Trials

OBJECTIVES: To assess the efficacy of several repurposed drugs to prevent hospitalisation or death in patients aged 65 or more with recent symptomatic SARS-CoV-2 infection (COVID-19) and no criteria for hospitalisation. TRIAL DESIGN: Phase III, multi-arm (5) and multi-stage (MAMS), randomized, open-label controlled superiority trial. Participants will be randomly allocated 1:1:1:1:1 to the following strategies: Arm 1: Control arm Arms 2 to 5: Experimental treatment arms Planned interim analyses will be conducted at regular intervals. Their results will be reviewed by an Independent Data and Safety Monitoring Board. Experimental arms may be terminated for futility, efficacy or toxicity before the end of the trial. New experimental arms may be added if new evidence suggests that other treatments should be tested. A feasibility and acceptability substudy as well as an immunological substudy will be conducted alongside the trial. PARTICIPANTS: Inclusion criteria are: 65-year-old or more; Positive test for SARS-CoV-2 on a nasopharyngeal swab; Symptoms onset within 3 days before diagnosis; No hospitalisation criteria; Signed informed consent; Health insurance. Exclusion criteria are: Inability to make an informed decision to participate (e.g.: dementia, guardianship); Rockwood Clinical Frailty Scale ≥7; Long QT syndrome; QTc interval > 500 ms; Heart rate 5.5 mmol/L or <3.5 mmol/L; Ongoing treatment with piperaquine, halofantrine, dasatinib, nilotinib, hydroxyzine, domperidone, citalopram, escitalopram, potent inhibitors or inducers of cytochrome P450 CYP3A4 isoenzyme, repaglinide, azathioprine, 6-mercaptopurine, theophylline, pyrazinamide, warfarin; Known hypersensitivity to any of the trial drugs or to chloroquine and other 4-aminoquinolines, amodiaquine, mefloquine, glafenine, floctafenine, antrafenine, ARB; Hepatic porphyria; Liver failure (Child-Pugh stage ≥B); Stage 4 or 5 chronic kidney disease (GFR <30 mL/min/1.73 m²); Dialysis; Hypersentivity to lactose; Lactase deficiency; Abnormalities in galactose metabolism; Malabsorption syndrome; Glucose-6-phosphate dehydrogenase deficiency; Symptomatic hyperuricemia; Ileus; Colitis; Enterocolitis; Chronic hepatitis B virus disease. The trial is being conducted in France in the Bordeaux, Corse, Dijon, Nancy, Paris and Toulouse areas as well as in the Grand Duchy of Luxembourg. Participants are recruited either at home, nursing homes, general practices, primary care centres or hospital outpatient consultations. INTERVENTION AND COMPARATOR: The four experimental treatments planned in protocol version 1.2 (April 8(th), 2020) are: (1) Hydroxychloroquine 200 mg, 2 tablets BID on day 0, 2 tablets QD from day 1 to 9; (2) Imatinib 400 mg, 1 tablet QD from day 0 to 9; (3) Favipiravir 200 mg, 12 tablets BID on day 0, 6 tablets BID from day 1 to 9; (4) Telmisartan 20 mg, 1 tablet QD from day 0 to 9. The comparator is a complex of vitamins and trace elements (AZINC Forme et Vitalité®), 1 capsule BID for 10 days, for which there is no reason to believe that they are active on the virus. In protocol version 1.2 (April 8th, 2020): People in the control arm will receive a combination of vitamins and trace elements; people in the experimental arms will receive hydroxychloroquine, or favipiravir, or imatinib, or telmisartan. MAIN OUTCOME: The primary outcome is the proportion of participants with an incidence of hospitalisation and/or death between inclusion and day 14 in each arm. RANDOMISATION: Participants are randomized in a 1:1:1:1:1 ratio to each arm using a web-based randomisation tool. Participants not treated with an ARB or ACEI prior to enrolment are randomized to receive the comparator or one of the four experimental drugs. Participants already treated with an ARB or ACEI are randomized to receive the comparator or one of the experimental drugs except telmisartan (i.e.: hydroxychloroquine, imatinib, or favipiravir). Randomisation is stratified on ACEI or ARBs treatment at inclusion and on the type of residence (personal home vs. nursing home). BLINDING (MASKING): This is an open-label trial. Participants, caregivers, investigators and statisticians are not blinded to group assignment. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): A total of 1057 participants will be enrolled if all arms are maintained until the final analysis and no additional arm is added. Three successive futility interim analyses are planned, when the number of participants reaches 30, 60 and 102 in the control arm. Two efficacy analyses (interim n°3 and final) will be performed successively. TRIAL STATUS: This describes the Version 1.2 (April 8(th), 2020) of the COVERAGE protocol that was approved by the French regulatory authority and ethics committee. The trial was opened for enrolment on April 15(th), 2020 in the Nouvelle Aquitaine region (South-West France). Given the current decline of the COVID-19 pandemic in France and its unforeseeable dynamic in the coming months, new trial sites in 5 other French regions and in Luxembourg are currently being opened. A revised version of the protocol was submitted to the regulatory authority and ethics committee on June 15(th), 2020. It contains the following amendments: (i) Inclusion criteria: age ≥65 replaced by age ≥60; time since first symptoms <3 days replaced by time since first symptoms <5 days; (ii) Withdrawal of the hydroxychloroquine arm (due to external data); (iii) increase in the number of trial sites. TRIAL REGISTRATION: The trial was registered on Clinical Trials.gov on April 22(nd), 2020 (Identifier: NCT04356495): and on EudraCT on April 10(th), 2020 (Identifier: 2020-001435-27). FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2)

