Cystatin C is glucocorticoid responsive, directs recruitment of Trem2+ macrophages, and predicts failure of cancer immunotherapy.

Cystatin C (CyC), a secreted cysteine protease inhibitor, has unclear biological functions. Many patients exhibit elevated plasma CyC levels, particularly during glucocorticoid (GC) treatment. This study links GCs with CyC's systemic regulation by utilizing genome-wide association and structural equation modeling to determine CyC production genetics in the UK Biobank. Both CyC production and a polygenic score (PGS) capturing predisposition to CyC production were associated with increased all-cause and cancer-specific mortality. We found that the GC receptor directly targets CyC, leading to GC-responsive CyC secretion in macrophages and cancer cells. CyC-knockout tumors displayed significantly reduced growth and diminished recruitment of TREM2+ macrophages, which have been connected to cancer immunotherapy failure. Furthermore, the CyC-production PGS predicted checkpoint immunotherapy failure in 685 patients with metastatic cancer from combined clinical trial cohorts. In conclusion, CyC may act as a GC effector pathway via TREM2+ macrophage recruitment and may be a potential target for combination cancer immunotherapy.

Practical Considerations for Single-Cell Genomics.

The single-cell revolution in the field of genomics is in full bloom, with clever new molecular biology tricks appearing regularly that allow researchers to explore new modalities or scale up their projects to millions of cells and beyond. Techniques abound to measure RNA expression, DNA alterations, protein abundance, chromatin accessibility, and more, all with single-cell resolution and often in combination. Despite such a rapidly changing technology landscape, there are several fundamental principles that are applicable to the majority of experimental workflows to help users avoid pitfalls and exploit the advantages of the chosen platform. In this overview article, we describe a variety of popular single-cell genomics technologies and address some common questions pertaining to study design, sample preparation, quality control, and sequencing strategy. As the majority of relevant publications currently revolve around single-cell RNA-seq, we will prioritize this genomics modality in our discussion. © 2022 Wiley Periodicals LLC.

Cardiac rehabilitation for older adults: current evidence and future potential.

INTRODUCTION: Growth of the older adult demographic has resulted in an increased number of older patients with cardiovascular disease (CVD) in combination with comorbid diseases and geriatric syndromes. Cardiac rehabilitation (CR) is utilized to promote recovery and improve outcomes, but remains underutilized, particularly by older adults. CR provides an opportunity to address the distinctive needs of older adults, with focus on CVD as well as geriatric domains that often dominate management and outcomes. AREAS COVERED: Utility of CR for CVD in older adults as well as pertinent geriatric syndromes (e.g. multimorbidity, frailty, polypharmacy, cognitive decline, psychosocial stress, and diminished function) that affect CVD management. EXPERT OPINION: Mounting data substantiate the importance of CR as part of recovery for older adults with CVD. The application of CR as a standard therapy is especially important as the combination of CVD and geriatric syndromes catalyzes functional decline and can trigger progressive clinical deterioration and dependency. While benefits of CR for older adults with CVD are already evident, further reengineering of CR is necessary to better address the needs of older candidates who may be frail, especially as remote and hybrid formats of CR are becoming more widespread.

Measurement Error, Reliability, and Minimum Detectable Change in the Mini-Mental State Examination, Montreal Cognitive Assessment, and Color Trails Test among Community Living Middle-Aged and Older Adults.

BACKGROUND: Knowing the reliability of cognitive tests, particularly those commonly used in clinical practice, is important in order to interpret the clinical significance of a change in performance or a low score on a single test. OBJECTIVE: To report the intra-class correlation (ICC), standard error of measurement (SEM) and minimum detectable change (MDC) for the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Color Trails Test (CTT) among community dwelling older adults. METHODS: 130 participants aged 55 and older without severe cognitive impairment underwent two cognitive assessments between two and four months apart. Half the group changed rater between assessments and half changed time of day. RESULTS: Mean (standard deviation) MMSE was 28.1 (2.1) at baseline and 28.4 (2.1) at repeat. Mean (SD) MoCA increased from 24.8 (3.6) to 25.2 (3.6). There was a rater effect on CTT, but not on the MMSE or MoCA. The SEM of the MMSE was 1.0, leading to an MDC (based on a 95% confidence interval) of 3 points. The SEM of the MoCA was 1.5, implying an MDC95 of 4 points. MoCA (ICC = 0.81) was more reliable than MMSE (ICC = 0.75), but all tests examined showed substantial within-patient variation. CONCLUSION: An individual's score would have to change by greater than or equal to 3 points on the MMSE and 4 points on the MoCA for the rater to be confident that the change was not due to measurement error. This has important implications for epidemiologists and clinicians in dementia screening and diagnosis.

