Longitudinal Molecular Trajectories of Diffuse Glioma in Adults

The evolutionary processes that drive universal therapeutic resistance in adult patients with diffuse glioma remain unclear ¹² . Here we analysed temporally separated DNA-sequencing data and matched clinical annotation from 222 adult patients with glioma. By analysing mutations and copy numbers across the three major subtypes of difuse glioma, we found that driver genes detected at the initial stage of disease were retained at recurrence, whereas there was little evidence of recurrence-specifc gene alterations. Treatment with alkylating agents resulted in a hypermutator phenotype at diferent rates across the glioma subtypes, and hypermutation was not associated with diferences in overall survival. Acquired aneuploidy was frequently detected in recurrent gliomas and was characterized by IDH mutation but without co-deletion of chromosome arms 1p/19q, and further converged with acquired alterations in the cell cycle and poor outcomes. The clonal architecture of each tumour remained similar over time, but the presence of subclonal selection was associated with decreased survival. Finally, there were no differences in the levels of immunoediting between initial and recurrent gliomas. Collectively, our results suggest that the strongest selective pressures occur during early glioma development and that current therapies shape this evolution in a largely stochastic manner

Increasing frailty is associated with higher prevalence and reduced recognition of delirium in older hospitalised inpatients: results of a multi-centre study

Purpose Delirium is a neuropsychiatric disorder delineated by an acute change in cognition, attention, and consciousness. It is common, particularly in older adults, but poorly recognised. Frailty is the accumulation of deficits conferring an increased risk of adverse outcomes. We set out to determine how severity of frailty, as measured using the CFS, affected delirium rates, and recognition in hospitalised older people in the United Kingdom. Methods Adults over 65 years were included in an observational multi-centre audit across UK hospitals, two prospective rounds, and one retrospective note review. Clinical Frailty Scale (CFS), delirium status, and 30-day outcomes were recorded. Results The overall prevalence of delirium was 16.3% (483). Patients with delirium were more frail than patients without delirium (median CFS 6 vs 4). The risk of delirium was greater with increasing frailty [OR 2.9 (1.8–4.6) in CFS 4 vs 1–3; OR 12.4 (6.2–24.5) in CFS 8 vs 1–3]. Higher CFS was associated with reduced recognition of delirium (OR of 0.7 (0.3–1.9) in CFS 4 compared to 0.2 (0.1–0.7) in CFS 8). These risks were both independent of age and dementia. Conclusion We have demonstrated an incremental increase in risk of delirium with increasing frailty. This has important clinical implications, suggesting that frailty may provide a more nuanced measure of vulnerability to delirium and poor outcomes. However, the most frail patients are least likely to have their delirium diagnosed and there is a significant lack of research into the underlying pathophysiology of both of these common geriatric syndromes

Improving protein coreference resolution by simple semantic classification

<p>Abstract</p> <p>Background</p> <p>Current research has shown that major difficulties in event extraction for the biomedical domain are traceable to coreference. Therefore, coreference resolution is believed to be useful for improving event extraction. To address coreference resolution in molecular biology literature, the Protein Coreference (COREF) task was arranged in the BioNLP Shared Task (BioNLP-ST, hereafter) 2011, as a supporting task. However, the shared task results indicated that transferring coreference resolution methods developed for other domains to the biological domain was not a straight-forward task, due to the domain differences in the coreference phenomena.</p> <p>Results</p> <p>We analyzed the contribution of domain-specific information, including the information that indicates the protein type, in a rule-based protein coreference resolution system. In particular, the domain-specific information is encoded into semantic classification modules for which the output is used in different components of the coreference resolution. We compared our system with the top four systems in the BioNLP-ST 2011; surprisingly, we found that the minimal configuration had outperformed the best system in the BioNLP-ST 2011. Analysis of the experimental results revealed that semantic classification, using protein information, has contributed to an increase in performance by 2.3% on the test data, and 4.0% on the development data, in F-score.</p> <p>Conclusions</p> <p>The use of domain-specific information in semantic classification is important for effective coreference resolution. Since it is difficult to transfer domain-specific information across different domains, we need to continue seek for methods to utilize such information in coreference resolution.</p