[The mortality cost of carbon dioxide emissions from a steel plant in Southern Italy: a climate change health impact assessment]. / Il "mortality cost" delle emissioni di CO2 di uno stabilimento siderurgico nel Sud Italia: una valutazione degli impatti sanitari derivanti dal cambiamento climatico.

OBJECTIVES: to quantify the temperature-related global health impacts of the Taranto steel plant CO2e emissions. DESIGN: using the risk functions available in the literature, a prospective global health impact assessment of the marginal CO2e emissions declared by the steel plant for 2020 was conducted. SETTING AND PARTICIPANTS: world population in the period 2020-2100. MAIN OUTCOMES MEASURES: deaths in the period 2020-2100 attributable to the marginal CO2e emitted by the Taranto steel plant in 2020. RESULTS: considering the central estimates in the baseline emission scenario (4.1°C warming by 2100), the Taranto steel plant 2020 CO2e emissions will cause 1,876 deaths worldwide between 2020 and 2100. The largest part will be attributable to steelmaking processes, accounting for 1,093 deaths. The same emissions will cause 5.56 × 10-4 deaths worldwide between 2020 and 2100 per tonne of steel produced in 2020, i.e. one death for every 1,799 tonnes of steel. If the 2020 CO2e emissions of the steel plant had been reduced by 25%, 50% or 75%, the deaths avoided in the world in the period 2020-2100 would have been 469, 938 and 1,407 respectively. CONCLUSIONS: estimates predict a probably significant mortality impact worldwide by the end of the century associated with the greenhouse gases emissions of the Taranto steel plant. Just reducing emissions by 50% in a single year could maybe avoid over 900 deaths worldwide by the end of the century. This confirms the importance of implementing incisive policies to reduce greenhouse gases emissions in all sectors.

Spatial distribution of kidney disease in the contaminated site of Taranto (Italy).

BACKGROUND: Exposure to heavy metals has been associated with kidney disease. We investigated the spatial distribution of kidney disease in the industrially contaminated site of Taranto. METHODS: Cases were subjects with a first hospital discharge diagnosis of kidney disease. Cases affected by specific comorbidities were excluded. Standardized Hospitalization Ratios (SHRs) were computed for low/high exposure area and for modeled spatial distribution of cadmium and fine particulate matter. RESULT: Using the high/low exposure approach, in subjects aged 20-59 years residing in the high exposure area a significant excess of hospitalization was observed in males and a non-significant excess in females. No excesses were observed in subjects aged 60 years and over. The analysis by the modeling approach did not show a significant association with the greatest pollution impact area. CONCLUSION: Due to the excesses of hospitalization observed in the high/low exposure approach, a continuing epidemiological surveillance of residents and occupational groups is warranted.

[Intercensal reconstruction of population and descriptive epidemiological measures in Italy: what is the impact on the cancer incidence rates?]. / La ricostruzione intercensuaria della popolazione e le misure di epidemiologia descrittiva in Italia: qual è l'impatto sui tassi di incidenza dei tumori?

OBJECTIVES: to test the effect on cancer incidence rates when using precensal computation (computed population) or intercensal reconstruction of population (reconstructed population). DESIGN: comparison between computed and reconstructed population by area and period in 2002-2011; evaluation of the effect on cancer rates using Italian cancer registries data. Setting e participants: population data from the Italian National Institute for Statistics, cancer data from Italian cancer registries; specific analysis involves data from Parma (Emilia-Romagna Region, Northern Italy) and Taranto (Apulia Region, Southern Italy) cancer registries. MAIN OUTCOME MEASURES: ratio between computed and reconstructed population by area, gender, age, and period; ratio between corresponding age-standardized incidence rates. RESULTS: Italian population estimates by precensal computation for years 2002-2011 was generally higher than that obtained by intercensal reconstruction especially in 2011, when this has been found in more than 86% of Italian Municipalities. In the same year a smaller proportion of Municipalities (11%) showed an inverse population ratio. Among the most populated Municipalities, the City of Milan showed the higher precensal to intercensal population ratio (1.076), while the City of Taranto showed the lower precensal to intercensal population ratio (0.956). The ratios between age standardized rates obtained with precensal population to those obtained with intercensal population show similar differences; in particular, for all cancer in males and females they were, respectively, 0.985 and 0.982 in the Province of Parma, 0.974 and 0.968 in the City of Parma, 1.023 and 1.013 in the Province of Taranto, and 1.08 and 1.051 in the City of Taranto. CONCLUSION: using precensal population as denominator for the year 2002- 2011 produces a remarkable distortion of both temporal trend and geographical comparisons. It is, therefore, necessary that researchers take into account this possible distortion when reporting descriptive measures in the years between the last two censuses in Italy.

