Clinical Pharmacokinetics and Dose Recommendations for Posaconazole in Infants and Children.

OBJECTIVES: The objectives of this study were to investigate the population pharmacokinetics of posaconazole in immunocompromised children, evaluate the influence of patient characteristics on posaconazole exposure and perform simulations to recommend optimal starting doses. METHODS: Posaconazole plasma concentrations from paediatric patients undergoing therapeutic drug monitoring were extracted from a tertiary paediatric hospital database. These were merged with covariates collected from electronic sources and case-note reviews. An allometrically scaled population-pharmacokinetic model was developed to investigate the effect of tablet and suspension relative bioavailability, nonlinear bioavailability of suspension, followed by a step-wise covariate model building exercise to identify other important sources of variability. RESULTS: A total of 338 posaconazole plasma concentrations samples were taken from 117 children aged 5 months to 18 years. A one-compartment model was used, with tablet apparent clearance standardised to a 70-kg individual of 15 L/h. Suspension was found to have decreasing bioavailability with increasing dose; the estimated suspension dose to yield half the tablet bioavailability was 99 mg/m2. Diarrhoea and proton pump inhibitors were also associated with reduced suspension bioavailability. CONCLUSIONS: In the largest population-pharmacokinetic study to date in children, we have found similar covariate effects to those seen in adults, but low bioavailability of suspension in patients with diarrhoea or those taking concurrent proton pump inhibitors, which may in particular limit the use of posaconazole in these patients

Extensive population genetic structure in the giraffe

<p>Abstract</p> <p>Background</p> <p>A central question in the evolutionary diversification of large, widespread, mobile mammals is how substantial differentiation can arise, particularly in the absence of topographic or habitat barriers to dispersal. All extant giraffes (<it>Giraffa camelopardalis</it>) are currently considered to represent a single species classified into multiple subspecies. However, geographic variation in traits such as pelage pattern is clearly evident across the range in sub-Saharan Africa and abrupt transition zones between different pelage types are typically not associated with extrinsic barriers to gene flow, suggesting reproductive isolation.</p> <p>Results</p> <p>By analyzing mitochondrial DNA sequences and nuclear microsatellite loci, we show that there are at least six genealogically distinct lineages of giraffe in Africa, with little evidence of interbreeding between them. Some of these lineages appear to be maintained in the absence of contemporary barriers to gene flow, possibly by differences in reproductive timing or pelage-based assortative mating, suggesting that populations usually recognized as subspecies have a long history of reproductive isolation. Further, five of the six putative lineages also contain genetically discrete populations, yielding at least 11 genetically distinct populations.</p> <p>Conclusion</p> <p>Such extreme genetic subdivision within a large vertebrate with high dispersal capabilities is unprecedented and exceeds that of any other large African mammal. Our results have significant implications for giraffe conservation, and imply separate <it>in situ </it>and <it>ex situ </it>management, not only of pelage morphs, but also of local populations.</p

Physical comorbidities in men with mood and anxiety disorders: a population-based study

Background : The mind-body nexus has been a topic of growing interest. Further data are however required to understand the specific relationship between mood and anxiety disorders and individual physical health conditions, and to verify whether these psychiatric disorders are linked to overall medical burden. Methods : This study examined data collected from 942 men, 20 to 97 years old, participating in the Geelong Osteoporosis Study. A lifetime history of mood and anxiety disorders was identified using the Structured Clinical Interview for DSM-IV-TR Research Version, Non-patient edition (SCID-I/NP). The presence of medical conditions (lifetime) was self-reported and confirmed by medical records, medication use or clinical data. Anthropometric measurements and socioeconomic status (SES) were determined and information on medication use and lifestyle was obtained via questionnaire. Logistic regression models were used to test the associations. Results : After adjustment for age, socioeconomic status, and health risk factors (body mass index, physical activity and smoking), mood disorders were associated with gastro oesophageal reflux disease (GORD), recurrent headaches, blackouts and/or epilepsy, liver disorders and pulmonary disease in older people, whilst anxiety disorders were significantly associated with thyroid, GORD and other gastrointestinal disorders, and psoriasis. Increased odds of high medical burden were associated with both mood and anxiety disorders. Conclusions : Our study provides further population-based evidence supporting the link between mental and physical illness in men. Understanding these associations is not only necessary for individual management, but also to inform the delivery of health promotion messages and health care

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

Networking expertise: Discursive coalitions and collaborative networks of experts in a public creationism controversy in the UK

Experts do play a particular role in public socio-scientific debates, even more so if they form heterogeneous coalition with other actors and experts. A case study about a public science education controversy surrounding the teaching of evolution/creationism in the UK press is used to investigate in detail how connections and coalitions between experts and other actors involved in the controversy emerged and played out. The research focuses on the question of what role collaborative and other networks of experts played in terms of influence, visibility, credibility, consensus and weight of argument. Issues that are considered in the research are the status of the members of the coalitions forming during the debate and how it is displayed in media representations and letters and petitions, and also how these networks and coalitions of experts perform in relation to each other

Cross-translational studies in human and Drosophila identify markers of sleep loss

