Multivariable model of postoperative delirium in cardiac surgery patients: proteomic and demographic contributions.

Background: Delirium following cardiac surgery is common, morbid, and costly, but may be prevented with risk stratification and targeted intervention. Preoperative protein signatures may identify patients at increased risk for worse postoperative outcomes, including delirium. In this study, we aimed to identify plasma protein biomarkers and develop a predictive model for postoperative delirium in older patients undergoing cardiac surgery, while also uncovering possible pathophysiological mechanisms. Methods: SOMAscan analysis of 1,305 proteins in the plasma from 57 older adults undergoing cardiac surgery requiring cardiopulmonary bypass was conducted to define delirium-specific protein signatures at baseline (PREOP) and postoperative day 2 (POD2). Selected proteins were validated in 115 patients using the ELLA multiplex immunoassay platform. Proteins were combined with clinical and demographic variables to build multivariable models that estimate the risk of postoperative delirium and bring light to the underlying pathophysiology. Results: A total of 115 and 85 proteins from SOMAscan analyses were found altered in delirious patients at PREOP and POD2, respectively (p<0.05). Using four criteria including associations with surgery, delirium, and biological plausibility, 12 biomarker candidates (Tukey's fold change (|tFC|)>1.4, Benjamini-Hochberg (BH)-p<0.01) were selected for ELLA multiplex validation. Eight proteins were significantly altered at PREOP, and seven proteins at POD2 (p<0.05), in patients who developed postoperative delirium compared to non-delirious patients. Statistical analyses of model fit resulted in the selection of a combination of age, sex, and three proteins (angiopoietin-2 (ANGPT2); C-C motif chemokine 5 (CCL5); and metalloproteinase inhibitor 1 (TIMP1); AUC=0.829) as the best performing predictive model for delirium at PREOP. The delirium-associated proteins identified as biomarker candidates are involved with inflammation, glial dysfunction, vascularization, and hemostasis, highlighting the multifactorial pathophysiology of delirium. Conclusion: Our study proposes a model of postoperative delirium that includes a combination of older age, female sex, and altered levels of three proteins. Our results support the identification of patients at higher risk of developing postoperative delirium after cardiac surgery and provide insights on the underlying pathophysiology. ClinicalTrials.gov ( NCT02546765 ).

Perceived stress, resilience, well-being, and COVID 19 response in Isha yoga practitioners compared to matched controls: A research protocol.

OBJECTIVES: The COVID-19 pandemic has been a significant stressor worldwide and reports of psychological distress, depression, sedentary lifestyles, and overall decreased wellbeing are increasing. Yoga practices have been found to improve mental and physical health. The purpose of this randomized controlled trial is to compare Isha yoga practitioners to controls on perceived stress, resilience, wellbeing, and protection and recovery from COVID-19. Trial Design. In this prospective randomized control trial, the effects of yoga practices are being compared between seasoned yoga practitioners with two controls who are age (±3 years), gender matched, and living in the same neighborhood. METHODS: Participants will be asked to complete a series of web-based surveys at baseline, six weeks, and 12 weeks. These surveys include validated scales and objective questions on COVID-19 infection and medical history. The validated questionnaires assess stress, mood states, resilience, and overall wellbeing. Questionnaires, weekly activity diaries, and medical history, will be collected using REDCap. RESULTS: We hypothesize that routine yoga practice during the COVID-19 pandemic will reduce stress, enhance well-being, and provide protective effects against COVID-19. CONCLUSION: With the growing concern about the physical and mental impacts of COVID-19 and increased interest in alternative practices such as yogic practices, this study will contribute to the growing body of evidence about the safety and efficacy of yoga for emotional, mental, and physical health conditions.

An observational cohort study to produce and evaluate an improved tool to screen older women with back pain for osteoporotic vertebral fractures (Vfrac): study protocol.

The aim of this study is to produce an easy to use checklist for general practitioners to complete whenever a woman aged over 65 years with back pain seeks healthcare. This checklist will produce a binary output to determine if the patient should have a radiograph to diagnose vertebral fracture. PURPOSE: People with osteoporotic vertebral fractures are important to be identified as they are at relatively high risk of further fractures. Despite this, less than a third of people with osteoporotic vertebral fractures come to clinical attention due to various reasons including lack of clear triggers to identify who should have diagnostic spinal radiographs. This study aims to produce and evaluate a novel screening tool (Vfrac) for use in older women presenting with back pain in primary care based on clinical triggers and predictors identified previously. This tool will generate a binary output to determine if a radiograph is required. METHODS: The Vfrac study is a two-site, pragmatic, observational cohort study recruiting 1633 women aged over 65 years with self-reported back pain. Participants will be recruited from primary care in two sites. The Vfrac study will use data from two self-completed questionnaires, a simple physical examination, a lateral thoracic and lateral lumbar radiograph and information contained in medical records. RESULTS: The primary objective is to develop an easy-to-use clinical screening tool for identifying older women who are likely to have vertebral fractures. CONCLUSIONS: This article describes the protocol of the Vfrac study; ISRCTN16550671.

Tumour necrosis factor-mediated macrophage activation in the target organ is critical for clinical manifestation of uveitis.

Clinically available anti-tumour necrosis factor (TNF) biologics, which inhibit both soluble (sTNF) and transmembrane forms (tmTNF) of TNF, eliminating all TNF signalling, have successfully treated autoimmune diseases including uveitis. These have potentially serious side effects such as reactivation of latent Mycobacterium tuberculosis and, therefore, more specific inhibition of TNF signalling pathways may maintain clinical efficacy while reducing adverse effects. To determine the effects of specific pharmacological inhibition of sTNF on macrophage activation and migration, we used a mouse model of uveitis (experimental autoimmune uveoretinitis; EAU). We show that selective inhibition of sTNF is sufficient to suppress EAU by limiting inflammatory CD11b(+) macrophages and CD4(+) T cell migration into the eye. However, inhibition of both sTNF and tmTNF is required to inhibit interferon-γ-induced chemokine receptor 2, CD40, major histocompatibility complex class II and nitric oxide (NO) up-regulation, and signalling via tmTNF is sufficient to mediate tissue damage. In confirmation, intravitreal inhibition of sTNF alone did not suppress disease, and inflammatory cells that migrated into the eye were activated, generating NO, thus causing structural damage to the retina. In contrast, intravitreal inhibition of both sTNF and tmTNF suppressed macrophage activation and therefore disease. We conclude that sTNF is required for inflammatory cell infiltration into target tissue, but at the tissue site inhibition of both sTNF and tmTNF is required to inhibit macrophage activation and to protect from tissue damage.