Safety of a quadrivalent meningococcal serogroups A,C, W and Y conjugate vaccine (MenACWY-CRM) administered with routine infant vaccinations: Results of an open-label,randomized, phase 3b controlled study in healthy infants

Background

The highest risk for invasive meningococcal disease (IMD) is in infants aged <1 year. Quadrivalent meningococcal conjugate vaccination has the potential to prevent IMD caused by serogroups A, C, W and Y. This phase 3b, multinational, open-label, randomized, parallel-group, multicenter study evaluated the safety of a 4-dose series of MenACWY-CRM, a quadrivalent meningococcal conjugate vaccine, concomitantly administered with routine vaccinations to healthy infants.

Methods

Two-month-old infants were randomized 3:1 to receive MenACWY-CRM with routine vaccines or routine vaccines alone at ages 2, 4, 6 and 12 months. Adverse events (AEs) that were medically attended and serious adverse events (SAEs) were collected from all subjects from enrollment through 18 months of age. In a subset, detailed safety data (local and systemic solicited reactions and all AEs) were collected for 7 days post vaccination. The primary objective was a non-inferiority comparison of the percentages of subjects with ≥1 severe systemic reaction during Days 1–7 after any vaccination of MenACWY-CRM plus routine vaccinations versus routine vaccinations alone (criterion: upper limit of 95% confidence interval [CI] of group difference <6%).

Results

A total of 7744 subjects were randomized with 1898 in the detailed safety arm. The percentage of subjects with severe systemic reactions was 16% after MenACWY-CRM plus routine vaccines and 13% after routine vaccines alone (group difference 3.0% (95% CI −0.8, 6.4%). Although the non-inferiority criterion was not met, post hoc analysis controlling for significant center and group-by-center differences revealed that MenACWY-CRM plus routine vaccinations was non-inferior to routine vaccinations alone (group difference −0.1% [95% CI −4.9%, 4.7%]). Rates of solicited AEs, medically attended AEs, and SAEs were similar across groups.

Conclusion

In a large multinational safety study, a 4-dose series of MenACWY-CRM concomitantly administered with routine vaccines was clinically acceptable with a similar safety profile to routine vaccines given alone.     

Psychometric evaluation of the functional assessment of HIV Infection (FAHI) questionnaire and its usefulness in clinical trials

Purpose  

To evaluate psychometric properties of the Functional Assessment of Human Immunodeficiency Virus Infection (FAHI) questionnaire, a 47-item disease-specific instrument evaluating Health-Related Quality of Life (HRQL) in human immunodeficiency virus (HIV)-infected patients.     

The Role of Chelation in the Treatment of Other Metal Poisonings

These proceedings will review the role of chelation in five metals—aluminum, cadmium, chromium, cobalt, and uranium—in order to illustrate various chelation concepts. The process of “chelation” can often be oversimplified, leading to incorrect assumptions and risking patient harm. For chelation to be effective, two critical assumptions must be fulfilled: the presumed “metal toxicity” must correlate with a given body or a particular compartment burden, and reducing this compartmental or the body burden (through chelation) attenuates toxicity. Fulfilling these assumptions requires an established dose–response relationship, a validated, reproducible means of toxicity assessment (clinical, biochemical, or radiographical), and an appropriate assessment mechanisms of body or compartment burden. While a metal might “technically” be capable of chelation (and readily demonstrable in urine or feces), this is an insufficient endpoint. Clinical relevance must be affirmed. Deferoxamine is an accepted chelator for appropriately documented aluminum toxicity. There is a very minimal treatment window in order to address chelation in cadmium toxicity. In acute toxicity, while no definitive chelation benefit is described, succimer (DMSA), diethylenetriaminepentaacetate (DTPA), and potentially ethylenediaminetetraacetic acid (EDTA) have been considered. In chronic toxicity, chelation is unsupported. There is little evidence to suggest that currently available chromium chelators are efficacious. Similarly, scant human evidence exists with which to provide recommendation for cobalt chelation. DTPA has been recommended for cobalt radionuclide chelation, although DMSA, EDTA, and N-acetylcysteine have also been suggested. DTPA is unsupported for uranium chelation. Sodium bicarbonate is currently recommended, although animal evidence is conflicting.     

Fully enzymic method of plasma triglyceride determination using an immobilized glycerol dehydrogenase nylon-tube reactor

A new, enzymic method of triglyceride determination in serum and plasma by use of an immobilized glycerol dehydrogenase nylon-tube reactor, integrated into the flow system of an AutoAnalyzer II (Technicon) is described. The combination of this reactor, stable for 1500–2000 tests, with the lipolytic enzymes which are added in solution yields a reliable and reproducible assay, which correlates well with the commonly used fully enzymic triglyceride determination. Using this new method, the cost can be reduced to about one-third of that of the other method.     

A plea for intra-laboratory reference limits. Part 2. A bimodal retrospective concept for determining reference limits from intra-laboratory databases demonstrated by catalytic activity concentrations of enzymes.

BACKGROUND: The current recommendations for establishing intra-laboratory reference limits (RLs) cannot be fulfilled by most laboratories because of the expense involved. In the current study, a bimodal method was developed to derive RLs from data stored in a laboratory information system without any assumption concerning the distribution of the diseased subgroup. METHODS: A smoothed kernel density function (D(mix)) was estimated for the distribution of combined data for non-diseased and diseased adult subjects. It was assumed that the "central" part of the distribution represents the non-diseased population, which was defined and used to estimate a Gaussian distribution of either the original values or Box-Cox transformed data. This normal distribution was now considered the distribution of the non-diseased subgroup (D(nd)). Percentiles were calculated to obtain retrospective RLs. The density function of the diseased subgroup (D(d)) was calculated by subtracting the non-diseased density function from D(mix) (D(d)=D(mix)-D(nd)). The intersection point of the D(nd) and D(d) curves identified the RL with the highest diagnostic efficiency. RESULTS: The model was applied to catalytic activity concentrations of several enzymes with data from different laboratories. The RLs obtained were similar to recently published consensus values. Differences between laboratories were small but significant. Gender stratification was necessary for alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutymaltransferse (gamma-GT), not significant for lipase and amylase and inconsistent among the laboratories for alkaline phosphatase (AP) and lactate dehydrogenase (LDH). Age stratification was only tested for two groups (18-49 and >or=50 years) and was significant for AST (females only), gamma-GT and lipase, not significant for amylase and inconsistent for AP, LDH and ALT. For gamma-GT, further stratification for age in decades was necessary for males. Creatine kinase MB (CK-MB) values were not stratified owing to the low number of data available. CONCLUSIONS: Retrospective RLs derived from intra-laboratory data pools for the catalytic activity concentration of enzymes using a modified procedure plausibly agreed with published consensus values. However, most RLs varied significantly among laboratories, thus supporting the "old" plea for intra-laboratory RLs.     

The role of polyomaviruses in human disease

The human polyomaviruses, BK virus and JC virus, have long been associated with serious diseases including polyomavirus nephropathy and progressive multifocal leukoencephalopathy. Both viruses establish ubiquitous, persistent infections in healthy individuals. Reactivation can occur when the immune system is impaired, leading to disease progression. Recently, the human polyomavirus family has expanded with the identification of three new viruses (KI, WU and Merkel cell polyomavirus), all of which may prove to be involved in human disease. This review describes the general aspects of human polyomavirus infections and pathogenicity. Current topics of investigation and future directions in the field are also discussed.