[Childhood cancer incidence in Apulia Region (Southern Italy), 2003-2008]. / Incidenza dei tumori maligni infantili in Puglia, 2003-2008.

OBJECTIVES: to investigate, for the first time, the incidence rates of malignant childhood cancers (children aged 0-14 years) in Apulia Region (Southern Italy) in the period 2003-2008. DESIGN: to compute incidence rates of childhood cancers from Apulia Region Cancer Registry database compared with the corresponding results published in 2012 by the Italian cancer registries network (AIRTUM),where data from the Apulia population were not included, because not available. SETTING AND PARTICIPANTS: we selected all incident cases of malignant tumours (behaviour: /3 of ICD-O-3 classification) in children aged 0-14 registered in the Apulia cancer registry. Local health unit (LHU) of Lecce (section of the Apulia cancer registry) collected data from 2003 to 2006; LHU of Taranto, BT, and Brindisi collected data from 2006 to 2008. MAIN OUTCOME MEASURES: we computed crude, age specific, and directly standardised rates (DSR), with 95% confidence intervals, of all malignant tumours, all categories and 5 subgroups of the ICCC-3 classification; standardised incidence ratios (SIR) for all childhood malignant tumours using the rates of the AIRTUM Pool 2003-2008 as reference . RESULTS: incident cases were 183. DSR (x106) of all childhood malignant tumours are: Apulia Region 169.7 (95%CI 145.9- 196.4); Brindisi 160.4 (95%CI 106.2-232.9); BT 177.7 (95%CI 122.7-248.7); Lecce 144.3 (95%CI 111.1-184.2); Taranto 216.2 (95%CI 163.0-281.4). SIR estimates are: Apulia Region 102.9 (95%CI 88.5-119.0); Brindisi 100.2 (95%CI 66.6-144.9); BT 105.4 (95%CI 73.0-147.2); Lecce 85.5 (95%CI 66.0-109.0); Taranto 134.6 (95%CI 101.7-174.8). Main incidence measures for all ICCC-3 categories and five subgroups of childhood cancers in Apulia are also reported. CONCLUSIONS: in Apulia Region, we estimated a DSR for all childhood malignant tumours very close to that of the AIRTUM Pool. DSRs for each ICCC-3 category look comparable with the data from the national survey too. When data of each LHU were analysed, the SIR estimate makes it evident an excess of all malignant childhood cancers in the LHU of Taranto. Other results of particular cancers and specific age groups also provide suggestions for further investigations.

Sex, environment, and death rate in a dementia cohort: a seven-years Bayesian survival analysis using medications data from a contaminated area in Italy.

