Post-marketing active surveillance of Guillain Barré Syndrome following COVID-19 vaccination in persons aged ≥12 years in Italy: A multi-database self-controlled case series study.

BACKGROUND: Recently published studies have reported association of COVID-19 vaccine ChAdOx1-S (Vaxzevria) with Guillain Barré Syndrome (GBS). Less is known about the safety of other COVID-19 vaccines with respect to GBS outcome. This study investigated the association of COVID-19 vaccines with GBS in more than 15 million persons aged ≥12 years in Italy. METHODS: Study population was all individuals aged ≥12 years who received at least one dose of COVID-19 vaccines, admitted to emergency care/hospital for GBS from 27 December 2020-30 September 2021 in Italy. Identification of GBS cases and receipt of at least one dose of mRNA-1273 (Elasomeran), BNT162b2 (Tozinameran), ChAdOx1-S (Vaxzevria) and Ad26.COV2.S (Janssen) through record linkage between regional health care and vaccination registries. Relative Incidence (RI) was estimated Self-controlled case series method adapted to event-dependent exposure using in the 42-day exposure risk period after each dose compared with other observation periods. RESULTS: Increased risk of GBS was found after first (RI = 6.83; 95% CI 2.14-21.85) and second dose (RI = 7.41; 2.35-23.38) of mRNA-1273 and first dose of ChAdOx1-S (RI = 6.52; 2.88-14.77). Analysis by age found an increased risk among those aged≥60 years after first (RI = 8.03; 2.08-31.03) and second dose (RI = 7.71; 2.38-24.97) of mRNA-1273. The first dose of ChAdOx1-S was associated with GBS in those aged 40-59 (RI = 4.50; 1.37-14.79) and in those aged ≥ 60 years (RI = 6.84; 2.56-18.28). CONCLUSIONS: mRNA-1273 and ChAdOx1-S vaccines were associated with an increased risk of GBS however this risk resulted in a small number of excess cases. Limitations were loss of GBS outpatient cases and imprecision of the estimates in the subgroup analysis due to a low number of events.

Postmarketing observational study on the safety of 2021/2022 and 2022/2023 influenza vaccination campaigns in Italy: TheShinISS-Vax|Flu study protocol.

INTRODUCTION: The purpose of TheShinISS-Vax|Flu study is to examine the association between influenza vaccines and adverse events requiring hospital admission or emergency care during the influenza vaccination campaigns 2021/2022 and 2022/2023 in Italy. METHODS AND ANALYSIS: This is a Self-Controlled Case Series multiregional study using linked routinely collected data from regional healthcare databases of the participating regions. Study participants will be persons aged ≥6 months, unvaccinated or who have received influenza vaccine during the influenza vaccination campaigns in the seasons 2021/2022 and 2022/2023 in Italy and who have experienced the outcome of interest for the first time during the study period (1 September 2021-30 June 2022 and 1 September 2022-30 June 2023 for the first and second vaccination campaigns, respectively). Risk periods will be specifically defined for each outcome and further subdivided into periods of 7 days. The exposures will be the first or second dose of the influenza vaccines administered during the two vaccination campaigns. Statistical analysis will be conducted separately for the data of the two campaigns. Exposure risk period will be compared with baseline risk period defined as any time of observation out of the risk periods. The modified SCCS method will be applied to handle event-dependent exposure and mortality and fitted using unbiased estimating equations to estimate relative incidences and excess of cases per 100 000 vaccinated by dose, age, sex and type of vaccine. Calendar period will be included as time-varying confounder in the model, where appropriate. ETHICS AND DISSEMINATION: The study received the approval from the National ethics committee for clinical trials of public research bodies and other national public institutions (PRE BIO CE n.0036723, 23/09/2022). Results will be published in peer-reviewed journals and reports in accordance with the publication policies of the Italian National Institute of Health and of the Italian Medicines Agency.

Postmarketing active surveillance of myocarditis and pericarditis following vaccination with COVID-19 mRNA vaccines in persons aged 12 to 39 years in Italy: A multi-database, self-controlled case series study.

