Differential Network Analysis Reveals Metabolic Determinants Associated with Mortality in Acute Myocardial Infarction Patients and Suggests Potential Mechanisms Underlying Different Clinical Scores Used To Predict Death.

We present here the differential analysis of metabolite-metabolite association networks constructed from an array of 24 serum metabolites identified and quantified via nuclear magnetic resonance spectroscopy in a cohort of 825 patients of which 123 died within 2 years from acute myocardial infarction (AMI). We investigated differences in metabolite connectivity of patients who survived, at 2 years, the AMI event, and we characterized metabolite-metabolite association networks specific to high and low risks of death according to four different risk parameters, namely, acute coronary syndrome classification, Killip, Global Registry of Acute Coronary Events risk score, and metabolomics NOESY RF risk score. We show significant differences in the connectivity patterns of several low-molecular-weight molecules, implying variations in the regulation of several metabolic pathways regarding branched-chain amino acids, alanine, creatinine, mannose, ketone bodies, and energetic metabolism. Our results demonstrate that the characterization of metabolite-metabolite association networks is a promising and powerful tool to investigate AMI patients according to their outcomes at a molecular level.

NMR-based metabolomics identifies patients at high risk of death within two years after acute myocardial infarction in the AMI-Florence II cohort.

BACKGROUND: Risk stratification and management of acute myocardial infarction patients continue to be challenging despite considerable efforts made in the last decades by many clinicians and researchers. The aim of this study was to investigate the metabolomic fingerprint of acute myocardial infarction using nuclear magnetic resonance spectroscopy on patient serum samples and to evaluate the possible role of metabolomics in the prognostic stratification of acute myocardial infarction patients. METHODS: In total, 978 acute myocardial infarction patients were enrolled in this study; of these, 146 died and 832 survived during 2 years of follow-up after the acute myocardial infarction. Serum samples were analyzed via high-resolution 1H-nuclear magnetic resonance spectroscopy and the spectra were used to characterize the metabolic fingerprint of patients. Multivariate statistics were used to create a prognostic model for the prediction of death within 2 years after the cardiovascular event. RESULTS: In the training set, metabolomics showed significant differential clustering of the two outcomes cohorts. A prognostic risk model predicted death with 76.9% sensitivity, 79.5% specificity, and 78.2% accuracy, and an area under the receiver operating characteristics curve of 0.859. These results were reproduced in the validation set, obtaining 72.6% sensitivity, 72.6% specificity, and 72.6% accuracy. Cox models were used to compare the known prognostic factors (for example, Global Registry of Acute Coronary Events score, age, sex, Killip class) with the metabolomic random forest risk score. In the univariate analysis, many prognostic factors were statistically associated with the outcomes; among them, the random forest score calculated from the nuclear magnetic resonance data showed a statistically relevant hazard ratio of 6.45 (p = 2.16×10-16). Moreover, in the multivariate regression only age, dyslipidemia, previous cerebrovascular disease, Killip class, and random forest score remained statistically significant, demonstrating their independence from the other variables. CONCLUSIONS: For the first time, metabolomic profiling technologies were used to discriminate between patients with different outcomes after an acute myocardial infarction. These technologies seem to be a valid and accurate addition to standard stratification based on clinical and biohumoral parameters.

Survival of cancer patients in Italy. / La sopravvivenza dei pazienti oncologici in Italia.