Oscillometric measure of blood pressure detects association between orthostatic hypotension and depression in population based study of older adults.

BACKGROUND: White matter hyperintensities may contribute to depression by disrupting neural connections among brain regions that regulate mood. Orthostatic hypotension (OH) may be a risk factor for white matter hyperintensities and accumulating evidence, although limited suggests it may play a role in the development of late-life depression. The aim of this study was to examine the relationship between an oscillometric measure of orthostatic hypotension and depression in population based sample of older adults. METHODS: We analysed data on adults aged 60 and over from the first wave of The Irish Longitudinal Study on Ageing (TILDA). Depression was assessed using the Center for Epidemiologic Studies--Depression (CES-D) scale and OH was assessed by a sit-to-stand orthostatic stress test; two seated blood pressure measurements were followed by a single standing blood pressure measurement. Participants self reported whether they felt dizzy, light-headed or unsteady on standing. RESULTS: Participants with symptomatic OH (SOH, n=20) had the highest mean CES-D score (mean 8.6, SE 1.6) when compared to participants with asymptomatic OH (AOH) (mean 5.6, SE .48) and participants with no OH (mean 5.2, SE .14) and this difference was significant for both comparisons (p<0.001). Linear regression analysis adjusted for socio-demographic and clinical characteristics showed that SOH was associated with higher CES-D scores (unstandardised B coefficient = 2.24; 95% CI .301 - 4.79; p =0.05) compared to participants without OH. AOH was not associated with higher CES-D scores (unstandardised B coefficient =.162; 95% CI -.681, 1.00; p= 0.70). CONCLUSIONS: Symptomatic orthostatic hypotension is associated with depression in older adults and needs to be considered in studies examining the relationship between vascular disease and depression in older adults.

Age and sex differences in prevalence and clinical correlates of depression: first results from the Irish Longitudinal Study on Ageing.

OBJECTIVE: The risk of depression is increased by physical illness; however, the nature of this relationship is complex and unclear. Here, we explore the prevalence and clinical correlates of depression, with particular emphasis on factors representing consequences or physical manifestations of disease and identify age and gender differences in their effects. METHODS: A population-representative sample of 8175 community-dwelling adults aged 50 years and over participated in the first wave of The Irish Longitudinal Study on Ageing. The primary outcome measure was clinically significant depressive symptoms defined by a score of 16 or greater on the 20-item Centre for Epidemiologic Studies Depression scale. RESULTS: Overall, 10% (95% CI: 9-11%) of adults reported clinically significant depressive symptoms. Physical illness is associated with depressive symptoms only in adults 65 years and older; in adults aged 50-64 years, the association is mediated by medication use, and this age difference is statistically significant (p < 0.00). Irrespective of age, chronic pain and incontinence were stronger predictors of depression in men (interaction effects p < 0.00) CONCLUSIONS: Our findings identify age-specific and gender-specific clinical markers for depression risk among the older population, which may identify those more likely to present with depression in community settings.

Using timed up-and-go to identify frail members of the older population.

BACKGROUND: Fried's definition of frailty is widely used but its measurement is problematic. Timed up-and-go (TUG) is a simple measure of mobility that may be a useful proxy for frailty. Here, we describe the distribution of frailty and TUG in the older population of Ireland and discuss the extent to which TUG identifies the frail and prefrail populations. METHODS: A total of 1,814 participants of The Irish Longitudinal Study on Ageing aged 65 and older completed a comprehensive health assessment. Frailty was defined by having three or more of low gait speed, low grip strength, unintentional weight loss, self-reported exhaustion, and low physical activity. ROC curves were used to identify how well TUG discriminates the frail and prefrail populations and whether TUG improves on gait speed as a single objective measure of frailty. RESULTS: Among the Irish population aged 65 and older, 7.7% were frail and 44.0% were prefrail. TUG identifies frail members of the population well (AUC = 0.87) but is less able to discriminate the nonfrail from the prefrail or frail populations (AUC = 0.73). TUG captures the components of frailty that become more common with age but does not discriminate the components that do not, for example, unintended weight loss or exhaustion. There is no advantage in using TUG instead of gait speed with respect to identifying frailty. CONCLUSIONS: TUG is a sensitive and specific measure of frailty that offers advantages in its measurement where the full application or interpretation of Fried's criteria is impracticable; however, TUG cannot be used to reliably identify prefrail individuals.

