Are autopsies on minors a taboo?: The experience of Milan in a 19-year retrospective study.

Forensic autopsy is an important tool for the proper management of non-natural deaths in minors. However, it seems that autopsy in minors is a practice which may not be performed routinely. In this framework, we conducted a study analyzing autopsies of minors (under 18 years of age in Italy) performed at the Institute of Forensic Medicine in Milan in the period 2001-2019. For the period 2015-2019, we extrapolated all deaths due to non-natural causes in minors to investigate how many and which of these deaths were not subjected to forensic autopsy. Of the total, 344 minors (235 males and 109 females) underwent autopsies, with an overall downward trend of about 80% since 2004. Most autopsies occurred between the ages of 0 and 1 year, and the fewest between the ages of 5 and 9 years. The place of death was home in most cases, and accidental death was most common, followed by natural death, suicide, and homicide, with prevalence varying by age group. Blunt force trauma predominated among accidental death in all age groups, followed by asphyxia. Similar findings were observed for suicides, although there was a more differentiated pattern for suicides between the ages of 15 and 17 years. Among homicides, blunt force trauma, asphyxia, and gunshot wounds were fairly evenly distributed across all age groups. Between 2015 and 2019, a total of 86 minors died of a non-natural cause, and a forensic autopsy was performed in only 33 cases (38%). Our data shows that fewer and fewer autopsies are being performed over the last years, which indicates a dangerous lack of forensic investigation of children and adolescent deaths, with enormous implications for prevention of child abuse.

Asbestos exposure and asbestosis mortality in Italian cement-asbestos cohorts: Dose-response relationship and the role of competing death causes.

OBJECTIVES: In Italy, asbestos was used intensively until its ban in 1992, which was extended for asbestos cement factories until 1994. The aim of this study was to evaluate the dose-response between asbestos exposure and asbestosis mortality across a pool of Italian occupational cohorts, taking into account the presence of competing risks. METHODS: Cohorts were followed for vital status and the cause of death was ascertained by a linkage with mortality registers. Cause-specific (CS) Cox-regression models were used to evaluate the dose-exposure relationship between asbestosis mortality and the time-dependent cumulative exposure index (CEI) to asbestos. Fine and Gray regression models were computed to assess the effect of competing risks of death. RESULTS: The cohort included 12,963 asbestos cement workers. During the follow-up period (1960-2012), of a total of 6961 deaths, we observed 416 deaths attributed to asbestosis, 879 to lung cancer, 400 to primary pleural cancer, 135 to peritoneal cancer, and 1825 to diseases of the circulatory system. The CS model showed a strong association between CEI and asbestosis mortality. Dose-response models estimated an increasing trend in mortality even below a CEI of 25 ff/mL-years. Lung cancer and circulatory diseases were the main competing causes of death. CONCLUSIONS: Asbestos exposure among Italian asbestos-cement workers has led to a very high number of deaths from asbestosis and asbestos-related diseases. The increasing risk trend associated with excess deaths, even at low exposure levels, suggests that the proposed limit values would not have been adequate to prevent disability and mortality from asbestosis.

Estimated number of deaths attributable to NO2, PM10, and PM2.5 pollution in the Municipality of Milan in 2019.

BACKGROUND: there is growing evidence that exposure to environmental pollutants affects health, including mortality, chronic diseases, and acute diseases. The World Health Organisation has recently revised downwards the safety thresholds for exposure to environmental pollutants. The City of Milan (CoM) has particularly high levels of pollution; this is due both to the presence of various emission sources and to climatic and orographic conditions. OBJECTIVES: to describe the health effects of exposure to pollutants, measured by deaths due to environmental exposure to NO2, PM10, and PM2.5 in 2019. DESIGN: observational study. Using a pollutant concentration estimation model, annual mean values of NO2, PM10, and PM2.5 were estimated for the CoM in 2019. The number of deaths attributable to each exposure was estimated using risk functions available in the literature; the values recommended by the new World Health Organisation guidelines were used as counterfactual exposure limits. SETTING AND PARTICIPANTS: the population assisted by the Agency for Health Protection of Milan and resident in the CoM on 01.01.2019, aged 30 years or older. The place of residence was georeferenced and the population was followed up until 31.12.2019. Deaths and their causes were obtained from the Causes of Death Registry. MAIN OUTCOME MEASURES: deaths attributable to exposure from non-accidental causes, cardiovascular diseases, respiratory diseases, and lung cancer were estimated. RESULTS: in 2019, the estimated annual average level of NO2 was 36.6 µg/m3, that of PM10 was 24.9 µg/m3, and that of PM2.5 was 22.4 µg/m3, with levels varying across the city area. Concerning exposure to NO2, in 2019 10% of deaths for natural causes were estimated to be attributable to annual mean levels of NO2 above 10 µg/m3. As regard PM2.5, 13% of deaths for natural causes and 18% of deaths from lung cancer were attributable to an annual mean level above 5 µg/m3. The impact of exposure to particulate matter on mortality does not seem to be the same in all the areas of the CoM. CONCLUSIONS: the health impact of exposure to airborne particulate matter in the CoM population is high. It is important that citizens, policy-makers, and stakeholders address this issue, because of its impact on both health and healthcare costs.

