Particle beam microstructure reconstruction and coincidence discrimination in PET monitoring for hadron therapy.

Positron emission tomography is one of the most mature techniques for monitoring the particles range in hadron therapy, aiming to reduce treatment uncertainties and therefore the extent of safety margins in the treatment plan. In-beam PET monitoring has been already performed using inter-spill and post-irradiation data, i.e. while the particle beam is off or paused. The full beam acquisition procedure is commonly discarded because the particle spills abruptly increase the random coincidence rates and therefore the image noise. This is because random coincidences cannot be separated by annihilation photons originating from radioactive decays and cannot be corrected with standard random coincidence techniques due to the time correlation of the beam-induced background with the ion beam microstructure. The aim of this paper is to provide a new method to recover in-spill data to improve the images obtained with full-beam PET acquisitions. This is done by estimating the temporal microstructure of the beam and thus selecting input PET events that are less likely to be random ones. The PET detector we used was the one developed within the INSIDE project and tested at the CNAO synchrotron-based facility. The data were taken on a PMMA phantom irradiated with 72 MeV proton pencil beams. The obtained results confirm the possibility of improving the acquired PET data without any external signal coming from the synchrotron or ad hoc detectors.

Monte Carlo simulation tool for online treatment monitoring in hadrontherapy with in-beam PET: A patient study.

Hadrontherapy is a method for treating cancer with very targeted dose distributions and enhanced radiobiological effects. To fully exploit these advantages, in vivo range monitoring systems are required. These devices measure, preferably during the treatment, the secondary radiation generated by the beam-tissue interactions. However, since correlation of the secondary radiation distribution with the dose is not straightforward, Monte Carlo (MC) simulations are very important for treatment quality assessment. The INSIDE project constructed an in-beam PET scanner to detect signals generated by the positron-emitting isotopes resulting from projectile-target fragmentation. In addition, a FLUKA-based simulation tool was developed to predict the corresponding reference PET images using a detailed scanner model. The INSIDE in-beam PET was used to monitor two consecutive proton treatment sessions on a patient at the Italian Center for Oncological Hadrontherapy (CNAO). The reconstructed PET images were updated every 10 s providing a near real-time quality assessment. By half-way through the treatment, the statistics of the measured PET images were already significant enough to be compared with the simulations with average differences in the activity range less than 2.5 mm along the beam direction. Without taking into account any preferential direction, differences within 1 mm were found. In this paper, the INSIDE MC simulation tool is described and the results of the first in vivo agreement evaluation are reported. These results have justified a clinical trial, in which the MC simulation tool will be used on a daily basis to study the compliance tolerances between the measured and simulated PET images.

Relation of study quality, concordance, take home message, funding, and impact in studies of influenza vaccines: systematic review.

OBJECTIVE: To explore the relation between study concordance, take home message, funding, and dissemination of comparative studies assessing the effects of influenza vaccines. DESIGN: Systematic review without meta-analysis. DATA EXTRACTION: Search of the Cochrane Library, PubMed, Embase, and the web, without language restriction, for any studies comparing the effects of influenza vaccines against placebo or no intervention. Abstraction and assessment of quality of methods were carried out. DATA SYNTHESIS: We identified 259 primary studies (274 datasets). Higher quality studies were significantly more likely to show concordance between data presented and conclusions (odds ratio 16.35, 95% confidence interval 4.24 to 63.04) and less likely to favour effectiveness of vaccines (0.04, 0.02 to 0.09). Government funded studies were less likely to have conclusions favouring the vaccines (0.45, 0.26 to 0.90). A higher mean journal impact factor was associated with complete or partial industry funding compared with government or private funding and no funding (differences between means 5.04). Study size was not associated with concordance, content of take home message, funding, and study quality. Higher citation index factor was associated with partial or complete industry funding. This was sensitive to the exclusion from the analysis of studies with undeclared funding. CONCLUSION: Publication in prestigious journals is associated with partial or total industry funding, and this association is not explained by study quality or size.

Interventions for the interruption or reduction of the spread of respiratory viruses.