Effects of fear of falling and activity restriction on normal and dual task walking in community dwelling older adults.

Fear of falling (FOF) is associated with poor physical and psychosocial health and can have debilitating consequences especially when it leads to activity restriction. This study examined whether normal and dual task gait disruptions were independently associated with FOF and activity restriction or if they were fully explained by impaired health status. Data was obtained from The Irish Longitudinal Study on Ageing (TILDA). Community dwelling adults ≥65 years, with a Mini-Mental State Examination score ≥18 and who completed a gait assessment (n=1307) were divided into three groups: no FOF, FOF but no activity restriction (FOF-NAR), FOF with activity restriction (FOF-AR). Physical, psychosocial and cognitive measures were obtained and gait characteristics were assessed using a GAITRite(®) mat during normal and dual task (cognitive) walking. After adjusting for sociodemographics, physical, mental and cognitive health, FOF was associated with reduced gait speed and stride length and increased double support phase and step width in normal and dual task conditions; these changes were most pronounced in those who restrict activities as a result of FOF. These gait changes may be associated with an increased fall risk, however some changes especially increased step width may also reflect positive, compensatory adaptations to FOF. The results also highlight the importance of treating underlying health impairments and preventing the transition from FOF to activity restriction.

Education is positively associated with macular pigment: the Irish Longitudinal Study on Ageing (TILDA).

PURPOSE: The three carotenoids lutein, zeaxanthin, and meso-zeaxanthin, are found at the macula and referred to as macular pigment (MP). This study was undertaken to investigate determinants of MP in a large randomly selected sample from the Republic of Ireland (as part of The Irish Longitudinal Study on Ageing [TILDA]). METHODS: MP optical density (MPOD) was measured using customized heterochromatic flicker photometry in 4373 participants. Sociodemographic and self reported health data was obtained using computer assisted personal interview (CAPI). RESULTS: Mean (SD) MPOD for the study group was 0.203 (0.156) with a range of 0 to 1.01. MPOD was higher for participants with secondary education (mean [SD] = 0.205 [0.148]) than for those with only primary education or no education (mean [SD] = 0.183 [0.113]; P < 0.001). MPOD was also higher for those with tertiary education (mean [SD] = 0.232 [0.231]) compared with primary/no education or secondary education (P < 0.001 for both comparisons). CONCLUSIONS: We report that MP is lower amongst those participants of a population-representative study who did not have secondary or third level education when compared with participants who had such education. Given the emerging evidence that MP is important for visual performance and comfort, and given the putative protection that this pigment confers against AMD (especially important in the context of increased risk of AMD in this social group), public health measures aimed at improving diet for this at-risk population need to be considered.

Association between timed up-and-go and memory, executive function, and processing speed.

OBJECTIVES: To determine which cognitive tests are independently associated with performance on the Timed Up-and-Go Test (TUG). DESIGN: Data were obtained from Wave 1 of The Irish Longitudinal Study on Ageing (TILDA), a population-based study assessing health, economic, and social aspects of aging. SETTING: Community-dwelling adults completed a home based interview and a health center-based assessment. PARTICIPANTS: TILDA participants aged 50 and older with a Mini-Mental State Examination (MMSE) score of 10 or greater (N = 4,998). MEASUREMENTS: Participants completed a battery of cognitive assessments including the Montreal Cognitive Assessment (MoCA), Color Trails Test, word and letter fluency, choice reaction time, sustained attention, prospective memory, word recall, and picture memory. Linear regression was used to determine univariate and multivariate associations between TUG and each cognitive test. RESULTS: Slower TUG time was associated with poorer performance on all cognitive tests in univariate analysis (P < .05). In multivariate analysis, poorer performance on the MoCA, letter fluency, Color Trail 1, cognitive reaction time, mean sustained attention response time, and prospective memory were independently associated with slower TUG time (P < .05). CONCLUSION: Slower TUG time is independently associated with poorer performance on global cognition, executive function, and memory tests and slower processing speed. This highlights that TUG is more than just a simple mobility task and suggests that a comprehensive cognitive assessment is important for individuals with mobility difficulties.

Depression, anxiety and cardiovascular disease: which symptoms are associated with increased risk in community dwelling older adults?

