Characterisation of premature cell senescence in Alzheimer's disease using single nuclear transcriptomics.

Aging is associated with cell senescence and is the major risk factor for AD. We characterized premature cell senescence in postmortem brains from non-diseased controls (NDC) and donors with Alzheimer's disease (AD) using imaging mass cytometry (IMC) and single nuclear RNA (snRNA) sequencing (> 200,000 nuclei). We found increases in numbers of glia immunostaining for galactosidase beta (> fourfold) and p16INK4A (up to twofold) with AD relative to NDC. Increased glial expression of genes related to senescence was associated with greater ß-amyloid load. Prematurely senescent microglia downregulated phagocytic pathways suggesting reduced capacity for ß-amyloid clearance. Gene set enrichment and pseudo-time trajectories described extensive DNA double-strand breaks (DSBs), mitochondrial dysfunction and ER stress associated with increased ß-amyloid leading to premature senescence in microglia. We replicated these observations with independent AD snRNA-seq datasets. Our results describe a burden of senescent glia with AD that is sufficiently high to contribute to disease progression. These findings support the hypothesis that microglia are a primary target for senolytic treatments in AD.

A single nuclear transcriptomic characterisation of mechanisms responsible for impaired angiogenesis and blood-brain barrier function in Alzheimer's disease.

Brain perfusion and blood-brain barrier (BBB) integrity are reduced early in Alzheimer's disease (AD). We performed single nucleus RNA sequencing of vascular cells isolated from AD and non-diseased control brains to characterise pathological transcriptional signatures responsible for this. We show that endothelial cells (EC) are enriched for expression of genes associated with susceptibility to AD. Increased ß-amyloid is associated with BBB impairment and a dysfunctional angiogenic response related to a failure of increased pro-angiogenic HIF1A to increased VEGFA signalling to EC. This is associated with vascular inflammatory activation, EC senescence and apoptosis. Our genomic dissection of vascular cell risk gene enrichment provides evidence for a role of EC pathology in AD and suggests that reducing vascular inflammatory activation and restoring effective angiogenesis could reduce vascular dysfunction contributing to the genesis or progression of early AD.

Assessing the Accuracy of International Classification of Diseases (ICD) Coding for Delirium.

OBJECTIVE: We assessed the accuracy of the ICD-10 code for delirium (F05) and its relationship with delirium discharge summary documentation. METHODS: We performed a retrospective chart review at three academic hospitals. The Chart-based Delirium Identification Instrument (CHART-DEL) was used to identify 108 hospitalized patients aged ≥65 years with delirium, and 758 patients without delirium as controls. We assessed the proportion of patients who received the F05 code and calculated the sensitivity and specificity. We compared the rates of F05 code received between patients with and without "delirium" documented in the discharge summary. RESULTS: Among delirious patients, 46.3% received a F05 code, which has a sensitivity of 46.3% and specificity of 99.6% for delirium. Of charts with "delirium" in the discharge summary (n = 67), 67.2% were appropriately coded. CONCLUSIONS: Current ICD-10 data inadequately capture delirium. Delirium documentation in the discharge summary is associated with improved delirium coding.

Assessing the learning needs of physical medicine and rehabilitation residents to develop a geriatric medicine and rehabilitation curriculum.

BACKGROUND: Older adults with functional impairment are cared for by physiatrists in rehabilitation, but physiatrist training in geriatric-related competencies remains suboptimal. To develop a geriatric rehabilitation (GR) curriculum and explore opportunities for improvement, a needs assessment of stakeholders was conducted to understand physical medicine and rehabilitation (PMR) residents' comfort levels and learning needs in geriatrics. METHODS: A mixed-methods design was employed. PMR residents (n = 18) and practicing physiatrists (n = 40) completed a questionnaire; and PMR residents, physiatrists and key informants (n = 9; n = 4; n = 6) participated in focus groups and semi-structured interviews to explore geriatric experiences of trainees and educational needs in geriatrics and rehabilitation. Data were qualitatively analyzed using constructivist-grounded theory. RESULTS: Residents and physiatrists highlighted similar topics as areas of low comfort in knowledge. Interviews prioritized critical geriatric topics (gait assessment, falls, cognitive impairment, movement disorders, and polypharmacy) and highlighted disposition planning and end-of-life care as areas needing further curriculum support. Challenges in delivering geriatric education were also identified. CONCLUSION: What emerged from the needs assessment was a series of critical geriatric educational priorities for the development of a GR curriculum for physiatry trainees - arising at an opportune time given the shift toward competency-based residency education.

