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BackgroundCase reports of Guillain Barrè syndrome (GBS) following the Coronavirus Disease 2019 (COVID-19) vaccines administration have been reported. This study investigated the risk of GBS after vaccination with anti-COVID-19 vaccines (BNT162b2/Tozinameran; mRNA-1273/Elasomeran, ChAdOx1-S and Ad26.COV2-S) in the population aged ≥12 years in Italy.MethodsWe conducted a self-controlled case series study (SCCS) using national data on COVID-19 vaccination linked to emergency care/hospital discharge databases. The outcome was the first diagnosis of GBS between 27 December 2020 and 30 September 2021.Exposure risk period were days 0 (vaccination day) through 42 days following each of the 2 vaccine doses. The remaining periods were considered as non at risk (baseline) period.The SCCS model, adapted to event-dependent exposures, was fitted using unbiased estimating equations to estimate relative incidences (RIs) and excess of cases (EC) per 100,000 vaccinated by dose and vaccine product. Calendar period was included as time-varying confounder in the model.ResultsThe study included 15,986,009 persons who received at least one dose of Covid-19 vaccine. During the 42-day risk interval there were a total of 67 cases of GBS after the first dose and 41 cases after the second dose. In the 42-day risk interval, increased risks were observed after the administration of first dose (RI=6.83; 95% CI 2.14-21.85) and second dose (RI=7.41; 95% CI 2.35-23.38) for mRNA-1273 vaccine, corresponding to 0.4 and 0.3 EC per 100,000 vaccinated, respectively. Increased risk was also observed after the first dose of ChAdOx1-S vaccine (RI=6.52; 95% CI 2.88-14.77), corresponding to 1.0 EC per 100,000 vaccinated. There was no evidence of increased risk of GBS after vaccination with BNT162b2 and Ad26.COV2-S vaccines.In the subgroup analysis by sex an increased risk of GBS was observed among both males and females after mRNA-1273 vaccine. in males an increased risk was observed after the first dose, with a borderline significance (RI=5.26; 95% CI 0.94-29.42; p=0.06) and the second dose (RI=16.50; 95% CI 3.01-90.56) and in females after the first dose (RI=13.44; 95% CI 2.83-63.80). There was also evidence of an increased risk after a first dose of ChAdOx1-S in males (RI=4.94; 95% CI 1.84-13.28) and females (RI=7.14; 95% CI 1.94-26.19).In the subgroup analysis by age, there was evidence of an increased risk of GBS with mRNA-1273 vaccine among those aged ≥60 years after the first (RI=8.03; 95% CI 2.08-31.03) and second dose (RI=7.71; 95% CI 2.38-24.97). After a first dose of ChAdOx1-S there was evidence of an increased risk of GBS in those aged 40-59 (RI=4.50; 95% CI 1.37-14.79) and in those aged ≥60 years (RI=6.84; 95% CI 2.56-18.28). There was no evidence of increased risk of GBS after vaccination with BNT162b2 and Ad26.COV2-S vaccines in the subgroup analysis by age and sex.Study limitations include that the outcome was not validated through review of clinical records, the possibility of time-dependent residual confounding and the imprecision of the obtained estimates in the subgroup analysis due to the very low number of events.ConclusionsIt is important the continuous monitoring of the suspected adverse events of the COVID-19 vaccines as key component of any vaccination program. Results from this large SCCS study showed an increased risk of GBS after first and second dose of mRNA-1273 and first dose of ChAdOx1-S. However, these findings were compatible with a small number of EC. Our data are reassuring regarding BNT162b and Ad26.COV2-S vaccines with respect to GBS outcome. No increased risk of GBS was detected following each of BNT162b vaccine dose nor any increased risk after Ad26.COV2-S vaccine dose.

BackgroundIn immunosuppression after transplantation, several multi-drug approaches are used, involving calcineurin inhibitors (CNI: tacrolimus-TAC or cyclosporine-CsA), antimetabolites (antiMs), mammalian target of rapamycin inhibitors (mTORis), and corticosteroids. However, data on immunosuppressive therapy by organ and its space–time variability are lacking.MethodsAn Italian multicentre observational cohort study was conducted using health information systems. Patients with incident transplant during 2009–2019 and resident in four regions (Veneto, Lombardy, Lazio, and Sardinia) were enrolled. The post-transplant immunosuppressive regimen was evaluated by organ, region, and year.ResultsThe most dispensed regimen was triple-drug therapy for the kidneys [tacrolimus (TAC) + antiM + corticosteroids = 41.5%] and heart [cyclosporin + antiM + corticosteroids = 36.6%] and double-drug therapy for liver recipients (TAC + corticosteroids = 35.4%). Several differences between regions and years emerged with regard to agents and the number of drugs used.ConclusionA high heterogeneity in immunosuppressive therapy post-transplant was found. Further studies are needed in order to investigate the reasons for this variability and to evaluate the risk–benefit profile of treatment schemes adopted in clinical practice.

The influenza vaccination is a priority during pregnancy due to infection-related-outcomes. The study aim is to assess the acceptance by women of influenza vaccination during pregnancy based on Health Belief Model (HBM).A multicentre observational study was carried out with a convenience sample of 300 respondents.Most women (53.7%) declared that they worried to contract influenza during pregnancy and 80.7% of them agreed that there is a risk of contracting influenza during the first months of life. Vaccine benefits (adjOR 4.3 CI 95% 1.7-10.9 p0.01), information on vaccination (adjOR 2.6 CI 95% 1.2-5.5 p0.01) and trust in guidelines (adjOR 3.5 CI 95% 1.6-7.3 p0.01) are some factors associated with intent/vaccination during pregnancy.HBM confirms its effectiveness in explaining/predicting health behaviours. It is necessary to create trust in the vaccinations through an integrated work of health professionals to set up training programs and to provide effective health communication.

