Amyotrophic Lateral Sclerosis and soccer: an internet survey of 29 Italian players

Objectives  Some epidemiological studies have shown a very high risk of  Amyotrophic Lateral Sclerosis (ALS) in Italian male soccer players. Subsequently, the sports newspapers and news agencies have spread the news of 51 male soccer players with reported ALS. Design  We searched for male Italian national soccer players quoted in at least two Internet web sites or in books of journalists from January 1, 1950 to July 31, 2016 with a reported diagnosis of ALS. Results. Thirty nine male soccer players with reported ALS were identified. These subjects were born from 1905 to 1973 (32 deceased 6 living and 1 unknown). In the group of 29 soccer players for which the information was available the mean age at diagnosis was 45.3± 12.2 years; the mean age at onset of symptoms was 46.4± 12.1 years; the mean age at death was 50.9± 12.3 years. An inverse statistically correlation between year of birth and age at onset of symptoms was observed, with a more younger age at onset of symptoms for soccer players born in the recent years (r =-0.65 p<0.01). Conclusions. The ALS Italian male soccer have a clear anticipation of the age of diagnosis respect to European ALS patients. The findings support the possible relation between the soccer and the occurrence of ALS. We believe that an increase in research activity is urgently needed in this field

Survival of Hospitalized COVID-19 Patients in Northern Italy: A Population-Based Cohort Study by the ITA-COVID-19 Network

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 &gt;= 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

Renin-Angiotensin-Aldosterone System Inhibitors and Risk of Death in Patients Hospitalised with COVID-19: A Retrospective Italian Cohort Study of 43,000 Patients

Introduction The epidemic due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been spreading globally, raising increasing concerns. There are several controversial hypotheses on the potentially harmful or beneficial effects of antihypertensive drugs acting on the renin-angiotensin-aldosterone system (RAAS) in coronavirus disease 2019 (COVID-19). Furthermore, there is accumulating evidence, based on several observational studies, that angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) do not increase the risk of contracting SARS-CoV-2 infection. On the other hand, conflicting findings regarding the role of ACEIs/ARBs as prognosis modifiers in COVID-19 hospitalised patients have been reported. Objective The aim of this large-scale, retrospective cohort study was to investigate whether prior exposure to ACEIs and/or ARBs was associated with all-cause mortality among over 40,000 hospitalised COVID-19 patients compared with calcium channel blockers (CCBs), a potential therapeutic alternative. Methods This study was conducted using COVID-19 registries linked to claims databases from Lombardy, Veneto and Reggio Emilia (overall, 25% of Italian population). Overall, 42,926 patients hospitalised between 21 February and 21 April 2020 with a diagnosis of COVID-19 confirmed by real-time polymerase chain reaction tests were included in this study. All-cause mortality occurring in or out of hospital, as reported in the COVID-19 registry, was estimated. Using Cox models, adjusted hazard ratios (HRs) of all-cause mortality (along with 95% confidence intervals [CIs]) were estimated separately for ACEIs/ARBs and other antihypertensives versus CCBs and non-use. Results Overall, 11,205 in- and out-of-hospital deaths occurred over a median of 24 days of follow-up after hospital admission due to COVID-19. Compared with CCBs, adjusted analyses showed no difference in the risk of death among ACEI (HR 0.97, 95% CI 0.89-1.06) or ARB (HR 0.98, 95% CI 0.89-1.06) users. When non-use of antihypertensives was considered as a comparator, a modest statistically significant increase in mortality risk was observed for any antihypertensive use. However, when restricting to drugs with antihypertensive indications only, these marginal increases disappeared. Sensitivity and subgroup analyses confirmed our main findings. Conclusions ACEI/ARB use is not associated with either an increased or decreased risk of all-cause mortality, compared with CCB use, in the largest cohort of hospitalised COVID-19 patients exposed to these drugs studied to date. The use of these drugs therefore does not affect the prognosis of COVID-19. This finding strengthens recommendations of international regulatory agencies about not withdrawing/switching ACEI/ARB treatments to modify COVID-19 prognosis

TheShinISS-Vax. Vaccini a mRNA Covid-19 e miocardite/pericardite in soggetti con malattia reumatica in Italia

