Background Impaired clinical insight in schizophrenia is associated with poor treatment adherence and outcomes. Previous research on the influence of symptoms, cognition, and antipsychotic exposure has been inconclusive and restricted to multi-episode samples. We examined time-specific associations between overall psychopathology, cognitive functioning, antipsychotic D₂ receptor mechanisms, antipsychotic exposure and dosage, and insight, whether these associations changed over time, and whether dosage moderated them. Methods In 144 individuals with schizophrenia, including antipsychotic-naïve and previously treated participants, multiple regressions were conducted at five cross-sectional time points and examined changes in associations over one year. Insight was assessed using PANSS item G12. Symptom severity was represented by the sum of the remaining PANSS items (mPANSS). Antipsychotic exposure was quantified as cumulative Defined Daily Doses and classified as dopamine antagonists (DA) or partial agonists (DPA). Cognitive functioning was expressed as a mean t-score. Results Greater symptom severity was consistently associated with poorer insight across time points and was the only variable showing a linear increase in strength over time. Higher DPA doses were associated with poorer insight at baseline and 12 months, but improved insight at 12 weeks. Higher cognitive functioning was associated with better insight at baseline and interacted with lower doses at 6 weeks and 12 months. No consistent associations were observed in antipsychotic-naïve participants. Conclusion Clinical insight was most consistently associated with symptom severity, with an increasingly robust association over time, highlighting the need to assess insight across the symptom spectrum, including when symptoms are mild and independently of antipsychotic dosage.
Surgical management remains the cornerstone in the management of gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs), yet surgical indications and procedures are often inconsistent. To inform the development of a research agenda to strengthen the evidence in NETs surgical care, we conducted a scoping review to map the existing literature on surgery for gastro-entero-pancreatic (GEP) NETs. The scoping review was conducted following the expanded framework of Arksey and O’Malley. A literature search was run on MEDLINE, Embase, and Scopus in October 2024 for studies published since 2000 reporting on any surgical intervention, performed under general or loco-regional anesthesia on adults with GEP-NETs at any stage. Among the 10,000 studies screened, 260 were included. Publications included were mostly reviews covering a broad range of topics. Of the 120 original investigations, 96.7
Tissue detection is a crucial first step in most digital pathology applications. By applying image segmentation algorithms, all tissue is delineated and background discarded from further analyses, improving both computational efficiency and analytical results. Details of the segmentation algorithm are rarely reported, and there is a lack of studies investigating the downstream effects of a poor segmentation algorithm. Disregarding tissue detection quality could jeopardize patient safety if diagnostically relevant parts of the specimen are excluded from analysis in clinical applications. This study aims to determine whether performance of downstream tasks is sensitive to the tissue detection method, and to compare the performance of a classical and an AI-based tissue detection approach. To this end, we trained an AI model for Gleason grading of prostate cancer in whole slide images (WSIs) using two different tissue detection algorithms: thresholding (classical) and UNet++ (AI). A total of 33,823 WSIs scanned on seven digital pathology scanners were used to train the segmentation AI model. The downstream Gleason grading algorithm was trained and tested using 70,524 WSIs from 13 clinical sites scanned on 13 different scanners. On the slides where tissue could be detected by both algorithms, no significant difference in overall Gleason grading performance was observed. There was a decrease from 118 (0.43%) to 24 (0.09%) fully undetected tissue samples when switching from thresholding-based tissue detection to AI-based, suggesting this AI model may be more reliable than the classical model for avoiding total failures on slides with unusual appearance. Moreover, tissue detection dependent clinically significant variations in AI grading were observed in 3.5% of malignant slides, highlighting the role of tissue detection for optimal clinical performance of diagnostic AI.
Background Fatigue, impaired sleep quality and daytime sleepiness, common in neurodegenerative and immune-mediated diseases, are debilitating and have serious societal and economic implications. Currently, measurement of these symptoms largely relies on self-reported questionnaires, which are burdensome for patients and lack sensitivity, granularity and reliability. Methods Building on a preceding feasibility study and qualification advice of the European Medicines Agency, the Clinical Observational Study of the European project Identifying Digital Endpoints to Assess FAtigue, Sleep and acTivities of daily living in Neurodegenerative disorders and Immune-mediated inflammatory diseases (IDEA-FAST) investigates the relationship between digital and clinical parameters of the target concepts of fatigue, reduced sleep quality and daytime sleepiness. Results Between 2022 and 2025, 2000 people are being recruited at 24 European sites – 500 with Parkinson's disease, 500 with inflammatory bowel disease, 200 with each of the following diseases: Huntington's disease, rheumatoid arthritis, systemic lupus erythematosus, primary Sjögren's syndrome and 200 healthy volunteers. Participants are followed over a 24-week period with four visits, each including a 1-week assessment phase at home using CE-certified digital health (including active and passive) technologies. The latter collect information on physical activity, physiology, cognition as well as social interaction and behaviour as core dimensions of the target concepts. Conclusion This study will help to develop reliable, valid and efficient digital endpoints of fatigue, impaired sleep quality and daytime sleepiness for use in future clinical studies and trials.
