Search

Summary Background & aims Longevity also carries its dark side of age-related chronic diseases, dementia being one of the worst and the most prevalent. Since dementia lacks effective treatments, preventing or delaying it is highly desirable. Dietary habits and nutrition have been found to be important modifiable risk factors for many chronic diseases, but evidence on the role of diet on the risk of dementia is still limited, particularly among the very old. Aim of the present work is to study the association of the Mediterranean diet and its components with prevalent and incident dementia in the oldest-old. Methods We analyzed data from the Monzino 80-plus study, a population-based study in subjects 80 years or older in the Varese province, Italy. A validated food frequency questionnaire was used to collect information on 23 different foods consumed in the previous year. A Mediterranean diet score was calculated and its components were classified into tertiles. Multivariable models for dementia prevalence and incidence were adjusted for demographic and clinical characteristics. Results Information on nutrition was available for 1390 subjects in the cross-sectional study and 512 subjects in the longitudinal study, mean respective ages 93 and 92. Greater adherence to Mediterranean diet, greater consumption of eggs, fruits and vegetables, carbohydrates, and greater food intake were associated with a lower prevalence of dementia. Increasing number of portions per week and consumption of legumes significantly decreased the incidence of dementia during the 3.6 year mean follow-up: corresponding hazard ratios of highest vs. lowest tertiles (95% confidence intervals) were 0.66 (0.46–0.95) and 0.68 (0.47–0.97), respectively. Conclusion Oldest-old eating less and having diets with less variety and nutrient density were more frequent among subjects with dementia. The longitudinal analysis confirmed oldest-old subjects who eat more portions, as well as those who have a higher intake of legumes, are at decreased risk of developing dementia even though reverse causality cannot be completely ruled out.

To assess the accuracy of hospice staff in predicting survival of subjects admitted to hospice, exploring the factors considered most helpful by the hospice staff to accurately predict survival. Five physicians and 11 nurses were asked to predict survival at admission of 827 patients. Actual and predicted survival times were divided into ≤ 1 week, 2–3 weeks, 4–8 weeks, and ≥ 2 months and the accuracy of the estimates was calculated. The staff members were each asked to score 17 clinical variables that guided them in predicting survival and we analyzed how these variables impacted the accuracy. Physicians’ and nurses’ accuracy of survival of the patients was 46% and 40% respectively. Survival was underestimated in 20% and 12% and overestimated in 34% and 48% of subjects. Both physicians and nurses considered metastases, comorbidities, dyspnea, disability, tumor site, neurological symptoms, and confusion very important in predicting patients’ survival with nurses assigning more importance to intestinal symptoms and pain too. All these factors, with the addition of cough and/or bronchial secretions, were associated with physicians’ greater accuracy. In the multivariable models, intestinal symptoms and confusion continued to be associated with greater predictive accuracy. No factors appreciably raised nurses’ accuracy. Some clinical symptoms rated as relevant by the hospice staff could be important for predicting survival. However, only intestinal symptoms and confusion significantly improved the accuracy of physicians’ predictions, despite the high prevalence of overestimated survival.

AIM Insulin is the preferred treatment for the control of diabetes in hospital, but it raises the risk of hypoglycaemia, often because oral intake of carbohydrates in hospitalized persons is lower than planned. Our aim was to assess the effect on the incidence of hypoglycaemia of giving prandial insulin immediately after a meal depending on the amount of carbohydrate ingested. METHODS A prospective pre-post intervention study in hospitalized persons with diabetes eating meals with stable doses of carbohydrates present in a few fixed foods. Foods were easily identifiable on the tray and contained fixed doses of carbohydrates that were easily quantifiable by nurses as multiples of 10 g (a 'brick'). Prandial insulin was given immediately after meals in proportion to the amount of carbohydrates eaten. RESULTS In 83 of the first 100 people treated with the 'brick diet', the oral carbohydrate intake was lower than planned on at least one occasion (median: 3 times; Q1-Q3: 2-6 times) over a median of 5 days. Compared with the last 100 people treated with standard procedures, postprandial insulin given on the basis of ingested carbohydrate significantly reduced the incidence of hypoglycaemic events per day, from 0.11 ± 0.03 to 0.04 ± 0.02 (P

Introduction: There are limited data on prevalence of dementia in centenarians and near-centenarians (C/NC), its determinants, and whether the risk of dementia continues to rise beyond 100. Methods: Participant-level data were obtained from 18 community-based studies (N = 4427) in 11 countries that included individuals ≥95 years. A harmonization protocol was applied to cognitive and functional impairments, and a meta-analysis was performed. Results: The mean age was 98.3 years (SD = 2.67); 79% were women. After adjusting for age, sex, and education, dementia prevalence was 53.2% in women and 45.5% in men, with risk continuing to increase with age. Education (OR 0.95;0.92–0.98) was protective, as was hypertension (odds ratio [OR] 0.51;0.35–0.74) in five studies. Dementia was not associated with diabetes, vision and hearing impairments, smoking, and body mass index (BMI). Discussion: Among the exceptional old, dementia prevalence remains higher in the older participants. Education was protective against dementia, but other factors for dementia-free survival in C/NC remain to be understood.