An IL1RL1 genetic variant lowers soluble ST2 levels and the risk effects of APOE-ε4 in female patients with Alzheimer's disease.

Changes in the levels of circulating proteins are associated with Alzheimer's disease (AD), whereas their pathogenic roles in AD are unclear. Here, we identified soluble ST2 (sST2), a decoy receptor of interleukin-33-ST2 signaling, as a new disease-causing factor in AD. Increased circulating sST2 level is associated with more severe pathological changes in female individuals with AD. Genome-wide association analysis and CRISPR-Cas9 genome editing identified rs1921622 , a genetic variant in an enhancer element of IL1RL1, which downregulates gene and protein levels of sST2. Mendelian randomization analysis using genetic variants, including rs1921622 , demonstrated that decreased sST2 levels lower AD risk and related endophenotypes in females carrying the Apolipoprotein E (APOE)-ε4 genotype; the association is stronger in Chinese than in European-descent populations. Human and mouse transcriptome and immunohistochemical studies showed that rs1921622 /sST2 regulates amyloid-beta (Aß) pathology through the modulation of microglial activation and Aß clearance. These findings demonstrate how sST2 level is modulated by a genetic variation and plays a disease-causing role in females with AD.

The frequency and quality of delirium documentation in discharge summaries.

BACKGROUND: The National Institute for Health and Care Excellence recommends documenting all delirium episodes in the discharge summary using the term "delirium". Previous studies demonstrate poor delirium documentation rates in discharge summaries and no studies have assessed delirium documentation quality. The aim of this study was to determine the frequency and quality of delirium documentation in discharge summaries and explore differences between medical and surgical services. METHODS: This was a multi-center retrospective chart review. We included 110 patients aged ≥ 65 years identified to have delirium during their hospitalization using the Chart-based Delirium Identification Instrument (CHART-DEL). We assessed the frequency of any delirium documentation in discharge summaries, and more specifically, for the term "delirium". We evaluated the quality of delirium discharge documentation using the Joint Commission on Accreditation of Healthcare Organization's framework for quality discharge summaries. Comparisons were made between medical and surgical services. Secondary outcomes included assessing factors influencing the frequency of "delirium" being documented in the discharge summary. RESULTS: We identified 110 patients with sufficient chart documentation to identify delirium and 80.9 % of patients had delirium documented in their discharge summary ("delirium" or other acceptable term). The specific term "delirium" was reported in 63.6 % of all delirious patients and more often by surgical than medical specialties (76.5 % vs. 52.5 %, p = 0.02). Documentation quality was significantly lower by surgical specialties in reporting delirium as a diagnosis (23.5 % vs. 57.6 %, p < 0.001), documenting delirium workup (23.4 % vs. 57.6 %, p = 0.001), etiology (43.3 % vs. 70.4 %, p = 0.03), treatment (36.7 % vs. 66.7 %, p = 0.02), medication changes (44.4 % vs. 100 %, p = 0.002) and follow-up (36.4 % vs. 88.2 %, p = 0.01). CONCLUSIONS: The frequency of delirium documentation is higher than previously reported but remains subpar. Medical services document delirium with higher quality, but surgical specialties document the term "delirium" more frequently. The documentation of delirium in discharge summaries must improve to meet quality standards.

A mixed methods evaluation of a 4-week geriatrics curriculum in strengthening knowledge and comfort among orthopaedic surgery residents.