The Incidence of AIDS-Defining Illnesses at a Current CD4 Count ≥200 Cells/µL in the Post-Combination Antiretroviral Therapy Era

The incidence of AIDS was higher in patients with a current CD4 count of 500-749 cells/µL compared to 750-999 cells/µL, but did not decrease further at higher CD4 levels. Results were similar in those virologically suppressed on combination antiretroviral therapy, suggesting immune reconstitution is incomplete until CD4 >750/µ

Long-term Mortality in HIV-Positive Individuals Virally Suppressed for >3 Years With Incomplete CD4 Recovery

Virally suppressed HIV-positive individuals on combination antiretroviral therapy who do not achieve a CD4 count >200 cells/µL have substantially increased long-term mortality. The increased mortality was seen across different patient groups and for all causes of deat

Single-heartbeat electromechanical wave imaging with optimal strain estimation using temporally unequispaced acquisition sequences

Electromechanical Wave Imaging (EWI) is a non-invasive, ultrasound-based imaging method capable of mapping the electromechanical wave (EW) in vivo, i.e., the transient deformations occurring in response to the electrical activation of the heart. Achieving the optimal imaging frame rates, in terms of the elastographic signal-to-noise ratio, to capture the EW in a full-view of the heart poses a technical challenge due to the limitations of conventional imaging sequences, in which the frame rate is low and tied to the imaging parameters. To achieve higher frame rates, EWI is typically performed in multiple small regions of interest acquired over separate heartbeats, which are then combined into a single view. However, the reliance on multiple heartbeats has previously precluded the method from its application in non-periodic arrhythmias such as fibrillation. Moreover, the frame rates achieved remain sub-optimal, because they are determined by the imaging parameters rather than being optimized to image the EW. In this paper, we develop a temporally-unequispaced acquisition sequence (TUAS) for which a wide range of frame rates are achievable independently of the imaging parameters, while maintaining a full view of the heart at high beam density. TUAS is first used to determine the optimal frame rate for EWI in a paced canine heart in vivo. The feasibility of performing single-heartbeat EWI during ventricular fibrillation is then demonstrated. These results indicate that EWI can be performed optimally, within a single heartbeat, during free breathing, and implemented in real time for periodic and non-periodic cardiac events

Packing arc-disjoint cycles in tournaments

A tournament is a directed graph in which there is a single arc between every pair of distinct vertices. Given a tournament T on n vertices, we explore the classical and parameterized complexity of the problems of determining if T has a cycle packing (a set of pairwise arc-disjoint cycles) of size k and a triangle packing (a set of pairwise arc-disjoint triangles) of size k. We refer to these problems as Arc-disjoint Cycles in Tournaments (ACT) and Arc-disjoint Triangles in Tournaments (ATT), respectively. Although the maximization version of ACT can be seen as the linear programming dual of the well-studied problem of finding a minimum feedback arc set (a set of arcs whose deletion results in an acyclic graph) in tournaments, surprisingly no algorithmic results seem to exist for ACT. We first show that ACT and ATT are both NP-complete. Then, we show that the problem of determining if a tournament has a cycle packing and a feedback arc set of the same size is NP-complete. Next, we prove that ACT and ATT are fixed-parameter tractable, they can be solved in 2^{O(k log k)} n^{O(1)} time and 2^{O(k)} n^{O(1)} time respectively. Moreover, they both admit a kernel with O(k) vertices. We also prove that ACT and ATT cannot be solved in 2^{o(sqrt{k})} n^{O(1)} time under the Exponential-Time Hypothesis

