Appropriateness of direct oral anticoagulant prescribing in older subjects with atrial fibrillation discharged from acute medical wards.

AIMS: Knowledge on the prescriptive practice of direct oral anticoagulants (DOACs) in older subjects with atrial fibrillation (AF) hospitalized in acute medical wards is limited. This study aimed to evaluate the prevalence and appropriateness of DOAC prescriptions in hospitalized older subjects with AF, discharged from acute medical wards. METHODS: We analysed a cohort of 609 subjects with AF, aged ≥65 years (mean age 85 years) enrolled from 39 geriatric and nephrology wards in Italy. DOAC prescriptive appropriateness was evaluated according to the summary of product characteristics (smPC), 2019 Beers and STOPP criteria, and drug-drug interactions (DDIs). RESULTS: At hospital discharge, 33% of patients with AF were prescribed with DOAC, 26% with vitamin-K antagonist, while 41% did not receive any anticoagulant. Among subjects on DOAC therapy, 31% presented a violation of the smPC criteria (mainly underdosage-17%), while 48% and 18% presented a Beers/STOPP inappropriate prescription, or a DDI, respectively. Older age, lower body mass index (BMI), cancer and higher estimated glomerular filtration rate (eGFR) were independently associated with DOAC underdosage or missed prescription (age: adjusted odds ratio [aOR] 1.06, 95% confidence interval [95% CI] 1.00-1.12 for underdosage; eGFR: aOR 1.04, 95% CI 1.02-1.07 for underdosage; BMI: aOR 0.95, 95% CI 0.91-0.99 for missed prescription; cancer: aOR 1.93, 95% CI 1.19-3.13 for missed prescription). CONCLUSIONS: This study showed a suboptimal DOAC prescriptive practice in older in-patients, with frequent missed prescription and DOAC underdosage. Contrary to current recommendations, physicians appear overly concerned by bleeding risk in real-life older and frailer subjects. Strategies should be developed to promote appropriate DOAC prescription in the hospital setting.

Safety and Tolerability of Antimicrobial Agents in the Older Patient.

Older patients are at high risk of infections, which often present atypically and are associated with high morbidity and mortality. Antimicrobial treatment in older individuals with infectious diseases represents a clinical challenge, causing an increasing burden on worldwide healthcare systems; immunosenescence and the coexistence of multiple comorbidities determine complex polypharmacy regimens with an increase in drug-drug interactions and spread of multidrug-resistance infections. Aging-induced pharmacokinetic and pharmacodynamic changes can additionally increase the risk of inappropriate drug dosing, with underexposure that is associated with antimicrobial resistance and overexposure that may lead to adverse effects and poor adherence because of low tolerability. These issues need to be considered when starting antimicrobial prescriptions. National and international efforts have been made towards the implementation of antimicrobial stewardship (AMS) interventions to help clinicians improve the appropriateness and safety of antimicrobial prescriptions in both acute and long-term care settings. AMS programs were shown to decrease consumption of antimicrobials and to improve safety in hospitalized patients and older nursing home residents. With the abundance of antimicrobial prescriptions and the recent emergence of multidrug resistant pathogens, an in-depth review of antimicrobial prescriptions in geriatric clinical practice is needed. This review will discuss the special considerations for older individuals needing antimicrobials, including risk factors that shape risk profiles in geriatric populations as well as an evidence-based description of antimicrobial-induced adverse events in this patient population. It will highlight agents of concern for this age group and discuss interventions to mitigate the effects of inappropriate antimicrobial prescribing.

Frailty modifies the effect of polypharmacy and multimorbidity on the risk of death among nursing home residents: Results from the SHELTER study.

Background: Frailty, disability, and polypharmacy are prevalent in nursing home (NH) residents, often co-occurring with multimorbidity. There may be a complex interplay among them in terms of outcomes such as mortality. Aims of the study were to (i) assess whether nursing home residents with polypharmacy (5-9 medications) or hyperpolypharmacy (≥10 drugs), have an increased risk of death and (ii) whether any association is modified by the co-presence of frailty or disability. Methods: Cohort study with longitudinal mortality data including 4,023 residents from 50 European and 7 Israeli NH facilities (mean age = 83.6 years, 73.2% female) in The Services and Health for Elderly in Long Term care (SHELTER) cohort study. Participants were evaluated with the interRAI-LongTerm Care assessment tool. Frailty was evaluated with the FRAIL-NH scale. Hazard ratio (HR) of death over 12 months was assessed with stratified Cox proportional hazards models adjusted for demographics, facilities, and cognitive status. Results: 1,042 (25.9%) participants were not on polypharmacy, 49.8% (n = 2,002) were on polypharmacy, and 24.3% (n = 979) on hyperpolypharmacy. Frailty and disability mostly increased risk of death in the study population (frailty: HR = 1.85, 95%CI 1.49-2.28; disability: HR = 2.10, 95%CI 1.86-2.47). Among non-frail participants, multimorbidity (HR = 1.34, 95%CI = 1.01-1.82) and hyperpolypharmacy (HR = 1.61, 95%CI = 1.09-2.40) were associated with higher risk of death. Among frail participants, no other factors were associated with mortality. Polypharmacy and multimorbidity were not associated with mortality after stratification for disability. Conclusions: Frailty and disability are the strongest predictors of death in NH residents. Multimorbidity and hyperpolypharmacy increase mortality only in people without frailty. These findings may be relevant to identify patients who could benefit from tailored deprescription.

