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Summary: Background: We apply endoscopic ultrasound-guided fine needle aspiration biopsy to cytopathologically diagnose and sample nucleic acids from primary tumours regardless of the disease stage. Methods: 397 patients with proven pancreatic adenocarcinoma were included and followed up in a multicentre prospective study. DNA and mRNA were extracted from materials of primary tumours obtained by endoscopic ultrasound-guided fine needle aspiration biopsy and analysed using targeted deep sequencing and RNAseq respectively. Findings: The variant allele frequency of the KRAS mutation was used to evaluate the tumour cellularity, ranging from 15 to 20% in all cells, regardless of the tumour stage. The molecular profile of metastatic primary tumours significantly differed from other types of tumours, more frequently having TP53 mutations (p = 0.0002), less frequently having RNF43 mutations, and possessing more basal-like mRNA component (p = 0.001). Molecular markers associated with improved overall survival were: mutations in homologous recombination deficiency genes in patients who received first-line platinum-based chemotherapy (p = 0.025) and wild-type TP53 gene in patients with locally advanced tumours who received radio-chemotherapy (p = 0.01). The GemPred transcriptomic profile was associated with a significantly better overall survival in patients with locally advanced or metastatic pancreatic cancer who received a gemcitabine-based first-line treatment (p = 0.019). Interpretation: The combination of genomic and transcriptomic analyses of primary pancreatic tumours enables us to distinguish metastatic tumours from other tumour types. Our molecular strategy may assist in predicting overall survival outcomes for platinum or gemcitabine-based chemotherapies, as well as radio-chemotherapy. Funding: Institut National Du Cancer (BCB INCa_7294), CHU of Toulouse, Inserm and Ligue Nationale Contre le Cancer (CIT program).

Introduction Several randomised controlled trials have demonstrated that novel oral anticoagulants are safer compared with vitamin K antagonists for the management of non-valvular atrial fibrillation (NVAF) to prevent thromboembolic events in the general population. There is a growing interest in the use of apixaban in patients with end-stage renal disease (ESRD) undergoing peritoneal dialysis (PD) but there is a lack of randomised data in this population.Methods and analysis APIDP2 is a prospective parallel, randomised, open-label, blinded endpoint trial involving patients with ESRD undergoing chronic PD who have NVAF. A total of 178 participants will be recruited from 20 French PD centres. Eligible patients will be randomly assigned to receive either apixaban at a reduced dose of 2.5 mg two times per day (dose determined with the previous pharmacokinetic study APIDP1) or dose-adjusted to international normalised ratio (INR) target (2–3) coumadin therapy. Anticoagulation to prevent thromboembolic events will be initiated or changed according to the randomisation for a duration of 1 year. The primary outcome is a major or clinically relevant non-major bleeding from randomisation up to month 12, assessed according to the International Society on Thrombosis and Haemostasis Score. Secondary outcomes encompass an efficacy composite criterion combining stroke or transient ischaemic attack (TIA), cardiovascular death and thrombosis including myocardial infarction cumulated at 12 months. Bleeding events will be also classified according to Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) and Thrombolysis In Myocardial Infarction (TIMI) criteria and pharmacodynamics outcomes will evaluate the time within the INR target range of 2–3 in the warfarin arm over 1 year, and anti-Xa apixaban activity in case of bleeding events and at 1 month, 6 months and 12 months of follow-up in the apixaban arm. To demonstrate that apixaban is safer than warfarin at 1 year, assuming two interim analyses after 60 and 118 patients, a bilateral alpha risk of 5% and a power of 80%, 178 patients are needed in this randomised trial (effect size found from the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) Study among patients with creatinine clearance 25–30 ml/min), that is, 89 patients per group.Ethics and dissemination The study has been approved by the ethics committee Comité de Protection des Personnes Sud Est III – Lyon - FRANCE, CT number 2023-507544-37-00. Written informed consent is required for each participant. Findings will be presented at scientific meetings and published in peer-reviewed journals.Trial registration ClinicalTrials.gov, NCT06045858; European Clinical Trial System, CT number 2023-507544-37-00.

Abstract Background Postoperative atrial fibrillation (PoAF) after cardiac surgery has a high incidence of 30%, but its management is controversial. Two strategies are recommended without evidence of a superiority of one against the other: rate control with beta-blocker or rhythm control with amiodarone. Landiolol is a new-generation beta-blocker with fast onset and short half-life. One retrospective, single-center study compared landiolol to amiodarone for PoAF after cardiac surgery with a better hemodynamic stability and a higher rate of reduction to sinus rhythm with landiolol, justifying the need for a multicenter randomized controlled trial. Our aim is to compare landiolol to amiodarone in the setting of PoAF after cardiac surgery with the hypothesis of a higher rate of reduction to sinus rhythm with landiolol during the 48 h after the first episode of POAF. Methods The FAAC trial is a multicenter single-blind two parallel-arm randomized study, which planned to include 350 patients with a first episode of PoAF following cardiac surgery. The duration of the study is 2 years. The patients are randomized in two arms: a landiolol group and an amiodarone group. Randomization (Ennov Clinical®) is performed by the anesthesiologist in charge of the patient if PoAF is persistent for at least 30 min after correction of hypovolemia, dyskalemia, and absence of pericardial effusion on a transthoracic echocardiography done at bedside. Our hypothesis is an increase of the percentage of patients in sinus rhythm from 70 to 85% with landiolol in less than 48 h after onset of PoAF (alpha risk = 5%, power = 90%, bilateral test). Discussion The FAAC trial was approved by the Ethics Committee of EST III with approval number 19.05.08. The FAAC trial is the first randomized controlled trial comparing landiolol to amiodarone for PoAF after cardiac surgery. In case of higher rate of reduction with landiolol, this beta-blocker could be the drug of choice used in this context as to reduce the need for anticoagulant therapy and reduce the risk of complications of anticoagulant therapy for patients with a first episode of postoperative atrial fibrillation after cardiac surgery. Trial registration ClinicalTrials.gov NCT04223739. Registered on January 10, 2020.