BACKGROUND: In 2014, the University of Toronto Faculty of Medicine implemented a 4-week "Orthogeriatrics" rotation for orthopaedic surgery residents. We sought to assess the rotation's impact on trainees' knowledge, attitudes, and behaviours toward caring for older adults, and explore areas for improvement. METHODS: We used a mixed methods concurrent triangulation design. The Geriatrics Clinical Decision-Making Assessment (GCDMA) and Geriatric Attitudes Scale (GAS) compared knowledge, attitudes, and behaviours between trainees who were or were not exposed to the curriculum. Rotation evaluations and semi-structured interviews with trainees and key informants explored learning experiences and the curriculum's impact on resident physician growth and development in geriatric competencies. RESULTS: Among trainees who completed the GCDMA (n = 19), those exposed to the rotation scored higher in knowledge compared to the unexposed cohort (14.4 ± 2.1 vs. 11.3 ± 2.0, p < 0.01). The following themes emerged from the qualitative analysis of 29 stakeholders: Increased awareness and comfort regarding geriatric medicine competencies, appreciation of the value of orthogeriatric collaboration, and suggestions for curriculum improvement. CONCLUSIONS: These results suggest that the Orthogeriatrics curriculum strengthens knowledge, behaviour, and comfort towards caring for older adults. Our study aims to inform further curriculum development and facilitate dissemination of geriatric education in surgical training programs across Canada and the world.

Use of the Consultation Letter Rating Scale among Geriatric Medicine Postgraduate Trainees.

OBJECTIVES: The implementation of competency-based evaluations increases the emphasis on in-training assessment. The Consultation Letter Rating Scale (CLRS), published by the Royal College of Physicians and Surgeons of Canada, is a tool that assesses written-communication competencies. This multisite project evaluated the tool's validity, reliability, feasibility, and acceptability for use in postgraduate geriatric medicine training. METHODS: Geriatric medicine trainees provided consultation letters from the 2017-2018 academic year. Geriatricians reviewed a standardized module and completed the tool for all the deidentified letters. The reviewers recorded the time used to complete the tool for each letter and completed a survey on content validity. Trainees completed a survey on the tool's usefulness. Responses were reviewed independently by two authors for thematic content. The unweighted and the weighted κ were used to measure interrater reliability. RESULTS: A total of 10 of 11 (91%) eligible trainees each provided five letters that were reviewed independently by six geriatricians, leading to a total of 300 assessments. A very small portion (4% [N = 12]) of assessments was incomplete. An average of 4.82 minutes (standard deviation = 3.17) was used to complete the tool. There was high interrater agreement for overall scores, with a multiple-rater weighted κ of 83% (95% confidence interval = 76%-89%). The interrater agreement was lower for the individual components. Both raters and trainees found the comments more useful than the numerical ratings. CONCLUSIONS: Our results support the use of the CLRS for facilitating feedback on the quality of consult letters to improve written-communication competencies among geriatric medicine trainees. J Am Geriatr Soc 67:2157-2160, 2019.

Adverse drug events and associated factors in heart failure therapy among the very elderly.

INTRODUCTION: Heart failure (HF) is common in older adults and standard therapy involves the use of multiple medications. We assessed the nature, frequency, and factors associated with adverse drug events (ADEs) associated with standard HF therapy among older adults greater than 75 years of age. The efficacy and predictors of ADEs were assessed in this patient population, as well. METHODS: Systematic review using standardized databases including MEDLINE, Ageline, and CINAHL from January 1st 1988 to January 1st, 2010 and references from published literature. Randomized trials and studies with observational, cohort, and cross-sectional design were included. Two investigators independently selected the studies and extracted the data (kappa = 0.86). RESULTS: Twenty-five studies were identified. ADEs were reported in 13/23 (57%) studies. Syncope, bradycardia, and hypotension as a result of beta blockers occurred in greater frequency compared to younger populations. Spironolactone therapy resulted in increased rates of hyperkalemia, acute renal failure, and medication discontinuation. Factors associated with ADEs included advanced age, poor left ventricular function, and increasing New York Heart Association Class. Efficacy of beta blockers and ACE inhibitors appears to extend to the elderly population, but the magnitude of effect size is unclear. Very few studies reported associations between ADE and patients' comorbidities (4/13 studies, 31%) or functional status (3/13 studies, 23%). CONCLUSION: ADEs in CHF therapy among the very elderly occurred at a greater frequency, but were generally poorly characterized in the literature despite a relatively common occurrence. Further studies are warranted.