Improving the prognostic value of multimorbidity through the integration of selected biomarkers to the comprehensive geriatric assessment: An observational retrospective monocentric study.

Background: Multimorbidity (MM) burdens individuals and healthcare systems, since it increases polypharmacy, dependency, hospital admissions, healthcare costs, and mortality. Several attempts have been made to determine an operational definition of MM and to quantify its severity. However, the lack of knowledge regarding its pathophysiology prevented the estimation of its severity in terms of outcomes. Polypharmacy and functional impairment are associated with MM. However, it is unclear how inappropriate drug decision-making could affect both conditions. In this context, promising circulating biomarkers and DNA methylation tools have been proposed as potential mortality predictors for multiple age-related diseases. We hypothesize that a comprehensive characterization of patients with MM that includes the measure of epigenetic and selected circulating biomarkers in the medical history, in addition to the functional capacity, could improve the prognosis of their long-term mortality. Methods: This monocentric retrospective observational study was conducted as part of a project funded by the Italian Ministry of Health titled "imProving the pROgnostic value of MultimOrbidity through the inTegration of selected biomarkErs to the comprehensive geRiatric Assessment (PROMOTERA)." This study will examine the methylation levels of thousands of CpG sites and the levels of selected circulating biomarkers in the blood and plasma samples of older hospitalized patients with MM (n = 1,070, age ≥ 65 years) recruited by the Reportage Project between 2011 and 2019. Multiple statistical approaches will be utilized to integrate newly measured biomarkers into clinical, demographic, and functional data, thus improving the prediction of mortality for up to 10 years. Discussion: This study's results are expected to: (i) identify the clinical, biological, demographic, and functional factors associated with distinct patterns of MM; (ii) improve the prognostic accuracy of MM patterns in relation to death, hospitalization-related outcomes, and onset of new comorbidities; (iii) define the epigenetic signatures of MM; (iv) construct multidimensional algorithms to predict negative health outcomes in both the overall population and specific disease and functional patterns; and (v) expand our understanding of the mechanisms underlying the pathophysiology of MM.

A focus on CKD reporting and inappropriate prescribing among older patients discharged from geriatric and nephrology units throughout Italy: A nationwide multicenter retrospective cross-sectional study.

Older hospitalized patients with chronic kidney disease (CKD) are part of the geriatric population with a substantial risk of potentially inappropriate medication (PIM) use. The high rates of multimorbidity and polypharmacy, along with the progressive decline of eGFR, contribute to increasing the risk of drug-drug and drug-disease interactions, overdosing, and adverse drug reactions (ADRs). In this multicenter cross-sectional study, we aimed to evaluate the prevalence of CKD under-reporting and PIMs among older patients discharged from acute geriatric and nephrology units throughout Italy. Renal function was determined by estimated glomerular filtration rate (eGFR) through the Berlin Initiative Study (BIS) equation; the prevalence of PIMs was calculated by revising drug prescriptions at discharge according to STOPP criteria, Beers criteria, and summaries of product characteristics (smPCs). A descriptive analysis was performed to compare the clinical and pharmacological characteristics of patients in the two distinct settings; univariate and multivariate logistic regression models were performed to explore factors associated with CKD under-reporting in the discharge report forms and PIM prevalence. Overall, the study population consisted of 2,057 patients, aged 83 (77-89) years, more commonly women, with a median of seven (5-10) drugs prescribed at discharge. CKD under-reporting was present in 50.8% of the study population, with higher rates in geriatric vs. nephrology units (71.1% vs. 10.2%, p < 0.001). 18.5% of the study population was discharged with at least one renally inappropriate medication; factors associated with at least one contraindicated drug at discharge were the number of drugs (PR 1.09, 95% CI 1.14-1.19); atrial fibrillation (PR 1.35, 95% CI 1.01-1.81); diabetes (PR 1.61, 95% CI 1.21-2.13); being hospitalized in nephrology units (PR 1.62, 95% CI 1.14-2.31), CKD stage 3b (PR 2.35, 95% CI 1.34-4.13), and stage 4-5 (PR 14.01, 95% CI 7.36-26.72). Conversely, CKD under-reporting was not associated with the outcome. In summary, CKD under-reporting and inappropriate medication use were common in older patients discharged from hospital; the relatively high number of PIMs in both nephrology and geriatric settings underlines the need to improve appropriate prescribing during hospital stay and to decrease the risk of ADRs and side effects in this highly vulnerable population.

