Effects of cognitive reserve on cognitive frailty among older adults: A population-based prospective cohort study.

AIM: We investigated the effect of lifespan cognitive reserve and its components on cognitive frailty among older adults. METHODS: A total of 4922 participants aged ≥65 years were recruited in 2008 and were followed up in 2011 from the Chinese Longitudinal Healthy Longevity Survey. Cognitive frailty was determined through the simultaneous presence of physical frailty (pre-frailty or frailty) and mild cognitive impairment, excluding concurrent dementia. The assessment of physical frailty and mild cognitive impairment was based on the Fatigue, Resistence, Ambulation, Illness, Loss of weight (FRAIL) (Fatigue, Resistence, Ambulation, Illness, Loss) and Mini-Mental State Examination scale, respectively. The lifespan cognitive reserve consisted of education attainment, occupational complexity and later-life leisure activities. We used logistic regression models to estimate the risk of cognitive frailty associated with the lifespan cognitive reserve and its components. RESULTS: A higher level of lifespan cognitive reserve, higher educational attainment or leisure activities engagement, but not occupational complexity, were associated with lower risk of incident cognitive frailty. Furthermore, cognitive, social and physical activities were associated with lower risk of incident cognitive frailty. CONCLUSION: Cognitive reserve, particularly educational attainment and leisure activities, can protect from cognitive frailty. This implicates that individuals should accumulate cognitive reserve in their lifespan, and older adults should actively participate in leisure activities to prevent cognitive frailty. Geriatr Gerontol Int 2024; 24: 398-403.

The measurement properties and feasibility of FRAIL scale in older adults: A systematic review and meta-analysis.

Frailty is a prevalent condition amongst older adults, significantly affecting their quality of life. The FRAIL tool has been purposefully designed for clinical application by assisting healthcare professionals in identifying and managing frailty-related issues in older adults, making it a preferred choice for assessing frailty across diverse older populations. This review aimed to synthesize the measurement properties and feasibility of FRAIL. Guided by COSMIN guidelines, seven databases were searched from inception to 31 Mar 2023. The measurement properties were extracted for quality appraisal of the populations in the studied samples. Where possible, random-effects meta-analysis and meta-regression were used for quantitative synthesis. Eighteen articles containing 273 tests were drawn from 14 different populations. We found that populations testing for criterion validity had high-quality ratings, while construct validity ratings varied based on health status and geographical region. Test-retest reliability had sufficient quality ratings, while scale agreement had sufficient ratings in only four out of 14 populations tested. Responsiveness ratings were insufficient in seven out of eight populations, with inconsistent ratings in one population. Our analysis of missing data across three articles showed a 16.3% rate, indicating good feasibility of the FRAIL. FRAIL is a feasible tool for assessing frailty of older adults in community settings, with good criterion validity and test-retest reliability. However, more research is needed on construct validity and responsiveness.

Quality of life in sarcopenia measured with the SarQoL questionnaire: A meta-analysis of individual patient data.

Age-related sarcopenia, resulting from a gradual loss in skeletal muscle mass and strength, is pivotal to the increased prevalence of functional limitation among the older adult community. The purpose of this meta-analysis of individual patient data is to investigate the difference in health-related quality of life between sarcopenic individuals and those without the condition using the Sarcopenia Quality of Life (SarQoL) questionnaire. A protocol was published on PROSPERO. Multiple databases and the grey literature were searched until March 2023 for studies reporting quality of life assessed with the SarQoL for patients with and without sarcopenia. Two researchers conducted the systematic review independently. A two-stage meta-analysis was performed. First, crude (mean difference) and adjusted (beta coefficient) effect sizes were calculated within each database; then, a random effect meta-analysis was applied to pool them. Heterogeneity was measured using the Q-test and I2 value. Subgroup analyses were performed to investigate the source of potential heterogeneity. The strength of evidence of this association was assessed using GRADE. From the 413 studies identified, 32 were eventually included, of which 10 were unpublished data studies. Sarcopenic participants displayed significantly reduced health-related quality of life compared with non-sarcopenic individuals (mean difference = -12.32; 95 % CI = [-15.27; -9.37]). The model revealed significant heterogeneity. Subgroup analyses revealed a substantial impact of regions, clinical settings, and diagnostic criteria on the difference in health-related quality of life between sarcopenic and non-sarcopenic individuals. The level of evidence was moderate. This meta-analysis of individual patient data suggested that sarcopenia is associated with lower health-related quality of life measured with SarQoL.

