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Aim: Skeletal muscle mass to visceral fat area ratio (SVR) has been recognised as an index of sarcopenic obesity. SVR is associated with type 2 diabetes mellitus (T2DM), metabolic syndrome and arterial stiffness which are known risk factors for cognitive dysfunction. We aimed to investigate association between SVR and cognitive function in patients with T2DM., Methods: This was a cross-sectional study of 1326 patients with T2DM and mean age 61.3 ± 8.0 years. SVR was assessed based on bioelectrical impedance measurements of muscle mass and visceral fat area (VFA). Cognitive function was assessed using Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Linear regression was used to examine the association between SVR in quartiles and RBANS score, adjusting for demographics, education, presence of depressive symptoms, clinical covariates and medications., Results: The lower SVR quartiles were negatively associated with RBANS total score in the unadjusted analysis. The corresponding coefficients for Quartiles 1 and 2 SVR were -3.79 (95 % CI -5.39 to -2.19; p < 0.001) and -1.47 (95 % CI -2.86 to -0.07; p = 0.039) in fully adjusted analysis. The negative association between Quartile 1 SVR and RBANS score was evident in immediate memory, delayed memory, visuo-spatial construction, language and attention domains. Muscle mass and VFA alone had weaker associations with RBANS scores., Conclusion: Our study demonstrated, for the first time, an independent association between reduced SVR and lower cognitive function. This is evident in global and multiple cognitive domains. The synergistic effects of reduced muscle mass and visceral obesity may be more pronounced than their independent effects on cognitive function., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have influenced the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

Competing Interests: None

Competing Interests: None

Introduction: Healthy ageing (HA) indices typically use full questionnaire, performance- or blood-based assessment of functional ability which are time-consuming and resource-intensive. We developed and validated a simple and brief Healthy Ageing Questionnaire (HAQ) index with comparable measurement accuracy., Methods: The 15-item HAQ (scored 0-100) was developed using data of 500 participants in the Singapore Study of Successful Ageing (SSOSA), a sub-cohort of the Singapore Longitudinal Ageing Study (SLAS-2). Its construct, concurrent, and predictive validity were evaluated in 2,161 participants in the SLAS-2 who were non-participants of the SSOSA., Results: The HAQ index (mean = 64.0, SD = 11.8) showed a coherent 3-factor structure (Cronbach's alpha = 0.735). HAQ scores were higher among participants who were female, highly educated, not living alone, non-smoking, non-alcohol drinkers, not at risk of malnutrition, were robust or pre-frail, not disabled, had no or &lt;5 medical conditions, and no recent fall or hospitalization. It was positively correlated with Mini-Mental State Examination and life satisfaction, and negatively correlated with age, logMAR vision, 5 times sit-and-stand, and timed-up-and-go. The HAQ index was significantly correlated but showed modest concordance with the Rowe-Kahn SA index. Increasing HAQ index quintiles were associated with decreased mortality risks from 40.6 to 9.7 deaths per 1,000 person-years; covariate-adjusted hazard ratio for the highest Q5 levels (HAQ score &gt;70) was 0.44 (95% CI = 0.28-0.67). Using receiver operating characteristics analysis of predictive accuracy for survival, the area under the curve of HAQ was 0.675, and Rowe-Kahn SA index was 0.660 (p = 0.361)., Conclusion: The HAQ is a brief and accurate HA index that is potentially useful across diverse settings and purposes in research, healthcare, and policy-making., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Introduction: The detection of systemic risk factors aids in the formulation of strategies to prevent multimorbidity and its associated mortality impact. We aimed to determine the associations of inflammatory, metabolic, malnutrition, and frailty indexes with multimorbidity onset and progression and their predictions of multimorbidity-associated mortality risk., Methods: A prospective cohort study (Singapore Longitudinal Aging Study [SLAS]) of 5,089 community-dwelling older adults aged ≥55 years in two waves of recruitment (SLAS-1: March 2005-September 2007, SLAS-2: January 2013-August 2018). Baseline variables included inflammatory (neutrophil-lymphocyte ratio (NLR), lymphocyte-monocyte ratio (LMR)) and metabolic profiles (atherogenic index of plasma (AIP), triglyceride-glucose index of insulin resistance (TyG)), physical frailty, and nutritional risk (Mini Nutritional Assessment-Short Form (MNA-SF), Nutritional Screening Initiative (NSI), Elderly Nutritional Indicators for Geriatric Malnutrition Assessment (ENIGMA)). At follow-up, 3-5 years after the baseline interview, incident multimorbidity (≥2 chronic diseases) was determined among multimorbidity-free participants (N = 1,657) and worsening multimorbidity (increase of ≥2 chronic diseases) among participants with baseline multimorbidity (N = 1,207). Mortality in all participants and those with multimorbidity (N = 2,291) was determined up to 31 December, 2016. Odds ratio (OR), hazard ratio (HR), and 95% confidence intervals (95% CI) were estimated in multivariate logistic and Cox regression models, in base model adjustments for age, sex, ethnicity, housing type, smoking, and a number of comorbidities, and further stepwise selection adjustment for other systemic risk indexes., Results: At baseline, NLR, LMR, AIP, TyG, physical frailty, ENIGMA, NSI, and MNA-SF were significantly associated with prevalent multimorbidity (p < 0.001). Among multimorbidity-free participants, LMR, TyG, and ENIGMA were significantly associated with incident multimorbidity in both the base model and further stepwise selection models: LMR (OR = 0.87, 95% CI: 0.81-0.94), TyG (OR = 1.36, 95% CI: 1.06-1.75), and ENIGMA (OR = 1.15, 95% CI: 1.02-1.30). Among participants with baseline multimorbidity, NLR, LMR, and TyG significantly predicted worsened multimorbidity at follow-up in base model analysis, and LMR (OR = 0.72, 95% CI: 0.60-0.86) and TyG (OR = 1.96, 95% CI: 1.24-3.09) remained as independent predictors in further stepwise selection models. Among participants with prevalent multimorbidity, NLR, TyG, frailty, MNA, and ENIGMA were significantly associated with mortality risk with base model adjustments and further stepwise selection models: NLR (HR = 1.20, 95% CI: 1.10-1.32), TyG (HR = 1.27, 95% CI: 1.04-1.54), frailty (HR = 1.22, 95% CI: 1.10-1.36), ENIGMA (HR = 1.13, 95% CI: 1.05-1.22), MNA (HR = 0.91, 95% CI: 0.85-0.97). A combined systemic risk index shows increasing quartiles, adjusted for age, sex, housing, and smoking status, significantly predicting mortality risk., Discussion/conclusion: The onset and progression of multimorbidity and its mortality impact are driven by systemic factors, including inflammation, metabolic dysfunction (insulin resistance), malnutrition, and frailty. The measurement of these systemic factors using simple, inexpensive clinical and blood chemistry tools can help in strategies to prevent and reduce its mortality impact., (© 2023 S. Karger AG, Basel.)