Monoclonal gammopathy of undetermined significance (MGUS) and clonal hematopoiesis (CH) are 2 preclinical clonal expansions of hematopoietic cells whose prevalence rises with age, reaching almost 10% in people of aged 70 years and older. The increased risk of myeloid malignancies in patients with myeloma is well defined, and the study of the association between CH and MGUS could help explain this phenomenon. Here, we analyzed a fully clinically annotated dataset of 777 older subjects (median age, 91 years) previously screened for prevalence of CH. The prevalence of MGUS and CH was 9.6% and 17.3%, respectively. We detected CH in 9.7% of the patients with MGUS and MGUS in 5.5% of the patients with CH. We did not find a significant correlation between the presence of MGUS and CH. Furthermore, the 2 conditions showed a differential association with clinical and laboratory covariates, suggesting that MGUS and CH may represent age-associated unrelated clonal drifts of hematopoietic cells. Confirmatory studies are needed to assess the relevance of CH in plasma cell disorders. This trial was registered at www.clinicaltrials.gov as #NCT03907553.

Introduction Relationship between age and dementia at extreme old ages is still an open question, yet population-based studies in this high-risk age segment are rare. Methods The Monzino 80-plus is a population-based study among residents 80 years and older in the Varese province, Italy. Of 1371 eligible individuals, 1294 (94.4%), of whom 64 are centenarians, were included in the incidence study. Results Since 2002, 584 new cases of all-cause dementia were identified over 15 years. The overall incidence rate was 7.9 per 100 person-years. Dementia risk rose with age (IRR: 1.06), with the cubic model providing the best fit (R2 = 0.91–0.96). Cumulative incidences of dementia unadjusted and adjusted for competing mortality risk progressively diverged with age. Conclusion Dementia incidence also keeps rising in nonagenarians and centenarians. Slowing down in growing risk of developing dementia with age is mainly attributable to increasing competing risk of death and resulting selective survival of individuals at lower risk of dementia.

Clonal hematopoiesis of indeterminate potential (CHIP) is associated with increased risk of cancers and inflammation-related diseases. This phenomenon becomes common in persons aged ≥80 years, in whom the implications of CHIP are not well defined. We performed a mutational screening in 1794 persons aged ≥80 years and investigated the relationships between CHIP and associated pathologies. Mutations were observed in one-third of persons aged ≥80 years and were associated with reduced survival. Mutations in JAK2 and splicing genes, multiple mutations (DNMT3A, TET2, and ASXL1 with additional genetic lesions), and variant allele frequency ≥0.096 had positive predictive value for myeloid neoplasms. Combining mutation profiles with abnormalities in red blood cell indices improved the ability of myeloid neoplasm prediction. On this basis, we defined a predictive model that identifies 3 risk groups with different probabilities of developing myeloid neoplasms. Mutations in DNMT3A, TET2, ASXL1, or JAK2 were associated with coronary heart disease and rheumatoid arthritis. Cytopenia was common in persons aged ≥80 years, with the underlying cause remaining unexplained in 30% of cases. Among individuals with unexplained cytopenia, the presence of highly specific mutation patterns was associated with myelodysplastic-like phenotype and a probability of survival comparable to that of myeloid neoplasms. Accordingly, 7.5% of subjects aged ≥80 years with cytopenia had presumptive evidence of myeloid neoplasm. In summary, specific mutational patterns define different risk of developing myeloid neoplasms vs inflammatory-associated diseases in persons aged ≥80 years. In individuals with unexplained cytopenia, mutational status may identify those subjects with presumptive evidence of myeloid neoplasms.

Clonal, pre-clinical expansions of hematopoietic cells are increasingly recognized. Clonal hematopoiesis of indeterminate potential (CHIP) has been recently described. It is characterized by the presence of mutations usually involved in myeloid neoplasia in people without any sign of hematological malignancy. Well before CHIP, another pre-clinical clonal expansion has been described for plasma cells (PC) based on the presence of a serum monoclonal protein, namely monoclonal gammopathy of undetermined significance (MGUS). Despite both being frequent, the association between these two bone marrow (BM) clonal entities has not been determined yet. Since the incidence of MGUS and CHIP rises with age reaching >10% of people >70y, we analyzed a unique oldest-old population dataset to define a possible association between these two different BM clonal disorders. We analyzed a cohort of 777 patients with a median age of 91 years (range, 81 - 104), significantly higher than previous studies on MGUS. 579 (74.5%) were females and 198 (25.5%) males. CHIP was assessed in all but 45 through sequencing of a myeloid specific gene panel. Serum protein electrophoresis was available in all of them to assess the prevalence of MGUS. The prevalence of CHIP and MGUS were 17.5% (128/732) and 9.5% (74/777), respectively. Importantly, CHIP and MGUS did not associate in our cohort but rather showed a non-significant trend towards anti-correlation (Fisher's Exact test, p-val = 0.09). We then tested associations with different clinical and laboratory features, finding that, as expected, MGUS associated with higher concentration of gamma-globulins (Wilcoxon test, p-val = 0.01414), but also with absolute lower levels of albumin (Wilcoxon test, p-val = 0.01398). No significant association was found with the mean corpuscular value (MCV), hemoglobin levels or age. These results were confirmed by a logistic univariate model, in which also the male gender resulted associated with the presence of a monoclonal component with borderline significance. Then, to further corroborate our results we performed univariate linear regression analyses. Given that CHIP and MGUS are mainly considered two aging conditions, we investigated in linear regression models the impact of age, as a continuous variable, on other clinical features. In particular, we observed that the increase of age was significantly correlated with lower albumin levels (F-stat: 1.921e+04, Adj R-squared: 0.9288, p-val: < 2.2e-16), decreasing hemoglobin concentration (F-stat: 1.434e+05, Adj R-squared: 0.9898, p-val < 2.2e-16), increasing levels of gamma-globulins (F-stat: 9.21e+04, Adj R-squared: 0.9843, p-val < 2.2e-16) and higher MCV (F-stat: 18.04, Adj R-squared: 0.01144, p-val 2.3e-05). Then, a significant anti-correlation between gamma-globulin and serum albumin levels was also confirmed (F-stat: 2.807e+04, Adj R-squared: 0.9501, p-val < 2.2e-16). Finally, we implemented two different multivariate logistic models using as independent variables the presence or absence of MGUS or CHIP, respectively. In these models, the presence of a monoclonal component was only positively associated with a higher level of gamma-globulins (Est: 0.16238, p-val = 0.00079) and not with increasing age (Est: 0.02680, p-val = 0.31819). Interestingly, the presence of an MGUS confirmed a tendency to an anti-correlation with the presence of CHIP (Est: -0.78959, p-val = 0.06468). On the contrary, CHIP as independent variable resulted significantly correlated with increasing age (Est: 0.07396, p-val = 0.00021). The spectrum of mutations in CHIP cases with or without MGUS was not significantly different, with DNMT3A and TET2 being the most frequently mutated genes. Our study shows that, in a large cohort of oldest-old patients, CHIP and MGUS are not correlated but follow two seemingly independent patterns, showing a tendency to a mutual exclusivity and associating with different clinical and laboratory values. One limitation of our study is the skewing towards female sex, where MGUS is less prevalent, but this is explained by the cohort's median age knowing that females have a longer expected life. Based on this, our findings that CHIP but not MGUS increased with age in our cohort suggest different selective pressures in this extreme age range. These results warrant further investigation as to whether there could be age-specific drivers for MGUS, and their clinical relevance. Disclosures Bolli: Amgen: Honoraria; Takeda: Honoraria; Janssen: Consultancy, Honoraria; Celgene/BMS: Consultancy, Honoraria.

