A Panel Study on Lung Function and Bronchial Inflammation among Children Exposed to Ambient SO2 from an Oil Refinery.

To determine the acute effects on respiratory function of children exposed to sulphur dioxide (SO2), we conducted two population-based longitudinal investigations near a major oil refinery. We enrolled 233 children, age 8⁻14, in Sarroch (Italy). The first study entailed five monthly spirometric visits (Panel 5). In a subgroup, children positive for history of respiratory symptoms were tested weekly (20 times) with spirometry and fractional exhaled nitric oxide (FeNO) measurement (Panel 20). Baseline questionnaires and daily diaries were recorded. SO2, NO2, PM10 and O3 were measured by monitoring stations. Multiple regression models were fitted. Using a multipollutant model, we found that a 10 µg/m³ SO2 increase at lag0⁻2 days determined a percent variation (PV) of -3.37 (90% confidence interval, CI: -5.39; -1.30) for forced expiratory volume after one second (FEV1) in Panel 5 and a PV = -3.51 (90% CI: -4.77; -2.23) in Panel 20. We found a strong dose-response relation: 1-h SO2 peaks >200 µg/m³ at lag2 days = FEV1 PV -2.49. For FeNO, we found a PV = 38.12 (90% CI: 12.88; 69.01) for each 10 µg/m³ SO2 increase at 8-h time lag and a strong dose-response relation. Exposure to SO2 is strongly associated with reduction of lung function and an increase in airway inflammation. This new evidence of harmful effects of SO2 peaks should induce regulatory intervention.

Risk factors for death, stroke, and bleeding in 28,628 patients from the GARFIELD-AF registry: Rationale for comprehensive management of atrial fibrillation.

BACKGROUND: The factors influencing three major outcomes-death, stroke/systemic embolism (SE), and major bleeding-have not been investigated in a large international cohort of unselected patients with newly diagnosed atrial fibrillation (AF). METHODS AND RESULTS: In 28,628 patients prospectively enrolled in the GARFIELD-AF registry with 2-year follow-up, we aimed at analysing: (1) the variables influencing outcomes; (2) the extent of implementation of guideline-recommended therapies in comorbidities that strongly affect outcomes. Median (IQR) age was 71.0 (63.0 to 78.0) years, 44.4% of patients were female, median (IQR) CHA2DS2-VASc score was 3.0 (2.0 to 4.0); 63.3% of patients were on anticoagulants (ACs) with or without antiplatelet (AP) therapy, 24.5% AP monotherapy, and 12.2% no antithrombotic therapy. At 2 years, rates (95% CI) of death, stroke/SE, and major bleeding were 3.84 (3.68; 4.02), 1.27 (1.18; 1.38), and 0.71 (0.64; 0.79) per 100 person-years. Age, history of stroke/SE, vascular disease (VascD), and chronic kidney disease (CKD) were associated with the risks of all three outcomes. Congestive heart failure (CHF) was associated with the risks of death and stroke/SE. Smoking, non-paroxysmal forms of AF, and history of bleeding were associated with the risk of death, female sex and heavy drinking with the risk of stroke/SE. Asian race was associated with lower risks of death and major bleeding versus other races. AC treatment was associated with 30% and 28% lower risks of death and stroke/SE, respectively, compared with no AC treatment. Rates of prescription of guideline-recommended drugs were suboptimal in patients with CHF, VascD, or CKD. CONCLUSIONS: Our data show that several variables are associated with the risk of one or more outcomes, in terms of death, stroke/SE, and major bleeding. Comprehensive management of AF should encompass, besides anticoagulation, improved implementation of guideline-recommended therapies for comorbidities strongly associated with outcomes, namely CHF, VascD, and CKD. TRIAL REGISTRATION: ClinicalTrials.gov NCT01090362.

Why are outcomes different for registry patients enrolled prospectively and retrospectively? Insights from the global anticoagulant registry in the FIELD-Atrial Fibrillation (GARFIELD-AF).