Introduction: Studies have analyzed the effects of industrial installations on the environment and human health in Taranto, Southern Italy. Literature documented associations between different variables and dementia mortality among both women and men. The present study aims to investigate the associations between sex, environment, age, disease duration, pandemic years, anti-dementia drugs, and death rate. Methods: Data from the regional medication registry were used. All women and men with an anti-dementia medication between 2015 and 2021 were included and followed-up to 2021. Bayesian mixed effects logistic and Cox regression models with time varying exposures were fitted using integrated nested Laplace approximations and adjusting for patients and therapy characteristics. Results: A total of 7,961 person-years were observed. Variables associated with lower prevalence of acetylcholinesterase inhibitors (AChEIs) medication were male sex (OR 0.63, 95% CrI 0.42-0.96), age 70-79 years (OR 0.17, 95% CrI 0.06-0.47) and ≥ 80 years (OR 0.08, 95% CrI 0.03-0.23), disease duration of 2-3 years (OR 0.43, 95% CrI 0.32-0.56) and 4-6 years (OR 0.21, 95% CrI 0.13-0.33), and pandemic years 2020 (OR 0.50, 95% CrI 0.37-0.67) and 2021 (OR 0.47, 95% CrI 0.33-0.65). Variables associated with higher mortality were male sex (HR 2.14, 95% CrI 1.75-2.62), residence in the contaminated site of national interest (SIN) (HR 1.25, 95% CrI 1.02-1.53), age ≥ 80 years (HR 6.06, 95% CrI 1.94-18.95), disease duration of 1 year (HR 1.50, 95% CrI 1.12-2.01), 2-3 years (HR 1.90, 95% CrI 1.45-2.48) and 4-6 years (HR 2.21, 95% CrI 1.60-3.07), and pandemic years 2020 (HR 1.38, 95% CrI 1.06-1.80) and 2021 (HR 1.56, 95% CrI 1.21-2.02). Variables associated with lower mortality were therapy with AChEIs alone (HR 0.69, 95% CrI 0.56-0.86) and in combination with memantine (HR 0.54, 95% CrI 0.37-0.81). Discussion: Male sex, age, disease duration, and pandemic years appeared to be associated with lower AChEIs medications. Male sex, residence in the SIN of Taranto, age, disease duration, and pandemic years seemed to be associated with an increased death rate, while AChEIs medication seemed to be associated with improved survival rate.

Gender differences, environmental pressures, tumor characteristics, and death rate in a lung cancer cohort: a seven-years Bayesian survival analysis using cancer registry data from a contaminated area in Italy.

Introduction: In Taranto, Southern Italy, adverse impacts on the environment and human health due to industrial installations have been studied. In the literature, associations have been reported between gender, environmental factors, and lung cancer mortality in women and men. The aim of this study was to investigate the relationships between gender, residence in areas with high environmental pressures, bronchus/lung cancer characteristics, and death rate. Methods: Data from the Taranto Cancer Registry were used, including all women and men with invasive bronchus/lung cancer diagnosed between 1 January 2016 and 31 December 2020 and with follow-up to 31 December 2022. Bayesian mixed effects logistic and Cox regression models were fitted with the approach of integrated nested Laplace approximation, adjusting for patients and disease characteristics. Results: A total of 2,535 person-years were observed. Male gender was associated with a higher prevalence of histological grade 3 (OR 2.45, 95% CrI 1.35-4.43) and lung squamous-cell carcinoma (OR 3.04, 95% CrI 1.97-4.69). Variables associated with higher death rate were male gender (HR 1.24, 95% CrI 1.07-1.43), pathological/clinical stage II (HR 2.49, 95% CrI 1.63-3.79), III (HR 3.40, 95% CrI 2.33-4.97), and IV (HR 8.21, 95% CrI 5.95-11.34), histological grade 3 (HR 1.80, 95% CrI 1.25-2.59), lung squamous-cell carcinoma (HR 1.18, 95% CrI 1.00-1.39), and small-cell lung cancer (HR 1.62, 95% CrI 1.31-1.99). Variables associated with lower death rate were other-type lung cancer (HR 0.65, 95% CrI 0.44-0.95), high immune checkpoint ligand expression (HR 0.75, 95% CrI 0.59-0.95), lung localization (HR 0.73, 95% CrI 0.62-0.86), and left localization (HR 0.85, 95% CrI 0.75-0.95). Discussion: The results among patients with lung cancer did not show an association between residence in the contaminated site of national interest (SIN) and the prevalence of the above mentioned prognostic factors, nor between residence in SIN and death rate. The findings confirmed the independent prognostic values of different lung cancer characteristics. Even after adjusting for patients and disease characteristics, male gender appeared to be associated with a higher prevalence of poorly differentiated cancer and squamous-cell carcinoma, and with an increased death rate.

