Mixtures of opposing phosphorylations within hexamers precisely time feedback in the cyanobacterial circadian clock.

Circadian oscillations are generated by the purified cyanobacterial clock proteins, KaiA, KaiB, and KaiC, through rhythmic interactions that depend on multisite phosphorylation of KaiC. However, the mechanisms that allow these phosphorylation reactions to robustly control the timing of oscillations over a range of protein stoichiometries are not clear. We show that when KaiC hexamers consist of a mixture of differentially phosphorylated subunits, the two phosphorylation sites have opposing effects on the ability of each hexamer to bind to the negative regulator KaiB. We likewise show that the ability of the positive regulator KaiA to act on KaiC depends on the phosphorylation state of the hexamer and that KaiA and KaiB recognize alternative allosteric states of the KaiC ring. Using mathematical models with kinetic parameters taken from experimental data, we find that antagonism of the two KaiC phosphorylation sites generates an ultrasensitive switch in negative feedback strength necessary for stable circadian oscillations over a range of component concentrations. Similar strategies based on opposing modifications may be used to support robustness in other timing systems and in cellular signaling more generally.

Costs of Clock-Environment Misalignment in Individual Cyanobacterial Cells.

Circadian rhythms are endogenously generated daily oscillations in physiology that are found in all kingdoms of life. Experimental studies have shown that the fitness of Synechococcus elongatus, a photosynthetic microorganism, is severely affected in non-24-h environments. However, it has been difficult to study the effects of clock-environment mismatch on cellular physiology because such measurements require a precise determination of both clock state and growth rate in the same cell. Here, we designed a microscopy platform that allows us to expose cyanobacterial cells to pulses of light and dark while quantitatively measuring their growth, division rate, and circadian clock state over many days. Our measurements reveal that decreased fitness can result from a catastrophic growth arrest caused by unexpected darkness in a small subset of cells with incorrect clock times corresponding to the subjective morning. We find that the clock generates rhythms in the instantaneous growth rate of the cell, and that the time of darkness vulnerability coincides with the time of most rapid growth. Thus, the clock mediates a fundamental trade-off between growth and starvation tolerance in cycling environments. By measuring the response of the circadian rhythm to dark pulses of varying lengths, we constrain a mathematical model of a population's fitness under arbitrary light/dark schedules. This model predicts that the circadian clock is only advantageous in highly regular cycling environments with frequencies sufficiently close to the natural frequency of the clock.

SARC-F and modified versions using arm and calf circumference: Diagnostic performance for sarcopenia screening and the impact of obesity.

AIM: SARC-F is limited by low sensitivity for sarcopenia identification. As surrogates of muscle mass, mid-arm circumference (MAC) and/or calf circumference have been proposed as additions to SARC-F to enhance sarcopenia identification. The aim of this study was to evaluate the diagnostic performance of SARC-F, SARC-CalF, SARC-F + MAC, and SARC-CalF + MAC in sarcopenia detection, and to assess the impact of obesity on their diagnostic performance. METHODS: We studied 230 healthy non-frail community-dwelling older adults age >50 years. We performed receiver operating characteristic curve analysis for SARC-F, SARC-CalF, SARC-F + MAC and SARC-CalF + MAC against sarcopenia diagnosed by the Asian Working Group for Sarcopenia (AWGS) 2019 as the reference standard. Obesity was defined by high waist circumference (men ≥90 cm, women ≥80 cm). We performed subgroup analysis to compare between obese and non-obese groups. RESULTS: The prevalence of sarcopenia was 27.0% by AWGS 2019. SARC-CalF + MAC had the best diagnostic performance (area under the curve [AUC] 0.74, 95% confidence interval [CI] 0.67-0.81; sensitivity 66.1%; specificity 69.1%), followed by SARC-CalF (AUC 0.70, 95% CI 0.62-0.78; sensitivity 21.0%; specificity 95.8%). SARC-F (AUC 0.57, 95% CI 0.49-0.66; sensitivity 0%; specificity 100%) performed significantly worsethan its modified versions (P < 0.05). There was higher accuracy of sarcopenia identification in obese compared with non-obese groups for SARC-F + MAC (AUC 0.75, 95% CI 0.65-0.85 vs. 0.58, 95% CI 0.46-0.70) and SARC-CalF + MAC (AUC 0.75, 95% CI 0.66-0.85 vs. 0.70, 95% CI 0.59-0.81). CONCLUSIONS: The addition of arm circumference to SARC-CalF confers better diagnostic accuracy for sarcopenia identification, especially in the obese group. Thus, MAC may complement SARC-CalF for community screening of sarcopenia amongst healthy community-dwelling older adults by increasing sensitivity for the detection of sarcopenic obesity. Geriatr Gerontol Int 2024; 24: 182-188.