Introduction: This paper provides a summary of findings on the public's knowledge and attitudes towards dementia. We aim to investigate if the attitudes of Singaporeans towards dementia have changed over the years by adopting a questionnaire used in a similar study in 2012., Methods: A cross-sectional, descriptive study was conducted through the dissemination of an existing, online questionnaire to participants above 16 years of age. Out of 1,500 subjects, results from 1,373 participants were analysed. Descriptive statistics were used to analyse and compare results from the 2012 study while a latent class analysis was performed to understand the categories of study participants based on varying levels of attitudes, knowledge and stigma., Results: The mean age of study participants was 43.8 (SD = 15.7). Majority of the participants were females (76.5%), between 51 and 60 years of age (29.6%) and belonged to the Chinese ethnic group (77.8%). Results demonstrated that there were significant differences in attitudes towards dementia between 2012 and 2021. There was a 70.2% improvement in stigma-associated attitudes and an increase in correct responses to 4 out of 5 questions in the knowledge section., Conclusion: Findings of this study suggest that the general public has a better knowledge and more positive attitude towards dementia. This could have been attributed to higher literacy levels of the current study population and effectiveness of established outreach initiatives in Singapore. However, further research with a more balanced representation of ethnic and cultural groups would offer more comprehensive insights into dementia health literacy., (© 2023 S. Karger AG, Basel.)

Background: Motor and gait disturbances are evident in early Alzheimer and non-Alzheimer dementias and may predict the likelihood of mild cognitive impairment (MCI) or progression to dementia., Objective: We investigated the Timed-Up-and-Go (TUG) measure of functional mobility in predicting cognitive decline and incident MCI or early dementia (MCI-dementia)., Design: Prospective cohort study with 4.5 years follow-up., Setting: Population based., Participants: 2,544 community-dwelling older adults aged 55+ years., Methods: Participants with baseline data on TUG, fast gait speed (GS), knee extension strength (KES) and performance-oriented mobility assessment (POMA) gait and balance were followed up for cognitive decline (Mini-Mental State Exam; MMSE drop of ≥2, among 1,336 dementia-free participants) and incident MCI-dementia (among 1,208 cognitively normal participants). Odds ratio (OR) and 95% confidence intervals (95% CI) were adjusted for age, sex, education, smoking, physical, social and productive activity, multi-morbidity, metabolic syndrome and MMSE., Results: Per standard deviation increase in TUG, POMA, GS and KES were significantly associated with incident MCI-dementia: TUG (OR = 2.84, 95% CI = 2.02-3.99), GS (OR = 2.17, 95% CI = 1.62-2.91), POMA (OR = 1.88, 95% CI = 1.22-2.92) and KES (OR = 1.52, 95% CI = 1.15-2.02). Adjusted OR remained significant only for TUG (OR = 1.52, 95% CI = 1.01-2.31) and GS (OR = 1.53, 95% CI = 1.08-2.16). Areas under the curve (AUC) for TUG (AUC = 0.729, 95% CI = 0.671-0.787) were significantly greater than GS (AUC = 0.683, 95% CI = 0.619-0.746), KES (AUC = 0.624, 95% CI = 0.558-0.689) and POMA (AUC = 0.561, 95% CI = 0.485-0.637). Similar associations with cognitive decline were significant though less pronounced, and adjusted ORs remained significant for TUG, GS and POMA., Conclusion: Functional mobility decline precedes incident MCI and early dementia. The TUG appears to be especially accurate in predicting the future risks of adverse cognitive outcomes., Trial Registration: ClinicalTrials.gov NCT03405675. Registered 23 January 2018 (retrospectively registered)., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Aims: To examine the longitudinal association between skeletal muscle mass (SMM) loss and cognitive decline over time in type 2 diabetes mellitus (T2DM)., Methods: We conducted a prospective cohort study of 453 patients from SMART2D cohort with follow-up intervals of 1.6 to 6.4 years. Baseline and follow-up measurements included bio-impedance analysis (BIA) measure of skeletal muscle mass index (SMI) and Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) measure of cognitive function. We examined the association between annual rate of SMI and RBANS scores using linear regression, adjusting for demographics, education, depression, clinical co-variables and presence of apolipoprotein E4 (APOE) Ɛ 4 allele., Results: The mean age of participants was 60.3 ± 7.4 years. Compared to patients with Tertile 1 SMI change, the group with greater SMI decline (Tertile 3 SMI change) experienced 0.30 decline in RBANS total score (95%CI -0.57 to -0.03; p = 0.030) in the adjusted analysis. RBANS scores for subdomains in immediate memory and visuo-spatial/construction were lower in Tertile 3 SMI change group with corresponding coefficients -0.54 (95%CI -1.01 to -0.06; p = 0.026), and -0.71 (95%CI -1.30 to -0.12; p = 0.019) respectively., Conclusion: In patients with T2DM, BIA measure of muscle mass loss over time was independently associated with cognitive decline globally and in the domains of memory and visuo-spatial/construction., Competing Interests: Declaration of competing interest The authors report no potential conflicts of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

There is a lack of evidence supporting an association between folate and vitamin B12 exposure with cognitive outcomes. We examined serum folate and vitamin B12 and plasma homocysteine in 690 cognitively-normal adults (aged ≥ 55) from the Singapore Longitudinal Aging Study (SLAS-2) followed-up over 4.5 years on incident neurocognitive disorder (NCD): mild cognitive impairment (MCI) and dementia. At follow-up, 5.7% (39) of participants developed NCD (34 MCI and 5 dementia). Comparing with those who remained cognitively-normal, participants progressed to NCD had significantly lower mean baseline vitamin B12 (420 [SD ± 221] vs. 510 [SD ± 290] pmol/L, p = 0.026), higher homocysteine (14.6 [SD ± 4.2] vs. 12.9 [SD ± 4.3], p = 0.018) and lower one-carbon index (Z-scores: -0.444 [SD ± 0.819] vs. -0.001 [SD ± 0.990], p = 0.006). Adjusted for confounders, significant associations with incident NCD were found for lower vitamin B12 (per-SD OR = 2.10, 95%CI = 1.26-3.52), higher homocysteine (per-SD OR = 1.96, 95%CI = 1.18-3.24) and lower one-carbon index (per-SD OR = 1.67, 95%CI = 1.06-2.64). Folate was not significantly associated with progression to NCD. Notably, low B12 in the presence of high folate was significantly associated with incident NCD (adjusted OR = 3.81, 95%CI = 1.04-13.9). Low B12, high homocysteine, low B12 in the presence of high folate, and a one-carbon index of hypo-methylation were independently associated with progression to NCD among cognitively normal.