Environmental pressures, tumor characteristics, and death rate in a female breast cancer cohort: a seven-years Bayesian survival analysis using cancer registry data from a contaminated area in Italy.

Introduction: In Taranto, Southern Italy, adverse impacts on the environment and human health due to industrial installations have been studied. In the literature, few associations have been reported between environmental factors and breast cancer mortality in women. The aim of this study was to investigate the relationships between residence in areas with high environmental pressures, female breast cancer characteristics, and death rate. Methods: Data from the Taranto Cancer Registry were used, including all women with invasive breast cancer diagnosed between 01 January 2015 and 31 December 2020 and with follow-up to 31 December 2021. Bayesian mixed effects logistic and Cox regression models were fitted with the approach of integrated nested Laplace approximation, adjusting for patients and disease characteristics. Results: A total of 10,445 person-years were observed. Variables associated with higher death rate were residence in the contaminated site of national interest (SIN) (HR 1.22, 95% CrI 1.01-1.48), pathological/clinical stage III (HR 2.77, 95% CrI 1.93-3.97) and IV (HR 17.05, 95% CrI 11.94-24.34), histological grade 3 (HR 2.50, 95% CrI 1.20-5.23), Ki-67 proliferation index of 21-50% (HR 1.42, 95% CrI 1.10-1.83) and > 50% (HR 1.81, 95% CrI 1.29-2.55), and bilateral localization (HR 1.65, 95% CrI 1.01-2.68). Variables associated with lower death rate were estrogen and/or progesterone receptor positivity (HR 0.61, 95% CrI 0.45-0.81) and HER2/neu oncogene positivity (HR 0.59, 95% CrI 0.44-0.79). Discussion: The findings confirmed the independent prognostic values of different female breast cancer characteristics. Even after adjusting for patients and disease characteristics, residence in the SIN of Taranto appeared to be associated with an increased death rate.

[Environment and health in Taranto, southern Italy: epidemiological studies and public health recommendations]. / Ambiente e salute a Taranto: studi epidemiologici e indicazioni di sanità pubblica.