Introduzione. Diversi studi osservazionali analitici hanno evidenziato un aumentato rischio di miocardite/pericardite nella popolazione generale. Per quanto riguarda le persone con malattie reumatiche, le informazioni sul profilo di sicurezza dei vaccini Covid-19 sono ad oggi scarse. In particolare, non si dispone, per questa popolazione, di ampi studi epidemiologici con disegno metodologicamente robusto che analizzano il rischio di miocardite/pericardite associato ai vaccini a mRNA. Obiettivo dello studio è valutare l’associazione tra vaccini mRNA Covid-19 e rischio di miocarditi/pericarditi in soggetti di età ≥12 anni con malattie reumatiche in Italia. Questa analisi è un approfondimento dello studio multiregionale TheShinISS-Vax condotto dall’Istituto Superiore di Sanità per valutare l’associazione tra vaccini mRNA Covid-19 e l’insorgenza di miocarditi/pericarditi nella popolazione generale in Italia. Metodi. È stato utilizzato un disegno di studio Self-Controlled Case Series (SCCS) con dati provenienti da archivi sanitari correnti di cinque regioni italiane (Lombardia, Friuli-Venezia Giulia, Veneto, Lazio ed Emilia-Romagna). Utilizzando un approccio di analisi distribuite con record linkage a livello regionale, è stata identificata la popolazione di vaccinati con prima e seconda dose di vaccini mRNA Covid-19 (BN162b2, mRNA-1273) tra il 27/12/2020 e il 30/09/2021 di età ≥12 anni. Il sottogruppo della popolazione con malattia reumatica ha incluso tutti i soggetti presenti in almeno uno dei seguenti archivi: archivio dei ricoveri ospedalieri (ICD-9-CM 446.5, 710, 714, 720, 725, 696), archivio delle esenzioni per patologia (codici 006, 028, 030, 045, 054, 067), archivio delle prescrizioni farmaceutiche (ATC L04, H02A) negli anni precedenti la vaccinazione. A partire da questa popolazione sono stati selezionati, attraverso gli accessi al pronto soccorso e/o i ricoveri ospedalieri, tutti i casi incidenti di miocardite/pericardite insorti nel periodo di studio (ICD-9-CM 391.2, 398.0, 422, 429.0, 420, 391.0, 393, 423.1, 423.2, 423.9). L’esposizione è stata definita come la prima o la seconda dose dei vaccini in studio; il periodo di rischio è stato identificato come 21 giorni dalla prima o seconda dose di vaccino e suddiviso in sotto-periodi di rischio prespecificati di 7 giorni; il tempo di osservazione al di fuori del periodo di rischio è stato definito come il periodo di non esposizione. Attraverso il metodo SCCS “modificato per 23 esposizioni evento-dipendenti” sono state stimate le Incidenze Relative (IR) e i rispettivi Intervalli di Confidenza al 95% (IC95%). Nel modello è stata inclusa come covariata tempo-dipendente la componente stagionale. Risultati. Nel periodo in studio, tra i 12.540.263 di vaccinati a mRNA sono stati identificati 289.623 (2,3%) soggetti affetti da malattia reumatica, di cui 30.667 di età inferiore ai 40 anni. Nei soggetti reumatici si sono osservati 230 (0,08%) casi di miocardite/pericardite, 27 nel periodo di rischio e 203 nel periodo di non esposizione. Non è stato riscontrato alcun incremento di rischio sia nei 21 giorni successivi alla vaccinazione (prima dose IR=0,65; IC95% 0,36-1,18; seconda dose IR=0,82; IC95% 0,45-1,48) sia nella sotto-finestra di rischio di 7 giorni (prima dose IR=0,89; IC95% 0,39-2,07; seconda dose IR=0,87; IC95% 0,35-2,15). Nel sottogruppo dei soggetti reumatici al di sotto dei 40 anni sono stati osservati 27 casi di miocardite/pericardite (0,09%), di cui solo 2 nella finestra di rischio di 21 giorni. Da notare che nella popolazione generale dei vaccinati sono stati osservati 3.065 (0,02%) casi di miocardite/pericardite, di cui 510 nella finestra di rischio [0- 21) e 2.555 nel periodo di riferimento. In tale popolazione, il modello SCCS evidenzia un aumento del rischio di miocarditi/pericarditi in seguito alla seconda dose nell’analisi dei vaccini a mRNA (IR=1,51; IC95% 1,24-1,84). Conclusioni. Dai risultati di questo studio non emerge un aumentato rischio di miocardite/pericardite associato ai vaccini a mRNA nei soggetti con malattia reumatica di età ≥12 anni, come invece osservato nella popolazione generale. Secondo le nostre conoscenze, si tratta del primo studio di popolazione che analizza il rischio di miocarditi/pericarditi dei vaccini a mRNA in un’ampia coorte di soggetti con malattia reumatica in cinque Regioni italiane e che utilizza il SCCS quale metodologia di riferimento nella valutazione della sicurezza delle vaccinazioni. Per questo tipo di studi, che analizzano eventi rari in sottogruppi di popolazione, si sottolinea l’importanza di condurre studi multiregionali con un’ampia adesione delle Regioni per avere la possibilità di produrre evidenze robuste a supporto di decisioni nella clinica e nella sanità pubblica anche per patologie, come le reumatiche, scarsamente rappresentate e analizzate

