Cardiac sympathetic innervation and mortality risk scores in patients with heart failure.

INTRODUCTION: In the risk stratification and selection of patients with heart failure (HF) eligible for implantable cardioverter-defibrillator (ICD) therapy, 123 I-meta-IodineBenzylGuanidine (123 I-mIBG) scintigraphy has emerged as an effective non-invasive method to assess cardiac adrenergic innervation. Similarly, clinical risk scores have been proposed to identify patients with HF at risk of all-cause mortality, for whom the net clinical benefit of device implantation would presumably be lower. Nevertheless, the association between the two classes of tools, one suggestive of arrhythmic risk, the other of all-cause mortality, needs further investigation. OBJECTIVE: To test the relationship between the risk scores for predicting mortality and cardiac sympathetic innervation, assessed through myocardial 123 I-mIBG imaging, in a population of patients with HF. METHODS: In HF patients undergoing 123 I-mIBG scintigraphy, eight risk stratification models were assessed: AAACC, FADES, MADIT, MADIT-ICD non-arrhythmic mortality score, PACE, Parkash, SHOCKED and Sjoblom. Cardiac adrenergic impairment was assessed by late heart-to-mediastinum ratio (H/M) <1.6. RESULTS: Among 269 patients suffering from HF, late H/M showed significant negative correlation with all the predicting models, although generally weak, ranging from -0.15 (p = .013) for PACE to -0.32 (p < .001) for FADES. The scores showed poor discrimination for cardiac innervation, with areas under the curve (AUC) ranging from 0.546 for Parkash to 0.621 for FADES. CONCLUSION: A weak association emerged among mortality risk scores and cardiac innervation, suggesting to integrate in clinical practice tools indicative of both arrhythmic and general mortality risks, when evaluating patients affected by HF eligible for device implantation.

Frailty and hyperactive delirium in hospitalized older patients with COVID-19: an insight from GeroCovid registry.

BACKGROUND: Delirium is an acute neuropsychiatric condition associated with unfavourable outcomes, frequent in older hospitalized people. In the context of the SARS-CoV-2 pandemic, few studies have specifically focused on the inflammatory status of older, frail patients with hyperactive delirium (HD) hospitalized for COVID-19. AIM: To identify biological correlates of HD at hospital admission and to assess the independent effect of delirium and physical frailty on in-hospital mortality. METHODS: Data were retrospectively extracted by the multicenter registry GeroCovid Observational Study. Individuals aged ≥ 60 years were included if the information on the presence of HD, frailty based on the modified Fried criteria and inflammatory status had been collected. The risk of mortality was evaluated using a Kaplan-Meier estimator, according to frailty and delirium. Logistic and restricted cubic-spline regressions were employed to assess the relationship between inflammatory markers and HD. RESULTS: Three-hundred-thirty-seven older adults were included in the analysis [mean age (SD) 77.1 (9.5) years, 50.1% females], and 11.5% presented with HD. A significant association of both PaO2/FiO2 ratio (p = 0.015) and serum lactate dehydrogenase (p = 0.04) with delirium was observed. By Cox multivariable regression, frail and non-frail patients with HD had a 4.42 and 2.85 higher mortality risk compared with non-frail, non-delirious patients. CONCLUSIONS: Hyperactive delirium at hospital admission is related with markers of lung failure among older adults, especially when physical frailty coexists. Delirium is associated with increased in-hospital mortality risk, which is doubled by the coexistence of physical frailty.

Predicting mortality and re-hospitalization for heart failure: a machine-learning and cluster analysis on frailty and comorbidity.