Rate advancement measurement for lung cancer and pleural mesothelioma in asbestos-exposed workers.

INTRODUCTION: Exposure to asbestos increases the risk of lung cancer and mesothelioma. Few studies quantified the premature occurrence of these diseases in asbestos-exposed workers. Focus on premature disease onset (rate advancement or acceleration) can be useful in risk communication and for the evaluation of exposure impact. We estimated rate advancement for total mortality, lung cancer and pleural mesothelioma deaths, by classes of cumulative asbestos exposure in a pooled cohort of asbestos cement (AC) workers in Italy. METHOD: The cohort study included 12 578 workers from 21 cohorts, with 6626 deaths in total, 858 deaths from lung cancer and 394 from pleural malignant neoplasm (MN). Rate advancement was estimated by fitting a competitive mortality Weibull model to the hazard of death over time since first exposure (TSFE). RESULT: Acceleration time (AT) was estimated at different TSFE values. The highest level of cumulative exposure compared with the lowest, for pleural MN AT was 16.9 (95% CI 14.9 to 19.2) and 33.8 (95% CI 29.8 to 38.4) years at TSFE of 20 and 40 years, respectively. For lung cancer, it was 13.3 (95% CI 12.0 to 14.7) and 26.6 (95% CI 23.9 to 29.4) years, respectively. As for total mortality, AT was 3.35 (95% CI 2.98 to 3.71) years at 20 years TSFE, and 6.70 (95% CI 5.95 to 7.41) at 40 years TSFE. CONCLUSION: The current study observed marked rate advancement after asbestos exposure for lung cancer and pleural mesothelioma, as well as for total mortality.

Trends in mortality from non-natural causes in children and adolescents (0-19 years) in Europe from 2000 to 2018.

BACKGROUND: Non-natural mortality in children and adolescents is a global public health problem that varies widely from country to country. Data on child and adolescent maltreatment are not readily available, and mortality due to violent causes is also underestimated. METHODS: Injury-related mortality rates (overall and by specific causes) from 2000 to 2018 in selected European countries were analysed to observe mortality patterns in children and adolescents using data from the Eurostat database. Age-standardized mortality rates per 100,000 person-years were calculated for each country. Joinpoint regression analysis with a significance level of 0.05 and 95% confidence intervals was performed for mortality trends. RESULTS: Children and adolescent mortality from non-natural causes decreased significantly in Europe from 10.48 around 2005 to 5.91 around 2015. The Eastern countries (Romania, Bulgaria, Poland, Slovakia, Czech Republic) had higher rates; while Spain, Denmark, Italy, and the United Kingdom had the lowest. Rates for European Country declined by 5.10% per year over the entire period. Larger downward trends were observed in Ireland, Spain and Portugal; smaller downward trends were observed for Eastern countries (Bulgaria, Czech Republic, Poland, Slovakia) and Finland. Among specific causes of death, the largest decreases were observed for accidental causes (-5.9%) and traffic accidents (-6.8%). CONCLUSIONS: Mortality among children and adolescents due to non-natural causes has decreased significantly over the past two decades. Accidental events and transport accidents recorded the greatest decline in mortality rates, although there are still some European countries where the number of deaths among children and adolescents from non-natural causes is high. Social, cultural, and health-related reasons may explain the observed differences between countries.

[Reduction of adverse outcome due to COVID-19 infection in a high-risk population: evaluation of an informative intervention through active call by General Practitioners]. / Riduzione degli outcome sfavorevoli dovuti all'infezione da COVID-19 su una popolazione ad alto rischio: valutazione di un intervento informativo mediante chiamata attiva da parte dei medici di medicina generale.