BACKGROUND: Viral epidemics or pandemics such as of influenza or severe acute respiratory syndrome (SARS) pose a significant threat. Antiviral drugs and vaccination may not be adequate to prevent catastrophe in such an event. OBJECTIVES: To systematically review the evidence of effectiveness of interventions to interrupt or reduce the spread of respiratory viruses (excluding vaccines and antiviral drugs, which have been previously reviewed). SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2006, Issue 4); MEDLINE (1966 to November 2006); OLDMEDLINE (1950 to 1965); EMBASE (1990 to November 2006); and CINAHL (1982 to November 2006). SELECTION CRITERIA: We scanned 2300 titles, excluded 2162 and retrieved the full papers of 138 trials, including 49 papers of 51 studies. The quality of three randomised controlled trials (RCTs) was poor; as were most cluster RCTs. The observational studies were of mixed quality. We were only able to meta-analyse case-control data. We searched for any interventions to prevent viral transmission of respiratory viruses (isolation, quarantine, social distancing, barriers, personal protection and hygiene). Study design included RCTs, cohort studies, case-control studies, cross-over studies, before-after, and time series studies. DATA COLLECTION AND ANALYSIS: We scanned the titles, abstracts and full text articles using a standardised form to assess eligibility. RCTs were assessed according to randomisation method, allocation generation, concealment, blinding, and follow up. Non-RCTs were assessed for the presence of potential confounders and classified as low, medium, and high risk of bias. MAIN RESULTS: The highest quality cluster RCTs suggest respiratory virus spread can be prevented by hygienic measures around younger children. Additional benefit from reduced transmission from children to other household members is broadly supported in results of other study designs, where the potential for confounding is greater. The six case-control studies suggested that implementing barriers to transmission, isolation, and hygienic measures are effective at containing respiratory virus epidemics. We found limited evidence that the more uncomfortable and expensive N95 masks were superior to simple surgical masks. The incremental effect of adding virucidals or antiseptics to normal handwashing to decrease respiratory disease remains uncertain. The lack of proper evaluation of global measures such as screening at entry ports and social distancing prevent firm conclusions about these measures. AUTHORS' CONCLUSIONS: Many simple and probably low-cost interventions would be useful for reducing the transmission of epidemic respiratory viruses. Routine long-term implementation of some of the measures assessed might be difficult without the threat of a looming epidemic.

Vaccines for preventing influenza in healthy adults.

BACKGROUND: Different types of influenza vaccines are currently produced world-wide. Healthy adults are at present targeted only in North America. Despite the publication of a large number of clinical trials, there is still substantial uncertainty about the clinical effectiveness of influenza vaccines and this has a negative impact on their acceptance and uptake. OBJECTIVES: To identify, retrieve and assess all studies evaluating the effects (efficacy, effectiveness and harms) of vaccines against influenza in healthy adults. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 4, 2005) which contains the Cochrane Acute Respiratory Infections Group trials register; MEDLINE (January 1966 to January 2006); and EMBASE (1990 to January 2006). We wrote to vaccine manufacturers and first or corresponding authors of studies in the review. SELECTION CRITERIA: Any randomised or quasi-randomised studies comparing influenza vaccines in humans with placebo, no intervention. Live, attenuated, or killed vaccines or fractions of them administered by any route, irrespective of antigenic configuration were assessed. Only studies assessing protection from exposure to naturally occurring influenza in healthy individuals aged 16 to 65 years were considered. Comparative non-randomised studies were included if they assessed evidence of the possible association between influenza vaccines and serious harms. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. MAIN RESULTS: Forty-eight reports were included: 38 (57 sub-studies) were clinical trials providing data about effectiveness, efficacy and harms of influenza vaccines and involved 66,248 people; 8 were comparative non-randomised studies and tested the association of the vaccines with serious harms; 2 were reports of harms which could not be introduced in the data analysis. Inactivated parenteral vaccines were 30% effective (95% CI 17% to 41%) against influenza-like illness, and 80% (95% CI 56% to 91%) efficacious against influenza when the vaccine matched the circulating strain and circulation was high, but decreased to 50% (95% CI 27% to 65%) when it did not. Excluding the studies of the 1968 to 1969 pandemic, effectiveness was 15% (95% CI 9% to 22%) and efficacy was 73% (95% CI 53% to 84%). Vaccination had a modest effect on time off work, but there was insufficient evidence to draw conclusions on hospital admissions or complication rates. Inactivated vaccines caused local tenderness and soreness and erythema. Spray vaccines had more modest performance. Monovalent whole-virion vaccines matching circulating viruses had high efficacy (VE 93%, 95% CI 69% to 98%) and effectiveness (VE 66%, 95% CI 51% to 77%) against the 1968 to 1969 pandemic. AUTHORS' CONCLUSIONS: Influenza vaccines are effective in reducing cases of influenza, especially when the content predicts accurately circulating types and circulation is high. However, they are less effective in reducing cases of influenza-like illness and have a modest impact on working days lost. There is insufficient evidence to assess their impact on complications. Whole-virion monovalent vaccines may perform best in a pandemic.

