Identification, Geochemical Characterisation and Significance of Bitumen among the Grave Goods of the 7th Century Mound 1 Ship-Burial at Sutton Hoo (Suffolk, UK)

Acknowledgments: We would like to thank Antony Simpson for formatting the figures for publication. We are indebted to Dr Sonja Marzinzik and Dr Sue Brunning, former and current curators of the Department of Britain, Europe and Prehistory at the British Museum, for facilitating access to the Sutton Hoo finds. Carbon and hydrogen isotopic measurements were carried out by Iso-Analytical Limited. We are grateful to colleagues and others who read and commented on the manuscript in draft. Funding: This research was supported by funding from the European Commission Research Executive Agency (REA) via the Marie Curie Actions – Intra-European Fellowships for Career Development funding scheme (FP7-MC-IEF), Grant Agreement No. 253942, awarded to PB and RJS for project AMPT (Ancient Maritime Pitch and Tar: a multi-disciplinary study of sources, technology and preservation). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD

Development of a natural ingredient – Natural preservative: A case study

AbstractLately, the cosmetic and personal care market has been more and more driven toward natural ingredients by the rising consumers' awareness about personal health and safety and their will for safer cosmetics free of harmful chemicals. Preservatives are no exception to the rule: evidence or suspicion of the toxicity of certain synthetic preservatives that have been around for decades pushed the cosmetic industry forward to seek for natural alternatives, as the selection of natural preservatives already available is quite limited. Sourcing active metabolites and developing new natural ingredients are long-term procedures that are thoroughly described in the present paper, via the example of the design of a natural preservative based on the Santolina chamaecyparissus extract, and of the assessments of its preservative effectiveness

Outcome of the first Medicines Utilisation Research in Africa Group meeting to promote sustainable and rational medicine use in Africa

The first MURIA (Medicines Utilisation Research in Africa) group workshop and symposium brought researchers together from across Africa to improve their knowledge on drug utilisation (DU) methodologies as well as exchange ideas. As a result, progress DU research to formulate future strategies to enhance the rational use of medicines. Anti-infectives was the principal theme for the one day symposium following the workshops. This included presentations on the inappropriate use of antibiotics as well as ways to address this. Concerns with adverse drug reactions and adherence to anti-retroviral medicines was also discussed, with poor adherence remaining a challenge. There were also concerns with the underutilisation of generics. These discussions resulted in a number of agreed activities before the next conference in 2016

Ancient and modern DNA reveal dynamics of domestication and cross-continental dispersal of the dromedary

Dromedaries have been fundamental to the development of human societies in arid landscapes and for long-distance trade across hostile hot terrains for 3,000 y. Today they continue to be an important livestock resource in marginal agro-ecological zones. However, the history of dromedary domestication and the influence of ancient trading networks on their genetic structure have remained elusive. We combined ancient DNA sequences of wild and early-domesticated dromedary samples from arid regions with nuclear microsatellite and mitochondrial genotype information from 1,083 extant animals collected across the species’ range. We observe little phylogeographic signal in the modern population, indicative of extensive gene flow and virtually affecting all regions except East Africa, where dromedary populations have remained relatively isolated. In agreement with archaeological findings, we identify wild dromedaries from the southeast Arabian Peninsula among the founders of the domestic dromedary gene pool. Approximate Bayesian computations further support the “restocking from the wild” hypothesis, with an initial domestication followed by introgression from individuals from wild, now-extinct populations. Compared with other livestock, which show a long history of gene flow with their wild ancestors, we find a high initial diversity relative to the native distribution of the wild ancestor on the Arabian Peninsula and to the brief coexistence of early-domesticated and wild individuals. This study also demonstrates the potential to retrieve ancient DNA sequences from osseous remains excavated in hot and dry desert environments

Population Pharmacokinetic Modeling of Dolutegravir to Optimize Pediatric Dosing in HIV-1-Infected Infants, Children, and Adolescents

