Moduli/Inflaton Mixing with Supersymmetry Breaking Field

A heavy scalar field such as moduli or an inflaton generally mixes with a field responsible for the supersymmetry breaking. We study the scalar decay into the standard model particles and their superpartners, gravitinos, and the supersymmetry breaking sector, particularly paying attention to decay modes that proceed via the mixing between the scalar and the supersymmetry breaking field. The impacts of the new decay processes on cosmological scenarios are also discussed; the modulus field generically produces too much gravitinos, and most of the inflation models tend to result in too high reheating temperature and/or gravitino overproduction

Curvatons in Supersymmetric Models

We study the curvaton scenario in supersymmetric framework paying particular attention to the fact that scalar fields are inevitably complex in supersymmetric theories. If there are more than one scalar fields associated with the curvaton mechanism, isocurvature (entropy) fluctuations between those fields in general arise, which may significantly affect the properties of the cosmic density fluctuations. We examine several candidates for the curvaton in the supersymmetric framework, such as moduli fields, Affleck-Dine field, $F$- and $D$-flat directions, and right-handed sneutrino. We estimate how the isocurvature fluctuations generated in each case affect the cosmic microwave background angular power spectrum. With the use of the recent observational result of the WMAP, stringent constraints on the models are derived and, in particular, it is seen that large fraction of the parameter space is excluded if the Affleck-Dine field plays the role of the curvaton field. Natural and well-motivated candidates of the curvaton are also listed.Comment: 34 pages, 5 figure

Astrophysical and Cosmological Implications of Large Volume String Compactifications

We study the spectrum, couplings and cosmological and astrophysical implications of the moduli fields for the class of Calabi-Yau IIB string compactifications for which moduli stabilisation leads to an exponentially large volume V ~ 10^{15} l_s^6 and an intermediate string scale m_s ~ 10^{11}GeV, with TeV-scale observable supersymmetry breaking. All K\"ahler moduli except for the overall volume are heavier than the susy breaking scale, with m ~ ln(M_P/m_{3/2}) m_{3/2} ~ (\ln(M_P/m_{3/2}))^2 m_{susy} ~ 500 TeV and, contrary to standard expectations, have matter couplings suppressed only by the string scale rather than the Planck scale. These decay to matter early in the history of the universe, with a reheat temperature T ~ 10^7 GeV, and are free from the cosmological moduli problem (CMP). The heavy moduli have a branching ratio to gravitino pairs of 10^{-30} and do not suffer from the gravitino overproduction problem. The overall volume modulus is a distinctive feature of these models and is an M_{planck}-coupled scalar of mass m ~ 1 MeV and subject to the CMP. A period of thermal inflation can help relax this problem. This field has a lifetime ~ 10^{24}s and can contribute to dark matter. It may be detected through its decays to 2\gamma or e^+e^-. If accessible the e^+e^- decay mode dominates, with Br(\chi \to 2 \gamma) suppressed by a factor (ln(M_P/m_{3/2}))^2. We consider the potential for detection of this field through different astrophysical sources and find that the observed gamma-ray background constrains \Omega_{\chi} <~ 10^{-4}. The decays of this field may generate the 511 keV emission line from the galactic centre observed by INTEGRAL/SPI.Comment: 31 pages, 2 figures; v2. refs adde

Moduli-Induced Gravitino Problem.

We investigate the cosmological moduli problem by studying a modulus decay in detail and find that the branching ratio of the gravitino production is generically of O(0.01-1), which causes another cosmological disaster. Consequently, the cosmological moduli problem cannot be solved simply by making the modulus mass heavier than 100 TeV. We also illustrate our results by explicitly calculating the branching ratio into the gravitinos in the mixed modulus--anomaly/KKLT- and racetrack-type models.Comment: 5 pages, 1 figure. v2: minor changes, note adde

Long-term safety and efficacy of patisiran for hereditary transthyretin-mediated amyloidosis with polyneuropathy: 12-month results of an open-label extension study