[Haemocoagulative modifications correlated with pregnancy]. / Modificazioni emocoagulative correlate allo stato gravidico.

AIM: The aim of this paper was to establish the physiologic changes in the coagulation and fibrinolytic systems during normal pregnancy. METHODS: One-hundred and twenty normal pregnant women were investigated in a longitudinal study involving 3 measurements: blood samples were collected at 12, 24 and 36 weeks of gestation and were assayed for prothrombin time, antithrombin III (ATIII) activity, protein C activity, protein S (PS) activity, prothrombin fragments 1+2, type 1 plasminogen activator inhibitor activity, tissue plasminogen activator antigen, plasminogen, activated protein C resistance, factors VII and VIII levels and D dimer. Student t-test, one way analysis of variance (ANOVA) and Fisher test were used for statistical analysis. RESULTS: Factor VII and factor VIII were always increased with respect to controls. Variance analysis showed a statistically significant reduction for anticoagulants (PS) and a rise for F1+2 and D dimer. With regard to fibrinolysis, there was an increase both for t-PA and PA1-1 during pregnancy. Moreover, the increased activity of factors of haemostasis was accompanied by an increase of activity and concentration of ATIII and acquired activated protein C resistance. CONCLUSIONS: These findings suggest that normal pregnancy is associated with an hypercoagulable state, resulting into a moderate risk for thrombosis during the different trimesters of pregnancy. Also broad spectrum assays which measure a range of trombin/fibrin formation in serum have become an established mean to identify activation of blood coagulation and/or fibrinolysis. There is a considerable interest in the application of these assays to the diagnosis of other acquired hypercoagulable states; such as thrombophilia during pregnancy. From the viewpoint of coagulation/fibrinolysis changes, the follow-up of thrombophilia markers could be recommended when levels of coagulation parameters exceed the normal values during pregnancy.

Vaccines for preventing influenza in the elderly.