Aims: Retrospective and prospective observational studies are designed to reflect real-world evidence on clinical practice, but can yield conflicting results. The GARFIELD-AF Registry includes both methods of enrolment and allows analysis of differences in patient characteristics and outcomes that may result. Methods and results: Patients with atrial fibrillation (AF) and ≥1 risk factor for stroke at diagnosis of AF were recruited either retrospectively (n = 5069) or prospectively (n = 5501) from 19 countries and then followed prospectively. The retrospectively enrolled cohort comprised patients with established AF (for a least 6, and up to 24 months before enrolment), who were identified retrospectively (and baseline and partial follow-up data were collected from the emedical records) and then followed prospectively between 0 and 18 months (such that the total time of follow-up was 24 months; data collection December 2009 and October 2010). In the prospectively enrolled cohort, patients with newly diagnosed AF (≤6 weeks after diagnosis) were recruited between March 2010 and October 2011 and were followed for 24 months after enrolment. Differences between the cohorts were observed in clinical characteristics, including type of AF, stroke prevention strategies, and event rates. More patients in the retrospectively identified cohort received vitamin K antagonists (62.1% vs. 53.2%) and fewer received non-vitamin K oral anticoagulants (1.8% vs. 4.2%). All-cause mortality rates per 100 person-years during the prospective follow-up (starting the first study visit up to 1 year) were significantly lower in the retrospective than prospectively identified cohort (3.04 [95% CI 2.51-3.67] vs. 4.05 [95% CI 3.53-4.63]; P = 0.016). Conclusion: Interpretations of data from registries that aim to evaluate the characteristics and outcomes of patients with AF must take account of differences in registry design and the impact of recall bias and survivorship bias that is incurred with retrospective enrolment. Clinical trial registration: http://www.clinicaltrials.gov. Unique identifier for GARFIELD-AF (NCT01090362).

Impact of gender on event rates at 1†year in patients with newly diagnosed non-valvular atrial fibrillation: contemporary perspective from the GARFIELD-AF registry.

OBJECTIVES: Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) explored the impact of gender, risk factors and anticoagulant (AC) treatment on 1-year outcomes in patients with non-valvular atrial fibrillation (NVAF). DESIGN: GARFIELD-AF is a prospective non-interventional registry. SETTING: Investigator sites (n=1048) are representative of the care settings/locations in each of the 35 countries. PARTICIPANTS: Patients ≥18yrs with newly diagnosed (≤6 weeks' duration) NVAF and ≥1 investigator-determined stroke risk factors. MAIN OUTCOME MEASURES: Event rates per 100 person-years were estimated from the Poisson model and HRs and 95% CIs calculated. RESULTS: Of 28 624 patients (women 44.4%; men 55.6%) enrolled, there were more elderly (≥75 years) women (46.9%) than men (30.4%). All-cause mortality rates per 100 person-years (95% CI) for women and men were 4.48 (4.12 to 4.87) and 4.04 (3.74 to 4.38), respectively, stroke/systemic embolism (SE) (1.62 (1.41 to 1.87) and 1.17 (1.01 to 1.36)) and major bleeding (0.93 (0.78 to 1.13) and 0.79 (0.66 to 0.95)). After adjustment for baseline risk factors in treated and untreated patients, HRs (95% CI) for women (relative to men) for stroke/SE rates were 1.3-fold higher in women (HR 1.30 (1.04 to 1.63)), and similar for major bleeding (1.13 (0.85 to 1.50)) and all-cause mortality (1.05 (0.92 to 1.19)). Antithrombotic treatment patterns in men and women were almost identical. 63.8% women and 62.9% men received AC± antiplatelets. Relative to no AC treatment, the reduction in stroke/SE rates with AC treatment was greater (p=0.01) in men (HR 0.45 (0.33 to 0.61)) than women 0.77 (0.57 to 1.03). All-cause mortality reduction with AC treatment was similar (women: 0.65 (0.54 to 0.77); men: 0.57 (0.48 to 0.68)). The risk of major bleeding when treated with AC versus no AC was 2.33 (1.41 to 3.84) in men and 1.86 (1.16 to 2.99) in women (p value=0.53). CONCLUSIONS: Women have a higher risk of stroke/SE and the reduction in stroke/SE events rates with AC treatment is less in women than in men. TRIAL REGISTRATION NUMBER: NCT01090362.

Evolving antithrombotic treatment patterns for patients with newly diagnosed atrial fibrillation.

OBJECTIVE: We studied evolving antithrombotic therapy patterns in patients with newly diagnosed non-valvular atrial fibrillation (AF) and ≥1 additional stroke risk factor between 2010 and 2015. METHODS: 39 670 patients were prospectively enrolled in four sequential cohorts in the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF): cohort C1 (2010-2011), n=5500; C2 (2011-2013), n=11 662; C3 (2013-2014), n=11 462; C4 (2014-2015), n=11 046. Baseline characteristics and antithrombotic therapy initiated at diagnosis were analysed by cohort. RESULTS: Baseline characteristics were similar across cohorts. Median CHA2DS2-VASc (cardiac failure, hypertension, age ≥75 (doubled), diabetes, stroke (doubled)-vascular disease, age 65-74 and sex category (female)) score was 3 in all four cohorts. From C1 to C4, the proportion of patients on anticoagulant (AC) therapy increased by almost 15% (C1 57.4%; C4 71.1%). Use of vitamin K antagonist (VKA)±antiplatelet (AP) (C1 53.2%; C4 34.0%) and AP monotherapy (C1 30.2%; C4 16.6%) declined, while use of non-VKA oral ACs (NOACs)±AP increased (C1 4.2%; C4 37.0%). Most CHA2DS2-VASc ≥2 patients received AC, and this proportion increased over time, largely driven by NOAC prescribing. NOACs were more frequently prescribed than VKAs in men, the elderly, patients of Asian ethnicity, those with dementia, or those using non-steroidal anti-inflammatory drugs, and current smokers. VKA use was more common in patients with cardiac, vascular, or renal comorbidities. CONCLUSIONS: Since NOACs were introduced, there has been an increase in newly diagnosed patients with AF at risk of stroke receiving guideline-recommended therapy, predominantly driven by increased use of NOACs and reduced use of VKA±AP or AP alone. TRIAL REGISTRATION NUMBER: NCT01090362; Pre-results.

