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Objective: To evaluate the association between dairy products consumption and the probability of frailty transitions in community-dwelling older adults., Design: Longitudinal study., Setting and Participants: We included 863 community-dwelling participants ≥65 years from the Chianti region in Italy., Mesurements: Habitual dietary intake of dairy products (i.e., milk, yogurt, and cheese) was assessed in daily servings using a validated food frequency questionnaire (FFQ) at baseline, 3-, 6-, and 9-years of follow-up. Frailty status at each visit was defined using the Fried criteria, and the probability of transitions between different frailty status and death was assessed through multistate models. The associations between dairy product intakes and frailty transitions during the 9-year period were expressed as hazard ratios (HRs) derived from proportional intensity models., Results: The mean age at baseline was 74 ± 7 years and 46% of the participants were male. There were no statistically significant associations between the consumption of total, fermented, or non-fermented dairy products and the probabilities of transition from robust or from pre-frail to any of the other frailty conditions or to death. Conversely, a direct association between the consumption of fermented dairy products and the probability of transition from frail to pre-frail was observed in a model adjusted for age, sex, and energy intake (HR per serving/day  = 1.90, 95%CI 1.12-3.22). This association was primarily related to yogurt consumption (HR per serving/day  = 4.07, 95%CI 1.38-12.02), as the association with cheese consumption was not significant (HR per serving/day  = 1.57, 95%CI 0.91-2.71). In the fully adjusted model, only the association between yogurt consumption and frail to pre-frail transition remained statistically significant (HR per serving/day  = 3.68, 95%CI 1.10-12.31)., Conclusion: Dairy products, such as milk, yogurt, and cheese, are unlikely to play a predominant role in frailty development in an Italian community-dwelling older population. However, it is advisable to maintain a moderate consumption of dairy products, especially fermented ones, as part of a well-balanced diet to promote healthy aging., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interests., (Copyright © 2025. Published by Elsevier Masson SAS.)

Background: Once the pandemic ended, SARS-CoV-2 became endemic, with flare-up phases. COVID-19 disease can still have a significant clinical impact, especially in older patients with multimorbidity and frailty., Objective: This study aims at evaluating the main characteristics associated to in-hospital mortality among data routinely collected upon admission to identify older patients at higher risk of death., Methods: The present study used data from Gerocovid-acute wards, an observational multicenter retrospective-prospective study conducted in geriatric and internal medicine wards in subjects ≥60 years old during the COVID-19 pandemic. Seventy-one routinely collected variables, including demographic data, living arrangements, smoking habits, pre-COVID-19 mobility, chronic diseases, and clinical and laboratory parameters were integrated into a web-based machine learning platform (Just Add Data Bio) to identify factors with the highest prognostic relevance. The use of artificial intelligence allowed us to avoid variable selection bias, to test a large number of models and to perform an internal validation., Results: The dataset was split into training and test sets, based on a 70:30 ratio and matching on age, sex, and proportion of events; 3,520 models were set out to train. The three predictive algorithms (optimized for performance, interpretability, or aggressive feature selection) converged on the same model, including 12 variables: pre-COVID-19 mobility, World Health Organization disease severity, age, heart rate, arterial blood gases bicarbonate and oxygen saturation, serum potassium, systolic blood pressure, blood glucose, aspartate aminotransferase, PaO2/FiO2 ratio and derived neutrophil-to-lymphocyte ratio., Conclusion: Beyond variables reflecting the severity of COVID-19 disease failure, pre-morbid mobility level was the strongest factor associated with in-hospital mortality reflecting the importance of functional status as a synthetic measure of health in older adults, while the association between derived neutrophil-to-lymphocyte ratio and mortality, confirms the fundamental role played by neutrophils in SARS-CoV-2 disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Fedecostante, Sabbatinelli, Dell’Aquila, Salvi, Bonfigli, Volpato, Trevisan, Fumagalli, Monzani, Antonelli Incalzi, Olivieri and Cherubini.)

Systemic inflammation significantly increases the risk of short- and long-term mortality in geriatric hospitalized patients. To predict mortality in older patients with various age-related diseases and infections, including COVID-19, inflammatory biomarkers such as the C-reactive protein (CRP) to albumin ratio (CAR), and related scores and indexes, i.e. Glasgow Prognostic Score (GPS), modified GPS (mGPS), and high sensitivity (hs)-mGPS, have been increasingly utilized. Despite their easy affordability and widespread availability, these biomarkers are predominantly assessed for clinical purposes rather than predictive applications, leading to their underutilization in hospitalized older patients. In this study, we investigated the association of CAR, GPS, mGPS, and hs-mGPS with short-term mortality in 3,206 geriatric hospitalized patients admitted for acute conditions, irrespective of admission diagnosis. We observed that unit increases of CAR, and the highest classes of GPS, mGPS, and hs-mGPS were significantly associated with a two- to threefold increased risk of death, even adjusting the risk for different confounding variables. Interestingly, a hs-mGPS of 2 showed the highest effect size. Furthermore, gender analysis indicated a stronger association between all CRP-albumin based parameters and mortality in men, underscoring the gender-specific relevance of inflammation-based circulating parameters in mortality prediction. In conclusion, scores based on serum CRP and albumin levels offer additional guidance for the stratification of in-hospital mortality risk in older patients by providing additional information on the degree of systemic inflammation., (© 2024. The Author(s).)

Constipation and fecal impaction are common issues with the potential for significant morbidity in older people presenting to the Emergency Department (ED). While many of these patients present with classical symptoms of constipation or fecal impaction, atypical presentations are also frequent. These atypical presentations may include paradoxical diarrhea, fecal incontinence, urinary retention or overflow incontinence, hyperactive or hypoactive delirium, anorexia/dysphagia, and syncope. In addition, various clinical conditions (such as dementia, Parkinson's disease, dehydration, and hypothyroidism) and medications (such as opiate analgesics, anticholinergics, diuretics, calcium channel blockers, anti-parkinsonian drugs, and oral iron supplements) are associated with constipation and should be considered during the diagnostic process in the ED. This narrative review specifically focuses on the prevalence, presentation, diagnoses, and management of constipation in older ED patients., (© 2024. The Author(s), under exclusive licence to Società Italiana di Medicina Interna (SIMI).)