Case-Finding for Sarcopenia in Community-Dwelling Older Adults: Comparison of Mini Sarcopenia Risk Assessment with SARC-F and SARC-CalF.

BACKGROUND: We compared the diagnostic performance of the short five-item and full seven-item Mini Sarcopenia Risk Assessment Questionnaire (MSRA-5 and MSRA-7) against the Strength, Assistance walking, Rise from a chair, Climb stairs, and Falls (SARC-F) and SARC-F with calf circumference (SARC-CalF) scales for sarcopenia in healthy community-dwelling older adults. METHODS: We conducted a post-hoc cross-sectional secondary data analysis of a prospective cohort study, using data from 230 older adults (mean age 67.2±7.4 years, 92% Chinese, and 73% female) from the "Longitudinal Assessment of Biomarkers for characterization of early Sarcopenia and Osteosarcopenic Obesity in predicting frailty and functional decline in community-dwelling Asian older adults Study" (GeriLABS-2) conducted between December 2017 and March 2019 in Singapore. We performed receiver operating characteristic curve analysis to ascertain the area under the curve (AUC) for sarcopenia diagnosis using the Asian Working Group for Sarcopenia 2019 consensus criteria. We applied the Delong method to compare the AUCs of the four instruments. RESULTS: The MSRA-5 and MSRA-7 demonstrated poor diagnostic performance (AUC of 0.511, 95% confidence interval [CI] 0.433-0.589 and AUC of 0.526, 95% CI 0.445-0.606, respectively), compared to that in SARC-CalF (AUC of 0.739, 95% CI 0.671-0.808) and SARC-F (AUC of 0.564, 95% CI 0.591-0.636). The SARC-CalF demonstrated significantly superior discriminatory ability compared to that in the SARC-F, MSRA-5, and MSRA-7 (all p<0.01). The MSRA-5 demonstrated lower sensitivity (0.464) and specificity (0.597) than in the SARC-CalF (0.661 and 0.738, respectively), whereas the MSRA-7 had higher specificity (0.887) and lower sensitivity (0.145). CONCLUSION: Conclusions: The poor diagnostic performances of the MSRA-5 and MSRA-7 in our study suggest limitations of self-reported questionnaires for assessing general and dietary risk factors for sarcopenia in healthy and culturally diverse community-dwelling older adults. Studies in different populations are needed to ascertain the utility of the MSRA for the community detection of sarcopenia.

Frailty Screening and Detection of Geriatric Syndromes in Acute Inpatient Care: Impact on Hospital Length of Stay and 30-Day Readmissions.