Background Atrial fibrillation (AF) and dementia are largely prevalent and incident in progressively older subjects, suggesting a link between the two conditions. While in the general population there are several findings supporting a causal relationship between AF and dementia, it is unclear whether or not this association is still present in individuals aged 80 and older. Results So far, the few studies that analysed this issue did not provide enough evidence supporting the causative role of AF in increasing the risk of cognitive decline or dementia in patients aged 80 and older. Conversely, a relevant role of optimal anticoagulation control in determining a significant reduction in the risk of cognitive decline is suggested, in AF subjects aged 80 years or older. Conclusions Further data, coming from population-based studies specifically investigating very old individuals and based upon large samples and comprehensive cognitive assessments, are needed to fully elucidate the relationship between AF and dementia in very old individuals.

Background: Clonal hematopoiesis of indeterminate potential (CHIP) is associated with increased risk of cancers and inflammation-related diseases. The phenomenon becomes very common in oldest-old individuals, in whom the implications of CHIP are not well defined. Here we investigate the relationships between CHIP and associated pathologies in people aged >80 years. Methods: We performed a mutational screening in 1794 oldest-old individuals enrolled in two population-based studies (“Health_&_Anemia” and “Monzino_80+”). Findings: Clonal mutations were observed in one third of oldest-old individuals and were associated with reduced survival and increased risk of cancers. Mutations in JAK2 and splicing genes (SF3B1, SRSF2, U2AF1, ZRSR2), multiple mutations (DNMT3A, TET2, ASXL1) combined with additional genetic lesions) and variant allele frequency ≥0.14 had positive predictive value for myeloid neoplasms. Combining mutation profiles with abnormalities in red blood cell indices improved the ability of myeloid neoplasm prediction. On this basis, we defined a predictive model that identifies 3 risk groups with different probabilities of developing myeloid neoplasms. Mutations in DNMT3A, TET2, ASXL1 or JAK2 (most occurring as single lesion) were associated with coronary heart disease and rheumatoid arthritis. Cytopenia (most including anemia) was a common finding in oldest-old population (>20%), the underlying cause remaining unexplained in 30% of cases. Among individuals with unexplained cytopenia, the presence of highly-specific mutation patterns was associated with a myeloid neoplasms-like phenotype and a probability of survival comparable to that of myeloid neoplasms. Accordingly, 7.5% of oldest-old subjects with cytopenia had presumptive evidence of myeloid neoplasm. Interpretation: Specific mutational patterns define different risk of developing cancers vs. inflammatory-associated diseases in oldest-old population. In individuals with unexplained cytopenia, mutational status may identify those subjects with presumptive evidence of myeloid neoplasms. Trial Registration: (ClinicalTrials.gov number:NCT03907553) Funding: Supported by European Union; Cariplo Foundation, Italy; Italian Association for Cancer Research; Italian Ministry of Health and Research. Declaration of Interests: The Authors declare no competing interests. Ethics Approval Statement: Study procedures were in accordance with the Declaration of Helsinki. Ethics Committees of Humanitas Research Hospital and Mario Negri Pharmacological Institute, Milan Italy approved the study. Written informed consent was obtained prior to blood sampling.

Aim In this study, the relationship between kidney function, cognitive performance, functional abilities and mood was investigated in a community-dwelling Italian oldest-old population. Methods Serum creatinine was used to calculate estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease formula, for 415 oldest-old without dementia participating in the 'Health and Anemia' study, a prospective, observational cohort study. The cross-sectional associations of kidney function with cognitive performance on several neuropsychological tests, basic and instrumental functional abilities and mood were analyzed using univariate and multivariable linear regression models. Results Cognitive performance and functional ability significantly worsened with decreasing kidney function. After adjusting for age, sex, education, comorbidity index of the Cumulative Illness Rating Scale (CIRS), body mass index, bone fracture and serum ferritin levels the associations of eGFR categories with basic and instrumental functional abilities continued to be statistically significant whereas that with global cognitive functions did not. No significant independent association was found between renal function and mood. Conclusions Oldest-old with reduced kidney function showed greater basic and instrumental functional disabilities, while cognitive function, although decreased with decreasing eGFR, was no longer significantly associated with eGFR categories after adjusting for confounders.