Aims: Type 2 diabetes mellitus (T2DM) has been shown to be associated with cognitive decline and dementia. As earlier onset of diabetes implies a longer disease duration and an increased risk to complications, we sought to investigate the effect of T2DM onset on cognitive function of our patients., Methods: We administered the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) to T2DM patients aged 45-85 from our SMART2D cohort. We assessed the association of the T2DM onset age (both continuous and stratified into 3 groups: early-onset ≤40 (n = 326), middle-aged onset 41-64 (n = 703) and late-onset ≥65 years old (n = 38)) and RBANS cognitive indices in 1067 patients. Potential mediation of this association by vascular compliance using mediation analysis was investigated., Results: T2DM onset associates significantly with RBANS total score. Patients with early T2DM onset have lower RBANS total score as compared to patients with middle-aged onset (β = -2.01, p = 0.0102) and those with late-onset (β = -5.80, p = 0.005). This association was partially mediated by pulse pressure index (25.8%), with indirect effect of 0.028 (Bootstrapped-CI: 0.008-0.047)., Conclusions: Association of early-onset T2DM with cognitive impairment is partly mediated by diminished vascular compliance. Appropriate screening and assessment of cognitive function is important for early intervention and management of cognitive impairment., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: ad hoc approaches are used to create composite indexes of intrinsic capacity (IC) based on five domains recommended by the World Health Organization for healthy ageing. We examined how combinations of domain-specific measures determine measurement performances of composite IC indexes., Methods: in this population-based prospective cohort study, community-dwelling older persons (N = 2,906) aged 55 years and above were recruited. We used 12 domain-specific measures: cognition (Mini-Mental State Examination, MMSE), psychological (Geriatric Depression Scale, GDS), locomotion (Timed Up-and Go [TUG], GV, Knee Extension Strength, Performance Orientated Mobility Assessment), sensory (logarithm of the Minimum Angle of Resolution [LogMAR] vision and Whisper Test hearing) and vitality (forced expiratory volume in 1 second pulmonary function, Elderly Nutritional Indicators for Geriatric Malnutrition Assessment [ENIGMA], Nutritional Screening Initiative) to derive 144 composite 2- to 5-domain functional health indexes (FHI), and evaluated their abilities to predict 9-year mortality and their associations with health determinants., Results: with 5-domain FHI, TUG, logMAR and MMSE showed the largest factor loadings (0.65-0.75). All single-domain FHI were significantly associated with mortality risks. Area under the receiver operating characteristic curve (AUC) values of mortality prediction increased with the number of domains (from mean 0.615 for single-domain FHI to mean 0.705 for 5-domain FHI), but the difference between 3-domain versus 4-domain FHI (P = 0.082) or versus 5-domain FHI (P = 0.109) was not statistically significant. Highest AUCs (P < 0.001) of best performing FHI were single-domain TUG: 0.735; 2-domain TUG + ENIGMA: 0.743; 3-domain TUG + LogMAR + ENIGMA: 0.762; 4-domain TUG + MMSE + LogMAR + ENIGMA: 0.757; 5-domain TUG + MMSE + GDS + LogMAR + ENIGMA: 0.751. FHI showed excellent construct validity based on correlations with known health determinants., Conclusions: among Singaporean older adults, cognition, sensory and locomotion are predominant IC domains. A multi-domain IC index performs better with more domain measures, but a minimalist 3-domain index performs just as robustly as a 4- or 5-domain index., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction: Person-centred care (PCC) is synonymous with best practice in the care of persons with dementia. Despite this, PCC is not routinely assessed, and there is no validated tool for in the acute care setting. We aimed to validate the Person-Centred Assessment Tool (P-CAT) in an acute setting., Methods: P-CAT was administered independently to a total of 161 nurses (n = 16, from a specialized dementia unit with PCC training; n = 116, geriatric wards; n = 30, medical/surgical wards). The word "residents" was replaced with "patients" in P-CAT. We employed confirmatory factor analysis with principal component extraction to verify the previously reported three- and two-factor solutions. A one-way between-groups ANOVA was then used to investigate group differences in the P-CAT score (total scale and subscale)., Results: Factor analysis revealed a two-factor solution (explained variance 42.28%): (i) extent of personalizing care and (ii) amount of organizational and environmental support. Out of the 13 items, only 2 items did not load as expected. The internal consistency reliability of the scale was satisfactory (Cronbach's α = 0.77). Nurses' P-CAT scores were significantly different across ward settings [Welch's F(2,37.20) = 13.01, p < 0.001, ω2 = 0.09], with the highest among those PCC trained. Post hoc analyses revealed a significant difference in mean subscale scores between PCC-trained nurses and nurses from the other two ward settings. P-CAT scores were not significantly correlated with age, r(159) = 0.01, p = 0.861, or with nursing experience, r(159) = 0.04, p = 0.615., Discussion/conclusion: P-CAT possesses adequate validity and reliability as a quantitative assessment tool of PCC in the acute care setting., (© 2022 S. Karger AG, Basel.)

Objectives: To present the local evidence and final recommendations of the Clinical Practice Guidelines workgroup convened by the Chapter of Geriatricians and the Society for Geriatric Medicine Singapore. The aim is to develop contextualized evidence-based recommendations that facilitate adoption of the Asian Working Group for Sarcopenia (AWGS) 2019 consensus into current practice in Singapore., Methods: The workgroup drew upon the AWGS'2019 consensus, updated literature review of Singapore studies till 31 Dec 2020, and evidence from recent systematic reviews. From 40 local studies included for data extraction, we constructed evidence tables organized as: definition and epidemiology; diagnosis and evaluation; and treatment and intervention. Twenty recommendations - case-finding, diagnosis, treatment, prevention, research - were developed, and graded for strength and quality using the GRADE approach. Consensus from an expert panel(N=23) was achieved after two rounds of the modified Delphi process., Results: The local prevalence of sarcopenia among community-dwelling older adults ranged from 13.6% to 25%. Most studies adopted the AWGS'2019 and AWGS'2014 criteria. Reported case finding tools include SARC-F, calf circumference (CC) and SARC-CalF. Gender-specific AWGS cut-offs for appendicular skeletal mass were used to define low muscle mass. Different protocols and dynamometers were used to assess handgrip strength, whilst gait speed and 5-times chair stand were commonly used to assess physical performance., Recommendations: We conditionally recommend a case-finding approach in at-risk older adults using validated case-finding tools. Screen-positive individuals should be assessed for 'possible sarcopenia' and underlying causes. For diagnosis, we conditionally recommend using the AWGS'2019 algorithm, and dual-energy X-ray absorptiometry when necessary to determine low lean mass for a confirmatory diagnosis of sarcopenia. For treatment, we strongly recommend resistance-based exercises and conditionally recommend a quality protein-rich diet/protein supplementation, with Vitamin D supplementation for insufficiency (<30 micrograms/L). For prevention, we recommend regular resistance-based physical activity and adequate protein intake (≥1.0g/kg bodyweight). We encourage more research to address local evidence gaps., Competing Interests: None declared by all authors.