BACKGROUND: Machine-learning techniques have been recently utilized to predict the probability of unfavorable outcomes among elderly patients suffering from heart failure (HF); yet none has integrated an assessment for frailty and comorbidity. This research seeks to determine which machine-learning-based phenogroups that incorporate frailty and comorbidity are most strongly correlated with death or readmission at hospital for HF within six months following discharge from hospital. METHODS: In this single-center, prospective study of a tertiary care center, we included all patients aged 65 and older discharged for acute decompensated heart failure. Random forest analysis and a Cox multivariable regression were performed to determine the predictors of the composite endpoint. By k-means and hierarchical clustering, those predictors were utilized to phenomapping the cohort in four different clusters. RESULTS: A total of 571 patients were included in the study. Cluster analysis identified four different clusters according to frailty, burden of comorbidities and BNP. As compared with Cluster 4, we found an increased 6-month risk of poor outcomes patients in Cluster 1 (very frail and comorbid; HR 3.53 [95% CI 2.30-5.39]), Cluster 2 (pre-frail with low levels of BNP; HR 2.59 [95% CI 1.66-4.07], and in Cluster 3 (pre-frail and comorbid with high levels of BNP; HR 3.75 [95% CI 2.25-6.27])). CONCLUSIONS: In older patients discharged for ADHF, the cluster analysis identified four distinct phenotypes according to frailty degree, comorbidity, and BNP levels. Further studies are warranted to validate these phenogroups and to guide an appropriate selection of personalized, model of care.

Role of frailty on cardiac rehabilitation in hospitalized older patients.

BACKGROUND: Cardiovascular diseases are the leading cause of mortality, morbidity, and disability in the world, especially in the older adults. A relevant proportion of patients admitted to Cardiac Rehabilitation (CR) may suffer from frailty, a complex geriatric syndrome with multifactorial aetiology. AIMS: The hypothesis underlying the study is that frailty complicates the management of older patients undergoing CR. The main objective is, therefore, to determine the relationship between frailty and CR outcomes in hospitalized older adults. METHODS: The participants have been recruited among patients aged ≥ 65 years admitted at the hospital for CR. A Comprehensive Geriatric Assessment (CGA)-based Frailty Index (FI) was created following a standard procedure. The outcome was measured as the ratio between 6-min walk test (6MWT) distance at the end of CR and normal predicted values for a healthy adult of same age and gender, according to reference equations. RESULTS: The study population consisted of 559 elderly patients, 387 males (69.2%), with age of 72 (69-76) years. The most frequent diagnosis at admission was ischaemic heart disease (231, 41.5%) and overall 6MWT ratio was 0.62 ± 0.21. At the multivariable regression analysis, gender, diagnosis and FI were significantly and independently associated with 6MWT ratio (p ≤ 0.0001, p ≤ 0.001 and p ≤ 0.0001, respectively), while no significant association emerged for age. CONCLUSION: FI resulted independently correlated to 6MWT ratio in a population of older patients undergoing in-hospital CR programs. Frailty is a multifactorial geriatric syndrome whose assessment is essential for prognostic evaluation of older patients, also in CR clinical setting.

Endothelial Progenitor Cells and Rheumatoid Arthritis: Response to Endothelial Dysfunction and Clinical Evidences.

Rheumatoid Arthritis (RA) is a chronic autoimmune inflammatory disease characterized by the swelling of multiple joints, pain and stiffness, and accelerated atherosclerosis. Sustained immune response and chronic inflammation, which characterize RA, may induce endothelial activation, damage and dysfunction. An equilibrium between endothelial damage and repair, together with the preservation of endothelial integrity, is of crucial importance for the homeostasis of endothelium. Endothelial Progenitor Cells (EPCs) represent a heterogenous cell population, characterized by the ability to differentiate into mature endothelial cells (ECs), which contribute to vascular homeostasis, neovascularization and endothelial repair. A modification of the number and function of EPCs has been described in numerous chronic inflammatory and auto-immune conditions; however, reports that focus on the number and functions of EPCs in RA are characterized by conflicting results, and discrepancies exist among different studies. In the present review, the authors describe EPCs' role and response to RA-related endothelial modification, with the aim of illustrating current evidence regarding the level of EPCs and their function in this disease, to summarize EPCs' role as a biomarker in cardiovascular comorbidities related to RA, and finally, to discuss the modulation of EPCs secondary to RA therapy.

