Fine Detection of Human Motion During Activities of Daily Living as a Clinical Indicator for the Detection and Early Treatment of Chronic Diseases: The E-Mob Project

Methods to measure physical activity and sedentary behaviors typically quantify the amount of time devoted to these activities. Among patients with chronic diseases, these methods can provide interesting behavioral information, but generally do not capture detailed body motion and fine movement behaviors. Fine detection of motion may provide additional information about functional decline that is of clinical interest in chronic diseases. This perspective paper highlights the need for more developed and sophisticated tools to better identify and track the decomposition, structuration, and sequencing of the daily movements of humans. The primary goal is to provide a reliable and useful clinical diagnostic and predictive indicator of the stage and evolution of chronic diseases, in order to prevent related comorbidities and complications among patients.

Age, gender, and residence differences in prevalence and patterns of multimorbidity among older Chinese: Evidence from Chinese Longitudinal Healthy Longevity Survey

Background With the dramatic acceleration of ageing in China, multimorbidity among the older adults has become increasingly common，which are associated with more functional decline and higher health care utilization and mortality. Understanding demographic differences of patterns of multimorbidity is in favor of making targeted intervention strategies. The purpose of this study was to reveal age- specific, gender- specific, and residence- specific prevalence and patterns of multimorbidity among older adults in China. Methods The present analysis is based on the 2018 wave of Chinese Longitudinal Health Longevity Survey (CLHLS). We selected 13 chronic diseases from the CLHLS survey, and information was collected based on self-report. Multimorbidity was defined as the coexistence of two or more chronic diseases from 13 chronic diseases in the same individual. Descriptive statistical analysis was used to examine multimorbidity according to age, sex, and residence. Patterns and trends of chronic disease pairs and multimorbidity were explored using association rule mining. Results 9,660 individuals aged 65-117 years in the CLHLS were analyzed in this study. Overall, 74.4% of all participants had one or more morbidities, and 42.4% were multimorbid. The prevalence of individual chronic diseases ranged from 1.5% for cancer to 41.8% for hypertension, and each disease was often accompanied by one or more other chronic diseases. The prevalence of multimorbidity does not always increase with age. The subgroups with the highest prevalence of multimorbidity was 80-89 years old (48.2%), female (45.0%) and urban (47.2%) group. Prevalence of the hypertension- diabetes pattern decreases with age and is higher in women than in men. The prevalence of hypertension- depression pattern was at the highest among the 90-117 years and rural older adults, while the other groups were hypertension-heart disease. Moreover, it was noteworthy that the multimorbidity rate of dyslipidemia is the highest at 95.5% among the 13 chronic diseases. Conclusions The prevalence of multimorbidity among older Chinese was substantial, and patterns of multimorbidity differed in age, sex, and residence. Future efforts are needed to identify possible prevention strategies and guidelines targeted demographic differences of multimorbid patients to promote health in older adults.

Consecutive-Day Ventricular and Atrial Cardiomyocyte Isolations from the Same Heart: Shifting the Cost–Benefit Balance of Cardiac Primary Cell Research

Freshly isolated primary cardiomyocytes (CM) are indispensable for cardiac research. Experimental CM research is generally incompatible with life of the donor animal, while human heart samples are usually small and scarce. CM isolation from animal hearts, traditionally performed by coronary artery perfusion of enzymes, liberates millions of cells from the heart. However, due to progressive cell remodeling following isolation, freshly isolated primary CM need to be used within 4–8 h post-isolation for most functional assays, meaning that the majority of cells is essentially wasted. In addition, coronary perfusion-based isolation cannot easily be applied to human tissue biopsies, and it does not straightforwardly allow for assessment of regional differences in CM function within the same heart. Here, we provide a method of multi-day CM isolation from one animal heart, yielding calcium-tolerant ventricular and atrial CM. This is based on cell isolation from cardiac tissue slices following repeated (usually overnight) storage of the tissue under conditions that prolong CM viability beyond the day of organ excision by two additional days. The maintenance of cells in their near-native microenvironment slows the otherwise rapid structural and functional decline seen in isolated CM during attempts for prolonged storage or culture. Multi-day slice-based CM isolation increases the amount of useful information gained per animal heart, improving reproducibility and reducing the number of experimental animals required in basic cardiac research. It also opens the doors to novel experimental designs, including exploring same-heart regional differences.

Depressive Symptoms and Malnutrition are Associated with Other Geriatric Syndromes and Increase Risk for 30-Day Readmission in Hospitalized Older Adults: A Prospective Cohort Study