Inadequate sleep has become endemic, which imposes a substantial burden for public health and safety. At present, there are no objective tests to determine if an individual has gone without sleep for an extended period of time. Here we describe a novel approach that takes advantage of the evolutionary conservation of sleep to identify markers of sleep loss. To begin, we demonstrate that IL-6 is increased in rats following chronic total sleep deprivation and in humans following 30 h of waking. Discovery experiments were then conducted on saliva taken from sleep-deprived human subjects to identify candidate markers. Given the relationship between sleep and immunity, we used Human Inflammation Low Density Arrays to screen saliva for novel markers of sleep deprivation. Integrin αM (ITGAM) and Anaxin A3 (AnxA3) were significantly elevated following 30 h of sleep loss. To confirm these results, we used QPCR to evaluate ITGAM and AnxA3 in independent samples collected after 24 h of waking; both transcripts were increased. The behavior of these markers was then evaluated further using the power of Drosophila genetics as a cost-effective means to determine whether the marker is associated with vulnerability to sleep loss or other confounding factors (e.g., stress). Transcript profiling in flies indicated that the Drosophila homologues of ITGAM were not predictive of sleep loss. Thus, we examined transcript levels of additional members of the integrin family in flies. Only transcript levels of scab, the Drosophila homologue of Integrin α5 (ITGA5), were associated with vulnerability to extended waking. Since ITGA5 was not included on the Low Density Array, we returned to human samples and found that ITGA5 transcript levels were increased following sleep deprivation. These cross-translational data indicate that fly and human discovery experiments are mutually reinforcing and can be used interchangeably to identify candidate biomarkers of sleep loss

Population structure of the malaria vector Anopheles moucheti in the equatorial forest region of Africa

<p>Abstract</p> <p>Background</p> <p><it>Anopheles moucheti </it>is a major malaria vector in forested areas of Africa. However, despite its important epidemiological role, it remains poorly known and insufficiently studied. Here, levels of genetic differentiation were estimated between different <it>A. moucheti </it>populations sampled throughout its distribution range in Central Africa.</p> <p>Methods</p> <p>Polymorphism at ten microsatellite markers was compared in mosquitoes sampled in Cameroon, the Democratic Republic of Congo and an island on Lake Victoria in Uganda. Microsatellite data were used to estimate genetic diversity within populations, their relative long-term effective population size, and the level of genetic differentiation between them.</p> <p>Results</p> <p>All specimens collected in Tsakalakuku (Democratic Republic of Congo) were identified as <it>A. m. bervoetsi </it>while other samples consisted of <it>A. m. moucheti</it>. Successful amplification was obtained at all microsatellite loci within all <it>A. m. moucheti </it>samples while only six loci amplified in <it>A. m. bervoetsi</it>. Allelic richness and heterozygosity were high for all populations except the island population of Uganda and <it>A. m. bervoetsi</it>. High levels of genetic differentiation were recorded between <it>A. m. bervoetsi </it>and each <it>A. m. moucheti </it>sample as well as between the island population of <it>A. m. moucheti </it>and mainland populations. Significant isolation by distance was evidenced between mainland populations.</p> <p>Conclusion</p> <p>High levels of genetic differentiation supports complete speciation of <it>A. m. bervoetsi </it>which should henceforth be recognized as a full species and named <it>A. bervoetsi</it>. Isolation by distance is the main force driving differentiation between mainland populations of <it>A. m. moucheti</it>. Genetically and geographically isolated populations exist on Lake Victoria islands, which might serve as relevant field sites for evaluation of innovative vector control strategies.</p

Tracing the legacy of the early Hainan Islanders - a perspective from mitochondrial DNA

<p>Abstract</p> <p>Background</p> <p>Hainan Island is located around the conjunction of East Asia and Southeast Asia, and during the Last Glacial Maximum (LGM) was connected with the mainland. This provided an opportunity for the colonization of Hainan Island by modern human in the Upper Pleistocene. Whether the ancient dispersal left any footprints in the contemporary gene pool of Hainan islanders is debatable.</p> <p>Results</p> <p>We collected samples from 285 Li individuals and analyzed mitochondrial DNA (mtDNA) variations of hypervariable sequence I and II (HVS-I and II), as well as partial coding regions. By incorporating previously reported data, the phylogeny of Hainan islanders was reconstructed. We found that Hainan islanders showed a close relationship with the populations in mainland southern China, especially from Guangxi. Haplotype sharing analyses suggested that the recent gene flow from the mainland might play important roles in shaping the maternal pool of Hainan islanders. More importantly, haplogroups M12, M7e, and M7c1* might represent the genetic relics of the ancient population that populated this region; thus, 14 representative complete mtDNA genomes were further sequenced.</p> <p>Conclusions</p> <p>The detailed phylogeographic analyses of haplogroups M12, M7e, and M7c1* indicated that the early peopling of Hainan Island by modern human could be traced back to the early Holocene and/or even the late Upper Pleistocene, around 7 - 27 kya. These results correspond to both Y-chromosome and archaeological studies.</p