Quality of Vitamin K Antagonist Control and 1-Year Outcomes in Patients with Atrial Fibrillation: A Global Perspective from the GARFIELD-AF Registry.

AIMS: Vitamin K antagonists (VKAs) need to be individually dosed. International guidelines recommend a target range of international normalised ratio (INR) of 2.0-3.0 for stroke prevention in atrial fibrillation (AF). We analysed the time in this therapeutic range (TTR) of VKA-treated patients with newly diagnosed AF in the ongoing, global, observational registry GARFIELD-AF. Taking TTR as a measure of the quality of patient management, we analysed its relationship with 1-year outcomes, including stroke/systemic embolism (SE), major bleeding, and all-cause mortality. METHODS AND RESULTS: TTR was calculated for 9934 patients using 136,082 INR measurements during 1-year follow-up. The mean TTR was 55.0%; values were similar for different VKAs. 5851 (58.9%) patients had TTR<65%; 4083 (41.1%) TTR≥65%. The proportion of patients with TTR≥65% varied from 16.7% in Asia to 49.4% in Europe. There was a 2.6-fold increase in the risk of stroke/SE, 1.5-fold increase in the risk of major bleeding, and 2.4-fold increase in the risk of all-cause mortality with TTR<65% versus ≥65% after adjusting for potential confounders. The population attributable fraction, i.e. the proportion of events attributable to suboptimal anticoagulation among VKA users, was 47.7% for stroke/SE, 16.7% for major bleeding, and 45.4% for all-cause mortality. In patients with TTR<65%, the risk of first stroke/SE was highest in the first 4 months and decreased thereafter (test for trend, p = 0.021). In these patients, the risk of first major bleed declined during follow-up (p = 0.005), whereas in patients with TTR≥65%, the risk increased over time (p = 0.027). CONCLUSION: A large proportion of patients with AF had poor VKA control and these patients had higher risks of stroke/SE, major bleeding, and all-cause mortality. Our data suggest that there is room for improvement of VKA control in routine clinical practice and that this could substantially reduce adverse outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT01090362.

Vitamin K antagonist control in patients with atrial fibrillation in Asia compared with other regions of the world: Real-world data from the GARFIELD-AF registry.

OBJECTIVE: To compare the distribution of international normalized ratios (INRs) in patients receiving vitamin K antagonist (VKA) for newly diagnosed atrial fibrillation in Eastern and Southeastern Asia and in other regions of the world (ORW) represented in the ongoing, global observational study GARFIELD-AF. METHODS AND RESULTS: 3621 and 13,541 patients were recruited prospectively in 2010-2013 from Asia and ORW, respectively. At baseline, excluding patients with unknown antithrombotic treatment, 1356 (37.8%) in Asia and 7081 (53.3%) in ORW received VKA (±antiplatelets). INR readings during 1-year follow-up were analyzed for VKA-treated patients with ≥3 measurements (878 [64.7%] patients in Asia, 4452 [62.9%] in ORW). VKA-treated patients in Asia were younger than those in ORW (mean 67.1 vs 71.3years), with a lower CHA2DS2-VASc score (3.0 vs 3.5), but a similar HAS-BLED score (1.3 vs 1.4). Mean INR was lower in Asia than in ORW (2.0 vs 2.4). The proportion of time in the therapeutic range, defined using the multinational target of 2.0-3.0, was substantially lower in Asia (31.1% vs 54.1%). In Asia and ORW, 59.3% and 28.2% of INRs were <2, and 9.6% and 17.7% were >3, respectively. The same trend was found in different age groups (<65, 65-74, ≥75years). CONCLUSION: GARFIELD-AF data demonstrate a difference in the distribution of INRs in patients from Asia versus other regions under current real-world practice. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362.

Two-year outcomes of patients with newly diagnosed atrial fibrillation: results from GARFIELD-AF.

