Impact of prior or concomitant seasonal influenza vaccination on MF59-adjuvanted H1N1v vaccine (Focetria) in adult and elderly subjects.

BACKGROUND: When H1N1v vaccines become widely available, most elderly subjects will have already received their seasonal influenza vaccination. Adults seeking H1N1v vaccination may be offered seasonal vaccine as well. We investigated prior seasonal vaccination in adult and elderly subjects, and concomitant vaccination with seasonal vaccine in adults, on the tolerability and immunogenicity of the Novartis MF59-adjuvanted H1N1v vaccine, Focetria. METHODS: A total of 264 adult (four groups) and 154 elderly (three groups) subjects were enrolled. The licensure study cohorts for plain (Agrippal) and MF59-adjuvanted (Fluad) 2009-2010 seasonal vaccines were invited to receive Focetria 3 months later, with seasonal vaccine-naïve controls, and adults who received Focteria and seasonal vaccine concomitantly. Immunogenicity of all vaccines was assessed by haemagglutination inhibition on Days 1 and 22, safety and reactogenicity were monitored using patient diaries. RESULTS: All adult and elderly groups met all the European CHMP licensing criteria for H1N1v, as did adults receiving concomitant seasonal vaccine for the three seasonal strains. Vaccines were generally well tolerated, causing no SAEs, and profiles typical of MF59-adjuvanted vaccines. Reactions were mainly mild or moderate and transient, and unaffected by prior or concomitant seasonal vaccination except for elderly subjects previously given MF59-adjuvanted seasonal vaccine, whose reaction rates to Focetria were about half those seen in groups receiving their first MF59 vaccine. CONCLUSION: One dose of MF59-adjuvanted H1N1v vaccine met the licensure criteria for adult and elderly subjects 3 months after seasonal vaccination, or concomitantly with seasonal vaccine in adults, without impacting the tolerability or immunogenicity of either vaccine, thus facilitating mass influenza immunisation campaigns.

Mechanisms of PCBs mixture toxicity on isolated rat hepatocytes.

Exposure of isolated hepatocytes to a polychlorinated biphenyl mixture induced a rapid loss of cell viability. The effect was not dose-dependent. The biochemical effects in the cellular toxicity did not involve glutathione content, protein sulfhydryl groups and lipid peroxidation. A transient increase in cytosolic Ca2+ was observed after exposing the hepatocytes to the polychlorinated biphenyl mixture. Our findings indicate that polychlorinated biphenyls are able to kill hepatocytes and suggest that elevation of cytosolic Ca2+ concentration could be responsable of the toxicity.

[Environmental dust in a plant for the production of polyvinyl chloride]. / Studio sulla polverosità ambientale di un impianto per la produzione di cloruro di polivinile.

The results of an investigation on environmental dust concentration and individual dust exposure in a drying and sacking section of an "emulsion" and "suspension" PVC plant are reported; data on environmental concentration and individual dust exposure have been obtained by gravimetric techniques using similar personal and static dust samplers. Morphology and particle size distribution have been studied by electron microscopy on airborne dust specimens. Morphological analysis showed remarkable differences concerning shape and size between particles sampled in the "suspension" polymer and "emulsion" polymer sacking sections. Remarkably high mean values concerning dustness have been observed: 1.30 mg/m3 (min. 0.15; max. 18.4 mg/m3) for environmental concentration and 5.39 mg/m3 (min. 0.28; max. 45.6 mg/m3) for individual exposure.

[Determination of the pneumoconiosis hazard in the cork industry]. / Accertamento del rischio pneumoconiogeno nell'industria del sughero.

The AA. have carried out an epidemiological investigation in order to control the prevalence of chronic respiratory diseases on a group of 385 people working in several cork industries in North Sardinia. At the same time an environmental investigation has been carried out. Standard questionnaire (CECA questionnaire) for chronic bronchitis and pulmonary emphysema, standard chest X-ray film, spyrographic investigation, ECG and sputum analysis for acid resistent bacteria have been used for epidemiological investigation. Environmental dust concentration and individual dust exposure, environmental concentration of sulphur oxides, nitrogen oxides, carbon mono- and dioxide, ammonia nad microclimatic conditions have been studied. Examination of medical data shows only a low degree of respiratory pathology in contrast with results of other authors, probably because of different methods used for epidemiological investigation and data interpretation and because of different environmental and working conditions.

[Effects of the body in personal sampling of noise]. / Effetto del corpo nel campionamento personale di rumore.

In acoustic free fields the human body changes the energy distribution surrounding it, mainly under narrow band or pure tone noise conditions. Hence, sound levels measured close to the body should be intrinsically incorrect if performed via personal sampling. An experiment was carried out to verify whether this statement is still valid in a diffuse field, such as occurs in industrial workplaces. Noise measurements were made in diffuse field laboratory conditions without the presence of a person (steady state) and were repeated close to the ear of a person (perturbed state). The measurements were carried out with integrating precision sound level meters and also with personal noise dose meters. The trials were repeated in an industrial environment. The states 1/3 octave band levels were matched, as also were the equivalent continuous levels. These findings show that in diffuse fields the human body does not significantly affect equivalent continuous level measurements performed near the body. The mean differences between equivalent continuous levels measured by sound level meter were less than 0.3 dBA, and ranged from -0.6 to 0 dBA between levels measured by sound level meter and by personal noise dose meter. The results of the trial performed in the plant showed closer differences between steady and perturbed states and between sound level meter and personal noise dose meter measurements.

