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Background: In 2005 the Italian Medicines Agency (AIFA) started a program on independent research on drugs, with the aim to promote clinical research in areas of limited commercial interest. For 3 years (2005-2007) an area of the program was reserved to studies in the field of rare diseases. There is a concern that public funding of research may be wasted. We investigated the outcome of the program., Methods: We conducted a cohort study on the projects that were funded by the AIFA in the area of rare diseases. The outcomes were the proportion of published studies, time to publication, impact factor of the publishing journals and relevance for clinical practice. We retrieved published articles through a literature search in peer reviewed biomedical journals indexed by Pubmed. We used the Kaplan-Meier method to estimate the cumulative probability of publication by time from project starting to publication., Results: During the period 2005-2007, 62 projects were funded in the area of rare diseases. Most of the studies (n 39; 63%) had a randomized design and in 22 (35%) the control group received an active treatment. For 39 studies (63%) we retrieved a publication in a peer reviewed journal. The median time to publication was 74 months and, at the maximum period of follow up (109 months), the cumulative probability of publication reached 77%. The median impact factor was 5.4 (range 1.4-52.4). Considering the clinical relevance, more than 30% of the published articles presented conclusive findings; an additional 10% of the studies reached potential breakthrough findings., Conclusions: Even though it takes time to set up and conduct a funding program for independent research on drugs, the results are highly rewarding. Independent funding is crucial in supporting studies aimed at answering questions that are relevant for clinical practice despite the lack of sufficient commercial interest.

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.

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 minimum spanning tree (MST) model was applied to identify the history of transmission of hepatitis C virus (HCV) infection in an outbreak involving five children attending a pediatric oncology-hematology outpatient ward between 1992 and 2000. We collected blood samples from all children attending since 1992, all household contacts, and one health care worker positive for antibody to HCV (anti-HCV). HCV RNA detection was performed with these samples and with smears of routinely collected bone marrow samples. For all isolates, we performed sequence analysis and phylogenetic tree analysis of hypervariable region 1 of the E2 gene. The MST model was applied to clinical-epidemiological and molecular data. No additional cases were detected. All children, but not the health care worker, showed genotype 3a. On six occasions, all but one child had shared the medication room with another patient who later seroconverted. HCV RNA detection in bone marrow smears revealed, in some cases, a delay of several months in anti-HCV responses. Sequence analysis and phylogenetic tree analysis revealed a high identity among the isolates. The MST model applied to molecular data, together with the clinical-epidemiological data, allowed us to identify the source of the outbreak and the most probable patient-to-patient chain of transmission. The management of central venous catheters was suspected to be the probable route of transmission. In conclusion, the MST model, supported by an exhaustive clinical-epidemiological investigation, appears to be a useful tool in tracing the history of transmission in outbreaks of HCV infection.

Background/aims: To evaluate the strength of association between parenterally transmitted viral hepatitis and specific types of invasive procedures., Methods: Data from the surveillance system for type-specific acute viral hepatitis (SEIEVA) during the period 1994-1999 were used. The association of acute hepatitis B virus (HBV) and hepatitis C virus (HCV) infection with the potential risk factors (odds ratios (OR)) was estimated comparing 3120 hepatitis B and 1023 hepatitis C cases with 7158 hepatitis A cases, used as controls, by multiple logistic regression analysis., Results: Most procedures resulted in being associated with the risk of acquiring acute HBV or HCV. The strongest associations were: for HBV infection, abdominal surgery (adjusted OR = 3.9; 95% confidence intervals (CI) = 2.0-7.5), oral surgery (OR = 2.7; 95% CI = 1.6-4.5) and gynaecological surgery (OR = 2.6; 95% CI = 1.2-5.5); for HCV infection, obstetric/gynaecological interventions (OR = 12.1; 95% CI = 5.6-26.3), abdominal surgery (OR = 7.0; 95% CI = 3.2-14.9) and ophthalmological surgery (OR = 5.2; 95% CI = 1.1-23.2). Biopsy and/or endoscopy were associated with HCV, but not with HBV infection., Conclusions: Invasive procedures represent an important mode of HBV and HCV transmission. Since a large proportion of the adult general population is exposed to these procedures and an effective HCV vaccine is not yet available, non-immunological means of controlling iatrogenic modes of transmission are extremely important.

