Drug utilization in patients starting haemodialysis with a focus on cardiovascular and antidiabetic medications: an epidemiological study in the Lazio region (Italy), 2016-2020.

BACKGROUND: Entering dialysis is a critical moment in patients' healthcare journey, and little is known about drug therapy around it. A study funded by the Italian Medicines Agency offered the opportunity to leverage data from the Lazio Regional Dialysis and Transplant Registry (RRDTL) and perform an observational study on drug use patterns before and after initiating chronic dialysis. METHODS: Individuals initiating dialysis in 2016-2020 were identified from RRDTL, excluding patients with prior renal transplantation, stopping dialysis early, or dying within 12 months. Use of study drugs, predefined by clinicians, in the two years around the index date was retrieved from the drug claims register and described by semester. For each drug group, proportions of users (min 2 claims in 6 months) by semester, and intensity of treatment in terms of Defined Daily Doses (DDDs) for cardiovascular and antidiabetic agents were compared across semesters, stratifying by sex and age. RESULTS: In our cohort of 3,882 patients we observed a general increase in drug use after initiating dialysis, with the mean number rising from 5.5 to 6.2. Cardiovascular agents accounted for the highest proportions, along with proton pump inhibitors and antithrombotics over all semesters. Dialysis-specific therapies showed the most evident increase, in particular anti-anaemics (iron 4-fold, erythropoietins almost 2-fold), anti-parathyroids (6-fold), and chelating agents (4-fold). Use of cardiovascular and antidiabetic drugs was characterised by significant variations in terms of patterns and intensity, with some differences between sexes and age groups. CONCLUSIONS: Entering dialysis is associated with increased use of specific drugs and goes along with adaptations of chronic therapies.

Trend and determinants of mortality in incident hemodialysis patients of the Lazio region.

BACKGROUND: . In the last decades some studies observed a moderate progressive decrease in short-term mortality in incident hemodialysis patients. The aim of the study is to analyse the mortality trends in patients starting hemodialysis using the Lazio Regional Dialysis and Transplant Registry. METHODS: . Patients who started chronic hemodialysis between 2008 and 2016 were included. Annual 1-year and 3-year Crude Mortality Rate*100 Person Years (CMR*100PY) overall, by gender and age classes were calculated. Cumulative survival estimates at 1 year and 3 years since the date of starting hemodialysis were presented as Kaplan-Meier curves for the three periods and compared using the log-rank test. The association between periods of incidence in hemodialysis and 1-year and 3-year mortality were investigated by means of unadjusted and adjusted Cox regression models. Potential determinants of both mortality outcomes were also investigated. RESULTS: . Among 6,997 hemodialysis patients (64.5% males, 66.1% over 65 years old) 923 died within 1 year and 2,253 within 3 years form incidence; CMR*100PY were 14.1 (95%CI: 13.2-15.0) and 13.7 (95%CI: 13.2-14.3), respectively; both remained unchanged over the years. Even after stratification by gender and age classes no significant changes emerged. Kaplan-Meier mortality curves did not show any statistically significant differences in survival at 1 year and 3 years from hemodialysis incidence across periods. No statistically significant associations were found between periods and 1-year and 3-year mortality. Factors associated with a greater increase in mortality are: being over 65 years, born in Italy, not being self-sufficient, having systemic versus undetermined nephropathy, having heart disease, peripheral vascular disease, cancer, liver disease, dementia and psychiatric illness, and receiving dialysis by catheter rather than fistula. CONCLUSIONS: . The study shows that the mortality rate in patients with end-stage renal disease starting hemodialysis in the Lazio region was stable over 9 years.

The additional value of lung cancer screening program in identifying unrecognized diseases.