[Polychlorobiphenyl content in adipose tissue of subjects not exposed professionally]. / Contenuto di PCB nel tessuto adiposo di soggetti non esposti professionalmente.

Polychlorinated biphenyl (PCB) levels were determined in 52 samples of adipose tissue removed during surgery from patients residing in a central region of Sardinia who had no previous occupational exposure. The average PCB value of the whole group was 0.72 microgram/g (range 0.11-2.81 micrograms/g); in males the average value (means = 0.97 microgram/g) was significantly higher than in females (means = 0.60 microgram/g). A positive correlation was observed between age and PCB levels in adipose tissue. This analysis could be usefully performed in occupationally exposed subjects so as to better assess the exposure level.

CHF5074 Reduces Biomarkers of Neuroinflammation in Patients with Mild Cognitive Impairment: A 12-Week, Double-Blind, Placebo-Controlled Study.

As neuroinflammation is an early event in the pathogenesis of Alzheimer's disease, new selective anti-inflammatory drugs could lead to promising preventive strategies. We evaluated the safety, tolerability, pharmacokinetics and pharmacodynamics of CHF5074, a new microglial modulator, in a 12-week, double-blind, placebo-controlled, parallel groups, ascending dose study involving 96 MCI patients. Subjects were allocated into three successive study cohorts to receive ascending, titrated doses of CHF5074 (200, 400 or 600 mg/day) or placebo. Vital signs, cardiac safety, neuropsychological performance and safety clinical laboratory parameters were assessed on all subjects. Plasma samples were collected throughout the study for measuring drug concentrations, soluble CD40 ligand (sCD40L) and TNF-α. At the end of treatment, cerebrospinal fluid (CSF) samples were optionally collected after the last dose to measure drug levels, ß-amyloid1-42 (Aß42), tau, phospho-tau181, sCD40L and TNF-α. Ten patients did not complete the study: one in the placebo group (consent withdrawn), two in the 200-mg/day treatment group (consent withdrawn and unable to comply) and seven in the 400-mg/day treatment group (five AEs, one consent withdrawn and one unable to comply). The most frequent treatment-emergent adverse events were diarrhea, dizziness and back pain. There were no clinically significant treatment-related clinical laboratory, vital sign or ECG abnormalities. CHF5074 total body clearance depended by gender, age and glomerular filtration rate. CHF5074 CSF concentrations increased in a dose-dependent manner. At the end of treatment, mean sCD40L and TNF-α levels in CSF were found to be inversely related to the CHF5074 dose (p=0.037 and p=0.001, respectively). Plasma levels of sCD40L in the 600-mg/day group were significantly lower than those measured in the placebo group (p=0.010). No significant differences between treatment groups were found in neuropsychological tests but a positive dose-response trend was found on executive function in APOE4 carriers. This study shows that CHF5074 is well tolerated in MCI patients after a 12-week titrated treatment up to 600 mg/day and dose-dependently affects central nervous system biomarkers of neuroinflammation.

Associations of the correlates of protection and implication on the statistical power for demonstrating non-inferiority: application of a re-sampling method on a large phase III influenza vaccine clinical trial.

BACKGROUND: In the later stage of the clinical development of new vaccines it is required to demonstrate their efficacy with the immunogenicity measures established as correlates for disease protection. Evaluation of interpandemic trivalent influenza vaccines is commonly assessed by three immunogenicity measures for each strain in different age groups: Seroprotection, Seroconversion and Geometric Mean Titers. US and European guidelines with respect to this topic have been issued for the licensure of new influenza vaccines. The statistical power of comparative trials, which consider these endpoint variables, could be affected to the extent that these measures are correlated. Results from a large non-inferiority trial in the clinical development of a novel cell-derived influenza vaccine have been analyzed with the aim of evaluating how statistical dependency between the above-mentioned three immunogenicity measures might affect the power to demonstrate non-inferiority. METHODS: The statistical non-inferiority criteria, which were met in the trial, were applied to different subsets (n=250, n=370 and n=500) using a re-sampling method from the original dataset (re-samples=10,000). RESULTS: The measures of immunogenicity were highly correlated, and the fulfillment or failure of any of the non-inferiority criteria for a specific measure partially predicted the same outcome for the other measures. Due to this dependency within each strain, the levels of power obtained by re-sampling methods were always higher than those obtained by theoretical calculations, which were based on the assumptions of independency between the three measures of immunogenicity. Seroconversion and Geometric Mean Ratio (GMR) showed a higher correlation. A failure in the fulfillment of the non-inferiority criteria for GMR predicted the failure for Seroconversion in >76% of cases. CONCLUSIONS: The correlation between different measures of immunogenicity should be taken into account when evaluating statistical power for non-inferiority in influenza vaccine trials and in establishing sample sizes. Statistical approaches that include either all three measures of immunogenicity or both Seroconversion and the ratio of GMTs as co-primary non-inferiority endpoints might create redundancy and could increase the probability of not meeting at least one non-inferiority criterion by chance, due to multiplicity.