AIMS: The relationship between outcomes and time after diagnosis for patients with non-valvular atrial fibrillation (NVAF) is poorly defined, especially beyond the first year. METHODS AND RESULTS: GARFIELD-AF is an ongoing, global observational study of adults with newly diagnosed NVAF. Two-year outcomes of 17 162 patients prospectively enrolled in GARFIELD-AF were analysed in light of baseline characteristics, risk profiles for stroke/systemic embolism (SE), and antithrombotic therapy. The mean (standard deviation) age was 69.8 (11.4) years, 43.8% were women, and the mean CHA2DS2-VASc score was 3.3 (1.6); 60.8% of patients were prescribed anticoagulant therapy with/without antiplatelet (AP) therapy, 27.4% AP monotherapy, and 11.8% no antithrombotic therapy. At 2-year follow-up, all-cause mortality, stroke/SE, and major bleeding had occurred at a rate (95% confidence interval) of 3.83 (3.62; 4.05), 1.25 (1.13; 1.38), and 0.70 (0.62; 0.81) per 100 person-years, respectively. Rates for all three major events were highest during the first 4 months. Congestive heart failure, acute coronary syndromes, sudden/unwitnessed death, malignancy, respiratory failure, and infection/sepsis accounted for 65% of all known causes of death and strokes for <10%. Anticoagulant treatment was associated with a 35% lower risk of death. CONCLUSION: The most frequent of the three major outcome measures was death, whose most common causes are not known to be significantly influenced by anticoagulation. This suggests that a more comprehensive approach to the management of NVAF may be needed to improve outcome. This could include, in addition to anticoagulation, interventions targeting modifiable, cause-specific risk factors for death. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov. Unique identifier: NCT01090362.

Comparison of international normalized ratio audit parameters in patients enrolled in GARFIELD-AF and treated with vitamin K antagonists.

Vitamin K antagonist (VKA) therapy for stroke prevention in atrial fibrillation (AF) requires monitoring of the international normalized ratio (INR). We evaluated the agreement between two INR audit parameters, frequency in range (FIR) and proportion of time in the therapeutic range (TTR), using data from a global population of patients with newly diagnosed non-valvular AF, the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF). Among 17 168 patients with 1-year follow-up data available at the time of the analysis, 8445 received VKA therapy (±antiplatelet therapy) at enrolment, and of these patients, 5066 with ≥3 INR readings and for whom both FIR and TTR could be calculated were included in the analysis. In total, 70 905 INRs were analysed. At the patient level, TTR showed higher values than FIR (mean, 56·0% vs 49·8%; median, 59·7% vs 50·0%). Although patient-level FIR and TTR values were highly correlated (Pearson correlation coefficient [95% confidence interval; CI], 0·860 [0·852-0·867]), estimates from individuals showed widespread disagreement and variability (Lin's concordance coefficient [95% CI], 0·829 [0·821-0·837]). The difference between FIR and TTR explained 17·4% of the total variability of measurements. These results suggest that FIR and TTR are not equivalent and cannot be used interchangeably.

Prescription patterns of antiepileptic drugs in young women: development of a tool to distinguish between epilepsy and psychiatric disorders.

BACKGROUND: Antiepileptic drugs (AEDs) are also prescribed for therapeutic indications other than epilepsy (EPI), namely, psychiatric disorders (PSY). Our aim was to develop an algorithm able to distinguish between EPI and PSY among childbearing age women based on differences in AED exposure in these patient groups. METHODS: Two groups of women (18-45 years) with EPI or PSY treated with AEDs in the first semester of 2010 or 2011 were extracted from paper or electronic medical charts of specialized centers. Through the prescription database of Bologna Local Health Authority (Italy), AEDs, treatment schedule and co-treatments were collected for each patient. A prescription-based hierarchical classification system was developed. The algorithm obtained was subsequently validated on internal and external data. RESULTS: Eighty-one EPI and 94 PSY subjects were recruited. AED monotherapy was the most common choice in both groups (69% EPI vs 79% PSY). Some AEDs were used only in EPI, others exclusively in PSY. Co-treatments with antipsychotics (6% vs 67%), lithium (0% vs 9%), and antidepressants (7% vs 70%) were fewer in EPI than in PSY. The hierarchical classification system identified antipsychotics, SSRIs (Selective Serotonin Reuptake Inhibitors), and number of AEDs as variables to discriminate EPI and PSY, with an overall error rate estimate of 9.7% (95%CI: 5.3% to 14.1%). CONCLUSION: Among the differences between EPI and PSY, prescription data alone allowed an algorithm to be developed to diagnose each childbearing age woman receiving AEDs. This approach will be useful to stratify patients for risk estimates of AED-treated patients based on administrative databases. Copyright © 2016 John Wiley & Sons, Ltd.