OBJECTIVES: Population-based survival statistics are fundamental to assess the efficacy of services offered to improve cancer patients' prognosis. This study aims to update cancer survival estimates for the Italian population, as well as provide new measures, such as the crude probability of death, which takes into account the possibility of dying from causes other than cancer, and the change in life expectancy after a cancer diagnosis, to properly address various questions. RESULTS: The study includes 1,932,450 cancer cases detected by the Network of Italian Cancer Registries (AIRTUM) from 1994 to 2011 and provides estimates for 38 cancer sites and for allsites cancer. For most common cancers diagnosed from 2005 to 2009, age-standardized 5-year net survival was: colon-rectum - males 65%, females 65%; lung - males 15%, females 19%; breast 87%; prostate 91%. For cancer sites such as stomach, colon, rectum, lung, skin melanoma, breast, cervix, prostate, and kidney, 5-year net survival is consistent between Central and Northern Italy, while it is a few percentage points lower in Southern Italy. Funnel plots expose these differences more in detail by showing the survival estimates in 13 Italian regions. For all sites but skin, 5- and 10-year net survival increased by about 10 percentage points in men and 7 points in women from 1994 to 2011. DISCUSSION: Specific articles deal with results on solid and haematological malignancies, international comparisons and analysis of time trends of incidence, mortality, and survival in combination for key cancer sites, aiming to interpret overall progress in the control of cancer in Italy.

Gender differences in statin prescription rates, adequacy of dosing, and association of statin therapy with outcome after heart failure hospitalization: a retrospective analysis in a community setting.

PURPOSE: The existence of gender differences in the management of statin therapy among patients with chronic heart failure (HF) is still poorly investigated. We aimed at exploring the effect of gender on statin prescription rates and adequacy of dosing and on the association between statin therapy and all-cause 1-year mortality, after HF hospitalization in a community setting. METHODS: Statin prescription rates, adequacy of dosing (estimated as a PDD/DDD ratio >0.80), and 1-year mortality were retrospectively assessed in 2088 consecutive patients discharged from 5 local community hospitals with a definite diagnosis of HF after a mean length of stay of 7.6 days. The effect of gender was explored using multivariable logistic and Cox analyses adjusting to confounders. RESULTS: Women showed a lower statin prescription rate (25.7 vs 35.3%, P < 0.0001) and a lower prevalence of adequate statin dose (32.6 vs 42.3%, P < 0.0001) than men. Female gender was independently associated with a 24% lower probability of statin prescription and a 48% higher probability of inadequate statin dose. Statin prescription and adequacy of dosing were associated with 35 and 44% decreases in the risk of 1-year mortality, respectively, irrespective of gender. A nested case/control analysis confirmed that adequate statin dose was associated with 48% lower 1-year mortality, again without interaction with gender. CONCLUSIONS: In patients with chronic HF, female gender is independently associated with lower statin prescription rates and higher probability of inadequate dose. Statin therapy in these subjects is associated with improved 1-year survival in both men and women. This prognostic benefit is not affected by gender.

[Use of regional health administrative databases to estimate the prevalence of mental disorders and health service utilization in a Local Health Unit of Tuscany Region (Central Italy)]. / Uso dei flussi informativi sanitari regionali per stimare la prevalenza dei disturbi mentali e il ricorso ai servizi sanitari nella popolazione di una Asl della Toscana.

OBJECTIVES: prevalence estimation of mental disorders and mental health services (SSM) utilization in 2011, using the administrative regional health databases (hospital discharge records, pharmaceutical prescriptions) and the Regional Database on Mental Health (SIRSM). STUDY DESIGN: descriptive population-based study. SETTING AND PARTICIPANTS: residents in a Local Health Unit (Florence) of Tuscany Region (Central Italy) who have access to SSM and/or to hospital departments of psychiatry/neuropsychiatry and/ or have psycholeptic/psychoanalectic prescriptions. MAIN OUTCOME MEASURES: frequencies; crude and age-standardized prevalence of patients who have access to the SSM or have admission to a hospital psychiatric ward or have psycholeptic/psychoanalectic prescriptions. RESULTS: a high prevalence (11.2%) of residents had at least one contact with health services for mental health problems, mostly (84%) for drug prescriptions only (20% of patients had a unique prescription during 2011). Depression is the most important disease (9.8% of residents had at least one prescription of antidepressants); mood disorders are the most common cause of adult access to SSM (35%-36%) and hospitalization in psychiatric ward (about 36% of admissions). Only a small proportion (about 15%) of patients with mental health problems have access to the SSM, presumably those with more severe diseases. CONCLUSIONS: results show that the information of the SIRSM database, together with pharmaceutical prescriptions (psycholeptic/ psychoanalectic) and hospitalisation in psychiatric ward, is a useful tool for assessing the prevalence of mental health problems in a population.