Background and Objective: HIV treatment options remain limited in children. Dolutegravir is a potent and well-tolerated, once-daily HIV-1 integrase inhibitor recommended for HIV-1 infection in both adults and children down to 4 weeks of age. To support pediatric dosing of dolutegravir in children, we used a population pharmacokinetic model with dolutegravir data from the P1093 and ODYSSEY clinical trials. The relationship between dolutegravir exposure and selected safety endpoints was also evaluated. // Methods: A population pharmacokinetic model was developed with data from P1093 and ODYSSEY to characterize the pharmacokinetics and associated variability and to evaluate the impact of pharmacokinetic covariates. The final population pharmacokinetic model simulated exposures across weight bands, doses, and formulations that were compared with established adult reference data. Exploratory exposure–safety analyses evaluated the relationship between dolutegravir pharmacokinetic parameters and selected clinical laboratory parameters and adverse events. // Results: A total of N = 239 participants were included, baseline age ranged from 0.1 to 17.5 years, weight ranged from 3.9 to 91 kg, 50% were male, and 80% were black. The final population pharmacokinetic model was a one-compartment model with first-order absorption and elimination, enabling predictions of dolutegravir concentrations in the pediatric population across weight bands and doses/formulations. The predicted geometric mean trough concentration was comparable to the adult value following a 50-mg daily dose of dolutegravir for all weight bands at recommended doses. Body weight, age, and formulation were significant predictors of dolutegravir pharmacokinetics in pediatrics. Additionally, during an exploratory exposure–safety analysis, no correlation was found between dolutegravir exposure and selected safety endpoints or adverse events. // Conclusions: The dolutegravir dosing in children ≥ 4 weeks of age on an age/weight-band basis provides comparable exposures to those historically observed in adults. Observed pharmacokinetic variability was higher in this pediatric population and no additional safety concerns were observed. These results support the weight-banded dosing of dolutegravir in pediatric participants currently recommended by the World Health Organization

Dolutegravir dosing for children with HIV weighing less than 20 kg: pharmacokinetic and safety substudies nested in the open-label, multicentre, randomised, non-inferiority ODYSSEY trial.

BACKGROUND: Dolutegravir-based antiretroviral therapy is a preferred first-line treatment for adults and children living with HIV; however, very little pharmacokinetic data for dolutegravir use are available in young children. We therefore aimed to evaluate dolutegravir dosing and safety in children weighing 3 kg to less than 20 kg by assessing pharmacokinetic parameters and safety data in children taking dolutegravir within the ODYSSEY trial. METHODS: We did pharmacokinetic substudies nested within the open-label, multicentre, randomised, non-inferiority ODYSSEY trial. We enrolled children from seven research centres in South Africa, Uganda, and Zimbabwe. Children weighing 3 kg to less than 14 kg received 5 mg dispersible tablets of dolutegravir according to WHO weight bands: 5 mg for children weighing 3 kg to less than 6 kg and younger than 6 months, 10 mg for children weighing 3 kg to less than 6 kg and aged 6 months or older, 15 mg for children weighing 6 kg to less than 10 kg, and 20 mg for children weighing 10 kg to less than 14 kg. Children weighing 14 kg to less than 20 kg received a 25 mg film-coated tablet once per day early in the trial or 25 mg dispersible tablets (five 5 mg tablets once per day) later in the trial. A minimum of eight children per weight band or dose was targeted for 24 h pharmacokinetic profiling at steady state. The primary pharmacokinetic parameter was the trough concentration 24 h after observed dolutegravir intake (Ctrough). Pharmacokinetic targets were based on adult dolutegravir Ctrough and the 90% effective concentration (EC90; ie, 0·32 mg/L). Safety was evaluated in eligible children consenting to pharmacokinetic substudies. FINDINGS: Between May 25, 2017, and Aug 15, 2019, we enrolled 72 children aged between 3 months and 11 years. 71 children were included in the safety population and 55 (76%) of 72 children contributed 65 evaluable pharmacokinetic profiles. Geometric mean Ctrough in children on dispersible tablets in weight bands between 3 kg and less than 20 kg ranged between 0·53-0·87 mg/L, comparable to the adult geometric mean Ctrough of 0·83 mg/L. Variability was high with coefficient of variation percentages ranging between 50% and 150% compared with 26% in adults. Ctrough below EC90 was observed in four (31%) of 13 children weighing 6 kg to less than 10 kg taking 15 mg dispersible tablets, and four (21%) of 19 weighing 14 kg to less than 20 kg taking 25 mg film-coated tablets. The lowest geometric mean Ctrough of 0·44 mg/L was observed in children weighing 14 kg to less than 20 kg on 25 mg film-coated tablets. Exposures were 1·7-2·0 times higher on 25 mg dispersible tablets versus 25 mg film-coated tablets. 19 (27%) of 71 children had 29 reportable grade 3 or higher adverse events (13 serious adverse events, including two deaths), none of which were related to dolutegravir. INTERPRETATION: Weight-band dosing of paediatric dolutegravir dispersible tablets provides appropriate drug exposure in most children weighing 3 kg to less than 20 kg, with no safety signal. 25 mg film-coated tablets did not achieve pharmacokinetic parameters in children weighing 14 kg to less than 20 kg, which were comparable to adults, suggesting dosing with dispersible tablets is preferable or a higher film-coated tablet dose is required. FUNDING: Paediatric European Network for Treatment of AIDS Foundation, ViiV Healthcare, and UK Medical Research Council