Comparison of international normalized ratio audit parameters in patients enrolled in GARFIELD-AF and treated with vitamin K antagonists

Vitamin K antagonist (VKA) therapy for stroke prevention in atrial fibrillation (AF) requires monitoring of the international normalized ratio (INR). We evaluated the agreement between two INR audit parameters, frequency in range (FIR) and proportion of time in the therapeutic range (TTR), using data from a global population of patients with newly diagnosed non-valvular AF, the Global Anticoagulant Registry in the FIELD–Atrial Fibrillation (GARFIELD-AF). Among 17 168 patients with 1-year follow-up data available at the time of the analysis, 8445 received VKA therapy (±antiplatelet therapy) at enrolment, and of these patients, 5066 with ≥3 INR readings and for whom both FIR and TTR could be calculated were included in the analysis. In total, 70 905 INRs were analysed. At the patient level, TTR showed higher values than FIR (mean, 56·0% vs 49·8%; median, 59·7% vs 50·0%). Although patient-level FIR and TTR values were highly correlated (Pearson correlation coefficient [95% confidence interval; CI], 0·860 [0·852–0·867])...

Does sex affect anticoagulant use for stroke prevention in nonvalvular atrial fibrillation? The prospective global anticoagulant registry in the FIELD-Atrial Fibrillation.

BACKGROUND: Among patients with atrial fibrillation (AF), women are at higher risk of stroke than men. Using prospective cohort data from a large global population of patients with nonvalvular AF, we sought to identify any differences in the use of anticoagulants for stroke prevention in women and men. METHODS AND RESULTS: This was a prospective multicenter observational registry with 858 randomly selected sites in 30 countries. A total of 17 184 patients with newly diagnosed (≤6 weeks) nonvalvular AF and ≥1 additional investigator-defined stroke risk factor(s) were recruited (March 2010 to June 2013). The main outcome measure was the use of anticoagulants (vitamin K antagonists, factor Xa inhibitors, and direct thrombin inhibitors) for stroke prevention at AF diagnosis. Of 17 184 patients enrolled, 43.8% were women. More women than men were at moderate-to-high risk of stroke (CHADS2 score ≥2: 65.1% versus 54.7%). Rates of anticoagulant use were not different overall (60.9% of men versus 60.8% of women) and in patients with a CHADS2 score ≥2 (adjusted odds ratio for women versus men, 1.00; 95% confidence interval, 0.92-1.09). In patients at low risk (CHA2DS2-VASc of 0 in men and 1 in women), 41.8% of men and 41.1% of women received an anticoagulant. In patients at high risk (CHA2DS2-VASc score ≥2), 35.4% of men and 38.4% of women did not receive an anticoagulant. CONCLUSIONS: These contemporary global data show that anticoagulant use for stroke prevention is no different in men and women with nonvalvular AF. Thromboprophylaxis was, however, suboptimal in substantial proportions of men and women, with underuse in those at moderate-to-high risk of stroke and overuse in those at low risk. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362.

Quality indicators in acute stroke care: a prospective observational survey in 13 Italian regions.

BACKGROUND AND AIMS: Quality monitoring has great relevance in stroke care. The Project "How to guarantee adherence to effective interventions in stroke care" aimed to estimate adherence to acute-phase guidelines in stroke care in Italy. METHODS: A prospective observational study was performed in 27 hospitals of 13 Italian Regions. Adherence to 15 process indicators was evaluated, comparing also stroke units (SU) with conventional wards. An overall score of care, defined as the sum of achieved indicators, was calculated. A multilevel hierarchical model described performance at patient, hospital and regional level. RESULTS: Overall, 484 consecutive stroke patients (mean age, 73.4 years; 52.7 % males) were included. Total score ranged from 2 to 15 (mean 8.5 ± 2.4). SU patients were more often evaluated with the National Institutes of Health Stroke Scale (NIHSS) within 24 h, had more frequently an assessment of pre- and post-stroke disability, and a CT scan the same or the day after admission. Regional-hospital- and patient-level variability explained, respectively, 25, 34, and 41 % of total score variance. In multivariate models, patients >80 years vs. younger showed a change in total score of -0.45 (95 % CI -0.79 to -0.12), and those with NIHSS ≥14 vs. ≤5 of -0.92 (95 % CI -1.53 to -0.30). A negative change means a worse adjusted average adherence to process indicators. SU admission increased total score of 1.55 (95 % CI 0.52-2.58). CONCLUSIONS: Our data confirm the need of quality monitoring in stroke care. Although SU patients showed a better adherence to quality indicators, overall compliance was unsatisfactory.

[Environmental indicators in EpiAir2 project: air quality data for epidemiological surveillance]. / Indicatori ambientali nello studio EpiAir2: i dati di qualità dell'aria per la sorveglianza epidemiologica.