[Trends in occurrence, treatment, and outcomes of acute myocardial infarction in Tuscany Region (Central Italy), 1997-2010]. / Trend temporali di occorrenza, trattamento ed esiti dell'infarto miocardico acuto in Toscana, 1997-2010.

OBJECTIVES: to describe trends in attack rate, treatment, and outcomes of acute myocardial infarction (AMI) in Tuscany Region (Central Italy). DESIGN: population-based epidemiological study using the Tuscany Acute Myocardial Infarction Registry. SETTING AND PARTICIPANTS: cases have been identified by record linkage between the hospital discharge database and the mortality registry, and divided into hospitalised AMI (1997-2012) and out-of-hospital coronary deaths (1997-2010). Details on hospitalised cases based on the presence/absence of ST-segment elevation (STEMI / NSTEMI) can be detected for the period 2001-2012. MAIN OUTCOMEMEASURES: distribution by calendar time, gender, and type of event of absolute frequencies, age-standardised attack rates (per 100,000; standard Tuscany population, 2001) and percentages (standard: total hospitalised cases in 2011) of invasive cardiac procedures and 28-day case fatality in hospitalised cases. RESULTS: a reduction in both out-of-hospital coronary deaths and STEMI hospitalisations (attack rates, respectively, - 2.3% and -3.9% in males, -3.3% and -4.1% in females) and an increase in NSTEMI hospitalisations (+13.1% in males and +13.3% in females) were shown. The use of invasive cardiac procedures (PCI, coronary angiography) in hospitalised cases shows a considerable increase over time both in STEMI and in NSTEMI. The proportion, however, always remains lower in the whole period after the age of 70 and in women. The short term prognosis in hospitalised AMI cases shows an improvement over time, which, however, disappears when stratified by type of AMI. This trend is mainly related to the different weight that STEMI and NSTEMI have on incidence over time (increase in attack rates for NSTEMI and reduction for STEMI, with worst prognosis). CONCLUSIONS: results confirm the important changes in epidemiology, clinical presentation, and treatment of acute coronary disease in Tuscany, previously identified in the international literature. Differences in coronary reperfusion treatment of hospitalised cases still persist by age and gender. Additional efforts are needed to ensure equity in access to the best treatment for AMI.

Ozone short-term exposure and acute coronary events: a multicities study in Tuscany (Italy).

OBJECTIVE: Many studies have investigated the potential role of ozone exposure in cardiovascular mortality and morbidity. The effects on specific cardiovascular outcome and the role of individual susceptibility are less studied. This paper focuses on the short-term effects of ozone on acute coronary events and it investigates comorbidities as indicators of personal susceptibility. SETTING AND PATIENTS: This study was conducted in five urban areas of the Tuscany region (Italy) covering the period January 2002-December 2005. Air quality and meteorological data from urban background monitoring sites were collected. Hospital admissions for acute myocardial infarction and out-of-hospital coronary deaths were extracted from administrative database. DESIGN: Both time series and case-crossover designs were applied. The confounding effects of some time-dependent variables, such as temperature, were taken into account. Some potential susceptibility factors were investigated. Pooled estimates were derived from random-effect meta-analysis. RESULTS: During the warm season 4555 hospitalized acute myocardial infarctions and 1931 out-of-hospital coronary deaths occurred. Authors estimated a 6.3% (95% confidence interval, 1.2%, 11.7%) increase in out-of-hospital coronary deaths for a 10 µg/m3 increase in ozone (lag 0-5). Results also suggested higher risks for females, elderly, and patients previously hospitalized for cerebrovascular and artery diseases. CONCLUSIONS: This study adds further evidence to the relation between cardiovascular diseases and ozone exposure, showing an adverse effect on out-of-hospital coronary deaths, but not on hospitalized acute myocardial infarctions. Some susceptible subgroups, such as females, elderly, and patients affected by some chronic diseases, are likely to be at major risk.