BACKGROUND: A systematic examination of low-dose CT (LDCT) scan, beside lung nodules, may disclose the presence of undiagnosed diseases, improving the efficacy and the cost/efficacy of these programs. The study was aimed at evaluating the association between LDCT scan findings and non-oncologic and oncologic diseases. METHODS: The LDCT scan of participants to the "Un Respiro per la vita"® lung cancer screening program were checked and abnormal findings, beside lung nodules, recorded. First admission to the acute care because of cardiovascular (CD), respiratory (RD) and oncological diseases (OD) in the following three years were retrieved. The association of LDCT scan abnormal findings with CD, RD and OD was assessed through univariable and multivariable logistic regression models. RESULTS: Mean age of 746 participants was 62 years (SD:5), 62% were male. 11 (1.5%) received a diagnosis of lung cancer. 16.1% participants were admitted to the acute care in the following three years: 8.6% for CD, 4.3% for RD and 5.2% for OD. Valve calcification (OR 2.02, p:0.02) and mucus plugs (OR 3.37, p:0.04) were positively associated with CD, while sub-pleural fibrosis had a protective role (OR 0.47, p:0.01). Lung nodules > 8 mm (OR 5.54, p: < 0.01), tracheal deviation (OR 6.04, p:0.01) and mucus plugs (OR 4.00, p:0.04) were positively associated with OD admissions. Centrilobular emphysema OR for RD admissions was 1.97 (p:0.06). CONCLUSIONS: The observed association between selected LDCT findings and ensuing CD, RD and OD suggests that the information potential of LCDT goes beyond the screening of lung cancer.

[Mortality inequalities in Rome: the role of individual education and neighbourhood real estate market]. / Differenziali di mortalità a Roma: il ruolo dell'istruzione e dei prezzi immobiliari del quartiere di residenza.

OBJECTIVES: to investigate the association between real estate prices, education, and mortality. DESIGN: cohort study. SETTING AND PARTICIPANTS: residents in Rome at the 2011 Italian Census, not living in institutions, and living in the address reported in the Census survey. People aged 18-99 years were followed from 2011 to 2016 using anonymous record linkage procedures with administrative databases. The Census includes several individual information, such as gender, age, education, residential neighbourhood. Data and cause of death were collected from mortality register. Real estate prices (euros/m2) were available for each neighbourhood. MAIN OUTCOME MEASURES: adjusted Cox regression models (hazard ratios - HRs and 95%CIs) were used to estimate the association among individual education, real estate price in the neighbourhood, and mortality. RESULTS: the subjects selected were 2,051,376 (54% women, 22.5% with high education level). During the follow-up, 127,352 subjects died. Taking into account gender, age, marital status, and real estate prices, education level was strongly associated with all-cause mortality; compared to highly educated the higher mortality, risk was 35% (95%CI 32%-37%) for low education level and 16% (95%CI 14%-19%) for medium education level. Taking into account the same factors and education level, each increase of 1,000 euros in price/m2 was inversely associated with mortality (HR 0.96, 95%CI 0.96-0.97). CONCLUSIONS: there is an independent association between the two indicators and mortality in Rome. A simple indicator such as real estate prices can be used to tackle inequalities.

[A&F to monitor and promote quality in healthcare during the COVID-19 emergency: the EASY-NET work]. / A&F per il monitoraggio e la promozione della qualità delle cure in emergenza COVID-19: il lavoro di EASY-NET.

We are presenting here the findings of the reaction to the COVID-19 epidemic during the period March to June 2020 of those centres participating in the research EASY-NET which is on-going in Italy, funded by the Ministry of Health and co-founded by the Regional Health Authorities. The objective of EASY-NET is to evaluate the effectiveness of the audit and feedback (A&F) strategies in different clinical and organizational settings in seven regions. As a negative consequence of the COVID-19 epidemic, the activities of the project have suddenly slowed down; nevertheless, the COVID-19 epidemic represented an opportunity to apply the A&F methodology and support the healthcare within the regional authorities in order to manage and monitor the impact of this new disease. The reaction to the crisis on behalf of EASY-NET was inconsistent across the participating regions for various reasons. Factors which influenced the reaction levels in relation to the rapidity and efficiency of the implementation of the A&F strategies were as follows: the varying epidemiological impact of the COVID-19 epidemic in the various territories, the different clinical and organizational context and availability of expert research teams together with A&F procedures which had already been tested before the start of the epidemic.

[Covid-19 and clinical-epidemiological research in Italy: proposal of a research agenda on priority topics by the Italian association of epidemiology]. / Covid-19 e ricerca clinico-epidemiologica in Italia: proposta di un'agenda di ricerca su temi prioritari da parte dell'Associazione italiana di epidemiologia.