In Italy, improved sanitation and living conditions have led to a decline in the rate of hepatitis A infection among children generating an increasing proportion of adults susceptible to this virus. Shellfish consumption is a major source of infection while person to person transmission is important in the spread of infection and in the maintenance of outbreaks. Thus prevention of secondary HAV infection is a crucial point. A randomised controlled trial of hepatitis A vaccine in household contacts of people with sporadic HAV infection in Italy has shown a protective efficacy of 82% (CI 20-96%). The two secondary infections in the vaccine group were symptomless, suggesting that the disease expression may be weaker in vaccinated subjects.

Background: Hepatitis A vaccination stops outbreaks of hepatitis A infection, but its efficacy against infection after exposure has not been proven. We investigated the use of hepatitis A vaccine to prevent secondary infections with hepatitis A virus (HAV)., Methods: We did a randomised controlled trial of hepatitis A vaccine in household contacts of people with sporadic HAV infection (index cases). Households (index cases and contacts) were randomly assigned to the vaccine group or unvaccinated group, according to the study week in which they were enrolled. All household contacts in the vaccine group received vaccination at the time of entry to the study., Findings: During 45 days of follow-up, secondary infection had occurred in ten (13.3%) of 75 households (two families had two cases each) in the untreated group and in two (2.8%) of 71 households in the vaccine group. The protective efficacy of the vaccine was 79% (95% CI 7-95). The number of secondary infections among household contacts was 12 (5.8%) of 207 in the unvaccinated group and two (1.0%) of 197 in the vaccinated group. Therefore, 18 individuals needed to be vaccinated to prevent one secondary infection., Interpretation: Hepatitis A vaccine is effective in the prevention of secondary infection of HAV and should be recommended for household contacts of primary cases of HAV infection.

In 1996, the vaccination coverage against hepatitis B virus among 3,157 healthcare workers in Italy was inversely related to the level of hepatitis B virus endemicity in the area of residence. Youngest age and lowest years of employment were independent predictors of the likelihood of vaccine acceptance.

The sexual transmission of hepatitis C virus (HCV) has long been debated. The prevalence of infected at-risk partners varies from 0% to 30%. In a prospective study, the risk of infection was quantified in steady heterosexual partners and the prophylactic effect of normal human polyvalent immune serum globulin (ISG) was evaluated. A total of 899 at-risk partners of HCV-infected patients were enrolled in a single-blind randomized controlled trial and assigned to receive every 2 month 4 mL of intramuscular ISG from unscreened donors (450 partners) or placebo (499 partners). Seven partners developed acute HCV infection (increased aminotransferase levels and appearance of HCV-RNA): six of the placebo group (incidence density [ID] 12.00/1,000 person year; 95% confidence interval [CI] 3.0 to 21.61), and only one of the ISG-treated group (ID 1.98/1,000 person year; 95% CI 0 to 5.86). The risk of infection was significantly higher in controls versus treated individuals (p = 0.03). Six couples had genotype 1b (85%), and one couple had genotype 1a; HCV sequence homology strongly supported sexual transmission. Our trial demonstrates that HCV infection can be sexually transmitted and quantifies the risk of sexual transmission: for every year of at-risk sexual relationship, almost 1% of the partners became infected. Intramuscular ISG is safe and well tolerated. Unlike ISG from screened donors, ISG from donors unscreened for anti-HCV contains high titers of anti-gpE1/gpE2 neutralizing antibodies and high neutralizing activity. Anti-HCV hyperimmune globulin could be prepared from anti-HCV-positive blood units and could be used to protect sexual partners and in other at-risk situations of exposure to HCV infection.