Impact of body mass index on cardiac adrenergic derangement in heart failure patients: a 123I-mIBG imaging study.

PURPOSE: To assess the impact of body mass index (BMI) on cardiac adrenergic derangement, measured by iodine-123 meta-iodobenzylguanidine (123I-mIBG) imaging in heart failure (HF) patients. Overweight and obesity represent relevant health issues, and augmented sympathetic tone has been described in patients with increased BMI. An extensive literature supports that HF-dependent cardiac denervation, measured through mIBG parameters, is an independent predictor of cardiovascular outcomes and mortality. However, the influence of BMI on cardiac mIBG uptake has not been largely investigated. METHODS: We prospectively enrolled patients with systolic HF, collecting demographic, clinical, echocardiographic data, and mIBG imaging parameters. In order to detect the factors associated with mIBG parameters, a model building strategy, based on the Multivariable Fractional Polynomial algorithm, has been employed. RESULTS: We studied 249 patients with systolic HF, mean age of 66.4 ± 10.6 years, and mean left ventricular ejection fraction (LVEF) of 30.7% ± 6.4, undergoing cardiac 123I-mIBG imaging to assess HF severity and prognosis. Seventy-eight patients (31.3%) presented a BMI ≥ 30 kg/m2 and obese patients showed a significant reduction in early heart to mediastinum (H/M) ratio (1.66 ± 0.19 vs. 1.75 ± 0.26; p = 0.008) and a trend to reduction in washout rate (33.6 ± 18.3 vs. 38.1 ± 20.1; p = 0.092) compared with patients with BMI < 30 kg/m2. Multiple regression analysis revealed that BMI, age, and LVEF were significantly correlated with early and late H/M ratios. CONCLUSIONS: Results of the present study indicate that BMI, together with LVEF and age, is independently correlated with cardiac mIBG uptake in HF patients.

Predisposing factors to heart failure in diabetic nephropathy: a look at the sympathetic nervous system hyperactivity.

Diabetes mellitus (DM) and heart failure (HF) are frequent comorbidities among elderly patients. HF, a leading cause of mortality and morbidity worldwide, is characterized by sympathetic nervous system hyperactivity. The prevalence of diabetes mellitus (DM) is rapidly growing and the risk of developing HF is higher among DM patients. DM is responsible for several macro- and micro-angiopathies that contribute to the development of coronary artery disease (CAD), peripheral artery disease, retinopathy, neuropathy and diabetic nephropathy (DN) as well. Independently of CAD, chronic kidney disease (CKD) and DM increase the risk of HF. Individuals with diabetic nephropathy are likely to present a distinct pathological condition, defined as diabetic cardiomyopathy, even in the absence of hypertension or CAD, whose pathogenesis is only partially known. However, several hypotheses have been proposed to explain the mechanism of diabetic cardiomyopathy: increased oxidative stress, altered substrate metabolism, mitochondrial dysfunction, activation of renin-angiotensin-aldosterone system (RAAS), insulin resistance, and autonomic dysfunction. In this review, we will focus on the involvement of sympathetic system hyperactivity in the diabetic nephropathy.

ß-Adrenergic Receptor Signaling and Heart Failure: From Bench to Bedside.

Despite improvements in management and therapeutic approach in the last decades, heart failure is still associated with high mortality rates. The sustained enhancement in the sympathetic nervous system tone, observed in patients with heart failure, causes alteration in ß-adrenergic receptor signaling and function. This latter phenomenon is the result of several heart failure-related molecular abnormalities involving adrenergic receptors, G-protein-coupled receptor kinases, and ß-arrestins. This article summarizes novel encouraging preclinical strategies to reactivate ß-adrenergic receptor signaling in heart failure, including pharmacologic and gene therapy approaches, and attempts to translate acquired notions into the clinical setting.

Frailty and Parkinson's disease: the role of diabetes mellitus.