BACKGROUND: Frailty is prevalent in acute care and is associated with negative outcomes. While a comprehensive geriatric assessment to identify geriatric syndromes is recommended after identifying frailty, more evidence is needed to support this approach in the inpatient setting. This study examined the association between frailty and geriatric syndromes and their impact on outcomes in acutely admitted older adults. METHODS: A total of 733 individuals aged ≥65 years admitted to the General Surgery Service of a tertiary hospital were assessed for frailty using the Clinical Frailty Scale (CFS) and for geriatric syndromes using routine nursing admission assessments, including cognitive impairment, falls, incontinence, malnutrition, and poor oral health. Multinomial logistic regression and Cox regression were used to evaluate the associations between frailty and geriatric syndromes and their concomitant impact on hospital length of stay (LOS) and 30-day readmissions. RESULTS: Greater frailty severity was associated with an increased likelihood of geriatric syndromes. Individuals categorized as CFS 4-6 and CFS 7-8 with concomitant geriatric syndromes had 29% and 35% increased risks of a longer LOS, respectively. CFS 4-6 was significantly associated with functional decline (relative risk ratio =1.46; 95% confidence interval [CI], 1.03-2.07) and 30-day readmission (hazare ratio=1.78; 95% CI, 1.04-3.04), whereas these associations were not significant for CFS 7-8. CONCLUSION: Geriatric syndromes in frail individuals can be identified from routine nursing assessments and represent a potential approach for targeted interventions following frailty identification. Tailored interventions may be necessary to achieve optimal outcomes at different stages of frailty. Further research is required to evaluate interventions for older adults with frailty in a wider hospital context.

Diagnosis and outcomes of cachexia in Asia: Working Consensus Report from the Asian Working Group for Cachexia.

Chronic diseases often lead to metabolic disorders, causing anabolic resistance and increased energy consumption, which result in cachexia. Cachexia, in turn, can lead to major clinical consequences such as impaired quality of life, shortened life expectancy, and increased healthcare expenditure. Existing international diagnostic criteria for cachexia employ thresholds derived from Western populations, which may not apply to Asians due to differing body compositions. To address this issue, the Asian Working Group for Cachexia (AWGC) was initiated. The AWGC comprises experts in cachexia research and clinical practice from various Asian countries and aims to develop a consensus on diagnostic criteria and significant clinical outcomes for cachexia in Asia. The AWGC, composed of experts in cachexia research and clinical practice from several Asian countries, undertook three-round Delphi surveys and five meetings to reach a consensus. Discussions were held on etiological diseases, essential diagnostic items for cachexia, including subjective and objective symptoms and biomarkers, and significant clinical outcomes. The consensus highlighted the importance of multiple diagnostic factors for cachexia, including chronic diseases, either or both weight loss or low body mass index, and at least one of the following: anorexia, decreased grip strength (<28 kg in men and <18 kg in women), or elevated C-reactive protein levels (>5 mg/L [0.5 mg/dL]). The AWGC proposed a significant weight change of 2% or more over a 3-6 month period and suggested a tentative cut-off value of 21 kg/m2 for low body mass index in diagnosing cachexia. Critical clinical outcomes were determined to be mortality, quality of life as assessed by tools such as EQ-5D or the Functional Assessment of Anorexia/Cachexia Therapy, and functional status as measured by the Clinical Frailty Scale or Barthel Index, with significant emphasis on patient-reported outcomes. The AWGC consensus offers a comprehensive definition and user-friendly diagnostic criteria for cachexia, tailored specifically for Asian populations. This consensus is set to stimulate future research and enhance the multidisciplinary approach to managing cachexia. With plans to develop further guidelines for the optimal treatment, prevention, and care of cachexia in Asians, the AWGC criteria are expected to drive research across chronic co-morbidities and cancer in Asia, leading to future refinement of diagnostic criteria.

Differential effects of white matter hyperintensities and regional amyloid deposition on regional cortical thickness.

White matter hyperintensities (WMH) and ß-amyloid (Aß) accumulation have both been linked to neurodegeneration in Alzheimer's disease (AD). However, the independent effects of global WMH and regional Aß on the corresponding regional cortical thickness have not been investigated. Here, we evaluated 280 cognitively normal (CN), 450 mild cognitive impairment (MCI), and 63 individuals with AD dementia separately. In CN individuals, only WMH was associated with lower cortical thickness in fronto-temporal regions, independent of regional Aß deposition in the corresponding cortical regions. In MCI individuals, the spatial pattern of independent WMH associations was predominantly in temporal and cingulate regions, while independent regional Aß associations were now evident in temporal regions. No regional interactions were found. In non-demented individuals and MCI individuals alone, we found that global WMH, composite regional Aß burden and cortical thickness in AD-associated regions all independently predicted progression to AD dementia. Our findings suggest that the independent effects of global WMH and regional Aß on regional cortical thickness are spatially different, converging in temporal regions in MCI individuals.