BackgroundAmyotrophic lateral sclerosis (ALS) is a chronic neurodegenerative rare disease that affects motor neurons in the brain, brainstem, and spinal cord, resulting in progressive weakness and atrophy of voluntary skeletal muscles. Although much has been achieved in understanding the disease pathogenesis, treatment options are limited, and in Europe, riluzole is the only approved drug. Recently, some other drugs showed minor effects.MethodsThe TUDCA-ALS trial is a phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trial. The study aims to enroll 320 patients in 25 centers across seven countries in Europe. Enrolled patients are randomized to one of two treatment arms: TUDCA or identical placebo by oral route. The study measures disease progression during the treatment period and compares it to natural progression during a no-treatment run-in phase. Clinical data and specific biomarkers are measured during the trial. The study is coordinated by a consortium composed of leading European ALS centers.ConclusionThis trial is aimed to determine whether TUDCA has a disease-modifying activity in ALS. Demonstration of TUDCA efficacy, combined with the validation of new biomarkers, could advance ALS patient care.Clinical trial registrationClinicalTrials.gov, identifier: NCT03800524.

Objectives To ascertain if the use of hydroxychloroquine(HCQ)/cloroquine(CLQ) and other conventional DMARDs (cDMARDs) and rheumatic diseases per se may be associated with COVID-19-related risk of hospitalization and mortality. Methods This case–control study nested within a cohort of cDMARD users was conducted in the Lombardy, Veneto, Tuscany and Lazio regions and Reggio Emilia province. Claims databases were linked to COVID-19 surveillance registries. The risk of COVID-19-related outcomes was estimated using a multivariate conditional logistic regression analysis comparing HCQ/CLQ vs MTX, vs other cDMARDs and vs non-use of these drugs. The presence of rheumatic diseases vs their absence in a non-nested population was investigated. Results A total of 1275 patients hospitalized due to COVID-19 were matched to 12 734 controls. Compared with recent use of MTX, no association between HCQ/CLQ monotherapy and COVID-19 hospitalization [odds ratio (OR) 0.83 (95% CI 0.69, 1.00)] or mortality [OR 1.19 (95% CI 0.85, 1.67)] was observed. A lower risk was found when comparing HCQ/CLQ use with the concomitant use of other cDMARDs and glucocorticoids. HCQ/CLQ was not associated with COVID-19 hospitalization as compared with non-use. An increased risk for recent use of either MTX monotherapy [OR 1.19 (95% CI 1.05, 1.34)] or other cDMARDs [OR 1.21 (95% CI 1.08, 1.36)] vs non-use was found. Rheumatic diseases were not associated with COVID-19-related outcomes. Conclusion HCQ/CLQ use in rheumatic patients was not associated with a protective effect against COVID-19-related outcomes. The use of other cDMARDs was associated with an increased risk when compared with non-use and, if concomitantly used with glucocorticoids, also vs HCQ/CLQ, probably due to immunosuppressive action.

At the beginning of the COVID-19 pandemic, healthcare workers were faced with difficult decisions about maternity care practices. The evidence-based practices recommended by the WHO/UNICEF Baby Friendly Hospital Initiative (BFHI) were confirmed by Italian national guidance.To describe, in a number of facilities that are part of a national Baby-Friendly network, the adherence to some steps of BFHI standards during the COVID-19 emergency.We conducted a cross-sectional online survey, inviting all hospitals interested in the Initiative, to fill out a semi-structured questionnaire.Out of the 68 participating hospitals, 30.9% were hubs and 69.1% spokes. During May 2020, 61.8% of hospitals had COVID-19 and non-COVID-19 clinical pathways, while 38.8% were only non-COVID-19. None was dedicated exclusively to COVID-19 pathways. The BFHI was effective in guaranteeing ≥80% exclusive breastfeeding, the presence of companion of mother's choice, skin-to-skin and rooming-in. The type of accreditation was associated with the presence of a companion of the mother's choice during labour (p=0.022) and with skin-to-skin (p0.001). According to the narratives, increased interpersonal distance made interactions with mothers difficult and the absence of a birth companion was reported as a major issue.The BFHI is a highly-structured, evidence-based care model. Investing in strong collaborative care approaches contributes to hospitals' preparedness.

Background: To verify whether, in patients on metformin (MET) monotherapy for type 2 diabetes (T2D), the add-on of a dipeptidyl peptidase inhibitor (DPP4i) compared to a sulfonylurea (SU) can delay the time to the subsequent treatment intensification (TI).Methods: Population-based administrative data banks from four Italian geographic areas were used. Patients aged ≥18 years on MET monotherapy receiving first DPP4i or SU dispensing between 2008 and 2015 (cohort entry) were followed up to the occurrence of TI (insulin dispensing or add-on of a third non-insulin hypoglicemic >180 days after cohort entry), treatment discontinuation, switch, cancer, death, TI occurrence within, end of data availability, end of study period (31 December 2016), whichever came first. Patients on MET + DPP4i were matched 1:1 with those on MET + SU by sex, age, year of cohort entry, and data bank. Hazard Ratio (HR) and 95% confidence intervals (95%CI) were estimated using multivariable Cox regression model including matching variables and potential confounders measured at baseline. Different sensitivity analyses were performed: i) matching at 180 days after cohort entry, ii) intent to treat (ITT) analysis, iii) matching by duration of MET monotherapy, iv) matching by propensity score.Results: The matched study cohort included 10,600 patients. Overall, 763 TI were observed (4.5/100 person-years; mean follow-up = 1.6 years). The primary analysis showed no difference in time to TI between the two groups (HR = 1.02; 95% CI = 0.88–1.19). Sensitivity analyses confirmed this result, except from the ITT analysis (HR = 1.27; 1.13–1.43).Conclusion: The use of a DPP4i rather than a SU as add-on to MET monotherapy was not associated with a delay in treatment intensification.