BACKGROUND: currently, individuals at risk of adverse outcomes for COVID-19 can access to vaccination and pharmacological interventions. But, during the first epidemic wave, there were no treatments or therapeutic strategies available to reduce adverse outcomes in patients at risk. OBJECTIVES: to assess the impact of an intervention at 15-month follow-up developed by the Agency for Health Protection of the Metropolitan Area of Milan (ATS Milan) based on telephone triage and consultation by the General Practitioners (GPs) for patient with high-risk for adverse outcomes. DESIGN: intervention on population. SETTING AND PARTICIPANTS: a total of 127,292 patients in the ATS aged ≥70 years and with comorbidities associated with an increased risk of dying from COVID-19 infection were identified. Using a specific information system, patients were assigned to their GPs for telephone triage and consultation. GPs inform them about the risks of the disease, non-pharmacological prevention measures, and precautions in contacts with family members and other persons. No specific clinical intervention was carried out, only an information/training intervention was performed. MAIN OUTCOME MEASURES: by the end of May 2020, 48.613 patients had been contacted and 78.679 had not been contacted. Hazard Ratios (HRs) of infection hospitalisation and death at 3 and 15 months were estimated using Cox regression models adjusted by confounder. RESULTS: no differences in gender, age class distribution, prevalence of specific diseases, and Charlson Index were found between the two groups (treated such as called patients and not called). Called patients had a higher propensity for influenza and antipneumococcal vaccination and have more comorbidities and greater access to pharmacological therapies. Non-called patients have a greater risk for COVID-19 infection: HR was 3.88 (95%CI 3.48-4.33) at 3 months and 1.28 (95%CI 1.23-1.33) at 15 months; for COVID-19 hospitalization HR was 2.66 (95%CI 2.39-2,95) at 3 months and 1.31 (95%CI 1.25-1.37) at 15 months; for overall mortality HR was 2,52 (95%CI 2.35-2:72) at 3 months and 1.23 (95%CI 1.19-1.27) at 15 months. CONCLUSIONS: the results of this study show a reduction in hospitalization and deaths and support, in case of pandemic events, the implementation of new care strategies based on adapted stratification systems in order to protect the population's health. This study presents some limits: it is not randomized; a selection bias is present (called patients were those most in contact with the GPs); the intervention is indication-based (on march 2020, the actual benefit of protection and distancing for high-risk groups was unclear), and the adjustment is not able to fully control for confounding. However, this study points out the importance to develop information systems and improve methods to best protect the health of the population in setting of territorial epidemiology.

[Description of excess of overall and cause-specific mortality in the Agency for Health Protection of the Metropolitan Area of Milan (Lombardy Region, Northern Italy) in 2020]. / Descrizione degli eccessi di mortalità per tutte le cause e specifici per causa nell'ATS di Milano nel 2020.

BACKGROUND: as a result of the SARS-CoV-2 pandemic, a generalised mortality excess was recorded in 2020. However, the mortality for COVID-19 cannot fully explain the observed excesses. The analysis of cause-specific mortality could contribute to estimate the direct and indirect effects of the SARS-CoV-2 outbreak and to the monitoring mortality trends. OBJECTIVES: to describe the impact of the SARS-CoV-2 epidemic in overall and cause-specific mortality in population residing in the Agency for Health Protection (ATS) of Milan. Descriptive analysis of cause-specific mortality within thirty days of SARS-COV-2 infection. DESIGN: descriptive analysis of overall and cause-specific mortality in the ATS of Milan area in 2020 and comparison with a reference period (2015-2019). SETTING AND PARTICIPANTS: overall deaths in ATS of Milan in 2020 were collected, using the Local Registry of Causes of Death, and were classified according to the ICD-10 codes. MAIN OUTCOME MEASURES: total and weekly overall and cause-specific mortality, by age. RESULTS: in 2020, 44,757 deaths for all causes were observed in people residing in the ATS of Milan with percentage change of 35%. The leading cause of death in 2020 were cardiovascular disease and neoplasm; COVID-19 infection was the third cause. An excess of mortality was observed for most of all causes of deaths. Starting from 40-49-year age group, an increase of mortality was observed; the largest increase was observed in the group 70+ years. The largest increases were observed for endocrine, respiratory, and hypertensive diseases. On the contrary, for neoplasm, infectious (not COVID-19) diseases, traffic-related mortality, and cerebrovascular disease and ictus, a decrease of mortality was observed. The greater mortality increase was observed during the first pandemic wave. The leading cause of death after positive swab was COVID-19 infection, with little variation with age class. Other frequent causes of death were respiratory diseases, cardiovascular diseases, and neoplasm. CONCLUSIONS: the study showed a generalised increase for most causes of death; observed mortality trends may indicate delay in access to health care system, in diagnosis and treatment.

Boosters and time from the last anti-COVID-19 vaccine dose: lead public health choices by real-time epidemiological assessment.