BACKGROUND: Myocarditis and pericarditis following the Coronavirus Disease 2019 (COVID-19) mRNA vaccines administration have been reported, but their frequency is still uncertain in the younger population. This study investigated the association between Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) mRNA vaccines, BNT162b2, and mRNA-1273 and myocarditis/pericarditis in the population of vaccinated persons aged 12 to 39 years in Italy. METHODS AND FINDINGS: We 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 myocarditis/pericarditis between 27 December 2020 and 30 September 2021. Exposure risk period (0 to 21 days from the vaccination day, subdivided in 3 equal intervals) for first and second dose was compared with 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, age, sex, and vaccine product. Calendar period was included as time-varying confounder in the model. During the study period 2,861,809 persons aged 12 to 39 years received mRNA vaccines (2,405,759 BNT162b2; 456,050 mRNA-1273); 441 participants developed myocarditis/pericarditis (346 BNT162b2; 95 mRNA-1273). Within the 21-day risk interval, 114 myocarditis/pericarditis events occurred, the RI was 1.99 (1.30 to 3.05) after second dose of BNT162b2 and 2.22 (1.00 to 4.91) and 2.63 (1.21 to 5.71) after first and second dose of mRNA-1273. During the [0 to 7) days risk period, an increased risk of myocarditis/pericarditis was observed after first dose of mRNA-1273, with RI of 6.55 (2.73 to 15.72), and after second dose of BNT162b2 and mRNA-1273, with RIs of 3.39 (2.02 to 5.68) and 7.59 (3.26 to 17.65). The number of EC for second dose of mRNA-1273 was 5.5 per 100,000 vaccinated (3.0 to 7.9). The highest risk was observed in males, at [0 to 7) days after first and second dose of mRNA-1273 with RI of 12.28 (4.09 to 36.83) and RI of 11.91 (3.88 to 36.53); the number of EC after the second dose of mRNA-1273 was 8.8 (4.9 to 12.9). Among those aged 12 to 17 years, the RI was of 5.74 (1.52 to 21.72) after second dose of BNT162b2; for this age group, the number of events was insufficient for estimating RIs after mRNA-1273. Among those aged 18 to 29 years, the RIs were 7.58 (2.62 to 21.94) after first dose of mRNA-1273 and 4.02 (1.81 to 8.91) and 9.58 (3.32 to 27.58) after second dose of BNT162b2 and mRNA-1273; the numbers of EC were 3.4 (1.1 to 6.0) and 8.6 (4.4 to 12.6) after first and second dose of mRNA-1273. The main study limitations were that the outcome was not validated through review of clinical records, and there was an absence of information on the length of hospitalization and, thus, the severity of the outcome. CONCLUSIONS: This population-based study of about 3 millions of residents in Italy suggested that mRNA vaccines were associated with myocarditis/pericarditis in the population younger than 40 years. According to our results, increased risk of myocarditis/pericarditis was associated with the second dose of BNT162b2 and both doses of mRNA-1273. The highest risks were observed in males of 12 to 39 years and in males and females 18 to 29 years vaccinated with mRNA-1273. The public health implication of these findings should be considered in the light of the proven mRNA vaccine effectiveness in preventing serious COVID-19 disease and death.

Drugs and convalescent plasma therapy for COVID-19: a survey of the interventional clinical studies in Italy after 1 year of pandemic.

BACKGROUND: The 2019 novel coronavirus disease (COVID-19) pandemic has highlighted the importance of health research and fostered clinical research as never before. A huge number of clinical trials for potential COVID-19 interventions have been launched worldwide. Therefore, the effort of monitoring and characterizing the ongoing research portfolio of COVID-19 clinical trials has become crucial in order to fill evidence gaps that can arise, define research priorities and methodological issues, and eventually, formulate valuable recommendations for investigators and sponsors. The main purpose of the present work was to analyze the landscape of COVID-19 clinical research in Italy, by mapping and describing the characteristics of planned clinical trials investigating the role of drugs and convalescent plasma for treatment or prevention of COVID-19 disease. METHODS: During an 11-month period between May 2020 and April 2021, we performed a survey of the Italian COVID-19 clinical trials on therapeutic and prophylactic drugs and convalescent plasma. Clinical trials registered in the Italian Medicines Agency (AIFA) and ClinicalTrials.gov websites were regularly monitored. In the present paper, we report an analysis of study design characteristics and other trial features at 6 April 2021. RESULTS: Ninety-four clinical trials planned to be carried out in Italy were identified. Almost all of them (91%) had a therapeutic purpose; as for the study design, the majority of them adopted a parallel group (74%) and randomized (76%) design. Few of them were blinded (33%). Eight multiarm studies were identified, and two of them were multinational platform trials. Many therapeutic strategies were investigated, mostly following a drug repositioning therapeutic approach. CONCLUSIONS: Our study describes the characteristics of COVID-19 clinical trials planned to be carried out in Italy over about 1 year of pandemic emergency. High level quality clinical trials were identified, although some weaknesses in study design and replications of experimental interventions were observed, particularly in the early phase of the pandemic. Our findings provide a critical view of the clinical research strategies adopted for COVID-19 in Italy during the early phase of the pandemic. Further actions could include monitoring and follow-up of trial results and publications and focus on non-pharmacological research areas.