Translation, Cultural Adaptation, and Validation of the Cantonese Version of SarQoL in Hong Kong's Older Population: An Interviewer-Administered Questionnaire for Assessing Sarcopenia-Specific Quality of Life in Fieldwork Practice.

Objective: This study examined the psychometric properties of the Cantonese version of the SarQoL® questionnaire. Participants: A total of 118 (including 60 non-sarcopenic and 58 sarcopenic) community-dwelling older adults aged 65 years or above with Cantonese as their mother tongue. Methods: Translation and cultural adaptation of the SarQoL were conducted using a standardized protocol. To validate the Cantonese SarQoL, psychometric properties including discriminative power, reliability (including internal consistency and test-retest reliability), and construct validity (including convergent and divergent validity), as well as floor and ceiling effects, were assessed. Results: The translation of the questionnaire was completed without significant difficulties. Results indicated that the Cantonese SarQoL had (1) good discriminative power (sarcopenic participants had lower overall scores, mean = 66.1 vs 75.0, p < 0.001; the overall score was negatively predictive of the presence of sarcopenia, adjusted OR = 0.949, 95% CI = [0.912, 0.983]), (2) good internal consistency (Cronbach's alpha = 0.835; correlations between domain and overall scores ranged from 0.576 to 0.868), (3) excellent test-retest agreement (intraclass correlation coefficient = 0.801), (4) good construct validity (convergent: moderate to strong correlations were found between the overall score and almost all of the SF-36 and EQ-5D domains; divergent: weaker correlations were found between the overall score and SF-36 social functioning, ρ = -0.098, and EQ-5D self-care, ρ = -0.331), and (5) no floor or ceiling effect. Conclusion: The Cantonese SarQoL is valid and reliable, and thus can be used as an interviewer-administered questionnaire for assessing sarcopenia-specific quality of life in fieldwork practice.

Modular pooled discovery of synthetic knockin sequences to program durable cell therapies.

Chronic stimulation can cause T cell dysfunction and limit the efficacy of cellular immunotherapies. Improved methods are required to compare large numbers of synthetic knockin (KI) sequences to reprogram cell functions. Here, we developed modular pooled KI screening (ModPoKI), an adaptable platform for modular construction of DNA KI libraries using barcoded multicistronic adaptors. We built two ModPoKI libraries of 100 transcription factors (TFs) and 129 natural and synthetic surface receptors (SRs). Over 30 ModPoKI screens across human TCR- and CAR-T cells in diverse conditions identified a transcription factor AP4 (TFAP4) construct that enhanced fitness of chronically stimulated CAR-T cells and anti-cancer function in vitro and in vivo. ModPoKI's modularity allowed us to generate an ∼10,000-member library of TF combinations. Non-viral KI of a combined BATF-TFAP4 polycistronic construct enhanced fitness. Overexpressed BATF and TFAP4 co-occupy and regulate key gene targets to reprogram T cell function. ModPoKI facilitates the discovery of complex gene constructs to program cellular functions.

Healthy Ageing Should Be a Key Component of Ageing in Place: Case Study from Hong Kong.

As part of a knowledge-transfer project consisting of a series of three talks on the topic of healthy ageing and ageing in place, we explored what participants (older adults, students, the general public, as well as professionals in architecture, urban planning and property management) consider to be key requirements for ageing in place and healthy ageing. Feedback is captured using survey questionnaires and a post-talk discussion group. Safety, a comfortable and spacious environment, age-friendly facilities and meeting the needs of older adults, the availability of caring support and home maintenance services were the most frequently mentioned desirable features of ageing in place. Future models for different types of support for ageing in place may be explored by management companies working with the residents themselves, to develop a sustainable business model.