Background Patients hospitalised for COVID-19 may present with or acquire bacterial or fungal infections that can affect the course of the disease. The aim of this study was to describe the microbiological characteristics of laboratory-confirmed infections in hospitalised patients with severe COVID-19. Methods We reviewed the hospital charts of a sample of patients deceased with COVID-19 from the Italian National COVID-19 Surveillance, who had laboratory-confirmed bacterial or fungal bloodstream infections (BSI) or lower respiratory tract infections (LRTI), evaluating the pathogens responsible for the infections and their antimicrobial susceptibility. Results Among 157 patients with infections hospitalised from February 2020 to April 2021, 28 (17.8%) had co-infections (≤ 48 h from admission) and 138 (87.9%) had secondary infections (> 48 h). Most infections were bacterial; LRTI were more frequent than BSI. The most common co-infection was pneumococcal LRTI. In secondary infections, Enterococci were the most frequently recovered pathogens in BSI (21.7% of patients), followed by Enterobacterales, mainly K. pneumoniae, while LRTI were mostly associated with Gram-negative bacteria, firstly Enterobacterales (27.4% of patients, K. pneumoniae 15.3%), followed by A. baumannii (19.1%). Fungal infections, both BSI and LRTI, were mostly due to C. albicans. Antibiotic resistance rates were extremely high in Gram-negative bacteria, with almost all A. baumannii isolates resistant to carbapenems (95.5%), and K. pneumoniae and P. aeruginosa showing carbapenem resistance rates of 59.5% and 34.6%, respectively. Conclusions In hospitalised patients with severe COVID-19, secondary infections are considerably more common than co-infections, and are mostly due to Gram-negative bacterial pathogens showing a very high rate of antibiotic resistance.

Introduction COVID-19 case fatality rate in hospitalized patients varies across countries and studies. Reliable estimates, specific for age, sex, and comorbidities, are needed to monitor the epidemic, to compare the outcome in different settings, and to correctly design trials for COVID-19 interventions. The aim of this study was to provide population-based survival curves of hospitalized COVID-19 patients. Materials and methods A cohort study was conducted in three areas of Northern Italy, heavily affected by SARS-CoV-2 infection (Lombardy and Veneto Regions, and Reggio Emilia province), using a loco-regional COVID-19 surveillance system, linked to hospital discharge databases. We included all patients testing positive for SARS-CoV-2 RNA by RT-PCR on nasopharyngeal/throat swab samples who were hospitalized from 21 February to 21 April 2020. Kaplan-Meier survival estimates were calculated at 14 and 30 days for death in any setting, stratifying by age, sex, and the Charlson Index. Results Overall, 42,926 hospitalized COVID-19 patients were identified. Patients' median age was 69 years (IQR: 57-79), 62.6% were males, and 6.0% had a Charlson Index ≥3. Survival curves showed that 22.0% (95% CI 21.6-22.4) of patients died within 14 days and 27.6% (95% CI 27.2-28.1) within 30 days from hospitalization. Survival was higher in younger patients and in females. The negative impact of comorbidities on survival was more pronounced in younger age groups. Conclusion The high fatality rate observed in the study (28% at 30 days) suggests that studies should focus on death as primary endpoint during a follow-up of at least one month.

ObjectivesTo investigate the association between SARS-CoV-2 mRNA vaccines, BNT162b2 and mRNA-1273, and myocarditis/pericarditis.DesignSelf-Controlled Case Series study (SCCS) using national data on COVID-19 vaccination and emergency care/hospital admissions.SettingItalian Regions (Lombardia, Friuli Venezia Giulia, Veneto, Lazio).Participants2,861,809 individuals, aged 12-39 years, vaccinated with the first doses of mRNA vaccines (2,405,759 BNT162b2 and 456,050 mRNA-1273) between 27 December 2020 and 30 September 2021.Main outcome measuresFirst diagnosis of myocarditis/pericarditis within the study period. The incidence of events in the exposure risk periods (0-21 days from the vaccination day, subdivided in three equal intervals) for first and second dose was compared with baseline period. The SCCS model was fitted using conditional Poisson regression to estimate Relative Incidences (RI) and Excess of Cases (EC) per 100,000 vaccinated by dose, age, gender and brand.ResultsDuring the study period, 441 participants aged 12-39 years developed myocarditis/pericarditis (346 BNT162b2 and 95 mRNA-1273). During the 21-day risk interval there were 114 cases of myocarditis/pericarditis (74 BNT162b2 and 40 mRNA-1273) corresponding to a RI of 1.27 (0.87-1.85) and 2.16 (1.50-3.10) after first and second dose, respectively.An increased risk of myocarditis/pericarditis at [0-7) days was observed after first [RI=6.55; 95% Confidence Interval (2.73-15.72); EC per 100,000 vaccinated=2.0 (1.5-2.3)] and second dose [RI=7.59 (3.26-17.65); EC=5.5 (4.4-5.9)] of mRNA-1273 and after second dose of BNT162b2 [RI=3.39 (2.02-5.68); EC=0.8 (0.6-1.0)]. In males, an increased risk at [0-7) days was observed after first [RI=12.28, 4.09-36.83; EC=3.8 (3.1-4.0)] and second dose [RI=11.91 (3.88-36.53); EC=8.8 (7.2-9.4)] of mRNA-1273 and after second dose of BNT162b2 [RI=3.45 (1.78-6.68); EC=1.0 (0.6-1.2)]. In females, an increased risk at [0-7) days was observed after second dose of BNT162b2 [RI=3.38 (1.47-7.74); EC=0.7 (0.3-0.9)]. At [0-7) days an increased risk following second dose of BNT162b2 was observed in the 12-17 years old [RI=5.74, (1.52-21.72); EC=1.7 (0.7-1.9)] and in 18-29 years old [RI=4.02 (1.81-8.91); EC=1.1 (0.6-1.3)]. At [0-7) days an increased risk after first [RI=7.58 (2.62-21.94); EC=3.5 (2.4-3.8)] and second [RI=9.58 (3.32-27.58); EC=8.3 (6.7-9.2)] dose of mRNA-1273 was found in 18-29 years old and after first dose in 30-39 years old [RI=6.57 (1.32-32.63); EC=1.0 (0.3-1.1)].ConclusionsThis population-based study indicates that mRNA vaccines were associated with myocarditis/pericarditis in the population younger than 40 years, whereas no association was observed in older subjects. The risk increased after the second dose and in the youngest for both vaccines, remained moderate following vaccination with BNT162b2, while was higher in males following vaccination with mRNA-1273. The public health implication of these findings should be weighed in the light of the overall efficacy and safety profile of both vaccines.