Parkinson's disease (PD) is a chronic neurodegenerative disease associated with a progressive loss of dopaminergic neurons, clinically characterized by motor and non-motor signs. Frailty is a clinical condition of increased vulnerability and negative health outcomes due to the loss of multiple physiological reserves. Chronic hyperglycemia and insulin resistance, which characterize diabetes mellitus (DM), have been reported to alter dopaminergic activity, increase the risk of PD, and influence the development of frailty. Even though diabetes may facilitate the development of frailty in patients with PD, this relationship is not established and a revision of the current knowledge is necessary. Furthermore, the synergy between DM, PD, and frailty may drive clinical complexity, worse outcomes, and under-representation of these populations in the research. In this review, we aimed to discuss the role of diabetes in the development of frailty among patients with PD. We summarized the clinical characteristics and outcomes of patients with concomitant DM, PD, and frailty. Finally, interventions to prevent frailty in this population are discussed.

The relationship between muscle strength and epicardial fat in healthy adults.

BACKGROUND: Muscular strength and muscle mass are considered key factors for healthy ageing. Modification of body composition and redistribution of adipose tissue has been described in advanced age. Muscle strength has an important predictive role for health outcomes. However, little is known regarding the relationship between muscle strength and epicardial fat. METHODS AND MATERIALS: In a cohort of healthy adults following physical capacity evaluations, anthropometric measurements, handgrip strength (HGS), echocardiography and bioimpedance analysis (BIA) were performed. Kruskal-Wallis test, Spearman's correlation and regression analysis adjusted for confounders were applied. RESULTS: A total population of 226 adults, age range 18-83 years, were included. Epicardial fat thickness resulted significantly associated with age p < 0.001, HGS (p < 0.001). Regression analysis adjusted for confounders revealed an independent relationship between handgrip strength and epicardial fat thickness: regression coefficient: -1.34; R2 = 0.27 and p = 0.044. CONCLUSIONS: The relationship between epicardial fat and muscle strength is inverse and independent. Implementation of HGS measurement may be useful for the identification of subjects with excessive epicardial fat and cardiovascular risk. Measurement of epicardial fat could be helpful in the early detection of physical decline associated to ageing.

Time to negative conversion and cardiopulmonary performance in athletes with COVID-19.

Athletes with longer time to negative conversion for COVID-19 do not present reduction of exercise capacity. However, respiratory and ventilatory parameters are modified. https://bit.ly/3TMdrFL.

Intricate relationship between obstructive sleep apnea and dementia in older adults.

Numerous evidence reports direct correlation between cognitive impairment, Alzheimer's disease and sleep disorders, in particular obstructive sleep apnea. Both obstructive sleep apnea and Alzheimer's disease are highly prevalent conditions whose incidence increases with age. Several studies demonstrate how sleep-disordered breathing may lead to poor cognition, even though the underlying mechanisms of this association remain partially unclear. According to the most recent studies, obstructive sleep apnea may be considered a modifiable risk factor for cognitive dysfunction. In the present review, the authors aim to integrate recent research examining obstructive sleep apnea and Alzheimer's disease biomarkers, also focusing on the mechanisms that support this correlation, including but not limited to the role of hypoxia and cardiovascular risk. Moreover, the potential favourable effect of obstructive sleep apnea therapy on cognitive function is discussed, to evaluate the benefits deriving from appropriate treatment of sleep-disordered breathing on cognition.

Atrial Fibrillation and Dementia: Focus on Shared Pathophysiological Mechanisms and Therapeutic Implications.

OBJECTIVES: Atrial fibrillation (AF) and dementia are highly prevalent chronic and debilitating conditions, especially affecting the older population. This review focuses on possible common pathophysiological mechanisms that could explain the association between the 2 conditions. DESIGN: Narrative review. SETTING AND PARTICIPANTS: Evidence from epidemiologic, observational, and interventional studies evaluating prevalence and incidence of cognitive impairment in patients with AF. METHODS: Broad literature search between December 2022 and May 2023. Eligible categories for inclusion comprised interventional studies, observational studies, systematic reviews, and meta-analysis. RESULTS: Evidence from different cohorts has shown that AF increases the risk of dementia, although the association with dementia subtypes is not always unequivocal. According to recent evidence, common pathophysiological mechanisms include thromboembolism and hypercoagulable states, proinflammatory state, infection, cerebral hypoperfusion, and brain atrophy. Moreover, we reviewed the evidence on therapeutic measures to prevent dementia in patients with AF. CONCLUSIONS AND IMPLICATIONS: Screening for cognition in patients with AF is of paramount importance, given the shared risk factors and common pathophysiological mechanisms. More evidence is needed to clarify whether antiarrhythmic and anticoagulant therapy have an impact on cognitive outcomes in AF patients.