The ongoing vaccination campaign against hepatitis B (HB) for newborns of hepatitis B surface antigen (HBsAg) positive mothers and for 12-year-old subjects was evaluated in Naples, Italy, an area of relatively high HB endemicity. Subjects were recruited by a random sampling procedure. Among 2060 pregnant women studied, 1887 (91.6%) were screened for HBsAg. HBsAg prevalence was 2.5% (47/1887). Immunoprophylaxis according to the protocol (immunoglobulins within 24 h plus vaccine within 7 days after birth) was administered in 26 (55.3%) out of the 47 newborns of HBsAg positive mothers; vaccination was delayed (later than 7 days after birth) for 14 (29.8%) infants; in the remaining seven newborns (14.9%) were not given immunoglobulins at birth. All infants were vaccinated. Out of the 1000 adolescents sampled 130 (13%) were not found due to an inaccurate census list; 727 (83.3%) of the 870 investigated had received a three-dose HB vaccine series. Overall, the HB vaccination program in Italy is working well. However, further efforts should be made to improve the efficacy and effectiveness of the campaign.

An increased incidence of hepatitis A was observed in Naples from 1990-1991. A hospital-based case-control study was carried out to evaluate the relative importance of various risk factors. A hundred and ninety-eight cases and 238 hospital controls were recruited during the study period. The strongest association was contact with a jaundiced person among children. A correlation was also shown for children and adults with raw shellfish consumption and pre-school nursery attendance or presence in the household of children attending pre-school nurseries. History of travel and intravenous drug use were risk factors for adult subjects. Considering the relative importance of the specific risk factors we found that 38% of the acute hepatitis A cases were attributable to contact with a jaundiced person, 15% to presence in the household of children attending pre-school nurseries and 28% to raw shellfish consumption.

A case-control study was carried out comparing 333 case subjects with non-A, non-B hepatitis and 1095 hospital control subjects. Of 333 case subjects, 197 (59%) were positive for hepatitis C antibody (anti-HCV). Excluding blood transfusion and intravenous drug use, surgical intervention and dental therapy were strongly associated with anti-HCV-positive cases: in particular, obstetric and gynecology surgical intervention was found to be strongly associated with HCV positivity (odds ratio [OR] = 32; 95% confidence interval [CI] = 7, 147). Raw shellfish consumption was a risk factor for anti-HCV-negative cases (OR = 2.2; 95% CI = 1.0, 5.1), thus suggesting an enterically transmitted virus in sporadic non-A, non-B hepatitis in Italy.

We studied annual human immunodeficiency virus (HIV) seroprevalence and incidence in a large number of intravenous drug users attending drug treatment centers in three Italian urban areas. We also evaluated risk factors for HIV seropositivity and for HIV seroconversion. The results showed that HIV prevalence and incidence are declining. HIV prevalence declined dramatically in study participants that were < 25 years old. Prevalent HIV cases were associated with older age and longer duration of intravenous drug use; however, short duration of drug use increased the risk of seroconversion. The findings of our study suggest that comparing cross-sectional and longitudinal data contributes to a better understanding of the dynamics of the HIV epidemic among intravenous drug users.

The objectives of the present report were to give a baseline picture of hepatitis B notification incidence rates in children before the campaign of mass vaccination for newborns and adolescents (12-13 years old), and to study the role of different risk factors. Data from a specific national surveillance system of acute viral hepatitis (SEIEVA, Sistema Epidemiologico Integrato dell'Epatite Virale Acuta) were used and acute hepatitis B cases were compared to acute hepatitis A patients with the case-control study method to estimate the associations with the considered risk factors. Since the system began, one hundred and sixty-three local health departments have joined SEIEVA covering 30% of the Italian population. The incidence of acute hepatitis B notifications among 0-14 aged children was 9 per 100,000 in 1985 and 1 per 100,000 in 1990. Such decline in incidence was observed in both the North and the South of Italy. Surgical interventions, dental therapy and household contacts with a HBsAg chronic carrier were found to be associated with acute hepatitis B. The point estimate of the odds ratio was 10 for the latter risk factor. Other preventive measures in addition to vaccination are needed to control the risk of hepatitis B infection and other parenteral diseases due to surgical intervention and dental therapy.