Effectiveness of an mRNA vaccine booster dose against SARS-CoV-2 infection and severe COVID-19 in persons aged ≥60 years and other high-risk groups during predominant circulation of the delta variant in Italy, 19 July to 12 December 2021.

BACKGROUND: Consolidated information on the effectiveness of COVID-19 booster vaccination in Europe are scarce. RESEARCH DESIGN AND METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.

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<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<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.

Risk of SARS-CoV-2 infection and subsequent hospital admission and death at different time intervals since first dose of COVID-19 vaccine administration, Italy, 27 December 2020 to mid-April 2021.

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.

An analysis of the strategic plan development processes of major public organisations funding health research in nine high-income countries worldwide.

BACKGROUND: There have been claims that health research is not satisfactorily addressing healthcare challenges. A specific area of concern is the adequacy of the mechanisms used to plan investments in health research. However, the way organisations within countries devise research agendas has not been systematically reviewed. This study seeks to understand the legal basis, the actors and the processes involved in setting research agendas in major public health research funding organisations. METHODS: We reviewed information relating to the formulation of strategic plans by 11 public funders in nine high-income countries worldwide. Information was collected from official websites and strategic plan documents in English, French, Italian and Spanish between January 2019 and December 2019, by means of a conceptual framework and information abstraction form. RESULTS: We found that the formulation of a strategic plan is a common and well-established practice in shaping research agendas across international settings. Most of the organisations studied are legally required to present a multi-year strategic plan. In some cases, legal provisions may set rules for actors and processes and may establish areas of research and/or types of research to be funded. Commonly, the decision-making process involves both internal and external stakeholders, with the latter being generally government officials and experts, and few examples of the participation of civil society. The process also varies across organisations depending on whether there is a formal requirement to align to strategic priorities developed by an overarching entity at national level. We also found that, while actors and their interactions were traceable, information, sources of information, criteria and the mechanisms/tools used to shape decisions were made less explicit. CONCLUSIONS: A complex picture emerges in which multiple interactive entities appear to shape research plans. Given the complexity of the influences of different parties and factors, the governance of the health research sector would benefit from a traceable and standardised knowledge-based process of health research strategic planning. This would provide an opportunity to demonstrate responsible budget stewardship and, more importantly, to make efforts to remain responsive to healthcare challenges, research gaps and opportunities.

Policies on Conflicts of Interest in Health Care Guideline Development: A Cross-Sectional Analysis.

OBJECTIVE: To assess whether organisations that develop health care guidelines have conflict of interest (COI) policies and to review the content of the available COI policies. METHODS: Survey and content analysis of COI policies available in English, French, Spanish, and Italian conducted between September 2014 and June 2015. A 24-item data abstraction instrument was created on the basis of guideline development standards. RESULTS: The survey identified 29 organisations from 19 countries that met the inclusion criteria. From these organisations, 19 policies were eligible for inclusion in the content analysis. Over one-third of the policies (7/19, 37%) did not report or did not clearly report whether disclosure was a prerequisite for membership of the guideline panel. Strategies for the prevention of COI such as divestment were mentioned by only two organisations. Only 21% of policies (4/19) used criteria to determine whether an interest constitutes a COI and to assess the severity of the risk imposed. CONCLUSIONS: The finding that some organisations, in contradiction of widely available standards, still do not have COI policies publicly available is concerning. Also troubling were the findings that some policies did not clearly report critical steps in obtaining, managing and communicating disclosure of relationships of interest. This in addition to the variability encountered in content and accessibility of COI policies may cause confusion and distrust among guideline users. It is in the interest of guideline users and developers to design an agreed-upon, comprehensive, clear, and accessible COI policy.

European Reference Networks and Guideline Development and Use: Challenges and Opportunities.

BACKGROUND: The Directive 2011/24/EU [OJEU 2011, L88/45] on the application of patient rights in cross-border health care requires the European Commission to support Member States in the development of European reference networks (ERNs). These ERNs are meant to ease the access of patients to highly specialized health care and to facilitate the cooperation at the European Union level in particular medical domains where expertise is scarce, especially in the rare disease area. METHODS: The Directive 2011/24/EU [OJEU 2011, L88/45] and the recent Commission Delegated Decision [OJEU 2014, L147/71] as well as the Implementing Decision [OJEU 2014, L147/79] require ERNs and health care providers wishing to join ERNs to have the capacity of developing good practices guidelines. RESULTS: This provision results in a number of challenges but also opportunities for Member States with respect to guideline production. Member States could consider the importance of devoting resources to build efficient systems and capacities for the development and implementation of trustworthy guidelines. Furthermore, they could adopt a cooperative approach to optimize guideline production across countries. Finally, they could promote the establishment of new research governance based on systematically identified research gaps and prioritized as well as communicated research recommendations. CONCLUSION: Member States are at a decisive point in establishing the details to ensure the transparent and effective functioning of ERNs. Producing explicit plans for the development and use of trustworthy guidelines should be an essential part of this effort.