Visit-to-visit blood pressure variability is associated with intrinsic capacity decline: Results from the MAPT Study.

BACKGROUND: The effectiveness of the body physiological regulatory mechanisms declines in late life, and increased Blood Pressure Variability (BPV) may represent an alteration in cardiovascular homeostatic patterns. Intrinsic Capacity (IC) has been proposed by the World Health Organization as a marker of healthy aging, based on individual's functional abilities and intended at preserving successful aging. We aimed to investigate the association of visit-to-visit BPV with IC decline in a population of community-dwelling older adults. METHODS: The study population consisted of 1407 community-dwelling participants aged ≥70 years from the MAPT study evaluated during the 5-year follow-up. Systolic BPV (SBPV) and diastolic BPV (DBPV) were determined through six indicators. Cognition, psychology, locomotion and vitality constituted the four IC domains assessed. Total IC Z-score resulted from the sum of the four domains Z-scores divided by 4. The incidence of domain impairment over time was also assessed. RESULTS: Higher SBPV was significantly associated with poorer IC Z-scores in all linear mixed models [1-SD increase of CV%: ß(SE)=-0.010(0.001), p < 0.01]. Similar results were observed for DBPV [1-SD increase of CV%: ß(SE)=-0.003(0.001), p = 0.02]. Incident IC impairment was significantly higher in participants with greater SBPV, [HR=1.16 (95 % CI, 1.01-1.33), p = 0.03], while greater DBPV did not show a higher risk of incident IC impairment. CONCLUSIONS: Greater BPV is associated with IC decline over time. Our findings support BP instability as a presumable index of altered cardiovascular homeostatic mechanism, suggesting that BPV might be a clinical marker of aging and addressable risk factor for promoting healthy aging.

Impact of serum leptin and adiponectin levels on brain infarcts in patients with mild cognitive impairment and Alzheimer's disease: a longitudinal analysis.

Introduction: The adipokines leptin and adiponectin have been associated with atherosclerosis and the risk of cerebral infarcts. Pre-clinical studies, however, suggest a protective role against ischemic brain damage. In this study we analyzed the relationship between serum leptin and adiponectin levels and the onset or progression of brain infarcts in subjects with mild cognitive impairment (MCI) and Alzheimer's disease (AD). Methods: All data were extracted from the ADNI database. The final population included 566 subjects, with 58 healthy controls, 396 MCI and 112 AD. All patients with available serum leptin and adiponectin levels at baseline were selected. Demographics, neuropsychological test results, CSF biomarkers, regional brain metabolism with FDG-PET data and the number of brain infarcts on longitudinal MRI scans were extracted. Results: Leptin levels were significantly lower in patients with MCI than controls at baseline, while adiponectin levels were not different between the groups. Multivariate logistic regression analysis at baseline for the presence of brain infarcts showed a predictive value for leptin but not for adiponectin. Multivariate longitudinal analysis showed that age was the only significant predictor of brain infarcts development at 15-year follow-up, while serum leptin and adiponectin levels did not play a role in this population. Discussion: The evidence on the pathogenetic or protective role of adipokines on ischemic brain damage is mixed. In this MCI and AD population, serum leptin and adiponectin were not associated with the development of brain infarcts; therefore, these results do not support the use of adipokines as biomarkers of cerebrovascular pathology in this population.

Ventilatory efficiency in post-COVID-19 athletes.

