Timing and severity of inhibitor development in recombinant versus plasma-derived factor VIII concentrates: a SIPPET analysis

Essentials Recombinant factor VIII (rFVIII) was contrasted with plasma-derived FVIII (pdFVIII). In previously untreated patients with hemophilia A, rFVIII led to more inhibitors than pdFVIII. Inhibitors with rFVIII developed earlier, and the peak rate was higher than with pdFVIII. Inhibitors with rFVIII were more severe (higher titre) than with pdFVIII. Summary: Background The development of neutralizing antibodies (inhibitors) against factor VIII (FVIII) is the most severe complication in the early phases of treatment of severe hemophilia A. Recently, a randomized trial, the Survey of Inhibitors in Plasma-Product Exposed Toddlers (SIPPET) demonstrated a 2-fold higher risk of inhibitor development in children treated with recombinant FVIII (rFVIII) products than with plasma-derived FVIII (pdFVIII) during the first 50 exposure days (EDs). Objective/Methods In this post-hoc SIPPET analysis we evaluated the rate of inhibitor incidence over time by every 5 EDs (from 0 to 50 EDs) in patients treated with different classes of FVIII product, made possible by a frequent testing regime. Results The highest rate of inhibitor development occurred in the first 10 EDs, with a large contrast between rFVIII and pdFVIII during the first 5 EDs: hazard ratio 3.14 (95% confidence interval [CI], 1.01\ue2\u80\u939.74) for all inhibitors and 4.19 (95% CI, 1.18\ue2\u80\u9314.8) for high-titer inhibitors. For patients treated with pdFVIII, the peak of inhibitor development occurred later (6\ue2\u80\u9310 EDs) and lasted for a shorter time. Conclusion These results emphasize the high immunologic vulnerability of patients during the earliest exposure to FVIII concentrates, with the strongest response to recombinant FVIII products

Investigating lipid–lipid and lipid–protein interactions in model membranes by ToF-SIMS

With the chemical imaging capability of ToF-SIMS, biological molecules are identified and localized in membranes without any chemical labels. We have developed a model membrane system made with supported Langmuir–Blodgett (LB) monolayers. This simplified model can be used with different combinations of molecules to form a membrane, and thus represents a bottom-up approach to study individual lipid–lipid or lipid–protein interactions. We have used ternary mixtures of sphingomyelin (SM), phosphatidylcholine (PC), and cholesterol (CH) in the model membrane to study the mechanism of domain formation and interactions between phospholipids and cholesterol. Domain structures are observed only when the acyl chain saturation is different for SM and PC in the mixture. The saturated lipid, whether it is SM or PC, is found to be localized with cholesterol, while the unsaturated one is excluded from the domain area. More complicated model membranes which involve a functional membrane protein glycophorin are also investigated and different membrane properties are observed compared to the systems without glycophorin

Numerical Evaluation of T-stress under Mixed Mode Loading Through the Use of Coarse Meshes

The present paper investigates the employment of coarse meshes in evaluating the T-stress with the displacement method. Several finite element analyses have been carried out with different mesh refinements and accuracies. Mode I and mixed mode I/II loadings have been considered in finite element analyses. Under mode I loading, single and double edge notched geometries have been considered, while plate with central crack has been considerd for mixed mode loading condition. The analyses are compared with the results by the well-nown stress based approach, and showed that the displacement method permits the evaluation of the T-stress with the employment of coarse meshes. By the way, several precautions must be taken when dealing with coarse and very coarse meshes.Peer reviewe