A randomized placebo-controlled trial of nicotinamide riboside in older adults with mild cognitive impairment.

Nicotinamide riboside (NR) increases blood levels of NAD+, a cofactor central to energy metabolism, and improves brain function in some rodent models of neurodegeneration. We conducted a placebo-controlled randomized pilot study with the primary objective of determining safety of NR in older adults with mild cognitive impairment (MCI). Twenty subjects with MCI were randomized to receive placebo or NR using dose escalation to achieve, and maintain, a final dose of 1 g/day over a 10-week study duration. The primary outcome was post-treatment change from baseline measures of cognition (Montreal Cognitive Assessment, MoCA). Predefined secondary outcomes included post-treatment changes in cerebral blood flow (CBF); blood NAD+ levels; and additional neurocognitive, psychometric, and physical performance tests. DNA methylation was assessed in peripheral blood mononuclear cells (PBMCs) as an exploratory outcome. The target NR dose was safely achieved as evidenced by a 2.6-fold increase in blood NAD+ in the NR group (p < 0.001, 95% CI [17.77, 43.49]) with no between-group difference in adverse event reporting. MoCA and other neurocognitive and psychometric metrics remained stable throughout the study. NR reduced CBF in the default mode network (DMN) with greatest differences observed in the left inferior parietal lobe (IPL) (DMN p = 0.013, µ = 0.92, 95% CI [0.23, 1.62]; left IPL p = 0.009, µ = 1.66, 95% CI [0.5, 2.82]). Walking speed in the placebo group significantly improved across the study duration suggestive of a practice effect but did not change in the NR group (p = 0.0402 and p = 0.4698, respectively). Other secondary outcome measures remained stable. Global methylation analyses indicated a modest NR-associated increase in DNA methylation and concomitant reduction in epigenetic age as measured by PhenoAge and GrimAge epigenetic clock analyses. In summary, NR significantly increased blood NAD+ concentrations in older adults with MCI. NR was well tolerated and did not alter cognition. While CBF was reduced by NR treatment, statistical significance would not have withstood multiple comparisons correction. A larger trial of longer duration is needed to determine the potential of NR as a strategy to improve cognition and alter CBF in older adults with MCI. ClinicalTrials.gov NCT02942888.

Inflammatory markers and incident depression: Evidence in a population-based prospective study.

The association between pro-inflammatory cytokines and depression is widely acknowledged. However, longitudinal data that show they lead to depression are few. In a community-based sample of older individuals (n = 2761, ages = 55-98 y) in the Singapore Longitudinal Ageing Study (SLAS), we analyzed the associations between inflammatory markers (CRP, IL6, TNFα, and inflammation risk score) and depression (defined as the presence of depressive symptoms, depression history or treatment). Cross-sectional analysis showed that CRP, IL-6 and TNFα were significantly associated with depression at baseline. Longitudinal analysis controlling for a host of potentially confounding risk factors and initial depression revealed that IL-6, TNFα, and inflammation risk score were associated with elevated risk of depression at follow-ups. However, there was no significant association between CRP and subsequent depression after adjusting for sociodemographic, lifestyles and inflammatory medical condition variables. In summary, this prospective study shows that inflammation predicts depression in older adults, and suggests that the heterogeneous findings among studies may be due to differences in study population characteristics, depression, inflammatory markers, and the extent of adjusting for confounders.

Lifetime pathogen burden, inflammatory markers, and depression in community-dwelling older adults.