To describe the incidence of ischemic stroke, short-term mortality, recurrences, and prescription patterns.Data from administrative health databases of the Lombardy Region from 2002 to 2010 (about 4 million people) were analyzed for stroke incidence and recurrence, mortality, and drug prescriptions after an ischemic stroke.A total of 43,352 patients with a first hospital admission for ischemic stroke were identified. During 8 years, stroke incidence decreased from 3.2 of 1000 to 2.4 of 1000 (P.001) in people aged 65-74 years, from 7.1 of 1000 to 5.3 of 1000 (P.001) at ages 75-84 years and from 11.9 of 1000 to 9.4 of 1000 (P.001) at age 85 years or older. Stroke recurrences dropped by 30% (from 10.0% to 7.0%, P.001) and 30-day mortality rate also decreased. Prescription trends showed linear increase in antiplatelets and lipid-lowering drugs, respectively, from 60.2% to 65.0% (P.001) and from 19.1% to 34.6% (P.001), whereas antihypertensive prescriptions did not change appreciably. Anticoagulant prescription increased in patients with atrial fibrillation, from 64.8% to 72.1% in the 65-74 years age group, (P = .004) and from 40.2% to 53.7% in the 75-84 years age group (P.001); less than 20% of the 85 years or older age group were treated with anticoagulants (P.0001).Stroke incidence, recurrence, and 30-day mortality decreased from 2002 to 2010 concomitant with an increase in prescriptions of secondary stroke prevention drugs.

To assess the effectiveness, safety and feasibility of the revised, simplified nurse-managed version of our insulin infusion protocol, adapted to the new recommended glycaemic target of 140 to 180 mg/dL (Desio Diabetes Diagram i.v. 140-180).All clinical responses to the Desio Diabetes Diagram i.v. 140-180 in use for 3 years were recorded in patients with diabetes or hyperglycaemia admitted to our intensive cardiac care unit. To assess the feasibility, we asked nurses to complete an ad hoc questionnaire anonymously when the new insulin infusion protocol had been in use for 2 years.From December 2010 to December 2013, 276 patients (173 men, median age 75 years) were treated according to the Desio Diabetes Diagram i.v. 140-180. The median time to reach glycaemic target was 4 h (Q1-Q3 2-8) in 128 patients with blood glucose180 mg/dL and 2 h (Q1-Q3 1-4) in 82 patients with blood glucose140 mg/dL. Once the target had been reached, insulin infusion was maintained for a median of 38 h (Q1-Q3 24-48) with blood glucose between 140 and 180 mg/dL for 58.3% of the infusion time. Over a total of 11,863 h of infusion, seven blood glucose70 mg/dL occurred. The Desio Diabetes Diagram i.v. 140-180 protocol was considered easy to use by 93% of nurses.The Desio Diabetes Diagram i.v. 140-180 protocol, fully managed by nurses, with insulin and glucose intravenous infusion proved effective, safe and feasible in maintaining blood glucose between 140 and 180 mg/dL in patients with diabetes or hyperglycaemia admitted to the intensive cardiac care unit for acute cardiac events.

To describe prescribing patterns in elderly Italian diabetic patients of the Lombardy Region in 2000 and 2010 using an administrative database. Hospital admissions and mortality were also recorded and compared in the two index years.Analyses were performed on the whole cohort of elderly diabetic patients and across age groups. Direct age standardization was done, with data from the Lombardy Region database for 2005 used as reference to compare diabetic populations in the two index years. Logistic regression models were used to analyze changes in hospital admissions and mortality and to calculate odds ratios.Using data retrieved from the Lombardy Region database we identified 176,384 and 283,982 elderly diabetic patients in 2000 and 2010, respectively. The overall rates of patients treated with antidiabetic drugs were 92.5% in 2000 and 97.0% in 2010. Between 2000 and 2010 the prescribing of glibenclamide declined by 30.0% (from 52.9 to 22.9%, p 0.001) and that of biguanides rose by 17.4 % (from 47.5 to 64.8%, p 0.001). In 2010 thiazolidinediones, dipeptidyl peptidase-4 inhibitors and incretin mimetic drugs were seldom prescribed. Drugs for cardiovascular prevention rose in all age classes from 2000 to 2010, and the rates of hospital admission overall fell from 32.0 to 26.8% (p 0.001) during the same period, with the exception of those aged ≥85 years. Between 2000 and 2010 the mortality rate decreased in patients aged 65-74 years (from 3.4 to 2.9%, p 0.0001) and rose significantly in those aged ≥85 years.The drug prescription profile of elderly diabetic patients changed from 2000 to 2010, with a tendency toward recommended drugs. These changes may possibly be linked to the decrease in both hospital admissions and mortality in the diabetic group aged 65-74 years.