INTRODUCTION: in Taranto IPS (Italian polluted site, made up of 2 municipalities) the Decree defining site boundaries lists the presence of a refinery, a steel plant, a harbour area and waste landfills together with illegal dumping sites. Previous environmental and epidemiological investigations in the area documented the presence of environmental contamination and increased mortality from respiratory and cardiovascular diseases as well as a number of cancer sites; for these same health outcomes the cohort study of residents showed increased risk both in terms of mortality and morbidity. OBJECTIVE: to describe the health status of residents in Taranto IPS analyzing different health indicators available at municipal level, i.e. mortality (2003-2009), mortality time trend (1980-2008) and cancer incidence (2006-2007). METHODS: the analyses were carried out for residents in Taranto IPS. Mortality update (SENTIERI Project, 2003-2009) regards 63 single or grouped causes (all ages, both genders); for a selection of causes 0-1 and 0-14 age classes were analyzed (both genders combined). Standardized mortality ratio crude (SMR) and deprivation adjusted together with 90% confidence intervals (90%CI) were computed using regional rates for comparison. Mortality time trend (1980-2008, triennial intervals) were analyzed calculating standardized rates (0-99 years, both genders, per 100,000, Italian population at 2001 Census as reference) and 90%CI. Time trends were computed for all causes, all neoplasms (and lung cancer), cardiovascular diseases (and ischemic heart diseases), respiratory diseases (also acute and chronic) and all causes infant mortality (both genders combined). For cancer incidence (2006-2007) Standardized incidence ratio (SIR) and 90%CI were calculated for both genders; incidence rates of cancer registries of the macroarea South and Islands (2005-2007) and rates of Taranto Province excluding SIN municipalities (2006-2007) were used for comparison. RESULTS: in Taranto IPS mortality among men is in excess in both periods (SENTIERI Project 1995-2002 and 2003-2009) for all causes, all neoplasms (including lung and pleural cancer), dementia, cardiovascular diseases (including hypertension and ischemic heart diseases), respiratory diseases (including the acute ones) and digestive diseases (including liver cirrhosis). All causes infant mortality is in excess in both periods. Time trends show that Taranto IPS rates are higher than regional average in the majority of time intervals for most causes in both genders. Rates are often higher than national average form any triennial intervals. Among males, over the whole period, mortality in Taranto IPS is higher than regional and national average for causes as lung cancer, diseases of the respiratory system, including the chronic ones. Among females, since the early Nineties, lung cancer and ischemic heart diseases are in excess in Taranto IPS. Also infant mortality is higher for the whole period in Taranto IPS than regional and national averages. Cancer incidence results show excesses for cancer sites already indicated by mortality data. CONCLUSIONS: mortality analyzed in the context of SENTIERI Project (1995-2002 and 2003-2009), time trend mortality (1980-2008) and cancer incidence (2006- 2007) show, in both genders, excesses for causes for which an etiologic role of environmental exposure present in Taranto IPS are either ascertained or suspected on the basis of a priori evaluation of the epidemiological evidence. The finding of excess infant mortality is of the utmost importance in public health terms. Most diseases showing an increased risk have multifactorial etiology, therefore interventions of proven efficacy, such as smoking cessation, food education, measures for cardiovascular risk reduction and breast cancer and colon screening programmes should be planned. To build a climate of confidence and trust between citizens and public institutions study results and public health actions are to be communicated objectively and transparently.

Breast Cancer in Italy: Stage and Region Distribution.

Purpose: Describe breast cancer in Italy by age, geographical area, stage and sites of metastases. In addition, incident and prevalent cases by region are provided. Patients and Methods: This population-based study included all female patients with histologically confirmed breast cancer diagnosed in Italy between 2013 and 2019 in the eight participating Cancer Registries. Cases were described by geographic area (north, center, south), age group (<50, 50-69 and 70+) and site of metastases. In addition, the study also provided an estimate of the cases of metastatic breast cancer per single region. Results: Of the total 5731 cases, the number of unknown stage cases (eliminated from our analyses) was 545 (10.5% of cases); therefore, the study was conducted on 5186 cases. Overall, 333 (6.5%) of tumors were metastatic at diagnosis but the distribution by geographical area was different: 5.1% in the north, 7.4% in the center and 7.8% in the south. Related to age, 5.6% were diagnosed before the age of 50 and 5.6% within the screening target group (50-69 years), while in elderly women the percentage rose to 8.1%. As regards the site of the metastases, 27.1% developed metastasis to the bone, 12.4% to the liver, 8.6% to the lung and 2.6% to the brain; in 34.9%, multiple sites were already present at the beginning of the cancer. Overall, 3520 cases of incident mBC are estimated in Italia every year (520 in Lombardy in northern Italy, 350 in Lazio in the center, followed by 330 in Campania in the south), and finally they are out of 52,000 prevalent cases. Conclusion: A greater possibility of treating and living with the disease for a long time now requires careful monitoring of these tumors.

Industrial air pollution and mortality in the Taranto area, Southern Italy: A difference-in-differences approach.