Self-Reported Frailty Screening Tools: Comparing Construct Validity of the Frailty Phenotype Questionnaire and FRAIL.

OBJECTIVES: We examined the construct validity of 2 self-reported frailty questionnaires, the Frailty Phenotype Questionnaire (FPQ) and FRAIL, against the Cardiovascular Health Study frailty phenotype (CHS-FP). DESIGN: Cross-sectional data analysis of longitudinal prospective cohort study. SETTINGS AND PARTICIPANTS: We included data from 230 older adults (mean age: 67.2 ± 7.4 years) from the "Longitudinal Assessment of Biomarkers for characterization of early Sarcopenia and Osteosarcopenic Obesity in predicting frailty and functional decline in community-dwelling Asian older adults Study" (GeriLABS 2) recruited between December 2017 and March 2019. METHODS: We compared area under receiver operating characteristic curves (AUC), agreement, correlation, and predictive validity against outcome measures [Short Physical Performance Battery, 5 times repeat chair stand (RCS-5), Frenchay activities index, International Physical Activity Questionnaire, life-space assessment, Social Functioning Scale 8 (SFS-8), EuroQol-5 dimensions (utility value)] using logistic regression adjusted for age, gender, and vascular risk factors. We examined concurrent validity across robust versus prefrail/frail for inflammatory blood biomarkers [tumor necrosis factor receptor 1 and C-reactive protein (CRP)] and dual-energy x-ray absorptiometry body composition [bone mineral density (BMD); appendicular lean mass index (ALMI), and fat mass index (FMI)]. RESULTS: Prevalence of prefrail/frail was 25.7%, 14.8%, and 48.3% for FPQ, FRAIL, and CHS-FP, respectively. Compared with FRAIL, FPQ had better diagnostic performance (AUC = 0.617 vs 0.531, P = .002; sensitivity = 37.8% vs 18.0%; specificity = 85.6% vs 88.2%) and agreement (AC1-Stat = 0.303 vs 0.197). FPQ showed good predictive validity [RCS-5: odds ratio (OR) 2.38; 95% CI: 1.17-4.86; International Physical Activity Questionnaire: OR 3.62; 95% CI:1.78-7.34; SFS-8: OR 2.11; 95% CI: 1.64-5.89 vs FRAIL: all P > .05]. Only FRAIL showed concurrent validity for CRP, compared with both FPQ and FRAIL for TNF-R1. FRAIL showed better concurrent validity for BMD, FMI, and possibly ALMI, unlike FPQ (all P > .05). CONCLUSIONS AND IMPLICATIONS: Our results support complementary validity of FPQ and FRAIL in independent community-dwelling older adults. FPQ has increased case detection sensitivity with good predictive validity, whereas FRAIL demonstrates concurrent validity for inflammation and body composition. With better diagnostic performance and validity for blood biomarkers and clinical outcomes, FPQ has utility for early frailty detection in the community setting.

Calf Circumference Measurement Protocols for Sarcopenia Screening: Differences in Agreement, Convergent Validity and Diagnostic Performance.