The link between pathogen exposure and mental health has long been hypothesized, but evidence remains limited. We investigated the association of seropositivity to common pathogens and total pathogen burden with depression and mental health and explored the role of mediating inflammatory cytokines. We profiled in 884 participants in the Singapore Longitudinal Ageing Studies, mean (SD) age: 67.9 (8.1) years, their seropositivities for 11 pathogens (CMV, HSV 1, HSV 2, HHV-6, EBV, VZV, RSV, Dengue, Chikungunya, H. Pylori and Plasmodium) and pathogen burden, Geriatric Depression Scale (GDS) score at baseline and 3-4 and 6-8 years follow-up, and baseline Mental Component Score (MCS) of 12-Item Short Form Survey (SF-12). Inflammatory markers included CRP, TNF-α, IL-6, MIP-1α, sgp130, sTNF-RI, sTNF-RII, C3a, and MCP-2. Controlling for age, sex, ethnicity, education, marital status, living alone, and smoking status, high pathogen burden (7 + cumulative infections) compared to low pathogen burden (1-5 cumulative infections) was significantly associated with period prevalence (the highest GDS score from baseline and follow-up measurements) of depressive symptoms (OR = 2.36, 95% CI = 1.05-5.33) and impaired mental health (OR = 2.25, 95% CI = 1.18-4.30). CMV seropositivity and HSV1 seropositivity, which are highly prevalent and most widely studied, were associated with estimated 2-fold increased odds of depression, but only HSV1 seropositivity was significantly associated with depression after adjusting for confounders. Notably, adjusted for confounders, RSV, H. pylori and Plasmodium seropositivity were significantly associated with increased odds, and Dengue seropositivity was associated with unexpectedly deceased odds of depressive symptoms and impaired mental health. The association of pathogen exposure with depression and mental health were at least in parts explained by inflammatory markers. Adding certain inflammatory markers to the models attenuated or weakened the association. Bootstrap method showed that MIP-1α significantly mediated the association between pathogen burden and mental health. In conclusion, lifelong pathogen burden and specific infections are associated with depression and impaired mental health in older adults.

Improving bedside dispensing services through early medication discharge planning: a pre-post intervention study.

BACKGROUND: Delays in producing discharge prescriptions have hindered the provision of bedside dispensing services (BEDISC) that enable medication reconciliation and pharmaceutical intervention, which is an important element in transitional care medication safety. We aimed to assess the impact of early medication discharge planning on the delivery of BEDISC in terms of the rate of bedside dispensing, medication errors, and cost-saving from medication reconciliation by reusing patient's own medicines (POMs). METHODS: A pre-post intervention study was conducted at medical wards in a public tertiary hospital. During the intervention phase, a structured bedside dispensing process was delineated and conveyed to the doctors, nurses, and pharmacists. Regular verbal reminders were given to the doctors to prioritize discharge patients by producing the prescriptions once discharge decisions had been made and nurses to hand the prescriptions to ward pharmacists and not patients. Throughout the study, ward pharmacists were involved in medication reconciliation via screening of discharge prescriptions and reusing POMs, performed pharmaceutical interventions for any medication errors detected, and provided bedside dispensing with discharge counseling. Comparisons were made between bedside versus counter-dispensing at pre-post intervention phases using the chi-square test. RESULTS: A total of 1097 and 817 discharge prescriptions were dispensed in the pre-intervention and post-intervention phases, respectively. The bedside dispensing rate increased by 13.5% following remedial actions (p < 0.001). The number of prescriptions intervened due to detection of medication errors increased by 13.4% for bedside dispensing (p < 0.001) versus 4.7% for counter-dispensing (p = 0.002), post-intervention. Most medication errors fell under the category of inappropriate drug (44.5%), followed by inappropriate dose (12.8%). Reusing POMs resulted in cost-saving of MYR6,851.66 at pre-intervention and MYR7,032.98 at the post-intervention phase. Overall, the cost-saving from reusing POMs in both intervention phases was 52.7% (MYR13,884.64 out of the total MYR26.367.47), with the majority contributed by respiratory medications (40.2%) followed by cardiovascular (18%) and vitamins/minerals (17.5%). CONCLUSION: Pharmacist-coordinated early medication discharge planning has improved the delivery of bedside dispensing services, enhanced medication safety, and reduced medication costs.

Physiological Dysregulation, Frailty, and Impacts on Adverse Health and Functional Outcomes.

