BACKGROUND: We conducted a clinical trial of the safety and immunogenicity of modified vaccinia Ankara (MVA) to examine the effects of dose and route of administration. METHODS: Seventy-two healthy, vaccinia virus-naive subjects received 1 of 6 regimens of MVA (ACAM3000) or placebo consisting of 2 administrations given 1 month apart. RESULTS: MVA was generally well tolerated at all dose levels and by all routes. More pronounced local reactogenicity was seen with the intradermal and subcutaneous routes than with intramuscular administration. Binding antibodies to whole virus and neutralizing antibodies to the intracellular mature virion and extracellular enveloped virion forms of vaccinia virus were elicited by all routes of MVA administration and were greater for the higher dose by each route. Similar levels of neutralizing antibodies were seen at a 10-fold-lower dose given intradermally (1 x 10(7) median tissue culture infective doses [TCID(50)]), compared with responses after 1 x 10(8) TCID(50) given intramuscularly or subcutaneously. T cell immune responses to vaccinia virus were detected by an interferon gamma enzyme-linked immunospot assay but had no clear relationship to dose or route. CONCLUSIONS: These data suggest that intradermal immunization with MVA provides a dose-sparing effect by eliciting antibody responses similar in magnitude and kinetics to those elicited by the intramuscular or subcutaneous routes but at a 10-fold-lower dose.
 
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OBJECTIVES: To compare the safety, reactogenicity, and immunogenicity of an adjuvanted split virion H1N1 vaccine and a non-adjuvanted whole virion vaccine used in the pandemic immunisation programme in the United Kingdom. DESIGN: Open label, randomised, parallel group, phase II study. SETTING: Five UK centres (Oxford, Southampton, Bristol, Exeter, and London). PARTICIPANTS: Children aged 6 months to less than 13 years for whom a parent or guardian had provided written informed consent and who were able to comply with study procedures were eligible. Those with laboratory confirmed pandemic H1N1 influenza or clinically diagnosed disease meriting antiviral treatment, allergy to egg or any other vaccine components, or coagulation defects, or who were severely immunocompromised or had recently received blood products were excluded. Children were grouped by age: 6 months-<3 years (younger group) and 3-<13 years (older group). Recruitment was by media advertising and direct mailing. Recruitment visits were attended by 949 participants, of whom 943 were enrolled and 937 included in the per protocol analysis. INTERVENTIONS: Participants were randomised 1:1 to receive AS03(B) (tocopherol based oil in water emulsion) adjuvanted split virion vaccine derived from egg culture or non-adjuvanted whole virion vaccine derived from cell culture. Both were given as two doses 21 days apart. Reactogenicity data were collected for one week after immunisation by diary card. Serum samples were collected at baseline and after the second dose. MAIN OUTCOME MEASURES: Primary reactogenicity end points were frequency and severity of fever, tenderness, swelling, and erythema after vaccination. Immunogenicity was measured by microneutralisation and haemagglutination inhibition assays. The primary immunogenicity objective was a comparison between vaccines of the percentage of participants showing seroconversion by the microneutralisation assay (fourfold rise to a titre of >or=1:40 from before vaccination to three weeks after the second dose). RESULTS: Seroconversion rates were higher after the adjuvanted split virion vaccine than after the whole virion vaccine, most notably in the youngest children (163 of 166 participants with paired serum samples (98.2%, 95% confidence interval 94.8% to 99.6%) v 157 of 196 (80.1%, 73.8% to 85.5%), P<0.001) in children under 3 years and 226 of 228 (99.1%, 96.9% to 99.9%) v 95.9%, 92.4% to 98.1%, P=0.03) in those over 3 years). The adjuvanted split virion vaccine was more reactogenic than the whole virion vaccine, with more frequent systemic reactions and severe local reactions in children aged over 5 years after dose one (13 (7.2%, 3.9% to 12%) v 2 (1.1%, 0.1% to 3.9%), P<0.001) and dose two (15 (8.5%, 4.8% to 13.7%) v 2 (1.1%, 0.1% to 4.1%), P<0.002) and after dose two in those under 5 years (15 (5.9%, 3.3% to 9.6%) v 0 (0.0%, 0% to 1.4%), P<0.001). Dose two of the adjuvanted split virion vaccine was more reactogenic than dose one, especially for fever >or=38 masculineC in those aged under 5 (24 (8.9%, 5.8% to 12.9%) v 57 (22.4%, 17.5% to 28.1%), P<0.001). CONCLUSIONS: In this first direct comparison of an AS03(B) adjuvanted split virion versus whole virion non-adjuvanted H1N1 vaccine, the adjuvanted vaccine, while more reactogenic, was more immunogenic and, importantly, achieved high seroconversion rates in children aged less than 3 years. This indicates the potential for improved immunogenicity of influenza vaccines in this age group. TRIAL REGISTRATION: Clinical trials.gov NCT00980850; ISRCTN89141709.
 
