Sarah Richardson

A CD4 T cell gene signature for early rheumatoid arthritis implicates interleukin 6-mediated STAT3 signalling, particularly in anti-citrullinated peptide antibody-negative disease

Objective We sought clinically relevant predictive biomarkers present in CD4 T-cells, or in serum, that identified those patients with undifferentiated arthritis (UA) who subsequently develop rheumatoid arthritis (RA). Methods Total RNA was isolated from highly purified peripheral blood CD4 T cells of 173 early arthritis clinic patients. Paired serum samples were also stored. Microarray analysis of RNA samples was performed and differential transcript expression among 111 ‘training cohort’ patients confirmed using real-time quantitative PCR. Machine learning approaches tested the utility of a classification model among an independent validation cohort presenting with UA (62 patients). Cytokine measurements were performed using a highly sensitive electrochemiluminescence detection system. Results A 12-gene transcriptional ‘signature’ identified RA patients in the training cohort and predicted the subsequent development of RA among UA patients in the validation cohort (sensitivity 68%, specificity 70%). STAT3-inducible genes were over-represented in the signature, particularly in anti-citrullinated peptide antibody-negative disease, providing a risk metric of similar predictive value to the Leiden score in seronegative UA (sensitivity 85%, specificity 75%). Baseline levels of serum interleukin 6 (IL-6) (which signals via STAT3) were highest in anti-citrullinated peptide antibodies-negative RA and distinguished this subgroup from non-RA inflammatory synovitis (corrected p<0.05).Paired serum IL-6 measurements correlated strongly with STAT3-inducible gene expression. Conclusion The authors have identified IL-6-mediated STAT-3 signalling in CD4 T cells during the earliest clinical phase of RA, which is most prominent in seronegative disease. While highlighting potential biomarker(s) for early RA, the role of this pathway in disease pathogenesis awaits clarification.

Predicting outcome in older hospital patients with delirium: a systematic literature review

Delirium is a serious neuropsychiatric syndrome common in older hospitalised adults. It is associated with poor outcomes, however not all people with delirium have poor outcomes and the risk factors for adverse outcomes within this group are not well described. The objective was to report which predictors of outcome had been reported in the literature.

The Diagnosis of Delirium Superimposed on Dementia: An Emerging Challenge

Delirium occurring in patients with dementia is referred to as delirium superimposed on dementia (DSD). People who are older with dementia and who are institutionalized are at increased risk of developing delirium when hospitalized. In addition, their prior cognitive impairment makes detecting their delirium a challenge. The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition and the International Statistical Classification of Diseases and Related Health Problems, 10th Revision are considered the standard reference for the diagnosis of delirium and include criteria of impairments in cognitive processes such as attention, additional cognitive disturbances, or altered level of arousal. The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition and the International Statistical Classification of Diseases and Related Health Problems, 10th Revision does not provide guidance regarding specific tests for assessment of the cognitive process impaired in delirium. Importantly, the assessment or inclusion of preexisting cognitive impairment is also not addressed by these standards. The challenge of DSD gets more complex as types of dementia, particularly dementia with Lewy bodies, which has features of both delirium and dementia, are considered. The objective of this article is to critically review key elements for the diagnosis of DSD, including the challenge of neuropsychological assessment in patients with dementia and the influence of particular tests used to diagnose DSD. To address the challenges of DSD diagnosis, we present a framework for guiding the focus of future research efforts to develop a reliable reference standard to diagnose DSD. A key feature of a reliable reference standard will improve the ability to clinically diagnose DSD in facility-based patients and research studies.

Delirium superimposed on dementia: a survey of delirium specialists shows a lack of consensus in clinical practice and research studies

BACKGROUND Despite advances in delirium knowledge and the publication of best practice guidelines, uncertainties exist regarding assessment of Delirium Superimposed on Dementia (DSD). An international survey of delirium specialists was undertaken to evaluate current practice. METHODS Invitations to participate in an online survey were distributed by email among members of four international delirium associations with additional publication on their websites. The survey covered the assessment and diagnosis of DSD in clinical practice and research studies. Questions were structured around current practice and attitudes. RESULTS The 205 responders were mostly confident that they could detect DSD with 60% rating their confidence at 7 or above on a likert scale of 0 (none) to 10 (excellent). Seventy-six percent felt that Dementia with Lewy Bodies (DLB) was the most challenging dementia subtype in which to diagnose DSD. Several scales were used to assess for the presence of DSD including the Confusion Assessment Method (CAM) (54%), DSM-5 criteria (25%) and CAM-ICU (15%). Responders stated that attention (71%), fluctuation in cognitive status (65%), and arousability (41%) were the most clinically useful features to assess when diagnosing DSD. Motor fluctuations were also deemed important but 61% had no specific test to monitor these. CONCLUSIONS The largest survey of DSD practice to date demonstrates that despite good levels of confidence in recognizing DSD, there exists a lack of consensus concerning assessment and diagnosis globally. These findings suggest the need for the development of more research leading to precise diagnostic criteria and comprehensive guidelines regarding the assessment and diagnosis of DSD.

Novel immunotherapies for rheumatoid arthritis

#### Key points Immunotherapies are biological therapies that target specific aspects of rheumatoid arthritis (RA) pathogenesis Immunotherapies provide an alternative treatment for patients who fail to respond adequately to traditional disease-modifying agents such as methotrexate Four different

The Future Hospital: a blueprint for effective delirium care

ABSTRACT Delirium remains the most common hospital complication. Occurrence rates are set to rise as the population ages and, despite being preventable and treatable, delirium continues to be under-recognised. Given the adverse outcomes associated with delirium and the considerable financial burden, patients with delirium must be considered ‘core business’ for 21st century hospitals. We propose that the principles of care outlined by the Future Hospital Commission report provide an ideal blueprint for effective, evidence-based delirium prevention and management. In this context, we outline practical advice for clinicians to improve standards of care for patients with delirium in hospitals. Because negative cultural attitudes, coupled with a lack of ownership towards this highly complex group, remain a major challenge, we consider novel educational interventions that empower the multidisciplinary team. Further, improved outcomes for patients with delirium are likely to translate to wider benefits for the hospital population at large.

Peripheral blood CD4 T cell gene expression profiles as predictive biomarkers in early arthritis

CD4 T cells are thought to play a crucial role in the pathogenesis of rheumatoid arthritis (RA). Diagnosing the condition, particularly among patients who are seronegative for anticyclic citrullinated peptide (ACPA) antibodies, remains challenging in the clinic. The authors have explored the peripheral blood CD4 T cell transcriptome of early arthritis clinic attendees, looking for biomarkers of potential diagnostic utility. Total RNA from highly purified peripheral blood CD4 T cells of consenting patients with early arthritis naive to …