This study aims to assess the safety, virological, and clinical outcomes of convalescent plasma transfusion (CPT) in immunocompromised patients hospitalized for coronavirus disease 2019 (COVID‐19). ...We conducted a retrospective multicenter cohort study that included all immunosuppressed patients with COVID‐19 and RNAemia from May 2020 to March 2023 treated with CPT. We included 81 patients with hematological malignancies (HM), transplants, or autoimmune diseases (69% treated with anti‐CD20). Sixty patients (74%) were vaccinated, and 14 had pre‐CPT serology >264 BAU/mL. The median delay between symptom onset and CPT was 23 days 13−31. At D7 post‐CPT, plasma PCR was negative in 43/64 patients (67.2%), and serology became positive in 25/30 patients (82%). Post‐CPT positive serology was associated with RNAemia negativity (p < 0.001). The overall mortality rate at D28 was 26%, being higher in patients with non‐B‐cell HM (62%) than with B‐cell HM (25%) or with no HM (11%) (p = 0.02). Patients receiving anti‐CD20 without chemotherapy had the lowest mortality rate (8%). Positive RNAemia at D7 was associated with mortality at D28 in univariate analysis (HR: 3.05 1.14−8.19). Eight patients had adverse events, two of which were severe but transient. Our findings suggest that CPT can abolish RNAemia and ameliorate the clinical course in immunocompromised patients with COVID‐19.
To describe the characteristics, treatment and outcome of isolated ANCA-associated scleritis at diagnosis compared with idiopathic scleritis with negative ANCA tests.
This retrospective multicentre ...case-control study was performed within the French Vasculitis Study Group (FVSG) network and in three French tertiary ophthalmologic centres. Data from patients with scleritis without any systemic manifestation and with positive ANCA results were compared with those of a control group of patients with idiopathic scleritis with negative ANCA tests.
A total of 120 patients, including 38 patients with ANCA-associated scleritis and 82 control patients, diagnosed between January 2007 and April 2022 were included. The median follow-up was 28 months (IQR 10-60). The median age at diagnosis was 48 years (IQR 33-60) and 75% were females. Scleromalacia was more frequent in ANCA-positive patients (P = 0.027) and 54% had associated ophthalmologic manifestations, without significant differences. ANCA-associated scleritis more frequently required systemic medications, including glucocorticoids (76% vs 34%; P < 0.001), and rituximab (P = 0.03) and had a lower remission rate after the first- and second-line treatment. Systemic ANCA-associated vasculitis (AAV) occurred in 30.7% of patients with PR3- or MPO-ANCA, after a median interval of 30 months (IQR 16.3-44). Increased CRP >5 mg/l at diagnosis was the only significant risk factor of progression to systemic AAV adjusted hazard ratio 5.85 (95% CI 1.10, 31.01), P = 0.038.
Isolated ANCA-associated scleritis is mostly anterior scleritis with a higher risk of scleromalacia than ANCA-negative idiopathic scleritis and is more often difficult to treat. One-third of patients with PR3- or MPO-ANCA scleritis progressed to systemic AAV.
Summary
Acquired factor V inhibitor (AFVI) is an extremely rare disorder that may cause severe bleeding. To identify factors associated with bleeding risk in AFVI patients, a national, multicentre, ...retrospective study was made including all AFVI patients followed in 21 centres in France between 1988 and 2015. All patients had an isolated factor V (FV) deficiency <50% associated with inhibitor activity. Patients with constitutional FV deficiency and other causes of acquired coagulation FV deficiencies were excluded. The primary outcome was incident bleeding and factors associated with the primary outcome were identified. Thirty‐eight (74 36–100 years, 42·1% females) patients with AFVI were analysed. Bleeding was reported in 18 (47·4%) patients at diagnosis and in three (7·9%) during follow‐up (7 0·2–48.7 months). At diagnosis, FV was <10% in 31 (81·6%) patients. Bleeding at diagnosis was associated with a prolonged prothrombin time that strongly correlated with the AFVI level measured in plasma {r = 0·63, 95% confidence interval (CI) 0·36–0·80, P < 0·05}. Bleeding onset during follow‐up was associated with a slow AFVI clearance (P < 0·001). The corresponding receiver operating characteristics curve showed that AFVI clearance was predictive of bleeding onset with an AFVI clearance of seven months with a sensitivity of 100% (95% CI: 29–100) and a specificity of 86% (95% CI: 57–98, P = 0·02). Kaplan–Meier analysis showed that AFVI clearance >7 months increased the risk of bleeding by 8 (95% CI: 0·67–97, P = 0·075). Prothrombin time at diagnosis and time for clearance of FV inhibitor during follow‐up are both associated with bleeding in patients with AFVI.
The European Friedreich's Ataxia Consortium for Translational Studies (EFACTS) investigates the natural history of Friedreich's ataxia. We aimed to assess progression characteristics and to identify ...patient groups with differential progression rates based on longitudinal 4-year data to inform upcoming clinical trials in Friedreich's ataxia.