Measures of functional status are known to predict mortality more strongly than traditional disease risk markers in old adult populations. Few studies have compared the predictive accuracy of physical and functional measures for long-term mortality. In this prospective cohort study, community-dwelling older adults ( N = 2906) aged 55 + (mean age 66.6 ± 7.7 years) were followed up for mortality outcome up to 9 years (mean 5.8 years). Baseline assessments included Timed Up-and-Go (TUG), gait velocity (GV), knee extension strength, Performance Oriented Mobility Assessment, forced expiratory volume in 1 second, Mini-Mental State Examination (MMSE), Geriatric Depression Scale, frailty, and medical morbidity. A total of 111 (3.8%) participants died during 16976.7 person-years of follow up. TUG was significantly associated with mortality risk (HR = 2.60, 95% CI = 2.05-3.29 per SD increase; HR = 5.05, 95% CI = 3.27-7.80, for TUG score ≥ 9 s). In multivariate analysis, TUG remained significantly associated with mortality (HR = 1.64, 95% CI = 1.20-2.19 per SD increase; HR = 2.66, 95% CI = 1.67-4.23 for TUG score ≥ 9 s). In multivariable analyses, GV, MMSE, Frailty Index (FI) and physical frailty, diabetes and multi-morbidity were also significantly associated with mortality. However, TUG (AUC = 0.737) demonstrated significantly higher discriminatory accuracy than GV (AUC = 0.666, p < 0.001), MMSE (AUC = 0.63, p < 0.001), FI (AUC = 0.62, p < 0.001), physical frailty (AUC = 0.610, p < 0.001), diabetes (AUC = 0.582, p < 0.001) and multi-morbidity (AUC = 0.589, p < 0.001). TUG's predictive accuracy shows surpassing predictive accuracy for long-term mortality in community-dwelling older adults.

Background: Previous studies focusing on the association between gestational diabetes and breastfeeding duration have been inconclusive., Objectives: We aimed to determine whether maternal gestational hyperglycemia is associated with the duration of breastfeeding and the concentrations of markers linked to breastmilk production., Methods: Data from the prospective, multiethnic Growing Up in Singapore Towards Healthy Outcomes study were used to assess the association of fasting plasma glucose (FPG) and 2-h postglucose challenge (2hPG) measured at 26-28 wk of gestation with duration of breastfeeding and concentrations of protein, lactose, citrate, sodium, potassium, and zinc in breastmilk 3 wk postpartum., Results: Of the 1035 participants, 5.2% and 9.5% had elevated FPG and 2hPG, respectively, consistent with a diagnosis of gestational diabetes mellitus based on International Association of Diabetes and Pregnancy Study Groups criteria. FPG ≥5.1 mmol/L was associated with a crude reduction in median breastfeeding duration of 2.3 mo. In a model adjusted for maternal prepregnancy BMI and intention to breastfeed, FPG ≥5.1 mmol/L predicted earlier termination of any breastfeeding (adjusted HR: 1.47; 95% CI: 1.04, 2.08) but not full breastfeeding (adjusted HR: 1.08; 0.76, 1.55). 2hPG ≥8.5 mmol/L was not significantly associated with the durations of any (adjusted HR: 0.86; 95% CI: 0.62, 1.19) or full (adjusted HR: 0.85; 95% CI: 0.62, 1.18) breastfeeding. Maternal FPG was significantly and positively associated with breastmilk sodium (adjusted coefficient: 1.28; 95% CI: 1.08, 1.51) and sodium-to-potassium ratio (adjusted coefficient: 1.29; 95% CI: 1.08, 1.54) but not with other measured breastmilk components., Conclusions: Women with FPG ≥5.1 mmol/L during pregnancy breastfeed for a shorter duration. Future work involving measurement of milk production is needed to determine whether low milk production predicts breastfeeding duration among women with elevated FPG. This trial was registered at www.clinicaltrials.gov as NCT01174875., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Background: Fluid imbalance is associated with various clinical conditions, but the association between elevated extracellular-water to total-body-water (ECW/TBW) ratio, an indicator of fluid balance, and cognitive impairment is unknown. We aimed to investigate relationship between ECW/TBW ratio and cognitive function in type 2 diabetes mellitus., Methods: This study was a cross-sectional design, comparing 1233 patients aged 61.4 ± 8.0 years from the Singapore Study of Macro-angiopathy and Micro-vascular Reactivity in Type 2 Diabetes (SMART2D) cohort. ECW/TBW was measured using bioelectrical impedance method. Cognitive function was assessed with Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Multiple linear regression was used to examine association between ECW/TBW and RBANS scores, adjusting for demographics, education, clinical covariates, and apolipoprotein E allele., Results: In unadjusted analyses, there was an inverse dose-dependent association between ECW/TBW and RBANS total score. The associations persisted in fully adjusted model with β = -1.18 (95% confidence interval [CI] -2.19 to -0.17; P = 0.022) for slight edema and -2.33 (-3.99 to -0.67; P = 0.006) for edema. Slight edema and edema were significantly associated with reduced cognitive function in delayed memory and attention. There was significant association between edema but not slight edema, with reduced cognitive function in language. Pulse pressure accounted for 16.8% of association between ECW/TBW and RBANS total score., Conclusions: Our novel finding of an independent association between higher ECW/TBW and poorer cognitive function highlights the potential importance of maintaining body fluid balance in the management of cognitive impairment., (© 2020 Ruijin Hospital, Shanghai JiaoTong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Background: Mild cognitive impairment (MCI) is a critical pre-dementia target for preventive interventions. There are few brief screening tools based on self-reported personal lifestyle and health-related information for predicting MCI that have been validated for their generalizability and utility in primary care and community settings., Objective: To develop and validate a MCI risk prediction index, and evaluate its field application in a pilot community intervention trial project., Design: Two independent population-based cohorts in the Singapore Longitudinal Ageing Study (SLAS). We used SLAS1 as a development cohort to construct the risk assessment instrument, and SLA2 as a validation cohort to verify its generalizability., Setting: community-based screening and lifestyle intervention Participants: (1) SLAS1 cognitively normal (CN) aged ≥55 years with average 3 years (N=1601); (2) SLAS2 cohort (N=3051) with average 4 years of follow up. (3) 437 participants in a pilot community intervention project., Measurements: The risk index indicators included age, female sex, years of schooling, hearing loss, depression, life satisfaction, number of cardio-metabolic risk factors (wide waist circumference, pre-diabetes or diabetes, hypertension, dyslipidemia). Weighted summed scores predicted probabilities of MCI or dementia. A self-administered questionnaire field version of the risk index was deployed in the pilot community project and evaluated using pre-intervention baseline cognitive function of participants., Results: Risk scores were associated with increasing probabilities of progression to MCI-or-dementia in the development cohort (AUC=0.73) and with increased prevalence and incidence of MCI-or-dementia in the validation cohort (AUC=0.74). The field questionnaire risk index identified high risk individuals with strong correlation with RBANS cognitive scores in the community program (p<0.001)., Conclusions: The SLAS risk index is accurate and replicable in predicting MCI, and is applicable in community interventions for dementia prevention., Competing Interests: The authors declare that they have no competing interests.

Background: Person-centred care (PCC) is synonymous with best practice in the care of persons with dementia. However, the research focus has been in long-term care settings with less attention in acute hospitals. We aimed to study the perspectives and experiences of nurses implementing PCC in an acute hospital dementia unit (Care for Acute Mentally Infirm Elders [CAMIE])., Method: This was an exploratory qualitative study involving individual, face-to-face, semi-structured in-depth interviews. A purposive sample of 10 nurses participated in the interview. We employed an inductive thematic analysis approach to analyse the qualitative data., Results: The findings highlighted the positive experiences, for example, meaningful connection with patients and the challenges, for example, managing challenging behaviour in providing PCC. The initial challenges were due to a lack of prior knowledge and experience. Through formal and informal learning, the nurses built confidence and competence, and also provided support to one other. They emphasized the importance of teamwork and camaraderie in the CAMIE team but raised concerns about the negative perceptions of non-CAMIE nurses on the value of their work., Conclusion: Despite the challenges, adequate knowledge and robust organizational level support are the key support for nurses to embrace PCC as their care ethos in the acute care setting., (© 2021 S. Karger AG, Basel.)

