How local reference panels improve imputation in French populations

International audienceImputation servers offer the exclusive possibility to harness the largest public reference panelswhich have been shown to deliver very high precision in the imputation of European genomes. Manystudies have nonetheless stressed the importance of ‘study specific panels’ (SSPs) as an alternativeand have shown the benefits of combining public reference panels with SSPs. But such combinedapproaches are not attainable when using external imputation servers. To investigate how toconfront this challenge, we imputed 550 French individuals using either the University of Michiganimputation server with the Haplotype Reference Consortium (HRC) panel or an in‑house SSP of 850whole‑genome sequenced French individuals. With approximate geo‑localization of both our targetand SSP individuals we are able to pinpoint different scenarios where SSP‑based imputation wouldbe preferred over server‑based imputation or vice‑versa. This is achieved by showing to a high degreeof resolution the importance of the proximity of the reference panel to target individuals; with afocus on the clear added value of SSPs for estimating haplotype phase and for the imputation of rarevariants (minor allele‑frequency below 0.01). Such benefits were most evident for individuals fromthe same geographical regions in France as the SSP individuals. Overall, only 42.3% of all 125,442variants evaluated were better imputed with an SSP from France compared to an external referencepanel, however this rises to 58.1% for individuals from geographic regions well covered by the SSP.By investigating haplotype sharing and population fine‑structure in France, we show the importanceof including SSP haplotypes for imputation but also that they should ideally be combined with largepublic panels. In the absence of the unattainable results from a combined panel of the HRC and ourFrench SSP, we put forward a pragmatic solution where server‑based and SSP‑based imputationoutcomes can be combined based on comparing posterior genotype probabilities. We show that suchan approach can give a level of imputation accuracy in excess of what could be achieved with eitherstrategy alone. The results presented provide detailed insights into the accuracy of imputation thatshould be expected from different strategies for European populations

Adapted EXTREME regimen in the first-line treatment of fit, older patients with recurrent or metastatic head and neck squamous cell carcinoma (ELAN-FIT): a multicentre, single-arm, phase 2 trial

International audienceBackgroundA standard treatment for fit, older patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) is yet to be established. In the previous EXTREME trial, few older patients were included. We aimed to evaluate the efficacy and tolerance of an adapted EXTREME regimen in fit, older patients with recurrent or metastatic HNSCC.MethodsThis single-arm, phase 2 study was done at 22 centres in France. Eligible patients were aged 70 years or older and assessed as not frail (fit) using the ELAN Geriatric Evaluation (EGE) and had recurrent or metastatic HNSCC in the first-line setting that was not eligible for local therapy (surgery or radiotherapy), and an Eastern Cooperative Oncology Group performance status of 0–1. The adapted EXTREME regimen consisted of six cycles of fluorouracil 4000 mg/m2 on days 1–4, carboplatin with an area under the curve of 5 on day 1, and cetuximab on days 1, 8, and 15 (400 mg/m2 on cycle 1–day 1, and 250 mg/m2 subsequently), all intravenously, with cycles starting every 21 days. In patients with disease control after two to six cycles, cetuximab 500 mg/m2 was continued once every 2 weeks as maintenance therapy until disease progression or unacceptable toxicity. Granulocyte colony-stimulating factor was systematically administered and erythropoietin was recommended during chemotherapy. The study was based on the two-stage Bryant and Day design, combining efficacy and toxicity endpoints. The primary efficacy endpoint was objective response rate at week 12 after the start of treatment, assessed by central review (with an unacceptable rate of ≤15%). The primary toxicity endpoint was morbidity, defined as grade 4–5 adverse events, or cutaneous rash (grade ≥3) that required cetuximab to be discontinued, during the chemotherapy phase, or a decrease in functional autonomy (Activities of Daily Living score decrease ≥2 points from baseline) at 1 month after the end of chemotherapy (with an unacceptable morbidity rate of >40%). Analysis of the coprimary endpoints, and of safety in the chemotherapy phase, was based on the per-protocol population, defined as eligible patients who received at least one cycle of the adapted EXTREME regimen. Safety in the maintenance phase was assessed in all patients who received at least one dose of cetuximab as maintenance therapy. The study is registered with ClinicalTrials.gov, NCT01864772, and is completed.FindingsBetween Sept 27, 2013, and June 20, 2018, 85 patients were enrolled, of whom 78 were in the per-protocol population. 66 (85%) patients were male and 12 (15%) were female, and the median age was 75 years (IQR 72–79). The median number of chemotherapy cycles received was five (IQR 3–6). Objective response at week 12 was observed in 31 patients (40% [95% CI 30–51]) and morbidity events were observed in 24 patients (31% [22–42]). No fatal adverse events occurred. Four patients presented with a decrease in functional autonomy 1 month after the end of chemotherapy versus baseline. During chemotherapy, the most common grade 3–4 adverse events were haematological events (leukopenia [22 patients; 28%], neutropenia [20; 26%], thrombocytopenia [15; 19%], and anaemia [12; 15%]), oral mucositis (14; 18%), fatigue (11; 14%), rash acneiform (ten; 13%), and hypomagnesaemia (nine; 12%). Among 44 patients who received cetuximab during the maintenance phase, the most common grade 3–4 adverse events were hypomagnesaemia (six patients; 14%) and acneiform rash (six; 14%).InterpretationThe study met its primary objectives on objective response and morbidity, and showed overall survival to be as good as in younger patients treated with standard regimens, indicating that the adapted EXTREME regimen could be used in older patients with recurrent or metastatic HNSCC who are deemed fit with use of a geriatric evaluation tool adapted to patients with head and neck cancer, such as the EGE

