Inhibition of Inducible Nitric Oxide Synthase Expression by a Novel Small Molecule Activator of the Unfolded Protein Response

The transcription of inducible nitric oxide synthase (iNOS) is activated by a network of proinflammatory signaling pathways. Here we describe the identification of a small molecule that downregulates the expression of iNOS mRNA and protein in cytokine-activated cells and suppresses nitric oxide production in vivo. Mechanistic analysis suggests that this small molecule, erstressin, also activates the unfolded protein response (UPR), a signaling pathway triggered by endoplasmic reticulum stress. Erstressin induces rapid phosphorylation of eIF2α and the alternative splicing of XBP-1, hallmark initiating events of the UPR. Further, erstressin activates the transcription of multiple genes involved in the UPR. These data suggest an inverse relationship between UPR activation and iNOS mRNA and protein expression under proinflammatory conditions

The development and validation of a scoring tool to predict the operative duration of elective laparoscopic cholecystectomy

Background: The ability to accurately predict operative duration has the potential to optimise theatre efficiency and utilisation, thus reducing costs and increasing staff and patient satisfaction. With laparoscopic cholecystectomy being one of the most commonly performed procedures worldwide, a tool to predict operative duration could be extremely beneficial to healthcare organisations. Methods: Data collected from the CholeS study on patients undergoing cholecystectomy in UK and Irish hospitals between 04/2014 and 05/2014 were used to study operative duration. A multivariable binary logistic regression model was produced in order to identify significant independent predictors of long (> 90 min) operations. The resulting model was converted to a risk score, which was subsequently validated on second cohort of patients using ROC curves. Results: After exclusions, data were available for 7227 patients in the derivation (CholeS) cohort. The median operative duration was 60 min (interquartile range 45–85), with 17.7% of operations lasting longer than 90 min. Ten factors were found to be significant independent predictors of operative durations > 90 min, including ASA, age, previous surgical admissions, BMI, gallbladder wall thickness and CBD diameter. A risk score was then produced from these factors, and applied to a cohort of 2405 patients from a tertiary centre for external validation. This returned an area under the ROC curve of 0.708 (SE = 0.013, p  90 min increasing more than eightfold from 5.1 to 41.8% in the extremes of the score. Conclusion: The scoring tool produced in this study was found to be significantly predictive of long operative durations on validation in an external cohort. As such, the tool may have the potential to enable organisations to better organise theatre lists and deliver greater efficiencies in care

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

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Catalyst-free site-selective cross-aldol bioconjugations

The bioconjugation of proteins to small molecules serves as an invaluable tool for probing biological mechanisms and creating biomaterials. The most powerful bioconjugation stratagems are those which have rapid kinetics, are site-selective, can be conducted in aqueous solvent under mild conditions and do not require the use of additional potentially toxic catalysts. Herein we present spontaneous coupling via aldol ligation of proteins (SCALP) a catalyst-free “green” site-selective protein ligation between α-oxo aldehyde functionalised proteins and enolisable aldehyde probes at neutral pH, and demonstrate the utility of this system in the targeting of prostate cancer cells with functionalised nanobodies

Comparison of Two Sources of Clinical Audit Data to Assess the Delivery of Diabetes Care in Aboriginal Communities

The objective of this study was to determine the concordance between data extracted from two Clinical Decision Support Systems regarding diabetes testing and monitoring at Aboriginal Community Controlled Health Services in Australia. De-identified Pen CAT and Communicare Systems data were extracted from the services allocated to the intervention arm of a diabetes care trial, and intra-class correlations for each extracted item were derived at a service level. Strong to very strong correlations between the two data sources were found regarding the total number of patients with diabetes per service (Intra-class correlation [ICC] = 0.99), as well as the number (ICC = 0.98-0.99) and proportion (ICC = 0.96) of patients with diabetes by gender. The correlation was moderate for the number and proportion of Type 2 diabetes patients per service in the group aged 18-34 years (ICC = 0.65 and 0.8-0.82 respectively). Strong to very strong correlations were found for numbers and proportions of patients being tested for diabetes, and for appropriate monitoring of patients known to have diabetes (ICC = 0.998-1.00). This indicated a generally high degree of concordance between whole-service data extracted by the two Clinical Decision Support Systems. Therefore, the less expensive or less complex option (depending on the individual circumstances of the service) may be appropriate for monitoring diabetes testing and care. However, the extraction of data about subgroups of patients may not be interchangeable

A cross-sectional survey assessing the acceptability and feasibility of self-report electronic data collection about health risks from patients attending an Aboriginal community controlled health service

Background: Aboriginal Australians experience significantly worse health and a higher burden of chronic disease than non-Aboriginal Australians. Electronic self-report data collection is a systematic means of collecting data about health risk factors which could help to overcome screening barriers and assist in the provision of preventive health care. Yet this approach has not been tested in an Aboriginal health care setting. Therefore, the aim of this study was to examine the acceptability and feasibility of a health risk questionnaire administered on a touch screen laptop computer for patients attending an Aboriginal Community Controlled Health Service (ACCHS). Methods: In 2012, consecutive adult patients attending an ACCHS in rural New South Wales, Australia, were asked to complete a health risk survey on a touch screen computer. Health risk factors assessed in the questionnaire included smoking status, body mass index, and level of physical activity. The questionnaire included visual cues to improve accuracy and minimise literacy barriers and was completed while participants were waiting for their appointment. Results: A total of 188 participants completed the questionnaire, with a consent rate of 71%. The mean time taken to complete the questionnaire was less than 12 minutes. Over 90% of participants agreed that: the questionnaire instructions were easy to follow; the touch screen computer was easy to use; they had enough privacy; the questions were easy to understand; they felt comfortable answering all the questions. Conclusions: Results indicate that the use of a touch screen questionnaire to collect information from patients about health risk factors affecting Aboriginal Australians is feasible and acceptable in the ACCHS setting. This approach has potential to improve identification and management of at-risk individuals, therein providing significant opportunities to reduce the burden of disease among Aboriginal Australians