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2.  Risk of Guillain-Barré syndrome after 2010–2011 influenza vaccination 
European Journal of Epidemiology  2013;28(5):433-444.
Influenza vaccination has been implicated in Guillain Barré Syndrome (GBS) although the evidence for this link is controversial. A case–control study was conducted between October 2010 and May 2011 in seven Italian Regions to explore the relation between influenza vaccination and GBS. The study included 176 GBS incident cases aged ≥18 years from 86 neurological centers. Controls were selected among patients admitted for acute conditions to the Emergency Department of the same hospital as cases. Each control was matched to a case by sex, age, Region and admission date. Two different analyses were conducted: a matched case–control analysis and a self-controlled case series analysis (SCCS). Case–control analysis included 140 cases matched to 308 controls. The adjusted matched odds ratio (OR) for GBS occurrence within 6 weeks after influenza vaccination was 3.8 (95 % CI: 1.3, 10.5). A much stronger association with gastrointestinal infections (OR = 23.8; 95 % CI 7.3, 77.6) and influenza-like illness or upper respiratory tract infections (OR = 11.5; 95 % CI 5.6, 23.5) was highlighted. The SCCS analysis included all 176 GBS cases. Influenza vaccination was associated with GBS, with a relative risk of 2.1 (95 % CI 1.1, 3.9). According to these results the attributable risk in adults ranges from two to five GBS cases per 1,000,000 vaccinations.
PMCID: PMC3672511  PMID: 23543123
Influenza vaccination; Guillain-Barrè Syndrome; Case–control study; Self controlled case series
3.  Huangqi Injection (a Traditional Chinese Patent Medicine) for Chronic Heart Failure: A Systematic Review 
PLoS ONE  2011;6(5):e19604.
Chronic heart failure (CHF) is a global public health problem. Therefore, novel and effective drugs that show few side-effects are needed. Early literature studies indicated that Huangqi injection is one of the most commonly used traditional Chinese patent medicines for CHF in China. As a large number of clinical studies has been carried out and published, it is essential to evaluate the effectiveness and safety of Huangqi injection. Therefore, we carried out this systematic review under the support of the framework of the Joint Sino-Italian Laboratory (JoSIL).
To evaluate the efficacy and safety of Huangqi injection for CHF according to the available scientific knowledge.
An extensive search including PubMed, EMBASE, CBM, the Cochrane Library and Chinese literature databases was performed up to July 2008. Clinical trials regarding Huangqi injection for the treatment of CHF were searched for, irrespective of languages. The quality of each trial was assessed according to the Cochrane Reviewers' Handbook 5.0, and RevMan 5.0 provided by the Cochrane Collaboration and STATA 9.2 were used for data analysis.
After selection of 1,205 articles, 62 RCTs and quasi-RCTs conducted in China and published in Chinese journals were included in the review. The methodological quality of the trials was low. In most trials inclusion and exclusion criteria were not specified. Furthermore, only one study evaluated the outcomes for drug efficacy after an adequate period of time. For these reasons and because of the different baseline characteristics we did not conduct a meta-analysis.
Although available studies are not adequate to draw a conclusion on the efficacy and safety of Huangqi injection (a traditional Chinese patent medicine), we hope that our work could provide useful experience on further studies on Huangqi injections. The overall level of TCM clinical research needs to be improved so that the efficacy of TCM can be evaluated by the international community and possibly some TCM can enter into the international market.
PMCID: PMC3089614  PMID: 21573109
4.  Sudden Unexpected Deaths and Vaccinations during the First Two Years of Life in Italy: A Case Series Study 
PLoS ONE  2011;6(1):e16363.
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.
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.