BACKGROUND: Although recommended by the Asian Working Group for Sarcopenia 2019 consensus (AWGS'19) as a screening tool for sarcopenia, there remains no consensus regarding the position (sitting, standing) or laterality (right, left) for the measurement of calf circumference (CC). This study aimed to determine the agreement between CC measurements, correlations with muscle mass and function, and diagnostic performance for sarcopenia screening. METHODS: We studied 176 healthy community-dwelling older adults (mean age, 66.8±7.1 years) from the GERILABS-2 study. CC was measured using non-elastic tape in four ways: left and right sides in the sitting and standing positions. Sarcopenia was diagnosed using the AWGS'19 criteria. We produced Bland-Altman plots to assess the agreement, partial correlations for muscle mass and function to compare convergent validity, and area under the receiver operating characteristic curve (AUC) to compare diagnostic performance. RESULTS: The prevalence rate of sarcopenia was 17.4%. Sitting CC was larger than standing regardless of laterality (right 35.31±2.95 cm vs. 34.61±2.74 cm; left 35.37±2.96 cm vs. 34.70±2.83 cm; both p<0.001), consistent with the systematic bias on Bland-Altman plots showing the overestimation of sitting over standing measurements (right bias=0.70 cm; 95% confidence interval [CI], -0.48-1.88; left bias=0.67 cm, 95% CI, -0.35-1.68). After adjusting for age and sex, CC was significantly correlated with appendicular skeletal mass, hand grip strength, knee extension, gait speed, chair stand, and short physical performance battery. Although right-sided CC measurements had better diagnostic performance (AUC=0.817), the difference was not statistically significant compared to the other positions (p>0.05). The optimal cutoff was <34 cm for all measurements, except for the left standing position (cutoff <35 cm). CONCLUSION: Standing CC measurements are recommended for sarcopenia screening in community-dwelling older adults because of their good agreement without systematic bias, convergent validity, and diagnostic performance.

Cognitive Assessment by Telemedicine: Reliability and Agreement between Face-to-Face and Remote Videoconference-Based Cognitive Tests in Older Adults Attending a Memory Clinic.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has spurred the rapid adoption of telemedicine. However, the reproducibility of face-to-face (F2F) versus remote videoconference-based cognitive testing remains to be established. We assessed the reliability and agreement between F2F and remote administrations of the Abbreviated Mental Test (AMT), modified version of the Chinese Mini-Mental State Examination (mCMMSE), and Chinese Frontal Assessment Battery (CFAB) in older adults attending a memory clinic. METHODS: The participants underwent F2F followed by remote videoconference-based assessment by the same assessor within 3 weeks. Reliability was evaluated using intraclass correlation coefficients (ICC; two-way mixed, absolute agreement), the mean difference between remote and F2F-based assessments using paired-sample t-tests, and agreement using Bland-Altman plots. RESULTS: Fifty-six subjects (mean age, 76±5.4 years; 74% mild; 19% moderate dementia) completed the AMT and mCMMSE, of which 30 completed the CFAB. Good reliability was noted based on the ICC values-AMT: ICC=0.80, 95% confidence interval [CI] 0.68-0.88; mCMMSE: ICC=0.80, 95% CI 0.63-0.88; CFAB: ICC=0.82, 95% CI 0.66-0.91. However, remote AMT and mCMMSE scores were higher compared to F2F-mean difference (i.e., remote minus F2F): AMT 0.3±1.1, p=0.03; mCMMSE 1.3±2.9, p=0.001. Significant differences were observed in the orientation and recall items of the mCMMSE and the similarities and conflicting instructions of CFAB. Bland-Altman plots indicated wide 95% limits of agreement (AMT -1.9 to 2.6; mCMMSE -4.3 to 6.9; CFAB -3.0 to 3.8), exceeding the a priori-defined levels of error. CONCLUSION: While the remote and F2F cognitive assessments demonstrated good overall reliability, the test scores were higher when performed remotely compared to F2F. The discrepancies in agreement warrant attention to patient selection and environment optimization for the successful adaptation of telemedicine for cognitive assessment.

Validating the Centre of Excellence on Longevity Self-AdMinistered (CESAM) Questionnaire: An Online Self-Reported Tool for Frailty Assessment of Older Adults.