OBJECTIVE: construction of environmental indicators of air pollution suitable for epidemiological surveillance in 25 Italian cities for EpiAir2 project (2006-2010) and presentation of the results from a 10 years of surveillance system (2001-2010) in 10 Italian cities. DESIGN: data on particulate matter (PM10 and its fine fraction PM2.5), nitrogen dioxide (NO2), and ozone (O3), measured in the 2006-2010 calendar period, were collected. Meteorological data needed to estimate unbiased measures of the effect of pollutants are: temperature, relative humidity (estimated "apparent temperature"), and barometric pressure. In continuity with the previous EpiAir project, the same criteria for the selection of monitoring stations were applied and standard methods to estimate daily environmental indicators were used. Furthermore, it was checked the adequacy of the selected data to represent the population exposure. SETTING AND PARTICIPANTS: EpiAir2 project, relative to the period 2006-2010, involves the cities of Milano, Mestre-Venezia, Torino, Bologna, Firenze, Pisa, Roma, Taranto, Cagliari, and Palermo, already included in the previous study. The city of Treviso, Trieste, Padova, Rovigo, Piacenza, Parma, Ferrara, Reggio Emilia, Modena, Genova, Rimini, Ancona, Bari, Brindisi, and Napoli are added to the previous group. RESULTS: particulate matter concentrations have decreased in most cities during the study period, while concentrations of NO2 and ozone do not show a similar clear trend. The analysis of the trend showed annual mean values of PM10 higher than 40 µg/m(3) in some areas of the Po Valley, and annual mean values of NO2 higher than 40 µg/m(3) in the cities of Trieste, Milano, Padova, Torino, Modena, Bologna, Roma, and Napoli. CONCLUSION: the enlargement of the EpiAir project to 13 other cities has highlighted critical issues related to the different geographical areas under study. Results of EpiAir2 project point out the need of a monitoring system of air pollution concentrations in both urban and industrial sites, in order to obtain reliable estimates of exposure for resident populations and to evaluate the related time trend.

[Health technology assessment report: HPV DNA based primary screening for cervical cancer precursors]. / Health technology assessment report: ricerca del DNA di papillomavirus umano (HPV) come test primario per lo screening dei precursori del cancro del collo dell'utero.

UNLABELLED: OBJECTIVE OF THE PROJECT: The introduction of the HPV test as a primary screening test will cause important changes in the screening system based on cytology. The purposes of this report are: to define the best screening policies with HPV-based screening on the basis of the resulting efficacy and of undesired effects; comparing them to cytology-based screening; to identify their best conditions of application; to evaluate economic cost, feasibility and impact on the organisation of services of such policy in the Italian situation. CONTENTS: This report contains a section on efficacy and undesired effects based on a systematic review of literature conducted in strict coordination with the preparation of a supplement to the European Guidelines for quality assurance in cervical cancer screening. This chapter corresponds to a preliminary version of the chapter of the European Guidelines on primary screening with HPV. The sections on costs, impact on organisation, and social, ethical and legal impact reflect the Italian situation; they are based on a review of the available Italian data (including unpublished data, mainly from on-going pilot projects) and on a structured analysis of what will result if the proposed protocol is applied to the Italian situation. RESULTS: Efficacy and undesired effects. There is clear scientific evidence that a screening based on validated tests for the DNA of oncogenic HPV as primary test and applying an appropriate protocol is more effective than screening based on cytology in preventing invasive cancers of the uterine cervix. In addition, it entails a limited--if any--increase of the undesired effects both in terms of unneeded referral to diagnostic work-up and in terms of over-diagnosis and consequent overtreatment of spontaneously regressive lesions. The crucial elements of such protocol are the followings: HPV-positive women are not to be directly referred to colposcopy, but the use of triage systems is essential. The currently recommendable method is based on performing cytology in HPV positive women. If the result of this test is abnormal, the woman is immediately referred to colposcopy; if cytology is normal, the woman is invited to repeat a new HPV test after one year. In case such a test is still positive, the woman is referred to colposcopy; in case of negative result, the woman will be re-invited for a new screening round at the regular interval. In organised population-based screening programmes the interval after a negative