PMCID: PMC3027668  PMID: 21298113
5.  Use of Whole-Blood Samples in In-House Bulk and Single-Cell Antigen-Specific Gamma Interferon Assays for Surveillance of Mycobacterium tuberculosis Infections▿  
Tests based on the gamma interferon (IFN-γ) assay (IGA) are used as adjunctive tools for the diagnosis of Mycobacterium tuberculosis infection. Here we compared in-house and commercial whole-blood IGAs to identify a suitable assay for the surveillance of tuberculosis in population studies. The IGAs were selected on the basis of the ease with which they are performed and because they require a small amount of a biological sample and do not require cell purification. Since a “gold standard” for latently M. tuberculosis-infected individuals is not available, the sensitivities and the specificities of the IGAs were determined with samples from patients with clinically diagnosed active tuberculosis and in Mycobacterium bovis BCG-unvaccinated healthy controls. The in-house tests consisted of a bulk assay based on diluted whole blood and a single-cell assay based on IFN-γ intracellular staining. The commercial assays used were the QuantiFERON-TB-Gold (Q-TB) and the Q-TB in-tube tests. When the purified protein derivative was used as the antigen, in-house whole-blood intracellular staining was found to be highly discriminatory between active tuberculosis patients and BCG-vaccinated healthy controls, whereas the other IGAs did not discriminate between the two categories of patients. When M. tuberculosis-specific antigens were used, a very strong agreement between the results of the Q-TB in-tube assay and the clinical diagnosis was observed, while the Q-TB assay, performed according to the manufacturer's instructions, showed a significantly lower performance. Intriguingly, when the test was performed with RD1 proteins instead of peptides, its sensitivity was significantly increased. The in-house assay with diluted whole blood showed an elevated sensitivity and an elevated specificity, and the results agreed with the clinical diagnosis. Considering that the in-house assay uses 1/20 of the sample compared with the amount of sample used in the commercial IGA, it appears to be particularly promising for use in pediatric studies. Overall, the different assays showed different performance characteristics that need to be considered for surveillance of tuberculosis in population studies.
PMCID: PMC2238051  PMID: 18032595
6.  Mitigation Measures for Pandemic Influenza in Italy: An Individual Based Model Considering Different Scenarios 
PLoS ONE  2008;3(3):e1790.
Individual-based models can provide the most reliable estimates of the spread of infectious diseases. In the present study, we evaluated the diffusion of pandemic influenza in Italy and the impact of various control measures, coupling a global SEIR model for importation of cases with an individual based model (IBM) describing the Italian epidemic.
Methodology/Principal Findings
We co-located the Italian population (57 million inhabitants) to households, schools and workplaces and we assigned travel destinations to match the 2001 census data. We considered different R0 values (1.4; 1.7; 2), evaluating the impact of control measures (vaccination, antiviral prophylaxis -AVP-, international air travel restrictions and increased social distancing). The administration of two vaccine doses was considered, assuming that first dose would be administered 1-6 months after the first world case, and different values for vaccine effectiveness (VE). With no interventions, importation would occur 37–77 days after the first world case. Air travel restrictions would delay the importation of the pandemic by 7–37 days. With an R0 of 1.4 or 1.7, the use of combined measures would reduce clinical attack rates (AR) from 21–31% to 0.3–4%. Assuming an R0 of 2, the AR would decrease from 38% to 8%, yet only if vaccination were started within 2 months of the first world case, in combination with a 90% reduction in international air traffic, closure of schools/workplaces for 4 weeks and AVP of household and school/work close contacts of clinical cases. Varying VE would not substantially affect the results.
This IBM, which is based on country-specific demographic data, could be suitable for the real-time evaluation of measures to be undertaken in the event of the emergence of a new pandemic influenza virus. All preventive measures considered should be implemented to mitigate the pandemic.
PMCID: PMC2258437  PMID: 18335060
7.  Social Contacts and Mixing Patterns Relevant to the Spread of Infectious Diseases 
PLoS Medicine  2008;5(3):e74.
Mathematical modelling of infectious diseases transmitted by the respiratory or close-contact route (e.g., pandemic influenza) is increasingly being used to determine the impact of possible interventions. Although mixing patterns are known to be crucial determinants for model outcome, researchers often rely on a priori contact assumptions with little or no empirical basis. We conducted a population-based prospective survey of mixing patterns in eight European countries using a common paper-diary methodology.