Background: Hereditary transthyretin-mediated amyloidosis is a rare, inherited, progressive disease caused by mutations in the transthyretin (TTR) gene. We assessed the safety and efficacy of long-term treatment with patisiran, an RNA interference therapeutic that inhibits TTR production, in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy. Methods: This multicentre, open-label extension (OLE) trial enrolled patients at 43 hospitals or clinical centres in 19 countries as of Sept 24, 2018. Patients were eligible if they had completed the phase 3 APOLLO or phase 2 OLE parent studies and tolerated the study drug. Eligible patients from APOLLO (patisiran and placebo groups) and the phase 2 OLE (patisiran group) studies enrolled in this global OLE trial and received patisiran 0·3 mg/kg by intravenous infusion every 3 weeks with plans to continue to do so for up to 5 years. Efficacy assessments included measures of polyneuropathy (modified Neuropathy Impairment Score +7 [mNIS+7]), quality of life, autonomic symptoms, nutritional status, disability, ambulation status, motor function, and cardiac stress, with analysis by study groups (APOLLO-placebo, APOLLO-patisiran, phase 2 OLE patisiran) based on allocation in the parent trial. The global OLE is ongoing with no new enrolment, and current findings are based on the interim analysis of the patients who had completed 12-month efficacy assessments as of the data cutoff. Safety analyses included all patients who received one or more dose of patisiran up to the data cutoff. This study is registered with ClinicalTrials.gov, NCT02510261. Findings: Between July 13, 2015, and Aug 21, 2017, of 212 eligible patients, 211 were enrolled: 137 patients from the APOLLO-patisiran group, 49 from the APOLLO-placebo group, and 25 from the phase 2 OLE patisiran group. At the data cutoff on Sept 24, 2018, 126 (92%) of 137 patients from the APOLLO-patisiran group, 38 (78%) of 49 from the APOLLO-placebo group, and 25 (100%) of 25 from the phase 2 OLE patisiran group had completed 12-month assessments. At 12 months, improvements in mNIS+7 with patisiran were sustained from parent study baseline with treatment in the global OLE (APOLLO-patisiran mean change –4·0, 95 % CI –7·7 to −0·3; phase 2 OLE patisiran –4·7, –11·9 to 2·4). Mean mNIS+7 score improved from global OLE enrolment in the APOLLO-placebo group (mean change from global OLE enrolment −1·4, 95% CI –6·2 to 3·5). Overall, 204 (97%) of 211 patients reported adverse events, 82 (39%) reported serious adverse events, and there were 23 (11%) deaths. Serious adverse events were more frequent in the APOLLO-placebo group (28 [57%] of 49) than in the APOLLO-patisiran (48 [35%] of 137) or phase 2 OLE patisiran (six [24%] of 25) groups. The most common treatment-related adverse event was mild or moderate infusion-related reactions. The frequency of deaths in the global OLE was higher in the APOLLO-placebo group (13 [27%] of 49), who had a higher disease burden than the APOLLO-patisiran (ten [7%] of 137) and phase 2 OLE patisiran (0 of 25) groups. Interpretation: In this interim 12-month analysis of the ongoing global OLE study, patisiran appeared to maintain efficacy with an acceptable safety profile in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy. Continued long-term follow-up will be important for the overall assessment of safety and efficacy with patisiran. Funding: Alnylam Pharmaceuticals

Long-term safety and efficacy of patisiran for hereditary transthyretin-mediated amyloidosis with polyneuropathy: 12-month results of an open-label extension study

© 2020 Elsevier Ltd. All rights reserved.Background: Hereditary transthyretin-mediated amyloidosis is a rare, inherited, progressive disease caused by mutations in the transthyretin (TTR) gene. We assessed the safety and efficacy of long-term treatment with patisiran, an RNA interference therapeutic that inhibits TTR production, in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy. Methods: This multicentre, open-label extension (OLE) trial enrolled patients at 43 hospitals or clinical centres in 19 countries as of Sept 24, 2018. Patients were eligible if they had completed the phase 3 APOLLO or phase 2 OLE parent studies and tolerated the study drug. Eligible patients from APOLLO (patisiran and placebo groups) and the phase 2 OLE (patisiran group) studies enrolled in this global OLE trial and received patisiran 0·3 mg/kg by intravenous infusion every 3 weeks with plans to continue to do so for up to 5 years. Efficacy assessments included measures of polyneuropathy (modified Neuropathy Impairment Score +7 [mNIS+7]), quality of life, autonomic symptoms, nutritional status, disability, ambulation status, motor function, and cardiac stress, with analysis by study groups (APOLLO-placebo, APOLLO-patisiran, phase 2 OLE patisiran) based on allocation in the parent trial. The global OLE is ongoing with no new enrolment, and current findings are based on the interim analysis of the patients who had completed 12-month efficacy assessments as of the data cutoff. Safety analyses included all patients who received one or more dose of patisiran up to the data cutoff. This study is registered with ClinicalTrials.gov, NCT02510261. Findings: Between July 13, 2015, and Aug 21, 2017, of 212 eligible patients, 211 were enrolled: 137 patients from the APOLLO-patisiran group, 49 from the APOLLO-placebo group, and 25 from the phase 2 OLE patisiran group. At the data cutoff on Sept 24, 2018, 126 (92%) of 137 patients from the APOLLO-patisiran group, 38 (78%) of 49 from the APOLLO-placebo group, and 25 (100%) of 25 from the phase 2 OLE patisiran group had completed 12-month assessments. At 12 months, improvements in mNIS+7 with patisiran were sustained from parent study baseline with treatment in the global OLE (APOLLO-patisiran mean change -4·0, 95 % CI -7·7 to -0·3; phase 2 OLE patisiran -4·7, -11·9 to 2·4). Mean mNIS+7 score improved from global OLE enrolment in the APOLLO-placebo group (mean change from global OLE enrolment -1·4, 95% CI -6·2 to 3·5). Overall, 204 (97%) of 211 patients reported adverse events, 82 (39%) reported serious adverse events, and there were 23 (11%) deaths. Serious adverse events were more frequent in the APOLLO-placebo group (28 [57%] of 49) than in the APOLLO-patisiran (48 [35%] of 137) or phase 2 OLE patisiran (six [24%] of 25) groups. The most common treatment-related adverse event was mild or moderate infusion-related reactions. The frequency of deaths in the global OLE was higher in the APOLLO-placebo group (13 [27%] of 49), who had a higher disease burden than the APOLLO-patisiran (ten [7%] of 137) and phase 2 OLE patisiran (0 of 25) groups. Interpretation: In this interim 12-month analysis of the ongoing global OLE study, patisiran appeared to maintain efficacy with an acceptable safety profile in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy. Continued long-term follow-up will be important for the overall assessment of safety and efficacy with patisiran.info:eu-repo/semantics/publishedVersio