High-Energy Proton Testing of Sensitive Electronics for use on Modular Infrared Molecules and Ices Sensor (MIRMIS) Instrument

The Comet Interceptor (CI) mission is ESA\u27s first F class mission, selected in June 2019. This mission consists of three spacecraft: Spacecraft A (main spacecraft), Spacecraft B1 (supplied by the Japanese space agency JAXA), and Spacecraft B2. In this paper, we highlight the Modular Infrared Molecular and Ices Sensor (MIRMIS) instrument, which is integrated into the CI Spacecraft A\u27s scientific payload. In addition to hardware contributions from Finland (VTT Finland) and the UK (University of Oxford), the MIRMIS instrument team includes members from the University of Helsinki and NASA\u27s Goddard Space Flight Centre. MIRMIS covers the spectral range of 0.9 to ~25 μm. This paper presents the preliminary high-proton-energy radiation test results of MIRMIS’ near-infrared detector arraysensitive electronic components. Proton beam testing is performed to estimate Single Event Effects (SEE) on the PCB boards and SEE and Total Non-Ionizing Dose (TNID)/ Displacement Damage (DD) on the detectors. The tests were conducted at the Paul Scherrer Institute (PSI) Proton Irradiation Facility (PIF), Villigen, Switzerland. The levels for the tests were based on the mission requirements for the ESA Comet Interceptor mission: 3 years (at 1 AU- Segment 1) and 2 years (at 0.9 AU- Segment 2). The DD levels from the analysis were equivalent to 1e11 protons/cm2 with an energy of 50 MeV. The electronics are exposed to high-energy protons causing Single Event Effects (SEE) which may induce potentially destructive and non-destructive effects. The test items primarily included the InGaAs image sensors (SCD Cardinal640, standard and low noise), Xilinx Spartan-6 FPGAs (Field Programmable Gate Arrays), and other proximity electronics. The proton energies were varied from 50 to 200 MeV, at fluxes of 106 to 108 particles/cm2/s. No events were observed on the standard Cardinal640 sensor at target fluences between 1.00E+10 to 1.00E+11 particles/cm2. FPGAs did not show any susceptibility to TNID at fluences up to 1.00E+11 (particles/cm2)

Risdiplam in Patients Previously Treated with Other Therapies for Spinal Muscular Atrophy: An Interim Analysis from the JEWELFISH Study

INTRODUCTION: Risdiplam is a survival of motor neuron 2 (SMN2) splicing modifier for the treatment of patients with spinal muscular atrophy (SMA). The JEWELFISH study (NCT03032172) was designed to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of risdiplam in previously treated pediatric and adult patients with types 1-3 SMA. Here, an analysis was performed after all patients had received at least 1 year of treatment with risdiplam. METHODS: Patients with a confirmed diagnosis of 5q-autosomal recessive SMA between the ages of 6 months and 60 years were eligible for enrollment. Patients were previously enrolled in the MOONFISH study (NCT02240355) with splicing modifier RG7800 or treated with olesoxime, nusinersen, or onasemnogene abeparvovec. The primary objectives of the JEWELFISH study were to evaluate the safety and tolerability of risdiplam and investigate the PK after 2 years of treatment. RESULTS: A total of 174 patients enrolled: MOONFISH study (n = 13), olesoxime (n = 71 patients), nusinersen (n = 76), onasemnogene abeparvovec (n = 14). Most patients (78%) had three SMN2 copies. The median age and weight of patients at enrollment was 14.0 years (1-60 years) and 39.1 kg (9.2-108.9 kg), respectively. About 63% of patients aged 2-60 years had a baseline total score of less than 10 on the Hammersmith Functional Motor Scale-Expanded and 83% had scoliosis. The most common adverse event (AE) was upper respiratory tract infection and pyrexia (30 patients each; 17%). Pneumonia (four patients; 2%) was the most frequently reported serious AE (SAE). The rates of AEs and SAEs per 100 patient-years were lower in the second 6-month period compared with the first. An increase in SMN protein was observed in blood after risdiplam treatment and was comparable across all ages and body weight quartiles. CONCLUSIONS: The safety and PD of risdiplam in patients who were previously treated were consistent with those of treatment-naïve patients

Two-year efficacy and safety of risdiplam in patients with type 2 or non-ambulant type 3 spinal muscular atrophy (SMA)