The Effect of Social Isolation on Sarcopenia: A Longitudinal Study among the Middle-Aged and Older Population in China.

INTRODUCTION: Although social isolation is associated with premature death and somatic and mental diseases, evidence of its long-term effect on sarcopenia is scarce. This study aimed to examine the longitudinal association between social isolation and possible sarcopenia. METHODS: We extracted baseline and 4-year follow-up data from the China Health and Retirement Longitudinal Study and included participants aged 45 years or above. Social isolation was measured by factors including living alone, marital status, frequency of contact with adult children and friends, and participation in social activity. The change in social isolation from baseline to follow-up was classified into stable, progressive, and regressive groups. Possible sarcopenia was detected using the handgrip strength and five-time chair-stand test. Using mixed-effects logistic regression, we studied the effect of baseline isolation and the change in isolation status on possible sarcopenia at a 4-year follow-up. RESULTS: A total of 5,289 participants aged 45-90 years and without possible sarcopenia at baseline were included. After 4 years, possible sarcopenia was detected in 21.7% (1,146/5,289) of the participants. Compared with the low social isolation group, the middle (OR = 1.53, 95% confidence interval [CI] = 1.16-2.04, p = 0.003) and high social isolation groups (OR = 1.65, 95% CI = 1.26-2.18, p < 0.001) were associated with a higher risk of possible sarcopenia. Being not married/cohabiting (OR = 1.58, 95% CI = 1.19-2.10, p = 0.002), lack of contact with children (OR = 1.86, 95% CI = 1.21-2.85, p = 0.004), and lack of social activities (OR = 1.26, 95% CI = 1.04-1.53, p = 0.019) were associated with an increased risk of possible sarcopenia. Compared with the stable social isolation group, the progressive group was associated with a greater risk of possible sarcopenia (OR = 1.51, 95% CI = 1.17-1.95, p = 0.001). CONCLUSIONS: Social isolation is associated with an increased risk of possible sarcopenia. Progressive social isolation further elevates the risk. The most vulnerable groups are middle-aged and older people who live alone, are not socially active, and lack contact with their children.

High-yield genome engineering in primary cells using a hybrid ssDNA repair template and small-molecule cocktails.

Enhancing CRISPR-mediated site-specific transgene insertion efficiency by homology-directed repair (HDR) using high concentrations of double-stranded DNA (dsDNA) with Cas9 target sequences (CTSs) can be toxic to primary cells. Here, we develop single-stranded DNA (ssDNA) HDR templates (HDRTs) incorporating CTSs with reduced toxicity that boost knock-in efficiency and yield by an average of around two- to threefold relative to dsDNA CTSs. Using small-molecule combinations that enhance HDR, we could further increase knock-in efficiencies by an additional roughly two- to threefold on average. Our method works across a variety of target loci, knock-in constructs and primary human cell types, reaching HDR efficiencies of >80-90%. We demonstrate application of this approach for both pathogenic gene variant modeling and gene-replacement strategies for IL2RA and CTLA4 mutations associated with Mendelian disorders. Finally, we develop a good manufacturing practice (GMP)-compatible process for nonviral chimeric antigen receptor-T cell manufacturing, with knock-in efficiencies (46-62%) and yields (>1.5 × 109 modified cells) exceeding those of conventional approaches.

Subjective Social Status, Area Deprivation, and Gender Differences in Health among Chinese Older People.

This study examined the gender differences in the main and interactive effects of subjective social status and area deprivation on health among older adults in Hong Kong. Data for this study came from the baseline of MrOs and MsOs studies, including 4000 Chinese men and women ≥ 65 in Hong Kong. Subjective social status was assessed using the MacArthur Scale of subjective social status scale. Our results reaffirm that subjective social status is an independent indicator of health after adjusting for objective SES measures (e.g., education and income). Perceived rank on the community ladder was more closely related to health among older people than was the society ladder, particularly for women. Although area-level social deprivation was not significantly associated with the health of older people, it may moderate the effect of subjective social status on health. Women with a lower perceived status in the community were more likely to experience depressive symptoms but better grip strength when living in more deprived neighborhoods. The findings suggested that subjective social status provides important information for the physical and mental health of the older population. Policymakers may implement interventions to enhance the subjective social status of older adults. Given the greater contribution of relative status in the community to the health of women, these policies and interventions should target to improve women's perceived status in the community.