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BACKGROUND: We evaluated the efficacy of a maternal triple-drug antiretroviral regimen or infant nevirapine prophylaxis for 28 weeks during breast-feeding to reduce postnatal transmission of human immunodeficiency virus type 1 (HIV-1) in Malawi. METHODS: We randomly assigned 2369 HIV-1-positive, breast-feeding mothers with a CD4+ lymphocyte count of at least 250 cells per cubic millimeter and their infants to receive a maternal antiretroviral regimen, infant nevirapine, or no extended postnatal antiretroviral regimen (control group). All mothers and infants received perinatal prophylaxis with single-dose nevirapine and 1 week of zidovudine plus lamivudine. We used the Kaplan-Meier method to estimate the cumulative risk of HIV-1 transmission or death by 28 weeks among infants who were HIV-1-negative 2 weeks after birth. Rates were compared with the use of the log-rank test. RESULTS: Among mother-infant pairs, 5.0% of infants were HIV-1-positive at 2 weeks of life. The estimated risk of HIV-1 transmission between 2 and 28 weeks was higher in the control group (5.7%) than in either the maternal-regimen group (2.9%, P=0.009) or the infant-regimen group (1.7%, P<0.001). The estimated risk of infant HIV-1 infection or death between 2 and 28 weeks was 7.0% in the control group, 4.1% in the maternal-regimen group (P=0.02), and 2.6% in the infant-regimen group (P<0.001). The proportion of women with neutropenia was higher among those receiving the antiretroviral regimen (6.2%) than among those in either the nevirapine group (2.6%) or the control group (2.3%). Among infants receiving nevirapine, 1.9% had a hypersensitivity reaction. CONCLUSIONS: The use of either a maternal antiretroviral regimen or infant nevirapine for 28 weeks was effective in reducing HIV-1 transmission during breast-feeding. (ClinicalTrials.gov number, NCT00164736.)
 
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BACKGROUND: Few randomized controlled trials on lifestyle interventions have been reported in non-Western populations; none have been reported in Arab populations. METHODS: From 2 Muslim Arab communities in Israel, obese, nondiabetic women aged 35 to 54 years with 1 or more components of the metabolic syndrome were randomized to either an intensive (n = 100) or a moderate (control) (n = 101) 12-month lifestyle intervention. Women in the intensive intervention had 11 individual and 11 group counseling sessions per year with a dietitian and 22 physical activity group sessions per year. Women in the moderate intervention had 3 individual and 2 group dietary counseling sessions per year and no guided physical activity. Cultural issues were addressed in the design and conduct of both interventions. The primary outcome measure was change in the metabolic syndrome and its components. RESULTS: At 12 months, the intensive intervention group had median declines of 3.0 mg/dL (to convert to millimoles per liter, multiply by 0.0555) in fasting plasma glucose and 4.5 mg/dL (to convert to millimoles per liter, multiply by 0.0113) in triglyceride levels compared with median increases of 1 mg/dL in fasting plasma glucose and 5.8 mg/dL in triglyceride levels in the moderate intervention group (P = .01 and P = .02, respectively). The median waist circumference decreased by 5.4 cm in the intensive intervention group and by 3.1 cm in the moderate intervention group (P = .10). The prevalence of the metabolic syndrome decreased by 4.0% in the intensive intervention group and increased by 5.2% in the moderate intervention group (P = .12). CONCLUSION: The 12-month culturally sensitive intensive lifestyle intervention was effective in improving some of the metabolic syndrome components in obese Arab women. Trial Registration clinicaltrials.gov Identifier: NCT00273572.
 