Background: Delirium is strongly associated with poor health outcomes, yet it is frequently underdiagnosed. Limited research on delirium has been conducted in Nursing Homes (NHs). Our aim is to assess delirium prevalence and its associated factors, in particular pharmacological prescription, in this care setting., Methods: Data from the Italian "Delirium Day" 2016 Edition, a national multicenter point-prevalence study on patients aged 65 and older were analyzed to examine the associations between the prevalence of delirium and its subtypes with demographics and information about medical history and pharmacological treatment. Delirium was assessed using the Assessment test for delirium and cognitive impairment (4AT). Motor subtype was evaluated using the Delirium Motor Subtype Scale (DMSS)., Results: 955 residents, from 32 Italian NHs with a mean age of 84.72 ± 7.78 years were included. According to the 4AT, delirium was present in 260 (27.2%) NHs residents, mainly hyperactive (35.4%) or mixed subtypes (20.7%). Antidepressant treatment with selective serotonin reuptake inhibitors (SSRIs) was associated with lower delirium prevalence in univariate and multivariate analyses., Conclusions: The high prevalence of delirium in NHs highlights the need to systematically assess its occurrence in this care settings. The inverse association between SSRIs and delirium might imply a possible preventive role of this class of therapeutic agents against delirium in NHs, yet further studies are warranted to ascertain any causal relationship between SSRIs intake and reduced delirium incidence., (© 2024. The Author(s).)

Background: Coronavirus disease COVID-19 is a heterogeneous condition caused by SARS-CoV-2 infection. Generally, it is characterized by interstitial pneumonia that can lead to impaired gas-exchange, acute respiratory failure, and death, although a complex disorder of multi-organ dysfunction has also been described. The pathogenesis is complex, and a variable combination of factors has been described in critically ill patients. COVID-19 is a particular risk for older persons, particularly those with frailty and comorbidities. Blood bacterial DNA has been reported in both physiological and pathological conditions and has been associated with some haematological and laboratory parameters but, to date, no study has characterized it in hospitalized old COVID-19 patients The present study aimed to establish an association between blood bacterial DNA (BB-DNA) and clinical severity in old COVID-19 patients., Results: BB-DNA levels were determined, by quantitative real-time PCRs targeting the 16S rRNA gene, in 149 hospitalized older patients (age range 65-99 years) with COVID-19. Clinical data, including symptoms and signs of infection, frailty status, and comorbidities, were assessed. BB-DNA was increased in deceased patients compared to discharged ones, and Cox regression analysis confirmed an association between BB-DNA and in-hospital mortality. Furthermore, BB-DNA was positively associated with the neutrophil count and negatively associated with plasma IFN-alpha. Additionally, BB-DNA was associated with diabetes., Conclusions: The association of BB-DNA with mortality, immune-inflammatory parameters and diabetes in hospitalized COVID-19 patients suggests its potential role as a biomarker of unfavourable outcomes of the disease, thus it could be proposed as a novel prognostic marker in the assessment of acute COVID-19 disease., (© 2023. The Author(s).)

Herpesviridae reactivation such as cytomegalovirus (CMV) has been described in severe COVID-19 (COronaVIrusDisease-2019). This study aimed to understand if CMV reactivation in older COVID-19 patients is associated with increased inflammation and in-hospital mortality. In an observational single-center cohort study, 156 geriatric COVID-19 patients were screened for CMV reactivation by RT-PCR. Participants underwent a comprehensive clinical investigation that included medical history, functional evaluation, laboratory tests and cytokine assays (TNF-α, IFN-α, IL-6, IL-10) at hospital admission. In 19 (12.2%) of 156 COVID-19 patients, CMV reactivation was detected. Multivariate Cox regression models showed that in-hospital mortality significantly increased among CMV positive patients younger than 87 years (HR: 9.94, 95% CI: 1.66-59.50). Other factors associated with in-hospital mortality were C-reactive protein (HR: 1.17, 95% CI: 1.05-1.30), neutrophil count (HR: 1.20, 95% CI: 1.01-1.42) and clinical frailty scale (HR:1.54, 95% CI: 1.04-2.28). In patients older than 87 years, neutrophil count (HR: 1.13, 95% CI: 1.05-1.21) and age (HR: 1.15, 95% CI: 1.01-1.31) were independently associated with in-hospital mortality. CMV reactivation was also correlated with increased IFN-α and TNF-α serum levels, but not with IL-6 and IL-10 serum changes. In conclusion, CMV reactivation was an independent risk factor for in-hospital mortality in COVID-19 patients younger than 87 years old, but not in nonagenarians.

(1) Background: During the COVID-19 pandemic, rapid and reliable diagnostic tools are needed for detecting SARS-CoV-2 infection in urgent cases at admission to the hospital. We aimed to assess the performances of the rapid molecular VitaPCR™ test (Menarini Diagnostics) in a sample of older adults admitted to the Emergency Department of two Italian hospitals (2) Methods: The comparison between the rapid VitaPCR™ and the RT-PCR was performed in 1695 samples. Two naso-pharyngeal swab samplings from each individual were obtained and processed using the VitaPCR™ and the RT-PCR for the detection of SARS-CoV-2 (3) Results: VitaPCR™ exhibited good precision (<3% CV) and an almost perfect overall agreement (Cohen’s K = 0.90) with the RT-PCR. The limit of detection of the VitaPCR™ was 4.1 copies/µL. Compared to the RT-PCR, the sensitivity, the specificity, and the positive and negative predictive values of VitaPCR™ were 83.4%, 99.9%, 99.2% and 98.3%, respectively (4) Conclusions: The VitaPCR™ showed similar sensitivity and specificity to other molecular-based rapid tests. This study suggests that the VitaPCR™ can allow the rapid management of patients within the Emergency Department. Nevertheless, it is advisable to obtain a negative result by a RT-PCR assay before admitting a patient to a regular ward.