BACKGROUND: Depression is a risk factor for Cardiovascular Disease (CVD). It has been reported that somatic symptoms of depression and not cognitive symptoms are associated with increased risk although findings have been inconsistent. Few studies have examined whether co-morbid anxiety confers additive risk. METHODS: We conducted a cross sectional analysis of 7872 community dwelling adults aged 50 years and over from The Irish LongituDinal Study on Ageing (TILDA). Depressive and anxiety symptoms were assessed with Center for Epidemiologic Studies Depression (CES-D) scale and the anxiety subscale of the Hospital Anxiety and Depression Scale (HADS-A), respectively. We conducted logistic regression analyses to determine the relationship between depression, anxiety, individual depressive symptoms and CVD. We further determined whether co-morbid anxiety was associated with increased risk. RESULTS: Seven hundred and thirty eight (9.4%) study participants reported clinically significant depression. Depression was associated with 80% increased risk of CVD following adjustment for cardiovascular risk factors. Individual depressive symptoms most consistently associated with CVD included low mood, sadness, amotivation, fatigue, diminished appetite and concentration difficulties. Anxiety was associated with increased risk of CVD but did not confer additive risk in participants with depression. LIMITATIONS: Cross sectional design. CONCLUSION: Core symptoms of depression, which are both cognitive and somatic in nature, are associated with increased risk of CVD while co-morbid anxiety did not confer additive risk. It is important that clinicians give due regard both to both cognitive and somatic symptoms of depression when determining cardiovascular risk. Future longitudinal investigation should confirm these findings and explore potential pathological mechanisms.

Factors affecting continuous beat-to-beat orthostatic blood pressure response in community-dwelling older adults.

OBJECTIVE: To examine the effect of age, time of day, the timing of medication and food ingestion on orthostatic blood pressure response (OBP) in community-dwelling adults. METHODS: A nationally representative sample of 109 community-dwelling adults aged at least 50 years attended for health assessment in a pilot study of The Irish Longitudinal Study on Ageing. OBP was measured using continuous beat-to-beat plethysmography (Finometer) during active stand, and OBP with excessive artefacts were excluded. Nine outcome variables were supine systolic blood pressure (SBP), lowest standing SBP (nadir), standing SBP at 40, 60 and 120 s and the difference in supine SBP and nadir (delta SBP) and delta at 40, 60 and 120 s. Factors included for multiple linear regression analysis were age, time of assessment, interval from the last meal and whether regular medications were taken on the day. Subgroup analysis was performed on 103 respondents who were not on ß-blocker, fludrocortisone and Parkinson medications. RESULTS: There were 53 men, mean age 62.1 (SD=9.4) years. Older respondents (≥60 years) showed greater delta at 40 s by up to 12.9 mmHg. Delta SBP and delta 40, 60 and 120 were not significantly affected by the time of day or food ingestion. The effect of medications on delta 40 was no longer present in subgroup analysis. CONCLUSION: Age was the most significant determinant of OBP and was most strongly associated with greater delta at 40 s. This was independent of the time of day, food and medication ingestion. Continuous beat-to-beat plethysmography provides for a window into the pattern of OBP in community-dwelling adults aged 50 years and older.

The role of perceived risk in general practitioners' decisions to inform partners of HIV-infected patients.

OBJECTIVES: To investigate the role of physician and patient characteristics in determining risk perceptions and decision making in a hypothetical case where confidentiality may need to be broken to protect the partner of a patient who is infected with HIV. To identify if risk perceptions mediate the relation between physician and patient characteristics and confidentiality decisions. DESIGN: Analysis of a sample of 207 Irish general practitioners (GPs) randomly assigned to one of four experimental vignette conditions. METHODS: A single vignette scenario was presented to each GP within which a hypothetical male HIV patient was depicted as unwilling to disclose his HIV status to his partner. The hypothetical patient's use of protection (used, not used) and sexual orientation (heterosexual, homosexual) were varied systematically. GPs then estimated the risk the patient posed to the partner and the likelihood that they would break confidentiality to inform the partner of the patient's HIV status. RESULTS: Less experienced GPs and those who had broken confidentiality in the past were likely to indicate they would break confidentiality in response to the presented scenario. GPs were more likely to inform the partner when protection was not used during intercourse and when the relationship was heterosexual rather than homosexual. Risk perceptions partially mediated the relationship between the patient's use of protection and confidentiality decision ratings but did not explain the association between GP characteristics or patient sexuality and decision making. CONCLUSION: Physician background characteristics and HIV patient sexual practice and orientation are associated with hypothetical partner notification decisions. The perceived risk to the partner only partially explained the relation between patient use of protection and decision making.