Consolidated information on the effectiveness of COVID-19 booster vaccination in Europe are scarce. We assessed the effectiveness of a booster dose of an mRNA vaccine against any SARS-CoV-2 infection (symptomatic or asymptomatic) and severe COVID-19 (hospitalization or death) after over two months from administration among priority target groups (n = 18,524,568) during predominant circulation of the Delta variant in Italy (July–December 2021). Vaccine effectiveness (VE) against SARS-CoV-2 infection and, to a lesser extent, against severe COVID-19, among people ≥60 years and other high-risk groups (i.e. healthcare workers, residents in long-term-care facilities, and persons with comorbidities or immunocompromised), peaked in the time-interval 3–13 weeks (VE against infection = 67.2%, 95% confidence interval (CI): 62.5–71.3; VE against severe disease = 89.5%, 95% CI: 86.1–92.0) and then declined, waning 26 weeks after full primary vaccination (VE against infection = 12.2%, 95% CI: −4.7–26.4; VE against severe disease = 65.3%, 95% CI: 50.3–75.8). After 3–10 weeks from the administration of a booster dose, VE against infection and severe disease increased to 76.1% (95% CI: 70.4–80.7) and 93.0% (95% CI: 90.2–95.0), respectively. These results support the ongoing vaccination campaign in Italy, where the administration of a booster dose four months after completion of primary vaccination is recommended.

Few epidemiological studies have assessed the risk of parkinsonisms after prolonged use of neuroleptics. We aimed to examine the long-term risk of degenerative parkinsonisms (DP) associated with previous use of neuroleptics.All residents in Piedmont, Northern-west Italy, older than 39 years (2,526,319 subjects), were retrospectively followed up from 2013 to 2017. Exposure to neuroleptics was assessed through the regional archive of drug prescriptions. The development of DP was assessed using the regional archives of both drug prescriptions and hospital admissions. We excluded prevalent DP cases at baseline as well as those occurred in the first 18 months (short-term risk). The risk of DP associated with previous use of neuroleptics was examined through Cox regression, using a matched cohort design.The risk of DP was compared between 63,356 exposed and 316,779 unexposed subjects. A more than threefold higher risk of DP was observed among subjects exposed to antipsychotics, compared to those unexposed (HR = 3.27, 95% CI 3.00-3.57), and was higher for exposure to atypical than typical antipsychotics. The risk decreased after 2 years from therapy cessation but remained significantly elevated (HR = 2.38, 95% CI 1.76-3.21).These results indicate a high risk of developing DP long time from the start of use and from the cessation for both typical and atypical neuroleptics, suggesting the need of monitoring treated patients even after long-term use and cessation.

To investigate the association of the 2019–2020 influenza vaccine with prognosis of patients positive for SARS-CoV-2A, a large multi-database cohort study was conducted in four Italian regions (i.e., Lazio, Lombardy, Veneto, and Tuscany) and the Reggio Emilia province (Emilia-Romagna). More than 21 million adults were residing in the study area (42% of the population). We included 115,945 COVID-19 cases diagnosed during the first wave of the pandemic (February–May, 2020), 34.6% of these had been vaccinated against influenza. Three outcomes were considered: hospitalization, death, and intensive care unit (ICU) admission/death. The adjusted relative risk (RR) of being hospitalized in the vaccinated group when compared with the non-vaccinated group was 0.87 (95% CI: 0.86–0.88). This reduction in risk was not confirmed for death (RR = 1.04, 95% CI: 1.01–1.06), or for the combined outcome of ICU admission or death. In conclusion, our study, conducted on the vast majority of the population during the first wave of the pandemic in Italy, showed a 13% statistically significant reduction in the risk of hospitalization in some geographical areas and in the younger population. No impact of seasonal influenza vaccination on COVID-19 prognosis in terms of death and death or ICU admission was estimated.

To assess the real-world impact of vaccines on COVID-19 related outcomes, we analysed data from over 7 million recipients of at least one COVID-19 vaccine dose in Italy. Taking 0–14 days post-first dose as reference, the SARS-CoV-2 infection risk subsequently decreased, reaching a reduction by 78% (incidence rate ratios (IRR): 0.22; 95% CI: 0.21–0.24) 43–49 days post-first dose. Similarly, hospitalisation and death risks decreased, with 89% (IRR: 0.11; 95% CI: 0.09–0.15) and 93% (IRR: 0.07; 95% CI: 0.04–0.11) reductions 36–42 days post-first dose. Our results support ongoing vaccination campaigns.

Comparable clinical efficacy and safety of the reference rituximab (MABTHERA) and its biosimilars has been established in randomized trials. However, safety concerns are often raised when switching from reference to biosimilar products and between different biosimilars. In this prospective observational study we aimed at evaluating the safety of switching between reference and biosimilar rituximab (TRUXIMA and RIXATHON) at Trento General Hospital (Italy). All patients (n = 83) with Non Hodgkin’s Lymphoma (NHL, n = 72) and Chronic Lymphocytic Leukemia (CLL, n = 11) who received rituximab between March 2018 and March 2019 were asked to take part in the study. In 2017 and 2018 two tenders were carried out and two different biosimilars became available in the hospital, these were used sequentially. Thus, patients with or without previous treatments with the originator rituximab either received a biosimilar or were switched between different biosimilars. The incidence of adverse events in these groups of patients is described. The study population received 465 rituximab infusions and all received biosimilars. Fifty patients (60%) experienced at least one switch between different biosimilars or between rituximab originator and biosimilar, whereas 33 (40%) received one of the two biosimilars and one patient received reference rituximab. Adverse events (n = 146) were reported in 71 patients (84.5%). Treatment-related grade 3–4 events were reported in 5 patients (5.9%), whereas grade 1 rituximab related infusion events were observed in 6 patients (7.1%). No safety signal emerged in association with the use of a specific biosimilar nor with the practice of switching. Adverse events were similar, in terms of seriousness and frequency, to those described in the literature, providing further support to the clinical safety of rituximab biosimilars.

