International comparative field study evaluating the assay performance of AFSTYLA in plasma samples at clinical hemostasis laboratories.

Essentials AFSTYLA exhibits ≈50% underestimation in activity when the one-stage (OS) assay is utilized. A field study compared the performance of AFSTYLA with Advate in factor VIII activity assays. AFSTYLA activity can be monitored with both the chromogenic substrate and the OS assay. The consistent OS underestimation allows for a conversion factor to be applied to OS results. SUMMARY: Introduction AFSTYLA (antihemophilic factor [recombinant] single chain) is a novel B-domain truncated recombinant factor VIII (rFVIII). For AFSTYLA, an approximate 50% discrepancy was observed between results of the one-stage (OS) and chromogenic substrate (ChS) FVIII activity assays. An investigation was undertaken to test whether there is a linear relationship between ChS and OS assay results that would allow reliable clinical interpretation of results independent of the assay method used. Aims To provide confidence in future clinical monitoring, this field study investigated the performance of AFSTYLA and a full-length rFVIII (Advate® ) in FVIII activity assays routinely performed in clinical laboratories. Methods The comparison of AFSTYLA and Advate was performed in an international, multicenter and blinded field study of simulated post-infusion samples. The study documented the extent of variability between methods and laboratories and characterized the relationship between the ChS and OS assays. Results Results from 23 laboratories demonstrate that intra and interlaboratory variability in OS assays were similar for both products. When comparing within the OS assay format, there was a similar and reagent-correlated variability in response to different activators for both AFSTYLA and Advate. The OS underestimation was highly predictable and consistent across the complete range of FVIII plasma concentrations. Conclusion Post-infusion plasma AFSTYLA levels can be monitored in patients by the OS and ChS assays. The consistent and predictable difference between the two assay formats provides clinicians with adequate guidance on how to interpret the results of the OS assay using a single conversion factor.

Safety, efficacy and pharmacokinetics of rVIII-SingleChain in children with severe hemophilia A: results of a multicenter clinical trial.

Essentials rVIII-SingleChain is a novel recombinant factor VIII with covalently bonded heavy and light chains. Efficacy, safety and pharmacokinetics were studied in pediatric patients with severe hemophilia A. Across all prophylaxis regimens, the median annualized spontaneous bleeding rate was 0.00. rVIII-SingleChain showed excellent hemostatic efficacy and a favorable safety profile. SUMMARY: Background rVIII-SingleChain is a novel B-domain truncated recombinant factor VIII (rFVIII) comprised of covalently bonded FVIII heavy and light chains, demonstrating a high binding affinity to von Willebrand factor. Objectives This phase III study investigated the safety, efficacy and pharmacokinetics of rVIII-SingleChain in previously treated pediatric patients < 12 years of age with severe hemophilia A. Patients/Methods Patients could be assigned to prophylaxis or on-demand therapy by the investigator. For patients assigned to prophylaxis, the treatment regimen and dose were based on the bleeding phenotype. For patients receiving on-demand therapy, dosing was guided by World Federation of Hemophilia recommendations. The primary endpoint was treatment success, defined as a rating of 'excellent' or 'good' on the investigator's clinical assessment of hemostatic efficacy for all treated bleeding events. Results The study enrolled 84 patients (0 to < 6 years, n = 35; ≥ 6 to < 12 years, n = 49); 81 were assigned to prophylaxis and three to an on-demand regimen. Patients accumulated a total of 5239 exposure days (EDs), with 65 participants reaching > 50 EDs. In the 347 bleeds treated and evaluated by the investigator, hemostatic efficacy was rated as excellent or good in 96.3%. The median annualized spontaneous bleeding rate was 0.00 (Q1, Q3: 0.00, 2.20), and the median annualized bleeding rate was 3.69 (Q1, Q3: 0.00, 7.20) across all prophylaxis regimens. No participant developed an inhibitor. Conclusions rVIII-SingleChain is a novel rFVIII molecule showing excellent hemostatic efficacy and a favorable safety profile in a clinical study in children < 12 years of age with severe hemophilia A.