OBJECTIVES: Subjective health measures are often used to assess frailty, but the validity of self-reported online tools to identify frailty remains to be established. We aimed to assess concurrent, known-groups, convergent and predictive validity of the Centre of Excellence on Longevity Self-AdMinistered (CESAM) questionnaire for frailty assessment of older adults in an outpatient setting. DESIGN: Cross-sectional analysis of 120 participants. SETTING AND PARTICIPANTS: Participants of age ≥65 were recruited from an outpatient geriatric clinic. Individuals who had severe neurological, cognitive, or motor deficits were excluded. METHODS: We assessed concurrent validity with area under receiver operating characteristic curve (AUC) against the Frailty Index (FI) and Clinical Frailty Scale (CFS). We analyzed known-groups validity between CESAM scores with frailty status (CFS and FI), Modified Barthel Index (MBI), and modified Chinese Mini-Mental State Examination (mCMMSE) using 1-way analysis of variance. We evaluated convergent validity using correlations with MBI, the Lawton index, mCMMSE, and Geriatric Depression Scale (GDS). Associations between CESAM-identified frailty for clinician-diagnosed geriatric syndromes, and health-related quality of life (HRQoL) was analyzed using regression analysis. RESULTS: The CESAM questionnaire demonstrated excellent diagnostic performance for frailty using FI ≥0.25 (AUC = 0.88; 95% CI: 0.82-0.94; P < .001) and CFS ≥4 (AUC = 0.78; 95% CI: 0.68-0.88; P < .001). CESAM scores increased significantly with increasing frailty (both CFS and FI), lower MBI, and lower mCMMSE scores (all P < .001), indicating concurrent validity. The moderate-good correlation of CESAM scores with MBI (r = -0.61; P < 0.001), Lawton Index (r = -0.54; P < .001), mCMMSE (r = -0.53; P < .001) and GDS (r = 0.58; P < .001) supports convergent validity. Using a cutoff of ≥8 for frailty identification, CESAM-identified frailty was associated with cognitive impairment (OR = 3.7; 95% CI: 1.7-8.2; P = .001) depression (OR = 4.0; 95% CI: 1.7-9.6; P = .002), falls (OR = 3.1; 95% CI: 1.2-8.2; P = .021) and poorer HRQoL (ß = -0.1; 95% CI: -0.2 to -0.02; P = .017). CONCLUSION AND IMPLICATIONS: Our results support the validity of an online self-reported tool to identify frailty and geriatric syndromes in an outpatient setting, an approach that is potentially applicable for remote screening of frailty.

Nutrition Mediates the Relationship between Osteosarcopenia and Frailty: A Pathway Analysis.

Osteosarcopenia is associated with increased risk of adverse outcomes such as falls and fractures. Its association with frailty is less well-described, particularly in independent community-dwelling older adults. Although nutrition plays a crucial role in maintaining bone and muscle health, the complex relationship between osteosarcopenia and nutrition in the pathogenesis of frailty remains to be elucidated. In this cross-sectional analysis of 230 independent, community-dwelling individuals (mean age 67.2 ± 7.4 years), we examined the associations between osteosarcopenia with nutritional status and frailty, and the mediating role of nutrition in the association between osteosarcopenia and frailty. Osteosarcopenia was defined as fulfilling both the Asian Working Group for Sarcopenia 2019 consensus definition (low relative appendicular skeletal muscle mass adjusted for height, in the presence of either of either low handgrip strength or slow gait speed) and T-score ≤ -2.5 SD on bone mineral densitometry. We assessed frailty using the modified Fried criteria and nutrition using the Mini-Nutritional Assessment. We performed multiple linear regression, followed by pathway analysis to ascertain whether nutrition mediates the relationship between osteosarcopenia and frailty. Our study population comprised: 27 (11.7%) osteosarcopenic, 35 (15.2%) sarcopenic, 36 (15.7%) osteoporotic and 132 (57.4%) normal (neither osteosarcopenic, sarcopenic nor osteoporotic). Osteosarcopenia (ß = 1.1, 95% CI 0.86-1.4) and sarcopenia (ß = 1.1, 95% CI 0.90-1.4) were significantly associated with frailty, but not osteoporosis. Nutrition mediated the association between osteosarcopenia and frailty (indirect effect estimate 0.09, bootstrap 95% CI 0.01-0.22). In conclusion, osteosarcopenia is associated with frailty and poorer nutritional status, with nutrition mediating the association between osteosarcopenia and frailty. Our findings support early nutritional assessment and intervention in osteosarcopenia to mitigate the risk of frailty.

The Simplified Nutritional Appetite Questionnaire (SNAQ) as a Screening Tool for Risk of Malnutrition: Optimal Cutoff, Factor Structure, and Validation in Healthy Community-Dwelling Older Adults.