Background: healthy dietary patterns have been associated with lower risk for age-related cognitive decline. However, little is known about the specific role of dietary fibre on cognitive decline in older adults., Objective: this study aimed to examine the association between dietary fibre and cognitive decline in older adults and to assess the influence of genetic, lifestyle and clinical characteristics in this association., Design and Participants: the Invecchiare in Chianti, aging in the Chianti area study is a cohort study of community-dwelling older adults from Italy. Cognitive function, dietary and clinical data were collected at baseline and years 3, 6, 9 and 15. Our study comprised 848 participants aged ≥ 65 years (56% female) with 2,038 observations., Main Outcome and Measures: cognitive decline was defined as a decrease ≥3 units in the Mini-Mental State Examination score during consecutive visits. Hazard ratios for cognitive decline were estimated using time-dependent Cox regression models., Results: energy-adjusted fibre intake was not associated with cognitive decline during the 15-years follow-up (P > 0.05). However, fibre intake showed a significant interaction with Apolipoprotein E (APOE) haplotype for cognitive decline (P = 0.02). In participants with APOE-ɛ4 haplotype, an increase in 5 g/d of fibre intake was significantly associated with a 30% lower risk for cognitive decline. No association was observed in participants with APOE-ɛ2 and APOE-ɛ3 haplotypes., Conclusions and Relevance: dietary fibre intake was not associated with cognitive decline amongst older adults for 15 years of follow-up. Nonetheless, older subjects with APOE-ɛ4 haplotype may benefit from higher fibre intakes based on the reduced risk for cognitive decline in this high-risk group., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Piacenza, Di Rosa, Fedecostante, Madotto, Montesanto, Corsonello, Cherubini, Provinciali, Soraci, Lisa, Bustacchini, Bonfigli and Lattanzio.)

Hospitalization for acute SARS-CoV-2 infection confers an almost five-fold higher risk of post-discharge, all-cause mortality compared to controls from the general population. A negative impact on the functional autonomy of older patients, especially in cases of severe disease and prolonged hospitalization, has been recently described. However, little is known about the determinants of cause-specific mortality and loss of independence (LOI) in the activities of daily living (ADL) following COVID-19 hospitalization. Thus, the current prospective, multicenter study is aimed at identifying the determinants of post-discharge cause-specific mortality and the loss of autonomy in at least one ADL function. Older patients hospitalized for a SARS-CoV-2 infection were consecutively enrolled in an e-Registry from 1 March 2020, until 31 December 2020. After at least six months from discharge, patients were extensively re-evaluated according to a common protocol at the outpatient clinic of eight tertiary care Italian hospitals. Of 193 patients [109 (56.4%) men, mean age 79.9 ± 9.1 years], 43 (22.3%) died during follow-up. The most common causes of death were cardiovascular diseases (46.0%), respiratory failure (26.5%), and gastrointestinal and genitourinary diseases (8.8% each). Pre-morbid ADLs qualified as an independent mortality risk factor [adjusted HR 0.77 (95%CI: 0.63-0.95)]. Of 132 patients, 28 (21.2%) lost their independence in at least one ADL. The adjusted risk of LOI declined with a lower frailty degree [aOR 0.03 (95%CI: 0.01-0.32)]. In conclusion, at long-term follow-up after hospitalization for acute SARS-CoV-2 infection, more than 40% of older patients died or experienced a loss of functional independence compared to their pre-morbid condition. Given its high prevalence, the loss of functional independence after hospitalization for COVID-19 could be reasonably included among the features of the "Long COVID-19 syndrome" of older patients.

Background: In general, plant protein intake was inversely associated with mortality in studies in middle-aged adults. Our aim was to evaluate the long-term associations of animal and plant protein intake with mortality in older adults., Methods: A prospective cohort study including 1 139 community-dwelling older adults (mean age 75 years, 56% women) living in Tuscany, Italy, followed for 20 years (InCHIANTI study) was analyzed. Dietary intake by food frequency questionnaires and clinical information were assessed 5 times during the follow-up. Protein intakes were expressed as percentages of total energy. Time-dependent Cox regression models adjusted for confounders were used to assess the association between plant and animal protein intake, and mortality., Results: During the 20 years of follow-up (mean: 12 years), 811 deaths occurred (292 of cardiovascular- and 151 of cancer-related causes). Animal protein intake was inversely associated with all-cause (hazard ratio [HR] per 1% of total energy from protein increase, 95% confidence interval [CI]: 0.96, 0.93-0.99) and cardiovascular mortality (HR per 1% of total energy from protein increase, 95% CI: 0.93, 0.87-0.98). Plant protein intake showed no association with any of the mortality outcomes, but an interaction with baseline hypertension was found for all-cause and cardiovascular mortality (p < .05)., Conclusions: Animal protein was inversely associated with all-cause and cardiovascular mortality in older adults. Further studies are needed to provide recommendations on dietary protein intake for older adults., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Dysphagia is a frequent condition in older nursing home residents (NHRs) which may cause malnutrition and death. Nevertheless, its prevalence is still underestimated and there is still debate about the appropriateness and efficacy of artificial nutrition (AN) in subjects with severe dysphagia. The aim is to assess the prevalence of dysphagia in European and Israeli NHRs, its association with mortality, and the relationship of different nutritional interventions, i.e. texture modified diets and AN-with weight loss and mortality., Methods: A prospective observational study of 3451 European and Israeli NHRs older than 65 years, participating in the SHELTER study from 2009 to 2011, at baseline and after 12 months. All residents underwent a standardized comprehensive evaluation using the interRAI Long Term Care Facility (LTCF). Cognitive status was assessed using the Cognitive Performance Scale (CPS), functional status using Activities of Daily Living (ADL) Hierarchy scale. Trained staff assessed dysphagia at baseline by clinical observation. Data on weight loss were collected for all participants at baseline and after 12 months. Deaths were registered by NH staff., Results: The prevalence of dysphagia was 30.3%. During the one-year follow-up, the mortality rate in subjects with dysphagia was significantly higher compared with that of non-dysphagic subjects (31.3% vs 17.0%,p = 0,001). The multivariate analysis showed that NHRs with dysphagia had 58.0% higher risk of death within 1 year compared with non-dysphagic subjects (OR 1.58, 95% CI, 1.31-1.91). The majority of NHRs with dysphagia were prescribed texture modified diets (90.6%), while AN was used in less than 10% of subjects. No statistically significant difference was found concerning weight loss and mortality after 12 months following the two different nutritional treatments., Conclusions: Dysphagia is prevalent among NHRs and it is associated with increased mortality, independent of the nutritional intervention used. Noticeably, after 12 months of nutritional intervention, NHRs treated with AN had similar mortality and weight loss compared to those who were treated with texture modified diets, despite the clinical conditions of patients on AN were more compromised., (© 2022. The Author(s).)