BACKGROUND: the Covid-19 pandemic has provoked a huge of clinical and epidemiological research initiatives, especially in the most involved countries. However, this very large effort was characterized by several methodological weaknesses, both in the field of discovering effective treatments (with too many small and uncontrolled trials) and in the field of identifying preventable risks and prognostic factors (with too few large, representative and well-designed cohorts or case-control studies). OBJECTIVES: in response to the fragmented and uncoordinated research production on Covid-19, the   italian Association of Epidemiology (AIE) stimulated the formation of a working group (WG) with the aims of identifying the most important gaps in knowledge and to propose a structured research agenda of clinical and epidemiological studies considered at high priority on Covid-19, including recommendations on the preferable methodology. METHODS: the WG was composed by 25 subjects, mainly epidemiologists, statisticians, and other experts in specific fields, who have voluntarily agreed to the proposal. The agreement on a list of main research questions and on the structure of the specific documents to be produced were defined through few meetings and cycles of document exchanges. RESULTS: twelve main research questions on Covid-19 were identified, covering aetiology, prognosis, interventions, follow-up and impact on general and specific populations (children, pregnant women). For each of them, a two-page form was developed, structured in: background, main topics, methods (with recommendations on preferred study design and warnings for bias prevention) and an essential bibliography. CONCLUSIONS: this research agenda represents an initial contribution to direct clinical and epidemiological research efforts on high priority topics with a focus on methodological aspects. Further development and refinements of this agenda by Public Health Authorities are encouraged.

Febrile events in acute lymphoblastic leukemia: a prospective observational multicentric SEIFEM study (SEIFEM-2012/B ALL).

The purpose of the present study is to estimate the current incidence of febrile events (FEs) and infectious episodes in acute lymphoblastic leukemia (ALL) and evaluate the outcome. We analyzed data on all FEs in a cohort of patients affected by ALL admitted to 20 Italian hematologic centers during 21 months of observation from April 1, 2012 to December 31, 2013. Data about treatment phase, steroids, neutropenia, type and site of infection, and outcome of infection were collected. The population comprehended 271 ALL adult patients. Median age was 46 years old (range 19-75), M/F 1.1:1. We collected 179 FEs occurring during 395 different phases of treatment in 127 patients (45.3% incidence): remission induction treatment 53.1%, consolidation/maintenance 35.7%, treatment for a first or second relapse 44.3%, and refractory disease 85.7%. The incidence of FUO (fever of unknown origin) was 55/395 (13.9%). In the remaining cases, bacteria caused 92 FEs (23.2%), fungi 17 (4.3%), viruses 5 (1%). Mixed infections occurred in 10 cases mainly fungal+bacterial (9/10 cases). Neutropenia was mostly present at onset of FE (89.9% of FEs). Mortality rate was 11.7% (21/179) while 16 deaths occurred with evidence of infection (8.9%). Age > 60 years, neutropenia, poor performance status, steroids, refractory disease, and mixed infections significantly correlated with infection-related mortality. A statistically significant association with mortality was observed also for pulmonary localization and bacteremia. Our study describes the real-life epidemiological scenario of infections in ALL and identifies a subset of patients who are at higher risk for infection-related mortality.

Effects of metal-rich particulate matter exposure on exogenous and endogenous viral sequence methylation in healthy steel-workers.

BACKGROUND: Inhaled particles have been shown to produce systemic changes in DNA methylation. Global hypomethylation has been associated to viral sequence reactivation, possibly linked to the activation of pro-inflammatory pathways occurring after exposure. This observation provides a rationale to investigate viral sequence (both exogenous and endogenous) methylation in association to metal-rich particulate matter exposure. To verify this hypothesis, we chose the Wp promoter of the Epstein-Barr Virus (EBV-Wp) and the promoter of the human-endogenous-retrovirus w (HERV-w), respectively as a paradigm of an exogenous and an endogenous retroviral sequence, to be investigated by bisulfite PCR Pyrosequencing. We enrolled 63 male workers in an electric furnace steel plant, exposed to high level of metal-rich particulate matter. RESULTS: Comparing samples obtained in the first day of a work week (time 0-baseline, after 2 days off work) and the samples obtained after 3 days of work (time 1-post exposure), the mean methylation of EBV-Wp was significantly higher at baseline compared to post-exposure (meanbaseline = 56.7%5mC; meanpost-exposure = 47.9%5mC; p-value = 0.009), whereas the mean methylation of HERV-w did not significantly differ. Individual exposure to inhalable particles and metals was estimated based on measures in all working areas and time spent by the study subjects in each area. In a regression model adjusted for age, body mass index and smoking, PM and metal components had a positive association with EBV-Wp methylation (i.e. PM10: ß = 5.99, p-value < 0.038; nickel: ß = 17.82, p-value = 0.02; arsenic: ß = 13.59, p-value < 0.015). CONCLUSIONS: The difference observed comparing baseline and post-exposure samples may be suggestive of a rapid change in EBV methylation induced by air particles, while correlation between EBV methylation and PM/metal exposure may represent a more stable adaptive mechanism. Future studies investigating a larger panel of viral sequences could better elucidate possible mechanisms and their role in pro-inflammatory pathways leading to systemic health effects.

