Hepatitis C viral evolution in genotype 1 treatment-naïve and treatment-experienced patients receiving telaprevir-based therapy in clinical trials

Background: In patients with genotype 1 chronic hepatitis C infection, telaprevir (TVR) in combination with peginterferon and ribavirin (PR) significantly increased sustained virologic response (SVR) rates compared with PR alone. However, genotypic changes could be observed in TVR-treated patients who did not achieve an SVR. Methods: Population sequence analysis of the NS3•4A region was performed in patients who did not achieve SVR with TVR-based treatment. Results: Resistant variants were observed after treatment with a telaprevir-based regimen in 12% of treatment-naïve patients (ADVANCE; T12PR arm), 6% of prior relapsers, 24% of prior partial responders, and 51% of prior null responder patients (REALIZE, T12PR48 arms). NS3 protease variants V36M, R155K, and V36M+R155K emerged frequently in patients with genotype 1a and V36A, T54A, and A156S/T in patients with genotype 1b. Lower-level resistance to telaprevir was conferred by V36A/M, T54A/S, R155K/T, and A156S variants; and higher-level resistance to telaprevir was conferred by A156T and V36M+R155K variants. Virologic failure during telaprevir treatment was more common in patients with genotype 1a and in prior PR nonresponder patients and was associated with higher-level telaprevir-resistant variants. Relapse was usually associated with wild-type or lower-level resistant variants. After treatment, viral populations were wild-type with a median time of 10 months for genotype 1a and 3 weeks for genotype 1b patients. Conclusions: A consistent, subtype-dependent resistance profile was observed in patients who did not achieve an SVR with telaprevir-based treatment. The primary role of TVR is to inhibit wild-type virus and variants with lower-levels of resistance to telaprevir. The complementary role of PR is to clear any remaining telaprevir-resistant variants, especially higher-level telaprevir-resistant variants. Resistant variants are detectable in most patients who fail to achieve SVR, but their levels decline over time after treatment

Safety of growth hormone replacement in survivors of cancer and intracranial and pituitary tumours: a consensus statement

Growth hormone (GH) has been used for over 35 years, and its safety and efficacy has been studied extensively. Experimental studies showing the permissive role of GH/insulin-like growth factor 1 (IGF-I) in carcinogenesis have raised concerns regarding the safety of GH replacement in children and adults who have received treatment for cancer and those with intracranial and pituitary tumours. A consensus statement was produced to guide decision-making on GH replacement in children and adult survivors of cancer, in those treated for intracranial and pituitary tumours and in patients with increased cancer risk. With the support of the European Society of Endocrinology, the Growth Hormone Research Society convened a Workshop, where 55 international key opinion leaders representing 10 professional societies were invited to participate. This consensus statement utilized: (1) a critical review paper produced before the Workshop, (2) five plenary talks, (3) evidence-based comments from four breakout groups, and (4) discussions during report-back sessions. Current evidence reviewed from the proceedings from the Workshop does not support an association between GH replacement and primary tumour or cancer recurrence. The effect of GH replacement on secondary neoplasia risk is minor compared to host- and tumour treatment-related factors. There is no evidence for an association between GH replacement and increased mortality from cancer amongst GH-deficient childhood cancer survivors. Patients with pituitary tumour or craniopharyngioma remnants receiving GH replacement do not need to be treated or monitored differently than those not receiving GH. GH replacement might be considered in GH-deficient adult cancer survivors in remission after careful individual risk/benefit analysis. In children with cancer predisposition syndromes, GH treatment is generally contraindicated but may be considered cautiously in select patients

Utilisation des représentations continues des mots et des paramètres prosodiques pour la détection des erreurs dans les transcriptions automatiques de la parole

International audienc

COMETS AVIS 2019-40 - les publications à l'heure de la science ouverte

COMETS Comité d'éthique du CNRS Avis n°2019-4

Comets Opinion 2019-40 - Publications In The Open Science Era

COMETS CNRS ethics committee Opinion n°2019-4

Pharmacokinetics of Tenofovir Disoproxil Fumarate and Ritonavir-Boosted Saquinavir Mesylate Administered Alone or in Combination at Steady State

