Aim\nMethods\nResults\nDiscussion\nSystematic Review Registration\nTraditionally, early phase clinical trials in oncology have been performed in patients based on safety risk-benefit assessment.... Show moreAim\nMethods\nResults\nDiscussion\nSystematic Review Registration\nTraditionally, early phase clinical trials in oncology have been performed in patients based on safety risk-benefit assessment. Therapeutic transition to immuno-oncology may open new opportunities for studies in healthy volunteers, which are conducted faster and are less susceptible to confounders. Aim of this study was to investigate to what extent this approach is utilized and whether pharmacodynamic endpoints are evaluated in these early phase trials. We conducted a comprehensive review of clinical trials with healthy volunteers using immunotherapies potentially relevant for oncology.\nLiterature searches according to PRISMA guidelines and after registration in PROSPERO were conducted in PubMed, Embase, Web of Science and Cochrane databases with the cut-off date 20 October 2020, using search terms of relevant targets in immuno-oncology. Articles describing clinical trials with immunotherapeutics in healthy volunteers with a mechanism relevant for oncology were included. "Immunotherapeutic" was defined as compounds exhibiting effects through immunological targets. Data including study design and endpoints were extracted, with specific attention to pharmacodynamic endpoints and safety.\nIn total, we found 38 relevant immunotherapeutic compounds tested in HVs, with 86% of studies investigating safety, 82% investigating the pharmacokinetics (PK) and 57% including at least one pharmacodynamic (PD) endpoint. Most of the observed adverse events (AEs) were Grade 1 and 2, consisting mostly of gastrointestinal, cutaneous and flu-like symptoms. Severe AEs were leukopenia, asthenia, syncope, headache, flu-like reaction and liver enzymes increase. PD endpoints investigated comprised of cytokines, immune and inflammatory biomarkers, cell counts, phenotyping circulating immune cells and ex vivo challenge assays.\nHealthy volunteer studies with immuno-oncology compounds have been performed, although not to a large extent. The integration of healthy volunteers in well-designed proof-of-mechanism oriented drug development programs has advantages and could be pursued more in the future, since integrative clinical trial protocols may facilitate early dose selection and prevent cancer patients to be exposed to non-therapeutic dosing regimens.\nhttps://www.crd.york.ac.uk/prospero/display_record.php?RecordID=210861, identifier CRD42020210861. Show less
Abstract The Egyptian-Greek contact situation has lasted almost a thousand years and many documents have been preserved to us from this period. In this paper, we apply a new quantitative approach... Show moreAbstract The Egyptian-Greek contact situation has lasted almost a thousand years and many documents have been preserved to us from this period. In this paper, we apply a new quantitative approach to this rich corpus of documentary papyri to map the relationships between the linguistic variables (the variant spellings) and several non-linguistic variables. A multidimensional scaling of the co-occurrences of the linguistic variables shows that there is a strong association between most of the Greek variant spellings that can be explained by Egyptian phonological transfer, while others do not typically co-occur with them. Several new linguistic variables not yet connected to Egyptian phonological transfer also show a strong relation with the first group of features, some of them representing the same phonological transfer processes. A comparison of the contexts in which these variables are used allows us to further substantiate this observation: several of the previously and newly Egyptian-associated variables turn out to have a strong correlation with bilingual Egyptian-Greek documents or occur in Egyptian dominated environments. The spelling variants are chronologically dependent and different features are typically associated with different historical periods illustrating changes taking place in the Egyptian Greek contact variety over time. A multiple correspondence analysis shows that the variables strongly interact, illustrating the importance of a multifactorial approach combining various linguistic and non-linguistic factors. Show less
When Lucretius invokes Calliope as his dux at the end of the proem to Book VI (92-95), the echo of I 1 in VI 94 reinforces a more general correspondence between Calliope and Venus, whom Lucretius... Show moreWhen Lucretius invokes Calliope as his dux at the end of the proem to Book VI (92-95), the echo of I 1 in VI 94 reinforces a more general correspondence between Calliope and Venus, whom Lucretius had invoked as his socia in the proem to Book I (24). This paper argues that the two goddesses share the same double identity, as they both represent a twofold aspect of the poem, namely the profound interdependence of form and content. This twofold aspect is cunningly embodied in an interlingual pun on Epicurus’ name, which makes him an ἐπίκουρος to his own philosophy. Show less
Experiments with indigenous languages as medium of instruction have been ongoing in francophone Africa. These experiments have not been generalized to all schools by educational authorities and... Show moreExperiments with indigenous languages as medium of instruction have been ongoing in francophone Africa. These experiments have not been generalized to all schools by educational authorities and have been limited to the first few years of primary education. A more generalized approach to using indigenous languages as medium of instruction can contribute to improve the outcomes of education. However, when is such a development likely to occur and which languages should be chosen? This article explores these questions using the case of Burkina Faso as an example. We show that it will be practically possible to use a limited number of indigenous languages as medium of instruction, rather than all languages spoken in the country. In order to do so, we introduce an approximate assessment of which languages are easy to learn and to teach, for speakers of which other languages. We demonstrate that a gradual transition towards indigenous languages will become a necessity if the present trend of increased participation in education continues into the future. In order for this to happen, careful planning and preparation will be essential; we conclude with a brief examination of what such planning and preparation might consist of. Show less
Adolescent decision-making has been characterized as risky, and a heightened reward sensitivity may be one of the aspects contributing to riskier choice-behavior. Previous studies have targeted... Show moreAdolescent decision-making has been characterized as risky, and a heightened reward sensitivity may be one of the aspects contributing to riskier choice-behavior. Previous studies have targeted reward-sensitivity in adolescence and the neurobiological mechanisms of reward processing in the adolescent brain. In recent examples, researchers aim to disentangle the contributions of risk- and reward-sensitivity to adolescent risk-taking. Here, we discuss recent findings of adolescent's risk preferences and the associated neural mechanisms. We highlight potential frameworks that target individual differences in risk preferences in an effort to understand adolescent risk-taking, and with an ultimate goal of leveraging undesirable levels of risk taking. Show less