Representativeness of the "Fiesole Misurata" study database for use in pharmaco-epidemiological investigations on adherence to antihypertensive medications.

BACKGROUND AND AIMS: Poor adherence to medications is a major health concern especially among older subjects. To plan future studies to improve adherence, an epidemiological study, called "Fiesole Misurata", was conducted. The aim of the present paper was to verify the representativeness of the database in evaluating the AntiHyperTensives (AHTs)-taking behaviour. METHODS: Demographic records of all subjects aged ≥65 years (n = 2,228) living in the community of Fiesole (Florence, Italy) was retrieved from the Registry Office of Fiesole Municipality. The corresponding healthcare records were obtained from administrative archives of the Local Health Authority (claim dataset). Moreover, a cohort of subjects aged ≥65 years (n = 385) living in the community was screened by means of a multidimensional geriatric evaluation (cross-sectional dataset). RESULTS: In claim dataset, biyearly prevalences of hospitalization for ischemic cardiomyopathy, heart failure, and stroke were 3.7, 3.0, and 3.2%, respectively. In the cross-sectional dataset, prevalences were 11.2, 6.7, and 7.1%, respectively. The most used drugs were angiotensin-converting enzyme inhibitors (43.6% in the claim dataset, 45.3% in the cross-sectional dataset) and diuretics (35.6% and 47.0%, respectively). Among the incident users of AHTs, 63.5% was highly adherent (≥80%) over the first 6 months of follow-up, while 14.3 and 22.2% were intermediate (40-79%) and low (<40%) adherent. The percentage of high adherers decreased with time and reached 31.2% at the 24th month. CONCLUSIONS: These findings indicate that "Fiesole Misurata" study database can be used to develop future strategies aimed at improving the adherence to AHTs in older individuals.

[Population-based registries of Acute Myocardial Infarction in Italy]. / La registrazione su base di popolazione dell'incidenza dell'infarto miocardico acuto in Italia.

The purpose of this study is to discuss some issues related to changes in the diagnostic detection of acute myocardial infarction (AMI) and to present international and national experiences of registration of the major coronary events (MONICA project, EUROCISS project, National Register of the major coronary events, experiences based on the use of current health databases). This paper does not take into account activities aimed to assess quality of care given to patients with AMI and/or acute coronary syndromes (ACS), developed in clinical settings or using current data. In Italy there have been few experiences in registration of AMI and/or ACS, some of them are still in progress. Despite the importance of ACS in terms of public health and health care resources utilisation, these initiatives have not led to a registration network with consistent and comparable recording criteria. This problem is very relevant in relation to the significant changes that have occurred in the past, and which continue to occur, in diagnostic and therapeutic criteria. Currently, the geographic and temporal trends of coronary heart disease are only provided by the current data of hospitalization and mortality, with the limits that these databases involve. The presence of ACS registries could provide standardized diagnostic criteria and comparability of results between different areas of the Country, contributing to a better understanding of the epidemiological dynamics of AMI in Italy.

[Policies for the promotion of sustainable mobility and the reduction of traffic-related air pollution in the cities participating in the EpiAir2 project]. / Le politiche per la promozione della mobilità sostenibile e la riduzione dell'inquinamento atmosferico causato dal traffico veicolare nelle città partecipanti allo studio EpiAir2.