Methods and Findings
7,290 participants recorded characteristics of 97,904 contacts with different individuals during one day, including age, sex, location, duration, frequency, and occurrence of physical contact. We found that mixing patterns and contact characteristics were remarkably similar across different European countries. Contact patterns were highly assortative with age: schoolchildren and young adults in particular tended to mix with people of the same age. Contacts lasting at least one hour or occurring on a daily basis mostly involved physical contact, while short duration and infrequent contacts tended to be nonphysical. Contacts at home, school, or leisure were more likely to be physical than contacts at the workplace or while travelling. Preliminary modelling indicates that 5- to 19-year-olds are expected to suffer the highest incidence during the initial epidemic phase of an emerging infection transmitted through social contacts measured here when the population is completely susceptible.
To our knowledge, our study provides the first large-scale quantitative approach to contact patterns relevant for infections transmitted by the respiratory or close-contact route, and the results should lead to improved parameterisation of mathematical models used to design control strategies.
Surveying 7,290 participants in eight European countries, Joël Mossong and colleagues determine patterns of person-to-person contact relevant to controlling pathogens spread by respiratory or close-contact routes.
Editors' Summary
To understand and predict the impact of infectious disease, researchers often develop mathematical models. These computer simulations of hypothetical scenarios help policymakers and others to anticipate possible patterns and consequences of the emergence of diseases, and to develop interventions to curb disease spread. Whether to prepare for an outbreak of infectious disease or to control an existing outbreak, models can help researchers and policy makers decide how to intervene. For example, they may decide to develop or stockpile vaccines or antibiotics, fund vaccination or screening programs, or mount health promotion campaigns to help citizens minimize their exposure to the infectious agent (e.g., handwashing, travel restrictions, or school closures).
Respiratory infections, including the common cold, flu, and pneumonia, are some of the most prevalent infections in the world. Much work has gone into modeling how many people would be affected by respiratory diseases under various conditions and what can be done to limit the consequences.
Why Was This Study Done?
Mathematical models have tended to use contact rates (the number of other people that a person encounters per day) as one of their main elements in predicting the outcomes of epidemics. In the past, contact rates were not based on direct observations, but were assumed to follow a certain pattern and calibrated against other indirect data sources such as serological or case notification data. This study aimed to estimate contact rates directly by asking people who they have met during the course of one day. This allowed the researchers to study in more detail different patterns of contacts, such as those between different groups of people (such as age groups) and in different social settings. This is particularly important for respiratory diseases, which are spread through the air and by close contact with an infected individual or surface.
What Did the Researchers Do and Find?
The researchers wanted to examine the social contacts that people have in order to better understand how respiratory infections might spread. They recruited 7,290 people from eight European countries (Belgium, Germany, Finland, Great Britain, Italy, Luxembourg, The Netherlands, and Poland) to participate in their study. They asked the participants to fill out a diary that documented their physical and nonphysical contacts for a single day. Physical contacts included interactions such as a kiss or a handshake. Nonphysical contacts were situations such as a two-way conversation without skin-to-skin contact. Participants detailed the location and duration of each contact. Diaries also contained basic demographic information about the participant and the contact.
They found that these 7,290 participants had 97,904 contacts during the study, which averaged to 13.4 contacts per day per person. There was a great deal of diversity among the contacts, which challenges the idea that contact rates alone provide a complete picture of transmission dynamics. The researchers identified varied types of contacts, duration of contacts, and mixing patterns. For example, children had more contacts than adults, and those living in larger households had more contacts. Weekdays resulted in more daily contacts than Sundays. More intense contacts (of longer duration or more frequent) tended to be physical. Approximately 70% of contacts made on a daily basis lasted longer than an hour, whereas three-quarters of contacts with people who were not previously known lasted less than 15 minutes. While mixing patterns were very similar across the eight countries, people of the same age tended to mix with each other.