Short-term particulate matter exposure induces extracellular vesicle release in overweight subjects.

BACKGROUND: Extracellular vesicles (EVs) represent a plausible molecular mechanism linking particulate matter (PM) inhalation to its systemic effects. Microvesicles (MVs) are released from many cell types in response to various stimuli. Increased body mass index (BMI) could modify the response to PM exposure due to enhanced PM uptake and/or an underlying pro-oxidative state. We investigated the relationship between EV release and PM10/PM2.5 exposure in a cohort of 51 volunteers. Subjects were stratified based on their BMI to evaluate whether overweight BMI is a determinant of hypersusceptibility to PM effects. RESULTS: Exposure to PM10/PM2.5 was assessed with a personal sampler worn for 24hours before plasma collection and confirmed with monitoring station data. Size and cellular origin of plasma EVs were characterized by Nanosight analysis and flow cytometry, respectively. Multivariate regression models were run after log-transformation, stratifying subjects based on BMI (≥ or <25kg/m2). PM exposure resulted in increased release of EVs, with the maximum observed effect for endothelial MVs. For PM10 and PM2.5, the adjusted geometric mean ratio and 95% confidence interval were 3.47 (1.30, 9.27) and 3.14 (1.23, 8.02), respectively. Compared to those in normal subjects, PM-induced EV alterations in overweight subjects were more pronounced, with visibly effect in all MV subtypes, particularly endothelial MVs. CONCLUSIONS: Our findings emphasize the role of EV release after PM exposure and the susceptibility of overweight subjects. Larger studies with accurate exposure assessment and complete EVs characterization/content analysis, could further clarify the molecular mechanism responsible for PM effects and of hypersusceptibility of overweight subjects.

Extracellular vesicle-packaged miRNA release after short-term exposure to particulate matter is associated with increased coagulation.

BACKGROUND: Exposure to particulate matter (PM) is associated with increased incidence of cardiovascular disease and increased coagulation, but the molecular mechanisms underlying these associations remain unknown. Obesity may increase susceptibility to the adverse effects of PM exposure, exacerbating the effects on cardiovascular diseases. Extracellular vesicles (EVs), which travel in body fluids and transfer microRNAs (miRNAs) between tissues, might play an important role in PM-induced cardiovascular risk. We sought to determine whether the levels of PM with an aerodynamic diameter ≤ 10 µm (PM10) are associated with changes in fibrinogen levels, EV release, and the miRNA content of EVs (EV-miRNAs), investigating 1630 overweight/obese subjects from the SPHERE Study. RESULTS: Short-term exposure to PM10 (Day before blood drawing) was associated with an increased release of EVs quantified by nanoparticle tracking analysis, especially EVs derived from monocyte/macrophage components (CD14+) and platelets (CD61+) which were characterized by flow cytometry. We first profiled miRNAs of 883 subjects by the QuantStudio™ 12 K Flex Real Time PCR System and the top 40 EV-miRNAs were validated through custom miRNA plates. Nine EV-miRNAs (let-7c-5p; miR-106a-5p; miR-143-3p; miR-185-5p; miR-218-5p; miR-331-3p; miR-642-5p; miR-652-3p; miR-99b-5p) were downregulated in response to PM10 exposure and exhibited putative roles in cardiovascular disease, as highlighted by integrated network analysis. PM10 exposure was significantly associated with elevated fibrinogen levels, and five of the nine downregulated EV-miRNAs were mediators between PM10 exposure and fibrinogen levels. CONCLUSIONS: Research on EVs opens a new path to the investigation of the adverse health effects of air pollution exposure. EVs have the potential to act both as markers of PM susceptibility and as potential molecular mechanism in the chain of events connecting PM exposure to increased coagulation, which is frequently linked to exposure and CVD development.