IntroductionFew epidemiological studies have assessed the risk of parkinsonisms after prolonged use of neuroleptics. We aimed to examine the long-term risk of degenerative parkinsonisms (DP) associated with previous use of neuroleptics.MethodsAll residents in Piedmont, Northern-west Italy, older than 39 years (2,526,319 subjects), were retrospectively followed up from 2013 to 2017. Exposure to neuroleptics was assessed through the regional archive of drug prescriptions. The development of DP was assessed using the regional archives of both drug prescriptions and hospital admissions. We excluded prevalent DP cases at baseline as well as those occurred in the first 18 months (short-term risk). The risk of DP associated with previous use of neuroleptics was examined through Cox regression, using a matched cohort design.ResultsThe risk of DP was compared between 63,356 exposed and 316,779 unexposed subjects. A more than threefold higher risk of DP was observed among subjects exposed to antipsychotics, compared to those unexposed (HR = 3.27, 95% CI 3.00–3.57), and was higher for exposure to atypical than typical antipsychotics. The risk decreased after 2 years from therapy cessation but remained significantly elevated (HR = 2.38, 95% CI 1.76–3.21).ConclusionsThese results indicate a high risk of developing DP long time from the start of use and from the cessation for both typical and atypical neuroleptics, suggesting the need of monitoring treated patients even after long-term use and cessation.

ObjectivesTo estimate the effectiveness of mRNA vaccines against SARS-CoV-2 infection and severe covid-19 at different time after vaccination.DesignRetrospective cohort study.SettingItaly, 27 December 2020 to 7 November 2021.Participants33 250 344 people aged ≥16 years who received a first dose of BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna) vaccine and did not have a previous diagnosis of SARS-CoV-2 infection.Main outcome measuresSARS-CoV-2 infection and severe covid-19 (admission to hospital or death). Data were divided by weekly time intervals after vaccination. Incidence rate ratios at different time intervals were estimated by multilevel negative binomial models with robust variance estimator. Sex, age group, brand of vaccine, priority risk category, and regional weekly incidence in the general population were included as covariates. Geographic region was included as a random effect. Adjusted vaccine effectiveness was calculated as (1−IRR)×100, where IRR=incidence rate ratio, with the time interval 0-14 days after the first dose of vaccine as the reference.ResultsDuring the epidemic phase when the delta variant was the predominant strain of the SARS-CoV-2 virus, vaccine effectiveness against SARS-CoV-2 infection significantly decreased (PConclusionsThe results support the vaccination campaigns targeting high risk people, those aged ≥60 years, and healthcare workers to receive a booster dose of vaccine six months after the primary vaccination cycle. The results also suggest that timing the booster dose earlier than six months after the primary vaccination cycle and extending the offer of the booster dose to the wider eligible population might be warranted.

The effectiveness of the tiotropium Respimat® formulation in routine clinical practice is still an open issue due to concern about the generalizability of the Tiotropium Safety and Performance in Respimat® (TIOSPIR) trial findings. Our aim was to compare the incidence of acute respiratory events between new users of tiotropium Respimat® and HandiHaler®. The study population comprised patients aged ≥45 years resident in two Italian regions who received a first tiotropium prescription (HandiHaler® or Respimat®) between 1 July 2011 and 30 November 2013. The cohort was identified within the database of drug prescriptions reimbursed by the Italian National Health Service. Clinical outcomes were obtained from hospital records. The primary outcome was the first hospitalization for respiratory events, including chronic obstructive pulmonary disease (COPD) exacerbation, respiratory failure, hypoxemia/hyperventilation and pneumonia, during the exposure period. The hazard ratios were estimated for the propensity score matched groups with Cox regression. After matching, 31,334 patients with incident tiotropium prescriptions were included. Similar incidence rates of the primary outcome between the Respimat® and HandiHaler® users were identified (adjusted hazard ratio 0.95, 95% CI 0.84–1.07). No differences emerged in the subgroup analyses conducted according to the baseline characteristics of the tiotropium users. This study confirms the findings observed in the TIOSPIR trial in a more heterogeneous population that included patient subgroups with severe respiratory disease and unstable COPD.

IntroductionThe overuse of antibiotics is causing worldwide spread of antimicrobial resistance (AMR). Compared with other countries, Italy has both high antibiotic consumption rates and high rates of AMR. Due to the fact that around 90% of antibiotics are prescribed by general practitioners (GPs), this study aims to measure the impact of knowledge, attitudes and sociodemographic and workplace-related factors on the quality of antibiotic prescriptions filled by GPs in the Italian Region of Sardinia.Methods and analysisKnowledge, attitude, sociodemographic and workplace-related factors deemed to influence physicians prescribing behaviour will be evaluated in a cross-sectional study conducted among all GPs of the Italian Region of Sardinia (n=1200). A knowledge and attitudes questionnaire (Knowledge and Attitudes on Antibiotics and Resistance - Italian version: ITA-KAAR) accompanied by a sociodemographic form will be linked to drug prescription data reimbursed by the National Health System. European Surveillance of Antibiotic Consumption quality indicators for outpatient antibiotic use will be calculated from drug prescription records. Every GP will be deemed to have demonstrated an adequate quality of prescriptions of antibiotics if half of the indicator score plus one is better than the median of the region. A multivariate Poisson regression model with robust variance estimation will be used to evaluate the impact of the determinants of antibiotic prescriptions on the actual prescribing quality of each physician.Ethics and disseminationThe project has been approved by the ethics committee of the Regional Health Trust of Sardinia (176/2019/CE, 24 September 2019). The results will be useful to inform evidence-based interventions to tackle irrational antibiotic use in the community.