BACKGROUND: the levels of anti-SARS-CoV-2 antibodies after the second vaccine dose decline in the following months; the administration of an additional vaccine dose (booster) is able to restore the immune system in the short period significantly reducing the risk of a severe disease. In the winter of 2021, a new particularly infectious variant caused the urgent need to increase the coverage of the booster dose. OBJECTIVES: to present, using real data, an evaluation of the efficacy of the booster dose in reducing the severe disease of SARS-CoV-2 infection in terms of hospital admissions, intensive care and death from all causes. DESIGN: descriptive study of vaccine adherence; associative study of the factors linked with adherence of vaccination and COVID-19 symptoms; associative study of vaccine effectiveness against hospital admission and mortality. SETTING AND PARTICIPANTS: population-based study in the Milan and Lodi provinces (Lombardy Region, Northern Italy) with subjects aged >=19 years alive at 01.10.2021, not residing in a nursery home, followed up to 31.12.2021. MAIN OUTCOME MEASURES: COVID-19 symptoms, hospitalization for COVID-19, intensive care hospitalization, and all-cause mortality in the period 01.10.2021-31.12.2021. RESULTS: the cohort included 2,936,193 patients at 01.10.2021: at the end of the follow-up period (31.12.2021), 378,616 (12.9%) had no vaccine, 128,879 (4.3%) had only 1 dose, 412,227 (14.0%) had a 2nd dose given since less than 4 months, 725. 806 (25%) had a 2nd dose given since 4-7 months, 74,152 (2.5%) had a 2nd dose given since 7+ months, 62,614 (2.1%) had a 2nd dose and have had the disease, and 1,153,899 (39.3%) received the booster. In the study period (01.10.2021-31.12.2021), characterized by a very high prevalence of the omicron variant, 121,620 cases (antigenic/molecular buffer positive), 3,661 hospitalizations for COVID-19, 162 ICU hospitalizations, and 7,508 deaths from all causes were identified. Compared to unvaccinated people, subjects who had the booster dose had half the risk of being symptomatic, in particular for asthenia, muscle pain, and dyspnoea which are the most commons COVID-19 symptoms. In comparison with the subjects who had the booster dose, the unvaccinated had a 10-fold risk of hospitalization for COVID-19, a 9-fold risk of intensive care, and a 3-fold risk of dying. CONCLUSIONS: this work highlights the vaccination efficacy in reducing serious adverse events for those who undergo the booster and the need to implement specific engagement policies to bring to a booster those who had taken the second dose since the longest time.

First SARS-CoV-2 vaccine booster and influenza vaccination: risk assessment of COVID-19 hospitalisation and death.

BACKGROUND: the influenza and SARS-CoV-2 viruses share a common respiratory symptomatology and transmission mode. COVID-19 and influenza R0 overlapped in the first epidemic wave. In autumn 2021-winter 2022, the influenza epidemic had a delayed onset compared to pre-COVID-19 years and lower incidence rates than in the pre-pandemic period. The SARS-CoV-2 and influenza vaccination campaign overlapped in 2021-2022. OBJECTIVES: to evaluate in the SARS-CoV-2 vaccinated cohort the effect of different timing of influenza vaccination on hospitalisations for COVID-19 and overall mortality. DESIGN: prospective cohort study. SETTING AND PARTICIPANTS: subjects aged 65 years or older who were administered the first booster dose of SARS-COV-2 vaccine between 01.10.2021 and 01.03.2022. Based on the date of influenza vaccination, subjects were divided into the following 4 different mutually exclusive groups: 1. two vaccinations in the same vaccination session; 2. influenza vaccination following SARS-CoV-2 vaccination; 3. influenza vaccination preceding SARS-CoV-2 vaccination; 4. no influenza vaccination. Using Cox regression models, hazard ratio (HR) and corresponding 95% confidence intervals (95% CI) of hospitalisation and death were estimated for the influenza-vaccinated subjects compared to influenza-unvaccinated subjects. MAIN OUTCOME MEASURES: ordinary hospital admissions for COVID-19 and general mortality. RESULTS: the cohort included 618,964 subjects: 16.3% received two vaccinations in the same vaccination session, 8.5% received the influenza vaccination after SARS-CoV-2 vaccination, 33.9% received it before and 41.1% did not receive an influenza vaccination. Those vaccinated against both SARS-CoV-2 and influenza had a combined HR of 0.73 (0.62-0.86) of hospitalisation for COVID-19 and 0.55 (0.49-0.62) of overall mortality compared to those vaccinated against SARS-CoV-2 only. CONCLUSIONS: influenza vaccination combined with SARS-CoV-2 vaccination increases the protective effect against hospitalisations and overall mortality compared to SARS-CoV-2 vaccination alone. Both organisational and communication actions aimed to promote and encourage vaccination are required.

Evaluation of the anti-COVID-19 vaccination campaign in the Metropolitan Area of Milan (Lombardy Region, Northern Italy).