Effects of particulate matter exposure on multiple sclerosis hospital admission in Lombardy region, Italy.

BACKGROUND: Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the central nervous system, characterized by recurrent relapses of inflammation that cause mild to severe disability. Exposure to airborne particulate matter (PM) has been associated with acute increases in systemic inflammatory responses and neuroinflammation. In the present study, we hypothesize that exposure to PM<10µm in diameter (PM10) might increase the occurrence of MS-related hospitalizations. METHODS: We obtained daily concentrations of PM10 from 53 monitoring sites covering the study area and we identified 8287 MS-related hospitalization through hospital admission-discharge records of the Lombardy region, Italy, between 2001 and 2009. We used a Poisson regression analysis to investigate the association between exposure to PM10 and risk of hospitalization. RESULTS: A higher RR of hospital admission for MS relapse was associated with exposure to PM10 at different time intervals. The maximum effect of PM10 on MS hospitalization was found for exposure between days 0 and 7: Hospital admission for MS increased 42% (95%CI 1.39-1.45) on the days preceded by one week with PM10 levels in the highest quartile. The p-value for trend across quartiles was<0.001. CONCLUSIONS: These data support the hypothesis that air pollution may have a role in determining MS occurrence and relapses. Our findings could open new avenues for determining the pathogenic mechanisms of MS and potentially be applied to other autoimmune diseases.

MicroRNAs are associated with blood-pressure effects of exposure to particulate matter: Results from a mediated moderation analysis.

AIMS: Exposure to particulate air pollution is associated with increased blood pressure (BP), a well-established risk factor for cardiovascular disease. To elucidate the mechanisms underlying this relationship, we investigated whether the effects of particulate matter of less than 10µm in aerodynamic diameter (PM10) on BP are mediated by microRNAs. METHODS AND RESULTS: We recruited 90 obese individuals and we assessed their PM10 exposure 24 and 48h before the recruitment day. We performed multivariate linear regression models to investigate the effects of PM10 on BP. Using the TaqMan® Low-Density Array, we experimentally evaluated and technically validated the expression levels of 377 human miRNAs in peripheral blood. We developed a mediated moderation analysis to estimate the proportion of PM10 effects on BP that was mediated by miRNA expression. PM10 exposure 24 and 48h before the recruitment day was associated with increased systolic BP (ß=1.22mmHg, P=0.019; ß=1.24mmHg, P=0.019, respectively) and diastolic BP (ß=0.67mmHg, P=0.044; ß=0.91mmHg, P=0.007, respectively). We identified nine miRNAs associated with PM10 levels 48h after exposure. A conditional indirect effect (CIE=-0.1431) of PM10 on diastolic BP, which was mediated by microRNA-101, was found in individuals with lower values of mean body mass index. CONCLUSIONS: Our data provide evidence that miRNAs are a molecular mechanism underlying the BP-related effects of air pollution exposure, and indicate miR-101 as epigenetic mechanism to be further investigated.

Microvesicle-associated microRNA expression is altered upon particulate matter exposure in healthy workers and in A549 cells.

Cardiovascular disease risk has been consistently linked with particulate matter (PM) exposure. Cell-derived microvesicles (MVs) are released into plasma and transfer microRNAs (miRNAs) between tissues. MVs can be produced by the respiratory system in response to proinflammatory triggers, enter the circulatory system and remotely modify gene expression in cardiovascular tissues. However, whether PM affects MV signaling has never been investigated. In this study, we evaluated expression of microRNAs contained within plasma MVs upon PM exposure both in vivo and in vitro. In the in vivo study, we isolated plasma MVs from healthy steel plant workers before and after workplace PM exposure. We measured the expression of 88 MV-associated miRNAs by real-time polymerase chain reaction. To assess a possible source of the MV miRNAs identified in vivo, we measured their miRNA expression in PM-treated A549 pulmonary cell lines in vitro. MiRNA profiling of plasma MVs showed 5.62- and 13.95-fold increased expression of miR-128 and miR-302c, respectively, after 3 days of workplace PM exposure (P < 0.001). According to Ingenuity Pathway Analysis, miR-128 is part of coronary artery disease pathways, and miR-302c is part of coronary artery disease, cardiac hypertrophy and heart failure pathways. In vitro experiments confirmed a dose-dependent expression of miR-128 in MVs released from A549 cells after 6 h of PM treatment (P = 0.030). MiR-302c was expressed neither from A549 cells nor in reference lung RNA. These results suggest novel PM-activated molecular mechanisms that may mediate the effects of air pollution and could lead to the identification of new diagnostic and therapeutic interventions.