The relevance of geriatric assessments on the association between chronic kidney disease stages and mortality among older people: a secondary analysis of a multicentre cohort study.

BACKGROUND: age-adapted definition of chronic kidney disease (CKD) does not take individual risk factors into account. We aimed at investigating whether functional impairments influence CKD stage at which mortality increases among older people. METHODS: our series consisted of 2,372 outpatients aged 75 years or more enrolled in a multicentre international prospective cohort study. The study outcome was 24-month mortality. Kidney function was assessed by estimated glomerular filtration rate (eGFR) and albumin-to-creatinine ratio (ACR). Geriatric assessments included handgrip strength, short physical performance battery (SPPB), cognitive impairment, dependency in basic activities of daily living (BADL) and risk of malnutrition. Analysis was carried out by Cox regression, before and after stratification by individual functional impairments. Survival trees including kidney function and functional impairments were also investigated, and their predictivity assessed by C-index. RESULTS: overall, mortality was found to increase starting from eGFR = 30-44.9 ml/min/1.73 m2 (hazard ratio [HR] = 3.28, 95% confidence interval [CI] = 1.81-5.95) to ACR = 30-300 mg/g (HR = 1.96, 95%CI = 1.23-3.10). However, in survival trees, an increased risk of mortality was observed among patients with impaired handgrip and eGFR = 45-59.9 ml/min/1.73 m2, as well as patients with ACR < 30 mg/g and impaired handgrip and SPPB. Survival tree leaf node membership had greater predictive accuracy (C-index = 0.81, 95%CI = 0.78-0.84 for the eGFR survival tree and C-index = 0.77, 95%CI = 0.71-0.81 for the ACR survival tree) in comparison with that of individual measures of kidney function. CONCLUSIONS: physical performance helps to identify a proportion of patients at an increased risk of mortality despite a mild-moderate impairment in kidney function and improves predictive accuracy of individual measures of kidney function.

A magnetic resonance imaging-based nomogram for predicting clinically significant prostate cancer at radical prostatectomy.

PURPOSE: To develop a nomogram incorporating clinical and multiparametric magnetic resonance imaging (mpMRI) parameters for the detection of clinically significant prostate cancer (csCaP) at radical prostatectomy (RP). MATERIALS AND METHODS: We retrospectively analyzed all consecutive patients who underwent robotic RP between 2016 and 2020. All patients underwent a 1.5-T mp-MRI according to the PI-RADS-v2 scoring system. RP specimens were examined with the whole-mount technique. csCaP definition: any tumor with a volume larger than 0.5 cm3 or with a Gleason score ≥7. Univariable logistic regression models explored the association between clinical and imaging data and the risk of csCaP. Significant variables (P < 0.05) were selected into multivariable regression models to identify independent predictors. A nomogram was designed to select the significant relevant predictors. The nomogram was internally validated in terms of discrimination and calibration. Receiver operating characteristics of the area under the curve was used to assess the discrimination ability of the nomogram. To assess the predictive performance of mpMRI, the accuracy of the mpMRI-based nomogram was compared with that excluding either PI-RADS score or mpMRI IL size. RESULTS: The analysis involved 393 patients. The median age was 65(9) years. The median prostate specific antigen was 5.81(3.76) ng/ml. 363 had csCaP. PI-RADS v2 score of 4-5, prostate specific antigen density of 0.15 or more, and mpMRI index lesion (IL) size were significantly associated with csCaP in the multivariable regression analyses. Based on these variables, a diagnostic model was developed. The full model yielded an area under the curve of 0.77 (95%CI:0.75-0.80) which was significantly better than those excluding mpMRI findings (P = 0.02) Decision curve analysis showed a slight but significant net benefit associated with the use of the mp-MRI based nomograms compared with those excluding either PI-RADS score (Delta net benefit 0.0278) or mpMRI maximum IL size (Delta net benefit 0.0111). CONCLUSIONS: The nomogram constructed in this study can assist urologists in assessing an individual's risk of csCaP at RP.

Design and methodology of the chronic kidney disease as a dysmetabolic determinant of disability among older people (CKD-3D) study: a multicenter cohort observational study.

