Medicine (RMH) - Research Publications
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ItemNo Preview AvailableUnresolved inflammation during hospitalization is associated with post-discharge institutionalization and mortality in geriatric rehabilitation inpatients: The RESORT cohort(PERGAMON-ELSEVIER SCIENCE LTD, 2021-12)BACKGROUND: Inflammation contributes to adverse health outcomes in community-dwelling populations. Little is known about inflammation in hospitalized older adults and its association with adverse outcomes. This study aimed to evaluate the association of the inflammatory markers C-reactive protein (CRP) and albumin measured during acute and geriatric rehabilitation hospitalization with institutionalization and mortality in geriatric rehabilitation inpatients. METHODS: Within the REStORing health of acutely unwell adulTs (RESORT) cohort, CRP and albumin were measured as part of usual care during acute and geriatric rehabilitation hospitalization. Inflammatory markers are presented as median, peak (CRP: maximum; albumin: minimum), variation (interquartile range) and direction of change (increased CRP or decreased albumin: positive or negative difference between last measurement and median of preceding measurements). Logistic regression was used to determine the associations between inflammatory markers and institutionalization at three-month and all-cause mortality at three- and twelve-month post-discharge. RESULTS: Geriatric rehabilitation inpatients (n = 1846) with a median age of 83.3 years (interquartile range 77.6-88.3) and 56.6% of female were included. Increased CRP during geriatric rehabilitation was associated with institutionalization. Higher median, peak and increased levels of CRP during geriatric rehabilitation but not during acute hospitalization were associated with higher mortality. Lower CRP variation during acute hospitalization but higher CRP variation during geriatric rehabilitation was associated with higher mortality. Lower median level of albumin during both hospitalizations were associated with higher mortality. CONCLUSIONS: Inflammation characterized by lower albumin during acute hospitalization and, higher CRP and lower albumin during geriatric rehabilitation was associated with mortality in geriatric rehabilitation inpatients. Increased CRP during geriatric rehabilitation was associated with institutionalization. Unresolved inflammation in geriatric rehabilitation might indicate ongoing disease activity leading to adverse outcomes.
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ItemNo Preview AvailableTargeting impaired nutrient sensing with repurposed therapeutics to prevent or treat age-related cognitive decline and dementia: A systematic review(ELSEVIER IRELAND LTD, 2021-05)BACKGROUND: Dementia is a debilitating syndrome that significantly impacts individuals over the age of 65 years. There are currently no disease-modifying treatments for dementia. Impairment of nutrient sensing pathways has been implicated in the pathogenesis of dementia, and may offer a novel treatment approach for dementia. AIMS: This systematic review collates all available evidence for Food and Drug Administration (FDA)-approved therapeutics that modify nutrient sensing in the context of preventing cognitive decline or improving cognition in ageing, mild cognitive impairment (MCI), and dementia populations. METHODS: PubMed, Embase and Web of Science databases were searched using key search terms focusing on available therapeutics such as 'metformin', 'GLP1', 'insulin' and the dementias including 'Alzheimer's disease' and 'Parkinson's disease'. Articles were screened using Covidence systematic review software (Veritas Health Innovation, Melbourne, Australia). The risk of bias was assessed using the Cochrane Risk of Bias tool v 2.0 for human studies and SYRCLE's risk of bias tool for animal studies. RESULTS: Out of 2619 articles, 114 were included describing 31 different 'modulation of nutrient sensing pathway' therapeutics, 13 of which specifically were utilized in human interventional trials for normal ageing or dementia. Growth hormone secretagogues improved cognitive outcomes in human mild cognitive impairment, and potentially normal ageing populations. In animals, all investigated therapeutic classes exhibited some cognitive benefits in dementia models. While the risk of bias was relatively low in human studies, this risk in animal studies was largely unclear. CONCLUSIONS: Modulation of nutrient sensing pathway therapeutics, particularly growth hormone secretagogues, have the potential to improve cognitive outcomes. Overall, there is a clear lack of translation from animal models to human populations.
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ItemAlbumin and C-reactive protein relate to functional and body composition parameters in patients admitted to geriatric rehabilitation after acute hospitalization: findings from the RESORT cohort(SPRINGER, 2022-06)PURPOSE: Albumin and C-reactive protein (CRP) are non-specific markers of inflammation, which could affect muscle tissue during acute hospitalization. We investigated the association between albumin and CRP during acute hospitalization with functional and body composition parameters in patients admitted to geriatric rehabilitation. METHODS: The REStORing Health of Acutely Unwell AdulTs (RESORT) cohort includes geriatric rehabilitation patients assessed for change in activities of daily living (ADL, using the Katz index) during acute hospitalization, and subsequently for Katz ADL, gait speed (GS), handgrip strength (HGS) and skeletal muscle mass index (SMI) at geriatric rehabilitation admission. Albumin and CRP average (median), variation (interquartile range), and maximum or minimum were collected from serum samples, and were examined for their association with functional and body composition parameters using multivariable linear regression analysis adjusted for age, sex and length of acute hospital stay. RESULTS: 1769 Inpatients were included for analyses (mean age 82.6 years ± 8.1, 56% female). Median length of acute hospitalization was 7 [IQR 4, 13] days and median number of albumin and CRP measurements was 5 [IQR 3, 12] times. ADL declined in 89% of patients (median - 3 points, IQR - 4, - 2). Lower average albumin, higher albumin variation and lower minimum albumin were associated with larger declines in ADL and with lower ADL, GS, HGS and SMI at geriatric rehabilitation admission. Higher average and maximum CRP were associated with lower GS. CONCLUSION: Inflammation, especially lower albumin concentrations, during acute hospitalization is associated with lower physical function at geriatric rehabilitation admission.