Background: Multi-system physiological dysregulation (PD) may represent a biological endo-phenotype of clinical frailty. We investigated the co-occurrence of PD with physical frailty and its contributions to the known impact of frailty on adverse health outcomes. Methods: Data of 2,725 participants from the Singapore Longitudinal Aging Studies (SLAS-2), included baseline measures of physical frailty and PD derived from Mahalanobis distance (Dm) value of 23 blood biomarkers. We analyzed their concurrent association and their impacts on 9-year mortality, MMSE cognition, GDS depression, number of medications, disability, and hospitalization at baseline and follow up (mean 4.5 years). Results: Global PD (Log10Dm, mean = 1.24, SD = 0.24) was significantly but weakly associated with pre-frailty-and-frailty. Controlling for age, sex and education, pre-frailty-and-frailty (HR = 2.12, 95% CI = 1.51-3.00) and PD (HR = 3.88, 95% CI = 2.15-6.98) predicted mortality. Together in the same model, mortality HR associated with pre-frailty-and-frailty (HR = 1.83, 95% CI = 1.22-2.73) and PD (HR = 3.06, 95% CI = 1.60-5.85) were reduced after additionally adding global PD to the prediction model. The predictive accuracy for mortality were both approximately the same (PD: AUC = 0.62, frailty: AUC = 0.64), but AUC was significantly increased to 0.68 when combined (p < 0.001). Taken into account in the same model, frailty remained significantly associated with all health and functional outcomes, and PD was significantly associated with only MMSE, disability and medications used. In secondary analyses, there were mixed associations of system-specific PDs with frailty and different adverse outcomes. Conclusions: Co-existing PD and physical frailty independently predict mortality and functional and health outcomes, with increased predictive accuracy when combined. PD appears to be a valid representation of a biological endo-phenotype of frailty, and the potential utility of such subclinical measures of frailty could be further studied.

Endoplasmic reticulum stress response and bile acid signatures associate with multi-strain seroresponsiveness during elderly influenza vaccination.

The elderly are an important target for influenza vaccination, and the determination of factors that underlie immune responsiveness is clinically valuable. We evaluated the immune and metabolic profiles of 205 elderly Singaporeans administered with Vaxigrip. Despite high seroprotection rates, we observed heterogeneity in the response. We stratified the cohort into complete (CR) or incomplete responders (IR), where IR exhibited signs of accelerated T cell aging. We found a higher upregulation of genes associated with the B-cell endoplasmic-reticulum stress response in CR, where XBP-1 acts as a key upstream regulator. B-cells from IR were incapable of matching the level of XBP-1 upregulation observed in CR after inducing ER stress with tunicamycin in vitro. Metabolic signatures also distinguished CR and IR - as CR presented with a greater diversity of bile acids. Our findings suggest that the ER-stress pathway activation could improve influenza vaccination in the elderly.

Hyperactivation of monocytes and macrophages in MCI patients contributes to the progression of Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is the most common neurodegenerative disease ultimately manifesting as clinical dementia. Despite considerable effort and ample experimental data, the role of neuroinflammation related to systemic inflammation is still unsettled. While the implication of microglia is well recognized, the exact contribution of peripheral monocytes/macrophages is still largely unknown, especially concerning their role in the various stages of AD. OBJECTIVES: AD develops over decades and its clinical manifestation is preceded by subjective memory complaints (SMC) and mild cognitive impairment (MCI); thus, the question arises how the peripheral innate immune response changes with the progression of the disease. Therefore, to further investigate the roles of monocytes/macrophages in the progression of AD we assessed their phenotypes and functions in patients at SMC, MCI and AD stages and compared them with cognitively healthy controls. We also conceptualised an idealised mathematical model to explain the functionality of monocytes/macrophages along the progression of the disease. RESULTS: We show that there are distinct phenotypic and functional changes in monocyte and macrophage populations as the disease progresses. Higher free radical production upon stimulation could already be observed for the monocytes of SMC patients. The most striking results show that activation of peripheral monocytes (hyperactivation) is the strongest in the MCI group, at the prodromal stage of the disease. Monocytes exhibit significantly increased chemotaxis, free radical production, and cytokine production in response to TLR2 and TLR4 stimulation. CONCLUSION: Our data suggest that the peripheral innate immune system is activated during the progression from SMC through MCI to AD, with the highest levels of activation being in MCI subjects and the lowest in AD patients. Some of these parameters may be used as biomarkers, but more holistic immune studies are needed to find the best period of the disease for clinical intervention.

Effects of multi-domain lifestyle interventions on sarcopenia measures and blood biomarkers: secondary analysis of a randomized controlled trial of community-dwelling pre-frail and frail older adults.