OBJECTIVES: to present an evaluation of the campaign for vaccination against COVID-19 in the territory covered by the Agency for Health Protection of the Metropolitan Area of Milan from 01.01.2021 to 30.09.2021. DESIGN: descriptive study of vaccine adherence; predictive study of the factors associated with vaccine adherence, efficacy of vaccination in terms of hospitalization and mortality, and factors that increase the risk of hospital admission following full vaccination. SETTING AND PARTICIPANTS: population-based study with subjects aged >18 years eligible for vaccination (N. 2,981,997). An information system obtained by integrating various administrative healthcare sources made it possible to analyse socioeconomic characteristics, COVID-19 related hospitalizations, and general mortality in subjects eligible for vaccination. MAIN OUTCOME MEASURES: full vaccination (2 doses); COVID-19-related hospitalizations, COVID-19-related hospitalizations occurring more than 15 days after the second dose, general mortality. RESULTS: in the first nine months of the vaccination campaign, 74.7% of the subjects (N. 2,228,915) was fully vaccinated, whereas 15.6% (N. 465,829) did not even receive one dose. Women have a lower probability of getting vaccinated than men; the 50-59 years and 70+ years age groups emerge as the most problematic to reach, while the younger one (<40) is the most adherent. A social gradient emerged, with residents of more disadvantaged areas progressively less incline to get vaccinated than those living in more affluent areas. Adherence is greater in Italian citizenship and is likely to increase with an increase in the number of chronic conditions. Hospitalizations amounted to 1.22% (N. 5,672) in the unvaccinated population compared to 0.05% (N. 1,013) in the vaccinated population; general mortality was 4.51% (N. 15,198) in the unvaccinated population against 0.32% (N. 8.733) in the vaccinated population. Sociodemographic factors and the presence of previous health conditions are important predictors of hospitalization outcomes even within the fully vaccinated population. Specifically, the highest hazard ratios are found in subjects with heart failure (HR 2.15; 95%CI 1.83-2.53), in immunocompromised patients (HR 2.02; 95%CI 1.52-2.69), and in transplant recipients (HR 1.92; 95%CI 1.10-3.33). CONCLUSIONS: vaccination campaign adherence is affected by the sociodemographic characteristics of the population and is a determining factor in preventing hospitalizations for COVID-19 and death. The persistent higher risk of hospitalization in chronic subjects following the second dose emphasizes the need to direct booster doses to the more vulnerable. Information systems proved to be effective monitoring tools in the absence of specific trials.

Development of a multivariable model predicting mortality risk from comorbidities in an Italian cohort of 18,286 confirmed COVID-19 cases aged 40 years or older.

OBJECTIVES: to develop a risk prediction model for 30-day mortality from COVID­19 in an Italian cohort aged 40 years or older. DESIGN: a population-based retrospective cohort study on prospectively collected data was conducted. SETTING AND PARTICIPANTS: the cohort included all swab positive cases aged 40 years older (No. 18,286) among residents in the territory of the Milan's Agency for Health Protection (ATS-MI) up to 27.04.2020. Data on comorbidities were obtained from the ATS administrative database of chronic conditions. MAIN OUTCOME MEASURES: to predict 30-day mortality risk, a multivariable logistic regression model, including age, gender, and the selected conditions, was developed following the TRIPOD guidelines. Discrimination and calibration of the model were assessed. RESULTS: after age and gender, the most important predictors of 30-day mortality were diabetes, tumour in first-line treatment, chronic heart failure, and complicated diabetes. The bootstrap-validated c-index was 0.78, which suggests that this model is useful in predicting death after COVID-19 infection in swab positive cases. The model had good discrimination (Brier score 0.13) and was well calibrated (Index of prediction accuracy of 14.8%). CONCLUSIONS: a risk prediction model for 30-day mortality in a large COVID-19 cohort aged 40 years or older was developed. In a new epidemic wave, it would help to define groups at different risk and to identify high-risk subjects to target for specific prevention and therapeutic strategies.

Penetrance of Glucocerebrosidase (GBA) Mutations in Parkinson's Disease: A Kin Cohort Study.

BACKGROUND: Homozygous glucocerebrosidase mutations cause Gaucher disease, whereas heterozygous mutations are the most important genetic risk factor for Parkinson's disease (PD). The penetrance of heterozygous glucocerebrosidase mutations for PD is variable (10%-30%), depends on the population studied, and has only been assessed in Gaucher disease or familial PD. The aim of this study was to assess the penetrance of glucocerebrosidase mutations in PD in unselected PD patients. METHODS: The penetrance of glucocerebrosidase mutations was estimated using the kin-cohort method. RESULTS: Data on family history were available for 63 of 123 PD glucocerebrosidase mutation carriers, identified among 2843 unrelated consecutive PD patients. Three hundred eighty-one first-degree relatives were analyzed. The risk of developing PD was 10% at 60 years, 16% at 70 years, and 19% at 80 years. CONCLUSIONS: The estimated penetrance of glucocerebrosidase mutations in unselected PD patients is higher than that estimated in Gaucher disease cohorts and lower than that estimated in familial PD cohorts. © 2020 International Parkinson and Movement Disorder Society.