Malnutrition is an independent marker of adverse outcomes in older adults. While the Simplified Nutritional Appetite Questionnaire (SNAQ) for anorexia has been validated as a nutritional screening tool, its optimal cutoff and validity in healthy older adults is unclear. This study aims to determine the optimal cutoff for SNAQ in healthy community-dwelling older adults, and to examine its factor structure and validity. We studied 230 community-dwelling older adults (mean age 67.2 years) who were nonfrail (defined by Fatigue, Resistance, Ambulation, Illnesses & Loss (FRAIL) criteria). When compared against the risk of malnutrition using the Mini Nutritional Assessment (MNA), the optimal cutoff for SNAQ was ≤15 (area under receiver operating characteristic (ROC) curve: 0.706, sensitivity: 69.2%, specificity: 61.3%). Using exploratory factor analysis, we found a two-factor structure (Factor 1: Appetite Perception; Factor 2: Satiety and Intake) which accounted for 61.5% variance. SNAQ showed good convergent, discriminant and concurrent validity. In logistic regression adjusted for age, gender, education and MNA, SNAQ ≤15 was significantly associated with social frailty, unlike SNAQ ≤4 (odds ratio (OR) 1.99, p = 0.025 vs. OR 1.05, p = 0.890). Our study validates a higher cutoff of ≤15 to increase sensitivity of SNAQ for anorexia detection as a marker of malnutrition risk in healthy community-dwelling older adults, and explicates a novel two-factor structure which warrants further research.

Social Frailty Is Independently Associated with Mood, Nutrition, Physical Performance, and Physical Activity: Insights from a Theory-Guided Approach.

Notwithstanding the increasing body of evidence that links social determinants to health outcomes, social frailty is arguably the least explored among the various dimensions of frailty. Using available items from previous studies to derive a social frailty scale as guided by the Bunt social frailty theoretical framework, we aimed to examine the association of social frailty, independently of physical frailty, with salient outcomes of mood, nutrition, physical performance, physical activity, and life-space mobility. We studied 229 community-dwelling older adults (mean age 67.22 years; 72.6% females) who were non-frail (defined by the FRAIL criteria). Using exploratory factor analysis, the resultant 8-item Social Frailty Scale (SFS-8) yielded a three-factor structure comprising social resources, social activities and financial resource, and social need fulfilment (score range: 0-8 points). Social non-frailty (SNF), social pre-frailty (SPF), and social frailty (SF) were defined based on optimal cutoffs, with corresponding prevalence of 63.8%, 28.8%, and 7.4%, respectively. In logistic regression adjusted for significant covariates and physical frailty (Modified Fried criteria), there is an association of SPF with poor physical performance and low physical activity (odds ratio, OR range: 3.10 to 6.22), and SF with depressive symptoms, malnutrition risk, poor physical performance, and low physical activity (OR range: 3.58 to 13.97) compared to SNF. There was no significant association of SPF or SF with life-space mobility. In summary, through a theory-guided approach, our study demonstrates the independent association of social frailty with a comprehensive range of intermediary health outcomes in more robust older adults. A holistic preventative approach to frailty should include upstream interventions that target social frailty to address social gradient and inequalities.

Validating a Standardised Approach in Administration of the Clinical Frailty Scale in Hospitalised Older Adults.