Susceptibility to particle health effects, miRNA and exosomes: rationale and study protocol of the SPHERE study.

BACKGROUND: Despite epidemiological findings showing increased air pollution related cardiovascular diseases (CVD), the knowledge of the involved molecular mechanisms remains moderate or weak. Particulate matter (PM) produces a local strong inflammatory reaction in the pulmonary environment but there is no final evidence that PM physically enters and deposits in blood vessels. Extracellular vesicles (EVs) and their miRNA cargo might be the ideal candidate to mediate the effects of PM, since they could be potentially produced by the respiratory system, reach the systemic circulation and lead to the development of cardiovascular effects.The SPHERE ("Susceptibility to Particle Health Effects, miRNAs and Exosomes") project was granted by ERC-2011-StG 282413, to examine possible molecular mechanisms underlying the effects of PM exposure in relation to health outcomes. METHODS/DESIGN: The study population will include 2000 overweight (25 < BMI < 30 kg/cm2) or obese (BMI ≥ 30 kg/cm2) subjects presenting at the Center for Obesity and Work (Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy).Each subject donates blood, urine and hair samples. Extensive epidemiological and clinical data are collected. Exposure to PM is assigned to each subject using both daily PM10 concentration series from air quality monitors and pollutant levels estimated by the FARM (Flexible air Quality Regional Model) modelling system and elaborated by the Regional Environmental Protection Agency.The recruitment period started in September 2010 and will continue until 2015. At December 31, 2013 we recruited 1250 subjects, of whom 87% lived in the province of Milan.Primary study outcomes include cardiometabolic and respiratory health effects. The main molecular mechanism we are investigating focuses on EV-associated microRNAs. DISCUSSION: SPHERE is the first large study aimed to explore EVs as a novel potential mechanism of how air pollution exposure acts in a highly susceptible population. The rigorous study design, the availability of banked biological samples and the potential to integrate epidemiological, clinical and molecular data will also furnish a powerful base for investigating different complementary molecular mechanisms. Our findings, if confirmed, could lead to the identification of potentially reversible alterations that might be considered as possible targets for new diagnostic and therapeutic interventions.

EASY-NET Program: Effectiveness of an Audit and Feedback Intervention in the Emergency Care for Acute Conditions in the Lazio Region.

The EASY-NET network program (NET-2016-02364191)-effectiveness of audit and feedback (A&F) strategies to improve health practice and equity in various clinical and organizational settings), piloted a novel and more structured A&F strategy. This study compared the effectiveness of the novel strategy against the sole periodic dissemination of indicators in enhancing the appropriateness and timeliness of emergency health interventions for patients diagnosed with acute myocardial infarction (AMI) and ischemic stroke in the Lazio Region. The efficacy of the intervention was assessed through a prospective quasi-experimental design employing a pre- and post-intervention (2021-2022) comparison with a control group. Participating hospitals in the Lazio Region, where professional teams voluntarily engaged in the intervention, constituted the exposed group, while the control group exclusively engaged in routine reporting activities. Effectiveness analysis was conducted at the patient level, utilizing regional health information systems to compute process and outcome indicators. The effectiveness of the intervention was evaluated using difference-in-difference models, comparing pre- and post-intervention periods between exposed and control groups. Estimates were calculated in terms of the difference in percentage points (PP) between absolute risks. Sixteen facilities for the AMI pathway and thirteen for the stroke pathway participated in the intervention. The intervention yielded a reduction in the proportion of 30-day readmissions following hospitalization for ischemic stroke by 0.54 pp in the exposed patients demonstrating a significant difference of -3.80 pp (95% CI: -6.57; -1.03; 5453 patients, 63.7% cases) in the exposed group compared to controls. However, no statistically significant differences attributable to the implemented A&F intervention were observed in other indicators considered. These results represent the first evidence in Italy of the impact of A&F interventions in an emergency setting, utilizing aggregated data from hospitals involved in the Lazio Region's emergency network.