Large community-acquired Legionnaires' disease outbreak caused by Legionella pneumophila serogroup 1, Italy, July to August 2018.

In July 2018, a large outbreak of Legionnaires' disease (LD) caused by Legionella pneumophila serogroup 1 (Lp1) occurred in Bresso, Italy. Fifty-two cases were diagnosed, including five deaths. We performed an epidemiological investigation and prepared a map of the places cases visited during the incubation period. All sites identified as potential sources were investigated and sampled. Association between heavy rainfall and LD cases was evaluated in a case-crossover study. We also performed a case-control study and an aerosol dispersion investigation model. Lp1 was isolated from 22 of 598 analysed water samples; four clinical isolates were typed using monoclonal antibodies and sequence-based typing. Four Lp1 human strains were ST23, of which two were Philadelphia and two were France-Allentown subgroup. Lp1 ST23 France-Allentown was isolated only from a public fountain. In the case-crossover study, extreme precipitation 5-6 days before symptom onset was associated with increased LD risk. The aerosol dispersion model showed that the fountain matched the case distribution best. The case-control study demonstrated a significant eightfold increase in risk for cases residing near the public fountain. The three studies and the matching of clinical and environmental Lp1 strains identified the fountain as the source responsible for the epidemic.

Describing the epidemic trends of COVID-19 in the area covered by Agency for Health Protection of the Metropolitan Area of Milan.

OBJECTIVES: to describe the epidemic trends of COVID-19 over time and by area in the territory covered by Milan's Agency for Health Protection (ATS-MI) from February to May 2020. DESIGN: descriptive study of COVID-19 cases. SETTING AND PARTICIPANTS: a new information system was developed to record COVID-19 cases with positive nasopharyngeal swab. Patients resident in the area covered by ATS-MI with symptom onset between February and May 2020 were selected. Different epidemic periods were considered based on the timeline of the various regional and national containment measures. MAIN OUTCOME MEASURES: case fatality ratios, incidence rates, and reproduction number by epidemic period and sub-area of ATS-MI. RESULTS: a total of 27,017 swab-positive COVID-19 cases were included. Mean age was 65 years and males were 45%. Incidence in the ATS-MI area was 776 per 100,000 population. The number of deaths was 4,660, the crude case fatality ratio was 17.3%, higher in males (21.2%) than in females (14.0%). The estimated reproduction number registered its peak (3.0) in the early stages of the epidemic and subsequently decreased. Territorial differences were observed in the epidemic spread, with a higher incidence in the Lodi area. CONCLUSIONS: estimated incidence and case fatality ratios were higher than national estimates for Italy. Each ATS-MI area had different epidemic spread patterns.

Assessment of the Overall Mortality during the COVID-19 Outbreak in the Provinces of Milan and Lodi (Lombardy Region, Northern Italy).

OBJECTIVES: to describe the overall mortality increase in the provinces of Milan and Lodi - area covered by the Agency for Health Protection of Milan - during the COVID-19 epidemic in the first four months of 2020, compare it with the same time period in the years 2016-2019, and evaluate to what extent the mortality can be directly attributed to the outbreak. DESIGN: cohort study. SETTING AND PARTICIPANTS: using a new information system developed during the pandemic, we gathered data on the number of daily deaths in the population residing in the provinces of Milan and Lodi by Local Health Unit (ASST) and age groups. To describe the case fatality of COVID-19, we performed a record linkage with a database specially constructed during the epidemic to identify deaths that occurred in confirmed cases. MAIN OUTCOME MEASURES: mortality and excess mortality were analysed by comparing the number of observed deaths in the first 4 months of 2020 with the average deaths of the years 2016-2019 in the same calendar period and with expected deaths, estimated using a Poisson model. Furthermore, a measure of relative risk was calculated as observed/expected ratio with a 95% confidence interval. RESULTS: the increase in mortality for all causes occurring in the study population in the first 4 months of 2020 was 48.8%, 30.8% for ages between 60 and 69, 43.9% for ages between 70 and 79, and 56.7% for subjects above 80 years of age. Focusing on the epidemic period, from 1 March to 30 April, the excess is quantifiable as more than 2-fold and mainly concerns the population over 60 years of age. The excess mortality was observed in all local health units (ASSTs). The highest increments were in the province of Lodi and the North-East of Milan (ASST Nord). In the ASSTs of Lodi and Melegnano-Martesana the mortality excess was detectable from March 15th, while for the other ASSTs the increase began in the first week of April. CONCLUSIONS: evaluation of overall mortality in the provinces of Milan and Lodi during the first wave of the Covid-19 epidemic showed a significant excess compared to the first 4 months of the years 2016-2019, mainly in the population over 60 years of age. However, this excess cannot be completely attributed directly to COVID-19 itself. This phenomenon was more intense in the Lodi ASST, with daily deaths up to 5 times higher than expected.