BACKGROUND: Influenza vaccination of elderly individuals is recommended worldwide and has been targeted toward the elderly and those at serious risk of complications. OBJECTIVES: Our aim was to review the evidence of efficacy, effectiveness and safety of influenza vaccines in individuals aged 65 years or older. SEARCH STRATEGY: We searched the following databases on The Cochrane Library, the Cochrane Central Register of Controlled Trials (CENTRAL), the Cochrane Database of Systematic Reviews, and the Database of Abstracts of Reviews of Effectiveness (Issue 1, 2006); MEDLINE (January 1966 to March Week 3 2006); EMBASE (Dialog 1974 to 1979; SilverPlatter 1980 to December 2005); Biological Abstracts (SilverPlatter 1969 to December 2004); and Science Citation Index (Web of Science 1974 to December 2004). SELECTION CRITERIA: We considered randomised, quasi-randomised, cohort and case-control studies assessing efficacy against influenza (laboratory-confirmed cases) or effectiveness against influenza-like illness (ILI) or safety. Any influenza vaccine given independently, in any dose, preparation or time schedule, compared with placebo or with no intervention was considered. DATA COLLECTION AND ANALYSIS: We grouped reports first according to the setting of the study (community or long-term care facilities) and then by level of viral circulation and vaccine matching. We further stratified by co-administration of pneumococcal polysaccharide vaccine (PPV) and by different types of influenza vaccines. We analysed the following outcomes: influenza, influenza-like illness, hospital admissions, complications and deaths. MAIN RESULTS: Sixty-four studies were included in the efficacy / effectiveness assessment, resulting in 96 data sets. In homes for elderly individuals (with good vaccine match and high viral circulation) the effectiveness of vaccines against ILI was 23% (6% to 36%) and non-significant against influenza (RR 1.04: 95% CI 0.43 to 2.51). We found no correlation between vaccine coverage and ILI attack rate. Well matched vaccines prevented pneumonia (VE 46%; 30% to 58%), hospital admission (VE 45%; 16% to 64%) and deaths from influenza or pneumonia (VE 42%, 17% to 59%). In elderly individuals living in the community, vaccines were not significantly effective against influenza (RR 0.19; 95% CI 0.02 to 2.01), ILI (RR 1.05: 95% CI 0.58 to 1.89), or pneumonia (RR 0.88; 95% CI 0.64 to 1.20). Well matched vaccines prevented hospital admission for influenza and pneumonia (VE 26%; 12% to 38%) and all-cause mortality (VE 42%; 24% to 55%). After adjustment for confounders, vaccine performance was improved for admissions to hospital for influenza or pneumonia (VE* 27%; 21% to 33%), respiratory diseases (VE* 22%; 15% to 28%) and cardiac disease (VE* 24%; 18% to 30%); and for all-cause mortality (VE* 47%; 39% to 54%). The public health safety profiles of the vaccines appear to be acceptable. AUTHORS' CONCLUSIONS: In long-term care facilities, where vaccination is most effective against complications, the aims of the vaccination campaign are fulfilled, at least in part. However, according to reliable evidence the usefulness of vaccines in the community is modest. The apparent high effectiveness of the vaccines in preventing death from all causes may reflect a baseline imbalance in health status and other systematic differences in the two groups of participants.

Vaccines for preventing influenza in healthy children.

BACKGROUND: In children and adults the consequences of influenza are mainly absences from school and work, however the risk of complications is greatest in children and people over 65 years old. OBJECTIVES: To appraise all comparative studies evaluating the effects of influenza vaccines in healthy children; assess vaccine efficacy (prevention of confirmed influenza) and effectiveness (prevention of influenza-like illness) and document adverse events associated with receiving influenza vaccines. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 1, 2005); OLD MEDLINE (1966 to 1969); MEDLINE (1969 to December 2004); EMBASE (1974 to December 2004); Biological Abstracts (1969 to December 2004); and Science Citation Index (1974 to December 2004). We wrote to vaccine manufacturers and a number of corresponding authors of studies in the review. SELECTION CRITERIA: Any randomised controlled trials (RCTs), cohort and case-control studies of any influenza vaccine in healthy children under 16 years old. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. MAIN RESULTS: Fifty-one studies involving 263,987 children were included. Seventeen papers were translated from Russian. Fourteen RCTs and 11 cohort studies were included in the analysis of vaccine efficacy and effectiveness. From RCTs, live vaccines showed an efficacy of 79% (95% confidence interval (CI) 48% to 92%) and an effectiveness of 33% (95% CI 28% to 38%) in children older than two years compared with placebo or no intervention. Inactivated vaccines had a lower efficacy of 59% (95% CI 41% to 71%) than live vaccines but similar effectiveness: 36% (95% CI 24% to 46%). In children under two, the efficacy of inactivated vaccine was similar to placebo. Thirty-four reports containing safety outcomes were included, 22 including live vaccines, 8 inactivated vaccines and 4 both types. The most commonly presented short-term outcomes were temperature and local reactions. The variability in design of studies and presentation of data was such that meta-analysis of safety outcome data was not feasible. AUTHORS' CONCLUSIONS: Influenza vaccines are efficacious in children older than two years but little evidence is available for children under two. There was a marked difference between vaccine efficacy and effectiveness. That no safety comparisons could be carried out emphasizes the need for standardisation of methods and presentation of vaccine safety data in future studies. It was surprising to find only one study of inactivated vaccine in children under two years, given recent recommendations to vaccinate healthy children from six months old in the USA and Canada. If immunisation in children is to be recommended as public-health policy, large-scale studies assessing important outcomes and directly comparing vaccine types are urgently required.