Le dispositif LOOP : innovation ludopédagogique pour la réussite étudiante

International audienceLe dispositif LOOP : innovation ludopédagogique pour la réussite étudiant

Propos introductifs

International audienc

Des formations différenciées pour des réussites plurielles : le cas d'écri+ (ANR-17-NCUN-00015)

International audienceDes formations différenciées pour des réussites plurielles : le cas d'écri+ (ANR-17-NCUN-00015

Oxygenation management during veno-arterial ECMO support for cardiogenic shock: a multicentric retrospective cohort study

International audienceBackgound Hyperoxemia is common and associated with poor outcome during veno-arterial extracorporeal membrane oxygenation (VA ECMO) support for cardiogenic shock. However, little is known about practical daily management of oxygenation. Then, we aim to describe sweep gas oxygen fraction (F S O 2 ), postoxygenator oxygen partial pressure (P POST O 2 ), inspired oxygen fraction (F I O 2 ), and right radial arterial oxygen partial pressure (P a O 2 ) between day 1 and day 7 of peripheral VA ECMO support. We also aim to evaluate the association between oxygenation parameters and outcome. In this retrospective multicentric study, each participating center had to report data on the last 10 eligible patients for whom the ICU stay was terminated. Patients with extracorporeal cardiopulmonary resuscitation were excluded. Primary endpoint was individual mean F S O 2 during the seven first days of ECMO support (F S O 2 mean (day 1−7) ). Results Between August 2019 and March 2022, 139 patients were enrolled in 14 ECMO centers in France, and one in Switzerland. Among them, the median value for F S O 2 mean (day 1−7) was 70 [57; 79] % but varied according to center case volume. Compared to high volume centers, centers with less than 30 VA-ECMO runs per year were more likely to maintain F S O 2 ≥ 70% (OR 5.04, CI 95% [1.39; 20.4], p = 0.017). Median value for right radial P a O 2 mean (day 1−7) was 114 [92; 145] mmHg, and decreased from 125 [86; 207] mmHg at day 1, to 97 [81; 133] mmHg at day 3 ( p < 0.01). Severe hyperoxemia (i.e. right radial P a O 2 ≥ 300 mmHg) occurred in 16 patients (12%). P POST O 2 , a surrogate of the lower body oxygenation, was measured in only 39 patients (28%) among four centers. The median value of P POST O 2 mean (day 1−7) value was 198 [169; 231] mmHg. By multivariate analysis, age (OR 1.07, CI95% [1.03–1.11], p < 0.001), F S O 2 mean (day 1−3) (OR 1.03 [1.00-1.06], p = 0.039), and right radial P a O 2 mean (day 1−3) (OR 1.03, CI95% [1.00-1.02], p = 0.023) were associated with in-ICU mortality. Conclusion In a multicentric cohort of cardiogenic shock supported by VA ECMO, the median value for F S O 2 mean (day 1−7) was 70 [57; 79] %. P POST O 2 monitoring was infrequent and revealed significant hyperoxemia. Higher F S O 2 mean (day 1−3) and right radial P a O 2 mean (day 1−3) were independently associated with in-ICU mortality

Ariane ou l'immortel féminin. Préface

Tsvetaeva, Marina Ivanovna (1892-1941). AuteurVoutev, Florian. TraducteurInternational audiencePréface de l'ouvrage

Actualité bioéthique

International audienc

Description of acoustical Gaussian beams from the electromagnetic scheme of approximations and the on-axis localized approximation

International audienc

Contributions to hyperbolic 1-parameter inequalities

In this paper, we provide classes of hyperbolic inequality chains depending on parameter $n$. New refinements as well as new results are offered. In particular, inequality chains will be proved, including the classical cases $n=1$ and $2$.\