primary HPV test should be at least 5 years. There is evidence that the 5-year cumulative risk of high-grade CIN after a negative HPV test is lower than the 3-year risk after a normal cytology. On the other hand, the probability of unneeded colposcopies and treatments would plausibly be relevant with 3-year intervals after a negative HPV test. HPV-based screening should not start before 30-35 years. There is evidence that below 30 years HPV-based screening leads to an increased overdiagnosis of CIN2 that would regress spontaneously, with consequent overtreatment. Some increase in overdiagnosis is plausible also between 30 and 34 years. Below such ages, cytological screening is the recommended test. Only tests for the DNA of oncogenic HPV, validated according to the European guidelines as for sensitivity and specificity for high-grade lesions, should be applied. There is no evidence that double testing with cytology and HPV is more protective than stand-alone HPV as primary test, although it entails a small and not relevant increase in sensitivity vs stand-alone HPV. On the contrary, there is evidence that double testing causes a substantial increase in referral to colposcopy and a decrease in its PPV. For this reason, if HPV is used as primary screening test, it is recommended not to add cytology in parallel. Cost and economic evaluation. It is estimated that, if the protocol described is applied, in the current Italian situation the overall costs of HPV-based screening are lower than those of conventional cytological screening applied at the current 3-year intervals, although the cost of each screening round is higher. Impact on organization. For reasons of quality and cost, both the interpretation of cytology and HPV testing require a centralisation. This need is particularly strong, in terms of costs, for HPV test execution. It is therefore recommended to perform the HPV test in a limited number of reference laboratories of large size. This also makes monitoring and evaluating the spontaneous activity easier. HPV-based screening entails problems of organisation related to the need of triage, to complex protocols and to reconversion of the activities of cytological interpretation. Social, ethical and legal impact. The communication of the result of the HPV test to women, particularly if positive, is a further crucial aspect in order to reduce not only the emotional impact, but also the possible risks that women are inappropriately managed or lost to follow-up. Great efforts must be put in the education of healthcare professionals, both directly involved in organised programmes or not, particularly private gynaecologists and general practitioners. RECOMMENDATIONS: In conclusion, the crucial requirement to introduce HPV-based screening programmes is the capacity to guarantee the application of appropriate screening protocols. If protocols do not respect the criteria described above they can cause relevant increase of undesired effects and costs compared to cytology-based screening. Therefore they should be avoided, except in studies able to provide clear evidence about human and economic costs. For this purpose, correct education and information both to healthcare professionals and to the population is needed. In the Italian situation, where organised screening and a relevant spontaneous activity coexist, their interaction is crucial. Actions directed to integrate them and to guarantee as more uniformity of interventions as possible are needed, in particular through the integration of registries and thorough monitoring and a progressive homogenization of protocols. In order to grant the safety of transition, it is needed that the HPV-based organised screening activities are strictly monitored and that the National Centre for Screening Monitoring (ONS) ensures coordination. Knowledge about HPV based screening is still rapidly evolving. It is possible that currently on-going researches suggest changes to the optimal protocols in the next few years, particularly as for the management of HPV positive women. In addition, studies on the validation of new assays were recently published and others are expected. It is suggested to exploit the organised screening activity to produce scientific evidence, in order to clarify the still uncertain aspects of optimal protocols. Different protocols in terms of screening intervals, age of application and management of HPV positive women should be studied in the frame of controlled implementation, through multicentre projects coordinated by ONS. Finally, it is suggested the creation of a National working group to promptly update the recommendations for screening and the list of assays to be considered as validated. On the bases of the results obtained in the first vaccinated cohorts reaching the screening age, for the future, it will be crucial to deliver specific recommendations to the population vaccinated against HPV during adolescence.