Few studies have comprehensively described changes in blood biomarkers of the physiological responses underlying sarcopenia reduction associated with lifestyle interventions. In this study, we performed secondary analyses of data in a randomized controlled trial of multi-domain lifestyle interventions (6-month duration physical exercise, nutritional enrichment, cognitive training, combination and standard care control) among 246 community-dwelling pre-frail and frail elderly, aged ≥65 years, with and without sarcopenia. Appendicular lean mass (ALM), lower limb strength, gait speed, and blood levels of markers of muscle metabolism, inflammation, anti-oxidation, anabolic hormone regulation, insulin signaling, tissue oxygenation were measured at baseline, 3-month and 6-month post-intervention. Multi-domain interventions were associated with significant (p < 0.001) reduction of sarcopenia at 3-month and 6-month post-intervention, improved gait speed, enhanced lower limb strength, and were equally evident among sarcopenic participants who were slower at baseline than non-sarcopenic participants. Active intervention was associated with significantly reduced inflammation levels. Sarcopenia status and reduction were associated with blood biomarkers related to muscle metabolism, steroid hormone regulation, insulin-leptin signaling, and tissue oxygenation. Physical, nutritional and cognitive intervention was associated with measures of sarcopenia reduction, together with changes in circulating biomarkers of anabolic and catabolic metabolism underlying sarcopenia.

Pathogen Burden, Blood Biomarkers, and Functional Aging in Community-Dwelling Older Adults.

BACKGROUND: Lifelong accumulation of latent or persistent or repeated infections may be a contributing factor to the deterioration of physical and cognitive function associated with functional aging, but the evidence is limited and the biological underpinnings are unclear. METHODS: We profiled the seropositivity for common viral, bacterial, and plasmodial pathogens of local importance in community-living older adults in 2 studies involving 745 older adults (mean age 67.0, SD: 7.7 years), and 142 older adults (mean age 72.7, SD: 8.3 years). Pathogen load was related to different sets of age-related physical and cognitive measures of functional aging and the Frailty Index (FI), and plasma levels of biomarkers of inflammation, innate and adaptive immunity, and other physiological functions. RESULTS: High pathogen load was associated with impaired gait speed (GS; p < .015), functional mobility (performance-oriented mobility assessment [POMA]; p < .029), cognitive function (Mini-Mental State Examination [MMSE]; p < .05), and increased FI; p < .05). High pathogen load was significantly associated with C3a complement activity (p < .001), matrix metalloproteinase-7, macrophage inflammatory protein-1α (p < .05), and monocyte chemoattractant protein 2 (p = .028). Blood biomarkers did not fully explain the observed association between pathogen load and functional aging measures. CONCLUSIONS: This study provides novel evidence linking lifelong cumulated numbers of latent, persistent, or repeated infection to functional aging, plausibly via inflammatory and immune and other biological factors.

Horticultural Therapy Reduces Biomarkers of Immunosenescence and Inflammaging in Community-Dwelling Older Adults: A Feasibility Pilot Randomized Controlled Trial.

BACKGROUND: With the challenges that aging populations pose to health care, interventions that facilitate alleviation of age-related morbidities are imperative. A prominent risk factor for developing age-related morbidities is immunosenescence, characterized by increased chronic low-grade inflammation, resulting in T-cell exhaustion and senescence. Contact with nature and associated physical activities have been shown to boost immunity in older adults and may be promoted in the form of horticultural therapy (HT). We aimed to examine the effects of HT on immunosenescence. METHOD: We conducted a randomized controlled trial with 59 older adults assigned to either the HT intervention or waitlist control group. Older adults in the HT intervention group underwent HT intervention program over 6 months. Venous blood was drawn at baseline and at the third and sixth month from the commencement of this study. For participants who attended all 3 blood collection time points (HT: n = 22; waitlist: n = 24), flow cytometry analysis was performed on whole blood samples to evaluate the kinetics of lymphocyte subsets over the intervention period, revealing the composition of CD4+ and CD8+ subsets expressing exhaustion markers-CD57, CTLA4, and KLRG1. Enzyme-linked immunosorbent assays were employed to measure changes in plasma IL-6 levels. RESULTS: HT is associated with increased numbers of naive CD8+ T cells and fewer CTLA4-expressing terminally differentiated effector CD4+ and CD8+ memory T cells re-expressing CD45RA (TEMRA). Furthermore, IL-6 levels were reduced during HT, and the frequencies of naive and TEMRA CD8+ T cells were found to be associated with IL-6 levels. CONCLUSION: HT is associated with a reduction in the levels of biomarkers that measure the extent of T-cell exhaustion and inflammaging in older adults. The positive effects of HT on T-cell exhaustion were associated with the reduction of IL-6 levels.