Background: The purpose of this study was to evaluate the prognostic impact of chest X-ray (CXR) score, frailty, and clinical and laboratory data on in-hospital mortality of hospitalized older patients with COVID-19., Methods: This retrospective study included 122 patients 65 years or older with positive reverse transcription polymerase chain reaction for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and with availability to CXRs on admission. The primary outcome of the study was in-hospital mortality. Statistical analysis was conducted using Cox regression. The predictive ability of the CXR score was compared with the Clinical Frailty Scale (CFS) and fever data using Area Under the Curve (AUC) and net reclassification improvement (NRI) statistics., Results: Of 122 patients, 67 died during hospital stay (54.9%). The CXR score (HR: 1.16, 95% CI, 1.04-1.28), CFS (HR: 1.27; 95% CI, 1.09-1.47), and presence of fever (HR: 1.75; 95% CI, 1.03-2.97) were significant predictors of in-hospital mortality. The addition of both the CFS and presence of fever to the CXR score significantly improved the prediction of in-hospital mortality (NRI, 0.460; 95% CI, 0.102 to 0.888; AUC difference: 0.117; 95% CI, 0.041 to 0.192, p = 0.003)., Conclusions: CXR score, CFS, and presence of fever were the main predictors of in-hospital mortality in our cohort of hospitalized older patients with COVID-19. Adding frailty and presence of fever to the CXR score statistically improved predictive accuracy compared to single risk factors.

Purpose: Under-prescription is defined as the omission of a medication that is indicated for the treatment of a condition or a disease, without any valid reason for not prescribing it. The aim of this review is to provide an updated overview of under-prescription, summarizing the available evidence concerning its prevalence, causes, consequences and potential interventions to reduce it., Methods: A PubMed search was performed, using the following keywords: under-prescription; under-treatment; prescribing omission; older adults; polypharmacy; cardiovascular drugs; osteoporosis; anticoagulant. The list of articles was evaluated by two authors who selected the most relevant of them. The reference lists of retrieved articles were screened for additional pertinent studies., Results: Although several pharmacological therapies are safe and effective in older patients, under-prescription remains widespread in the older population, with a prevalence ranging from 22 to 70%. Several drugs are underused, including cardiovascular, oral anticoagulant and anti-osteoporotic drugs. Many factors are associated with under-prescription, e.g. multi-morbidity, polypharmacy, dementia, frailty, risk of adverse drug events, absence of specific clinical trials in older patients and economic factors. Under-prescription is associated with negative consequences, such as higher risk of cardiovascular events, worsening disability, hospitalization and death. The implementation of explicit criteria for under-prescription, the use of the comprehensive geriatric assessment by geriatricians, and the involvement of a clinical pharmacist seem to be promising options to reduce under-prescription., Conclusion: Under-prescription remains widespread in the older population. Further studies should be performed, to provide a better comprehension of this phenomenon and to confirm the efficacy of corrective interventions.

Background: The aim of our study was to identify independent predictors of functional decline in older nursing home (NH) residents, taking into account both resident and facility characteristics., Methods: Longitudinal observational study involving 1,760 older (≥65 y) residents of NH participating in the SHELTER* study (57 NH in eight countries). All residents underwent a comprehensive geriatric assessment using the interRAI LTCF. Functional decline was defined as an increase of at least one point in the MDS Long Form ADL scale during a 1 year follow-up. Facility and country effects were taken into account., Results: During the study period 891 (50.6%), NH residents experienced ADL decline. Residents experiencing ADL decline were older, had lower disability at baseline, were more frequently affected by severe dementia and by urinary incontinence, and used more antipsychotics. In the mixed-effect logistic regression model, factors independently associated with a higher risk of functional decline were dementia and urinary incontinence, whereas the presence of a geriatrician was a protective factor., Conclusions: Both resident and facility characteristics are associated with the risk of functional decline in NH residents. Increasing the quality of healthcare by involving a geriatrician in residents' care might be an important strategy to improve the outcome of this vulnerable population., (© The Author(s) 2019. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Indoxyl sulfate (IxS), a highly albumin-bound uremic solute, accumulates in chronic kidney disease (CKD) due to reduced renal clearance. This study was designed to specifically investigate the role of human serum albumin (HSA) in IxS renal secretion via organic anion transporter 1 (OAT1) in a microfluidic system and subsequently apply quantitative translation of in vitro data to predict extent of change in IxS renal clearance in CKD stage IV relative to healthy. Conditionally immortalized human proximal tubule epithelial cells overexpressing OAT1 were incubated with IxS (5-200 μM) in the HSA-free medium or in the presence of either HSA or CKD-modified HSA. IxS uptake in the presence of HSA resulted in more than 20-fold decrease in OAT1 affinity (K m,u ) and 37-fold greater in vitro unbound intrinsic clearance (CL int,u ) versus albumin-free condition. In the presence of CKD-modified albumin, K m,u increased four-fold and IxS CL int,u decreased almost seven-fold relative to HSA. Fold-change in parameters exceeded differences in IxS binding between albumin conditions, indicating additional mechanism and facilitating role of albumin in IxS OAT1-mediated uptake. Quantitative translation of IxS in vitro OAT1-mediated CL int,u predicted a 60% decrease in IxS renal elimination as a result of CKD, in agreement with the observed data (80%). The findings of the current study emphasize the role of albumin in IxS transport via OAT1 and explored the impact of modifications in albumin on renal excretion via active secretion in CKD. For the first time, this study performed quantitative translation of transporter kinetic data generated in a novel microfluidic in vitro system to a clinically relevant setting. Knowledge gaps and future directions in quantitative translation of renal drug disposition from microphysiological systems are discussed.