Antivirals for influenza in healthy adults: systematic review.

BACKGROUND: Use of antivirals is recommended for the control of seasonal and pandemic influenza. Our aim was to review the evidence of efficacy, effectiveness, and safety of registered antivirals against naturally occurring influenza in healthy adults. METHODS: We searched various Databases to October, 2005, and contacted manufacturers and corresponding authors. We included randomised controlled trials comparing prophylactic (n=27) or treatment (n=27) efficacy against symptomatic or asymptomatic influenza. We did a meta-analysis and expressed prophylactic efficacy as a proportion (1-relative risk [RR]). For treatment trials, because of inconsistent and non-standardised reporting, we expressed continuous outcomes either as means or as hazard ratios. FINDINGS: We included 51 reports of 52 randomised controlled trials. Amantadine prevented 61% (95% CI 35-76) of influenza A cases and 25% (13-36) of cases of influenza-like illness, but caused nausea (OR 2.56, 1.37-4.79), insomnia and hallucinations (2.54, 1.50-4.31), and withdrawals because of adverse events (2.54, 1.60-4.06). There was no effect on asymptomatic cases (RR 0.85, 0.40-1.80). In treatment, amantadine significantly shortened duration of fever compared with placebo (by 0.99 days, -1.26 to -0.71), but had no effect on nasal shedding of influenza A viruses (0.93, 0.71-1.21). The fewer data for rimantadine showed comparable effects. In prophylaxis, compared with placebo, neuraminidase inhibitors have no effect against influenza-like illness (1.28, 0.45-3.66 for oral oseltamivir 75 mg daily, 1.51, 0.77-2.95 for inhaled zanamivir 10 mg daily). Higher doses appear to make no difference. The efficacy of oral oseltamivir 75 mg daily against symptomatic influenza is 61% (15-82), or 73% (33-89) at 150 mg daily. Inhaled zanamivir 10 mg daily is 62% efficacious (15-83). Neither neuraminidase inhibitor appeared effective against asymptomatic influenza. Oseltamivir induces nausea (OR 1.79, 1.10-2.93), especially at higher prophylactic doses (2.29, 1.34-3.92). Oseltamivir in a post-exposure prophylaxis role has a protective efficacy of 58.5% (15.6-79.6) for households and from 68% (34.9-84.2) to 89% (67-97) in contacts of index cases. In influenza cases, compared with placebo the hazard ratios for time to alleviation of symptoms were 1.33, 1.29-1.37 for zanamivir; 1.30, 1.13-1.50 for oseltamivir provided medication was started within 48 h of symptom onset. Viral nasal titres were significantly diminished by both drugs (weighted mean difference -0.62, -0.82 to -0.41). Oseltamivir at 150 mg daily was effective in preventing lower respiratory tract complications in influenza cases (OR 0.32, 0.18-0.57). We could find no credible data on the effects of oseltamivir on avian influenza. INTERPRETATION: The use of amantadine and rimantadine should be discouraged. Because of their low effectiveness, neuraminidase inhibitors should not be used in seasonal influenza control and should only be used in a serious epidemic or pandemic alongside other public-health measures.

Efficacy and effectiveness of influenza vaccines in elderly people: a systematic review.