Effects of choral singing versus health education on cognitive decline and aging: a randomized controlled trial.

We conducted a randomized controlled trial to examine choral singing's effect on cognitive decline in aging. Older Singaporeans who were at high risk of future dementia were recruited: 47 were assigned to choral singing intervention (CSI) and 46 were assigned to health education program (HEP). Participants attended weekly one-hour choral singing or weekly one-hour health education for two years. Change in cognitive function was measured by a composite cognitive test score (CCTS) derived from raw scores of neuropsychological tests; biomarkers included brain magnetic resonance imaging, oxidative damage and immunosenescence. The average age of the participants were 70 years and 73/93 (78.5%) were female. The change of CCTS from baseline to 24 months was 0.05 among participants in the CSI group and -0.1 among participants in the HEP group. The between-group difference (0.15, p=0.042) became smaller (0.12, p=0.09) after adjusting for baseline CCTS. No between-group differences on biomarkers were observed. Our data support the role of choral singing in improving cognitive health in aging. The beneficial effect is at least comparable than that of health education in preventing cognitive decline in a community of elderly people. Biological mechanisms underlying the observed efficacy should be further studied.

Pathogenic load and frailty in older adults: Singapore longitudinal ageing study.

Human evidence for the role of continuous antigenic stimulation from persistent latent infections in frailty is limited. We conducted a nested case-control study (99 deceased and 43 survivors) of participants aged 55 and above in a longitudinal ageing cohort followed up from 2003 to 2017. Using blood samples and baseline data collected in 2003-2004, we examined the association of pathogenic load (PL) count of seropositivity to 10 microbes (viruses, bacteria and mycoplasma) with cumulated deficit-frailty index (CD-FI) and the physical frailty (PF) phenotype, and mortality. Controlling for age, sex, education, smoking and alcohol histories, high PL (7-9) versus low PL (3-6) was associated with an estimated increase of 0.035 points in the CD-FI (Cohen's D=0.035 / 0.086, or 0.41). High PL was associated with 8.5 times odds of being physically frail (p=0.001), 2.8 times odds of being weak (p=0.010), 3.4 times odds of being slow (p=0.024), and mortality hazard ratio of 1.53 (p=0.046). There were no significant associations for specific pathogens, except marginal associations for Epstein-Barr virus and Chikungunya. Conclusion: A high pathogenic load of latent infections was associated with increased risks of frailty and mortality.

Mindfulness improves inflammatory biomarker levels in older adults with mild cognitive impairment: a randomized controlled trial.

Few randomized controlled trials investigated the effects of mindfulness intervention on older adults diagnosed with mild cognitive impairment (MCI). Furthermore, there have been hypotheses and theoretical mechanisms on the benefits of mindfulness intervention on biomarkers of stress, inflammation, and neuroplasticity implicated in MCI that warrant empirical evidence. We conducted a pilot randomized controlled trial to examine whether Mindful Awareness Practice (MAP) improved biomarker levels in older adults with MCI. Fifty-five community-dwelling older adults aged 60 and above were randomized into either the treatment arm, MAP, or the active control arm, the health education program (HEP). Researchers who were blinded to treatment allocation assessed the outcomes at baseline, 3-month, and 9-month follow-ups. Linear-mixed models were used to examine the effect of MAP on biomarker levels. MAP participants had significantly decreased high-sensitivity c-reactive protein (hs-CRP) levels at 9-month (ß = -0.307, 95% CI = -0.559 to -0.054 P = 0.018). Exploratory sub-group analyses by sex showed significantly decreased hs-CRP in females only (ß = -0.445, 95% CI = -0.700 to -0.189, P = 0.001), while stratification by MCI subtype showed hs-CRP decreased only in amnestic-MCI (aMCI) (ß = -0.569, 95% CI = -1.000 to -0.133, P = 0.012). Although total sample analyses were not significant, males had significantly decreased interleukin (IL)-6 (ß = -1.001, 95% CI = -1.761 to -0253, P = 0.011) and IL-1ß (ß = -0.607, 95% CI = -1.116 to -0.100, P = 0.021) levels at 3-month and non-significant improvements at 9-month time-point. MAP improved inflammatory biomarkers in sex- and MCI subtype-specific manners. These preliminary findings suggest the potential of mindfulness intervention as a self-directed and low-cost preventive intervention in improving pathophysiology implicated in MCI.