Nasal cell DNA methylation, inflammation, lung function and wheezing in children with asthma.

AIMS: DNA methylation is increasingly proposed as a mechanism for underlying asthma-related inflammation. However, epigenetic studies are constrained by uncertainties on whether samples that can be easily collected in human individuals can provide informative results. METHODS: Two nasal cell DNA samples were collected on different days by nasal brushings from 35 asthmatic children aged between 8 and 11 years old. We correlated DNA methylation of IL-6, iNOS, Alu and LINE-1 with fractional exhaled nitric oxide, forced expiratory volume in 1 s and wheezing. RESULTS: Fractional exhaled nitric oxide increased in association with lower promoter methylation of both IL-6 (+29.0%; p = 0.004) and iNOS (+41.0%; p = 0.002). Lower IL-6 methylation was nonsignificantly associated with wheezing during the week of the study (odds ratio = 2.3; p = 0.063). CONCLUSION: Our findings support the use of nasal cell DNA for human epigenetic studies of asthma.

Asthma symptoms, lung function, and markers of oxidative stress and inflammation in children exposed to oil refinery pollution.

OBJECTIVES: Little is known about the effects of exposure to petroleum refinery emissions on respiratory health in children. We evaluated lung function and markers of inflammation and oxidative stress in children and adolescents with and without asthma or wheezing symptoms living in a petrochemical polluted area (Sarroch, Sardinia) versus a reference area (Burcei). METHODS: Parents of 275/300 6- to 14-year-old children living in Sarroch and parents of 214/323 children living in Burcei answered a questionnaire on respiratory symptoms and risk factors. Measurements of forced expiratory volume after 1 second (FEV(1)) and of forced expiratory flow rates at 25-75% of vital capacity (FEF(25-75)) were available in 27 and 23 asthma/wheezing-positive subjects and in 7 and 54 asthma/wheezing-negative subjects in Sarroch and in Burcei, respectively; for fractional exhaled nitric oxide (FE(NO)) corresponding figures were 27 and 24 and 8 and 55 in Sarroch and in Burcei, respectively. Malondialdehyde-deoxyguanosine (MDA-dG) adduct levels in nasal mucosa were measured in 12- to 14-year-old adolescents (8 and 14 asthma/wheezing-positive and 20 and 28 asthma/wheezing-negative subjects in Sarroch and in Burcei, respectively). Air pollutants were assessed during 3 weeks, starting 1 week before lung function, FE(NO), and MDA-dG measurements. Generalized linear models were used to estimate the effect of the area of residence adjusting for confounders. RESULTS: Weekly average concentrations of sulfur dioxide were 6.9-61.6 µg/m(3) in Sarroch versus 0.3-7.6 µg/m(3) in the rural area of Burcei; of nitrogen dioxide, 5.2-28.7 µg/m(3) versus 1.7-5.3 µg/m(3); and of benzene, 1.8-9.0 µg/m(3) versus 1.3-1.5 µg/m(3), respectively. Children living in Sarroch versus children living in the reference area showed an increase in wheezing symptoms {adjusted prevalence ratio=1.70 [90% confidence interval (CI)=1.01; 2.86]}; a decrease in lung function [variation in FEV(1)=-10.3% (90% CI=-15.0; -6.0%) and in FEF(25-75)=-12.9% (90% CI=-20.7; -4.3%)]; an increase in bronchial inflammation [variation in FE(NO)=+35% (90% CI=11.7; 80.1%)]; and an increase in MDA-dG adducts of +83% (90% CI=22.9; 174.1%). CONCLUSIONS: Data from this small study are consistent with the role of environmental pollutants on lung function and inflammation.

Diagnostic accuracy of 64-slice computed tomography coronary angiography for the detection of in-stent restenosis: a meta-analysis.

BACKGROUND: We sought to evaluate the diagnostic accuracy of 64-slice multi-detector row computed tomography (MDCT) compared with invasive coronary angiography for in-stent restenosis (ISR) detection. METHODS: MEDLINE, Cochrane library, and BioMed Central database searches were performed until April 2009 for original articles. Inclusion criteria were (1) 64-MDCT was used as a diagnostic test for ISR, with >50% diameter stenosis selected as the cut-off criterion for significant ISR, using invasive coronary angiography and quantitative coronary angiography as the standard of reference; (2) absolute numbers of true positive, false positive, true negative, and false negative results could be derived. Standard meta-analytic methods were applied. RESULTS: Nine studies with a total of 598 patients with 978 stents included were considered eligible. On average, 9% of stents were unassessable (range 0-42%). Accuracy tests with 95% confidence intervals (CIs) comparing 64-MDCT vs invasive coronary angiography showed that pooled sensitivity, specificity, positive and negative likelihood ratio (random effect model) values were: 86% (95% CI 80-91%), 93% (95% CI 91-95%), 12.32 (95% CI 7.26-20.92), 0.18 (95% CI 0.12-0.28) for binary ISR detection. The symmetric area under the curve value was 0.94, indicating good agreement between 64-MDCT and invasive coronary angiography. CONCLUSIONS: 64-MDCT has a good diagnostic accuracy for ISR detection with a particularly high negative predictive value. However, still a relatively large proportion of stents remains uninterpretable. Accordingly, only in selected patients, 64-MDCT may serve as a potential alternative noninvasive method to rule out ISR.

Is human papillomavirus screening preferable to current policies in vaccinated and unvaccinated women? A cost-effectiveness analysis.

OBJECTIVES: Italy was the first European nation to offer free vaccination against human papillomavirus (HPV) types 16 and 18. The vaccination is actively encouraged and is available free of charge to 11-year-old girls. The introduction of new technologies such as HPV DNA testing and HPV vaccination requires cost-effectiveness analysis of cervical cancer strategies in Italy for both vaccinated and unvaccinated women. METHODS: A calibrated Markov model was developed to describe the natural history of HPV infection and cervical carcinogenesis. We performed a microsimulation generating the life histories of 10 million women. Changes in these life histories occur as consequences of prevention strategies. We estimated costs of screening activities using an activity-based costing analysis. We assessed lifetime risk due to cervical cancer, lifetime costs and quality-adjusted life-expectancy (QALE) for 18 scenarios. Strategies varied by screening interval (three and five years), primary and triage test (Pap test and HPV DNA test), and HPV 16 and 18 vaccination. RESULTS: The current screening policy (Pap test every three years) is more costly and less effective than HPV DNA test and Pap test triage every five years. For unvaccinated women an HPV DNA test every five years with a Pap test triage was cost-effective (ICER €5753/QALE). Vaccination followed by the same screening strategy was cost-effective (ICER €23,951/QALE) for women who are eligible to be vaccinated. CONCLUSIONS: Our findings strongly support changing the Pap screening policy to the use of HPV DNA as a primary test with Pap test triage for both vaccinated and unvaccinated women.