Analyzing these contact patterns and applying mathematical and statistical techniques, the researchers created a model of the initial phase of a hypothetical respiratory infection epidemic. This model suggests that 5- to 19-year-olds will suffer the highest burden of respiratory infection during an initial spread. The high incidence of infection among school-aged children in the model results from these children having a large number of contacts compared to other groups and tending to make contacts within their own age group.
What Do These Findings Mean?
This work provides insight about contacts that can be supplemental to traditional measurements such as contact rates, which are usually generated from household or workplace size and transportation statistics. Incorporating contact patterns into the model allowed for a deeper understanding of the transmission patterns of a hypothetical respiratory epidemic among a susceptible population. Understanding the patterning of social contacts—between and within groups, and in different social settings—shows how diverse contacts and mixing between individuals really are. Physical exposure to an infectious agent, the authors conclude, is best modeled by taking into account the social network of close contacts and its patterning.
Additional Information.
Please access these Web sites via the online version of this summary at doi:10.1371/journal.pmed.0050074..
Wikipedia has technical discussions on the assumptions used in mathematical models of epidemiology (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
Plans for pandemic influenza are explained for the Government of Canada, the United Kingdom's Health Protection Agency, and the United States Department of Health and Human Services
PMCID: PMC2270306  PMID: 18366252
8.  Health burden and economic impact of measles-related hospitalizations in Italy in 2002–2003 
BMC Public Health  2007;7:169.
A large measles outbreak occurred in Italy in 2002–2003. This study evaluates the health burden and economic impact of measles-related hospitalizations in Italy during the specified period.
Hospital discharge abstract data for measles hospitalizations in Italy during 2002–2003 were analysed to obtain information regarding number and rates of measles hospitalizations by geographical area and age group, length of hospital stay, and complications. Hospitalization costs were estimated on the basis of Diagnosis-Related Groups.
A total of 5,154 hospitalizations were identified, 3,478 (67%) of which occurred in children <15 years of age. Most hospitalizations occurred in southern Italy (71 %) and children below 1 year of age presented the greatest hospitalization rates (46.2/100,000 and 19.0/100,000, respectively in 2002 and 2003). Pneumonia was diagnosed in 594 cases (11.5%) and encephalitis in 138 cases (2.7%). Total hospital charges were approximately € 8.8 million.
The nationwide health burden associated with measles during the 2002–2003 outbreak was substantial and a high cost was incurred by the Italian National Health Service for the thousands of measles-related hospitalizations which occurred. By assuming that hospital costs represent 40–50% of the direct costs of measles cases, direct costs of measles for the two years combined were estimated to be between €17.6 – 22.0 million, which equates to the vaccination of 1.5–1.9 million children (3–4 birth cohorts) with one dose of MMR. The high cost of measles and the severity of its complications fully justify the commitment required to reach measles elimination.
PMCID: PMC1963450  PMID: 17650298
9.  PD-1 Expression in Acute Hepatitis C Virus (HCV) Infection Is Associated with HCV-Specific CD8 Exhaustion▿  
Journal of Virology  2006;80(22):11398-11403.
Hepatitis C virus (HCV)-specific CD8 cell exhaustion may represent a mechanism of HCV persistence. The inhibitory receptor PD-1 has been reported to be up-regulated in exhausted CD8 cells. Therefore, we studied PD-1 expression longitudinally during acute HCV infection. Most HCV-specific CD8 cells expressed PD-1 at the time of acute illness, irrespective of the final outcome. PD-1 expression declined with the acquisition of a memory phenotype and recovery of an efficient CD8 cell function in resolving HCV infections, whereas high levels were maintained when HCV persisted and HCV-specific CD8 cells remained dysfunctional. Blocking PD-1/PDL-1 interaction with an anti-PDL-1 antibody improved the capacity of expansion of virus-specific CD8 cells.