Objectives: In Singapore, the core curriculum for end-of-life (EOL) care used in nurse training courses is limited. Only 45% of nurses indicated familiarity with inpatient palliative care. Nurses who lack skills in palliative care may develop anxiety and negative attitudes towards caring for dying patients. We explored whether a two-day, multimodal EOL care workshop could reduce nurses' death anxiety and improve nurses' skills, knowledge, and attitude towards palliative care., Methods: Forty-five nurses participated in the workshop. At baseline before and at six weeks after, a 20-item knowledge-based questionnaire and the Death Attitude Profile-Revised (DAP-R) were administered. Six weeks post-workshop, in-depth interviews were conducted. We employed descriptive statistics, student paired samples t-test and inductive thematic analysis., Results: There was a significant improvement in nurses' knowledge score (p < 0.01) and reduction in their death anxiety score (p < 0.01). Fear of Death (p = 0.025) and Death Avoidance (p = 0.047) sub-scores decreased significantly. However, the remaining domains such as Neutral Acceptance, Approach Acceptance, and Escape Acceptance did not show any significant difference, although Escape Acceptance showed a trend towards a reduced score (p = 0.063). After the workshop, more nurses adopted the Neutral Acceptance stance (76.2%), and none of them fell into the Fear of Death subdomain. Most nurses interviewed reported a positive change in their knowledge, attitudes, and practice even after the workshop., Significance of Results: The multimodal palliative care workshop was useful in improving nurses' EOL knowledge and reducing their anxiety towards death. The positive change in nurses' attitudes and practices were noted to be sustained for at least six weeks after the intervention.

Objectives: To investigate risk factors of incident physical frailty., Design: A population-based observational longitudinal study., Setting: Community-dwelling elderly with age 55 years and above recruited from 2009 through 2011 in the second wave Singapore Longitudinal Ageing Study-2 (SLAS-2) were followed up 3-5 years later., Participants: A total of 1297 participants, mean age of 65.6 ±0.19, who were free of physical frailty., Measurements: Incident frailty defined by three or more criteria of the physical phenotype used in the Cardiovascular Health Study was determined at follow-up. Potential risk factors assessed at baseline included demographic, socioeconomic, medical, psychological factors, and biochemical markers., Results: A total of 204 (15.7%) participants, including 81 (10.87%) of the robust and 123 (22.28%) of the prefrail transited to frailty at follow-up. Age, no education, MMSE score, diabetes, prediabetes and diabetes, arthritis, ≥5 medications, fair and poor self-rated health, moderate to high nutritional risk (NSI ≥3), Hb (g/dL), CRP (mg/L), low B12, low folate, albumin (g/L), low total cholesterol, adjusted for sex, age and education, were significantly associated (p<0.05) with incident frailty. In stepwise selection models, age (year) (OR=1.07, 95%CI=1.03-1.10, p<0.001), albumin (g/L) (OR=0.85, 95%CI=0.77-0.94, p=0.002), MMSE score (OR=0.88, 95%CI=0.78-0.98, p=0.02), low folate (OR=3.72, 95%CI=1.17-11.86, p=0.03, and previous hospitalization (OR=2.26, 95%CI=1.01-5.04,p=0.05) were significantly associated with incident frailty., Conclusions: The study revealed multiple modifiable risk factors, especially related to poor nutrition, for which preventive measures and early management could potentially halt or delay the development of frailty., Competing Interests: The authors declare that they have no conflicts of interest.

Competing Interests: The authors declare that they have no conflicts of interest.

Although many persons with severe dementia (PWSDs) are cared for at home by their family caregivers, few studies have assessed end of life (EOL) care experiences of PWSDs. We present the protocol for the PISCES study (Panel study Investigating Status of Cognitively impaired Elderly in Singapore) which aims to describe the clinical course, health care utilization, and expenditures for community-dwelling PWSDs; and perceived burden, coping, resilience, anticipatory and prolonged grief among their caregivers. This ongoing multi-center prospective longitudinal study is recruiting primary informal caregivers of 250 PWSDs from major restructured public hospitals, community hospitals, home care foundations, and hospices in Singapore. Caregivers are surveyed every four months for two years or until the PWSD passes away and then at eight weeks and six months post-death to assess the bereavement of the caregiver. Survey questionnaires included validated tools to assess PWSDs' quality of life, suffering, behaviors, functional status, resource utilization; and caregiver's satisfaction with care, awareness of prognosis, care preferences, resilience, coping, perceived burden, distress, positive aspects of caregiving, anticipatory grief, and bereavement adjustment. We also conduct qualitative in-depth interviews with a sub-sample of caregivers. The survey data is being linked with medical and billing records of PWSDs. The study has been approved by an ethics board. Results from the study will be disseminated through publications and presentations targeting researchers, policy makers and clinicians interested in understanding and improving EOL care for PWSDs and their caregivers.

An 88-year-old woman presented with a 2-day history of inability to open her left eye with no ocular discomfort or blurred vision. She had a long-standing history of diabetes mellitus, hypertension and stroke disease. Examination revealed an isolated complete left eye ptosis with no pupillary involvement and intact extraocular movements. There were no other neurological deficits and fatigability was not elicited. Magnetic resonance imaging of the brain showed an acute infarct of the left red nucleus. Oculomotor nerve fascicles are widely separated in the midbrain before they exit at the interpeduncular fossa. A discrete lesion involving the most caudal fibres of the levator palpebrae is the most likely explanation. Although uncommon, this should be considered in patients with underlying cardiovascular risk factors., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

ABSTRACTThe MMSE is used to screen for cognitive impairment and estimate dementia severity. In clinical settings, conventional cut-off scores have been used to distinguish between dementia stages. However, these scores have not been validated for different populations. This study maps scores from the modified version of the MMSE to dementia stages delineated by the Diagnostic and Statistical Manual of Mental Disorders-3rd revised edition (DSM-III-R), the Clinical Dementia Rating (CDR) and Functional Assessment Staging Test (FAST). We used cross-sectional data from a tertiary hospital memory clinic. Subjects were stratified into "primary education and below" (PE) or "secondary education and above" (SE). Receiving operating characteristic (ROC) analyses and Cohen's κ were performed to determine MMSE cut-off scores for dementia stages. Our derived cut-off scores were lower compared to the conventional scores. Scores also differed between subjects of different education levels. MMSE cut-off scores were 19, 15, and 9 for CDR stages 1, 2, and 3 respectively in PE subjects, and 23, 17, and 10 for SE subjects. Cut-off scores were comparable for staging by DSM-III-R Criteria and FAST. There is a need for locally derived stage-specific MMSE cut-off scores for the Asian population adjusted for education.