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ItemNo Preview AvailableSenescence in tissue samples of humans with age-related diseases: A systematic review(ELSEVIER IRELAND LTD, 2021-07)BACKGROUND: Higher numbers of senescent cells have been implicated in age-related disease pathologies. However, whether different diseases have different senescent phenotypes is unknown. Here we provide a systematic overview of the current available evidence of senescent cells in age-related diseases pathologies in humans and the markers currently used to detect senescence levels in humans. METHODS: PubMed, Web of Science and EMBASE were systematically searched from inception to the 29th of September 2019, using keywords related to 'senescence', 'age-related diseases' and 'biopsies'. RESULTS: In total 12,590 articles were retrieved of which 103 articles were included in this review. The role of senescence in age-related disease has been assessed in 9 different human organ system and 27 different age-related diseases of which heart (27/103) and the respiratory systems (18/103) are the most investigated. Overall, 27 different markers of senescence have been used to determine cellular senescence and the cell cycle regulator p16ink4a is most often used (23/27 age-related pathologies). CONCLUSION: This review demonstrates that a higher expression of senescence markers are observed within disease pathologies. However, not all markers to detect senescence have been assessed in all tissue types.
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ItemTrajectories of functional performance recovery after inpatient geriatric rehabilitation: an observational study(WILEY, 2021-08)OBJECTIVE: To identify functional performance trajectories and the characteristics of people who receive inpatient geriatric rehabilitation after hospital admissions. DESIGN, SETTING, PARTICIPANTS: REStORing health of acutely unwell adulTs (RESORT) is an observational, prospective, longitudinal inception cohort study of consecutive patients admitted to geriatric rehabilitation wards at the Royal Melbourne Hospital. Recruitment commenced on 15 October 2017. MAIN OUTCOME MEASURES: Functional performance, assessed with the Activities of Daily Living (ADL) and Instrumental Activities of Daily Living (IADL) scales two weeks before acute hospitalisation, on admission to and discharge from geriatric rehabilitation, and three months after discharge from geriatric rehabilitation. RESULTS: A total of 618 rehabilitation patients were included in our analysis. For each of the two scales, three distinct functional performance trajectories were identified by latent class growth modelling: poor at baseline and 3-month follow-up (remained poor: ADL, 6.6% of patients; IADL, 42%), good at baseline but poor recovery (deteriorated: ADL, 33%; IADL, 20%), and good at baseline and good recovery (recovered: ADL, 60%; IADL, 35%). Higher Clinical Frailty Scale (CFS) score (v recovered, per point: odds ratio [OR], 2.51; 95% CI, 1.64-3.84) and cognitive impairment (OR, 6.33; 95% CI, 2.09-19.1) were associated with greater likelihood of remaining poor in ADL, and also with deterioration (CFS score: OR, 1.76; 95% CI, 1.45-2.13; cognitive impairment: OR, 1.87; 95% CI, 1.24-2.82). Higher CFS score (OR, 1.64; 95% CI, 1.37-1.97) and cognitive impairment (OR, 3.60; 95% CI, 2.31-5.61) were associated with remaining poor in IADL, and higher CFS score was also associated with deterioration (OR, 1.63; 95% CI, 1.33-1.99). CONCLUSIONS: Based on ADL assessments, most people who underwent inpatient geriatric rehabilitation regained their baseline functional performance. As higher CFS score and cognitive impairment were associated with poorer functional recovery, assessing frailty and cognition at hospital admission could assist intervention and discharge planning.
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ItemImmune capacity determines outcome following surgery or trauma: a systematic review and meta-analysis(SPRINGER HEIDELBERG, 2020-10)PURPOSE: Immunological functions are altered following physical injury. The magnitude of the immunological response is dependent on the initial injury. However, variability in the immune response exists within and between patients where only some patients are at risk of developing complications such as systemic inflammatory response syndrome after injury. This systematic review and meta-analysis assessed whether lipopolysaccharide (LPS) induced cytokine production capacity of leucocytes can be used as a functional test to predict the risk of developing complications after injury. METHODS: Medline, Embase and Web of Science were systematically searched to identify articles that investigated the association between LPS induced cytokine production capacity in leucocytes and any clinical outcome after surgery or trauma. Where sufficient information was supplied, a meta-analysis was performed to determine the overall clinical outcomes. RESULTS: A total of 25 articles out of 6765 abstracts identified through the literature search were included in this review. Most articles described a positive association between cytokine production capacity and the development of inflammatory complications (n = 15/25). Coincidingly, the meta-analysis demonstrated that TNFα (Hedges g: 0.63, 95% CI 0.23, 1.03), IL-6 (Hedges g: 0.76, 95% CI 0.41, 1.11) and IL-8 (Hedges g: 0.93, 95% CI 0.46, 1.39) production capacity was significantly higher, one day after injury, in patients who developed inflammatory complications compared to patients who did not following trauma or surgical intervention. No significant difference was observed for IL-1β. CONCLUSION: The associations of elevated LPS-induced cytokine production capacity with the risk of developing inflammatory complications are consistent with previous theories that proposed excessive inflammation is accompanied by anti-inflammatory mechanisms that results in a period of immunosuppression and increased risk of secondary complications. However, immunological biomarkers for risk stratification is still a developing field of research where further investigations and validations are required.