Immunological history governs human stem cell memory CD4 heterogeneity via the Wnt signaling pathway.

The diversity of the naïve T cell repertoire drives the replenishment potential and capacity of memory T cells to respond to immune challenges. Attrition of the immune system is associated with an increased prevalence of pathologies in aged individuals, but whether stem cell memory T lymphocytes (TSCM) contribute to such attrition is still unclear. Using single cells RNA sequencing and high-dimensional flow cytometry, we demonstrate that TSCM heterogeneity results from differential engagement of Wnt signaling. In humans, aging is associated with the coupled loss of Wnt/ß-catenin signature in CD4 TSCM and systemic increase in the levels of Dickkopf-related protein 1, a natural inhibitor of the Wnt/ß-catenin pathway. Functional assays support recent thymic emigrants as the precursors of CD4 TSCM. Our data thus hint that reversing TSCM defects by metabolic targeting of the Wnt/ß-catenin pathway may be a viable approach to restore and preserve immune homeostasis in the context of immunological history.

Systemic and Metabolic Signature of Sarcopenia in Community-Dwelling Older Adults.

BACKGROUND: Evidence suggests the pivotal contribution of nutrition as a modifiable risk factor for sarcopenia. The present cross-sectional study characterized the nutritional and metabolic profile of sarcopenia through an extensive exploration of a wide array of blood biomarkers related to muscle protein metabolism and transcriptomic signatures in community-dwelling elderly adults. METHODS: Among 189 older individuals with a mean age of 73.2 years, sarcopenia was diagnosed according to the Asian Working Group for Sarcopenia criteria based on appendicular lean mass measured by dual-energy X-ray absorptiometry scan, muscle strength, and gait speed. Nutritional status was evaluated using the mini-nutritional assessment (MNA). In addition, we assessed specific blood biomarkers of nutritional status (plasma essential amino acids [EAAs], vitamins), nicotine-derived metabolites, and an extensive microarray analysis from peripheral blood mononuclear cells. RESULTS: Malnutrition defined by low MNA score was independently associated with sarcopenia (p < .001). Sarcopenic elderly showed lower body mass index and leptin and higher adiponectin and high-density lipoproteins. Levels of EAAs including lysine, methionine, phenylalanine, threonine, as well as branched-chain AAs and choline, were inversely associated with sarcopenia. Furthermore, nicotine metabolites (cotinine and trans-3'-hydroxycotine) and vitamin B6 status were linked to one or more clinical and functional measures of sarcopenia. Differentially expressed genes and ingenuity pathway analysis supported the association of nutrition with sarcopenia. CONCLUSIONS: Herein, the characterization of a nutritional and metabolic signature of sarcopenia provides a firm basis and potential identification of specific targets and directions for the nutritional approach to the prevention and treatment of sarcopenia in aging populations.

Assessment of Sarcopenia Among Community-Dwelling At-Risk Frail Adults Aged 65 Years and Older Who Received Multidomain Lifestyle Interventions: A Secondary Analysis of a Randomized Clinical Trial.