Previous epidemiological studies reported a significantly higher risk of Amyotrophic Lateral Sclerosis (ALS) in Italian male soccer players. As a consequence, sports newspapers and news agencies focused on this issue and spread the news of 51 male soccer players with a reported diagnosis of ALS.We searched news on male Italian national soccer players with a reported diagnosis of ALS quoted from January 1, 1950 to July 31, 2016 in at least two Internet web sites or in books by journalists.A total of 39 male soccer players with a reported diagnosis of ALS were identified. Subjects were born from 1905 to 1973, 32 were currently deceased, 6 were still living, while the status of 1 player was unknown. All gathered information was available for 29 soccer players. The group had a mean age at diagnosis of 45.3 ± 12.2 years, a mean age at onset of symptoms of 46.4 ± 12.1 years, and a mean age at death of 50.9 ± 12.3 years. A significant inverse correlation between year of birth and age at onset of symptoms was observed, with a younger age at onset of symptoms in soccer players born in more recent years (r = -0.65, p0.01).Italian male soccer players with a reported diagnosis of ALS have a significantly younger age at diagnosis when compared to other European patients with ALS. Results support a possible relationship between soccer and the risk of ALS. We believe that further research is urgently needed in this field.

Surgical antibiotic prophylaxis (SAP) in children is poorly characterized. We investigated SAP for children undergoing elective surgical procedures. We prospectively investigated elective surgical procedures performed in children

The cardiovascular safety of tiotropium Respimat formulation in the routine clinical practice is still an open issue. Our aim was to compare the risk of acute myocardial infarction and heart rhythm disorders in incident users of either tiotropium Respimat or HandiHaler. The study population comprises patients aged ≥45 years, resident in two Italian regions with a first prescription of tiotropium (HandiHaler or Respimat) between 01/07/2011-30/11/2013. The cohort was identified through the database of prescriptions reimbursed by the Italian National Health Service. Comorbidities and clinical outcomes were obtained from hospital records. The primary outcome was the first hospitalization for acute myocardial infarction and/or for heart rhythm disorders during the exposure period. Hazard ratios were estimated in the propensity score-matched groups through Cox regression. After matching, 31,334 patients with incident prescription of tiotropium were included. The two groups were balanced with regard to baseline characteristics. Similar incidence rates of the primary outcome between Respimat and HandiHaler users were identified (adjusted hazard ratio 1.02, 95% CI 0.82-1.28). No risk difference between Respimat and HandiHaler emerged when considering clinical events separately. This large cohort study showed a comparable acute cardiovascular safety profile of the two tiotropium formulations.

The use of surgical antibiotic prophylaxis (SAP) in children is poorly characterized. Our aim was to evaluate the effectiveness of a quality improvement (QI) intervention targeting SAP in children, by means of a multicenter prospective intervention study, with a before and after design. We prospectively investigated elective surgical procedures performed in children

Background Qualitative and quantitative research investigating determinants of adherence to clinical guidelines (GLs) on surgical antibiotic prophylaxis (SAP) are scarce. We conducted a mixed-method study aimed at investigating barriers and at describing attitudes of healthcare professionals (HCPs) regarding SAP in three Italian children’s hospitals. Methods The study comprised two sequential phases: 1) collection of qualitative data through focus groups; 2) conduction of a survey on HCPs attitudes towards SAP. Focus groups were carried out in each hospital with a theoretical convenience sample of 10–15 HCPs. Categorical analysis was conducted. Emerging categories and additional topics derived by literature search were used to develop the survey questionnaire, which included 13 questions expressed through a 4-point Likert scale. Members of surgical teams were invited by e-mail to fill in the questionnaire. We summed up the points assigned to each 4-point Likert scale response and calculated a cumulative score expressing overall concordance to expected HCPs attitudes on SAP. We conducted univariate and multivariate analysis to evaluate the relationship among characteristics of respondents and concordance with expected attitudes. Results The main categories identified in the qualitative phase included determinants of general adherence to GLs (e.g., relevance of clinical judgment), individual determinants (e.g., poor knowledge on hospital data) and organizational/structural determinants (e.g., patient flows). A total of 357 HCPs participated in the survey (response rate: 82.1%). Among respondents, 75% reported that SAP should be performed with first or second-generation cephalosporins, 44% that 2–3 days of antibiotic administration are useful as a precaution after surgery, 32% that SAP is needed for all surgical procedures. At multivariate analysis, professional category (physicians vs nurses; OR: 3.31; 95%CI: 1.88–5.82), and hospital (hospital 1 and 2 vs hospital 3; ORs: 2.79, 95%CI: 1.22–6.36; 2.40, 95%CI: 1.30–4.43, respectively) were significantly and independently associated with higher concordance with expected attitudes on SAP. Conclusions Results from this study were useful to identify obstacles to appropriate SAP use in children. In our setting, findings support that a quality-improvement intervention should take into account local contexts, with development of hospital policies, education on SAP recommendations, and dissemination of data on adherence to recommendations.

Introduction The objective of the study was to estimate the prevalence of parkinsonism in the Province of Rome using antiparkinsonian prescription histories from 1986 to 1991. Methods A subject was defined as a case of parkinsonism if he/she had received "specific" and "consistent" antiparkinsonian therapy in the study period. Results In November 1990, 6,572 patients were defined as prevalent cases of parkinsonism. The crude prevalence ratio, for the total population of the Province of Rome, is 173.5 per 100,000 inhabitants (165.9 per 100,000 in men and 180.5 per 100,000 in women). The method was validated by record-linkage with clinical records of all patients visited during 1990 at the Department of Neurological Sciences of the University of Rome "La Sapienza". The sensitivity of the prevalence study was 83.6%. Conclusions The use of a computerized data base of all prescription data, routinely collected for administrative purposes, enabled us to obtain a prevalence estimate based on a very large population, with low costs and in a relatively short time.