Intrinsic capacity and 10-year mortality: Findings from a cohort of older people.

BACKGROUND AND OBJECTIVES: Longitudinal data with regard to the association between intrinsic capacity (IC) and mortality is required for prevention efforts. We examined the association between IC and 10-year mortality among older people. RESEARCH DESIGN AND METHODS: We recruited a cohort of 2032 Chinese people aged 70 years and older, 1371 of them could be traced over follow-up, of which 1096 died within 10 years. Of those who were traceable, 846 were complete cases regarding the data for the exposure, outcome and covariates. Multiple imputation was used to handle missing data. Nine indicators were included to represent the construct of IC. All-cause mortality was collected from the Death Registry. Multivariable Cox proportional hazard regression model and Kaplan-Meier estimator were used to assess the association between IC and mortality. RESULTS: The mean age of the 2032 participants was 79.7 years and 51 % were female. Compared with those in the lowest (best) quartile of IC, those in the highest (worst) quartile were associated with 1.48-fold (95 % CI 1.21-1.82) higher risk of mortality, after adjustment for sociodemographic variables. When past medical illnesses were further adjusted, the hazard ratio was attenuated (1.41; 95 % CI 1.15-1.73). Kaplan-Meier estimator for survival probability similarly showed a graded mortality pattern. The association between IC and mortality remained similar when the analysis was confined to community-dwelling older people. DISCUSSION AND IMPLICATIONS: IC is associated with mortality in a dose-response fashion. Assessment of IC should be instituted in community and institutional settings to enable formulation of early interventions.

Effects of social support on frailty trajectory classes among community-dwelling older adults: The mediating role of depressive symptoms and physical activity.

OBJECTIVES: To investigate whether and how social support influenced frailty progression through depressive symptoms and physical activity. METHODS: Of 1235 community-dwelling older adults enrolled at baseline, 778 (63.0%) undergoing at least one yearly follow-up were included in the final analysis. Data were collected on frailty, social support, depressive symptoms, physical activity and covariates. RESULTS: Two frailty trajectory classes were identified and labeled as alleviated frailty and deteriorated frailty. Subjective support prevented the deterioration of frailty through decreased depressive symptoms, while objective support and support utilization prevented the deterioration of frailty through increased physical activity. CONCLUSIONS: The pathways through which social support ameliorates frailty vary by support types. Subjective support interventions should be included in the multifactorial interdisciplinary management of frailty to address social and psychological vulnerabilities, along with objective support and support utilization interventions addressing physical inactivity.

Effects of reversible cognitive frailty on disability, quality of life, depression, and hospitalization: a prospective cohort study.

OBJECTIVES: Cognitive frailty, a potentially reversible condition describing the concurrence of physical frailty and mild cognitive impairment (MCI), has been recently proposed to incorporate subjective cognitive decline (SCD), a reversible pre-MCI state with more readily available cognitive reserve, as well as pre-physical frailty. Reversible cognitive frailty has been associated with dementia and mortality. We aimed to examine the association of reversible cognitive frailty with other adverse outcomes including disability, poor quality of life (QOL), depression, and hospitalization. METHODS: This was a cohort study with 1-year follow-up among 735 Chinese community-dwelling older adults with intact cognition. Reversible cognitive frailty was operationalized with the presence of pre-physical or physical frailty identified by the Frailty Phenotype and SCD identified by the simplified SCD questionnaire including four self-report cognitive domains of memory, naming, orientation, and mathematical reasoning. Adverse outcomes included incident Activities of Daily Living (ADL)-Instrumental ADL (IADL) disability, poor physical, mental and overall QOL, depression, and hospitalization over 1-year follow-up. RESULTS: The prevalence of reversible cognitive frailty was 27.8%. Participants with reversible cognitive frailty had higher risk of the incidence of ADL-IADL disability, poor physical QOL, poor mental QOL, poor overall QOL, and depression (Odds Ratios: 1.67-4.38, P < 0.05), but not higher risk of hospitalization over 1-year follow-up. CONCLUSION: Reversible cognitive frailty was not uncommon and associated with incident disability, poor QOL, and depression among community-dwelling older adults. Early identification of reversible cognitive frailty can facilitate targeted interventions and may promote independence in older adults.Supplemental data for this article is available online at http://dx.doi.org/10.1080/13607863.2021.2011835.

