Tafamidis delays neurological progression comparably across Val30Met and non-Val30Met genotypes in transthyretin familial amyloid polyneuropathy.

BACKGROUND AND PURPOSE: To better characterize the effects of tafamidis in non-Val30Met patients with transthyretin familial amyloid polyneuropathy, this post hoc analysis compared the neurological results from a 12-month, open-label study of non-Val30Met versus Val30Met patients at month 12 from the 18-month, double-blind, placebo-controlled registration study. A baseline covariate adjusted analysis was used to control for differences in baseline neurological severity. METHODS: Neurological function was assessed using the Neuropathy Impairment Score - Lower Limbs (NIS-LL) in three cohorts: Val30Met tafamidis (n = 64), Val30Met placebo (n = 61) and non-Val30Met tafamidis (n = 21). The change in NIS-LL from baseline to month 12 for Val30Met and non-Val30Met tafamidis-treated patients was compared with the change from baseline at month 12 for Val30Met placebo-treated patients using a mixed-effects model for repeated measures (MMRM). RESULTS: The baseline adjusted mean (standard error) change in NIS-LL values at month 12 was similar for Val30Met [1.60 (0.78)] and non-Val30Met [1.62 (1.43)] tafamidis-treated patients and less than that observed in the Val30Met placebo-treated group [4.72 (0.77); P = 0.0055 for Val30Met and P = 0.0592 for non-Val30Met]. Based on the MMRM, the magnitude of change in both tafamidis-treated cohorts was similar across the range of observed baseline NIS-LL values, and was consistently less than that observed in the Val30Met placebo-treated group at month 12. CONCLUSIONS: This baseline-adjusted analysis demonstrated that tafamidis treatment delayed neurological progression comparably in Val30Met and non-Val30Met patients across a range of baseline NIS-LL values. Neurological progression in these two genotype groups may be more similar than previously considered.

The failure of amalgam dental restorations due to cyclic fatigue crack growth.

In this study a restored mandibular molar with different Class II amalgam preparations was examined to analyze the potential for restoration failure attributed to cyclic fatigue crack growth. A finite element analysis was used to determine the stress distribution along the cavo-surface margin which results from occlusal loading of each restoration. The cyclic crack growth rate of sub-surface flaws located along the dentinal cavo-surface margin were determined utilizing the Paris law. Based on similarities in material properties and lack of fatigue property data for dental biomaterials, the cyclic fatigue crack growth parameters for engineering ceramics were used to approximate the crack growth behavior. It was found that flaws located within the dentine along the buccal and lingual margins can significantly reduce the fatigue life of restored teeth. Sub-surface cracks as short as 25 microm were found capable of promoting tooth fracture well within 25 years from the time of restoration. Furthermore, cracks longer than 100 microm reduced the fatigue life to less than 5 years. Consequently, sub-surface cracks introduced during cavity preparation with conventional dental burrs may serve as a principal source for premature restoration failure.