OBJECTIVE—The purpose of this study was to assess incidence of and risk factors for recurrent cardiovascular disease (CVD) in type 2 diabetes. RESEARCH DESIGN AND METHODS—We estimated the incidence of recurrent cardiovascular events in type 2 diabetic patients, aged 40–97 years, followed by a network of diabetes clinics. The analysis was conducted separately for 2,788 patients with CVD at enrollment (cohort A) and for 844 patients developing the first episode during the observation period (cohort B). RESULTS—During 4 years of follow-up, in cohort A the age-adjusted incidence of a recurrent event (per 1,000 person-years) was 72.7 (95% CI 58.3–87.1) in men and 32.5 (21.2–43.7) in women, whereas in cohort B it was 40.1 (17.4–62.9) in men and 22.4 (12.9–32.0) in women. After controls were included for potential predictors (familial CVD, obesity, smoking, diabetes duration, glycemic control, microvascular complications, geographic area, and antihypertensive and lipid-lowering treatment), male sex, older age, and insulin use were significant independent risk predictors (cohort A) and serum triglyceride levels ≥1.69 mmol/l emerged as the only metabolic (negative) prognostic factor (cohort B). In both cohorts, a prior CVD episode, especially myocardial infarction, was by far the strongest predictor of recurrent CVD. CONCLUSIONS—Approximately 6% of unselected diabetic patients in secondary prevention develop recurrent major CVD every year. Those with long-standing previous CVD show a higher incidence of recurrence. Male sex, age, high triglyceride levels, and insulin use are additional predictors of recurrence.

OBJECTIVE—Cardiovascular disease (CVD) is the main cause of morbidity/mortality in diabetes. We set forth to determine incidence and identify predictors (including microvascular complications and treatment) of first coronary heart disease (CHD) event in CVD-free type 2 diabetic patients. RESEARCH DESIGN AND METHODS—A cohort of 6,032 women and 5,612 men, sampled from a nationwide network of hospital-based diabetes clinics, was followed up for 4 years. Baseline assessment included retinopathy, nephropathy, and foot ulcers. First CHD events (myocardial infarction, coronary artery bypass grafting, percutaneous transluminal coronary angioplasty, and electrocardiogram-proven angina) were analyzed for 29,069 person-years. RESULTS—The age-standardized incidence rate (per 1,000 person-years) of first CHD event (n = 881) was 28.8 (95% CI 5.4–32.2) in men and 23.3 (20.2–26.4) in women. Major CHD (myocardial infarction, coronary artery bypass grafting, and percutaneous transluminal coronary angioplasty) was less frequent in women (5.8 [4.3–7.2]) than in men (13.1 [10.9–15.4]; a sex ratio of 0.5 [0.4–0.6]). Incidence rates of all outcomes were higher in patients with microvascular complications (for major CHD, age-adjusted rate ratios were 1.6 [1.2–2.21] in men and 1.5 [1.0–2.2] in women). By multivariate Cox analysis, age and diabetes duration were risk predictors common in both sexes. In men, glycemic control and treated hypertension were additional independent risk factors, but residing in the south was associated with a significant 29% risk reduction. In women, higher triglycerides/lower HDL cholesterol and microvascular complications were independent risk factors. CONCLUSIONS—In CVD-free patients with type 2 diabetes, risk of first CHD event depends on sex, geographic location, and presence of microvascular disease. Hyperglycemia and hypertension, particularly in men, and diabetic dyslipidemia, especially in women, are risk factors amenable to more aggressive treatment.

Objective To assess the risk of maternal, fetal, and neonatal outcomes associated with the administration of an MF59 adjuvanted A/H1N1 vaccine during pregnancy. Design Historical cohort study. Setting Singleton pregnancies of the resident population of the Lombardy region of Italy. Participants All deliveries between 1 October 2009 and 30 September 2010. Data on exposure to A/H1N1 pandemic vaccine, pregnancy, and birth outcomes were retrieved from regional databases. Vaccinated and non-vaccinated women were compared in a propensity score matched analysis to estimate risks of adverse outcomes. Main outcome measures Main maternal outcomes included type of delivery, admission to intensive care unit, eclampsia, and gestational diabetes; fetal and neonatal outcomes included perinatal deaths, small for gestational age births, and congenital malformations. Results Among the 86 171 eligible pregnancies, 6246 women were vaccinated (3615 (57.9%) in the third trimester and 2557 (40.9%) in the second trimester). No difference was observed in terms of spontaneous deliveries (adjusted odds ratio 1.02, 95% confidence interval 0.96 to 1.08) or admissions to intensive care units (0.95, 0.47 to 1.88), whereas a limited increase in the prevalence of gestational diabetes (1.26, 1.04 to 1.53) and eclampsia (1.19, 1.04 to 1.39) was seen in vaccinated women. Rates of fetal and neonatal outcomes were similar in vaccinated and non-vaccinated women. A slight increase in congenital malformations, although not statistically significant, was present in the exposed cohort (1.14, 0.99 to 1.31). Conclusions Our findings add relevant information about the safety of the MF59 adjuvanted A/H1N1 vaccine in pregnancy. Residual confounding may partly explain the increased risk of some maternal outcomes. Meta-analysis of published studies should be conducted to further clarify the risk of infrequent outcomes, such as specific congenital malformations.