Diabet. Med. 29, 385–392 (2012) Abstract Aims To describe trends in diagnosed diabetes prevalence, incidence and mortality from 2000 to 2007 in the most heavily populated Italian region. Methods We examined the prevalence and incidence rates of Type 1 and Type 2 diabetes and yearly mortality rates among individuals with diabetes from 2000 to 2007 using an administrative health database of prescription, disease-specific exemption and hospitalization records of more than 9 million inhabitants of Lombardy. Age- and sex-specific rates were calculated and temporal trends for subjects aged ≥ 30 years were analysed. Results The crude point diabetes prevalence rose from 3.0% in 2000 to 4.2% in 2007, a 40% increase. The incidence remained stable during the study period with a rate of 4/1000 per year. Overall mortality declined from 43.2/1000 in 2001 to 40.3/1000 in 2007 (6.7% decrease) at a rate slightly higher than that of the general population (4.8% decrease). Our projection in subjects aged ≥ 30 years indicates that the prevalence will rise continuously over the next years, reaching 11.1% in 2030. Conclusions The prevalence of diabetes increased substantially between 2000 and 2007, mainly because there are more patients with a new diagnosis each year than those who die. The increase observed by 2007 almost reached the World Health Organization prediction for 2030. Our analyses suggest that the increase will continue over the next few decades. These data are important for defining the burden of diabetes in the near future, to help in planning health services and ensure proper allocation of resources.

OBJECTIVE The study objectives were 1) to assess the effectiveness and safety of a standardized protocol for the transition to subcutaneous insulin and oral feeding in diabetic or hyperglycemic patients with acute coronary syndrome (ACS) who were receiving intravenous insulin and glucose at the time of the transfer from the intensive cardiac care unit to a general ward and 2) to identify predictors of transition outcome. RESEARCH DESIGN AND METHODS This was a prospective observational study. The protocol specifies that patients receive a 100% of their daily subcutaneous insulin requirement from the first day of oral feeding, calculated from the intravenous insulin rate during the final 12 h divided into two: 50% basal and 50% prandial. RESULTS In 142 patients (93 male, 49 female, age range 47–88 years, 135 with known diabetes) the first day after transition, 44.8% of blood glucose (BG) measurements were within the strict range of 100–140 mg/dL before meals and 100–180 mg/dL after meals, and 70.8% were within the broader ranges of 80–160 mg/dL and 80–200 mg/dL, respectively. Pre- or postprandial hypoglycemia (BG CONCLUSIONS This study shows the effectiveness and safety of a standardized protocol for the transition from intravenous to subcutaneous insulin in patients with ACS when regular oral feeding was resumed.

Purpose This study was designed to examine the prevalence of cholinesterase inhibitor (ChEI) use and the proportions of patients treated with ChEIs by using an administrative prescription database of prevalent and incident cases of mild to moderate Alzheimer's disease (AD) in relation to age and duration of therapy. Methods A prospective observational study covering individuals aged 65 years or older who received at least one prescription of ChEIs between 1 January 2002 and 31 December 2007 was conducted in three health administrative areas in the Lombardy Region, Italy. Results The prevalence of those who received at least one prescription for ChEIs rose from 0.5% in 2002 to 0.7% in 2004, reaching a plateau. Among estimated prevalent cases of mild to moderate AD, the prevalence of patients who received at least one prescription of ChEIs varied in different age groups, rising in those over 80 years and falling slightly in those under 80 years, particularly in patients aged 65–69 years (test for trend, p

Objective To investigate the prescribing patterns and the prevalence of polypharmacy in community-dwelling elderly people, and to analyze the association of chronic medications and number of drug prescriptions with age and sex. Methods All prescriptions for people aged 65 years or older reimbursed by the Italian National Health Service (NHS) and dispensed by retail pharmacies of the 15 local health units (LHU) in the Lombardy Region during 2005 were analyzed. Logistic regression analysis was used to assess the association between drug prescription (overall, chronic drugs, and polypharmacy) and age, sex, and LHU of residence. Results Eighty-eight percent of the 1 767 239 analyzed elderly received at least one drug prescription. The overall prescription rate was slightly higher for women than men (odds ratio [OR] 1.20; 95%CI 1.19–1.21). Seventy-six percent of the elderly received at least one chronic drug, 46% were exposed to polypharmacy, and 20% to chronic polypharmacy. At multivariate analysis, age and LHU residence of the elderly were the main determinants of drug exposure. A significant correlation was found between the overall prescription prevalence rate and exposure to chronic drugs and to chronic polypharmacy (rs = 0.79, p