Limitation in exercise capacity has not been described in athletes affected by SARS-CoV-2 infection. However, patients who have recovered from COVID-19 without cardiopulmonary impairment show exaggerated ventilatory response during exercise. Therefore, we aimed to evaluate the ventilatory efficiency (VEf) in competitive athletes recovered from COVID-19 and to characterize the ventilation versus carbon dioxide relationship (VE/VCO2 ) slope in this population. Thirty-seven competitive athletes with COVID-19 were recruited for this study. All participants underwent spirometry, echocardiography, and cardiopulmonary exercise testing (CPET). z-FVC values and end-title pressure of CO2 (PET CO2 ) were lower in the third tertile compared with the first tertile: -0.753 ± 0.473 vs. 0.037 ± 0.911, p = 0.05; 42.2 ± 2.7 vs. 37.1 ± 2.5 mmHg, p < 0.01. VE/VCO2 slope was significantly correlated to maximal VCO2 /VE and maximal VO2 /VE: coefficient = -0.5 R2 = 0.58, p < 0.0001 and coefficient = -0.3 R2 = 0.16, p = 0.008. Competitive athletes affected by SARS-CoV-2 infection, without cardio-respiratory disease sequel, may present ventilatory inefficiency (ViE), without exercise capacity limitation. FVC is higher in athletes with better ventilatory performance during exercise, and increased VE/VCO2 slope is inversely correlated to max VCO2 /VE and max VO2 /VE.

The impact of COVID-19 pandemic on well-being of Italian physicians: a report from the Italian Society of Internal Medicine (SIMI) national survey.

Over the past few years, COVID-19 pandemic has imposed a high toll worldwide, with a high burden of morbidity and mortality. Healthcare practitioners (HCPs) have been in the frontline since the beginning of the outbreak, and the high level of stress have affected their physical and mental status, as well as their relationships. We aimed at exploring the self-reported changes in comprehensive well-being in a cohort of Italian physicians. An online-based survey was administered to the members of the Italian Society of Internal Medicine (SIMI) between March and June 2021. The survey was based on 32 multiple-choice questions exploring self-reported physical and mental well-being, as well as changes in workloads, work-related feelings and physicians' relationship with patients, colleagues and families. 228 physicians (mean age: 35.7 ± 9.8 years) participated in the survey; 120 (52.6%) were residents, 196 (86.0%) worked in COVID-19 units and 65 (28.5%) had COVID-19 during the pandemic. A significant proportion of respondents reported to have experience onset or worsening of physical and mental symptoms, with insomnia/sleep disorders (58.3%) and mood swings (47.8%) being the most common, respectively. The burden of physical and mental consequences was broadly higher among residents compared to specialists, with the former reporting more frequently an increase in the number of worked hours (p = 0.020) and being more frequently infected with COVID-19 (35.0% vs. 21.3, p = 0.032). Moreover, familiar and doctor-patient relationships were also considerably affected. Physicians have been suffering a wide spectrum of physical, mental and relational consequences during COVID-19 pandemic, with youngest doctors being more likely to present several physical and mental health symptoms. Further studies are needed to evaluate long-term consequences of COVID-19 pandemic on the well-being of HCPs, and potential preventive strategies.

Biomarkers of mitochondrial dysfunction and inflammaging in older adults and blood pressure variability.

