Long-term survival in people with transthyretin amyloid cardiomyopathy who took tafamidis: A Plain Language Summary

WHAT IS THIS PLAIN LANGUAGE SUMMARY ABOUT?: This summary presents the results from an ongoing, long-term extension study that followed an earlier study called ATTR-ACT. People who took part in this extension study and ATTR-ACT have a type of heart disease known as transthyretin amyloid cardiomyopathy (ATTR-CM for short), which causes heart failure and death. In ATTR-ACT, people took either a medicine called tafamidis or a placebo (a pill that looks like the study drug but does not contain any active ingredients) for up to 2½ years. So far, in the long-term extension study, people have continued taking tafamidis, or switched from taking a placebo to tafamidis, for another 2½ years. Researchers looked at how many people died in ATTR-ACT and the extension study. The long-term extension study is expected to end in 2027, so these are interim (not final) results. WHAT DID RESEARCHERS FIND OUT?: In the extension study of ATTR-ACT, the risk of dying was lower in people who took tafamidis continuously throughout ATTR-ACT and the extension study than in people who took placebo in ATTR-ACT and switched to tafamidis in the extension study. WHAT DO THE RESULTS MEAN?: Taking tafamidis increases how long people with ATTR-CM live. People with ATTR-CM who take tafamidis early and continuously are more likely to live longer than those who do not. These results highlight the importance of early detection and treatment in people with ATTR-CM. Clinical Trial Registration: NCT01994889 (ClinicalTrials.gov) Clinical Trial Registration: NCT02791230 (ClinicalTrials.gov)

Molecular Mechanics of the α-Actinin Rod Domain: Bending, Torsional, and Extensional Behavior

α-Actinin is an actin crosslinking molecule that can serve as a scaffold and maintain dynamic actin filament networks. As a crosslinker in the stressed cytoskeleton, α-actinin can retain conformation, function, and strength. α-Actinin has an actin binding domain and a calmodulin homology domain separated by a long rod domain. Using molecular dynamics and normal mode analysis, we suggest that the α-actinin rod domain has flexible terminal regions which can twist and extend under mechanical stress, yet has a highly rigid interior region stabilized by aromatic packing within each spectrin repeat, by electrostatic interactions between the spectrin repeats, and by strong salt bridges between its two anti-parallel monomers. By exploring the natural vibrations of the α-actinin rod domain and by conducting bending molecular dynamics simulations we also predict that bending of the rod domain is possible with minimal force. We introduce computational methods for analyzing the torsional strain of molecules using rotating constraints. Molecular dynamics extension of the α-actinin rod is also performed, demonstrating transduction of the unfolding forces across salt bridges to the associated monomer of the α-actinin rod domain

Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy.

BACKGROUND: Transthyretin amyloid cardiomyopathy is caused by the deposition of transthyretin amyloid fibrils in the myocardium. The deposition occurs when wild-type or variant transthyretin becomes unstable and misfolds. Tafamidis binds to transthyretin, preventing tetramer dissociation and amyloidogenesis. METHODS: In a multicenter, international, double-blind, placebo-controlled, phase 3 trial, we randomly assigned 441 patients with transthyretin amyloid cardiomyopathy in a 2:1:2 ratio to receive 80 mg of tafamidis, 20 mg of tafamidis, or placebo for 30 months. In the primary analysis, we hierarchically assessed all-cause mortality, followed by frequency of cardiovascular-related hospitalizations according to the Finkelstein-Schoenfeld method. Key secondary end points were the change from baseline to month 30 for the 6-minute walk test and the score on the Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS), in which higher scores indicate better health status. RESULTS: In the primary analysis, all-cause mortality and rates of cardiovascular-related hospitalizations were lower among the 264 patients who received tafamidis than among the 177 patients who received placebo (P<0.001). Tafamidis was associated with lower all-cause mortality than placebo (78 of 264 [29.5%] vs. 76 of 177 [42.9%]; hazard ratio, 0.70; 95% confidence interval [CI], 0.51 to 0.96) and a lower rate of cardiovascular-related hospitalizations, with a relative risk ratio of 0.68 (0.48 per year vs. 0.70 per year; 95% CI, 0.56 to 0.81). At month 30, tafamidis was also associated with a lower rate of decline in distance for the 6-minute walk test (P<0.001) and a lower rate of decline in KCCQ-OS score (P<0.001). The incidence and types of adverse events were similar in the two groups. CONCLUSIONS: In patients with transthyretin amyloid cardiomyopathy, tafamidis was associated with reductions in all-cause mortality and cardiovascular-related hospitalizations and reduced the decline in functional capacity and quality of life as compared with placebo. (Funded by Pfizer; ATTR-ACT ClinicalTrials.gov number, NCT01994889 .)

Effect of sputtering on ferromagnet-oxide-silicon spin injection contacts

The authors have fabricated metal-oxide-semiconductor (MOS) contacts on silicon for spin injection and detection and characterized them by internal photoemission and capacitance-voltage (C-V) measurements with the aim of extracting the metal- semiconductor effective work-function mismatch that determines the magnetoresistance between such contacts. The authors show that sputter deposition of these contacts induces high levels of negative charge in the oxide localized close to the metal-oxide interface. This is seen to affect the electrostatics of the MOS contact and could thereby impact its contact resistance, and in turn, the magnetoresistance that one can obtain. (C) 2011 American Vacuum Society. [DOI: 10.1116/1.3601119

Effect of Metal Gate Granularity Induced Random Fluctuations on Si Gate-All-Around Nanowire MOSFET 6-T SRAM Cell Stability

In this paper, we present a variability-aware 3-D mixed-mode device simulation study of Si Gate-All-Around (GAA) Nanowire MOSFET (NWFET) based 6-T SRAM bit-cell stability and performance considering metal-gate granularity (MGG) induced intrinsic device random fluctuations and quantum corrected room temperature drift-diffusion transport. The impact of MGG contributed intrinsic variability on Si GAA n- and p-NWFETs based SRAM cell Static Noise Margins (SNM), write and read delay time are statistically analyzed. Our statistical simulations predict acceptable stability for the Si NWFET 6-T SRAM cell with V DD downscaling up to 0.5 V. The simulation estimated mean hold SNM values follow a lowering trend with V DD downscaling, similar to the hold SNM experimental data reported in literature for Si GAA NWFET based SRAM arrays. We further show a linear variation in statistical variance of hold SNM with gate metal grain size and work function

Effect of Band-to-Band Tunneling on Junctionless Transistors

We evaluate the impact of band-to-band tunneling (BTBT) on the characteristics of n-channel junctionless transistors (JLTs). A JLT that has a heavily doped channel, which is fully depleted in the OFF state, results in a significant band overlap between the channel and drain regions. This overlap leads to a large BTBT of electrons from the channel to the drain in n-channel JLTs. This BTBT leads to a nonnegligible increase in the OFF-state leakage current, which needs to be understood and alleviated. In the case of n-channel JLTs, tunneling of electrons from the valence band of the channel to the conduction band of the drain leaves behind holes in the channel, which would raise the channel potential. This triggers a parasitic bipolar junction transistor formed by the source, channel, and drain regions induced in a JLT in the OFF state. Tunneling current is observed to be a strong function of the silicon body thickness and doping of a JLT. We present guidelines to optimize the device for high ON-to-OFF current ratio. Finally, we compare the OFF-state leakage of bulk JLTs with that of silicon-on-insulator JLTs