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Sex Differences in Neoplastic Progression in Barrett's Esophagus:A Multicenter Prospective Cohort Study

Recommendations in Barrett’s esophagus (BE) guidelines are mainly based on male patients. We aimed to evaluate sex differences in BE patients in (1) probability of and (2) time to neoplastic progression, and (3) differences in the stage distribution of neoplasia. We conducted a multicenter prospective cohort study including 868 BE patients. Cox regression modeling and accelerated failure time modeling were used to estimate the sex differences. Neoplastic progression was defined as highgrade dysplasia (HGD) and/or esophageal adenocarcinoma (EAC). Among the 639 (74%) males and 229 females that were included (median follow-up 7.1 years), 61 (7.0%) developed HGD/EAC. Neoplastic progression risk was estimated to be twice as high among males (HR 2.26, 95% CI 1.11–4.62) than females. The risk of HGD was found to be higher in males (HR 3.76, 95% CI 1.33–10.6). Time to HGD/EAC (AR 0.52, 95% CI 0.29–0.95) and HGD (AR 0.40, 95% CI 0.19–0.86) was shorter in males. Females had proportionally more EAC than HGD and tended to have higher stages of neoplasia at diagnosis. In conclusion, both the risk of and time to neoplastic progression were higher in males. However, females were proportionally more often diagnosed with (advanced) EAC. We should strive for improved neoplastic risk stratification per individual BE patient, incorporating sex disparities into new prediction models

Water Insecurity Is Associated With Lack of Viral Suppression and Greater Odds of Aids-Defining Illnesses Among Adults With HIV in Western Kenya

Reliable access to safe and acceptable water in sufficient quantities (i.e., water security) is important for medication adherence and limiting pathogen exposure, yet prior studies have only considered the role of food security as a social determinant of HIV-related health. Therefore, the objective of this analysis was to assess the relationships between household water insecurity and HIV-related outcomes among adults living with HIV in western Kenya (N = 716). We conducted a cross-sectional analysis of baseline data from Shamba Maisha (NCT02815579), a cluster randomized controlled trial of a multisectoral agricultural and asset loan intervention. Baseline data were collected from June 2016 to December 2017. We assessed associations between water insecurity and HIV-related outcomes, adjusting for clinical and behavioral confounders, including food insecurity. Each five-unit higher household water insecurity score (range: 0-51) was associated with 1.21 higher odds of having a viral load ≥ 1000 copies/mL (95% CI 1.07, 1.36) and 1.26 higher odds of AIDS-defining illness (95% CI 1.11, 1.42). Household water insecurity was not associated with CD4 cell count (B: 0.27; 95% CI -3.59, 13.05). HIV treatment and support programs should consider assessing and addressing water insecurity in addition to food insecurity to optimize HIV outcomes