The availability of a National Register of congenital hypothyroid infants allowed to perform descriptive studies on characteristics of the cases and the efficiency of the neonatal screening. Continuous and exhaustive recording of data concerning congenital hypothyroidism cases provided valuable epidemiological informations about congenital hypothyroidism in Italy. Moreover, the National Register allowed to develop a network of collaboration which can promote a population based case-control study. As the etiopathogenesis of congenital hypothyroidism has not been completely elucidated, performing of a case-control study can contribute to evidence the most important risk factors of congenital hypothyroidism and to improve the prevention also by prenatal diagnosis of this disease. Screening centers will be involved in the study and questionnaires of the National Register for congenital hypothyroidism will be used to record case and control informations. A biological bank concerning cases, controls and their parents, will be organized.

The National Type Specific Hepatitis Surveillance System (SEIEVA) and seroepidemiological studies have shown that in addition to newborns from mothers who are carriers for hepatitis B surface antigen (HBsAg), adolescents are at high risk of acquiring type B hepatitis virus because of increasing importance of the heterosexual transmission of this virus. In order to evaluate logistic problems and acceptance rate of adolescents to mass vaccination against hepatitis B, a pilot study was carried out among all 7th grade children registered in the 9 schools of an hepatitis B endemic area located in the suburbs of Naples. After meetings held by the local health department with school teachers and parents, 1219 out of 1250 (97.5%) invited children received the first dose of hepatitis B vaccine; 1215 and 1209 received, respectively, the second and third doses. Anti-hepatitis B surface antigen (anti-HBs) values were studied in 406 subjects one month after the third dose, and 21 out of 406 (5.2%) had anti-HBs values less than 10 IU/L. We consider 95% of subjects with anti-HBs values greater than 9 IU/L a good achievement for a field vaccination program. The high acceptance rate of vaccination found in our study outlines the importance of active offer of vaccination combined with school involvement.

The association between hepatitis A and domestic or international travel from Italy was investigated. Data from a nationwide surveillance system (SEIEVA) for type-specific acute viral hepatitis were used to compare 1102 hepatitis A cases with 3671 hepatitis B cases. An association between hepatitis A and travel was found in northern Italy, where most young and adult people are susceptible. Estimates of odds ratios vary dramatically according to geographical area of travel. Travellers to Mediterranean countries, Eastern Europe, Africa, Asia, and South and Central America had the highest education and age-adjusted odds ratios for hepatitis A, ranging from 6 to 25. Prophylaxis against hepatitis A for such travellers is recommended.

A specific surveillance system for acute viral hepatitis which uses weekly notification of cases and a standard risk factor questionnaire was started in Italy in 1984. From 1985 to 1988 153 Health Departments (27% of Italian population) joined the system. Estimated incidence of reported viral hepatitis was 30 per 100,000 in 1985 and 14 in 1988. The decline was impressive for hepatitis A, particularly in the south. Reduction of incidence was also evident for hepatitis B and Non-A, Non-B hepatitis, particularly in young adults. The decrease of viral hepatitis in Italy is consistent with recent seroepidemiological data. Shellfish consumption was the most frequent risk factor reported for hepatitis A cases at all ages. Hospitalization, surgical intervention, dental therapy and other percutaneous exposures still play a role in the transmission of parenteral hepatitis in Italy. Blood transfusions seem to be important only for Non-A, Non-B. Interventions other than vaccination to prevent B and Non-A, Non-B hepatitis due to hospitalization, surgical intervention, other percutaneous exposures and dental therapy are needed and can further contribute to the decline of hepatitis virus infection rates in Italy.

A village outbreak of 38 cases of serologically confirmed hepatitis A is described. The epidemic curve was a propagative one and all of the cases occurred in primary school-age or pre-school children. In 1984 the incidence in this age group was 5,000 per 100,000, about 50 times the corresponding national rate. Although 21 of the cases attended the single primary school, these cases were not clustered within school years or classes and examination of onset dates showed only four cases could have resulted from case transmission within classes. A matched triplet case-control study was undertaken to measure the risk associated with prior contact with a case within the acquaintance network and the risk of household contact with either of the two pre-school nurseries where inapparent transmission may have been occurring. Whereas a similar proportion of cases and controls had direct or indirect contact with the nurseries, 48% of cases, compared with 9% of controls, reported a previous case of jaundice within 6 weeks amongst their acquaintance network (matched triplet analysis P less than .0001).