BACKGROUND: A large steel plant close to the urban area of Taranto (Italy) has been operating since the sixties. Several studies conducted in the past reported an excess of mortality and morbidity from various diseases at the town level, possibly due to air pollution from the plant. However, the relationship between air pollutants emitted from the industry and adverse health outcomes has been controversial. We applied a variant of the "difference-in-differences" (DID) approach to examine the relationship between temporal changes in exposure to industrial PM10 from the plant and changes in cause-specific mortality rates at area unit level. METHODS: We examined a dynamic cohort of all subjects (321,356 individuals) resident in the Taranto area in 1998-2010 and followed them up for mortality till 2014. In this work, we included only deaths occurring on 2008-2014. We observed a total of 15,303 natural deaths in the cohort and age-specific annual death rates were computed for each area unit (11 areas in total). PM10 and NO2 concentrations measured at air quality monitoring stations and the results of a dispersion model were used to estimate annual average population weighted exposures to PM10 of industrial origin for each year, area unit and age class. Changes in exposures and in mortality were analyzed using Poisson regression. RESULTS: We estimated an increased risk in natural mortality (1.86%, 95% confidence interval [CI]: -0.06, 3.83%) per 1 µg/m3 annual change of industrial PM10, mainly driven by respiratory causes (8.74%, 95% CI: 1.50, 16.51%). The associations were statistically significant only in the elderly (65+ years). CONCLUSIONS: The DID approach is intuitively simple and reduces confounding by design. Under the multiple assumptions of this approach, the study indicates an effect of industrial PM10 on natural mortality, especially in the elderly population.

[Chronic obstructive pulmonary disease prevalence estimated using a standard algorithm based on electronic health data in various areas of Italy]. / Stima della prevalenza di broncopneumopatia cronico-ostruttiva basata su dati sanitari correnti, mediante l'uso di un algoritmo comune, in differenti aree italiane.

AIM: to estimate the prevalence of chronic obstructive pulmonary disease (COPD) by integrating various administrative health information systems. METHODS: prevalent COPD cases were defined as those reported in the hospital discharge registry (HDR) and cause of mortality registry (CMR) with codes 490*, 491*, 492*, 494* and 496* of the International diseases classification 9th revision. Annual prevalence was estimated in 35+ year-old residents in six Italian areas ofb different sizes, in the period 2002-2004. We included cases observed in the previous four years who were alive at the beginning of each year. RESULTS: in 2003, age-standardized prevalence rates varied from 1.6% in Venice to 5% in Taranto. Prevalence was higher in males and increased with age. The highest rates were observed in central (Rome) and southern (Taranto) cities, especially in the 35-64 age group. HDR contributed 91% of cases. Health-tax exemption registry would increase the prevalence estimate by 0.2% if used as a third data source. CONCLUSIONS: with respect to the National Health Status survey, COPD prevalence is underestimated by 1%-3%; this can partly be due to the selection of severe and exacerbated COPD by the algorithm used. However, age, gender and geographical characteristics of prevalent cases were comparable to national estimates. Including cases observed in previous years (longitudinal estimates) increased the point estimate (yearly) of prevalence two or three times in each area.

Environment and health in contaminated sites: the case of Taranto, Italy.

The National Environmental Remediation programme in Italy includes sites with documented contamination and associated potential health impacts (National Priority Contaminated Sites-NPCSs). SENTIERI Project, an extensive investigation of mortality in 44 NPCSs, considered the area of Taranto, a NPCS where a number of polluting sources are present. Health indicators available at municipality level were analyzed, that is, mortality (2003-2009), mortality time trend (1980-2008), and cancer incidence (2006-2007). In addition, the cohort of individuals living in the area was followed up to evaluate mortality (1998-2008) and morbidity (1998-2010) by district of residence. The results of the study consistently showed excess risks for a number of causes of death in both genders, among them: all causes, all cancers, lung cancer, and cardiovascular and respiratory diseases, both acute and chronic. An increased infant mortality was also observed from the time trends analysis. Mortality/morbidity excesses were detected in residents living in districts near the industrial area, for several disorders including cancer, cardiovascular, and respiratory diseases. These coherent findings from different epidemiological approaches corroborate the need to promptly proceed with environmental cleanup interventions. Most diseases showing an increase in Taranto NPCS have a multifactorial etiology, and preventive measures of proven efficacy (e.g., smoking cessation and cardiovascular risk reduction programs, breast cancer screening) should be planned. The study results and public health actions are to be communicated objectively and transparently so that a climate of confidence and trust between citizens and public institutions is maintained.