Background Klebsiella pneumoniae is an important pathogen of humans and animals. In the past five years, increasing reports of convergent strains that carry both virulence factors and antimicrobial resistance genes (ARGs) have raised serious public health concerns. The aim of this study is to describe the global diversity of plasmids carrying iuc3 (a key virulence factor in K pneumoniae associated with pigs and clinical isolates) from diverse settings, and their role in the emergence of convergent strains through hybridisation with plasmids carrying ARGs. Methods This population genomic analysis study was designed to describe both the global and local diversity of iuc3-carrying plasmids from diverse sources, and the co-occurrence of iuc3 with ARGs. We used all 4148 Klebsiella spp isolates from two large One-Health studies (SpARK, Italy, and OH-DART, Thailand), including 191 Klebsiella isolates from pigs, 635 from clinical isolates, 1040 from hospital and community carriage, and 2282 from other sources. Short-read sequencing of Klebsiella isolates was performed as part of the SpARK study. We sequenced Klebsiella isolates from the OH-DART (MicrobesNG, Birmingham, UK; HiSeq and NovaSeq, Illumina San Diego, CA, USA; GridION, Oxford Nanopore Technologies, Oxford, UK) and SpARK (MinION or GridION, Oxford Nanopore Technologies, Oxford, UK) studies. We also retrieved plasmid sequences carrying iuc3 from the National Centre for Biotechnology Information (NCBI). To ascertain the degree of diversity, evolutionary dynamics, and structuring across ecological and geographical axes, we detected ARGs and virulence loci, analysed clustering patterns and generated approximate maximum-likelihood phylogenetic trees. Findings We identified 48 K pneumoniae isolates with iuc3 in the SpARK data and 79 in the OH-DART data. Three (2·4%) of these 127 isolates were from clinical sources, 73 (57·5%) were from pig or pork meat. iuc3 isolates corresponded to multiple (n=47) host sequence types (STs), with ST35, ST45, ST881, ST25, and ST967 harbouring iuc3 in both datasets. We generated hybrid assemblies for 44 (SpARK) and 36 (OH-DART) isolates, plus a single iuc3 isolate from Germany. 53 (65·4%) of these isolates were from pigs, three (3·7%) from clinical sources, and 25 (30·9%) from other sources. There were an additional 48 iuc3 positive isolates from our collections for which only short read data was available. A single iuc3-positive Klebsiella oxytoca isolate from a pig farm was detected in the SpARK data, which was also sequenced. We identified 330 iuc3-positive isolates and 58 iuc3-carrying plasmid assemblies from NCBI, of which 83 (21·4%) were from clinical sources, 120 from pigs (30·9%), and 185 (47·7%) from other sources or of unknown provenance. These isolates were from K pneumoniae except two isolates of Klebsiella quasipneumoniae subsp similipneumoniae and one of Enterobacter hormaechei. The combined dataset of 517 iuc3 plasmids ranged in size from 110 375 bp to 365 580 bp and mostly corresponded to multiple IncFIB(K) and IncFII replicon types. We found seven convergent K pneumoniae plasmids in the Thai data: six from fresh markets and one from a neighbouring hospital. These plasmids emerged through the hybridisation of cocirculating iuc3 plasmids and plasmids encoding extended-spectrum β-lactamases (ESBLs), although none of these seven plasmids carried genes encoding carbapenemases. We also identified putative cocirculating parental plasmids carrying iuc3 and ESBL-encoding genes. Clustering and phylogenetic analysis resolved the iuc3 plasmid sequences into three groups, which were consistent using both complete plasmid sequences (n=139) and short-read data (n=517). In the complete plasmid sequence data, 66 strains contained group 1 plasmids, 38 strains contained group 2 plasmids, and 35 strains contained group 3 plasmids. Group 3 plasmids are mostly carried by isolates circulating in hospitals throughout Asia, with occasional examples in Europe and elsewhere, and carry multiple ARGs and potential virulence factors. By contrast, group 1 plasmids are commonly carried by porcine isolates in Europe, and group 2 are a heterogeneous mixture of geographical and ecological sources. Interpretation Plasmid hybridisation occurs frequently outside of the health-care environment and can lead to the convergence of resistance and virulence traits. Generating complete plasmid sequences from regional population-scale samples facilitates the identification of convergent plasmids and their putative parental plasmids. Three robust groups of iuc3 plasmids were resolved, which show both epidemiological and geographical differences; one of these groups was associated with clinical isolates in Asia and warrants targeted plasmid surveillance. Funding UKRI, JPIAMR, Evolution Education Trust, and a Schlumberger Foundation Fellowship.
