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Michal Zygarowicz,1,* Joanna Kacperczyk-Bartnik,2,3,* Janusz Sierdzinski,4 Cezary Wojtyla,5,6 Piotr Pierzynski,5,6 Grzegorz Manka,7 Mariusz Kiecka,7 Robert Z Spaczynski,8 Piotr Piekarski,9 Beata Banaszewska,10 Artur Jakimiuk,11,12 Tadeusz Issat,13 Wojciech Rokita14,15 ,†Jakub Mlodawski,14,15 Maria Szubert,3,16,17 Piotr Sieroszewski,16,18 Grzegorz Raba,19,20 Kamil Szczupak,19,20 Tomasz Kluz,21 Marek Kluza,21 Michal Lipa,3,22 Damian Warzecha,5,22 Miroslaw Wielgos,23,24 Ewa Koc-Zorawska,25,26 Marcin Zorawski,26,27 Piotr Laudanski5,6,28 1Students’ Scientific Group Affiliated to the Department of Obstetrics, Gynecology and Gynecological Oncology, Medical University of Warsaw, Warsaw, Poland; 2II Department of Obstetrics and Gynaecology, Medical University of Warsaw, Warsaw, Poland; 3Club 35. Polish Society of Gynecologists and Obstetricians, Wrocław, Poland; 4Department of Medical Informatics and Telemedicine, Medical University of Warsaw, Warsaw, Poland; 5OVIklinika Infertility Center, Warsaw, Poland; 6Women’s Health Research Institute, Calisia University, Kalisz, Poland; 7Angelius Provita Hospital, Katowice, Poland; 8Center for Gynecology, Obstetrics and Infertility Treatment Pastelova, Poznan, Poland; 9Division of Infertility and Reproductive Endocrinology, Department of Gynecology, Obstetrics and Gynecological Oncology, Poznan University of Medical Sciences, Poznan, Poland; 10Chair and Department of Laboratory Diagnostics, Poznan University of Medical Sciences, Poznan, Poland; 11Department of Obstetrics and Gynecology, Central Clinical Hospital of the Ministry of Interior, Warsaw, Poland; 12Center of Reproductive Health, Institute of Mother and Child in Warsaw, Warsaw, Poland; 13Department of Obstetrics and Gynecology, Institute of Mother and Child in Warsaw, Warsaw, Poland; 14Collegium Medicum Jan Kochanowski University in Kielce, Kielce, Poland; 15Clinic of Obstetrics and Gynecology, Provincial Combined Hospital in Kielce, Kielce

Sexual selection and sexual antagonism are important drivers of eco-evolutionary processes. The evolution of traits shaped by these processes depends on their genetic architecture, which remains poorly studied. Here, implementing a quantitative genetics approach using diallel crosses of the bulb mite, Rhizoglyphus robini, we investigated the genetic variance that underlies a sexually selected weapon that is dimorphic among males and female fecundity. Previous studies indicated that a negative genetic correlation between these two traits likely exists. We found male morph showed considerable additive genetic variance, which is unlikely to be explained solely by mutation-selection balance, indicating the likely presence of large-effect loci. However, a significant magnitude of inbreeding depression also indicates that morph expression is likely to be condition-dependent to some degree and that deleterious recessives can simultaneously contribute to morph expression. Female fecundity also showed a high degree of inbreeding depression, but the variance in female fecundity was mostly explained by epistatic effects, with very little contribution from additive effects. We found no significant genetic correlation, nor any evidence for dominance reversal, between male morph and female fecundity. The complex genetic architecture underlying male morph and female fecundity in this system has important implications for our understanding of the evolutionary interplay between purifying selection and sexually antagonistic selection.

Item does not contain fulltext, BACKGROUND: We evaluated the pharmacokinetics of tenofovir alafenamide fumarate (TAF) and tenofovir in a subset of African children enrolled in the CHAPAS-4 trial. METHODS: Children aged 3-15 years with human immunodeficiency virus infection failing first-line antiretroviral therapy were randomized to emtricitabine/TAF versus standard-of-care nucleoside reverse transcriptase inhibitor combination, plus dolutegravir, atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir. Daily emtricitabine/TAF was dosed according to World Health Organization (WHO)-recommended weight bands: 120/15 mg in children weighing 14 to <25 kg and 200/25 mg in those weighing ≥25 kg. At steady state, 8-9 blood samples were taken to construct pharmacokinetic curves. Geometric mean (GM) area under the concentration-time curve (AUC) and the maximum concentration (Cmax) were calculated for TAF and tenofovir and compared to reference exposures in adults. RESULTS: Pharmacokinetic results from 104 children taking TAF were analyzed. GM (coefficient of variation [CV%]) TAF AUClast when combined with dolutegravir (n = 18), darunavir/ritonavir (n = 34), or lopinavir/ritonavir (n = 20) were 284.5 (79), 232.0 (61), and 210.2 (98) ng*hour/mL, respectively, and were comparable to adult reference values. When combined with atazanavir/ritonavir (n = 32), TAF AUClast increased to 511.4 (68) ng*hour/mL. For each combination, tenofovir GM (CV%) AUCtau and Cmax remained below reference values in adults taking 25 mg TAF with a boosted protease inhibitors. CONCLUSIONS: In children, TAF combined with boosted PIs or dolutegravir and dosed according to WHO-recommended weight bands provides TAF and tenofovir concentrations previously demonstrated to be well tolerated and effective in adults. These data provide the first evidence for use of these combinations in African children. CLINICAL TRIALS REGISTRATION: ISRCTN22964075.