Role of asbestos clearance in explaining long-term risk of pleural and peritoneal cancer: a pooled analysis of cohort studies.

OBJECTIVES: Models based on the multistage theory of cancer predict that rates of malignant mesothelioma continuously increase with time since first exposure (TSFE) to asbestos, even after the end of external exposure. However, recent epidemiological studies suggest that mesothelioma rates level off many years after first exposure to asbestos. A gradual clearance of asbestos from the lungs has been suggested as a possible explanation for this phenomenon. We analysed long-term trends of pleural and peritoneal cancer mortality in subjects exposed to asbestos to evaluate whether such trends were consistent with the clearance hypothesis. METHODS: We used data from a pool of 43 Italian asbestos cohorts (51 801 subjects). The role of asbestos clearance was explored using the traditional mesothelioma multistage model, generalised to include a term representing elimination of fibres over time. RESULTS: Rates of pleural cancer increased until 40 years of TSFE, but remained stable thereafter. On the other hand, we observed a monotonic increase of peritoneal cancer with TSFE. The model taking into account asbestos clearance fitted the data better than the traditional one for pleural (p=0.004) but not for peritoneal (p=0.09) cancer. CONCLUSIONS: Rates of pleural cancer do not increase indefinitely after the exposure to asbestos, but eventually reach a plateau. This trend is well described by a model accounting for a gradual elimination of the asbestos fibres. These results are relevant for the prediction of future rates of mesothelioma and in asbestos litigations.

Cumulative asbestos exposure and mortality from asbestos related diseases in a pooled analysis of 21 asbestos cement cohorts in Italy.

BACKGROUND: Despite the available information on cancer risk, asbestos is used in large areas in the world, mostly in the production of asbestos cement. Moreover, questions are raised regarding the shape of the dose response relation, the relation with time since exposure and the association with neoplasms in various organs. We conducted a study on the relationship between cumulative asbestos exposure and mortality from asbestos related diseases in a large Italian pool of 21 cohorts of asbestos-cement workers with protracted exposure to both chrysotile and amphibole asbestos. METHODS: The cohort included 13,076 workers, 81.9% men and 18.1% women, working in 21 Italian asbestos-cement factories, with over 40 years of observation. Exposure was estimated by plant and period, and weighted for the type of asbestos used. Data were analysed with consideration of cause of death, cumulative exposure and time since first exposure (TSFE), and by gender. SMRs were computed using reference rates by region, gender and calendar time. Poisson regression models including cubic splines were used to analyse the effect of cumulative exposure to asbestos and TSFE on mortality for asbestos-related diseases. 95% Confidence Intervals (CI) were computed according to the Poisson distribution. RESULTS: Mortality was significantly increased for 'All Causes' and 'All Malignant Neoplasm (MN)', in both genders. Considering asbestos related diseases (ARDs), statistically significant excesses were observed for MN of peritoneum (SMR: men 14.19; women 15.14), pleura (SMR: 22.35 and 48.10), lung (SMR: 1.67 and 1.67), ovary (in the highest exposure class SMR 2.45), and asbestosis (SMR: 507 and 1023). Mortality for ARDs, in particular pleural and peritoneal malignancies, lung cancer, ovarian cancer and asbestosis increased monotonically with cumulative exposure. Pleural MN mortality increased progressively in the first 40 years of TSFE, then reached a plateau, while peritoneal MN showed a continuous increase. The trend of lung cancer SMRs also showed a flattening after 40 years of TSFE. Attributable proportions for pleural, peritoneal, and lung MN were respectively 96, 93 and 40%. CONCLUSIONS: Mortality for ARDs was associated with cumulative exposure to asbestos. Risk of death from pleural MN did not increase indefinitely with TSFE but eventually reached a plateau, consistently with reports from other recent studies.

Survival and dementia in GBA-associated Parkinson's disease: The mutation matters.