A phase I study was conducted to formally evaluate the steady-state pharmacokinetics (PK) of tenofovir disoproxil fumarate (TDF) and ritonavir (RTV)-boosted saquinavir mesylate (SQV) when coadministered in healthy volunteers. Forty subjects received multiple doses of TDF (300 mg, once daily) and SQV/RTV (1,000 mg/100 mg, twice daily) alone and together under steady-state conditions in an open-label, fixed sequence design. Blood samples for tenofovir (TFV) and SQV/RTV PK were drawn over respective 24- and 12-h dosing intervals, and drug concentrations were measured by liquid chromatography-tandem mass spectrometry. Safety was assessed periodically by clinical and laboratory monitoring. Thirty-two subjects completed the study and were fully evaluable; three subjects discontinued participation in the study due to adverse events, three subjects withdrew for personal reasons, and two subjects withdrew because of inadequate venous access for blood sampling. Steady-state TFV PK were not significantly altered upon coadministration with SQV/RTV. Steady-state SQV (administered as SQV/RTV) AUC(tau), C(max), and C(tau) increased 29, 22, and 47%, respectively, upon coadministration with TDF, and all subjects achieved a C(tau) of >100 ng/ml. These modestly increased SQV exposures are not clinically meaningful given its clinical use with RTV already results in >10-fold-higher SQV levels. Steady-state RTV AUC(tau) and C(max) levels were not significantly altered, whereas C(tau) was 23% higher upon coadministration of SQV/RTV and TDF. Thus, no clinically relevant interactions between TDF and RTV-boosted SQV were observed under conditions simulating clinical practice

Human Annotation of ASR Error Regions: is "gravity" a Sharable Concept for Human Annotators?

International audienceThis paper is concerned with human assessments of the severity of errors in ASR outputs. We did not design any guidelines so that each annotator involved in the study could consider the " seriousness " of an ASR error using their own scientific background. Eight human annotators were involved in an annotation task on three distinct corpora, one of the corpora being annotated twice, hiding this annotation in duplicate to the annotators. None of the computed results (inter-annotator agreement, edit distance, majority annotation) allow any strong correlation between the considered criteria and the level of seriousness to be shown, which underlines the difficulty for a human to determine whether a ASR error is serious or not

Low-Flow, Low-Gradient Severe Aortic Stenosis Despite Normal Ejection Fraction Is Associated With Severe Left Ventricular Dysfunction as Assessed by Speckle-Tracking Echocardiography: A Multicenter Study.

Background- Low-flow low-gradient (LFLG) is sometimes observed in severe aortic stenosis (AS) despite normal ejection fraction, but its frequency and mechanisms are still debated. We aimed to describe the characteristics of patients with LFLG AS and assess the presence of longitudinal left ventricular dysfunction in these patients. Methods and Results- In a multicenter prospective study, 340 consecutive patients with severe AS and normal ejection fraction were studied. Longitudinal left ventricular function was assessed by 2D-strain and global afterload by valvulo-arterial impedance. Patients were classified according to flow and gradient: low flow was defined as a stroke volume index ≤35 mL/m(2), low gradient as a mean gradient ≤40 mm Hg. Most patients (n=258, 75.9%) presented with high-gradient AS, and 82 patients (24.1%) with low-gradient AS. Among the latter, 52 (15.3%) presented with normal flow and low gradient and 30 (8.8%) with LFLG. As compared with normal flow and low gradient, patients with LFLG had more severe AS (aortic valve area=0.7±0.12 cm(2) versus 0.86±0.14 cm(2)), higher valvulo-arterial impedance (5.5±1.1 versus 4±0.8 mm Hg/mL/m(2)), and worse longitudinal left ventricular function (basal longitudinal strain=-11.6±3.4 versus -14.8±3%; P<0.001 for all). Conclusions- LFLG AS is observed in 9% of patients with severe AS and normal ejection fraction and is associated with high global afterload and reduced longitudinal systolic function. Patients with normal-flow low-gradient AS are more frequent and present with less severe AS, normal afterload, and less severe longitudinal dysfunction. Severe left ventricular longitudinal dysfunction is a new explanation to the concept of LFLG AS

Clinical predictive criteria associated with live birth following elective single embryo transfer

Objective: We aimed to define clinical criteria from the patients related to the occurrence of live birth in case of elective single embryo transfer (eSET). Study design: We analyzed retrospectively 409 eSET at day 2/3 between March 2005 and July 2012, proposed in case of (i) woman's age = 2 good quality embryos obtained (3-5/6-10 blastomeres at day 2/3 and = 30 kg/m(2), negatively associated with the occurrence of live birth. Conclusion: BMI appears to be the only clinical parameter statistically associated with delivery following eSET strategy in a good prognosis infertile population. (C) 2014 Elsevier Ireland Ltd. All rights reserved