Blood hypomethylation of inflammatory genes mediates the effects of metal-rich airborne pollutants on blood coagulation.

OBJECTIVES: Recent investigations have associated airborne particulate matter (PM) with increased coagulation and thrombosis, but underlying biological mechanisms are still incompletely characterised. DNA methylation is an environmentally sensitive mechanism of gene regulation that could potentially contribute to PM-induced hypercoagulability. We aimed to test whether altered methylation mediates environmental effects on coagulation. METHODS: We investigated 63 steel workers exposed to a wide range of PM levels, as a work-related condition with well-characterised prothrombotic exposure. We measured personal PM10 (PM≤10 µm in aerodynamic diameter), PM1 (≤1 µm) and air metal components. We determined leukocyte DNA methylation of NOS3 (nitric-oxide-synthase-3) and EDN1 (endothelin-1) through bisulfite-pyrosequencing and we measured ETP as a global coagulation-activation test after standardised triggers. RESULTS: ETP increased in association with PM10 (ß=20.0, 95% CI 3.0 to 37.0), PM1 (ß=80.8 95% CI 14.9 to 146.7) and zinc (ß=51.3, 95% CI 0.01 to 111.1) exposures. NOS3 methylation was negatively associated with PM10 (ß=-0.2, 95% CI -0.4 to -0.03), PM1 (ß=-0.8, 95% CI -1.4 to -0.1), zinc (ß=-0.9, 95% CI -1.4 to -0.3) and iron (ß=-0.7, 95% CI -1.4 to -0.01) exposures. Zinc exposure was negatively associated with EDN1 (ß=-0.3, 95% CI -0.8 to -0.1) methylation. Lower NOS3 (ß=-42.3; p<0.001) and EDN1 (ß=-14.5; p=0.05) were associated with higher ETP. Statistical mediation analysis formally confirmed NOS3 and EDN1 hypomethylation as intermediate mechanisms for PM-related coagulation effects. CONCLUSIONS: Our study showed for the first time, that gene hypomethylation contributes to environmentally induced hypercoagulability.

Developing a Questionnaire Evaluating Knowledge, Attitudes and Behaviors on Audit & Feedback among General Practitioners: A Mixed Methods Study.

BACKGROUND: Audit and Feedback (A&F) is one of the most common strategies used to improve quality in healthcare. However, there is still lack of awareness regarding the enabling factors and barriers that could influence its effectiveness. The aim of this study was to develop a questionnaire to measure the knowledge, attitudes and behaviors of general practitioners (GPs) regarding A&F. The study was performed in the context of the EASY-NET program (project code NET-2016-02364191). METHODS: The survey was developed according to two steps. Firstly, a scoping review was performed in order to map the literature on the existing similar instruments with the aim of identifying the sub-domains and possible items to include in a preliminary version of the questionnaire. In the second phase, the questionnaire was reviewed by a multidisciplinary group of experts and administrated to a convenience sample in a pilot survey. RESULTS: Ten papers were included in the scoping review. The survey target and development methodology were heterogenous among the studies. The knowledge, attitudes and behaviors domains were assessed in six, nine and seven studies, respectively. In the first step, 126 pertinent items were extracted and categorized as follows: 8 investigated knowledge, 93 investigated attitudes, and 25 investigated behaviors. Then, 2 sub-domains were identified for knowledge, 14 for attitudes and 7 for behavior. Based on these results, a first version of the survey was developed via consensus among two authors and then revised by the multidisciplinary group of experts in the field of A&F. The final version of the survey included 36 items: 8 in the knowledge domain, 19 in the attitudes domain and 9 in the behaviors domain. The results of the pilot study among 15 GPs suggested a good acceptability and item relevance and accuracy, with positive answers totaling 100% and 93.3% in the proposed questions. CONCLUSIONS: The methodology used has shown to be a good strategy for the development of the survey. The survey will be administrated before and after the implementation of an A&F intervention to assess both baseline characteristics and changes after the intervention.

EASY-NET Program: Methods and Preliminary Results of an Audit and Feedback Intervention in the Emergency Care for Acute Myocardial Infarction in the Lazio Region, Italy.