Smart Ultrasound Device for Non-Invasive Real-Time Myocardial Stiffness Quantification of the Human Heart

International audienceQuantitative assessment of myocardial stiffness is crucial to understand and evaluate cardiac biomechanics and function. Despite the recent progresses of ultrasonic shear wave elastography, quantitative evaluation of myocardial stiffness still remains a challenge because of myocardium location, motion, large elasticity changes and strong elastic anisotropy. In this paper we introduce a smart ultrasound approach for non-invasive real-time quantification of shear wave velocity (SWV) and elastic fractional anisotropy (FA) in locally transverse isotropic elastic medium such as the myocardium. We demonstrated, that this approach can quantify accurately SWV in the range of 1.5 to 6 m/s in transverse isotropic medium (FA<0.7) using numerical simulations. The approach was experimentally validated on calibrated phantoms and anisotropic ex vivo tissues. A mean absolute error of 0.22 m/s was found when compared to gold standard measurements. Finally, in vivo feasibility of myocardial anisotropic stiffness assessment was evaluated in four healthy volunteers on the antero-septo basal segment and on anterior free wall of the right ventricule (RV) in end-diastole. A mean longitudinal SWV of 1.08 ± 0.20 m/s was measured on the RV and 1.74 ± 0.51 m/s on the Septum with a good intra-volunteer reproducibility (± 0.18 m/s). This approach has the potential to become a clinical tool for the quantitative evaluation of myocardial stiffness and diastolic function

Improving decision-making and cognitive impulse control in bulimia nervosa by rTMS: An ancillary randomized controlled study

International audienceOBJECTIVE: Impaired decision-making and inhibitory control may be involved in the pathophysiology of psychiatric disorders like bulimia nervosa (BN). Their improvement after neuromodulation may underpin clinical improvement. We assessed the effects of rTMS on these cognitive functions in a sample of women with BN. METHODS: Thirty-nine participants (22 in a sham group and 17 in an rTMS group) were assessed before and after 10 high frequency rTMS sessions over the left dorsolateral prefrontal cortex (DLPFC). RESULTS: The between-group analyses revealed no differences in the final neuropsychological performances. The within-group analyses showed that inhibitory control improved in both the go/no-go task (p = .03) and the BIS cognitive impulsivity subscale (p = .01) in the rTMS group only. Switches toward good choices on the Iowa gambling task significantly improved in the rTMS group only (p = .002), and understanding of the task contingencies increased between the two assessments, also in the rTMS group only (p = .03). DISCUSSION: This preliminary evidence suggests that modulation of left DLPFC might improve two putative cognitive biomarkers of BN

Photoactivatable oligonucleotide probes to trap single-stranded DNA binding proteins: Updating the potential of 4-thiothymidine from a comparative study

Photoaffinity labeling (PAL) in combination with recent developments in mass spectrometry is a powerful tool for studying nucleic acid-protein interactions, enabling crosslinking of both partners through covalent bond formation. Such a strategy requires a preliminary study of the most judicious photoreactive group to crosslink efficiently with the target protein. In this study, we report a survey of three different photoreactive nucleobases (including a guanine functionalized with a benzophenone or a diazirine and the zero-length agent 4-thiothymine) incorporated in 30-mer oligonucleotides (ODN) containing a biotin moiety for selective trapping and enrichment of single-stranded DNA binding proteins (SSB). First, the conditions and efficiency of the photochemical reaction with a purified protein using human replication protein A as the relevant model was studied. Secondly, the ability of the probe as bait to photocrosslink and enrich SSB in cell lysate was addressed. Among the different ODN probes studied, we showed that 4-thiothymine was the most relevant: i) it allows efficient and specific trapping of SSB in whole cell extracts in a similar extent as the widely used diazirine, it features the advantages of a zero-length agent thus retaining the physicochemical properties of the ODN bait; iii) ODN including this photochemical agent are easily accessible. In combination with mass spectrometry, the probes incorporating this nucleobase are powerful tools for PAL strategies and can be added in the toolbox of the traditional photocrosslinkers for studying DNA-protein interactions. (C) 2018 Elsevier B.V. and Societe Francaise de Biochimie et Biologie Moleculaire (SFBBM). All rights reserved