Background: Readmission in older adults is typically complex with multiple contributing factors. We aim to examine how two prevalent and potentially modifiable geriatric conditions – depressive symptoms and malnutrition – relate to other geriatric syndromes and 30-day readmission in hospitalized older adults. Methods: Consecutive admissions of patients >65 years to a general medical department were recruited over 15 months. Patients were screened for depression, malnutrition, delirium, cognitive impairment, and frailty at admission. Medical records were reviewed for intermediary events including poor oral intake and functional decline during hospitalization. Unplanned readmission within 30-days of discharge was tracked through the hospital’s electronic health records and follow-up telephone interviews. We use directed acyclic graphs (DAGs) to depict the relationship of depressive symptoms and malnutrition with geriatric syndromes that constitute covariates of interest and 30-day readmission outcome. Multiple logistic regression was performed for the independent associations of depressive symptoms and malnutrition with 30-day readmission, adjusting for variables based on DAG-identified minimal adjustment set. Results: We recruited 1619 consecutive admissions, with mean age 76.4 (7.9) years and 51.3% females. 30-day readmission occurred in 331 (22.0%) patients. Depressive symptoms (OR 1.55, 95% CI 1.15-2.07), malnutrition (OR 1.59, 95% CI 1.14-2.23), higher comorbidity burden, hospitalization in the one-year preceding index admission, frailty, delirium, as well as functional decline and poor oral intake during the index admission, were more commonly observed among patients who were readmitted within 30 days of discharge (P<0.05). Patients with active depressive symptoms were significantly more likely to be frail (OR=1.62, 95% CI 1.22-2.16), had poor oral intake (OR=1.35, 95% CI 1.02-1.79) and functional decline during admission (OR=1.58, 95% CI 1.11-2.23). Malnutrition at admission was significantly associated with frailty, delirium, cognitive impairment and poor oral intake during hospitalization (P<0.05). In minimal adjustment set identified by DAG, depressive symptoms (OR=1.38, 95% CI 1.02-1.86) remained significantly associated with 30-day readmission. The association of malnutrition with 30-day readmission was attenuated after adjusting for age, ethnicity and depressive symptoms in the minimal adjustment set (OR=1.40, 95% CI 0.99-1.98, P=0.06). Conclusion: The observed causal associations support screening and targeted interventions for depressive symptoms and malnutrition during admission and in the post-acute period.

Metabolic Effects of Doxorubicin on the Rat Liver Assessed With Hyperpolarized MRI and Metabolomics

Doxorubicin (DOX) is a successful chemotherapeutic widely used for the treatment of a range of cancers. However, DOX can have serious side-effects, with cardiotoxicity and hepatotoxicity being the most common events. Oxidative stress and changes in metabolism and bioenergetics are thought to be at the core of these toxicities. We have previously shown in a clinically-relevant rat model that a low DOX dose of 2 mg kg–1 week–1 for 6 weeks does not lead to cardiac functional decline or changes in cardiac carbohydrate metabolism, assessed with hyperpolarized [1-13C]pyruvate magnetic resonance spectroscopy (MRS). We now set out to assess whether there are any signs of liver damage or altered liver metabolism using this subclinical model. We found no increase in plasma alanine aminotransferase (ALT) activity, a measure of liver damage, following DOX treatment in rats at any time point. We also saw no changes in liver carbohydrate metabolism, using hyperpolarized [1-13C]pyruvate MRS. However, using metabolomic analysis of liver metabolite extracts at the final time point, we found an increase in most acyl-carnitine species as well as increases in high energy phosphates, citrate and markers of oxidative stress. This may indicate early signs of steatohepatitis, with increased and decompensated fatty acid uptake and oxidation, leading to oxidative stress.

Age-associated changes in cumulus cells and follicular fluid: The local oocyte microenvironment as a determinant of gamete quality

The ovary is the first organ to age in humans with functional decline evident already in women in their early thirties. Reproductive aging is characterized by a decrease in oocyte quantity and quality which is associated with an increase in infertility, spontaneous abortions, and birth defects. Reproductive aging also has implications for overall health due to decreased endocrinological output. Understanding the mechanisms underlying reproductive aging has significant societal implications as women globally are delaying childbearing and medical interventions have greatly increased the interval between menopause and total lifespan. Age-related changes inherent to the female gamete are well-characterized and include defects in chromosome and mitochondria structure, function, and regulation. More recently, it has been appreciated that the extra-follicular ovarian environment may have important direct or indirect impacts on the developing gamete, and age-dependent changes include increased fibrosis, inflammation, stiffness, and oxidative damage. The cumulus cells and follicular fluid which directly surround the oocyte during its final growth phase within the antral follicle represent additional critical local microenvironments. Here we systematically review the literature and evaluate the studies that investigated the age-related changes in cumulus cells and follicular fluid. Our findings demonstrate unique genetic, epigenetic, transcriptomic, and proteomic changes with associated metabolomic alterations, redox status imbalance, and increased apoptosis in the local oocyte microenvironment. We propose a model of how these changes interact, which may explain the rapid decline in gamete quality with age. We also review the limitations of published studies and highlight future research frontiers.

