it. Its innovation lies in the progression of the DCM tool, the integration of the notion of affordances and architectural mapping techniques to propose a holistic depiction of the care experience of people with dementia
PSYSCAN multi-centre study:baseline characteristics and clinical outcomes of the clinical high risk for psychosis sample
No full textPredicting outcomes in individuals at clinical high risk (CHR) of developing psychosis remains challenging using clinical metrics alone. The PSYSCAN project aimed to enhance predictive value by integrating data across clinical, environmental, neuroimaging, cognitive, and peripheral blood biomarkers. PSYSCAN employed a naturalistic, prospective design across 12 sites (Europe, Australia, Asia, Americas). Assessments were conducted at baseline, 3, 6, and 12 months, with follow-ups at 18 and 24 months to evaluate clinical and functional outcomes. The study included 238 CHR individuals and 134 healthy controls (HC). At baseline, CHR and HC groups differed significantly in age, education, IQ, and vocational and relationship status. Cannabis and tobacco use did not significantly differ between groups, however CHR individuals had higher proportion of moderate to high risk of tobacco abuse. A substantial portion of the CHR sample met DSM criteria for anxiety (53.4%) and/or mood disorders (52.9%), with some prescribed antidepressants (38.7%), antipsychotics (13.9%), or benzodiazepines (16.4%). Over the follow-up period, 25 CHR individuals (10.5%) transitioned to psychosis. However, the CHR group as a whole showed improvements in functioning and attenuated psychotic symptoms. Similar to other recent multi-centre studies, the CHR cohort exhibits high comorbidity rates and relatively low psychosis transition rates. These findings highlight the clinical heterogeneity within CHR populations and suggest that outcomes extend beyond psychosis onset, reinforcing the need for broader prognostic models that consider functional and transdiagnostic outcomes.</p
Unleashing the power of text for credit default prediction:Comparing human-written and generative AI-refined texts
No full textThis study explores the integration of a representative large language model, ChatGPT, into lending decision-making with a focus on credit default prediction. Specifically, we use ChatGPT to analyse and interpret loan assessments written by loan officers and generate refined versions of these texts. Our comparative analysis reveals significant differences between generative artificial intelligence (AI)-refined and human-written texts in terms of text length, semantic similarity, and linguistic representations. Using deep learning techniques, we show that incorporating unstructured text data, particularly ChatGPT-refined texts, alongside conventional structured data significantly enhances credit default predictions. Furthermore, we demonstrate how the contents of both human-written and ChatGPT-refined assessments contribute to the models’ prediction and show that the effect of essential words is highly context-dependent. Moreover, we find that ChatGPT’s analysis of borrower delinquency contributes the most to improving predictive accuracy. We also evaluate the business impact of the models based on human-written and ChatGPT-refined texts, and find that, in most cases, the latter yields higher profitability than the former. This study provides valuable insights into the transformative potential of generative AI in financial services
Blood biomarkers of vascular dysfunction in small vessel disease progression: Insights from a longitudinal neuroimaging study
No full text‘Read My Lips, Not My Body’: A Thematic Analysis of Autistic People's Social Communication Preferences, Experiences, and Expectations
No full textAssociations of genetic factors with vascular diabetes complications: an umbrella review
No full textBackgroundTo comprehensively assess evidence from published systematic review and meta-analyses (SRMAs) on the genetics of vascular diabetes complications.MethodsA systematic literature search conducted in Medline and Embase identified 63 non-overlapping SRMAs. We re-conducted meta-analyses to compare diabetes with and without complications using multiple genetic models; evaluated associations using Venice criteria and Bayesian false-discovery probability (BFDP); and graded as highly credible, credible, and not credible. We also contrasted highly credible and credible associations to recent genome-wide association studies (GWASs).ResultsHighly credible evidence was discovered for single nucleotide polymorphisms (SNPs) rs1024611 at MCP-1 gene and SNP rs3025039 at VEGF gene with diabetic retinopathy (DR) in type 2 diabetes; SNP rs2268388 at ACACB gene, insertion/deletion (Ins/Del) variant at ACE gene, SNP rs1801133 at MTHFR gene, and SNP rs7903146 at TCF7L2 gene with diabetic kidney disease (DKD) in type 2 diabetes; and SNP rs4880 at SOD2 gene with diabetic peripheral neuropathy (DPN) in type 1 diabetes. Combining type 1 and 2 diabetes, highly credible evidence was discovered for insertion/deletion variant at ACE gene, SNP rs759853 at AKR1B1 gene, SNP rs1044498 at ENPP1 gene and DKD, and SNP rs1617640 at EPO gene for the combined endpoint of DR and DKD. None of these associations was directly replicated in the latest GWASs for DR and DKD, however, another SNP, rs55853916 at TCF7L2 gene had been detected as a GWAS hit for DKD.ConclusionsThis umbrella review rigorously assessed evidence on the genetics of vascular diabetes complications, complemented findings in recent GWASs and yielded insight into the optimal selection of genetic models for the design of GWASs on vascular diabetes complications. Mechanistic or bioinformatic studies are warranted to further assess the role of these genes in the pathology of vascular diabetes complications and their potential as drug targets.<br/
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