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

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication

Structural and Functional Investigation of the Sam68/p300 Protein Complex

Sam68 is an RNA-binding protein that is involved in a number of processes related to gene expression, including transcriptional events and pre-mRNA alternative splicing. Although the exact mechanism by which Sam68 exerts its role in transcriptional regulation remains largely unknown, its interaction with multiple transcription factors may enable Sam68 to act as a transcriptional repressor or activator. Previous research discovered a novel complex between Sam68 and transcription factors p300 and CBP. This interaction has been shown to reduce β-catenin-mediated transcription, alter CD44 alternative splicing and is targetable by the ICG-001/CWP family of small molecules. However, there is limited structural and functional information regarding the Sam68/p300 complex. Gathering a wider understanding of how these proteins interact, and their biological significance, is important for comprehending the mechanisms behind Sam68/p300-mediated regulation of transcription and splicing. Through the use of several techniques, the interaction interface was assigned to the CK region of Sam68 and the TAZ2 domain of p300. In vivo splicing assays suggest that p300 enhances Sam68-mediated splicing of Bcl-x and Mcl-1. This contrasts with RNA-Seq data suggesting that overexpression of p300 causes a global reduction in the number of genes undergoing differential alternative splicing by Sam68. Additionally, splicing analysis using RNASeq reveals that Sam68’s role in splicing can be both dependent and independent of transcriptional events. Evaluating the transcriptomic landscape with RNA-Seq provides definitive evidence for Sam68 function in gene expression regulation with events being both dependent and independent of p300. This role of Sam68 in gene regulation is likely to be primarily driven by mechanisms involving lncRNAs. Finally, the relationship between Sam68 and p300 in transcriptional and splicing events requires further investigation due to suboptimal levels of p300 associated with its overexpression. Nonetheless, this research provides additional evidence for the Sam68/p300 complex and has further characterised it both structurally and functionally.</p

Public reporting of colonoscopy quality is associated with an increase in endoscopist adenoma detection rate

BACKGROUND: Colonoscopy is the predominant method for colorectal cancer screening in the US. Prior studies have documented variation across physicians in colonoscopy quality as measured by the adenoma detection rate (ADR). ADR is the primary quality measure of colonoscopy exams and an indicator of the likelihood of subsequent patient colorectal cancer. There is interest in mechanisms to improve ADR. In Central Illinois, a local employer and a quality improvement organization partnered to publically report physician colonoscopy quality. OBJECTIVE: To assess whether this initiative was associated with an improvement in ADR. DESIGN: This study compares ADR before and after public reporting at a private practice endoscopy center of 11 gastroenterologists in Peoria, Illinois who participated in the initiative. To generate ADR, colonoscopy and pathology reports from exams performed over four years at the endoscopy center were analyzed using previously validated natural language processing software. SETTING: Central Illinois Endoscopy Center RESULTS: The ADR for colonoscopy in the pre-public reporting era was 25.1%, and after public reporting was 36.4% (increase of 11.3%, p<0.001). Detection of advanced adenomas increased from 10.0% to 12.7% (p<0.001). Each physician’s ADR increased (range of 4.3% to 17.4%). Similar increases in ADR were observed when the analysis was restricted to screening colonoscopy. LIMITATION: There was no concurrent control group to assess whether the increased ADR was due to a secular trend. CONCLUSION: A public reporting initiative on colonoscopy quality was associated with a relative forty-five percent increase in ADR and a 25% increase in advanced adenoma detection. Public reporting may be a means to improve colonoscopy quality