Induction of a functional, tight monolayer of renal epithelial cells on a synthetic membrane to be applied in a bioartificial kidney device requires for bio-activation of the membrane. The current golden standard in bio-activation is the combination of a random polymeric catechol (L-DOPA) coating and collagen type IV (Col IV). Here the possibility of replacing this with defined monomeric catechol functionalization on a biomaterial surface using supramolecular ureido-pyrimidinone (UPy)-moieties is investigated. Monomeric catechols modified with a UPy-unit are successfully incorporated and presented in supramolecular UPy-polymer films and membranes. Unfortunately, these UPy-catechols are unable to improve epithelial cell monolayer formation over time, solely or in combination with Col IV. L-DOPA combined with Col IV is able to induce a tight monolayer capable of transport on electrospun supramolecular UPy-membranes. This study shows that a random polymeric catechol coating cannot be simply mimicked by defined monomeric catechols as supramolecular additives. There is still a long way to go in order to synthetically mimic simple natural structures., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Drug-induced kidney injury in medicinal compound development accounts for over 20% of clinical trial failures and involves damage to different nephron segments, mostly the proximal tubule. Yet, currently applied cell models fail to reliably predict nephrotoxicity; neither are such models easy to establish. Here, we developed a novel three-dimensional (3D) nephrotoxicity platform on the basis of decellularized rat kidney scaffolds (DS) recellularized with conditionally immortalized human renal proximal tubule epithelial cells overexpressing the organic anion transporter 1 (ciPTEC-OAT1). A 5-day SDS-based decellularization protocol was used to generate DS, of which 100- μ m slices were cut and used for cell seeding. After 8 days of culturing, recellularized scaffolds (RS) demonstrated 3D-tubule formation along with tubular epithelial characteristics, including drug transporter function. Exposure of RS to cisplatin (CDDP), tenofovir (TFV), or cyclosporin A (CsA) as prototypical nephrotoxic drugs revealed concentration-dependent reduction in cell viability, as assessed by PrestoBlue and Live/Dead staining assays. This was most probably attributable to specific uptake of CDDP by the organic cation transporter 2 (OCT2), TFV through organic anion transporter 1 (OAT1), and CsA competing for P-glycoprotein-mediated efflux. Compared with 2D cultures, RS showed an increased sensitivity to cisplatin and tenofovir toxicity after 24-hour exposure (9 and 2.2 fold, respectively). In conclusion, we developed a physiologically relevant 3D nephrotoxicity screening platform that could be a novel tool in drug development., (Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.)

The accumulation of protein-bound toxins in dialyzed patients is strongly associated with their high morbidity and mortality. The bioartificial kidney device (BAK), containing proximal tubule epithelial cells (PTECs) seeded on functionalized synthetic hollow fibre membranes, may be a powerful solution for the active removal of those metabolites. In an earlier study, we developed an upscaled BAK containing conditionally immortalized human PTEC with functional organic cationic transporter 2. Here, we first extended this development to a BAK device having cells with the organic anionic transporter 1, capable of removing anionic uraemic wastes. We confirmed the quality of the conditionally immortalized human PTEC monolayer by confocal microscopy and paracellular inulin-fluorescein isothiocyanate leakage, as well as by the active transport of anionic toxin, indoxyl sulphate. Furthermore, we assessed the immune safety of our system by measuring the production of relevant cytokines by the cells after lipopolysaccharide stimulation. Upon lipopolysaccharide treatment, we observed a polarized secretion of proinflammatory cytokines by the cells: 10-fold higher in the extraluminal space, corresponding to the urine compartment, as compared with the intraluminal space, corresponding to the blood compartment. To the best of our knowledge, our work is the first to show this favourable cell polarization in a BAK upscaled device., (Copyright © 2018 John Wiley & Sons, Ltd.)

Background: Delirium is a common geriatric syndrome. Few studies have been conducted in nursing home (NH) residents. The aim of this project was to perform a point prevalence study of delirium in Italian NHs., Methods: Data collected in 71 NHs are presented. Inclusion criteria were age ≥65 years and native Italian speaker. Exclusion criteria were coma, aphasia, and end-of-life status. Sociodemographic and medical data were recorded. Delirium was assessed using the Assessment Test for Delirium and Cognitive Impairment (4-AT). Patients with a 4-AT score ≥4 were considered to have delirium. Motor subtype was evaluated using the Delirium Motor Subtype Scale (DMSS)., Results: A total of 1,454 patients were evaluated (mean age 84.4 ± 7.4 years, 70.2% female), of whom 535 (36.8%) had delirium. In multivariate logistic regression analysis, variables significantly associated with delirium were education (OR 0.94, 95% CI 0.91-0.97), dementia (OR 3.12, 95% CI 2.38-4.09), functional dependence (OR 6.13, 95% CI 3.08-12.19 for ADL score 0; OR 1.99, 95% CI 1.03-3.84 for ADL score 1-5), malnutrition (OR 4.87, 95% CI 2.68-8.84), antipsychotics (OR 2.40, 95% CI 1.81-3.18), and physical restraints (OR 2.48, 95% CI 1.71-3.59)., Conclusion: Delirium is common in older NH residents. Simple assessment tools might facilitate its recognition in this vulnerable population., (© 2018 S. Karger AG, Basel.)

