[The COVID-19 epidemic and total mortality: missed data and the incoming epidemiology]. / L'epidemia di COVID-19 e la mortalità totale: i dati che sono mancati e l'epidemiologia che verrà.

The generation of rapid information has been an important novelty in the COVID-19 pandemic and a challenge for epidemiology. The methodological frailty and uncertainty of rapid data use has been a consequence. We are talking about an 'intermezzo' epidemiology between the event and the production of consolidated data that opens up great opportunities to the use epidemiology for rapid public health decisions, provided a careful work to be done before emergencies. In Italy, an ad hoc national COVID-19 information system producing daily data that quickly became essential for public decision-making. Total and all-cause mortality data are derived from the traditional information system of the Italian National Institute of Statistics (Istat), which, at the onset of the pandemic, was unable to provide rapid total and all-causes mortality data at the national level and still produces them with a one- to two-month delay. National cause and place mortality data referred to the first epidemic wave (March and April 2020) was in May 2021 and recently updated (October 2022) for the whole year 2020. Nearly three years after the onset of the epidemic, we have no nationwide rapid information on the distribution of deaths by place of death (hospitals, nursing homes and other care facilities, home) neither on their breakdown in 'by COVID-19', 'with COVID-19', and 'non-COVID-19' deaths. The pandemic being still in progress, new problems arise (the long-term impact of COVID-19, the impact of lockdown policies, etcetera), whose solution cannot be postponed until peer reviewed papers are available. A fine-tuning of the rapid processing of interim data certainly requires the development of national and regional information systems, but first of all a methodologically robust 'intermezzo' epidemiology.

Plasma miRNA-based signatures in CRC screening programs.

Colorectal cancer (CRC) screening programs help diagnose cancer precursors and early cancers and help reduce CRC mortality. However, currently recommended tests, the fecal immunochemical test (FIT) and colonoscopy, have low uptake. There is therefore a pressing need for screening strategies that are minimally invasive and consequently more acceptable to patients, most likely blood based, to increase early CRC identification. MicroRNAs (miRNAs) released from cancer cells are detectable in plasma in a remarkably stable form, making them ideal cancer biomarkers. Using plasma samples from FIT-positive (FIT+) subjects in an Italian CRC screening program, we aimed to identify plasma circulating miRNAs that detect early CRC. miRNAs were initially investigated by quantitative real-time PCR in plasma from 60 FIT+ subjects undergoing colonoscopy at Fondazione IRCCS Istituto Nazionale dei Tumori, then tested on an internal validation cohort (IVC, 201 cases) and finally in a large multicenter prospective series (external validation cohort [EVC], 1121 cases). For each endoscopic lesion (low-grade adenoma [LgA], high-grade adenoma [HgA], cancer lesion [CL]), specific signatures were identified in the IVC and confirmed on the EVC. A two-miRNA-based signature for CL and six-miRNA signatures for LgA and HgA were selected. In a multivariate analysis including sex and age at blood collection, the areas under the receiver operating characteristic curve (95% confidence interval) of the signatures were 0.644 (0.607-0.682), 0.670 (0.626-0.714) and 0.682 (0.580-0.785) for LgA, HgA and CL, respectively. A miRNA-based test could be introduced into the FIT+ workflow of CRC screening programs so as to schedule colonoscopies only for subjects likely to benefit most.

The EUROMED CANCER network: state-of-art of cancer screening programmes in non-EU Mediterranean countries.

BACKGROUND: The EUROMED CANCER Network project aims to support non-EU Mediterranean countries in the development of cancer early detection and screening policies. METHODS: Through a structured questionnaire information from 15 countries (Albania, Algeria, Bosnia and Herzegovina (BiH), Croatia, Egypt, Jordan, UN Interim Administration Mission in Kosovo, Lebanon, Montenegro, Morocco, Palestinian National Authority, Serbia, Syria, Tunisia and Turkey) were collected on cancer epidemiology and control. RESULTS: Large differences between countries are evident. Breast cancer (BC) is the commonest cancer among women, though the incidence rate is much lower in non-EU than in EU Mediterranean countries. Conversely, cervical cancer (CC) is much more common in the former than in the latter countries. Colorectal cancer (CRC) is more frequent in Northern than in Eastern and Southern Mediterranean shores. Population-based cancer registries are available in few countries but most of them lack information on disease staging. Opportunistic screening for CC and BC is unevenly spread across and within countries; organised screening programmes are rare and do not meet international recommendations. BC and CC early detection is extensively considered a priority, while a few countries included CRC into their agenda. CONCLUSIONS: Collected data witnesses inadequacy of health information system and, in general, of the strategies for cancer control in the involved countries. A uniform approach for strengthening cancer control is not realistic neither feasible. Tailored preventive actions for cancer early detection have to be started concurrently with the development of a reliable health information system and, specifically, with cancer registration.