Comparison of centre and home-based health assessments: early experience from the Irish Longitudinal Study on Ageing (TILDA).

BACKGROUND: some cohort studies of ageing and health supplement questionnaire-based surveys with in-home measurements of biological parameters and others have required respondents to attend assessment centres. Centre-based assessments facilitate detailed measurements and novel technologies, but may differentially influence participation. The aim of this paper is to compare the characteristics of participants who attended a centre with those who chose a home assessment and those who did not have a health assessment. METHODS: trained field workers administered a computer-assisted personal interview (CAPI) to a random sample of community-dwelling people aged 50 and over in the participants' homes. All questionnaire respondents were invited to attend an assessment centre for a comprehensive physical assessment. Participants who refused or were unable to attend a centre were offered a home assessment. RESULTS: of the 291 participants who completed the CAPI, 176 had a health assessment: 138 in an assessment centre and 38 in their own home. The centre, home and no visit respondents differed in demographic characteristics, behavioural factors, physical functioning and health. Lower socio-economic status, physical inactivity and current smoking were the most robust predictors of non-participation in the health assessment. Home respondents had the highest levels of physical disability and were much weaker (grip strength) and slower (walking speed) than centre respondents. CONCLUSION: home and centre physical assessments are required to avoid systematically over-representing healthier and wealthier respondents.

Macular pigment optical density in an ageing Irish population: The Irish Longitudinal Study on Ageing.

PURPOSE: The 3 carotenoids lutein, zeaxanthin, and meso-zeaxanthin, which account for the 'yellow spot' at the macula and which are referred to as macular pigment (MP), are believed to play a role in visual function and protect against age-related macular degeneration (AMD) via their optical and antioxidant properties. This study was undertaken to compare MP optical density (MPOD) in a population aged > or =50 years with MPOD values from a normative database of subjects aged 18-60 years. METHODS: Seventy-nine subjects were recruited into this pilot study (The Irish Longitudinal Study on Ageing-TILDA). MPOD was measured using heterochromatic flicker photometry. Retinal fundus photographs, lifestyle data and general health data, were also obtained. RESULTS: The mean +/- SD age of the 79 subjects recruited into this study was 65 +/- 11 years. There was a moderate, but statistically significant, age-related decline in MPOD at 0.5 degrees in the TILDA data (r = -0.251, p = 0.045), which remained upon merging with a normative database of an additional 462 subjects aged between 18 and 67 years (r = -0.179, p = 0.000). CONCLUSIONS: We report an inverse association between MPOD and increasing age. Longitudinal data in a larger cohort of participants are required to satisfactorily investigate the relationship between the optical density of this pigment and age, and with risk for development and/or progression of AMD. This pilot study represents a first step in this endeavour.

Patient satisfaction with an emergency department psychiatric service.

PURPOSE: The purpose of this paper is to measure the rate of satisfaction of the sample population with an emergency department psychiatric service and to explore in open-ended questions, factors which contributed to these satisfaction ratings. DESIGN/METHODOLOGY/APPROACH: All psychiatric patients who attended the service and fulfilled the eligibility criteria during the study timeframe received the postal questionnaire (n = 55). The Client Satisfaction Questionnaire-8 was used, which is a brief, eight-item instrument designed to assess post-service satisfaction. It has good psychometric properties and has been validated for use in a psychiatric patient population. FINDINGS: It is found that 35 per cent of respondents scored a low level of satisfaction, 29 per cent a medium level and 36 per cent a high level of satisfaction. The qualitative data, completed by 73 per cent of respondents, provided a more in-depth view from the patient's perspective. RESEARCH LIMITATIONS/IMPLICATIONS: The response rate was low as predicted for this population. PRACTICAL IMPLICATIONS: The qualitative findings reveal positive feedback regarding the staff, but patients expressed dissatisfaction about the availability of beds, waiting times for assessment, communication by staff, deficiency of crisis services in the home and inadequate provision of information regarding services. This study identifies factors which contribute to the low satisfaction ratings and identify ways to improve the service. ORIGINALITY/VALUE: This mail patient survey provides valuable information for those planning and improving services for patients in the setting of the emergency department. The paper contributes to the limited number of studies of psychiatric services in this setting and identifies ways to improve patient satisfaction as supported by international evidence.