There is no denying the importance of multilingualism in the 21st century; increased travels, student exchanges, global business, diplomacy, and security are mediated by communication. Education is the key to building a strong multilingual world community that will work for peace and stability. However, it may be often overlooked that a successful educational system is measured in part by the investment that governments place in early education ("Equality and Education" OECD report 2012). The first part of this paper reviews the essential benefits of early foreign language exposure and learning for the development of the whole child. It also looks at the historical changes of Foreign Language in the Elementary School (FLES) in the United States, along with some comparisons to European trends. In the second part, the article describes a FLES initiative at the K-12 level, launched three years ago in partnership with Murray State University in Kentucky that aims to kindle a love of and interest for foreign languages at an early age and whose cutting-edge approach aligns itself with some of the recent studies and trends mentioned below.

Background Daptomycin stands as a key IV antibiotic in treating MRSA infections. However, patients facing challenges with difficult venous access require alternative administration routes. This study aimed to evaluate the pharmacokinetic (PK) profile and safety of subcutaneous (SC) daptomycin. Patients and methods In a two-period, two-treatment, single-blind crossover Phase I trial (ClinicalTrials.gov NCT04434300), participants with no medical history received daptomycin (10 mg/kg) both IV and SC in a random order, with a minimum 2 week washout period together with matched placebo (NaCl 0.9%). Blood samples collected over 24 h facilitated PK comparison. Monte Carlo simulations assessed the PTA for various dosing regimens. Adverse events were graded according to Common Terminology Criteria for Adverse Events(CTCAE) v5.0. Results Twelve participants (aged 30.9 ± 24.4 years; 9 male,75%) were included. SC daptomycin exhibited delayed (median T max 0.5 h for IV versus 4 h for SC) and lower peak concentration than IV (C max = 132.2 ± 16.0 μg/mL for IV versus 57.3 ± 8.6 μg/mL for SC; P  < 0.001). SC AUC0–24 (937.3 ± 102.5 μg·h/mL) was significantly lower (P  = 0.005) than IV AUC0–24 (1056.3 ± 123.5 μg·h/mL) but was deemed bioequivalent. PTA demonstrated target AUC0–24 attainment for 100% of simulated individuals, for both 8 and 10 mg/kg/24 h SC regimens. Adverse events (AEs) related to SC daptomycin were more frequent than for SC placebo (25 versus 13, P  = 0.016). No serious AEs were reported. Conclusions Single-dose SC daptomycin infusion proved to be safe, exhibiting a bioequivalent AUC0–24 compared with the IV route. The SC route emerges as a potential and effective alternative when IV administration is not possible. [ABSTRACT FROM AUTHOR]

El artículo analiza los discursos político-pedagógicos regionales de mediados de los años 90, en discusión con las políticas nacionales universitarias. Interroga en estos, las formas en que las/ los “intelectuales” locales responden al conjunto de medidas que el menemismo adoptó para la universidad pública argentina y que regularon las formas de producción y circulación del conocimiento. En el estudio se aborda la centralidad de estos discursos, respecto a los denominados “grandes centros urbanos” en los que se produce conocimiento legítimo y válido, asumiendo una definición amplificada de “intelectuales”. Finalmente, se delimitan dos ejes temporales: de 1983 a 1990 y de 1993 a 1996, bajo el presupuesto de que existe una tensión en torno de la recepción de las políticas de los años 90, que osciló entre las luchas y el rechazo a las mismas y la necesidad de consolidar y legitimar el ámbito académico de la Facultad de Ciencias de la Educación.

Abstract Background Among palliative care (PC) patients who are administered paracetamol, the subcutaneous (SC) route is often an alternative to the intravenous (IV) route. Yet pharmacological and clinical data on whether these are equivalent pharmacokinetically are lacking. Many French palliative teams are now empirically using paracetamol by the SC route, but there are no data to support this practice. This trial aims to compare the pharmacokinetic (PK) parameters of paracetomol between the IV and SC routes in PC patients. Methods/design This is a randomized, open, crossover study in two PC centers. The primary endpoints are AUC0-t, AUC0-∞, Cmax, Vd, and t1/2. All adverse events will be reported for a safety analysis. Twenty adult PC patients with an IV device having spontaneous pain not related to care, with a numeric pain rate scale > 3/10, or having a systematic prescription of paracetamol as the usual treatment will be included. All patients also have to meet all eligibility criteria. Conclusion This is the first study comparing PK parameters for IV paracetamol versus SC paracetamol in PC patients. Trial registration ClinicalTrials.gov, NCT03944044. Registered on 4 June 2019. Committee for the protection of persons (CPP) 18.09.05.58206 approval 4 October 2018. National Drug Safety Agency (ANSM; Agence Nationale de Sécurité Médicament) MEDAECNAT-2018-09-00009 approval 29 November 2018.

ABSTRACT The relationships between fish size and sagitta otolith measurements were calculated for the first time for 15 species belonging to six families from the northern Brazilian coast. A total of 220 fish were sampled from the bycatch landed by the bottom-trawl industrial shrimp-fishing fleet between August and September 2016. All species had strong relationships between otolith measurements and fish total length with the coefficient of determination (r 2) ranging between 0.71 and 0.99. The variable most strongly related to fish total length was found to be the sagittal otolith length (OL) with 98% of the variability. These relationships are a useful tool to estimate length and mass of preyed fish from otoliths found in stomach contents of marine predators.