Importance: There is little understanding of the outcomes associated with active lifestyle interventions for sarcopenia among older persons. Objective: To determine the association of 6-month multidomain lifestyle interventions (physical exercise, nutritional enhancement, cognitive training, combined treatment, and standard care) with change in sarcopenia status and physical function among adults 65 years and older. Design, Setting, and Participants: Post hoc secondary analysis of a parallel-group randomized clinical trial conducted from September 1, 2012, to September 1, 2014, at community centers providing services to elderly individuals in Singapore. Participants included a subsample of 92 community-dwelling prefrail or frail older persons with sarcopenia aged 65 years and older. Data were analyzed from June 1, 2017, to January 1, 2018. Interventions: The 5 intervention groups were a 6-month duration of physical exercise that included resistance and balance training, nutritional enhancement with a commercial oral nutrition supplement formula, cognitive training, a combination of the preceding 3 interventions, and standard care (control). Main Outcomes and Measures: Primary outcomes were changes in sarcopenia status and its components, appendicular skeletal muscle index (ASMI), knee extension strength (KES), and gait speed (GS) at 3 months and 6 months following the intervention. Sarcopenia was defined as the presence of both low ASMI and low KES and/or GS. Results: In 92 participants with sarcopenia, the mean (SD) age was 70.0 (4.7) years and 59 (64.1%) were female. Seventy-eight participants received active interventions and 14 received standard care. Of 92 total participants, the number who remained sarcopenic was reduced to 48 (of 73) after 3 months and 51 (of 75) after 6 months of intervention, indicating that 25 of 92 participants (27.2%) experienced sarcopenia reduction at 3 months and 24 of 92 (26.1%) had sarcopenia reduction at 6 months. Low KES was present in 88 of 92 patients (95.6%), and low GS in 30 of 92 patients (32.6%) at baseline. Among the components of sarcopenia, GS had the greatest change associated with active interventions, with 22 of 30 participants (73.3%) free of low GS at 6 months; in comparison, 17 of 88 participants (19.3%) were free of low KES at 6 months and 7 of 92 participants (7.6%) were free of low ASMI at 6 months. Men experienced greater reduction in sarcopenia than women (χ2 = 5.925; P = .02), as did those with younger age (t = -2.078; P = .04) or higher ASMI (mean [SD] ASMI, 5.74 [0.77] vs 5.14 [0.77] kg/m2; P = .002). Participants in the active intervention group experienced statistically significant decreases in sarcopenia score and its components at 3 months and 6 months from baseline (F = 14.138; P < .001), but the intervention was not associated with significant differences in ASMI, KES, and GS vs standard care. Conclusions and Relevance: This study suggests that older persons with sarcopenia are responsive to the effects of multidomain lifestyle interventions. Sarcopenia reduction was most pronounced through improved gait speed, and occurred more among those who were male, were younger, or had greater muscle mass.

Recurrent circadian fasting (RCF) improves blood pressure, biomarkers of cardiometabolic risk and regulates inflammation in men.

BACKGROUND: The effects of fasting on health in non-human models have been widely publicised for a long time and emerging evidence support the idea that these effects can be applicable to human practice. METHODS: In an open label longitudinal follow-up, a cohort of 78 adult men (aged 20 to 85 years) who fasted for 29 consecutive days from sunrise to sunset (16 h fasting-referred to as recurrent circadian fasting) in Pakistan, were studied. The primary outcomes of the fasting study was weight loss/recovery and the associated changes in blood pressure and circulating levels of surrogate markers linked to organ and system functions-including cardiovascular, metabolic and inflammation. Post-fasting outcomes include the regulation of physiological biomarkers. RESULTS: Recurrent circadian fasting with weight loss reduced blood pressure (140.6 vs. 124.2 mmHg) and markers of cardiovascular risk (~ 4-fold for resistin; triglycerides: p < 0.0001). Reduced glycemia (p < 0.0001) and the associated changes in the regulation of ketosis (ß-hydroxybutyrate) were accompanied by a metabolic shift (PPARß, osteoprotegerin), suggesting the involvement of the different physiological systems tested. Elevated orexin-A levels (p = 0.0183) in participants indicate sleep disturbance and circadian adaptation. All participants had CRP level < 2 mg/l during the fasting period and a similar trend was observed for TNFα. While most SASP molecules were decreased after the fasting period, heightened levels of IL-8 and IL-6 suggest that some inflammatory markers may be elevated by recurrent circadian fasting. Importantly, older adults reveal similar or more substantial benefits from fasting. CONCLUSIONS: Recurrent circadian fasting is beneficial at the cardiometabolic and inflammatory levels, especially for at-risk individuals-this is contingent on compliance towards the recommended dietary behaviour, which controls carbohydrate and caloric intake. These benefits from fasting may be particularly beneficial to older adults as they often exhibit abnormal cardiovascular, metabolic and inflammatory signatures.

Anesthesia Workspace Cleanliness and Safety: Implementation of a Novel Syringe Bracket Using 3D Printing Techniques.