BACKGROUND: Influenza vaccination of elderly individuals is recommended worldwide. Our aim was to review the evidence of efficacy and effectiveness of influenza vaccines in individuals aged 65 years or older. METHODS: We searched five electronic databases to December, 2004, in any language, for randomised (n=5), cohort (n=49), and case-control (n=10) studies, assessing efficacy against influenza (reduction in laboratory-confirmed cases) or effectiveness against influenza-like illness (reduction in symptomatic cases). We expressed vaccine efficacy or effectiveness as a proportion, using the formula VE=1-relative risk (RR) or VE*=1-odds ratio (OR). We analysed the following outcomes: influenza, influenza-like illness, hospital admissions, complications, and deaths. FINDINGS: In homes for elderly individuals (with good vaccine match and high viral circulation) the effectiveness of vaccines against influenza-like illness was 23% (95% CI 6-36) and non-significant against influenza (RR 1.04, 0.43-2.51). Well matched vaccines prevented pneumonia (VE 46%, 30-58) and hospital admission (VE 45%, 16-64) for and deaths from influenza or pneumonia (VE 42%, 17-59), and reduced all-cause mortality (VE 60%, 23-79). In elderly individuals living in the community, vaccines were not significantly effective against influenza (RR 0.19, 0.02-2.01), influenza-like illness (RR 1.05, 0.58-1.89), or pneumonia (RR 0.88, 0.64-1.20). Well matched vaccines prevented hospital admission for influenza and pneumonia (VE 26%, 12-38) and all-cause mortality (VE 42%, 24-55). After adjustment for confounders, vaccine performance was improved for admissions to hospital for influenza or pneumonia (VE* 27%, 21-33), respiratory diseases (VE* 22%, 15-28), and cardiac disease (VE* 24%, 18-30), and for all-cause mortality (VE* 47%, 39-54). INTERPRETATION: In long-term care facilities, where vaccination is most effective against complications, the aims of the vaccination campaign are fulfilled, at least in part. However, according to reliable evidence the usefulness of vaccines in the community is modest.

Vaccines for women to prevent neonatal tetanus.

BACKGROUND: Tetanus is an acute, often fatal, disease caused by an exotoxin produced by Clostridium tetani. It occurs in newborn infants born to mothers who do not have sufficient circulating antibodies to protect the infant passively, by transplacental transfer. Prevention may be possible by the vaccination of pregnant and/or non-pregnant women with tetanus toxoid, and the provision of clean delivery services. Tetanus toxoid consists of a formaldehyde-treated toxin which stimulates the production of antitoxin. OBJECTIVES: To assess the effectiveness of tetanus toxoid, administered to women of childbearing age or pregnant women, to prevent cases of, and deaths from, neonatal tetanus. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group Trials Register (December 2004) , The Cochrane Library (Issue 1, 2005), MEDLINE (1966 to December 2004), EMBASE (1974 to December 2004). We also used the results from handsearching and consultations with manufacturers and authors. SELECTION CRITERIA: Randomised or quasi-randomised trials evaluating the effects of tetanus toxoid in pregnant women or women of childbearing age on numbers of neonatal tetanus cases and deaths. DATA COLLECTION AND ANALYSIS: Three review authors independently assessed trials for inclusion, data extraction and trial quality. MAIN RESULTS: Two trials (10,560 infants) were included. One study (1919 infants) assessed the effectiveness of tetanus toxoid in preventing neonatal tetanus deaths. After a single dose, the relative risk (RR) was 0.57 (95% confidence interval (CI) 0.26 to 1.24), and the vaccine effectiveness was 43%. With a two or three dose course, the RR was 0.02 (95% CI 0.00 to 0.30); vaccine effectiveness was 98%. No effect was detected on causes of death other than tetanus. The RR of cases of neonatal tetanus after at least one dose of tetanus toxoid was 0.20 (95% CI 0.10 to 0.40); vaccine effectiveness was 80%. Another study, involving 8641 children, assessed the effectiveness of tetanus-diptheria toxoid in preventing neonatal mortality after one or two doses. The RR was 0.68 (95% CI 0.56 to 0.82); vaccine effectiveness was 32%. In preventing deaths at 4 to 14 days, the RR was 0.38 (95% CI 0.27 to 0.55), and vaccine effectiveness 62% (95% CI 45% to 73%). AUTHORS' CONCLUSIONS: Available evidence supports the implementation of immunisation practices on women of childbearing age or pregnant women in communities with similar, or higher, levels of risk of neonatal tetanus, to the two study sites. More information is needed on possible interference of vaccination by malaria chemoprophylaxis on the roles of malnutrition and vitamin A deficiency, and on the quality of tetanus toxoid production and storage.