OBJECTIVE: The objective of this work was to investigate survival, dementia, and genotype-phenotype correlations in patients with Parkinson's disease (PD) with and without mutations on the glucocerebrosidase gene (GBA). METHODS: We included 2,764 unrelated consecutive PD patients: 123 GBA carriers (67 mild-p.N370S and 56 severe mainly p.L444P) and 2,641 noncarriers. Brain perfusion and dopamine transporter imaging was analyzed, including dementia with Lewy Bodies (DLB) as an additional control group. RESULTS: Multivariable analysis adjusted by sex, age at onset, and disease duration attributed to GBA carriers a greater risk for dementia (hazard ratio [HR] = 3.16; p < 0.001) and death (HR = 1.85; p = 0.002) than noncarriers. When dementia was introduced in the model as a time-dependent covariate, the mortality risk remained greater in carriers (HR = 1.65; p = 0.016), suggesting that other clinical features are likely to contribute to reduced survival. At last examination, GBA carriers had worse motor symptoms, particularly nondopaminergic features. Carriers of severe mutations had greater risk for dementia compared to mild mutations (p < 0.001), but similar mortality risk. Consistent with clinical data, GBA carriers showed reduced posterior parietal and occipital cortical synaptic activity and nigrostriatal function than PD noncarriers. Neuroimaging features of carriers of mild mutations overlapped with PD noncarriers, whereas carriers of severe mutations were closer to DLB. INTERPRETATION: Survival is reduced in GBA carriers compared to noncarriers; this seems to be partially independent from the increased risk for early dementia. The risk for dementia is strongly modulated by type of mutation. In the clinical continuum between PD and DLB, patients with GBA mutations seem to localize midway, with carriers of severe mutations closer to DLB than to idiopathic PD. Ann Neurol 2016;80:662-673.

Italian pool of asbestos workers cohorts: mortality trends of asbestos-related neoplasms after long time since first exposure.

OBJECTIVE: Asbestos is a known human carcinogen, with evidence for malignant mesothelioma (MM), cancers of lung, ovary, larynx and possibly other organs. MM rates are predicted to increase with a power of time since first exposure (TSFE), but the possible long-term attenuation of the trend is debated. The asbestos ban enforced in Italy in 1992 gives an opportunity to measure long-term cancer risk in formerly exposed workers. METHODS: Pool of 43 previously studied Italian asbestos cohorts (asbestos cement, rolling stock, shipbuilding), with mortality follow-up updated to 2010. SMRs were computed for the 1970â€"2010 period, for the major causes, with consideration of duration and TSFE, using reference rates by age, sex, region and calendar period. RESULTS: The study included 51 801 subjects (5741 women): 55.9% alive, 42.6% died (cause known for 95%) and 1.5% lost to follow-up. Mortality was significantly increased for all deaths (SMR: men: 1.05, 95% CI 1.03 to 1.06; women: 1.17, 95% CI to 1.12 to 1.22), all malignancies combined (SMR: men: 1.17, 95% CI to 1.14 to 1.20; women: 1.33, 95% CI 1.24 to 1.43), pleural and peritoneal malignancies (SMR: men: 13.28 and 4.77, 95% CI 12.24 to 14.37 and 4.00 to 5.64; women: 28.44 and 6.75, 95% CI 23.83 to 33.69 and 4.70 to 9.39), lung (SMR: men: 1.26, 95% CI 1.21 to 1.31; women: 1.43, 95% CI 1.13 to 1.78) and ovarian cancer (SMR=1.38, 95% CI 1.00 to 1.87) and asbestosis (SMR: men: 300.7, 95% CI 270.7 to 333.2; women: 389.6, 95% CI 290.1 to 512.3). Pleural cancer rate increased during the first 40 years of TSFE and reached a plateau after. DISCUSSION: The study confirmed the increased risk for cancer of the lung, ovary, pleura and peritoneum but not of the larynx and the digestive tract. Pleural cancer mortality reached a plateau at long TSFE, coherently with recent reports.

Mortality in asbestos cement workers in Pavia, Italy: A cohort study.

BACKGROUND: The aim of this study was to describe the mortality of a cohort of asbestos-cement workers in the largest plant in the most industrialized Italian region (Lombardy). METHODS: A cohort study was carried out on 1818 subjects, corresponding to 47 536.1 person-years of observation. Standardized mortality ratios (SMRs) were computed for the major causes of death. RESULTS: Increased SMRs were observed for pleural, peritoneal and lung cancers, and for asbestosis (SMR 26.73, 95% Confidence Interval (CI) 20.99-33.55; 9.15, 95%CI 5.00-15.34; 1.48, 95%CI 1.27-1.72; and 368.05, 95%CI 214.40-589.29, respectively). No excess in mortality for laryngeal cancer was observed (SMR 0.70, 95%CI 0.30-1.39). An increased mortality for ovarian cancer (SMR 3.64, 95%CI 0.99-9.33) was observed, although it was not statistically significant. Among men, mortality for pleural malignant mesothelioma was observed to be related to the duration of exposure, though not to latency. CONCLUSIONS: The results of this study are generally consistent with present knowledge. Conversely, our results do not support the hypothesis that pleural malignant mesothelioma risk indefinitely increases after exposure, suggesting instead that the alternative hypothesis of a risk plateau or decrease after a time since first exposure of more than 40 years is more consistent with the observed data.