Comparative pharmacokinetics of rVIII-SingleChain and octocog alfa (Advate(®) ) in patients with severe haemophilia A.

BACKGROUND: rVIII-SingleChain, a novel recombinant factor VIII (rFVIII), has been designed as a B-domain truncated construct with covalently bonded heavy and light chains, aiming to increase binding affinity to von Willebrand factor (VWF). Preclinical studies confirmed greater affinity for VWF, giving improved pharmacokinetic and pharmacodynamic properties compared with full-length rFVIII. AIM: To investigate the pharmacokinetics of rVIII-SingleChain and compare them against those of full-length rFVIII. METHODS: This study enrolled 27 patients with severe haemophilia A in the AFFINITY clinical trial programme. After a 4-day washout period, all patients received a single infusion of 50 IU kg(-1) octocog alfa (Advate(®) ); after a ≥4-day postinfusion washout period, they received a single infusion of 50 IU kg(-1) rVIII-SingleChain. Blood samples for pharmacokinetic assessments of each product were collected before infusion (predose) and at 0.5, 1, 4, 8, 10, 24, 32, 48 and 72 h postinfusion for both products. RESULTS: rVIII-SingleChain had a longer mean half-life (t1/2 ) (14.5 vs. 13.3 h), lower mean clearance (CL) (2.64 vs. 3.68 mL h(-1) kg(-1) ), higher mean residence time (20.4 vs. 17.1 h) and larger mean AUCinf (2090 vs. 1550 IU?h dL(-1) ) than octocog alfa, respectively. The mean AUCinf after rVIII-SingleChain infusion was ~35% larger than after octocog alfa. A similar pattern was observed for AUC0-last . No serious adverse events or inhibitors were reported. CONCLUSIONS: rVIII-SingleChain has a favourable pharmacokinetic profile compared with octocog alfa and was well tolerated. The prolonged t1/2 , larger AUC and reduced CL of rVIII-SingleChain may permit longer dosing intervals, thereby improving patient adherence to prophylactic treatment.

Reversal of a hallmark of brain ageing: lipofuscin accumulation.

The prospect of removing cellular deposits of lipofuscin is of considerable interest because they may contribute to age related functional decline and disease. Here, we use a decapod crustacean model to circumvent a number of problems inherent in previous studies on lipofuscin loss. We employ (a) validated lipofuscin quantification methods, (b) an in vivo context, (c) essentially natural environmental conditions and (d) a situation without accelerated production of residual material or (e) application of pharmacological compounds. We use a novel CNS biopsy technique that produces both an anti-ageing effect and also permits longitudinal sampling of individuals, thus (f) avoiding conventional purely cross-sectional population data that may suffer from selective mortality biases. We quantitatively demonstrate that lipofuscin, accrued through normal ageing, can be lost from neural tissue. The mechanism of loss probably involves exocytosis and possibly blood transport. If non-disruptive ways to accelerate lipofuscin removal can be found, our results suggest that therapeutic reversal of this most universal manifestation of cellular ageing may be possible.

Interval estimation for Cohen's kappa as a measure of agreement.

Cohen's kappa statistic is a very well known measure of agreement between two raters with respect to a dichotomous outcome. Several expressions for its asymptotic variance have been derived and the normal approximation to its distribution has been used to construct confidence intervals. However, information on the accuracy of these normal-approximation confidence intervals is not comprehensive. Under the common correlation model for dichotomous data, we evaluate 95 per cent lower confidence bounds constructed using four asymptotic variance expressions. Exact computation, rather than simulation is employed. Specific conditions under which the use of asymptotic variance formulae is reasonable are determined.

Food safety and residues in Australian agricultural produce.