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BACKGROUND AND PURPOSE: The impact of air pollution on survival after stroke is unknown. We examined the impact of outdoor air pollution on stroke survival by studying a population-based cohort. METHODS: All patients who experienced their first-ever stroke between 1995 and 2005 in a geographically defined part of London, where road traffic contributes to spatial variation in air pollution, were followed up to mid-2006. Outdoor concentrations of nitrogen dioxide and particulate matter <10 microm in diameter modeled at a 20-m grid point resolution for 2002 were linked to residential postal codes. Hazard ratios were adjusted for age, sex, social class, ethnicity, smoking, alcohol consumption, prestroke functional ability, pre-existing medical conditions, stroke subtype and severity, hospital admission, and neighborhood socioeconomic deprivation. RESULTS: There were 1856 deaths among 3320 patients. Median survival was 3.7 years (interquartile range, 0.1 to 10.8). Mean exposure levels were 41 microg/m(3) (SD, 3.3; range, 32.2 to 103.2) for nitrogen dioxide and 25 microg/m(3) (SD, 1.3; range, 22.7 to 52) for particulate matter <10 microm in diameter. A 10-microg/m(3) increase in nitrogen dioxide was associated with a 28% (95% CI, 11% to 48%) increase in risk of death. A 10-microg/m(3) increase in particulate matter <10 mum in diameter was associated with a 52% (6% to 118%) increase in risk of death. Reduced survival was apparent throughout the follow-up period, ruling out short-term mortality displacement. CONCLUSIONS: Survival after stroke was lower among patients living in areas with higher levels of outdoor air pollution. If causal, a 10-microg/m(3) reduction in nitrogen dioxide exposure might be associated with a reduction in mortality comparable to that for stroke units. Improvements in outdoor air quality might contribute to better survival after stroke.
 
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OBJECTIVE: Familial Mediterranean fever (FMF) is an inherited disease characterized by attacks of febrile polyserositis. In children, attacks of fever alone, or with headache and malaise, may precede other forms of attacks. Our objective was clinical and genetic characterization of FMF and its development in pediatric patients who first presented with attacks of fever alone. METHODS: Clinical characterization and MEFV genotype of all FMF patients < 16 years of age at disease onset and first presenting with attacks of fever alone were analyzed and compared for age, sex, and disease duration with matched FMF patients presenting with serositis at the onset of the disease. RESULTS: There were 814 patients with FMF in our registry. Fifty patients formed the study group and 234 patients the control group. In the study group, the first (febrile) attacks appeared at a younger age than in the control group (1.7 +/- 1.6 yrs vs 5.0 +/- 4.1 yrs, respectively; p < 0.0001), diagnosis was made earlier (4.2 +/- 2.7 yrs vs 6.7 +/- 4.1 yrs; p < 0.0001), despite a trend for a longer delay in diagnosis. In the study group, attacks were shorter (1.6 +/- 0.8 days vs 2.1 +/- 1.0 days; p = 0.023) and homozygosity to the M694V mutation was more prevalent (46% vs 31%; p = 0.03). Attack rate, colchicine dose, and the MEFV mutation carrier rates were comparable between the groups. In 40/50 (80%) of the patients with fever alone, serositis had developed over a course of 2.9 +/- 2.2 years after disease onset. CONCLUSION: FMF in young children may begin with attacks of fever alone, but it progresses to typical FMF disease over the next 2.9 +/- 2.2 years. Our study demonstrates that clinical heterogeneity at presentation is more likely to indicate a feature of a disease in development, rather than to mark distinct phenotypes of FMF.
 
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OBJECTIVE: To develop a rapid quantitative real-time polymerase chain reaction (PCR) to detect herpes simplex virus (HSV) in the genital secretions of women that may be used in labor. METHODS: Samples of genital secretions from women in labor, swabs of active genital lesions, and swabs of buffer solution were analyzed using a newly developed rapid HSV PCR assay to detect HSV glycoprotein B gene and quantitate virion copy number. A previously validated TaqMan PCR to detect HSV glycoprotein B gene was performed as the comparator gold standard. Positivity determination that optimized sensitivity and specificity was determined with receiver operating characteristic curves. RESULTS: The median time to result for rapid HSV PCR was 2 hours (range 1.5-3.5 hours). A positivity determination rule that required both wells of the rapid test to detect 150 copies or greater of HSV per milliliter maximized specificity (96.7%) without appreciable loss of sensitivity (99.6%). Among positive samples, the correlation between the rapid test and TaqMan for the quantity of HSV isolated was excellent (R=0.96, P<.001). The rapid test had a positive predictive value of 96.7% and a negative predictive value of 99.6% in a population with HSV shedding prevalence of 10.8%, based on the prevalence of genital HSV previously found among HSV-2 seropositive women in labor. CONCLUSION: Rapid HSV PCR provides results with excellent sensitivity and specificity within a timeframe that could inform clinical decision making for identifying neonates at risk of neonatal HSV infection. LEVEL OF EVIDENCE: II.
 