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ItemRepurposing Proteostasis-Modifying Drugs to Prevent or Treat Age-Related Dementia: A Systematic Review(FRONTIERS MEDIA SA, 2018-10-30)Background: Dementia has a significant impact on quality of life of older individuals. Impaired proteostasis has been implicated as a potential cause of dementia, that can be therapeutically targeted to improve patient outcomes. This review aimed to collate all current evidence of the potential for targeting proteostasis with repurposed drugs as an intervention for age-related dementia and cognitive decline. Methods: PubMed, Web of Science and Embase databases were searched from inception until 4th July 2017 for studies published in English. Interventional studies of repurposed proteostasis-modifying drugs in Alzheimer's disease (AD), Parkinson's disease (PD), Lewy Body disease, vascular dementia, and cognitive aging, in either animal models or humans with change in cognition as the outcome were included. The SYRCLE and Cochrane tools were used to assess risk of bias for included studies. Results: Overall 47 trials, 38 animal and 9 human, were isolated for inclusion in this review. Drugs tested in animals and humans included lithium, rapamycin, rifampicin, and tyrosine kinase inhibitors. Drugs tested only in animals included Macrophage and Granulocyte-Macrophage Colony Stimulating Factors, methylene blue, dantrolene, geranylgeranylacetone, minocycline and phenylbutyric acid. Lithium (n = 10 animal, n = 6 human) and rapamycin (n = 12 animal, n = 1 human) were the most studied proteostasis modifying drugs influencing cognition. Nine of ten animal studies of lithium showed a statistically significant benefit in Alzheimer's models. Rapamycin demonstrated a significant benefit in models of vascular dementia, aging, and Alzheimer's, but may not be effective in treating established Alzheimer's pathology. Lithium and nilotinib had positive outcomes in human studies including Alzheimer's and Parkinson's patients respectively, while a human study of rifampicin in Alzheimer's failed to demonstrate benefit. Microdose lithium showed a strongly significant benefit in both animals and humans. While the risk of bias was relatively low in human studies, the risk of bias in animal studies was largely unclear. Conclusion: Overall, the collective findings support the hypothesis that targeting proteostasis for treatment of dementia may be beneficial, and therefore future studies in humans with repurposed proteostasis modifying drugs are warranted. Larger human clinical trials focusing on safety, efficacy, tolerability, and reproducibility are required to translate these therapeutics into clinical practice.
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ItemCellular senescence and chronological age in various human tissues: A systematic review and meta-analysis(WILEY, 2020-02)Senescent cells in tissues and organs are considered to be pivotal to not only the aging process but also the onset of chronic disease. Accumulating evidence from animal experiments indicates that the magnitude of senescence can vary within and between aged tissue samples from the same animal. However, whether this variation in senescence translates across to human tissue samples is unknown. To address this fundamental question, we have conducted a systematic review and meta-analysis of all available literature investigating the magnitude of senescence and its association with chronological age in human tissue samples. While senescence is higher in aged tissue samples, the magnitude of senescence varies considerably depending upon tissue type, tissue section, and marker used to detect senescence. These findings echo animal experiments demonstrating that senescence levels may vary between organs within the same animal.
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ItemPrevalence of sarcopenia in inpatients 70 years and older using different diagnostic criteria(WILEY, 2019-04)AIM: To compare prevalence rates of sarcopenia applying multiple diagnostic criteria in hospitalized older patients. DESIGN: Observational, longitudinal EMPOWER study. METHODS: A total of 378 hospitalized inpatients aged 70 years and older were recruited. Muscle mass and strength were measured using bioelectrical impedance analysis and handheld dynamometer respectively. Nine commonly used diagnostic criteria for sarcopenia were applied. Analyses were stratified for sex. RESULTS: Mean age was 79.7 years (SD 6.43) and 50.8% were males. Depending on the applied criterion, prevalence of sarcopenia ranged between 12.0-75.9% in males and 3.1-75.3% in females. Males had a higher prevalence of sarcopenia compared with females in all but one of the applied diagnostic criteria. In males, highest prevalence of sarcopenia was found using muscle mass as diagnostic criterion while in females this was observed when using muscle strength. Five male and one female hospitalized older patients were sarcopenic according to all applied diagnostic criteria.