[Investigative model for the evaluation of spatio-temporal clusters of childhood cancers]. / Modelli di indagine per la valutazione di cluster spazio-temporali di tumori infantili.

This paper describes the conceptual framework and the critical issues of investigations of clusters of childhood cancers and defines an investigative model for the health authorities responsible for assessing a suspected cluster, taking into account the guidelines available and considering the most recent advances of the Geographical Information System and of the specific statistical methodology. Three main investigation phases are identified: the first consists in the preliminary study on the health of population living in the area where the cases are defined and aetiological hypotheses are formulated; the second is the cluster evaluation study using statistical methods assessing the spatial heterogeneity and collecting information about potential risk factors; the third is the analytical epidemiological study to test aetiological hypotheses suggested by the previous phases. The residential cohort approach is the most valid to date to assess long-term effects, and allows to reconstruct the lifetime residential history from the population registry. The researchers' decision on how detailed about a suspected cluster the investigation has to be needs to take into account both the level of alarm in the population and the limited resources available. The concern about a suspected cluster of cancer cases should always be addressed, even if this implies to acknowledge limits of research and uncertainty in results interpretation.

Invitation strategies for colorectal cancer screening programmes: The impact of an advance notification letter.

AIM: To estimate the impact of an advance notification letter on participation in sigmoidoscopy (FS) and fecal immunochemical test (FIT) screening. METHODS: Eligible subjects, invited in 3 Italian population based programmes using FS and in 5 using FIT, were randomised (1:1:1), within GP, to: A) standard invitation letter; B) advance notification followed after 1month by the standard invitation; and C) B+indication to contact the general practitioner (GP) to get advice about the decision to be screened. We calculated the 9-month attendance and the incremental cost of each strategy. We conducted a phone survey to assess GP's utilization and predictors of participation. RESULTS: The advance notification was associated with a 20% increase in the attendance among 15,655 people invited for FS (B vs A - RR: 1.17, 95% CI: 1.10-1.25; C vs A - RR: 1.19, 95% CI: 1.12-1.27); the incremental cost ranged between 10 and 9 Euros. Participation in FIT screening (N=23,543) was increased only with simple pre-notification (B vs A - RR: 1.06, 95% CI: 1.02-1.10); the incremental cost was 22.5 Euros. GP consultation rate was not increased in group C. CONCLUSIONS: An advance notification represents a cost-effective strategy to increase participation in FS screening; its impact on the response to FIT screening was limited.

Effects of heat waves on mortality: effect modification and confounding by air pollutants.

BACKGROUND: Heat waves and air pollution are both associated with increased mortality. Their joint effects are less well understood. METHODS: We explored the role of air pollution in modifying the effects of heat waves on mortality, within the EuroHEAT project. Daily mortality, meteorologic, and air pollution data from nine European cities for the years 1990-2004 were assembled. We defined heat waves by taking both intensity and duration into account. The city-specific effects of heat wave episodes were estimated using generalized estimating equation models, adjusting for potential confounders with and without inclusion of air pollutants (particles, ozone, nitrogen dioxide, sulphur dioxide, carbon monoxide). To investigate effect modification, we introduced an interaction term between heat waves and each single pollutant in the models. Random effects meta-analysis was used to summarize the city-specific results. RESULTS: The increase in the number of daily deaths during heat wave episodes was 54% higher on high ozone days compared with low, among people age 75-84 years. The heat wave effect on high PM10 days was increased by 36% and 106% in the 75-84 year and 85+ year age groups, respectively. A similar pattern was observed for effects on cardiovascular mortality. Effect modification was less evident for respiratory mortality, although the heat wave effect itself was greater for this cause of death. The heat wave effect was smaller (15-30%) after adjustment for ozone or PM10. CONCLUSIONS: The heat wave effect on mortality was larger during high ozone or high PM10 days. When assessing the effect of heat waves on mortality, lack of adjustment for ozone and especially PM10 overestimates effect parameters. This bias has implications for public health policy.

Air pollution and multiple acute respiratory outcomes.