Background. Age-dependent clonal expansion of somatic mutations in the hematopoietic system is associated with an increased risk of hematological cancers (including myelodysplastic syndromes, MDS) and other illnesses (coronary heart disease and stroke). However, the presence of clonal hematopoiesis per se in a given individual has only limited predictive power. We hypothesized that the study of oldest-old population can define more specifically the relationship between mutations in the hematopoietic system and risk for MDS, inflammation and vascular diseases. Methods. We analyzed 1004 oldest-old subjects (median age 84.2y, range 80-105) included in the "Health and Anemia" population-based study [Haematologica 2010;95:1849]. Using peripheral blood DNA, we looked for somatic mutations in 47 genes recurrently mutated in hematologic cancers. Results. Clonal mutations were observed in 32.8% of individuals (range 1-5). The majority of variants occurred in 3 genes: DNMT3A (36.4%), TET2 (24.3%) and ASXL1 (6.5%). Mutations in splicing genes, PPM1D and TP53 were found in 7.4%, 5% and 2% of cases, respectively. The mutation frequencies increased with age, up to 50% in individuals aged over 90 years (P=.011). Clonal hematopoiesis was associated with a lower 5-y probability of survival (P=.03), and prognosis was even poorer in patients carrying ≥2 mutations (P=.002) We first focused on the relationship between clonal hematopoiesis and MDS phenotype. Carrying a somatic mutation with a variant allele frequency (VAF) ≥.10, carrying ≥2 mutations, spliceosome gene mutations and co-mutation patterns involving TET2, DNMT3A had a positive predictive value for MDS (from .85 to 1.0). The most frequent early phenotypic changes in patients who developed MDS included an increasing red blood cell distribution width (RDW) and mean corpuscular volume (MCV). Preliminary analyses suggested that the combination of mutations and non-mutational factors (RDW, MCV, after excluding iron/vitamin depletion and thalassemia) may improve the capability to capture individual risk of developing MDS with respect to molecular data alone (P=.01) We studied clonal evolution in 72 patients with multiple samples available over a period of 5y. Clonal hematopoiesis was found at baseline in 22 cases: 2 individuals acquired additional mutations during follow-up, and 5 displayed significant increase in VAF. In 9 subjects without clonal hematopoiesis, mutations were acquired during follow-up. RDW and MCV changes, induction of unexplained cytopenia and overt MDS phenotype were significantly restricted to subjects displaying clonal evolution. We hypothesized that in oldest-old populations MDS could be underdiagnosed (many patients are not considered for bone marrow aspiration because of age). Cytopenia was a common finding in our cohort (20%) the underlying cause remaining unexplained in 27% of cases. In patients with unexplained anemia, carrying a somatic mutation had a positive predictive value for persistent, progressive, multilineage cytopenia (findings consistent with a MDS phenotype) and shorter survival (from .8 to .94). On this basis, 8% of all cytopenias might be undiagnosed MDS. Finally, we investigated the association between clonal hematopoiesis with inflammatory and vascular diseases. Mutations in DNMT3A, TET2, and ASXL1 were each individually associated with risk of coronary heart disease and death, and preliminary analyses suggest that clonal hematopoiesis is also associated with increased risk of rheumatological diseases (P from .03 to.009). We identified mutations in macrophages isolated from synovial fluid of 4/17 patients with rheumatoid arthritis and from atherosclerotic plaques of 3/25 patients with carotid stenosis. Functional studies of macrophages (expression of specific chemokine and cytokine gene patterns) are ongoing. All these findings are under validation in an independent cohort of 800 subjects enrolled in the "Monzino 80-plus" study [Alzheimers Dement 2015;11:258]]. Conclusion. Clonal hematopoiesis was associated with reduced survival in an oldest-old population. Specific mutational profiles define different risks of developing MDS and inflammatory/vascular diseases. Non mutational factors, such as early changes in red blood cell indices, may improve the capability to identify patients at increased risk of developing myeloid cancers. Disclosures Meggendorfer: MLL Munich Leukemia Laboratory: Employment. Bolli:Celgene: Honoraria. Vassiliou:KYMAB: Consultancy, Equity Ownership; Celgene: Research Funding. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.

The objective of this study was to estimate the prevalence of antipsychotic use and investigate their association with behavioural and psychological symptoms of dementia (BPSD) and other clinical predictors. Patients with dementia, aged 65 and above and resident in 35 Alzheimer special care units were sequentially enrolled into a 18-month prospective observational study. Data on sociodemographic, cognitive, functional, behavioural and clinical characteristics and drug exposure were collected at baseline and at 6-month intervals up to 18 months. The prevalence of antipsychotic use and the association with BPSD and clinical predictors were analysed. Of the 349 patients with dementia enrolled in the study, 209 (60%) were taking at least one antipsychotic. Risperidone and promazine were the most frequently prescribed antipsychotic; 40.7% simultaneously received a benzodiazepine, 20% an antidepressant. More than 50% were still taking antipsychotics at 18 months of follow-up. No associations were found between antipsychotic use and level of cognitive impairment, basal activity of daily living disability and comorbidity. Multivariate analysis showed that the use of antipsychotics was highest in patients in the highest quartiles of Neuropsychiatric Inventory Scale score (III quartile, odds ratio: 1.63; 95% confidence interval: 1.19-2.23; IV quartile, odds ratio: 2.27; 95% confidence interval: 1.61-3.26). This study found high rate of use of antipsychotics in patients with dementia resident in Alzheimer special care units, frequent associations with other psychotropic medications and a strong correlation with BPSD.

Background: Studies comparing Alzheimer Special Care Units (ASCUs) with traditional nursing homes (NHs) have reported conflicting results. Objectives: To compare the characteristics and the effects on mortality, hospitalization, use of physical restraints, falls, and antipsychotics among patients admitted to ASCUs or to NHs. Methods: A sequential cohort of patients with dementia was recruited and followed for 18 months in a sample of randomly selected ASCUs and NHs. Data on socio-demographic, cognitive, functional, behavioral, and clinical characteristics, and drug exposure were collected at baseline and at 6-month intervals up to 18 months. Results: A total of 349 patients were enrolled in 35 ASCUs and 81 in 9 NHs. Patients admitted to ASCUs were younger, cognitively and functionally less impaired, but had more behavioral disturbances than those in NH. During follow-up, ASCU patients had a lower risk of hospitalization (odds ratio: 0.67; 95% confidence interval: 0.46-0.99; P = 0.04), and use of physical restraints (odds ratio: 0.66; 95% confidence interval: 0.51-0.86; P = 0.003), and showed a higher rate of withdrawal of antipsychotics (P= 0.003). No difference was found in mortality and falls. Propensity score analysis gives similar results. Conclusions: This study found that patients with dementia in ASCUs had different baseline clinical and functional characteristics from those in NHs. They had a lower rate of hospitalization and use of physical restraints at 6-month follow-up, and a higher probability of having antipsychotic agents withdrawn.