[National Guidelines System: the Italian experience]. / Il Sistema nazionale linee guida italiano.

The Italian's experience of the guidelines development group is discussed through the evaluation of its ten years of activity. Focus is placed on the Italian guidelines working group organization and on the kind of documents developed. The horizontal architecture of the system and the several partnerships settled over time allowed the definition of a small coordinating group connected with a multitude of territorial stakeholders, such as scientific societies and local health units pertaining to the Italian National Health System. Different kinds of documents were produced, as adaptations of already existing guidelines elaborated by international institutions, short reviews addressing specific clinical issues and consensus conferences aimed at providing clinical governance on issues which lack on evidence. The steps needed to produce a high quality guideline are presented, considering and comparing all the different international experiences, to define and discuss a common and well-structured methodology, and to face the ethical and epistemological implications of each method. The multidisciplinary of the working groups, the importance of the active surveillance on conflicts of interests, the definition of a minimum set of rules to be followed during the whole activity and the transparency of all the steps are the milestones of the Italian experience. The lack of a continuous and stable source of funding and the subsequent instability of the central structure are endangering all the knowledge and the experience gained during these years of activity. It is therefore crucial to guarantee and safeguard the role of a national, independent and public institution in the supervision of the guidelines development process and the provision of clinical governance.

Italian guidelines for noninvasive imaging assessment of focal liver lesions: development and conclusions.

OBJECTIVES: To develop guidelines for the noninvasive imaging assessment of focal liver lesions comparing different imaging modalities focused on (i) evaluating the imaging techniques in terms of (a) diagnostic accuracy; (b) role in the management of oncologic patients; (c) follow-up of benign lesions; and (ii) developing standard procedure for their use in patients with focal liver lesions that require targeted diagnostic characterization. METHODS: An explicit search strategy was used to conduct a systematic review of the literature in the English language from January 2000 to October 2007; the search covered PubMed, Embase, Pascal, SciSearch, and Cochrane Library databases. A panel of experts evaluated the selected studies and conveyed their view. RESULTS: The online search yielded 4960 titles and abstracts from which 176 studies were considered suitable for the final adherence-to-guidelines topic evaluation. An evidence grading system was not used as the guideline topic and the heterogeneity of the collected data did not fit with the currently used hierarchy of evidence. A panel of experts formulated several recommendations with grade and level which were expressed narratively and nonschematically. CONCLUSION: The recommendations reported in the study are based on an extensive literature evaluation and were developed by considering the appropriateness of the choice of the imaging techniques while noninvasively detecting and characterizing focal liver lesions.

Graft selection in arthroscopic anterior cruciate ligament reconstruction.

BACKGROUND: anterior cruciate ligament (ACL) surgical reconstruction is performed with the use of an autogenic, allogenic or synthetic graft. The document issued by the Italian National Guidelines System (SNLG, Sistema Nazionale Linee Guida) at the National Institute of Health aims to guide orthopaedic surgeons in selecting the optimal graft for ACL reconstruction using an evidence-based approach. MATERIALS AND METHODS: A monodisciplinary panel was formed to define a restricted number of clinical questions, develop specific search strategies and critically appraise the literature using the grading of recommendations assessment, development, and evaluation (GRADE) method. The final draft was shared by the panel and then sent to four external referees to assess its readability and clarity, its clinical relevance and the feasibility of recommendations. RESULTS: autograft shows moderate superiority compared with allograft, in relation to the relevant outcomes and the quality of selected evidence, after an appropriate risk-benefit assessment. Allograft shows higher failure rate and higher risk of infection. The panel recommends use of autografts; patellar tendon should be the first choice, due to its higher stability, while use of hamstring is indicated for subjects for whom knee pain can represent a particular problem (e.g., some categories of workers). CONCLUSIONS: autograft shows better performance compared with allograft and no significant heterogeneity in relation to relevant outcomes. The GRADE method allowed collation of all the information needed to draw up the recommendations, and to highlight the core points for discussion.

[Issues about the implementation of the guideline <>]. / Problemi di implementazione della linea guida <>.