Developmental deficits and staging of dynamics of age associated Alzheimer’s disease neurodegeneration and neuronal loss in subjects with Down syndrome

The increased life expectancy of individuals with Down syndrome (DS) is associated with increased prevalence of trisomy 21–linked early-onset Alzheimer’s disease (EOAD) and dementia. The aims of this study of 14 brain regions including the entorhinal cortex, hippocampus, basal ganglia, and cerebellum in 33 adults with DS 26–72 years of age were to identify the magnitude of brain region–specific developmental neuronal deficits contributing to intellectual deficits, to apply this baseline to identification of the topography and magnitude of neurodegeneration and neuronal and volume losses caused by EOAD, and to establish age-based staging of the pattern of genetically driven neuropathology in DS. Both DS subject age and stage of dementia, themselves very strongly correlated, were strong predictors of an AD-associated decrease of the number of neurons, considered a major contributor to dementia. The DS cohort was subclassified by age as pre-AD stage, with 26–41-year-old subjects with a full spectrum of developmental deficit but with very limited incipient AD pathology, and 43–49, 51–59, and 61–72-year-old groups with predominant prevalence of mild, moderately severe, and severe dementia respectively. This multiregional study revealed a 28.1% developmental neuronal deficit in DS subjects 26–41 years of age and 11.9% AD-associated neuronal loss in DS subjects 43–49 years of age; a 28.0% maximum neuronal loss at 51–59 years of age; and a 11.0% minimum neuronal loss at 61–72 years of age. A total developmental neuronal deficit of 40.8 million neurons and AD-associated neuronal loss of 41.6 million neurons reflect a comparable magnitude of developmental neuronal deficit contributing to intellectual deficits, and AD-associated neuronal loss contributing to dementia. This highly predictable pattern of pathology indicates that successful treatment of DS subjects in the fourth decade of life may prevent AD pathology and functional decline.

Determinants of trajectories of fatigability and mobility among older medical patients during and after hospitalization; an explorative study

Background Fatigability is an important marker of functional decline in community dwelling older people, yet its relationship with functional decline after hospitalization is unclear. The objectives of this study were to identify trajectories of fatigability and mobility over time and to examine the association between demographic and clinical characteristics and these trajectories in medical patients aged 70 years and older admitted to a Dutch tertiary care teaching hospital. Methods In this prospective cohort study with baseline (in-hospital), discharge, three-, and six-months post discharge follow-up measurements, fatigability was assessed by the physical subscale of the Pittsburgh Fatigability Scale (PFS). Mobility was assessed by the De Morton Mobility Index (DEMMI). Group-based trajectory modeling was used to identify joint trajectories of fatigability and mobility. Covariates included demographic (age, sex, living situation, education) and clinical characteristics (functional status, frailty status, depression, comorbidity, length of hospital stay). Results Among 44 patients, three distinct fatigability trajectories and two mobility trajectories were identified over the course from hospital admission up to six months after discharge. Subsequently, three joint trajectories were identified, including low fatigability and high mobility (11%), improving fatigability and high mobility (52%), and high fatigability and low mobility (36%). Controlling for baseline functional status, patients with a lower comorbidity score (OR: 0.27, 95%CI 0.10; 0.74) and higher frailty status (OR: 1.36, 95%CI: 1.07; 1.74) were more likely to be a member of the high fatigability and low mobility trajectories. Conclusions From hospital admission up to six months after discharge, three distinct trajectories of fatigability and mobility were identified among older medical patients. Our results should be interpreted with caution due to the small sample size, but may inspire other researchers to determine the value of fatigability assessment in identifying older medical patients at risk for developing mobility problems.

Cancer Therapy-Induced Cardiotoxicity—A Metabolic Perspective on Pathogenesis, Diagnosis and Therapy

Long-term cardiovascular complications of cancer therapy are becoming ever more prevalent due to increased numbers of cancer survivors. Cancer therapy-induced cardiotoxicity (CTIC) is an incompletely understood consequence of various chemotherapies, targeted anti-cancer agents and radiation therapy. It is typically detected clinically by a reduction in cardiac left ventricular ejection fraction, assessed by echocardiography. However, once cardiac functional decline is apparent, this indicates irreversible cardiac damage, highlighting a need for the development of diagnostics which can detect CTIC prior to the onset of functional decline. There is increasing evidence to suggest that pathological alterations to cardiac metabolism play a crucial role in the development of CTIC. This review discusses the metabolic alterations and mechanisms which occur in the development of CTIC, with a focus on doxorubicin, trastuzumab, imatinib, ponatinib, sunitinib and radiotherapy. Potential methods to diagnose and predict CTIC prior to functional cardiac decline in the clinic are evaluated, with a view to both biomarker and imaging-based approaches. Finally, the therapeutic potential of therapies which manipulate cardiac metabolism in the context of adjuvant cardioprotection against CTIC is examined. Together, an integrated view of the role of metabolism in pathogenesis, diagnosis and treatment is presented.

Relevance of a Novel Circuit-Level Model of Episodic Memories to Alzheimer’s Disease

The medial temporal lobe memory system has long been identified as the brain region showing the first histopathological changes in early Alzheimer’s disease (AD), and the functional decline observed in patients also points to a loss of function in this brain area. Nonetheless, the exact identity of the neurons and networks that undergo deterioration has not been determined so far. A recent study has identified the entorhinal and hippocampal neural circuits responsible for encoding new episodic memories. Using this novel model we describe the elements of the episodic memory network that are especially vulnerable in early AD. We provide a hypothesis of how reduced reelin signaling within such a network can promote AD-related changes. Establishing novel associations and creating a temporal structure for new episodic memories are both affected in AD. Here, we furnish a reasonable explanation for both of these previous observations.