Short-term effects of air pollutants on respiratory mortality and morbidity have been consistently reported but usually studied separately. To more completely assess air pollution effects, we studied hospitalisations for respiratory diseases together with out-of-hospital respiratory deaths. A time-stratified case-crossover study was carried out in six Italian cities from 2001 to 2005. Daily particulate matter (particles with a 50% cut-off aerodynamic diameter of 10 µm (PM10)) and nitrogen dioxide (NO2) associations with hospitalisations for respiratory diseases (n = 100 690), chronic obstructive pulmonary disease (COPD) (n = 38 577), lower respiratory tract infections (LRTI) among COPD patients (n = 9886) and out-of-hospital respiratory deaths (n = 5490) were estimated for residents aged ≥35 years. For an increase of 10 µg·m(-3) in PM10, we found an immediate 0.59% (lag 0-1 days) increase in hospitalisations for respiratory diseases and a 0.67% increase for COPD; the 1.91% increase in LRTI hospitalisations lasted longer (lag 0-3 days) and the 3.95% increase in respiratory mortality lasted 6 days. Effects of NO2 were stronger and lasted longer (lag 0-5 days). Age, sex and previous ischaemic heart disease acted as effect modifiers for different outcomes. Analysing multiple rather than single respiratory events shows stronger air pollution effects. The temporal relationship between the pollutant increases and hospitalisations or mortality for respiratory diseases differs.

Risk of childhood leukaemia and non-Hodgkin's lymphoma after parental occupational exposure to solvents and other agents: the SETIL Study.

AIM: In the context of the Italian Multicentric Epidemiological Study on Risk Factors for Childhood Leukaemia and Non-Hodgkin's Lymphoma (SETIL), the risk of childhood cancer was investigated in relation to parental occupational exposures. METHODS: All cases of childhood leukaemia and non-Hodgkin's lymphoma (NHL) in children aged 0-10 years were identified. Controls were chosen at random from the local population in each region. Parents were interviewed using a structured questionnaire. The collected data were blindly reviewed by expert industrial hygienists in order to estimate exposure to a list of agents. Statistical analyses were performed for each agent using unconditional multivariable logistic regression models, taking into account timing of exposure. RESULTS: 683 cases of acute childhood leukaemia, 97 cases of NHL and 1044 controls were identified. Increased risk of childhood leukaemia was found for maternal exposure to aliphatic (OR 4.3) or aromatic hydrocarbons (OR 3.8) in the preconception period, and for paternal exposure to diesel exhaust (OR 1.4), lead exposure (OR 1.7) and mineral oils (OR 1.4)[corrected]. Risk of NHL appeared to be related to paternal exposure to oxygenated solvents (OR 2.5) and petrol exhaust (OR 2.2). CONCLUSIONS: We found increased risk for childhood leukaemia associated with maternal occupational exposure to aromatic and aliphatic hydrocarbons, particularly in the preconception period; increased risks were also observed for paternal exposure to diesel exhaust fumes, mineral oils and lead. The risk of NHL appeared to be related to paternal exposure to oxygenated solvent and petrol exhausts.

Particulate air pollution and hospital admissions for cardiac diseases in potentially sensitive subgroups.

BACKGROUND: Although numerous studies have provided evidence of an association between ambient air pollution and acute cardiac morbidity, little is known regarding susceptibility factors. METHODS: We conducted a time-stratified case-crossover study in 9 Italian cities between 2001 and 2005 to estimate the short-term association between airborne particles with aerodynamic diameter <10 µm (PM10) and cardiac hospital admissions, and to identify susceptible groups. We estimated associations between daily PM10 and all cardiac diseases, acute coronary syndrome, arrhythmias and conduction disorders, and heart failure for 167,895 hospitalized subjects ≥ 65 years of age. Effect modification was assessed for age, sex, and a priori-defined hospital diagnoses (mainly cardiovascular and respiratory conditions) from the previous 2 years as susceptibility factors. RESULTS: The increased risk of cardiac admissions was 1.0% (95% confidence interval [CI] = 0.7% to 1.4%) per 10 µg/m PM10 at lag 0. The effect was slightly higher for heart failure (lag 0, 1.4% [0.7% to 2.0%]) and acute coronary syndrome (lag 0-1, 1.1% [0.4% to 1.9%]) than for arrhythmias (lag 0, 1.0% [0.2% to 1.8%]). Women were at higher risk of heart failure (2.0% [1.2% to 2.8%]; test for interaction, P = 0.022), whereas men were at higher risk of arrhythmias (1.9% [0.8% to 3.0%]; test for interaction, P = 0.020). Subjects aged 75-84 years were at higher risk of admissions for coronary events (2.6% [1.5% to 3.8%]; test for interaction, P = 0.001). None of the identified chronic conditions was a clear marker of susceptibility. CONCLUSIONS: An important effect of PM10 on hospitalizations for cardiac diseases was found in Italian cities. Sex and older age were susceptibility factors.