Vaccines for measles, mumps and rubella in children.

BACKGROUND: Public debate over the safety of the trivalent measles, mumps and rubella (MMR) vaccine, and the resultant drop in vaccination rates in several countries, persists despite its almost universal use and accepted effectiveness. OBJECTIVES: We carried out a systematic review to assess the evidence of effectiveness and unintended effects associated with MMR. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 4, 2004), MEDLINE (1966 to December 2004), EMBASE (1974 to December 2004), Biological Abstracts (from 1985 to December 2004), and Science Citation Index (from 1980 to December 2004). Results from reviews, handsearching and from the consultation of manufacturers and authors were also used. SELECTION CRITERIA: Eligible studies were comparative prospective or retrospective trials testing the effects of MMR compared to placebo, do-nothing or a combination of measles, mumps and rubella antigens on healthy individuals up to 15 years of age. These studies were carried out or published by 2004. DATA COLLECTION AND ANALYSIS: We identified 139 articles possibly satisfying our inclusion criteria and included 31 in the review. MAIN RESULTS: MMR was associated with a lower incidence of upper respiratory tract infections, a higher incidence of irritability, and similar incidence of other adverse effects compared to placebo. The vaccine was likely to be associated with benign thrombocytopenic purpura, parotitis, joint and limb complaints, febrile convulsions within two weeks of vaccination and aseptic meningitis (mumps) (Urabe strain-containing MMR). Exposure to MMR was unlikely to be associated with Crohn's disease, ulcerative colitis, autism or aseptic meningitis (mumps) (Jeryl-Lynn strain-containing MMR). We could not identify studies assessing the effectiveness of MMR that fulfilled our inclusion criteria even though the impact of mass immunisation on the elimination of the diseases has been largely demonstrated. AUTHORS' CONCLUSIONS: The design and reporting of safety outcomes in MMR vaccine studies, both pre- and post-marketing, are largely inadequate. The evidence of adverse events following immunisation with MMR cannot be separated from its role in preventing the target diseases.

Assessment of the efficacy and effectiveness of influenza vaccines in healthy children: systematic review.

BACKGROUND: We aimed to assess evidence of efficacy and effectiveness of live attenuated and inactivated influenza vaccines in children up to 16 years of age. METHODS: We searched the Cochrane Library, MEDLINE, EMBASE Biological Abstracts, and Science Citation Index to June, 2004, in any language, and contacted vaccine manufacturers and authors of relevant studies to identify additional data. We included randomised, cohort, and case-control studies comparing efficacy of vaccines against influenza (reduction in laboratory-confirmed cases), effectiveness of vaccines against influenza-like illness (reduction in symptomatic cases), or both, with placebo or no intervention. We analysed the following outcomes: influenza, influenza-like illness, admissions, school absences, complications, and secondary transmission. FINDINGS: We included 14 randomised controlled trials, eight cohort studies, one case-control study, and one randomised controlled trial of intraepidemic use of the vaccines. Live attenuated influenza vaccines had 79% efficacy and 38% effectiveness in children older than 2 years compared with placebo or no immunisation. Inactivated vaccines had lower efficacy (65%) than live attenuated vaccines, and in children aged 2 years or younger they had similar effects to placebo. Effectiveness of inactivated vaccines was about 28% in children older than 2 years. Vaccines were effective in reducing long school absences (relative risk 0.14 [95% CI 0.07-0.27]). Studies assessing the effects of vaccines against secondary cases, lower-respiratory tract disease, acute otitis media, and hospital stay suggested no difference with placebo or standard care, but lacked statistical power. INTERPRETATION: Influenza vaccines (especially two-dose live attenuated vaccines) are efficacious in children older than 2 years. Efficacy and effectiveness of the vaccines differed strikingly. Only two small studies assessed the effects of influenza vaccines on hospital admissions and no studies assessed reductions in mortality, serious complications, and community transmission of influenza. If influenza immunisation in children is to be recommended as public-health policy, large-scale studies assessing such important outcomes and undertaking direct comparisons of vaccines are urgently needed.