Assessment of the validity and acceptability of the online FRAIL scale in identifying frailty among older people in community settings.

OBJECTIVES: To assess the validity and acceptability of the online FRAIL scale in identifying frailty in community settings. METHODS: Frailty was assessed using the online version of the FRAIL scale (a simple frailty questionnaire). Validity of the scale was examined in a sample of 1882 persons aged 60 years or older (inlcuding a pilot sample of 65 persons for assessing the face validity) recruited from 24 elderly centres in Hong Kong. Convergent validity was estimated using correlation coefficients between scores on the FRAIL, SARC-F (a simple questionnaire for assessing sarcopenia) and AMIC (Abbreviated Memory Inventory for the Chinese). Predictive validity was examined by logistic regression using IADL (Instrumental Activities of Daily Living) limitations and hospitalization as outcomes. Acceptability of the scale was assessed from the perspective of a sub-sample of 205 older persons and 33 centre staff. RESULTS: Following minor revisions, all participants were able to understand and answer the online FRAIL scale. The FRAIL scale correlated with SARC-F (r = 0.627, p < 0.001) and AMIC (r = 0.302, p < 0.001). Being pre-frail and frail were associated with incident IADL limitations (OR = 1.58, 95 %CI = 1.11-2.25 and OR = 3.01, 95 %CI = 1.87-4.84, respectively) and incident hospitalization (OR = 1.38, 95 %CI = 1.03-1.85 and OR = 2.79, 95 %CI = 1.89-4.12, respectively) at year 2, after controlling for age, sex, marital status, and educational level. 77.8 % of participants agreed that the scale would enable them to understand their health status. However, only 35.0 % accepted a digital approach for conducting health assessment or accessing assessment results. 90.9 % of centre staff agreed that the scale could be used to identify their members who are potential candidates for frailty intervention. CONCLUSIONS: The online FRAIL scale is valid for use in community elderly centres in identifying frailty. Further effort is required to improve the acceptability of the online FRAIL scale among older persons.

Randomized Controlled Trial on the Effects of a Combined Intervention of Computerized Cognitive Training Preceded by Physical Exercise for Improving Frailty Status and Cognitive Function in Older Adults.

(1) Objective: This study examined the effects of a combined intervention of Brainastic computerized cognitive training (CCT) preceded by physical exercise (PE) for improving frailty status and cognitive function in older adults. (2) Methods: Older adults aged 50 years or older attending elderly centers, without frailty/history of cognitive impairment, were randomly allocated into either a 12-week (i) multi-domain CCT + PE (n = 117), (ii) two-domain CCT + PE (n = 116) or (iii) video watching + PE (i.e., control, n = 114). Brainastic is an online application for cognitive training through video games. The multi-domain CCT targeted memory, attention, executive function, flexibility and visuospatial ability while the two-domain CCT targeted memory and attention. PE included both aerobic and resistance exercises. Outcomes were changes in frailty levels as measured with a simple frailty questionnaire (FRAIL), global cognition as measured with the Rapid Cognitive Screen (RCS), total learning and verbal memory abilities as measured with the Hong Kong List Learning Test (HKLLT), and executive functions as measured with the Frontal Assessment Battery (FAB) over 12 weeks. (3) Results: Participants in the intervention groups (multi-/two-domain CCT + PE) showed greater improvements in frailty status, total learning ability and verbal memory ability than control participants (all p < 0.05). The multi-domain CCT did not outperform the two-domain CCT in improving frailty status or cognitive function. The training effects were independent of the baseline cognition of the participants. (4) Conclusions: A combined intervention of multi-/two-domain CCT preceded by PE seemed to convey benefit over video watching preceded by PE in improving frailty status and cognitive function among older adults attending elderly centers.