Sindrome della morte improvvisa del lattante (SIDS) in Sicilia: una valutazione dei principali determinanti di accudimento

Aim: to evaluate certain caring behaviors associated with the onset of sudden infant death syndrome (SIDS). Methods: a telephone questionnaire was administered between May and July 2017 to a sample of 1055 Sicilian mothers within 30 days of delivery. A multivariate logistic analysis was conducted considering outcome variables: the sleeping position of the children, exclusive breastfeeding and passive smoking. Results: 62% of the participants place their children in the supine position, 37.9% practice exclusive breastfeeding and 89.0% are not smokers. Being aged &lt; 32 years, having a low level of education and limited economic resources are risk factors for the non-supine positioning of children during sleep. A low level of education, primiparity, non-participation to an antenatal course expose mothers to a greater risk of not practicing exclusive breastfeeding at one month. Postpartum smoking is positively associated with a low level of education. Conclusions: the assessment of the main caring behaviors towards newborns and infants is essential for an effective campaign for reducing the risk of SIDS

Effectiveness of mRNA vaccines and waning of protection against SARS-CoV-2 infection and severe covid-19 during predominant circulation of the delta variant in Italy. Retrospective cohort study

Objectives: To estimate the effectiveness of mRNA vaccines against SARS-CoV-2 infection and severe covid-19 at different time after vaccination. Design: Retrospective cohort study. Setting: Italy, 27 December 2020 to 7 November 2021. Participants: 33 250 344 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 measures: SARS-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. Results: During 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 (P&lt;0.001) from 82% (95% confidence interval 80% to 84%) at 3-4 weeks after the second dose of vaccine to 33% (27% to 39%) at 27-30 weeks after the second dose. In the same time intervals, vaccine effectiveness against severe covid-19 also decreased (P&lt;0.001), although to a lesser extent, from 96% (95% to 97%) to 80% (76% to 83%). High risk people (vaccine effectiveness -6%, -28% to 12%), those aged ≥80 years (11%, -15% to 31%), and those aged 60-79 years (2%, -11% to 14%) did not seem to be protected against infection at 27-30 weeks after the second dose of vaccine. Conclusions: The 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

How Are the Interests of Incapacitated Research Participants Protected through Legislation? An Italian Study on Legal Agency for Dementia Patients

Patients with dementia may have limited capacity to give informed consent to participate in clinical research. One possible way to safeguard the patients' interests in research is the involvement of a proxy in the recruitment process. In Italy, the system of proxy is determined by the courts. In this study we evaluate the timing for appointment of a legal proxy in Italy and identify predictive variables of appointment.Subjects were recruited among the outpatients seeking medical advice for cognitive complaints at the Centre for Research and Treatment of Cognitive Dysfunctions, University of Milan, "Luigi Sacco" Hospital. The Centre was participating to the AdCare Study, a no-profit randomised clinical trial coordinated by the Italian National Institute of Health. The requirement that informed consent be given by a legal representative dramatically slowed down the recruitment process in AdCare, which was prematurely interrupted. The Centre for Research and Treatment of Cognitive Dysfunctions collected data on the timing required to appoint the legal representatives. Patients diagnosed with dementia and their caregivers were provided information on the Italian law on legal agency (law 6/2004). At each scheduled check-up the caregiver was asked whether she/he had applied to appoint a legal proxy for the patient and the time interval between the presentation of the law, the registration of the application at the law court chancellery and the sentence of appointment was registered. The study involved 169 demented patients. Seventy-eight patients (46.2%) applied to appoint a legal proxy. These subjects were usually younger, had been suffering from dementia for a longer time, had less than two children and made more use of memantine. The mean interval time between the presentation of the law and the patients' application to the law court chancellery was two months. The mean interval time between the patient's application to the law court chancellery and the sentence of appointment was four months.In Italy the requirement that legal representatives be appointed by the courts slows down subjects' participation in research. Other procedures for legal agency of the incapacitated patients may be adopted, taking as examples other EU countries' systems

Sudden Unexpected Deaths and Vaccinations during the First Two Years of Life in Italy: A Case Series Study