EFACTS is a prospective, observational cohort study based on an ongoing and open-ended registry. Patients with genetically confirmed Friedreich's ataxia were seen annually at 11 clinical centres in seven European countries (Austria, Belgium, France, Germany, Italy, Spain, and the UK). Data from baseline to 4-year follow-up were included in the current analysis. Our primary endpoints were the Scale for the Assessment and Rating of Ataxia (SARA) and the activities of daily living (ADL). Linear mixed-effect models were used to analyse annual disease progression for the entire cohort and subgroups defined by age of onset and ambulatory abilities. Power calculations were done for potential trial designs. This study is registered with ClinicalTrials.gov, NCT02069509.
Between Sept 15, 2010, and Nov 20, 2018, of 914 individuals assessed for eligibility, 602 patients were included. Of these, 552 (92%) patients contributed data with at least one follow-up visit. Annual progression rate for SARA was 0·82 points (SE 0·05) in the overall cohort, and higher in patients who were ambulatory (1·12 0·07) than non-ambulatory (0·50 0·07). ADL worsened by 0·93 (SE 0·05) points per year in the entire cohort, with similar progression rates in patients who were ambulatory (0·94 0·07) and non-ambulatory (0·91 0·08). Although both SARA and ADL showed slightly greater worsening in patients with typical onset (symptom onset at ≤24 years) than those with late onset (symptom onset ≥25 years), differences in progression slopes were not significant. For a 2-year parallel-group trial, 230 (115 per group) patients would be required to detect a 50% reduction in SARA progression at 80% power: 118 (59 per group) if only individuals who are ambulatory are included. With ADL as the primary outcome, 190 (95 per group) patients with Friedreich's ataxia would be needed, and fewer patients would be required if only individuals with early-onset are included.
Our findings for stage-dependent progression rates have important implications for clinicians and researchers, as they provide reliable outcome measures to monitor disease progression, and enable tailored sample size calculation to guide upcoming clinical trial designs in Friedreich's ataxia.
European Commission, Voyager Therapeutics, and EuroAtaxia.
The ALICE Experiment at CERN’s Large Hadron Collider (LHC) has undergone a major upgrade during LHC Long Shutdown 2 in 2019-2021, which includes a new computing system called O 2 (Online-Offline). To ...ensure the efficient operation of the upgraded experiment and of its newly designed computing system, a reliable, high performance, full-featured experiment control system has also been developed and deployed at LHC Point 2. The ALICE Experiment Control System (AliECS) is a microservices-oriented system based on state-of-the-art cluster management technologies that emerged recently in the distributed and high-performance computing ecosystem. It is designed, developed and maintained as a comprehensive solution and single entry point for control of experiment data acquisition (up to 3.5 TB/s) and processing. This communication describes the AliECS architecture by providing an in-depth overview of the system’s components, interfaces, features, and design elements, as well as its performance. It also reports on the experience with AliECS during the first year of ALICE Run 3 data taking with LHC beam, including integration and operational challenges, and lessons learned from real-world use.
Objective
To foster trial‐readiness of coenzyme Q8A (COQ8A)‐ataxia, we map the clinicogenetic, molecular, and neuroimaging spectrum of COQ8A‐ataxia in a large worldwide cohort, and provide first ...progression data, including treatment response to coenzyme Q10 (CoQ10).
Methods
Cross‐modal analysis of a multicenter cohort of 59 COQ8A patients, including genotype–phenotype correlations, 3D‐protein modeling, in vitro mutation analyses, magnetic resonance imaging (MRI) markers, disease progression, and CoQ10 response data.
Results
Fifty‐nine patients (39 novel) with 44 pathogenic COQ8A variants (18 novel) were identified. Missense variants demonstrated a pleiotropic range of detrimental effects upon protein modeling and in vitro analysis of purified variants. COQ8A‐ataxia presented as variable multisystemic, early‐onset cerebellar ataxia, with complicating features ranging from epilepsy (32%) and cognitive impairment (49%) to exercise intolerance (25%) and hyperkinetic movement disorders (41%), including dystonia and myoclonus as presenting symptoms. Multisystemic involvement was more prevalent in missense than biallelic loss‐of‐function variants (82–93% vs 53%; p = 0.029). Cerebellar atrophy was universal on MRI (100%), with cerebral atrophy or dentate and pontine T2 hyperintensities observed in 28%. Cross‐sectional (n = 34) and longitudinal (n = 7) assessments consistently indicated mild‐to‐moderate progression of ataxia (SARA: 0.45/year). CoQ10 treatment led to improvement by clinical report in 14 of 30 patients, and by quantitative longitudinal assessments in 8 of 11 patients (SARA: −0.81/year). Explorative sample size calculations indicate that ≥48 patients per arm may suffice to demonstrate efficacy for interventions that reduce progression by 50%.
Interpretation
This study provides a deeper understanding of the disease, and paves the way toward large‐scale natural history studies and treatment trials in COQ8A‐ataxia. ANN NEUROL 2020;88:251–263
BatFix: Repairing language model-based transpilation Ramos, Daniel; Lynce, Inês; Manquinho, Vasco ...
