Background and purpose
Hereditary transthyretin (hATTR) amyloidosis causes progressive polyneuropathy resulting from transthyretin (TTR) amyloid deposition throughout the body, including the ...peripheral nerves. The efficacy and safety of inotersen, an antisense oligonucleotide inhibitor of TTR protein production, were demonstrated in the pivotal NEURO‐TTR study in patients with hATTR polyneuropathy. Here, the long‐term efficacy and safety of inotersen are assessed in an ongoing open‐label extension (OLE) study.
Methods
Patients who completed NEURO‐TTR were eligible to enroll in the OLE (NCT02175004). Efficacy assessments included the modified Neuropathy Impairment Score plus seven neurophysiological tests composite score (mNIS + 7), the Norfolk Quality of Life – Diabetic Neuropathy (Norfolk QOL‐DN) questionnaire total score and the Short‐Form 36 Health Survey (SF‐36) Physical Component Summary (PCS) score. Safety and tolerability were also assessed.
Results
Overall, 97% (135/139) of patients who completed NEURO‐TTR enrolled in the OLE. Patients who received inotersen for 39 cumulative months in NEURO‐TTR and the OLE continued to show benefit; patients who switched from placebo to inotersen in the OLE demonstrated improvement or stabilization of neurological disease progression by mNIS + 7, Norfolk QOL‐DN and SF‐36 PCS. No new safety concerns were identified. There was no evidence of increased risk for grade 4 thrombocytopenia or severe renal events with increased duration of inotersen exposure.
Conclusion
Inotersen slowed disease progression and reduced deterioration of quality of life in patients with hATTR polyneuropathy. Early treatment with inotersen resulted in greater long‐term disease stabilization than delayed initiation. Routine platelet and renal safety monitoring were effective; no new safety signals were observed.
The objectives, instrumentation, methods and data leading up to launch of the NASA Living With a Star (LWS) Space Environment Testbed (SET) payload onboard the Air Force Research Laboratory ...Demonstration and Science Experiments (DSX) spacecraft are described. The experiments characterize the space radiation environment and how it affects hardware performance. The payload consists of a compact space weather instrument and a carrier containing four board experiments.
A comparison of two scrubbing mitigation schemes for Xilinx field programmable gate array devices is presented. The design of the scrubbers is briefly discussed along with an examination of ...mitigation limitations. Heavy ion data are then presented and analyzed.
Experimental results are presented on proton induced single-event-upsets (SEU) on a 65 nm silicon-on-insulator (SOI) SRAM. The low energy proton SEU results are very different for the 65 nm SRAM as ...compared with SRAMs fabricated in previous technology generations. Specifically, no upset threshold is observed as the proton energy is decreased down to 1 MeV; and a sharp rise in the upset cross-section is observed below 1 MeV. The increase below 1 MeV is attributed to upsets caused by direct ionization from the low energy protons. The implications of the low energy proton upsets are discussed for space applications of 65 nm SRAMs; and the implications for radiation assurance testing are also discussed.
We have compared the data retention of irradiated commercial NAND flash memories with that of unirradiated controls. For parts aged by baking at high temperature, there was a statistically ...significant difference between irradiated samples and unirradiated controls. For parts aged by repetitive Program/Erase (P/E) cycling, the effect of radiation was not statistically significant.
Variability of the space radiation environment is investigated with regard to parts categorization for total dose hardness assurance methods. It is shown that it can have a significant impact. A ...modified approach is developed that uses current environment models more consistently and replaces the radiation design margin concept with one of failure probability during a mission.
Silicon-germanium heterojunction bipolar transistor (SiGe HBT) heavy ion-induced current transients are measured using Sandia National Laboratories' microbeam and high- and low-energy broadbeam ...sources at the Grand Acce¿le¿rateur National d'Ions Lourds, Caen, France, and the University of Jyva¿skyla¿, Finland. The data were captured using a custom broadband IC package and real-time digital phosphor oscilloscopes with at least 16 GHz of analog bandwidth. These data provide detailed insight into the effects of ion strike location, range, and LET.
An advanced commercial 2Gbit NAND flash memory (90 nm technology, one bit/cell) has been characterized for TID and heavy ion SEE. Results are qualitatively similar to previous flash results in most ...respects, but we also detected a new dynamic failure mode
The low-energy proton energy spectra of all shielded space environments have the same shape. This shape is easily reproduced in the laboratory by degrading a high-energy proton beam, producing a ...high-fidelity test environment. We use this test environment to dramatically simplify rate prediction for proton direct ionization effects, allowing the work to be done at high-energy proton facilities, on encapsulated parts, without knowledge of the IC design, and with little or no computer simulations required. Proton direct ionization (PDI) is predicted to significantly contribute to the total error rate under the conditions investigated. Scaling effects are discussed using data from 65-nm, 45-nm, and 32-nm SOI SRAMs. These data also show that grazing-angle protons will dominate the PDI-induced error rate due to their higher effective LET, so PDI hardness assurance methods must account for angular effects to be conservative. We show that this angular dependence can be exploited to quickly assess whether an IC is susceptible to PDI.
The speed, tight timing requirements packaging and complicated error behavior of DDR2 and DDR3 SDRAMs pose significant challenges for single-event testing. Often, each new generation will require an ...expensive new tester with a state-of-the-art controller for the memory. We explore the trade-offs in the use of commercial FPGA based evaluation boards for radiation testing DDR2 and DDR3 SDRAMs. We evaluate the resulting data quality and discuss tester performance while also elucidating and comparing SEE susceptibilities in DDR2 and DDR3 SDRAMs.
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