Background Previous studies have stated that atrial fibrillation (AF) is associated with a higher risk of dementia. However, none have examined the competition between death and incident dementia in patients with AF. We evaluated the risk of incident dementia in patients with AF in comparison to people without this arrhythmia, considering of the competing risk of death. Methods AF and non-AF cohorts were identified using the large administrative database of the Lombardy Region and followed for ten years. Patients with incident dementia were identified if they had an ICD 9 code referring to dementia at hospital discharge or a prescription for any anti-dementia drug. The association of AF with dementia or death was assessed with the multivariable Cox proportional-regression model, sensitivity analysis with a 1:1 propensity score matching and competing-risk analysis. Results In 2003 a total of 27,431 patients were hospitalized for AF in the Lombardy Region, while the cohort of non-AF counted 1,600,200 people. AF was associated with a higher risk of dementia (17%) and death (51%) at multivariable Cox analysis. These results were confirmed by the model fitted after propensity score matching. However, competing risk analysis found the association between AF and incident dementia was no longer significant (HR 0.99; 95% CI 0.94–1.04). Conclusions In this real-world population the association between AF and dementia was no longer statistically significant when death was considered a competing risk.

To cross sectionally investigate the association of serum vitamin B(12) and folate concentrations with cognitive and functional ability in the very old in the general population.Serum vitamin B(12) and folate concentrations were assessed in 471 consenting subjects participating in the Monzino 80-plus study (mean age: 87.4 years), a door-to-door population-based survey among very old subjects living in Northern Italy. Cognitive and functional evaluations included Mini-Mental State Examination (MMSE), Instrumental Activities of Daily Living (IADL) and Spontaneous Behavior Interview-basic Activities of Daily Living (SBI-bADL).MMSE, IADL and SBI-bADL scores were all significantly correlated with folate concentrations (respectively: r = 0.36, r = -0.39, r = -0.35; p0.0001), while no significant associations were found with vitamin B(12) concentrations. When entered into multiple linear regression analyses with several covariates, folate showed a highly significant, curvilinear association with both cognitive and functional scores (p0.0001). Subjects in low and middle folate tertiles had significantly higher odds ratios for dementia (p0.0001; adjusted ORs = 5.40 and 6.56, lower 95% CIs 2.53 and 3.11, higher 95% CIs 12.73 and 15.29).Findings of this population-based study suggest that subclinical folate deficiency may represent a risk factor for the cognitive decline associated with aging that could contribute to AD as well as other dementia development.

The objective was to assess the effect of a structured intervention on caregiver stress and the institutionalization rate of patients with dementia and problem behaviors. Caregivers contacting the Federazione Alzheimer Italia (AI) to receive help, advice, or information in relation to problem behaviors of outpatients were enrolled. Eligible caregiver-patient dyads were randomized to receive either a structured intervention or the counseling AI usually provides (control group). After basal assessment, families were reassessed at 6 and 12 months. Problem behavior (particularly agitation) was the only variable significantly correlated (P = 0.006) with the baseline caregivers' stress score. Thirty-nine families completed the 12-month follow-up; the mean problem behavior score was significantly lower in the intervention than the control group (p < 0.03); the time needed for care of the patient increased by 0.5 +/- 9.7 hours/day in the control group and decreased by 0.3 +/- 4.1 in the intervention group (p = 0.4, Wilcoxon test). The main determinant of institutionalization seemed to be the level of caregiver stress (p = 0.03). In patients of the intervention group, there was a significant reduction in the frequency of delusions. This pilot study suggests that caregiver stress is relieved by a structured intervention. The number of families lost to follow-up, the relatively short duration of the study, and the ceiling effect due to the severity of the clinical characteristics of patients probably all partly dilute the observed findings.

Background. Hypoglycemia due to inadequate carbohydrate intake is a frequent complication of insulin treatment of diabetic in-patients.Objective.To assess the effectiveness of a nurse-managed protocol to prevent hypoglycemia during subcutaneous insulin treatment.Design. Prospective pre-post-intervention study.Methods. In 350 consecutive diabetic in-patients the incidence of hypoglycemia (blood glucose < 70 mg/dL) during subcutaneous insulin treatment was assessed before (phase A) and after (phase B) the protocol was adopted to permit (1) the patient to opt for substitutive food to integrate incomplete carbohydrate intake in the meal; (2) in case of lack of appetite or repeatedly partial intake of the planned food, prandial insulin administered at the end of the meal to be related to the actual amount of carbohydrates eaten; (3) intravenous infusion of glucose during prolonged fasting.Results. Eighty-four patients in phase A and 266 in phase B received subcutaneous insulin for median periods of, respectively, 7 (Q1–Q3 6–12) and 6 days (Q1–Q3 4–9). Hypoglycemic events declined significantly from 0.34 ± 0.33 per day in phase A to 0.19 ± 0.30 in phase B(P>0.001).Conclusions. A nurse-managed protocol focusing on carbohydrate intake reduced the incidence of hypoglycemia in patients with diabetes receiving subcutaneous insulin in hospital.

tiple targets may be more effective than single-target therapies, and make several experimentally testable predictions. These models took into account the dynamic interactions between biological and clinical factors, although the number of clinical factors was highly limited. Conclusions: Systems medicine has not yet been widely applied in the field of dementia research. However, the two computational models identified illustrate the potential of this paradigm to conceptualize dementia in a more realistic fashion. Further research is necessary to develop and validate models that incorporate a wider range of dynamically interacting biological, clinical and environmental factors. Ultimately systems medicine may provide the basis for more targeted multidrug therapies and complex interventions.