ACM transactions on software engineering and methodology,
07/2024, Letnik:
33, Številka:
6
Journal Article
Recenzirano
Odprti dostop
To keep up with changes in requirements, frameworks, and coding practices, software organizations might need to migrate code from one language to another. Source-to-source migration, or ...transpilation, is often a complex, manual process. Transpilation requires expertise both in the source and target language, making it highly laborious and costly. Languages models for code generation and transpilation are becoming increasingly popular. However, despite capturing code-structure well, code generated by language models is often spurious and contains subtle problems. We propose BatFix , a novel approach that augments language models for transpilation by leveraging program repair and synthesis to fix the code generated by these models. BatFix takes as input both the original program, the target program generated by the machine translation model, and a set of test cases and outputs a repaired program that passes all test cases. Experimental results show that our approach is agnostic to language models and programming languages. BatFix can locate bugs spawning multiple lines and synthesize patches for syntax and semantic bugs for programs migrated from Java to C++ and Python to C++ from multiple language models, including, OpenAI’s Codex .
Induced magnetospheres form around planetary bodies with atmospheres through the interaction of the solar wind with their ionosphere. Induced magnetospheres are highly dependent on the solar wind ...conditions and have only been studied with single spacecraft missions in the past. Without simultaneous measurements of solar wind variations and phenomena in the magnetosphere, establishing a link between both can only be done indirectly, using statistics over a large set of measurements. This gap in knowledge could be addressed by a multi-spacecraft plasma mission, optimized for studying global spatial and temporal variations in the magnetospheric system around Venus, which hosts the most prominent example of an induced magnetosphere in our solar system. The MVSE mission comprises four satellites, of which three are identical scientific spacecraft, carrying the same suite of instruments probing different regions of the induced magnetosphere and the solar wind simultaneously. The fourth spacecraft is the transfer vehicle which acts as a relay satellite for communications at Venus. In this way, changes in the solar wind conditions and extreme solar events can be observed, and their effects can be quantified as they propagate through the Venusian induced magnetosphere. Additionally, energy transfer in the Venusian induced magnetosphere can be investigated. The scientific payload includes instrumentation to measure the magnetic field, electric field, and ion–electron velocity distributions. This study presents the scientific motivation for the mission as well as requirements and the resulting mission design. Concretely, a mission timeline along with a complete spacecraft design, including mass, power, communication, propulsion and thermal budgets are given. This mission was initially conceived at the Alpbach Summer School 2022 and refined during a week-long study at ESA’s Concurrent Design Facility in Redu, Belgium.
•Multi-spacecraft plasma physics mission concept to Venus.•Dynamics of induced magnetospheres due to variations in the solar wind.•Magnetospheric reaction due to extreme solar events.
Epilepsy is the most common neurological disease in the world, affecting 50 million people, with the majority living in low- and middle-income countries (LMICs). A major focus of epilepsy treatment ...in LMICs has been task-sharing the identification and care for epilepsy by community health workers (CHWs). The present study aimed to assess the knowledge, attitudes, and practices (KAPs) of CHWs towards epilepsy in Mozambique.
One hundred and thirty-five CHWs completed a questionnaire that included socio-demographic characteristics and 44-items divided into six subscales pertaining to KAPs towards epilepsy (QKAP-EPI) across nine districts of Sofala, Mozambique. The internal consistency was examined to evaluate the reliability of the instrument (QKAP-EPI). The association between sociodemographic variables and QKAP-EPI subscales was examined using linear regression models.
The internal consistency was moderate for two subscales (causes of epilepsy, α = 0.65; medical treatment, α = 0.694), acceptable for cultural treatment (α = 0.797) and excellent for 2 subscales (safety and risks, α = 0.926; negative attitudes, α = 0.904). Overall, CHWs demonstrated accurate epilepsy knowledge (medical treatment: mean = 1.63, SD = 0.28; safety/risks: mean = 1.62, SD = 0.59). However, CHWs reported inaccurate epilepsy knowledge of the causes, negative attitudes, as well as culturally specific treatments for epilepsy, such as: "if a person with epilepsy burns when set on fire they cannot be treated". Knowledge about how to manage epileptic seizures varied across the different emergency care practices, from the accurate belief that it is not advisable to place objects in the individual's mouth during an epileptic seizure, to the wrong perception of the need to hold the person in seizures to control seizures. Heterogeneity in the level of epilepsy knowledge was observed among CHWs, when considering epilepsy according to the local names as treatable ("Dzumba") and other forms as untreatable ("Nzwiti").
CHWs knowledge of medical treatment and epilepsy safety/risks were adequate. However, information on the causes of epilepsy, stigmatizing attitudes, cultural treatment, and some knowledge of epileptic seizure management were low. These areas of poor knowledge should be the focus of educating CHWs in increasing their ability to provide quality care for patients with epilepsy in Mozambique.
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