Background The signal of an association between vaccination in the second year of life with a hexavalent vaccine and sudden unexpected deaths (SUD) in the two days following vaccination was reported in Germany in 2003. A study to establish whether the immunisation with hexavalent vaccines increased the short term risk of SUD in infants was conducted in Italy. Methodology/Principal Findings The reference population comprises around 3 million infants vaccinated in Italy in the study period 1999–2004 (1.5 million received hexavalent vaccines). Events of SUD in infants aged 1–23 months were identified through the death certificates. Vaccination history was retrieved from immunisation registries. Association between immunisation and death was assessed adopting a case series design focusing on the risk periods 0–1, 0–7, and 0–14 days after immunisation. Among the 604 infants who died of SUD, 244 (40%) had received at least one vaccination. Four deaths occurred within two days from vaccination with the hexavalent vaccines (RR = 1.5; 95% CI 0.6 to 4.2). The RRs for the risk periods 0–7 and 0–14 were 2.0 (95% CI 1.2 to 3.5) and 1.5 (95% CI 0.9 to 2.4). The increased risk was limited to the first dose (RR = 2.2; 95% CI 1.1 to 4.4), whereas no increase was observed for the second and third doses combined. Conclusions The RRs of SUD for any vaccines and any risk periods, even when greater than 1, were almost an order of magnitude lower than the estimates in Germany. The limited increase in RRs found in Italy appears confined to the first dose and may be partly explained by a residual uncontrolled confounding effect of age

Tauroursodeoxycholic acid in patients with amyotrophic lateral sclerosis

Background: Amyotrophic 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. Methods: The 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. Conclusion: This 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 registration: ClinicalTrials.gov, identifier: NCT03800524

Studio osservazionale comparativo del profilo di sicurezza delle formulazioni di tiotropio

Introduzione. Le Linee Guida per il trattamento della Broncopneumopatia Cronica Ostruttiva (BPCO) prevedono l’utilizzo di farmaci broncodilatatori e, tra questi, degli anticolinergici a lunga durata d’azione. Il tiotropio è il farmaco maggiormente utilizzato e in Italia sono in commercio due device: Handihaler® (dal 2004) e Respimat® (dal 2011). Le evidenze disponibili negli ultimi anni hanno fatto nascere dubbi sul profilo di sicurezza della formulazione Respimat®. Le differenze tra le popolazioni che utilizzano il farmaco nella normale pratica clinica e quelle incluse nei trial clinici potrebbero spiegare i risultati contrastanti tra gli RCT e gli studi osservazionali. Per verificare il segnale di rischio di malattie cardiovascolari, cerebrovascolari e disturbi del ritmo cardiaco è stato condotto uno studio di coorte retrospettivo tra gli utilizzatori incidenti di tiotropio Handihaler® e Respimat® nel periodo 2011-2013, nelle Regioni Lombardia e Umbria. Metodi. Le coorti sono state identificate attraverso le prescrizioni farmaceutiche SSN, che comprende l’erogazione attraverso le farmacie, la distribuzione diretta e per conto. Le informazioni sulle comorbidità e sugli esiti clinici sono state ottenute dalle Schede di Dimissione Ospedaliera (SDO). Gli eventi sono rappresentati da un ricovero per infarto del miocardio e/o per disturbi del ritmo cardiaco nel periodo di esposizione corrente (definito, a partire dalla data di prescrizione, come somma delle DDD più 15 giorni). Ogni soggetto è stato seguito dalla prima prescrizione di tiotropio fino alla prima delle seguenti date: fine del periodo di esposizione; passaggio da una formulazione di tiotropio all’altra (switch); ricovero per uno degli eventi in studio nel periodo corrente; fine dello studio (31.12.2013). Risultati. Sono stati identificati 120.434 soggetti con prescrizione incidente di tiotropio (77% Handihaler® e 23% Respimat®), con un'età media di 73 anni e un rapporto uomini/donne di 1,3. I due gruppi presentavano percentuali diverse nella maggior parte delle comorbidità e dell'uso di farmaci; le patologie più frequenti sono risultate tumori, malattie respiratorie, scompenso cardiaco, malattie cerebrovascolari, diabete e ipertensione. Sono stati osservati 645 eventi durante 159.589 mesi di esposizione corrente di Handihaler® (incidenza: 4,0 per 1.000 mesi persona) e 152 eventi durante 42.965 mesi del Respimat® (incidenza: 6,5 per 1.000 mesi persona). L'hazard ratio, Respimat® vs Handihaler®, è risultato pari a 0,86 (IC 95%: 0,72-1,02). Conclusioni. Questo studio su una popolazione di grande dimensioni, consente di fornire un ulteriore contributo alla valutazione della sicurezza d'uso delle formulazioni di tiotropio