A brief history of food safety in Australia in the context of the development of scientific knowledge is presented. Australia's food and food commodity residue and contamination surveillance and monitoring programs are outlined. Although chemical residues are perceived as a major health risk by the general community, the risk of food causing illness or death because of chemical residues is low. The major threat to human health from food is microbiological contamination, in terms of deaths, sickness and economic loss. The emerging influences in food safety are scientific and technical developments, deregulation, social and demographic factors, and the media. The risk of disruption of domestic and export markets by food safety issues is considerable. The emergence of international standards for food production and processing will enable commercial contractual arrangements to minimise the frequency of disruptive food safety incidents.

Programs for surveillance and monitoring of antibacterial residues in Australia, 1989 to 1993.

The development of a State-based confirmatory testing capability for antibiotic residues in meat in Australia has allowed the rapid feedback to producers failing to comply with antibiotic maximum residue limits. The identification of problem areas in various categories of livestock, and subsequent focused surveillance programs, has reduced the prevalence of antibacterial residues in both domestic and export meat products. Failure to observe withholding periods of antibacterial drugs after treatment is the most significant cause of non-compliance. In the period July 1991 to June 1993 the compliance rate for antibacterial residues for all species was 99.9%.

Monitoring and surveillance in abattoirs of residues of antibacterial substances--a description of programs in Australia and the USA.

Australia and the USA are major international meat exporting countries. Both countries conduct programs to monitor and survey for antibacterial residues. Australian programs use a urine screening test, whereas the US programs use tissue fluids as the test medium. The development of surveillance programs to provide rapid feedback to producers is a feature of the Australian programs. The programs in each country compare favourably with regard to numbers of animals tested, results and action taken to prevent residues. The results of the Australian programs justify the promotion of a 'clean food' image for Australian meat products with respect to antibacterial drugs.

Teaching About Culture and Health in Ontario Medical Schools: Learning about culture and health through patient-centered care.

Questionnaire surveys and on-site visits determined that culture and health are not a formal part of a curriculum for all students in any undergraduate or family medicine residency program in Ontario medical schools. Electives and other opportunities exist, but only some students benefit. Suggestions from the programs on how to improve such learning and make it universally available are noted. Patient-centered care is endorsed as a suitable model for learning about culture and health in the context of community teaching practices.

Differences in blood supply to the cerebral cortex between sheep and calves during slaughter.

Using methylene blue boli, injected via an intracardiac catheter, the blood supply to the brain in two one- to 10-day-old calves and three adult sheep was studied during and after severance of the common carotid arteries and jugular veins. Passage of dye through cerebral vessels could not be observed in the exposed cerebrum of sheep after bilateral severance of major blood vessels. When vessels were severed on one side only, the passage of dye was noted for at least 53 seconds. In calves, after bilateral severance, sequential boli of dye could be detected passing through the cerebral vessels for more than 100 seconds. These results provide an explanation and support for the belief that there are major differences in the onset of insensibility between sheep and calves subsequent to severance of the common carotid arteries and jugular veins. The differences in blood supply to the brain which were demonstrated could be accounted for by differences in the blood supply to the brain by the vertebral artery in sheep and cattle. The effects of slaughter on the blood supply to the eye are discussed as a possible explanation of the disparity between results of studies in this general field which have used retinal responses in their investigations and those which have not.

Prophylaxis in rheumatic and nonrheumatic mitral insufficiency.

Clinical, epidemologic, and experimental findings suggest that acquired mitral insufficiency should not invariably the attributed to rheumatic fever. In this series of childhood cases, more than 50 per cent of the instances of "pure" mitral insufficiency did not have an acceptable past history of rheumatic fever in terms of the Jones Criteria for the diagnosis of rheumatic fever. The authors therefore recommend that daily antibacterial prophylaxis should be limited to those children with valvular heart disease who have had at least one of the major manifestations of the Jones Criteria. But all cases or acquired valvular heart disease should remain under continued clinical observation, and be given antibacterial therapy to prevent bacterial endocarditis of the damaged valves whenever indicated.