Estimates of cancer burden in Puglia.

AIMS AND BACKGROUND: A regional population-based cancer registry that provides incidence and survival data has become active only recently. Since it is important to know the time trends of basic epidemiological indicators to understand the cancer burden in the region, this paper will provide incidence, prevalence and mortality estimates in the region for seven major cancers for the period 1970-2015. METHODS: The estimates were obtained by applying the MIAMOD method, a statistical back-calculation approach to derive incidence and prevalence figures starting from mortality and relative survival data. Survival was modeled on the basis of published data from the Italian cancer registries. RESULTS: The incidence rates are estimated to be still increasing for female breast cancer, colorectal cancer in men and skin melanoma in both sexes. By contrast, the incidence rates indicate a decreasing trend for cervix uteri cancer and stomach cancer, the latter both in men and women. For these cancers an analogous trend is observed for mortality, confirming the reduction of the risk factors related to these cancer types. The incidence rates for lung cancer and prostate cancer in men were estimated to rise, reach a peak, and then decrease in the last part of the considered period. Prevalence increased for all the considered cancers except cervix cancer. The increase was striking for breast cancer and less pronounced for stomach cancer in both genders. CONCLUSION: This paper provides a description of the burden of the major cancers until 2015. The results highlight the need to reinforce effective preventive measures to contrast cancers related to an unhealthy lifestyle and to increase the compliance with organized screening programs to reduce the colorectal and breast cancer burden.

Short-Term Effects of Nitrogen Dioxide on Mortality and Susceptibility Factors in 10 Italian Cities: The EpiAir Study.

BACKGROUND: Several studies have shown an association between nitrogen dioxide (NO2) and mortality. In Italy, the EpiAir multicentric study, "Air Pollution and Health: Epidemiological Surveillance and Primary Prevention," investigated short-term health effects of air pollution, including NO2. OBJECTIVES: To study the individual susceptibility, we evaluated the association between NO2 and cause-specific mortality, investigating individual sociodemographic features and chronic/acute medical conditions as potential effect modifiers. METHODS: We considered 276,205 natural deaths of persons > 35 years of age, resident in 10 Italian cities, and deceased between 2001 and 2005. We chose a time-stratified case-crossover analysis to evaluate the short-term effects of NO2 on natural, cardiac, cerebrovascular, and respiratory mortality. For each subject, we collected information on sociodemographic features and hospital admissions in the previous 2 years. Fixed monitors provided daily concentrations of NO2, particulate matter ≤ 10 µm in aerodynamic diameter (PM10) and ozone (O3). RESULTS: We found statistically significant associations with a 10-µg/m3 increase of NO2 for natural mortality [2.09% for lag 0-5; 95% confidence interval (CI), 0.96-3.24], for cardiac mortality (2.63% for lag 0-5; 95% CI, 1.53-3.75), and for respiratory mortality (3.48% for lag 1-5; 95% CI, 0.75-6.29). These associations were independent from those of PM10 and O3. Stronger associations were estimated for subjects with at least one hospital admission in the 2 previous years and for subjects with three or more specific chronic conditions. Some cardiovascular conditions (i.e., ischemic heart disease, pulmonary circulation impairment, heart conduction disorders, heart failure) and diabetes appeared to confer a strong susceptibility to air pollution. CONCLUSIONS: Our results suggest significant and likely independent effects of NO2 on natural, cardiac, and respiratory mortality, particularly among subjects with specific cardiovascular preexisting chronic conditions and diabetes.