INTRODUCTION: We developed a Clinical Frailty Scale algorithm (CFS-A) to minimise inter-rater variability and to facilitate wider application across clinical settings. We compared the agreement, diagnostic performance and predictive utility of CFS-A against standard CFS. MATERIALS AND METHODS: We retrospectively analysed data of 210 hospitalised older adults (mean age, 89.4 years). Two independent raters assessed frailty using CFS-A. Agreement between CFS-A raters and with previously completed CFS was determined using Cohen's Kappa. Area under receiver operator characteristic curves (AUC) for both measures were compared against the Frailty Index (FI). Independent associations between these measures and adverse outcomes were examined using logistic regression. RESULTS: Frailty prevalence were 81% in CFS and 96% in CFS-A. Inter-rater agreement between CFS-A raters was excellent (kappa 0.90, P <0.001) and there was moderate agreement between CFS-A and standard CFS (kappa 0.42, P <0.001). We found no difference in AUC against FI between CFS (0.91; 95% CI, 0.86-0.95) and CFS-A (0.89; 95% CI, 0.84-0.95; P <0.001). Both CFS (OR, 3.59; 95% CI, 2.28-5.67; P <0.001) and CFS-A (OR, 4.31; 95% CI, 2.41-7.69; P <0.001) were good predictors of mortality at 12 months. Similarly, CFS (OR, 2.59; 95% CI, 1.81-3.69; P <0.001) and CFS-A (OR, 3.58; 95% CI, 2.13-6.02; P <0.001) were also good predictors of institutionalisation and/or mortality after adjusting for age, sex and illness severity. CONCLUSION: Our study corroborated the results on inter-rater reliability, diagnostic performance and predictive validity of CFS-A which has the potential for consistent and efficient administration of CFS in acute care settings.

High protein copy number is required to suppress stochasticity in the cyanobacterial circadian clock.

Circadian clocks generate reliable ~24-h rhythms despite being based on stochastic biochemical reactions. The circadian clock in Synechococcus elongatus uses a post-translational oscillator that cycles deterministically in a test tube. Because the volume of a single bacterial cell is much smaller than a macroscopic reaction, we asked how clocks in single cells function reliably. Here, we show that S. elongatus cells must express many thousands of copies of Kai proteins to effectively suppress timing errors. Stochastic modeling shows that this requirement stems from noise amplification in the post-translational feedback loop that sustains oscillations. The much smaller cyanobacterium Prochlorococcus expresses only hundreds of Kai protein copies and has a simpler, hourglass-like Kai system. We show that this timer strategy can outperform a free-running clock if internal noise is significant. This conclusion has implications for clock evolution and synthetic oscillator design, and it suggests hourglass-like behavior may be widespread in microbes.

Biophysical clocks face a trade-off between internal and external noise resistance.

Many organisms use free running circadian clocks to anticipate the day night cycle. However, others organisms use simple stimulus-response strategies ('hourglass clocks') and it is not clear when such strategies are sufficient or even preferable to free running clocks. Here, we find that free running clocks, such as those found in the cyanobacterium Synechococcus elongatus and humans, can efficiently project out light intensity fluctuations due to weather patterns ('external noise') by exploiting their limit cycle attractor. However, such limit cycles are necessarily vulnerable to 'internal noise'. Hence, at sufficiently high internal noise, point attractor-based 'hourglass' clocks, such as those found in a smaller cyanobacterium with low protein copy number, Prochlorococcus marinus, can outperform free running clocks. By interpolating between these two regimes in a diverse range of oscillators drawn from across biology, we demonstrate biochemical clock architectures that are best suited to different relative strengths of external and internal noise.

IGFBPL1 Regulates Axon Growth through IGF-1-mediated Signaling Cascades.

Activation of axonal growth program is a critical step in successful optic nerve regeneration following injury. Yet the molecular mechanisms that orchestrate this developmental transition are not fully understood. Here we identified a novel regulator, insulin-like growth factor binding protein-like 1 (IGFBPL1), for the growth of retinal ganglion cell (RGC) axons. Expression of IGFBPL1 correlates with RGC axon growth in development, and acute knockdown of IGFBPL1 with shRNA or IGFBPL1 knockout in vivo impaired RGC axon growth. In contrast, administration of IGFBPL1 promoted axon growth. Moreover, IGFBPL1 bound to insulin-like growth factor 1 (IGF-1) and subsequently induced calcium signaling and mammalian target of rapamycin (mTOR) phosphorylation to stimulate axon elongation. Blockage of IGF-1 signaling abolished IGFBPL1-mediated axon growth, and vice versa, IGF-1 required the presence of IGFBPL1 to promote RGC axon growth. These data reveal a novel element in the control of RGC axon growth and suggest an unknown signaling loop in the regulation of the pleiotropic functions of IGF-1. They suggest new therapeutic target for promoting optic nerve and axon regeneration and repair of the central nervous system.