Risdiplam is an oral, survival of motor neuron 2 (SMN2) pre-mRNA splicing modifier approved for the treatment of spinal muscular atrophy (SMA). SUNFISH (NCT02908685) Part 2, a Phase 3, randomized, double-blind, placebo-controlled study, investigated the efficacy and safety of risdiplam in type 2 and non‑ambulant type 3 SMA. The primary endpoint was met: a significantly greater change from baseline in 32-item Motor Function Measure (MFM32) total score was observed with risdiplam compared with placebo at month 12. After 12 months, all participants received risdiplam while preserving initial treatment blinding. We report 24-month efficacy and safety results in this population. Month 24 exploratory endpoints included change from baseline in MFM32 and safety. MFM‑derived results were compared with an external comparator. At month 24 of risdiplam treatment, 32% of patients demonstrated improvement (a change of ≥ 3) from baseline in MFM32 total score; 58% showed stabilization (a change of ≥ 0). Compared with an external comparator, a treatment difference of 3.12 (95% confidence interval [CI] 1.67-4.57) in favor of risdiplam was observed in MFM-derived scores. Overall, gains in motor function at month 12 were maintained or improved upon at month 24. In patients initially receiving placebo, MFM32 remained stable compared with baseline (0.31 [95% CI - 0.65 to 1.28]) after 12 months of risdiplam; 16% of patients improved their score and 59% exhibited stabilization. The safety profile after 24 months was consistent with that observed after 12 months. Risdiplam over 24 months resulted in further improvement or stabilization in motor function, confirming the benefit of longer-term treatment

COVID-19 vaccine-readiness for anti-CD20-depleting therapy in autoimmune diseases

Although most autoimmune diseases are considered to be CD4 T cell- or antibody-mediated, many respond to CD20-depleting antibodies that have limited influence on CD4 and plasma cells. This includes rituximab, oblinutuzumab and ofatumumab that are used in cancer, rheumatoid arthritis and off-label in a large number of other autoimmunities and ocrelizumab in multiple sclerosis. Recently, the COVID-19 pandemic created concerns about immunosuppression in autoimmunity, leading to cessation or a delay in immunotherapy treatments. However, based on the known and emerging biology of autoimmunity and COVID-19, it was hypothesised that while B cell depletion should not necessarily expose people to severe SARS-CoV-2-related issues, it may inhibit protective immunity following infection and vaccination. As such, drug-induced B cell subset inhibition, that controls at least some autoimmunities, would not influence innate and CD8 T cell responses, which are central to SARS-CoV-2 elimination, nor the hypercoagulation and innate inflammation causing severe morbidity. This is supported clinically, as the majority of SARS-CoV-2-infected, CD20-depleted people with autoimmunity have recovered. However, protective neutralizing antibody and vaccination responses are predicted to be blunted until naive B cells repopulate, based on B cell repopulation kinetics and vaccination responses, from published rituximab and unpublished ocrelizumab (NCT00676715, NCT02545868) trial data, shown here. This suggests that it may be possible to undertake dose interruption to maintain inflammatory disease control, while allowing effective vaccination against SARS-CoV-29, if and when an effective vaccine is available

Minimizing plasma temperature for antimatter mixing experiments

The ASACUSA collaboration produces a beam of antihydrogen atoms by mixing pure positron and antiproton plasmas in a strong magnetic field with a double cusp geometry. The positrons cool via cyclotron radiation inside the cryogenic trap. Low positron temperature is essential for increasing the fraction of antihydrogen atoms which reach the ground state prior to exiting the trap. Many experimental groups observe that such plasmas reach equilibrium at a temperature well above the temperature of the surrounding electrodes. This problem is typically attributed to electronic noise and plasma expansion, which heat the plasma. The present work reports anomalous heating far beyond what can be attributed to those two sources. The heating seems to be a result of the axially open trap geometry, which couples the plasma to the external (300 K) environment via microwave radiation

Search for an interaction mediated by axion-like particles with ultracold neutrons at the PSI

We report on a search for a new, short-range, spin-dependent interaction using a modified version of the experimental apparatus used to measure the permanent neutron electric dipole moment at the Paul Scherrer Institute. This interaction, which could be mediated by axion-like particles, concerned the unpolarized nucleons (protons and neutrons) near the material surfaces of the apparatus and polarized ultracold neutrons stored in vacuum. The dominant systematic uncertainty resulting from magnetic-field gradients was controlled to an unprecedented level of approximately 4 pT/cm using an array of optically-pumped cesium vapor magnetometers and magnetic-field maps independently recorded using a dedicated measurement device. No signature of a theoretically predicted new interaction was found, and we set a new limit on the product of the scalar and the pseudoscalar couplings $g_sg_p\lambda^2 < 8.3 \times 10^{-28}\,\text{m}^2$ (95% C.L.) in a range of $5\,\mu\text{m} < \lambda < 25\,\text{mm}$ for the monopole-dipole interaction. This new result confirms and improves our previous limit by a factor of 2.7 and provides the current tightest limit obtained with free neutrons