[Audit system on quality of breast cancer diagnosis and treatment: results of quality indicators on screen-detected lesions in Italy, 2010]. / Il "progetto SQTM" sulla qualità di diagnosi e terapia entro i programmi di screening in Italia: risultati 2010.

This survey, conducted by the Italian breast screening network (GISMa), collects yearly individual data on diagnosis and treatment on about 50% of all screen-detected, operated lesions in Italy. The 2010 results show good overall quality and an improving trend over time. Critical issues were identified, including waiting times and compliance with the recommendations on not performing frozen section examination on small lesions. Preoperative diagnosis improved constantly over the years, but there is still a large variation between regions and programmes. For almost 90% of screen-detected invasive cancers the sentinel lymph node technique (SLN) was performed on the axilla, avoiding a large number of potentially harmful dissections. On the other hand, potential overuse of SLN for ductal carcinoma in situ deserves further investigation. The detailed results have been distributed, also by means of a web data warehouse, to regional and local screening programmes in order to allow multidisciplinary discussion and identification of the appropriate solutions to any issues documented by the data. It should be assigned priority to the problem of waiting times. Specialist Breast Units with adequate case volume and enough resources would provide the best setting for making monitoring effective in producing quality improvements with shorter waiting times.

Association between prescription of conventional or atypical antipsychotic drugs and mortality in older persons with Alzheimer's disease.

BACKGROUND/AIMS: To evaluate whether dementia patients prescribed antipsychotic drugs have a higher mortality compared to unexposed patients, and to investigate whether there are differences in mortality associated with exposure to conventional versus atypical antipsychotic drugs. METHODS: Retrospective population cohort study with information gathered from the Italian Health Information System. All 4,369 residents of Milan (Italy) aged 60 years or older who were newly prescribed an antidementia drug (donepezil, rivastigmine or galantamine) from January 2002 to June 2008 were included. All new users of antipsychotic drugs in this cohort were categorized according to conventional (n = 156) or atypical (n = 806) drug exposure. The mortality risks of users of conventional or atypical antipsychotics compared to nonusers were evaluated with survival analysis, considering exposure to antipsychotic drugs as a time-dependent variable. RESULTS: Mortality was increased two- and fivefold in users of atypical and conventional antipsychotics, respectively, with respect to nonusers. CONCLUSIONS: Dementia patients prescribed antipsychotic drugs had a higher risk of death. This risk was highest for those prescribed conventional antipsychotics. At least part of the excess mortality may be due to the underlying neuropsychiatric symptoms that prompted the use of antipsychotics rather than a direct medication effect.

Susceptibility factors to ozone-related mortality: a population-based case-crossover analysis.

RATIONALE: Acute effects of ozone on mortality have been extensively documented in clinical and epidemiological research. However, only a few studies have focused on subgroups of the population especially vulnerable to these effects. OBJECTIVES: To estimate the association between exposure to ozone and cause-specific mortality, and to evaluate whether individual sociodemographic characteristics or chronic conditions confer greater susceptibility to the adverse effects of ozone. METHODS: A case-crossover analysis was conducted in 10 Italian cities. Data on mortality were collected for the period 2001 to 2005 (April-September) for 127,860 deceased subjects. Information was retrieved on cause of death, sociodemographic characteristics, chronic conditions from previous hospital admissions, and location of death. Daily ozone concentrations were collected from background fixed monitors. MEASUREMENTS AND MAIN RESULTS: We estimated a 1.5% (95% confidence interval [CI], 0.9-2.1) increase in total mortality for a 10 microg/m(3) increase in ozone (8-h, lag 0-5). The effect lasted several days for total, cardiac and respiratory mortality (lag 0-5), and it was delayed for cerebrovascular deaths (lag 3-5). In the subgroup analysis, the effect was more pronounced in people older than 85 years of age (3.5%; 95% CI, 2.4-4.6) than in 35- to 64-year-old subjects (0.8%; 95% CI, -0.8 to 2.5), in women (2.2%; 95% CI, 1.4-3.1) than in men (0.8%; 95% CI, -0.1 to 1.8), and for out-of-hospital deaths (2.1%; 95% CI, 1.0-3.2), especially among patients with diabetes (5.5%; 95% CI, 1.4-9.8). CONCLUSIONS: A greater vulnerability of elderly people and women was indicated; subjects who died at home and had diabetes emerged as especially affected.

Audit on quality of breast cancer diagnosis and treatment in Italy, 2008-2009.