Within the EASY-NET network program (NET-2016-02364191), Work Package 1 Lazio evaluates the effectiveness of a structured audit and feedback (A&F) intervention compared with the web-based regional periodic publication of indicators in improving the appropriateness and timeliness of emergency healthcare for acute myocardial infarction (AMI). This work describes the A&F methodology and presents the results of the first feedback delivered. The intervention involves sending periodic reports via e-mail to participating hospitals. The feedback reports include a set of volume and quality (process and outcome) indicators, calculated by facility through the health information system of the Lazio Region and compared with regional mean, target values and values calculated for hospitals with similar volumes of activity. Health managers and clinicians of each participating hospital represent the "feedback recipients". They are invited to organize clinical and organizational audit meetings to identify possible critical issues in the care pathway and define, where necessary, improvement actions. A total of 16 facilities are involved. Twelve facilities present high volumes in all volume indicators, while three facilities present low volumes for each indicator. Concerning the quality indicators, four facilities do not present critical indicators or had average results, three facilities do not present critical indicators but show average results in at least one of the indicators and six facilities present a critical value for at least one of the indicators. The first report highlighted some critical issues in some facilities on several indicators. During the audit meetings, each facility analyzes these issues, defining appropriate improvement actions. The outcome of these actions will be monitored through subsequent reporting to support the continuous care quality improvement process.

Case Identification and Characterization of Migrants with Dementia in the Lazio Region Using Health Administrative Data.

BACKGROUND: A crucial step for planning effective public health policies for migrants with dementia is the collection of data on the local dimensions of the phenomenon and patients' characteristics. OBJECTIVE: This study aimed to identify and characterize migrants with dementia in the Lazio region using health administrative databases. METHODS: Residents with dementia aged 50 years or older, living in the Lazio region as of December 31, 2018, were identified using a validated algorithm based on hospital discharge(s), claims for antidementia drugs, and co-payment exemption for dementia. Migrants were defined as people born abroad and grouped in migrants from High Migratory Pressure Countries (HMPCs) and Highly Developed Countries (HDCs). Overall and age-specific prevalence rates were estimated in native- and foreign-born patients. RESULTS: Dementia was ascertained in 38,460 residents. Among them, 37,280 (96.9%) were born in Italy, 337 (0.9%) were migrants from HDCs, and 843 (2.2%) from HMPCs. Dementia prevalence was higher among natives (1.15%, 95% CI 1.14-1.16) relative to migrants from HDCs (0.60%, 95% CI 0.54-0.67) and HMPCs (0.29%, 95% CI 0.27-0.31). The prevalence of comorbidities did not differ between groups. Migrants with dementia had a lower likelihood of receiving antidementia treatments compared with natives (51.6% in migrants from HDCs, 49.3% in migrants from HMPCs, and 53.5% among Italians). CONCLUSION: Routinely collected data in healthcare administrative databases can support the identification of migrants with dementia. Migrants exhibited a lower age-standardized prevalence of registered dementia and lower access to dedicated treatments than Italians. These findings are suggestive of underdiagnosis and undertreatment of dementia in migrants.

[A&F: integrating research into practice and practice into research.] / A&F: integrare la ricerca nella pratica e la pratica nella ricerca.

This article proposes a focus on Audit & Feedback (A&F)'s sustainability. If on one side, it is essential to ask how to bring A&F interventions out of research programs into clinical practices and contexts of care. On the other, it is fundamental to ensure that the experiences gained within care contexts can inform research, helping to define the research objectives and questions whose development can support paths of change. The reflection starts from two research programs on A&F carried out in the United Kingdom, respectively, at the regional level (Aspire) in the field of primary care and at the national level (Affinitie and Enact) in the field of the transfusion system. Aspire raised awareness of the importance of establishing a primary care implementation laboratory, which randomizes practices to different types of feedback to evaluate the effectiveness, also to improve patient care. The national Affinitie and Enact programs served to 'inform' recommendations to improve the conditions for sustainable collaboration between A&F researchers and audit programs. They represent an example to understand how to incorporate research results within a national clinical audit program. Finally, starting from the complex experience of the Easy-Net research program, the reflection moves on to how it was possible to make A&F interventions sustainable in Italy beyond research projects, in clinical-care contexts in which the resources provisions make continuous and structured interventions difficult and impractical. The Easy-Net program envisages different clinical care settings, study designs, interventions, and recipients, which require different actions to adapt research results to the specific realities to which A&F's interventions are addressed.