PURPOSE: Wide variability persists in the preparation and storage of common anesthetic medications despite the recognition of anesthesia workspace standardization as a national quality improvement priority. Syringe contamination and medication swaps continue to pose significant hazards to patient safety. METHODS: We assessed differences in practice related to the availability of commonly prepared anesthetic medications. Using baseline provider surveys (n = 87) and anesthesia workspace audits (n = 80), we designed a custom syringe organization device using 3D printing techniques to serve as a cognitive aid and organizational tool. We iteratively tested and then deployed this device in all 60 operating rooms at a single institution, and then, repeated postintervention surveys (n = 79) and workspace audits (n = 75) one year after introduction. RESULTS: Implementation was associated with significant improvements in provider-reported medication availability during coverage and handoff situations (43.7% versus 76.2% reporting 95% confidence preintervention versus postintervention, p < 0.001). This was substantiated by audits of the anesthesia workspace which demonstrated reduced variability in the location (p < 0.001) and availability (p < 0.001) of key medications. Provider confidence in the cleanliness of syringes was also improved (p=0.01). A high degree of acceptance and compliance with the intervention was reported, with 80.4% of syringes observed to be stored in the device one year after implementation and approximately 95% of respondents reporting positive measures of usability and convenience. CONCLUSION: Use of a simple organizational device for syringes in the anesthesia workspace has numerous safety benefits. 3D printing offers improvements in adaptability and affordability compared with prior approaches.

Metformin Monotherapy Downregulates Diabetes-Associated Inflammatory Status and Impacts on Mortality.

Aging is the main risk factor for developing diabetes and other age-related diseases. One of the most common features of age-related comorbidities is the presence of low-grade chronic inflammation. This is also the case of metabolic syndrome and diabetes. At the subclinical level, a pro-inflammatory phenotype was shown to be associated with Type-2 diabetes mellitus (T2DM). This low to mid-grade inflammation is also present in elderly individuals and has been termed inflammaging. Whether inflammation is a component of aging or exclusively associated with age-related diseases in not entirely known. We used clinical data and biological readouts in a group of individuals stratified by age, diabetes status and comorbidities to investigate this aspect. While aging is the main predisposing factor for several diseases there is a concomitant increased level of pro-inflammatory cytokines. DM patients show an increased level of sTNFRll, sICAM-1, and TIMP-1 when compared to Healthy, Non-DM and Pre-DM individuals. These inflammatory molecules are also associated with insulin resistance and metabolic syndrome in Non-DM and pre-DM individuals. We also show that metformin monotherapy was associated with significantly lower levels of inflammatory molecules, like TNFα, sTNFRI, and sTNFRII, when compared to other monotherapies. Longitudinal follow up indicates a higher proportion of death occurs in individuals taking other monotherapies compared to metformin monotherapy. Together our finding shows that chronic inflammation is present in healthy elderly individuals and exacerbated with diabetes patients. Likewise, metformin could help target age-related chronic inflammation in general, and reduce the predisposition to comorbidities and mortality.

Identification of inflammatory and vascular markers associated with mild cognitive impairment.

Biochemical processes have been associated with the pathogenesis of mild cognitive impairment (MCI) and dementia, including chronic inflammation, dysregulation of membrane lipids and disruption of neurotransmitter pathways. However, research investigating biomarkers of these processes in MCI remained sparse and inconsistent. To collect fresh evidence, we evaluated the performance of several potential markers in a cohort of 57 MCI patients and 57 cognitively healthy controls. MCI patients showed obviously increased levels of plasma TNF-α (p = 0.045) and C-peptide (p = 0.004) as well as decreased levels of VEGF-A (p = 0.042) and PAI-1 (p = 0.019), compared with controls. In addition, our study detected significant correlations of plasma sTNFR-1 (MCI + Control: B = -6.529, p = 0.020; MCI: B = -9.865, p = 0.011) and sIL-2Rα (MCI + Control: B = -7.010, p = 0.007; MCI: B = -11.834, p = 0.003) levels with MoCA scores in the whole cohort and the MCI group. These findings corroborate the inflammatory and vascular hypothesis for dementia. Future studies are warranted to determine their potential as early biomarkers for cognitive deficits and explore the related mechanisms.