This survey, conducted by the Italian breast screening network (GISMa), collects individual data yearly on about 50% of all screen-detected, operated lesions in Italy. The 2008-2009 results show good overall quality of diagnosis and treatment and an improving trend over time. Critical issues were identified, including waiting times and compliance with the recommendations on not performing frozen section examination on small lesions. Pre-operative diagnosis reached the acceptable target, but there is a large variation between regions and programmes. For almost 90% of screen-detected invasive cancers the sentinel lymph node technique (SLN) was performed on the axilla, avoiding a large number of potentially harmful dissections. On the other hand, potential overuse of SLN deserves further investigation. The detailed results have been distributed, also by means of a web-based data warehouse, to regional and local screening programmes in order to allow multidisciplinary discussion and identification of the appropriate solutions to any problem documented by the data. Specialist breast units with adequate case volume and enough resources would provide the best setting for making audits effective in producing quality improvements with shorter waiting times.

Comparing different strategies for colorectal cancer screening in Italy: predictors of patients' participation.

OBJECTIVES: The objective of this study was to study predictors of patients' participation in colorectal cancer (CRC) screening. METHODS: Men and women, aged 55-64 years, were randomized to the following: (i) biennial fecal occult blood test (FOBT) delivered by mail (n=2,266); (ii) FOBT delivered by a general practitioner (GP)/screening facility (n=5,893); (iii) "once-only" sigmoidoscopy (FS) (n=3,650); (iv) FS followed by FOBT for screenees with negative FS (n=10,867); and (v) patient's choice between FS and FOBT (n=3,579). A stratified (by screening arm) random sample of attenders and nonattenders was contacted by trained interviewers 4 months after the initial invitation. Subjects giving their consent were administered a questionnaire (available online) investigating perceptions of individual CRC risk, attitudes toward prevention, adoption of health protective behaviors, and reasons for attendance/nonattendance. Adjusted prevalence odds ratios (ORs) were computed by multivariable logistic regression. RESULTS: The response rate was 71.9% (701 of 975) among nonattenders and 88.9% (773 of 870) among attenders. Adjusting for screening arm, center, gender, age, and education, participation was significantly higher among people who consulted their GP before undergoing screening (OR: 4.24; 95% confidence interval (CI): 3.11-5.78), who mentioned one first-degree relative with CRC (OR: 3.62; 95% CI: 2.02-6.49), who reported regular physical activity (OR: 1.85; 95% CI: 1.33-2.55), and who read the mailed information (letter only: OR: 1.85; 95% CI: 1.23-2.78; letter+leaflet: OR: 3.18; 95% CI: 2.12-4.76). People who considered screening to be ineffective (OR: 0.12; 95% CI: 0.08-0.19), those who considered it to be effective but reported even moderate levels of anxiety (OR: 0.32; 95% CI: 0.23-0.45), and those who mentioned previous knowledge of CRC screening tests were less likely to accept the invitation (OR: 0.49; 95% CI: 0.34-0.70). CONCLUSIONS: Adoption of health protective behaviors is associated with a higher attendance rate, whereas anxiety represents a strong barrier, even among people who deemed screening to be effective. Increasing the proportion of people who consult their GP when making a decision regarding screening might enhance participation.

Effects of pet exposure in the first year of life on respiratory and allergic symptoms in 7-yr-old children. The SIDRIA-2 study.

The effects of pet exposure on the development of respiratory symptoms have recently been the matter of vivid discussion. Our objective was to determine the effects of exposure to cat or dog in the first year of life on subsequent respiratory/allergic symptoms in children in a large Italian multicentre study. As part of the SIDRIA-2 Study (Studi Italiani sui Disturbi Respiratori dell'Infanzia e l'Ambiente 2002), the parents of 20016 children (median age 7 yr) provided information on indoor exposures at different times in life and respiratory/allergic symptoms through questionnaires. Logistic regression analyses were performed taking into account cat or dog exposure at different times in life and adjusting for the presence of the other pet, mould exposure, gender, age, parental education, maternal smoking during the first year of life, current passive smoking, family history of asthma/rhinitis/eczema and other potential confounders. Neither significant effects of dog exposure in the first year of life nor in other periods were found on respiratory/allergic symptoms after adjusting for the other covariates. Cat exposure in the first year of life was significantly and independently associated with current wheezing [OR (95% CI) 1.88 (1.33-2.68), p < 0.001] and current asthma [1.74 (1.10-2.78), p < 0.05] and border-line associated with current rhinoconjunctivitis [1.43 (0.97-2.11), p = 0.07]. No other effects of cat exposure were found on respiratory/allergic symptoms. Cat, but not dog, exposure in the first year of life is an independent risk factor for current wheezing, current asthma and current rhinoconjunctivitis at the age of 7.