OBJECTIVE: to describe transport policies adopted in recent years (2006-2010) by some Italian municipalities and their effectiveness. DESIGN AND SETTING: survey data refer to fifteen cities participating in the EpiAir2 project: Torino, Milano, Venezia, Bologna, Firenze, Pisa, Roma, Taranto, Palermo, Cagliari, Trieste, Genova, Ancona, Napoli, and Bari. RESULTS: this survey revealed strengths and weaknesses of the way in which these Italian cities address the promotion of sustainable mobility. As a general rule, the vehicle fleets have been renewed with a reduction of old-emission-standard vehicles. Italian cities reported a considerable delay in the development of underground and tram systems, and suburban rail networks, compared to other European urban areas. Regarding other aspects of urban mobility (supply/demand for public transport, low traffic and pedestrian zones, bike paths, car and bike sharing), this survey highlighted a great heterogeneity among Italian cities. CONCLUSION: differences between Italian cities are partly explained by structural and cultural features and also by local governance, specifically the political capability to design and adopt effective policies concerning urban transportation systems and their environmental impact. Various and fragmented initiatives are signs that Italy has not formulated a comprehensive and integrated strategy about sustainable mobility in urban areas yet.

[Mortality aftermyocardial infarction: when the health local organization network has a role in interpreting themarkers of theNational Agency for RegionalHealth Services]. / Mortalità dopo infarto miocardico: quanto la rete locale di organizzazione dell'assistenza conta nell'interpretazione di indicatori dell'Agenzia nazionale per i servizi sanitari regionali.

The Italian National Outcome Programme has assessed the performance of Italian hospitals regarding several clinical performance indicators, including 30-daymortality after admission for acute myocardial infarction. Risk adjustment was obtained using demographic and comorbidity data based on the hospital discharge databases in the index admission, as well as in those of the previous two years. Noticeably, the ICD-9-CM 410.7* classification coding for NSTEMI (Non-ST elevation myocardial infarction)myocardial infarction, i.e. the less severe form, was not used, due to known variability in its use. We found that hospital-specific adjusted relative risk of death versus the national mean, as computed by the programme, is negatively associated with the proportion of NSTEMI infarctions at each Tuscan and Florentine hospital, coherently with the hypothesis of a selection by the emergency network, which addresses STEMI (ST elevation myocardial infarction) patients to hospitals offering haemodynamic laboratory with reperfusive services. Individual level clinical data of 3,200 patients in the AMI-Florence study in the period April 2008-March 2010 found that ICD-9-CM410.7* is underused. The analysis based on hospital discharge diagnoses (410.7* vs. other 410* codes) cannot explain differences in mortality among Florentine hospitals, as opposed to the use of a classification of myocardial infarction type (STEMI vs. NSTEMI) based on clinical data collected in AMI-Florence.

Validity of Italian administrative healthcare data in describing the real-world utilization of infusive antineoplastic drugs: the study case of rituximab use in patients treated at the University Hospital of Siena for onco-haematological indications.

Introduction: Italian administrative healthcare databases are frequently used for studies on real-world drug utilization. However, there is currently a lack of evidence on the accuracy of administrative data in describing the use of infusive antineoplastics. In this study, we used rituximab as a case study to investigate the validity of the regional administrative healthcare database of Tuscany (RAD) in describing the utilization of infusive antineoplastics. Methods: We identified patients aged 18 years or older who had received ≥1 rituximab administration between 2011 and 2014 in the onco-haematology ward of the University Hospital of Siena. We retrieved this information from the Hospital Pharmacy Database (HPD-UHS) and linked the person-level information to RAD. Patients who had received ≥1dispensing of rituximab, single administration episodes, and patients treated for non-Hodgkin Lymphoma (nHL) or Chronic Lymphocytic Leukemia (CLL) were identified in RAD and validated using HPD-UHS as the reference standard. We identified the indications of use using algorithms based on diagnostic codes (ICD9CM codes, nHL=200*, 202*; CLL=204.1). We tested 22 algorithms of different complexity for each indication of use and calculated sensitivity and positive predictive value (PPV), with 95% confidence intervals (95%CI), as measures of validity. Results: According to HPD-UHS, 307 patients received rituximab for nHL (N=174), CLL (N=21), or other unspecified indications (N=112) in the onco-haematology ward of the University Hospital of Siena. We identified 295 rituximab users in RAD (sensitivity=96.1%), but PPV could not be assessed due to missing information in RAD on dispensing hospital wards. We identified individual rituximab administration episodes with sensitivity=78.6% [95%CI: 76.4-80.6] and PPV=87.6% [95%CI: 86.1-89.2]. Sensitivity of algorithms tested for identifying nHL and CLL ranged from 87.7% to 91.9% for nHL and from 52.4% to 82.7% for CLL. PPV ranged from 64.7% to 66.1% for nHL and from 32.4% to 37.5% for CLL. Discussion: Our findings suggest that RAD is a very sensitive source of information for identifying patients who received rituximab for onco-haematological indications. Single administration episodes were identified with good-to-high accuracy. Patients receiving rituximab for nHL were identified with high sensitivity and acceptable PPV, while the validity for CLL was suboptimal.