Objectives: Memory clinics play an important role in enabling early dementia diagnosis and intervention. Few studies have investigated the changing patient profiles at memory clinics over time. We studied the trend of patient characteristics in a geriatric medicine-led memory clinic over 12 years to improve services and care to meet their needs., Setting and Participants: Data from 2340 first-visit patients seen at a memory clinic from 2005-2017 were extracted from a registered database and analysed., Design: ANOVA, Pearson chi-square and non-parametric tests were used to describe and compare between patients with dementia (PWD) and patients with no dementia (PND)., Measurements: Data included diagnoses of dementia and mild cognitive impairment, age, education, MMSE scores and comorbidities., Results: Patients averaged 77.2 ± 8.3 years of age with mean MMSE score of 16.2 ± 6.7. Those diagnosed with dementia were older (78.3 ± 7.9 years) and almost half (48.4%) had moderate or moderately severe dementia (FAST 5-6). Over time, there was a growing proportion of patients with mild cognitive impairment (MCI) and mild Alzheimer's dementia. Many PWD had co-morbidities of hypertension (65.9%), hyperlipidemia (55.1%), diabetes (33.5%) and 28.4% were frail., Conclusions: The findings call for services to better diagnose and manage patients at the earlier stages of cognitive impairment and provide holistic interventions for those with frailty and other co-morbidities. The continued rise in number of patients presenting to memory clinics provides impetus to expedite integration of tertiary-based memory clinics with primary and community care providers to better support PWD and their families., Competing Interests: None.

Aims: Older adults who live alone are vulnerable physically, emotionally and socially. However, there is a trend towards children not living with their parents. We studied the willingness of teenagers today to live with and care for their aged parents tomorrow, and the reasons for their decision., Methods: A convenient sample of 1405 teenage students (M age  = 14.9 ± 1.30) in the north region of Singapore completed a purpose-designed questionnaire. Structural equation modeling was used to explore the relationships between teenagers' closeness to grandparents, challenges faced living with grandparents, positive and negative perceptions towards aging, and willingness to stay with aged parents in the future, stratified by sex. Thematic analysis was used to understand the reasons for their choice., Results: The majority (85.6%) chose to live with their parents, and the significant predictors were "closeness to grandparents" (P = 0.034) and "positive perceptions towards aging" (P < 0.01), but not "challenges in living with grandparents" (P = 0.391) or "negative perceptions" (P = 0.302). Among teenagers with positive perceptions, boys were more likely to live with their parents (P < 0.01). Conversely, among teenagers with negative perceptions, girls were more likely to do so (P = 0.026). Primary reasons for willingness included: "desire to care," "expression of love," "sense of responsibility" and "prompted by moral values.", Conclusions: Efforts should be undertaken to strengthen teenagers' relationships with grandparents, and promote positive perceptions towards aging to better sustain the family as a social safety net for aging and frail older adults. Geriatr Gerontol Int 2018; 18: 957-964., (© 2018 Japan Geriatrics Society.)

Accounting for cellular heterogeneity is essential in neonatal epigenome-wide association studies (EWAS) performed on heterogeneous tissues, such as umbilical cord tissue (CT) or cord blood (CB). Using a reference-panel-based statistical approach, the cell type composition of heterogeneous tissues can be estimated by comparison of whole tissue DNA methylation profiles with cell type-specific DNA methylation signatures. Currently, there is no adequate DNA methylation reference panel for CT, and existing CB panels have been generated on lower coverage Infinium HumanMethylation450 arrays. In this study, we generate a reference panel for CT and improve available CB panels by using the higher coverage Infinium MethylationEPIC arrays. We performed DNA methylation profiling of 9 cell types isolated from CT and CB samples from 14 neonates. In addition to these cell types, we profiled DNA methylation of unfractionated CT and CB. Cell type composition of these unfractionated tissue samples, as estimated by our reference panels, was in agreement with that obtained by flow cytometry. Expectedly, DNA methylation profiles from CT and CB were distinct, reflecting their mesenchymal and hematopoietic stem cell origins. Variable CpGs from both unfractionated CT and its isolated cell types were more likely to be located in open seas and intronic regions than those in CB. Cell type specific CpGs in CT were enriched in intercellular matrix pathways, while those from CB were enriched in immune-related pathways. This study provides an open source reference panel for estimation and adjustment of cellular heterogeneity in CT and CB, and broadens the scope of tissue utilization assessed in future neonatal EWAS studies.

Prospective study with a controlled arm to know if there are variations of measures of arterial stiffness with posture in subjects with hypertension on antihypertensive medications. We studied postural variations of measures of arterial stiffness in 21 subjects with diagnosed hypertension on antihypertensive medications and compared them with 21 normotensive subjects. All subjects underwent pulse-wave analysis on SphygmoCor in the morning between 8 am to 10 am initially in supine and then in sitting position after 3 minutes. Summary measures on demographics, and blood pressure characteristics at sitting and supine positions are obtained. Differences between characteristics at supine and sitting position are compared using nonparametric paired test of Wilcoxon signed-rank test. A value of p  < 0.05 was accepted as statistically significant. Antihypertensive medications decreased the supine aortic augmentation pressure (AAP) and augmentation index (AI) but not significantly. When subgroups of patients with antihypertensive treatment were analyzed, it was noted that angiotensin-converting enzyme inhibitor and angiotensin receptor blocker group (12) decreased AAP and AI significantly in supine position compared with patients on other antihypertensive medications (9) ( p -value 0.034 and 0.038, respectively). There was no significant difference in other groups of calcium channel blockers, β-blockers, or diuretics. However, in normotensive control arm, there was an increase in AAP and AI in the supine position. In hypertensive subjects, on antihypertensive, there was reduction in AAP and AI in supine position compared with those of normotensives. The significance of the decrease in AAP and AI in supine position on antihypertensive needs to be studied further.

Background/aims: The acute hospital ward can be unfamiliar and stressful for older patients with impaired cognition, rendering them prone to agitation and resistive to care. Extant literature shows that music therapy can enhance engagement and mood, thereby ameliorating agitated behaviours. This pilot study evaluates the impact of a creative music therapy (CMT) programme on mood and engagement in older patients with delirium and/or dementia (PtDD) in an acute care setting. We hypothesize that CMT improves engagement and pleasure in these patients., Methods: Twenty-five PtDD (age 86.5 ± 5.7 years, MMSE 6/30 ± 5.4) were observed for 90 min (30 min before, 30 min during, and 30 min after music therapy) on 3 consecutive days: day 1 (control condition without music) and days 2 and 3 (with CMT). Music interventions included music improvisation such as spontaneous music making and playing familiar songs of patient's choice. The main outcome measures were mood and engagement assessed with the Menorah Park Engagement Scale (MPES) and Observed Emotion Rating Scale (OERS)., Results: Wilcoxon signed-rank test showed a statistically significant positive change in constructive and passive engagement (Z = 3.383, p = 0.01) in MPES and pleasure and general alertness (Z = 3.188,p = 0.01) in OERS during CMT. The average pleasure ratings of days 2 and 3 were higher than those of day 1 (Z = 2.466, p = 0.014). Negative engagement (Z = 2.582, p = 0.01) and affect (Z = 2.004, p = 0.045) were both lower during CMT compared to no music., Conclusion: These results suggest that CMT holds much promise to improve mood and engagement of PtDD in an acute hospital setting. CMT can also be scheduled into the patients' daily routines or incorporated into other areas of care to increase patient compliance and cooperation.