PMCID: PMC1642188  PMID: 16956940
10.  Salmonella Typhimurium DT104, Italy 
Emerging Infectious Diseases  2006;12(8):1289.
PMCID: PMC3291205  PMID: 16972352
Keywords: Salmonella Typhimurium; DT104A; Italy
11.  Botulism and Preserved Green Olives 
Emerging Infectious Diseases  2005;11(5):781-782.
PMCID: PMC3320370  PMID: 15898180
botulism; outbreak; green olives; Italy
12.  Virus-Specific CD8+ Lymphocytes Share the Same Effector-Memory Phenotype but Exhibit Functional Differences in Acute Hepatitis B and C 
Journal of Virology  2002;76(24):12423-12434.
Hepatitis B and hepatitis C viruses (HBV and HCV) are both noncytopathic and can cause acute and chronic infections of the liver. Although they share tropism for the same organ, development of chronic hepatitis is much more frequent following HCV infection, suggesting different mechanisms of viral persistence. In this study, we show that circulating HBV- and HCV-specific tetramer-positive CD8 cells during the acute phase of hepatitis B and C belong almost entirely to an effector-memory subset (CCR7− CD45RA−). Despite this phenotypic similarity, HBV- and HCV-specific CD8 cells show striking functional differences. HBV-specific tetramer-positive CD8 cells express high perforin content ex vivo, expand vigorously, and display efficient cytotoxic activity and gamma interferon (IFN-γ) production upon peptide stimulation. A comparable degree of functional efficiency is maintained after the resolution of hepatitis B. In contrast, HCV-specific CD8 cells in the acute phase of hepatitis C express significantly lower levels of perforin molecules ex vivo and show depressed CD8 function in terms of proliferation, lytic activity, and IFN-γ production, irrespective of the final outcome of the disease. This defect is transient, because HCV-specific CD8 cells can progressively improve their function in patients with self-limited hepatitis C, while the CD8 function remains persistently depressed in subjects with a chronic evolution.
PMCID: PMC136708  PMID: 12438568
13.  Transmission of Hepatitis C Virus in a Gynecological Surgery Setting 
Journal of Clinical Microbiology  2001;39(8):2860-2863.
A cluster of hepatitis C virus (HCV) infections among gynecological patients who underwent surgical intervention in the same setting is described. An epidemiological investigation was conducted to identify the cases, the likely source of infection, and the route of transmission. Four recent HCV infections were identified. Based on molecular fingerprinting analysis and epidemiological investigation, transmission between the putative source patient (an HCV-positive woman who was the first patient of the surgical session) and outbreak patients was highly suggestive. All patients, including the source patient, were infected with HCV type 1b. Molecular characterization of HCV clones by sequence analysis of both structural envelope regions (20 clones from the source patient and 58 from the outbreak patients) and the nonstructural NS5 region of the viral genome (12 clones from the source patient and 32 from the outbreak patients) showed close homology between the viral isolates from the source and those from the outbreak patients that was higher than that observed between the viral isolates from the source and those from four unrelated, HCV type 1b-infected patients from the same geographical area (in the latter case, 33 clones were sequenced for the envelope regions and 30 were sequenced for the NS5 region). The mean percent divergence between clones was 4.69 for the envelope and 3.71 for the NS5 region in the source patient and the outbreak patients compared with 6.76 (P = 0.001) and 5.22 (P = 0.01) in the source patient and control patients, respectively. Among the risk factors investigated, only that of having undergone surgery in the morning session of the same day reached statistical significance (P = 0.003). The investigation showed that the source patient and outbreak patients shared only the administration of propofol in multidose vials. The study documents the risk of nosocomial transmission of HCV and the importance of infection control procedures in the operating room and highlights the crucial role of molecular strategies, especially sequence-based phylogenetic analysis of cloned viral isolates, in the investigation of HCV outbreaks.
PMCID: PMC88251  PMID: 11474004

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