Short-term association between ambient air pollution and risk of hospitalization for acute myocardial infarction: results of the cardiovascular risk and air pollution in Tuscany (RISCAT) study.

Air pollutant levels have been widely associated with increased hospitalizations and mortality from cardiovascular disease. In this study, the authors focused on pollutant levels and triggering of acute myocardial infarction (AMI). Data on AMI hospitalizations, air quality, and meteorologic conditions were collected in 6 urban areas of Tuscany (central Italy) during 2002-2005. Levels of particulate matter with an aerodynamic diameter ≤10 µm (PM(10)) (range of 4-year mean values, 28.15-40.68 µg/m(3)), nitrogen dioxide (range, 28.52-39.72 µg/m(3)), and carbon monoxide (range, 0.86-1.28 mg/m(3)) were considered, and increases of 10 µg/m(3) (0.1 mg/m(3) for carbon monoxide) were analyzed. A time-stratified case-crossover approach was applied. Area-specific conditional regression models were fitted, adjusting for time-dependent variables. Stratified analyses and analyses in bipollutant models were performed. Pooled estimates were derived from random-effects meta-analyses. Among 11,450 AMI hospitalizations, the meta-analytical odds ratio at lag(2) (2-day lag) was 1.013 (95% confidence interval (CI): 1.000, 1.026) for PM(10), 1.022 (95% CI: 1.004, 1.041) for nitrogen dioxide, and 1.007 (95% CI: 1.002, 1.013) for carbon monoxide. More susceptible subgroups were elderly persons (age ≥75 years), females, and older patients with hypertension and chronic obstructive pulmonary disease. This study adds to evidence for a short-term association between air pollutants and AMI onset, also evident at low pollutant levels, suggesting a need to focus on more vulnerable subjects.

Lifestyle modifications after acute coronary syndromes in a subset of the AMI-Florence 2 Registry.

OBJECTIVE: The aim of this study was to evaluate the adherence to recommendations for secondary prevention of cardiovascular diseases in patients with acute coronary syndromes (ACS). METHODS AND RESULTS: Physical examination, a careful medical interview with assessment for lifestyle habits, adherence to pharmacological therapy and blood analyses were performed in 130 patients at the time of the acute event and after 6 months of follow-up. At follow-up examination, 7 patients persisted to smoke (5.4%), 41 (31.5%) continued to have high blood pressure, 34 (26.1%) had high levels of total cholesterol, 38 (29.2%) high levels of triglycerides, 64 (49.2%) high levels of LDL-cholesterol and 46 (35.4%) low levels of HDL-cholesterol. Despite all treatments no significant change occurred. A high percentage of patients (47%) reported a lower daily consumption of fruit and vegetables with respect to the recommended daily portions, nearly the whole population (92.3%) did not reach the recommended portions of legumes per week recommended, and a consistent percentage of patients (81.5%) did not consume fish twice a week, as recommended. CONCLUSION: These findings demonstrate the difficulty of modifying the lifestyle habits in patients with ACS.

Impact of Rhabdomyosarcoma Treatment Modalities by Age in a Population-Based Setting.