We investigated the effects of angiotensin I (4 x 10(-9), 4 x 10(-8) and 4 x 10(-7) M) on myocardial contractility, heart rate and coronary perfusion in the isolated rat heart before and after inhibition of angiotensin-converting enzyme (ACE) by captopril (4 x 10(-4) M). We also studied the post-ischaemic recovery of cardiac function in isolated hearts subjected to global myocardial ischaemia and reperfused with various doses of angiotensin II (1 x 10(-9), 1 x 10(-8) and 1 x 10(-7) M). Angiotensin I significantly reduced coronary flow, the vasoconstrictor effect of a second identical dose was attenuated after inhibition of ACE with captopril. Angiotensin II reduced coronary flow to the same extent as angiotensin I at a concentration four times lower. Left ventricular developed pressure was reduced by angiotensin I and angiotensin II in a dose-dependent manner. Heart rate was not affected by angiotensin I and was significantly lowered by the highest doses (1 x 10(-8) and 1 x 10(-7) M) of angiotensin II. Post-ischaemic recoveries of vascular and contractile function were similar in control hearts and in hearts given angiotensin II during reperfusion. However, left ventricular end-diastolic pressure was increased by the highest dose (1 x 10(-7) M) of angiotensin II throughout reperfusion compared with controls or hearts receiving lower doses (NS). In conclusion the attenuated vasoconstrictor response to angiotensin I after captopril pre-treatment confirms the existence of an intracardiac renin-angiotensin system operative in vitro. Our results also suggest that angiotensin II, at a high concentration, may play a negative role in relaxation in the ischaemic-reperfused injured heart.

Background The impact of diabetes on cardiovascular disease in both sexes is known, but the specifics have not been fully clarified. We investigated whether sex-related differences exist in terms of management and hospitalization in patients with newly diagnosed diabetes. Methods We examined the rates of hospitalization for cardiovascular causes, mortality, treatments and management of patients with diabetes compared to subjects without, from administrative database. Interaction between sex and diabetes on clinical outcomes were calculated using a Cox regression model. Pharmacological treatments and recommended examinations by sex were calculated using logistic regression. Results From 2002 to 2006, 158,426 patients with diabetes and 314,115 subjects without were identified and followed up for a mean of 33 months (± 17.5). Diabetes confers a higher risk for all clinical outcomes. Females with diabetes have a risk profile for hospitalization for coronary heart disease comparable to males without (4.6% and 5.3%). Interaction between sex and diabetes shows that females with diabetes had an added 19% higher risk of total death (95% CI 1.13–1.24). No differences were observed in hospitalizations, although females with diabetes were less likely to undergo revascularization after myocardial infarction. Females received cardiovascular prevention drugs less frequently than males and had a slight tendency to get fewer examinations. Conclusion Diabetes is linked to a higher increase of mortality in females relative to males. This might reflect sex differences in the use of revascularization procedures or therapeutic regimens. Closer attention and implementation of standard care for females are necessary from the onset of diabetes.

Background: The risks, prevention and epidemiology of Alzheimer’s disease continue to remain uncertain despite extensive research. A few modifiable risk and preventive factors, such as low education, obesity, smoking, physical inactivity, and certain hormone therapies, have been reported from epidemiological studies. However, many studies have been limited by methodological quality and relatively small sample sizes, typically involving up to a few hundred Alzheimer’s disease cases and a few thousand participants. Studies from large-scale population-based cohorts with extensive exposure assessment and sufficiently long followup are critically needed. We describe the California Teachers Study cohort, established in 1995 primarily for breast cancer research, as a developing resource for large-scale etiologic Alzheimer’s disease research. Methods: The California Teachers Study consists of 133,479 women who have provided extensive exposure data over their life course including most putative risk factors for Alzheimer’s disease. Four waves of questionnaires have been sent since 1995. In the year 2000, we included neuropsychological test items that focused on visuospatial and language function. Results: Active and retired California public school professionals provided information on environmental and lifestyle factors that may be important for Alzheimer’s disease risk, including obesity, physical and social activity, medical history, medications, hormone use, diet, and demographic factors. In 2000-2001, w78,000 participants completeda clock drawing, cube drawing, and picture description task. Of these, w35,000 were 70 years or older in 2010. Assessment of Alzheimer’s disease in the cohort can be done by database linkage to California statewide hos pitalization data, which includes diagnoses after hospitalization, emergency department visits, and outpatient surgery. Conclusions:Large cohorts are needed in order to pursue risk and prevention research in Alzheimer’s disease, as recommended by the 2010 NIH State-ofthe-Science expert consensus conference. The California Teachers Study provides extensive high quality information on mostpotential environmental and lifestyle risk and protective factors, and represents a robust cohort for epidemiologic research, as a resource to conduct timely analyses using accrued cases, and for prospective outcomes research in Alzheimer’s disease.

We assessed the effects of idrapril, a novel angiotensin-converting enzyme inhibitor, and captopril in the isolated rat heart after ischaemia and reperfusion and measured angiotensin-converting enzyme activity in myocardial tissue. Hearts were perfused and subjected to global ischaemia and reperfusion. Idrapril (0.1, 1, 10, and 50 micrograms/ml), captopril (80 micrograms/ml) or vehicle were given before ischaemia and throughout reperfusion. Post-ischaemic recovery of coronary flow was significantly decreased with 50 micrograms/ml of idrapril (43 +/- 9% compared to 64 +/- 3% in controls) whereas heart rate was unaffected. Recovery of developed pressure and activity of cardiac angiotensin-converting enzyme were significantly reduced by idrapril in a dose-dependent manner. This study suggests that protection or lack of protection by idrapril on recovery of contractile function seems to depend on the degree of inhibition of tissue angiotensin-converting enzyme activity in the setting of acute heart ischaemic insult. Our results suggest that while a certain degree of inhibition of angiotensin-converting enzyme in the heart is beneficial, marked tissue inhibition may be deleterious.