Background: Despite older adults use emergency department more appropriately than other age groups, there is a significant share of admissions that can be considered potentially preventable., Objective: To identify socio-demographic characteristics and health care resources use of older adults admitted to emergency department for a potentially preventable visit., Design: Data come from the Multipurpose Survey "Health conditions and use of health services", edition 2012-2013. A stratified multi-stage probability design was used to select a sample using municipal lists of households., Subject: 50474 community dwelling Italians were interviewed. In this analysis, 27003 subjects aged 65 years or older were considered., Methods: Potentially preventable visits were defined as an emergency department visit that did not result in inpatient admission. Independent variables were classified based on the socio-behavioral model of Andersen-Newman. Descriptive statistics and a logistic regression model were developed., Results: In the twelve months before the interview 3872 subjects (14.3%) had at least one potentially preventable visit. Factors associated with an increased risk of a potentially preventable visit were older age (75-84 years: OR 1.096, CI 1.001-1.199; 85+years: OR 1.022, CI 1.071-1.391), at least one hospital admission (OR 3.869, IC 3.547-4.221), to waive a visit (OR 1.188, CI 1.017-1.389) or an exam (OR 1.300, CI 1.077-1.570). Factors associated with a lower risk were female gender (OR 0.893, CI 0.819-0.975), area of residence (Center: OR 0.850; CI 0.766-0.943; Islands: OR 0.617, CI 0.539-0.706, South: OR 0.560; CI 0.505-0.622), private paid assistance (OR 0.761, CI 0.602-0.962); a better health-related quality of life (PCS score 46-54: OR 0.744, CI 0.659-0.841; PCS score >55: OR 0.746, CI 0.644-0.865)., Conclusions: Our study identified several characteristics associated with an increased risk of potentially preventable visits to the emergency department. This might allow the development of specific interventions to prevent the access of at risk subjects to the emergency department.

As current kidney replacement therapies are not efficient enough for end-stage renal disease (ESRD) treatment, a bioartificial kidney (BAK) device, based on conditionally immortalized human proximal tubule epithelial cells (ciPTEC), could represent an attractive solution. The active transport activity of such a system was recently demonstrated. In addition, endocrine functions of the cells, such as vitamin D activation, are relevant. The organic anion transporter 1 (OAT-1) overexpressing ciPTEC line presented 1α-hydroxylase (CYP27B1), 24-hydroxylase (CYP24A1) and vitamin D receptor (VDR), responsible for vitamin D activation, degradation and function, respectively. The ability to produce and secrete 1α,25-dihydroxy-vitamin D₃, was shown after incubation with the precursor, 25-hydroxy-vitamin D₃. The beneficial effect of vitamin D on cell function and behavior in uremic conditions was studied in the presence of an anionic uremic toxins mixture. Vitamin D could restore cell viability, and inflammatory and oxidative status, as shown by cell metabolic activity, interleukin-6 (IL-6) levels and reactive oxygen species (ROS) production, respectively. Finally, vitamin D restored transepithelial barrier function, as evidenced by decreased inulin-FITC leakage in biofunctionalized hollow fiber membranes (HFM) carrying ciPTEC-OAT1. In conclusion, the protective effects of vitamin D in uremic conditions and proven ciPTEC-OAT1 endocrine function encourage the use of these cells for BAK application., Competing Interests: The authors declare no conflict of interest.

Patients with end-stage renal disease often undergo dialysis as a partial substitute for kidney function while waiting for their only treatment option: a kidney transplant. Several research directions emerged for alternatives in support of the ever-growing numbers of patients. Recent years brought big steps forward in the field, with researchers questioning and improving the current dialysis devices as well as moving towards the design of a bioengineered kidney. Whole-organ engineering is also being explored as a possibility, making use of animal or human kidney scaffolds for engineering a transplantable organ. While this is not a new strategy, having been applied so far for thin tissues, it is a novel approach for complex organs such as the kidneys. Kidneys can be decellularized and the remaining scaffold consisting of an extracellular matrix can be repopulated with (autologous) cells, aiming at growing ex vivo a fully transplantable organ. In a broader view, such organs might also be used for a better understanding of fundamental biological concepts and disease mechanisms, drug screening and toxicological investigations, opening new pathways in the treatment of kidney disease.Decellularization of whole organs has been widely explored and described; therefore, this manuscript only briefly reviews some important considerations with an emphasis on scaffold decontamination, but focuses further on recellularization strategies. Critical aspects, including cell types and sources that can be used for recellularization, seeding strategies and possible applications beyond renal replacement are discussed.

Patients with type 2 diabetes mellitus are at high risk for atherosclerotic disease, and proper blood pressure measurement is mandatory. The authors examined the prevalence of an interarm difference (IAD) in blood pressure and its association with cardiovascular risk factors and organ damage (nephropathy, retinopathy, left ventricular hypertrophy, and vascular damage) in a large diabetic population. A total of 800 consecutive patients with type 2 diabetes mellitus were evaluated with an automated simultaneous bilateral device (men: 422 [52.8%]; mean age: 68.1±12.2 years). Diabetic patients with systolic IAD ≥5 and systolic IAD ≥10 mm Hg showed an increased risk of having vascular damage (adjusted odds ratios: 1.73 and 2.49, respectively) and higher pulse pressure. IAD is highly prevalent in patients with diabetes, is associated with vascular damage, even for IAD ≥5 mm Hg, and should be accurately obtained to avoid underdiagnosis and undertreatment of hypertension., (©2016 Wiley Periodicals, Inc.)

The limited removal of metabolic waste products in dialyzed kidney patients leads to high morbidity and mortality. One powerful solution for a more complete removal of those metabolites might be offered by a bioartificial kidney device (BAK), which contains a hybrid "living membrane" with functional proximal tubule epithelial cells (PTEC). These cells are supported by an artificial functionalized hollow fiber membrane (HFM) and are able to actively remove the waste products. In our earlier studies, conditionally immortalized human PTEC (ciPTEC) showed to express functional organic cationic transporter 2 (OCT2) when seeded on small size flat or hollow fiber polyethersulfone (PES) membranes. Here, an upscaled "living membrane" is presented. We developed and assessed the functionality of modules containing three commercially available MicroPES HFM supporting ciPTEC. The HFM were optimally coated with L-Dopa and collagen IV to support a uniform and tight monolayer formation of matured ciPTEC under static culturing conditions. Both abundant expression of zonula occludens-1 (ZO-1) protein and limited diffusion of FITC-inulin confirm a clear barrier function of the monolayer. Furthermore, the uptake of 4-(4-(dimethylamino)styryl)-N-methylpyridinium iodide (ASP + ), a fluorescent OCT2 substrate, was studied in absence and presence of known OCT inhibitors, such as cimetidine and a cationic uremic solutes mixture. The ASP + uptake by the living upscaled membrane was decreased by 60% in the presence of either inhibitor, proving the active function of OCT2. In conclusion, this study presents a successful upscaling of a living membrane with active organic cation transport as a support for BAK device., (Copyright © 2016 Elsevier B.V. All rights reserved.)