Purpose: Rhabdomyosarcoma (RMS) has a worse prognosis in adults than in children, but there is evidence of a better outcome in the former if treated using a pediatric-like approach. This study describes treatment for RMS in patients more than 10 years old and examines to what extent treatment contributes to explain the different age-related survival observed and to what extent treatment centers impact treatment appropriateness. Methods: A retrospective population-based study was developed considering 104 RMS cases (excluding the pleomorphic subtype) diagnosed in Italy between 2000 and 2015. Patients were grouped by age (10-19 vs. 20-60 years old) and scored according to whether or not their chemotherapy was consistent with the schemes used in pediatric protocols (score 1 = chemotherapy in line with pediatric protocols). Treatment centers were grouped according to whether or not they have a pediatric-dedicated unit affiliated to the national pediatric oncology network (Associazione Italiana Ematologia Oncologia Pediatrica [AIEOP]). Results: Older patients were more likely to have tumors at unfavorable sites (p = 0.045). A treatment score of 1 was assigned to 85% of younger patients, but only to 32% of older patients (p < 0.001). Furthermore, the proportion of score 1 was higher in younger patients treated in centers with an AIEOP Unit. A multivariate model confirmed age as a significant prognostic factor (Hazard rate ratio [HR] = 2.06; p = 0.04) and showed a significant impact of treatment on survival (HR = 2.13; p = 0.03). Conclusions: Adult RMS patients are still relatively unlikely to be treated with pediatric protocols and in centers with a pediatric oncology expertise. This may explain the survival gap between older and younger patients.

Risk factors for disability in older persons over 3-year follow-up.

BACKGROUND: the identification of modifiable risk factors for preventing disability in older individuals is essential for planning preventive strategies. PURPOSE: to identify cross-sectional correlates of disability and risk factors for the development activities of daily living (ADL) and instrumental ADL (IADL) disability in community-dwelling older adults. METHODS: the study population consisted of 897 subjects aged 65-102 years from the InCHIANTI study, a population-based cohort in Tuscany (Italy). Factors potentially associated with high risk of disability were measured at baseline (1998-2000), and disability in ADLs and IADLs were assessed both at baseline and at the 3-year follow-up (2001-03). RESULTS: the baseline prevalence of ADL disability and IADL disability were, respectively, 5.5% (49/897) and 22.2% (199/897). Of 848 participants free of ADL disability at baseline, 72 developed ADL disability and 25 of the 49 who were already disabled had a worsening in ADL disability over a 3-year follow-up. Of 698 participants without IADL disability at baseline, 100 developed IADL disability and 104 of the 199 who already had IADL disability had a worsening disability in IADL over 3 years. In a fully adjusted model, high level of physical activity compared to sedentary state was significantly associated with lower incidence rates of both ADL and IADL disability at the 3-year follow-up visit (odds ratio (OR): 0.30; 95% confidence intervals (CI) 0.12-0.76 for ADL disability and OR: 0.18; 95% CI 0.09-0.36 for IADL disability). After adjusting for multiple confounders, higher energy intake (OR for difference in 100 kcal/day: 1.09; 95% CI 1.02-1.15) and hypertension (OR: 1.91; 95% CI 1.06-3.43) were significant risk factors for incident or worsening ADL disability. CONCLUSIONS: higher level of physical activity and lower energy intake may be protective against the development in ADL and IADL disability in older persons.

Real word evidence on rituximab utilization: Combining administrative and hospital-pharmacy data.