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OBJECTIVES: To determine whether children who received recommended vaccines on time during the first year of life had different neuropsychological outcomes at 7 to 10 years of age as compared with children with delayed receipt or nonreceipt of these vaccines. METHODS: Publicly available data, including age at vaccination, from a previous VaccineSafety Datalink study of thimerosal exposure and 42 neuropsychological outcomes were analyzed. Vaccine receipt was defined as timely when each vaccine was received within 30 days of the recommended age. Associations between timeliness and each outcome were tested in univariate analyses. Multivariable regression models were constructed for further assessment of the impact of timeliness on neuropsychological outcomes after adjustment for potential confounders. Secondary analyses were performed on a subset of children with the highest and lowest vaccine exposures during the first 7 months of life. RESULTS: Timely vaccination was associated with better performance on 12 outcomes in univariate testing and remained associated with better performance for 2 outcomes in multivariable analyses. No statistically significant differences favored delayed receipt. In secondary analyses, children with the greatest vaccine exposure during the first 7 months of life performed better than children with the least vaccine exposure on 15 outcomes in univariate testing; these differences did not persist in multivariable analyses. No statistically significant differences favored the less vaccinated children. CONCLUSIONS: Timely vaccination during infancy has no adverse effect on neuropsychological outcomes 7 to 10 years later. These data may reassure parents who are concerned that children receive too many vaccines too soon.
 
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BACKGROUND: There is evidence from North American trials that supported employment using the individual placement and support (IPS) model is effective in helping individuals with severe mental illness gain competitive employment. There have been few trials in other parts of the world. AIMS: To investigate the effectiveness and cost-effectiveness of IPS in the UK. METHOD: Individuals with severe mental illness in South London were randomised to IPS or local traditional vocational services (treatment as usual) (ISRCTN96677673). RESULTS: Two hundred and nineteen participants were randomised, and 90% assessed 1 year later. There were no significant differences between the treatment as usual and intervention groups in obtaining competitive employment (13% in the intervention group and 7% in controls; risk ratio 1.35, 95% CI 0.95-1.93, P = 0.15), nor in secondary outcomes. CONCLUSIONS: There was no evidence that IPS was of significant benefit in achieving competitive employment for individuals in South London at 1-year follow-up, which may reflect suboptimal implementation. Implementation of IPS can be challenging in the UK context where IPS is not structurally integrated with mental health services, and economic disincentives may lead to lower levels of motivation in individuals with severe mental illness and psychiatric professionals.
 
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OBJECTIVES: To systematically evaluate the effect of extracorporeal membrane oxygenation on survival in adults with acute respiratory failure and to help inform institutional decisions about implementing an extracorporeal membrane oxygenation program or transferring patients to experienced extracorporeal membrane oxygenation centers during the H1N1 influenza pandemic. DATA SOURCES: National Guideline Clearinghouse, MEDLINE, EMBASE, Agency for Healthcare Research and Quality Evidence-based Practice reports, National Institute for Health and Clinical Excellence, Cochrane Library, International Network of Agencies for Health Technology Assessment, and citation review. STUDY SELECTION: Studies of extracorporeal membrane oxygenation in adult acute respiratory failure, reporting mortality rates for at least 10 patients in extracorporeal membrane oxygenation and nonextracorporeal membrane oxygenation groups. DATA EXTRACTION: Mortality rates were abstracted for all patients and for patients with influenza. Risk ratios were meta-analyzed using random-effects methods and assessed for heterogeneity. DATA SYNTHESIS: There are no evidence-based clinical guidelines on the use of extracorporeal membrane oxygenation in patients with influenza. Three randomized controlled trials and three cohort studies evaluated extracorporeal membrane oxygenation in patients with acute respiratory failure; none reported specifically on patients with influenza. Meta-analysis of the randomized controlled trials revealed significant heterogeneity in risk of mortality. The summary risk ratio found by the meta-analysis was 0.93 (95% confidence interval, 0.71 to 1.22). The most recent trial found a reduction in mortality and severe disability at 6 months among patients in whom extracorporeal membrane oxygenation was considered. Observational studies suggest that extracorporeal membrane oxygenation for acute respiratory failure resulting from viral pneumonia is associated with improved mortality compared with other etiologies of acute respiratory failure. CONCLUSIONS: The best evidence to guide decisions regarding the use of extracorporeal membrane oxygenation for patients with influenza stems from trials of extracorporeal membrane oxygenation for acute respiratory failure of all etiologies, among which significant heterogeneity exists, and from case series describing outcomes of extracorporeal membrane oxygenation in patients with influenza. Thus, there is insufficient evidence to provide a recommendation for extracorporeal membrane oxygenation use among patients with respiratory failure resulting from influenza. However, clinicians should consider extracorporeal membrane oxygenation within the context of other salvage therapies for acute respiratory failure.
 
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