Interindividual variability in the epigenome has gained tremendous attention for its potential in pathophysiological investigation, disease diagnosis, and evaluation of clinical intervention. DNA methylation is the most studied epigenetic mark in epigenome-wide association studies (EWAS) as it can be detected from limited starting material. Infinium 450K methylation array is the most popular platform for high-throughput profiling of this mark in clinical samples, as it is cost-effective and requires small amounts of DNA. However, this method suffers from low genome coverage and errors introduced by probe cross-hybridization. Whole-genome bisulfite sequencing can overcome these limitations but elevates the costs tremendously. Methyl-Capture Sequencing (MC Seq) is an attractive intermediate solution to increase the methylome coverage in large sample sets. Here we first demonstrate that MC Seq can be employed using DNA amounts comparable to the amounts used for Infinium 450K. Second, to provide guidance when choosing between the 2 platforms for EWAS, we evaluate and compare MC Seq and Infinium 450K in terms of coverage, technical variation, and concordance of methylation calls in clinical samples. Last, since the focus in EWAS is to study interindividual variation, we demonstrate the utility of MC Seq in studying interindividual variation in subjects from different ethnicities.

Background: Post stroke cognitive impairment (PSCI), an important complication of strokes, has numerous risk factors. A scale adequately classifying risk of cognitive impairment 3-6 months after mild stroke will be useful for clinicians., Objective: To develop a risk score based on clinical and neuroimaging variables that will be useful in identifying mild ischemic stroke patients at high risk for PSCI., Methods: The risk score development cohort comprised of a retrospective dataset of 209 mild stroke patients with MRI confirmed infarcts, without pre-stroke cognitive impairment, and evaluated within 6 months post-stroke for PSCI. Logistic regression identified factors predictive of PSCI and a risk score was developed based on regression coefficients. The risk score was checked for stability using 10-fold cross-validation and validated in an independent prospective cohort of 185 ischemic mild stroke patients., Results: Within 6 months post-stroke, 37.32% developed PSCI in the retrospective dataset. A 15-point risk score based on age, education, acute cortical infarcts, white matter hyperintensity, chronic lacunes, global cortical atrophy, and intracranial large vessel stenosis was highly predictive of PSCI with an AUC of 0.829. 10.11% with low scores, 52.69% with moderate scores, and 74.07% with high scores developed PSCI. In the prospective validation cohort, the model had an AUC of 0.776, and exhibited similar accuracy and stability statistics at both 6 and 12 months., Conclusion: The seven item risk score adequately identified mild stroke patients who are at an increased risk of developing PSCI.

Background: The development of an effective brief dementia test will help in the early identification of dementia., Aim: This study investigates the diagnostic utility of a brief cognitive test for dementia which combines a short subjective informant-rated questionnaire (AD8) with an objective cognitive measure (Mini-Mental State Examination, MMSE) or its subcomponents., Methods: Subjects with mild dementia (Clinical Dementia Rating Scale score ≤1) were matched with community-dwelling, cognitively intact controls. MMSE and Clinical Dementia Rating Scale were administered to all subjects, while AD8 was completed by a reliable informant. Receiver operating characteristics analysis determined the diagnostic accuracies of AD8, MMSE, and AD8 combined with MMSE (AD8+MMSE). Stepwise logistic regression identified the subcomponents of MMSE which, combined with AD8, best discriminated dementia patients from controls., Results: The AD8 (area under the curve [AUC] = 0.92, 95% confidence interval [CI] 0.89-0.95) was superior to the MMSE (AUC = 0.87, 95% CI 0.83-0.92) in discriminating mild dementia patients from controls, and AD8+MMSE (AUC = 0.95, 0.92-0.98) increased its superior discrimination over MMSE alone. AD8 combined with three-item recall and intersecting pentagon copy (AUC = 0.95, 95% CI 0.92-0.97) performed as well as AD8 combined with full MMSE., Conclusion: AD8 combined with the MMSE subcomponents three-item recall and intersecting pentagon copy has excellent diagnostic utility and is a promising brief cognitive test for early dementia.

This study aimed to establish norm values for facial proportion indices among 12-year-old southern Chinese children, to determine lower facial proportion, and to identify gender differences in facial proportions.A random population sample of 514 children was recruited. Fifteen facial landmarks were plotted with ImageJ (V1.45) on standardized photos and 22 Facial proportion index values were obtained. Gender differences were analyzed by 2-sample t-test with 95% confidence interval. Repeated measurements were conducted on approximately 10% of the cases.The rate of adopted subjects was 52.5% (270/514). Intraclass correlation coefficient values (ICC) for intra- examiner reliability were >0.87. Population facial proportion index values were derived. Gender differences in 11 of the facial proportion indices were evident (P < 0.05).Upper face-face height (N- Sto/ N- Gn), vermilion height (Ls-Sto/Sto-Li), upper face height-biocular width (N-Sto/ExR-ExL) and nose -face height (N-Sn/N-Gn) indices were found to be larger among girls (P < 0.01). Males had larger lower face-face height (Sn -Gn/ N-Gn), mandibulo-face height (Sto-Gn/N-Gn), mandibulo-upper face height (Sto-Gn/N-Sto), nasal (AlR-AlL/N-Sn), upper lip height-mouth width (Sn-Sto/ChR-ChL), upper lip-upper face height (Sn-Sto/N-Sto) and upper lip-nose height (Sn-Sto/N-Sn) indices (P < 0.05).Population norm of facial proportion indices for 12-year-old Southern Chinese were derived and mean lower facial proportion were obtained. Sexual dimorphism is apparent.

Genomic imprinting is an epigenetic mechanism resulting in parental allele-specific gene expression. Defects in normal imprinting are found in cancer, assisted reproductive technologies, and several human syndromes. In mouse models, germline-derived DNA methylation is shown to regulate imprinting. Though imprinting is largely conserved between mammals, species- and tissue-specific domains of imprinted expression exist. Using the cynomolgus macaque (Macaca fascicularis) to assess primate-specific imprinting, we present a comprehensive view of tissue-specific imprinted expression and DNA methylation at established imprinted gene clusters. For example, like mouse and unlike human, macaque IGF2R is consistently imprinted, and the PLAGL1, INPP5F transcript variant 2, and PEG3 imprinting control regions are not methylated in the macaque germline but acquire this post-fertilization. Methylome data from human early embryos appear to support this finding. These suggest fundamental differences in imprinting control mechanisms between primate species and rodents at some imprinted domains, with implications for our understanding of the epigenetic programming process in humans and its influence on disease., (© 2015 Cheong et al.; Published by Cold Spring Harbor Laboratory Press.)