The development of a biotechnological platform for the removal of waste products (e.g. uremic toxins), often bound to proteins in plasma, is a prerequisite to improve current treatment modalities for patients suffering from end stage renal disease (ESRD). Here, we present a newly designed bioengineered renal tubule capable of active uremic toxin secretion through the concerted action of essential renal transporters, viz. organic anion transporter-1 (OAT1), breast cancer resistance protein (BCRP) and multidrug resistance protein-4 (MRP4). Three-dimensional cell monolayer formation of human conditionally immortalized proximal tubule epithelial cells (ciPTEC) on biofunctionalized hollow fibers with maintained barrier function was demonstrated. Using a tailor made flow system, the secretory clearance of human serum albumin-bound uremic toxins, indoxyl sulfate and kynurenic acid, as well as albumin reabsorption across the renal tubule was confirmed. These functional bioengineered renal tubules are promising entities in renal replacement therapies and regenerative medicine, as well as in drug development programs.

Background: The diagnosis of heart failure (HF) is often difficult and underestimated in very elderly comorbid patients, especially when an echocardiographic evaluation is not available or feasible., Aim: to evaluate NT-proBNP values and their correlation with in-hospital mortality in a population of very elderly hospitalized for medical conditions other than HF., Methods: We performed a prospective observational study on 403 very elderly admitted to an Internal Medicine and Geriatrics Department. Exclusion criterion was an admission diagnosis of HF. Patients with at least one symptom or sign compatible with HF were tested for NT-proBNP. NT-proBNP values < 300 pg/ml were considered as an age-independent exclusion criterion for HF (high negative predictive value), while NT-proBNP values ≥ 1800 pg/ml were considered as a diagnostic criterion. Main comorbidities and laboratory parameters were considered to adjust regression analyses between NT-proBNP and in-hospital mortality., Results: NT-proBNP values ≥ 1800 pg/ml were present in 61.0% of patients and 32.8% of patients laid between 300 ≤ NT-proBNP < 1800 pg/ml values. NT-proBNP values were associated with the main indices of disease severity/organ failure considered such as reduced eGFR, reduced albumin and elevated CRP. NT-proBNP values ≥ 1800 pg/ml and ln(NT-proBNP) values were significantly associated with in-hospital mortality independently from the main comorbidities and lab parameters considered. The patients, who were already taking ACE inhibitors/Angiotensin Receptor Blockers before admission, showed lower in-hospital mortality., Conclusions: Testing for NT-proBNP should be strongly recommended in the hospitalized very elderly, because of the very high prevalence of underlying HF and its impact on in-hospital mortality, to identify an underlying cardiac involvement that requires appropriate treatment.

Objectives: To identify independent predictors of the risk of functional decline in older nursing home (NH) residents., Design: A longitudinal observational study., Setting: Thirty-one NHs participating in the U.L.I.S.S.E. project, distributed throughout Italy., Participants: All older (≥65 years) long-term NH residents without complete disability and with at least one follow-up evaluation during the 12-month study period (n = 1263)., Measurements: All participants underwent a standardized comprehensive evaluation using the Italian version of the Minimum Data Set for NHs. The activities of daily living (ADLs) Long-Form scale was used to evaluate functional status. Facility characteristics were collected using an ad hoc designed questionnaire., Results: Of the NH residents, 40.4% experienced a decline in the ADL during the follow-up. The mixed effect logistic regression model showed that depression (odds ratio [OR] 1.45, confidence interval [CI] 1.16-1.81, P = .005) and the use of antipsychotics (OR 1.30, CI 1.06-1.60, P = .016) were associated with a higher probability of ADL decline, whereas the presence of a geriatrician (OR 0.60, CI 0.41-0.88, P = .015) and a higher than median hour per resident per week of nursing care (OR 0.55, CI 0.37-0.80, P = .006) were associated with a lower risk., Conclusions: Our findings suggest that preventing functional decline in NH residents might be possible by optimizing the management of depression and by reducing the current high prescription rate of antipsychotics. Moreover, the presence of a geriatrician, associated with an adequate amount of nursing care, seem to be important facilities characteristics to achieve this goal. These findings should be tested in large-scale pragmatic clinical trials., (Copyright © 2016 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

Introduction: The prevalence of systemic arterial hypertension in young adults is increasing worldwide in association with modifiable risk factors., Aim: To assess the prevalence of high blood pressure (BP) in young adults participating to a screening campaign during the World Hypertension Day (17/05/2014), and to determine the possible association with lifestyle factors., Methods: 493 individuals aged 18-35 years were selected in 13 Italian cities. All participants underwent BP measurement together with the administration of a questionnaire exploring: medical and drug history; traditional cardiovascular risk factors and diseases; dietary pattern; salt intake; sleep habits; mood disorders., Results: High BP (≥140/90 mmHg) was found in 54 individuals, with a prevalence of 11% and awareness of 28%. Those with high BP values were more frequently men, reported a higher BMI and a greater use of corticosteroids and non-steroidal anti-inflammatory drugs, and had a lower anxiety score. Concerning dietary habits, they were more likely to eat cheese/cold cuts ≥3 times/week, to have their meals out ≥1/day and to eat in fast foods ≥1/week. In the multiple logistic regression analysis, male sex [OR 3.19, 95% CI (1.33-7.63)], BMI [OR 1.14 95% CI (1.04-1.25)], eating in fast foods [OR 3.10 95% CI (1.21-7.95)], and anxiety [OR 0.85 95% CI (0.75-0.97)], were independently associated with high BP., Conclusions: High BP values were found in 11 % young adults. Male sex, adiposity and alimentary habits were the main determinants of high BP values, indicating that young men are a suitable target for healthy lifestyle interventions.