OBJECTIVE: to assess the feasibility in clinical practice of the recommendations included in the guideline <>. STUDY DESIGN: a prevalence study on clinical behaviour concerning drug prescription and hospitalization. Behaviours will be reassessed after a short follow-up (5 days). SETTING AND PARTICIPANTS: general practitioners and paediatricians have been enrolled, who will refer about the clinical behaviours adopted toward a series of consecutively enrolled patients with influenza-like syndrome. MAIN OUTCOMES MEASURES: compliance to the recommendations has been assessed, through the proportion of patients prescribed antibiotics, and anti-inflammatory/antipyretic and antiviral drugs. The use of diagnostic tests and the number of hospitalizations have been also assessed. RESULTS: clinicians, according to the recommendations included in the guideline, rarely use antiviral drugs and quick diagnostic tests, and mainly prescribe paracetamol for the treatment of pain and fever. On the other hand, they still prescribe antibiotics to more than 30% of patients on the basis of reasons not discussed in the guideline, and sometimes sustainable, even if they are not recommended. The lack of effectiveness of the recommendation concerning the use of antibiotics in guiding clinicians' behaviour, emerges particularly in two specific scenarios: the presence of comorbidities in elderly patients and the persistency of fever in children. CONCLUSIONS: the use of antibiotics in course of influenza-like syndrome is not necessarily inappropriate, and should be further investigated. Some specific characteristics shown by patients are relevant for frequency and severity, and could be interpreted as effect modifiers. Therefore recommendations should take into consideration such subgroups.

Italian evidence-based guidelines for the management of influenza-like syndrome in adults and children.

Specific clinical practice recommendations for the management of influenza like-illness were developed by a national multidisciplinary panel (Guideline Development Group, GDG), and included in the update of the evidence-based clinical practice guideline: "Management of influenza-like syndrome" issued by the Italian National Guidelines System (SNLG May 2008). The methodological process included: creation of a GDG, definition of key questions, search strategies, critical appraisal of the selected studies, development and grading of recommendations. Eight clinical questions were defined regarding: rapid tests for influenza, treatment, and hospitalization criteria. Eighty studies underwent critical appraisal. The GDG develops recommendations for each key question.

The Italian guidelines for early intervention in schizophrenia: development and conclusions.

AIM: The effectiveness of early intervention in schizophrenia is still under discussion. The guidelines described in the present paper were aimed at contributing to the current debate by providing Italian practitioners, families, patients and health managers with evidence-based information on early intervention. They also examined the diagnostic tools that are currently available for assessing different stages of psychotic disorders. METHODS: A multidisciplinary panel of experts (the Guidelines Development Group) used a set of key-questions to develop an explicit search strategy to conduct a systematic review of the literature published from January 2000 to June 2006. Trained personnel then selected papers from those yielded by the literature search. The Guidelines Development Group's final recommendations were scaled according to the Italian National Guidelines System grading system. RESULTS: The evidence available up to the time of the literature search does not allow for recommendation of early intervention targeting prodromal or at-risk patients to prevent progression from the prodromal phase to acute, full-blown psychosis, nor to improve prognosis. Conversely, identification and timely treatment of first-episode psychotic patients through specific early intervention programmes are highly recommended. CONCLUSIONS: The Italian Guidelines on early intervention in schizophrenia are based on a comprehensive assessment of an updated, large-scale body of literature. They draw specific, evidence-based conclusions to assist clinicians and stakeholders in the planning and implementation of appropriate intervention programmes. Further research is needed to ascertain the effectiveness of early intervention in delaying or preventing the conversion to psychosis and improving prognosis in prodromal or at-risk patients. Further investigation is also required for first-episode and critical period patients.

Euthanasia of companion animals: a legal and ethical analysis.

In Italy, the conditions under which euthanasia of small pets is justified are only partially regulated by law n. 281/1991, article 2 n. 6 and 9, by the later Ministry Circular n. 9 made on 10/03/1992 and by law n. 189/2004. Law n. 281/1991, besides delegating the job of birth control in cat and dog populations to the regions, has made it statutory that stray dogs may only be euthanised when they are 'seriously or incurably ill or proven to be dangerous'. The Ministry Circular underlines the fact that 'euthanasia of dogs is prohibited except in special justified cases'. On the other hand, due to the legal classification of animals as property, the owner has the right of ownership over his animal so that he can sell it and kill it (ius vitae ac necis). In this view a request for euthanasia is licit, whatever the animal's state of health may be. The authors feel that further legislation to regulate the question more completely would be opportune and thus they analyse the problems of legal-ethics and public health that a veterinarian faces when carrying out euthanasia, also bearing in mind the laws and codes of professional ethics. They suggest possible solutions which could be adopted by the competent authorities.