Social gradient of self-rated health in older people-the moderating/mediating role of sense of community.

BACKGROUND: Social gradients of self-rated health (SRH) of older people are evident in various settings. However, it is not clear whether improving older people's sense of community (SoC) could mitigate the social gradient. METHODS: People aged above 60 in five residential districts of Hong Kong were sampled using multistage sampling (n = 1,793). SoC was measured using the validated eight-item Brief Sense of Community Scale, with each item on a five-point Likert scale, forming a score from 8 to 40. SRH was considered as dichotomous (poor/not poor). Socioeconomic status (SES) was operationalised as monthly income, highest education attainment and self-rated disposable income (defined as whether the older person feel he/she has sufficient income). Causal mediation analysis using four-way decomposition was used to assess whether SoC mediates/moderates the association of SES and poor SRH. RESULTS: A social gradient of poor SRH by all measures of SES was observed [adjusted relative risk (RR) per standard deviation income increase = 0.92; 95% confidence interval (95% CI) 0.88-0.97; RR comparing lowest to highest education= 1.77; 95% CI: 1.48-2.11; RR comparing very insufficient to very sufficient disposable income = 1.74; 95% CI: 1.48-2.05]. Causal mediation analysis showed that SoC interacts with the association of education and SRH, with higher the SoC, stronger the education gradient. CONCLUSIONS: Our findings showed a social gradient of SRH in the older population in Hong Kong. This relationship was moderated by SoC, for which higher SoC is related to stronger SES-SRH gradient.

Functional CRISPR dissection of gene networks controlling human regulatory T cell identity.

Human regulatory T (Treg) cells are essential for immune homeostasis. The transcription factor FOXP3 maintains Treg cell identity, yet the complete set of key transcription factors that control Treg cell gene expression remains unknown. Here, we used pooled and arrayed Cas9 ribonucleoprotein screens to identify transcription factors that regulate critical proteins in primary human Treg cells under basal and proinflammatory conditions. We then generated 54,424 single-cell transcriptomes from Treg cells subjected to genetic perturbations and cytokine stimulation, which revealed distinct gene networks individually regulated by FOXP3 and PRDM1, in addition to a network coregulated by FOXO1 and IRF4. We also discovered that HIVEP2, to our knowledge not previously implicated in Treg cell function, coregulates another gene network with SATB1 and is important for Treg cell-mediated immunosuppression. By integrating CRISPR screens and single-cell RNA-sequencing profiling, we have uncovered transcriptional regulators and downstream gene networks in human Treg cells that could be targeted for immunotherapies.

Evaluation of SARS-CoV-2 serology assays reveals a range of test performance.

Appropriate use and interpretation of serological tests for assessments of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exposure, infection and potential immunity require accurate data on assay performance. We conducted a head-to-head evaluation of ten point-of-care-style lateral flow assays (LFAs) and two laboratory-based enzyme-linked immunosorbent assays to detect anti-SARS-CoV-2 IgM and IgG antibodies in 5-d time intervals from symptom onset and studied the specificity of each assay in pre-coronavirus disease 2019 specimens. The percent of seropositive individuals increased with time, peaking in the latest time interval tested (>20 d after symptom onset). Test specificity ranged from 84.3% to 100.0% and was predominantly affected by variability in IgM results. LFA specificity could be increased by considering weak bands as negative, but this decreased detection of antibodies (sensitivity) in a subset of SARS-CoV-2 real-time PCR-positive cases. Our results underline the importance of seropositivity threshold determination and reader training for reliable LFA deployment. Although there was no standout serological assay, four tests achieved more than 80% positivity at later time points tested and more than 95% specificity.