Contains fulltext : 300164.pdf (Publisher’s version ) (Open Access), BACKGROUND: Dolutegravir (DTG), combined with a backbone of 2 nucleoside reverse transcriptase inhibitors, is currently the preferred first-line treatment for human immunodeficiency virus (HIV) in childhood. CHAPAS4 is an ongoing randomized controlled trial investigating second-line treatment options for children with HIV. We did a nested pharmacokinetic (PK) substudy within CHAPAS4 to evaluate the DTG exposure in children with HIV taking DTG with food as part of their second-line treatment. METHODS: Additional consent was required for children on DTG enrolled in the CHAPAS4 trial to participate in this PK substudy. Children weighing 14-19.9 kg took 25 mg DTG as dispersible tablets and children ≥20 kg took 50 mg film-coated tablets. Steady-state 24-hour DTG plasma concentration-time PK profiling was done at t = 0 and 1, 2, 4, 6, 8, 12, and 24 hours after observed DTG intake with food. Reference adult PK data and pediatric data from the ODYSSEY trial were used primarily for comparison. The individual target trough concentration (Ctrough) was defined as 0.32 mg/L. RESULTS: Thirty-nine children on DTG were included in this PK substudy. The geometric mean (GM) area under the concentration-time curve over the dosing interval (AUC0-24h) was 57.1 hours × mg/L (coefficient of variation [CV%], 38.4%), which was approximately 8% below the average AUC0-24h in children in the ODYSSEY trial with comparable dosages, but above the adult reference. The GM (CV%) Ctrough was 0.82 mg/L (63.8%), which was comparable to ODYSSEY and adult reference values. CONCLUSIONS: This nested PK substudy shows that the exposure of DTG taken with food in children on second-line treatment is comparable with that of children in the ODYSSEY trial and adult references. Clinical Trials Registration.ISRCTN22964075.

This paper analyses the linguistic structure, creative modes of expression and stylistic properties of Miguel Ángel Asturias’s Legends of Guatemala (Leyendas de Guatemala, 1930). Furthermore, it attempts to classify Asturias’s prose fiction, which is often multifaceted, by defining the unique character of its complex linguistic mechanisms that create his debut short-story collection. All texts in Legends contain references not only to events of the Mayan cosmogony, mythological tropes and motifs (that have been developed and put into a new context), but also to their mimetic relationship with the ritual language used in the Popol Vuh. The word order variations and certain combinations of vowels and consonants, as well as the specific syntactic parallelisms and enumerations (stylistic and lexical “props”) imitate formulaic phrases which are important elements in oral style. Pre-Columbian themes – especially those chosen by the Guatemalan writer for the narrative content of his works – are full of visual symbols with rich folk meanings; the melodic sound of Asturias’s narration (and its internal rhythm) seems attuned to the worldview belonging to both particular and universal human communities., This paper analyses the linguistic structure, creative modes of expression and stylistic properties of Miguel Ángel Asturias’s Legends of Guatemala (Leyendas de Guatemala, 1930). Furthermore, it attempts to classify Asturias’s prose fiction, which is often multifaceted, by defining the unique character of its complex linguistic mechanisms that create his debut short-story collection. All texts in Legends contain references not only to events of the Mayan cosmogony, mythological tropes and motifs (that have been developed and put into a new context), but also to their mimetic relationship with the ritual language used in the Popol Vuh. The word order variations and certain combinations of vowels and consonants, as well as the specific syntactic parallelisms and enumerations (stylistic and lexical “props”) imitate formulaic phrases which are important elements in oral style. Pre-Columbian themes – especially those chosen by the Guatemalan writer for the narrative content of his works – are full of visual symbols with rich folk meanings; the melodic sound of Asturias’s narration (and its internal rhythm) seems attuned to the worldview belonging to both particular and universal human communities.