Supported by a specific act of the Italian Parliament.The committees and members of the Italian StudyGroup for the Di Bella Multitherapy Trials are asfollows. Research Coordinating Center: D. Greco,R. Raschetti, B. Caffari, F. Chiarotti, R. Da Cas, B.De Mei, G. Di Giovambattista, M. Maggini, F. Men-niti-Ippolito, S. Modigliani, P. Popoli, P. Ruggeri, S.Spila-Alegiani, C. Tomino, G. Traversa, P. Bruzzi, T.Gamucci. Steering Committee: G. Benagiano, D.Amadori, P. Bruzzi, E. Buiatti, E. Ciranni, F. Cog-netti, G. Colucci, P.F. Conte, G. Di Bella*, D. Greco,S. Iacobelli, F. Mandelli, E. Marubini, M. Massotti,S. Monfardini, F. Oleari, R. Raschetti, G. L. San-nazzari, L. Tomatis, U. Veronesi. (*Dr. G. Di Bella,the son of Dr. L. Di Bella, only participated in thefirst two meetings of the Steering Committee. Onmany occasions, he strongly disagreed with theperformance and results of the trials. No part ofthe current article has been discussed with orendorsed by Dr. G. Di Bella.) International ReviewBoard: P. Calabresi (Rhode Island), F. Cavalli (Bell-inzona, Switzerland), P. Kleihues (Lyon Cedex,France), J.G. Mc Vie (London, UK), H. Pinedo (Am-sterdam, The Netherlands), K. Sikora (Lyon Cedex,France), T. Tursz (Villejuif Cedex, France). Indepen-dent Endpoint Evaluation Committee: A. R. Bianco,R. Labianca, P. L. Rossi Ferrini, G. Simonetti, A.Sobrero. Investigators: Ancona—R. Cellerino, S.Antognoli, R. Berardi, R. Bracci, P. Lippe, F. Pulita;Aosta—F. Di Vito, D. Martinod, M. Musi; Avi-ano—A. Veronesi, R. Lazzarini; Bari—G. Colucci(Principal Investigator [PI]), V. Attolico, F. Giotta, M.Longo, E. Maiello; Bologna—S. Tura, F. Gherlin-zoni, M. Tani; Bolzano—H. Amor, P. Borona, F.Girardi, C. Graiff; Cagliari—G. Broccia, M. G. Co-rona, A. Desogus, V. Mascia, S. Pasqualucci; Ca-tania—G. Failla, M. R. Aiello, S. Cordio, P. Finoc-chiaro. Chieti—S. Iacobelli (PI), E. Melena, M. DeTursi, M. T. Scognamiglio, N. Tinari; Forli`—D.Amadori (PI), M. Maltoni, O. Nanni, F. Scardovi, P.Serra; Genoa—R. Rosso, F. Boccardo, A. Barp, T.Coli, M. Grimaldi; Milan—N. Cascinelli, L. Ascani,E. Bajetta, P. Bidoli, A. Cassata, D. De Candis, W.Giannessi, G. Procopio; Milan—S. Di Donato, A.Boiardi, D. Cerri, M. Eoli, A. Silvani; Milan—U.Veronesi (PI), M. Colleoni, N. Rotmensz; Na-ples—S. Monfardini (PI), G. Comella, A. De Mat-teis, A. Gravina, C. Gridelli, F. Perrone, M. R.Salzano, C. Sandomenico; Naples—C. Battista, G.Iodice, R. Fico, A. Nicchia; Padua—M. Lise, G. L.De Salvo, E. Di Lenardo, G. Iadicicco; Palermo—B.Agostara, I. Cafarelli; Perugia—M. Tonato, F.Radicchi, S. Sorbolini, O. Taschini; Pisa—P. F.Conte (PI), A. Carmignani, L. Del Mastro, A. Gen-nari, C. Orlandini; Potenza—L. Manzione, A. Di-nota, G. Lombardi; Reggio Calabria—G. Gasparini,M. G. Arena, M. Fanelli, F. Modafferi, A. Morabito;Rome—F. Mandelli (PI), P. Fazi, F. Mauro, M.Martelli, C. Ricci, M. Vignetti; Rome—F. Cognetti(PI), A. D’Alessio, S. De Marco, V. Ferraresi, T.Gamucci, D. Giannarelli, E. Magnani, P. Rellecati,E. M. Ruggeri, M. Zeuli; Turin—G. L. Sannazzari(PI), M. Borgognone, R. Chio`, A. Gasco, R. Ragona,M. Sacco, R. Soffietti, R. Verna, M. Tessa;Turin—A. Pileri; Trento—E. Galligioni, A. Lucenti,F. Moltrer, F. Paolazzi.The authors thank the Stabilimento ChimicoFarmaceutico Militare, Florence, Italy (Colonel G.Muzzi, Director), for the production of the melato-nin tablets and retinoid solution and the Group forthe supervision and control of custom-made drugsof the Istituto Superiore di Sanita`, Roma (E. Cir-anni, Director; R. Alimenti, S. Alimonti, G. Cavaz-zutti, L. Gagliardi, B. Gallinella, G. Incarnato, F. LaTorre, A. Mosca, G. Multari, L. Turchetto, L. Valvo).Address for reprints: Giuseppe Traversa, M.D., De-partment of Epidemiology and Biostatistics, IstitutoSuperiore di Sanita`, Viale Regina Elena 299, 00161Rome, Italy.Received April 26, 1999; revision received July 22,1999; accepted July 29, 1999.

A 10-fold increase of reported adverse events following influenza vaccination in the 1995-1996 campaign was reported. To evaluate the relative reactogenicity of different influenza vaccines a prospective observational study was conducted in 72 Italian local health units (LHU) in the period October-December 1996. Of the 16,637 enrolled individuals aged 65 or more, 27.4% reported the occurrence of at least one adverse event within 72 h of vaccination. The odds ratios, adjusted through a multivariate logistic model, were highest for whole vaccine recipients. Most of the observed events were of moderate clinical severity and were mainly represented by local symptoms. None of the products was found to show an unusual or concerning reactogenicity profile, and no severe events associated with immunization were reported.

Many case-control studies have shown a protective effect of vaccinations on the risk of sudden unexplained death (SUD). In this paper we compare the properties of different statistical methods in this situation, when the first vaccination appears to reduce the overall risk of an event (SUD). The first method is the self controlled case series (SCCS) method, which considers only subjects with an event during the observation time. This method yields unbiased estimates in the situation of non-censoring events. We show by simulation studies that the second method considered, the adjusted SCCS method, underestimates the parameter of interest, the effect of the first dose, when the general risk of SUD is lower in control periods after the first vaccination than in the period before vaccination. This type of bias could be eliminated by considering only cases who had received at least one vaccination. Additionally, we compare the adjusted SCCS method with the Cox model as a third method. Cox regression can take into account the time before the first vaccination, and this method yields unbiased estimates at modest effect sizes and short risk periods. We applied the SCCS method and Cox regression to data from the German study on sudden infant death (GeSID) and to a case series study from Italy (the HERA study) examining sudden unexpected deaths and vaccinations during the first 2 years of life. We show that the adjusted SCCS analysis with all cases underestimates the vaccination effect, as expected from the simulation analyses. Using Cox regression, we examined the general risk reduction after vaccination, as was the focus of the above mentioned studies. With a relative incidence of 0.8, our results were less pronounced than in the case-control analysis of the GeSID study (adjusted odds ratio: 0.51). SCCS analyses of both the GeSID and HERA studies yielded very similar estimates for the first and second vaccine doses.