Most physiopathological mechanisms underlying blood pressure variability (BPV) are implicated in aging. Vascular aging is associated with chronic low-grade inflammation occurring in late life, known as "inflammaging" and the hallmark "mitochondrial dysfunction" due to age-related stress. We aimed to determine whether plasma levels of the pleiotropic stress-related mitokine growth/differentiation factor 15 (GDF-15) and two inflammatory biomarkers, interleukin 6 (IL-6) and tumor necrosis factor receptor 1 (TNFR-1), are associated with visit-to-visit BPV in a population of community-dwelling older adults. The study population consisted of 1096 community-dwelling participants [median age 75 (72-78) years; 699 females, 63.7%] aged ≥ 70 years from the MAPT study. Plasma blood sample was collected 12 months after enrolment and BP was assessed up to seven times over a 4-year period. Systolic (SBPV) and diastolic BPV (DBPV) were determined through several indicators taking into account BP change over time, the order of measurements and formulas independent of mean BP levels. Higher values of GDF-15 were significantly associated with increased SBPV (all indicators) after adjustment for relevant covariates [adjusted 1-SD increase in GDF-15: ß (SE) = 0.07 (0.04), p < 0.044, for coefficient of variation%]. GDF-15 levels were not associated with DBPV. No significant associations were found between IL-6 and BPV, whereas TNFR1 was only partially related to DBPV. Unlike inflammation biomarkers, higher GDF-15 levels were associated with greater SBPV. Our findings support the age-related process of mitochondrial dysfunction underlying BP instability, suggesting that BPV might be a potential marker of aging.

Identification of Drugs Acting as Perpetrators in Common Drug Interactions in a Cohort of Geriatric Patients from Southern Italy and Analysis of the Gene Polymorphisms That Affect Their Interacting Potential.

BACKGROUND: Pharmacogenomic factors affect the susceptibility to drug-drug interactions (DDI). We identified drug interaction perpetrators among the drugs prescribed to a cohort of 290 older adults and analysed the prevalence of gene polymorphisms that can increase their interacting potential. We also pinpointed clinical decision support systems (CDSSs) that incorporate pharmacogenomic factors in DDI risk evaluation. METHODS: Perpetrator drugs were identified using the Drug Interactions Flockhart Table, the DRUGBANK website, and the Mayo Clinic Pharmacogenomics Association Table. Allelic variants affecting their activity were identified with the PharmVar, PharmGKB, dbSNP, ensembl and 1000 genome databases. RESULTS: Amiodarone, amlodipine, atorvastatin, digoxin, esomperazole, omeprazole, pantoprazole, simvastatin and rosuvastatin were perpetrator drugs prescribed to >5% of our patients. Few allelic variants affecting their perpetrator activity showed a prevalence >2% in the European population: CYP3A4/5*22, *1G, *3, CYP2C9*2 and *3, CYP2C19*17 and *2, CYP2D6*4, *41, *5, *10 and *9 and SLC1B1*15 and *5. Few commercial CDSS include pharmacogenomic factors in DDI-risk evaluation and none of them was designed for use in older adults. CONCLUSIONS: We provided a list of the allelic variants influencing the activity of drug perpetrators in older adults which should be included in pharmacogenomics-oriented CDSSs to be used in geriatric medicine.

Biomarkers of aging in frailty and age-associated disorders: State of the art and future perspective.

According to the Geroscience concept that organismal aging and age-associated diseases share the same basic molecular mechanisms, the identification of biomarkers of age that can efficiently classify people as biologically older (or younger) than their chronological (i.e. calendar) age is becoming of paramount importance. These people will be in fact at higher (or lower) risk for many different age-associated diseases, including cardiovascular diseases, neurodegeneration, cancer, etc. In turn, patients suffering from these diseases are biologically older than healthy age-matched individuals. Many biomarkers that correlate with age have been described so far. The aim of the present review is to discuss the usefulness of some of these biomarkers (especially soluble, circulating ones) in order to identify frail patients, possibly before the appearance of clinical symptoms, as well as patients at risk for age-associated diseases. An overview of selected biomarkers will be discussed in this regard, in particular we will focus on biomarkers related to metabolic stress response, inflammation, and cell death (in particular in neurodegeneration), all phenomena connected to inflammaging (chronic, low-grade, age-associated inflammation). In the second part of the review, next-generation markers such as extracellular vesicles and their cargos, epigenetic markers and gut microbiota composition, will be discussed. Since recent progresses in omics techniques have allowed an exponential increase in the production of laboratory data also in the field of biomarkers of age, making it difficult to extract biological meaning from the huge mass of available data, Artificial Intelligence (AI) approaches will be discussed as an increasingly important strategy for extracting knowledge from raw data and providing practitioners with actionable information to treat patients.