BACKGROUND: Chronic kidney disease (CKD) is a common condition in older people and represents a global health issue since it increases the risk of associated comorbidities and all-cause mortality. Furthermore, older people with reduced renal function might be at higher risk for developing functional limitation and disability. Moreover, the current creatinine-based measures of renal function are influenced by several factors in older population. The aims of the CKD-3D project are to perform an observational study to expand the knowledge about CKD-disability relationship and to investigate the use of novel biomarkers of kidney function. METHODS: An observational, multicenter, prospective cohort study will be conducted in 75 + old patients consecutively admitted to acute care wards of geriatric medicine at participating hospitals. The study planned to enroll 440 patients undergoing clinical and laboratory evaluations at baseline and after 12 months. Face-to-face follow-up at 6 months and telephone follow-up at 3 and 9 months will be carried out. Comprehensive Geriatric Assessment (CGA) and the measurement of Cystatin C, Beta-Trace Protein and Beta2-Microglobulin levels will be included. DISCUSSION: This study will provide useful information to prevent CKD-related disability by collecting real-life data over 1-year period. The combined approach of CGA and the investigation of innovative existing biomarkers will make it possible to develop new recommendations and guidelines for a patient-centered approach. It is believed that such a study may lead to an improvement of knowledge on CKD in elderly patients and may also have implications in daily clinical practice and in decision-making process.

Phenolic Substances in Foods and Anticarcinogenic Properties: A Public Health Perspective.

The interest in polyphenols from vegetable sources has been progressively increased because of the demonstrated correlation between their abundance in certain foods or food preparations of traditional importance and heritage, and the answer of anti-inflammatory strategies in hospitalized patients in the presence of polypehnol-rich foods (as a complementary therapy). Consequently, research involving the accessory role of polyphenols as anti-tumoral aids have been carried out with the aim of finding new additional strategies. The purpose of this paper to evaluate the role of phenolic compounds in foods with reference to health effects for human beings. The importance of these molecules has been evaluated by the health and safety perspectives in terms of: fight to cardiovascular diseases; prevention of chronic-degenerative disorders; general antioxidant properties; and anticarcinogenic features. Moreover, the role of polyphenols-rich foods as anticancer agents has been discussed with relation to two distinct "action plans" on the public hygiene level: the promotion of human health on the one side (for non-hospitalized and normal subjects), and reliable contrasting strategies in cancer patients.

Innate Immune Surveillance in the Central Nervous System Following Legionella pneumophila Infection.

BACKGROUND & OBJECTIVE: The innate immune response is a common occurrence in many neuroinflammatory diseases. Central Nervous System (CNS) resident immune cells are able to detect and react to infections and sterile trauma. Peripheral immune cell migration into CNS is regulated by the blood-brain barrier, although peripheral immune cells can invade CNS through meninges, choroid plexus, perivascular spaces, and cerebrospinal fluid. Consequently, in the brain, immune reactions can be mediated by both resident and peripheral immune cells. Both in the periphery and within the CNS, innate immune response is regulated by a wide array of pattern recognition receptors, including Tolllike, scavenger, Retinoic Acid-inducible Gene-1 like, and nucleotide-binding oligomerization domainslike responsible for inflammasome formation. Inflammasome pathway activation induces pyroptosis, a highly inflammatory cell death pattern that occurs to remove intracellular pathogens. Legionella pneumophila is an intracellular microorganism responsible for Legionnaires' disease, a lung infection always associated to neurological dysfunctions. Recent studies have been shown that Toll-like receptors, nucleotide-binding oligomerization domains-like receptors, and RIG-1 like, are activated by L. pneumophila. This flagellated bacterium is able to replicate in phagocytic cells, including macrophages and microglia, responding by activating inflammasome pathways that may be the cause of CNS dysfunction detected in several infected patients. CONCLUSION: The aim of this review is to bring together the latest findings concerning L. pneumophila infection and innate immune host cell responses. A deeper knowledge of these processes could allow the use of immunomodulatory compounds able to counteract CNS involvement following L. pneumophila infection.

The Role of Toll-Like Receptors in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: A New Promising Therapeutic Approach?

Perturbations in immune processes play an important role in chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME), a multifactorial disorder mainly characterized by severe and prolonged fatigue and tipically affecting a variety of bodily systems including the immune system. Recent reports have shown that CFS/ME is an inflammatory disorder may be associated with autoimmune responses, mainly characterized by reduced functional activity of most immune cells, including neutrophils, natural killer cells, monocytes/macrophage and dendritic cells, together with dysregulations in cytokine levels, responsible for changes in the adaptive immune system. Interactions between gut microorganisms and host immune function have been shown to contribute to aberrant inflammation in CFS/ME patients. Commensal and/or pathogen-associated molecular patterns detected by Toll-like receptors (TLRs) expressed on intestinal epithelial cells appear to trigger inflammatory signaling cascade leading to neuroinflammation and neurodegeneration. This paper examines the role of TLR-mediated innate immunity in CFS/ME with evaluation of the current literature, also discussing about innovative therapeutic approaches represented by immunomodulators TLR-targeting.