PURPOSE: To describe patterns of utilization, survival and infectious events in patients treated with rituximab at the University Hospital of Siena (UHS) to explore the feasibility of combining routinely collected administrative and hospital-pharmacy data for examining the real-world use of intravenous antineoplastic drugs. METHODS: A retrospective, longitudinal cohort study was conducted using data from the Hospital Pharmacy of Siena (HPS) and the Regional Administrative Database of Tuscany (RAD). Patients aged ≥18 years with ≥1 rituximab administration recorded between January 2012 and June 2016 were identified in the HPS database. Anonymized patient-level data were linked to RAD. Rituximab utilization during the first year of treatment was described using HPS. Hospital diagnoses of adverse infectious events that occurred during the first year of follow-up and four-year survival were observed using RAD. RESULTS: A total of 311 new users of rituximab were identified: 264 patients received rituximab for non-Hodgkin's lymphoma (NHL) and 47 were treated for chronic lymphocytic leukemia (CLL). Among new users with one complete year of follow-up (n = 203) over 95% received rituximab as the first-line treatment, and approximately 70% of them received 5-8 doses. No patient in the CLL group received >8 administrations. Four-year survival was approximately 70% in both CLL and NHL patients. Sepsis was the most frequent infectious event observed (5.1%). CONCLUSION: HPS and RAD provided complementary information on rituximab utilization, demonstrating their potential for future pharmacoepidemiological studies on antineoplastic medications administered in the Italian hospital setting. Overall, this general description of the real-world utilization of rituximab in patients treated for NHL and CLL at UHS was in line with treatment guidelines and current knowledge on the rituximab safety profile.

Patterns of care and cost profiles of women with breast cancer in Italy: EPICOST study based on real world data.

OBJECTIVES: To estimate total direct health care costs associated to diagnosis and treatment of women with breast cancer in Italy, and to investigate their distribution by service type according to the disease pathway and patient characteristics. METHODS: Data on patients provided by population-based Cancer Registries are linked at individual level with data on health-care services and corresponding claims from administrative databases. A combination of cross-sectional approach and a threephase of care decomposition model with initial, continuing and final phases-of-care defined according to time occurred since diagnosis and disease outcome is adopted. Direct estimation of cancer-related costs is obtained. RESULTS: Study cohort included 49,272 patients, 15.2% were in the initial phase absorbing 42% of resources, 79.7% in the continuing phase absorbing 44% of resources and 5.1% in the final phase absorbing 14% of resources. Hospitalization was the most important cost driver, accounting for over 55% of the total costs. CONCLUSIONS: This paper represents the first attempt in Italy to estimate the economic burden of cancer at population level taking into account the entire disease pathway and using multiple current health care databases. The evidence produced by the study can be used to better plan resources allocation. The model proposed is replicable to countries with individual health care information on services and claims.

The role of N-terminal PRO-brain natriuretic peptide and echocardiography for screening asymptomatic left ventricular dysfunction in a population at high risk for heart failure. The PROBE-HF study.

BACKGROUND: Screening for asymptomatic left ventricular dysfunction (ALVD) in subjects at risk for heart failure (HF) can affect clinical management. The aim of the present study is to examine the role of NT-pro BNP in the diagnosis of ALVD in subjects with hypertension and diabetes from primary care. METHODS AND RESULTS: A total of 1012 subjects with hypertension and/or diabetes and no symptoms or signs of HF were assessed by B-type natriuretic peptide (NT-proBNP) assay and echocardiography. Diastolic dysfunction was present in 368/1012 subjects (36.4%): 327 (32.4%) with mild diastolic dysfunction and 41 (4%) with a moderate-to-severe diastolic dysfunction. Systolic dysfunction was present in 11/1012 (1.1%). NT-proBNP levels were 170 +/- 206 and 859 +/- 661 pg/mL, respectively, in diastolic and systolic dysfunction and 92 +/- 169 in normal subjects (P < .0001). Pooling moderate-to-severe diastolic with systolic dysfunction, a total of 52 subjects (5.1 %) were obtained: best cutoff value of NT-proBNP was 125 pg/mL (males <67 years: sensitivity [Sens] 87.5%, specificity [Spec] 92.7%, negative predictive value [NPV] 99.5%, positive predictive value [PPV] 33.3%; females <67 years: Sens 100%, Spec 84.1%, NPV 100%, PPV 33.3%; males >or=67 years: Sens 100%, Spec 77.1%, NPV 100%, PPV 32.5%; females >or=67 years: Sens 100%, Spec 59.9%, NPV 100%, PPV 23%). CONCLUSIONS: The prevalence of ALVD in subjects at risk for HF is 5.1%. Because of its excellent NPV, NT-proBNP can be used by general practitioners to rule out ALVD in hypertensive or diabetic patients.