The bioartificial kidney (BAK) aims at improving dialysis by developing 'living membranes' for cells-aided removal of uremic metabolites. Here, unique human conditionally immortalized proximal tubule epithelial cell (ciPTEC) monolayers were cultured on biofunctionalized MicroPES (polyethersulfone) hollow fiber membranes (HFM) and functionally tested using microfluidics. Tight monolayer formation was demonstrated by abundant zonula occludens-1 (ZO-1) protein expression along the tight junctions of matured ciPTEC on HFM. A clear barrier function of the monolayer was confirmed by limited diffusion of FITC-inulin. The activity of the organic cation transporter 2 (OCT2) in ciPTEC was evaluated in real-time using a perfusion system by confocal microscopy using 4-(4-(dimethylamino)styryl)-N-methylpyridinium iodide (ASP(+)) as a fluorescent substrate. Initial ASP(+) uptake was inhibited by a cationic uremic metabolites mixture and by the histamine H2-receptor antagonist, cimetidine. In conclusion, a 'living membrane' of renal epithelial cells on MicroPES HFM with demonstrated active organic cation transport was successfully established as a first step in BAK engineering.

Ambulatory blood pressure monitoring (ABPM) is central in the management of hypertension. Factors related to BP, such as body mass index (BMI), may differently affect particular aspects of 24-hour ABPM profiles. However, the relevance of BMI, the most used index of adiposity, has been underappreciated in the determination of specific aspects of 24-hour ABPM profiles in hypertension. The authors evaluated the association between BMI and aspects of ABPM together with their associations with cardiac remodeling in 1841 patients. A positive association of BMI with 24-hour, daytime, and nighttime pulse pressure in untreated normal weight and overweight/obese hypertensive patients and a positive association of BMI with nocturnal BP parameters in treated overweight/obese hypertensive patients was observed. The clinical relevance of these findings was supported by the positive significant correlations of BMI-related BPs with left ventricular mass and atrial diameter., (© 2015 Wiley Periodicals, Inc.)

With the world-wide increase of patients with renal failure, the development of functional renal replacement therapies have gained significant interest and novel technologies are rapidly evolving. Currently used renal replacement therapies insufficiently remove accumulating waste products, resulting in the uremic syndrome. A more preferred treatment option is kidney transplantation, but the shortage of donor organs and the increasing number of patients waiting for a transplant warrant the development of novel technologies. The bioartificial kidney (BAK) is such promising biotechnological approach to replace essential renal functions together with the active secretion of waste products. The development of the BAK requires a multidisciplinary approach and evolves at the intersection of regenerative medicine and renal replacement therapy. Here we provide a concise review embracing a compact historical overview of bioartificial kidney development and highlighting the current state-of-the-art, including implementation of living-membranes and the relevance of extracellular matrices. We focus further on the choice of relevant renal epithelial cell lines versus the use of stem cells and co-cultures that need to be implemented in a suitable device. Moreover, the future of the BAK in regenerative nephrology is discussed., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The worldwide prevalence of obesity has nearly doubled, with an increase in obesity-related cardiovascular disease and mortality. Several factors are involved in the genesis of hypertension and hypertensive heart disease (HHD) in overweight/obesity. This review is focused on bridging factors between excessive adiposity and HHD, presenting a unifying hypothesis of vascular-metabolic syndrome, where an "handicap" of the natriuretic peptide system has a central role both in adipocyte dysmetabolism as well as in increased blood pressure and HHD.

Background: Hypertension plays a key role in chronic kidney disease (CKD), but CKD itself affects the blood pressure (BP) profile. The aim of this study was to assess the association of BP profile with CKD and the presence of cardiac organ damage., Methods: We studied 1805 patients, referred to our Hypertension Centre, in whom ABPM, blood tests, and echocardiography were clinically indicated. The glomerular filtration rate was estimated (eGFR) using the MDRD equation and CKD was defined as eGFR<60 mL/min/1.73 m(2). Cardiac organ damage was evaluated by echocardiography., Results: Among patients with CKD there were higher systolic blood pressure (SBP) during the night-time, greater prevalence of non-dippers (OR: 1.8) and increased pulse pressure (PP) during 24-hour period, daytime and night-time (all p<0.001). Patients with CKD had a greater LVM/h(2.7) index, and a higher prevalence of left ventricular hypertrophy and diastolic dysfunction (all p<0.001). Nocturnal SBP and PP correlated more strongly with cardiac organ damage (p<0.001). Patients with CKD had a greater Treatment Intensity Score (p<0.001) in the absence of a significantly greater BP control., Conclusions: CKD patients have an altered night-time pressure profile and higher PP that translate into a more severe cardiac organ damage. In spite of a greater intensity of treatment in most patients with CKD, BP control was similar to patients without CKD. Our findings indicate the need of a better antihypertensive therapy in CKD, better selected drugs, dosages and posology to provide optimal coverage of 24 hours and night-time BP.

Objective: Evaluation of seasonal influences on ambulatory blood pressure monitoring (ABPM) values in a very large population living in a mild-climate geographic area., Methods: Among patients referred to our Hypertension Center between September 2002 and January 2011 with a reliable ABPM, we considered those in the two hottest (July and August) vs. those in the two coldest (January and February) months., Results: Seven hundred and forty-two men (53.2%) and 653 women (46.8%) were studied; 1245 (89.3%) were hypertensive patients of which 795 (63.9%) were drug-treated. In winter, mean daytime SBP and DBP were higher (P = 0.001 and P < 0.001, respectively), but only 24-h DBP was significantly higher (P = 0.012). On the contrary, higher night-time SBP and pulse pressure were recorded in summer (P = 0.005 and P = 0.023, respectively). Uncontrolled hypertensive patients had the highest mean difference between winter and summer night-time SBP (127.1 ± 13.4 vs. 131.0 ± 12.6 mmHg; P = 0.001). In winter a dipping pattern was prevalent (58.2%), whereas in summer a nondipping pattern prevailed (61.9%; P < 0.001). Isolated nocturnal hypertension (INH) was present in 9.8% in winter vs. 15.2% in summer (P = 0.003)., Conclusion: Our data on a very large ABPM sample confirmed that hottest summer months are associated with lower daytime BP and also lower 24-h DBP. However, we found an inverse relationship regarding night-time BP, dipping pattern, and INH that were higher or more common in summer. These findings were even more evident in treated patients, especially when not at target. Different sleeping behaviors or improper dose reduction of drug therapy in summer may explain the findings.