CXCL14 is a chemokine that has previously been implicated in insulin resistance in mice. In humans, the role of CXCL14 in metabolic processes is not well established, and we sought to determine whether CXCL14 is a risk susceptibility gene important in fetal programming of metabolic disease. For this purpose, we investigated whether CXCL14 is differentially regulated in human umbilical cords of infants with varying birth weights. We found an elevated expression of CXCL14 in human low birth weight (LBW) cords, as well as in cords from nutritionally restricted Macaca fascicularis macaques. To further analyze the regulatory mechanisms underlying the expression of CXCL14, we examined CXCL14 in umbilical cord-derived mesenchymal stem cells (MSCs) that provide an in vitro cell-based system amenable to experimental manipulation. Using both whole frozen cords and MSCs, we determined that site-specific CpG methylation in the CXCL14 promoter is associated with altered expression, and that changes in methylation are evident in LBW infant-derived umbilical cords that may indicate future metabolic compromise through CXCL14.

Integrating the genotype with epigenetic marks holds the promise of better understanding the biology that underlies the complex interactions of inherited and environmental components that define the developmental origins of a range of disorders. The quality of the in utero environment significantly influences health over the lifecourse. Epigenetics, and in particular DNA methylation marks, have been postulated as a mechanism for the enduring effects of the prenatal environment. Accordingly, neonate methylomes contain molecular memory of the individual in utero experience. However, interindividual variation in methylation can also be a consequence of DNA sequence polymorphisms that result in methylation quantitative trait loci (methQTLs) and, potentially, the interaction between fixed genetic variation and environmental influences. We surveyed the genotypes and DNA methylomes of 237 neonates and found 1423 punctuate regions of the methylome that were highly variable across individuals, termed variably methylated regions (VMRs), against a backdrop of homogeneity. MethQTLs were readily detected in neonatal methylomes, and genotype alone best explained ∼25% of the VMRs. We found that the best explanation for 75% of VMRs was the interaction of genotype with different in utero environments, including maternal smoking, maternal depression, maternal BMI, infant birth weight, gestational age, and birth order. Our study sheds new light on the complex relationship between biological inheritance as represented by genotype and individual prenatal experience and suggests the importance of considering both fixed genetic variation and environmental factors in interpreting epigenetic variation., (© 2014 Teh et al.; Published by Cold Spring Harbor Laboratory Press.)

The Infinium Human Methylation450 BeadChip Array (Infinium 450K) is a robust and cost-efficient survey of genome-wide DNA methylation patterns. Macaca fascicularis (Cynomolgus macaque) is an important disease model; however, its genome sequence is only recently published, and few tools exist to interrogate the molecular state of Cynomolgus macaque tissues. Although the Infinium 450K is a hybridization array designed to the human genome, the relative conservation between the macaque and human genomes makes its use in macaques feasible. Here, we used the Infinium 450K array to assay DNA methylation in 11 macaque muscle biopsies. We showed that probe hybridization efficiency was related to the degree of sequence identity between the human probes and the macaque genome sequence. Approximately 61% of the Human Infinium 450K probes could be reliably mapped to the Cynomolgus macaque genome and contain a CpG site of interest. We also compared the Infinium 450K data to reduced representation bisulfite sequencing data generated on the same samples and found a high level of concordance between the two independent methodologies, which can be further improved by filtering for probe sequence identity and mismatch location. We conclude that the Infinium 450K array can be used to measure the DNA methylome of Cynomolgus macaque tissues using the provided filters. We also provide a pipeline for validation of the array in other species using a simple BLAST-based sequence identify filter., (Copyright © 2014 Ong et al.)

Large regions of recurrent genomic loss are common in cancers; however, with a few well-characterized exceptions, how they contribute to tumor pathogenesis remains largely obscure. Here we identified primate-restricted imprinting of a gene cluster on chromosome 20 in the region commonly deleted in chronic myeloid malignancies. We showed that a single heterozygous 20q deletion consistently resulted in the complete loss of expression of the imprinted genes L3MBTL1 and SGK2, indicative of a pathogenetic role for loss of the active paternally inherited locus. Concomitant loss of both L3MBTL1 and SGK2 dysregulated erythropoiesis and megakaryopoiesis, 2 lineages commonly affected in chronic myeloid malignancies, with distinct consequences in each lineage. We demonstrated that L3MBTL1 and SGK2 collaborated in the transcriptional regulation of MYC by influencing different aspects of chromatin structure. L3MBTL1 is known to regulate nucleosomal compaction, and we here showed that SGK2 inactivated BRG1, a key ATP-dependent helicase within the SWI/SNF complex that regulates nucleosomal positioning. These results demonstrate a link between an imprinted gene cluster and malignancy, reveal a new pathogenetic mechanism associated with acquired regions of genomic loss, and underline the complex molecular and cellular consequences of "simple" cancer-associated chromosome deletions.

Background: Babies born at lower gestational ages or smaller birthweights have a greater risk of poorer health in later life. Both the causes of these sub-optimal birth outcomes and the mechanism by which the effects are transmitted over decades are the subject of extensive study. We investigated whether a transcriptomic signature of either birthweight or gestational age could be detected in umbilical cord RNA., Methods: The gene expression patterns of 32 umbilical cords from Singaporean babies of Chinese ethnicity across a range of birthweights (1698-4151 g) and gestational ages (35-41 weeks) were determined. We confirmed the differential expression pattern by gestational age for 12 genes in a series of 127 umbilical cords of Chinese, Malay and Indian ethnicity., Results: We found that the transcriptome is substantially influenced by gestational age; but less so by birthweight. We show that some of the expression changes dependent on gestational age are enriched in signal transduction pathways, such as Hedgehog and in genes with roles in cytokine signalling and angiogenesis. We show that some of the gene expression changes we report are reflected in the epigenome., Conclusions: We studied the umbilical cord which is peripheral to disease susceptible tissues. The results suggest that soma-wide transcriptome changes, preserved at the epigenetic level, may be a mechanism whereby birth outcomes are linked to the risk of adult metabolic and arthritic disease and suggest that greater attention be given to the association between premature birth and later disease risk.

Introduction: Octamer-binding transcription factor 4 (Oct4) is a master regulator of early mammalian development. Its expression begins from the oocyte stage, becomes restricted to the inner cell mass of the blastocyst and eventually remains only in primordial germ cells. Unearthing the interactions of Oct4 would provide insight into how this transcription factor is central to cell fate and stem cell pluripotency., Methods: In the present study, affinity-tagged endogenous Oct4 cell lines were established via homologous recombination gene targeting in embryonic stem (ES) cells to express tagged Oct4. This allows tagged Oct4 to be expressed without altering the total Oct4 levels from their physiological levels., Results: Modified ES cells remained pluripotent. However, when modified ES cells were tested for their functionality, cells with a large tag failed to produce viable homozygous mice. Use of a smaller tag resulted in mice with normal development, viability and fertility. This indicated that the choice of tags can affect the performance of Oct4. Also, different tags produce a different repertoire of Oct4 interactors., Conclusions: Using a total of four different tags, we found 33 potential Oct4 interactors, of which 30 are novel. In addition to transcriptional regulation, the molecular function associated with these Oct4-associated proteins includes various other catalytic activities, suggesting that, aside from chromosome remodeling and transcriptional regulation, Oct4 function extends more widely to other essential cellular mechanisms. Our findings show that multiple purification approaches are needed to uncover a comprehensive Oct4 protein interaction network.