Link between Sum-Product and Gradient Projection Decoding of LDPC codes: an Intermediate Algorithm

Abstract-This paper investigates the connection between the classical Sum-Product (SP) decoder for Low Density Parity Check (LDPC) codes and the recently proposed Gradient Projection (GP) decoding scheme presented in [1]. A graphical model for GP is exhibited based on which we derive an intermediate algorithm which establishes a bridge between graphical based algorithms (SP and variants) and an optimization based algorithm (GP). A more practical decoding algorithm with improved performance and reduced complexity is also proposed. A complexity analysis is provided and performance are studied through Monte-Carlo simulations

Impact of Vutrisiran on Quality of Life and Physical Function in Patients with Hereditary Transthyretin-Mediated Amyloidosis with Polyneuropathy

INTRODUCTION: Hereditary transthyretin (ATTRv; v for variant) amyloidosis, also known as hATTR amyloidosis, is a progressive and fatal disease associated with rapid deterioration of physical function and patients' quality of life (QOL). Vutrisiran, a subcutaneously administered RNA interference (RNAi) therapeutic that reduces hepatic production of transthyretin, was assessed in patients with ATTRv amyloidosis with polyneuropathy in the pivotal HELIOS-A study. METHODS: The phase 3 open-label HELIOS-A study investigated the efficacy and safety of vutrisiran in patients with ATTRv amyloidosis with polyneuropathy, compared with an external placebo group from the APOLLO study of the RNAi therapeutic patisiran. Measures of QOL and physical function were assessed. RESULTS: At month 18, vutrisiran improved Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) total score (least squares mean difference [LSMD] in change from baseline [CFB]: –21.0; p = 1.84 × 10–10) and Norfolk QOL-DN domain scores, compared with external placebo. This benefit relative to external placebo was evident across all baseline polyneuropathy disability (PND) scores and most pronounced in patients with baseline PND scores I–II. Compared with external placebo, vutrisiran also demonstrated benefit in EuroQoL-Visual Analog Scale (EQ-VAS) score (LSMD in CFB: 13.7; nominal p = 2.21 × 10–7), 10-m walk test (LSMD in CFB: 0.239 m/s; p = 1.21 × 10–7), Rasch-built Overall Disability Score (LSMD in CFB: 8.4; p = 3.54 × 10–15), and modified body mass index (mBMI) (LSMD in CFB: 140.7; p = 4.16 × 10–15) at month 18. Overall, Norfolk QOL-DN, EQ-VAS, and mBMI improved from pretreatment baseline with vutrisiran, whereas all measures worsened from baseline in the external placebo group. At month 18, Karnofsky Performance Status was stable/improved from baseline in 58.2/13.1% with vutrisiran versus 34.7/8.1% with external placebo. CONCLUSION: Vutrisiran treatment provided significant clinical benefits in multiple measures of QOL and physical function in patients with ATTRv amyloidosis with polyneuropathy. Benefits were most pronounced in patients with earlier-stage disease, highlighting the importance of early diagnosis and treatment

TTR kinetic stabilizers and TTR gene silencing: a new era in therapy for familial amyloidotic polyneuropathies.

Transthyretin Familial Amyloid Polyneuropathy (TTR-FAP) is a rare disease with autosomal dominant transmission due to a point mutation of the TTR gene. By removing the main source of systemic mutant TTR, liver transplantation (LT) has become the reference therapy of this severe and fatal polyneuropathy of adult-onset, stopping disease progression in subgroup of patients. Recently, new therapeutic strategies have emerged, which intend to stabilize TTR or to silence the TTR gene. Amongst them, the TTR kinetic stabilizer tafamidis is the first drug approved in the EU. We shall review the natural history of TTR-FAP and the best indications for LT. Data on the efficacy, safety and tolerability of the TTR kinetic stabilizers, tafamidis and diflunisal, have been reviewed, from the pivotal Phase III clinical trials published in PubMed medical journals or presented at international meetings. We will review the ongoing phase III clinical trials of TTR gene silencing with RNAi therapeutics and ASO published in clinicaltrialgov. Due to the data on efficacy, tolerability, safety, tafamidis and diflunisal became the first line anti-amyloid treatment in stage 1 TTR-FAP. Both drugs slow progression of the disease. Only tafamidis got marketing authorization. We are waiting for results of the 2 phase III clinical trials of TTR gene silencing in varied stages of the disease

Early detection of skin and cardiac amyloid deposits among asymptomatic carriers of hereditary pathogenic transthyretin mutation with normal electroneuromyography

International audienc

Hijacking Europe: Counter‐European Strategies and Radical Right Mainstreaming during the Humanitarian Crisis Debate 2015–16*

Radical right European contestation is analyzed mainly as claims denouncing European integration. Less focus is put on narratives suggesting how a supposed 'truly European' political process should be and work. This paper explores how radical right actors use such counter-European claims within their competition strategies. Computer-assisted qualitative analysis of communication by Front National, Alternative for Germany and Fidesz during the humanitarian crisis debate 2015-16 demonstrates that radical right counter-Europeanism constitutes a nuanced tactical resource deployed to normalize nativist supply in the name of Europe. Unlike Eurorejectionist FN, Fidesz and AfD redefined Europe in nativist terms, attempting to draw legitimacy from association with European identity and cooperation. Concurrently, both actors justified Euronativism not only as antithetical to current EU values and political principles, but mainly as their more fundamental practice juxtaposed against 'not (truly) European elites', effectively 'hijacking' Europe from within. The findings deepen our understanding of radical right Europe-contesting competition strategies

Motor unit number index as an individual biomarker: Reference limits of intra-individual variability over time in healthy subjects.

Motor unit number index (MUNIX) is proposed to monitor neuromuscular disorders. Our objective is to determine the intra-individual variability over time of the MUNIX. In 11 different hospital centres, MUNIX was assessed twice, at least 3 months apart (range 90-360 days), in tibialis anterior (TA), abductor pollicis brevis (APB), abductor digiti minimi (ADM) and deltoid muscles in 118 healthy subjects. MUNIX sum score 2, 3 and 4 were respectively the sum of the MUNIX of the TA and ADM, of the TA, APB and ADM and of the TA, APB, ADM and deltoid muscles. The repeatability of the MUNIX was better for sum scores than for single muscle recordings. The variability of the MUNIX was independent of sex, age, interval between measurements and was lower for experienced than non-experienced operators. The 95th percentile of the coefficient of variability of the MUNIX sum score 2, 3 and 4 were respectively 22%, 18% and 15% for experienced operators. The MUNIX technique must be performed by experienced operators on several muscles to reduce its variability and improve its reliability. A variation of the MUNIX sum score ≥20% can be interpreted as a significant change of muscle innervation

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