Evaluation of the immunomodulatory effects of 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate in C57BL/6 mice.

2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate was designed to replace perfluorooctanoic acid (PFOA), which has been mostly phased out of U.S. production due to environmental persistence, detectable human and wildlife serum concentrations, and reports of systemic toxicity. In rodent models, PFOA exposure suppresses T cell-dependent antibody responses (TDAR) and vaccine responses in exposed humans. To determine replacement compound effects on TDAR and related parameters, male and female C57BL/6 mice were gavaged with 0, 1, 10, or 100 mg/kg/day for 28 days. Mice immunized with antigen on day 24 were evaluated for TDAR and splenic lymphocyte subpopulations five days later. Serum and urine were collected for test compound concentrations and liver peroxisome proliferation was measured. Relative liver weight at 10 and 100 mg/kg and peroxisome proliferation at 100 mg/kg were increased in both sexes. TDAR was suppressed in females at 100 mg/kg. T lymphocyte numbers were increased in males at 100 mg/kg; B lymphocyte numbers were unchanged in both sexes. Females had less serum accumulation and higher clearance than males, and males had higher urine concentrations than females at all times and doses. While this PFOA-replacement compound appears less potent at suppressing TDAR relative to PFOA, it produces detectable changes in parameters affected by PFOA; further studies are necessary to determine its full immunomodulatory profile and potential synergism with other per- and polyfluoroalkyl substances of environmental concern

Barriers to help-seeking among music festival attendees in New South Wales, Australia

Introduction: Prompt help-seeking behaviour by music festival attendees can reduce risks associated with drug use; however, little is known about perceived barriers to help-seeking when experiencing or witnessing illness at music festivals. We explored potential barriers and their association with festivalgoer characteristics. Methods: We conducted an on-site cross-sectional survey of attendees at New South Wales music festivals in 2019/2020. Perceived barriers to help-seeking in the hypothetical event of the respondent or a friend becoming unwell at the festival were assessed, and regression analyses were conducted to identify characteristics associated with these barriers. Results: Across six festivals, 1229 people were surveyed and four-fifths (83.2%) reported ≥1 barrier: 32.7% fear of getting in trouble with the police, 20.6% not knowing where to find help, 17.2% not knowing how unwell someone might be and 15.3% concern about friends or relatives finding out. In multivariable analyses, people of diverse sexuality and people using drugs that day had greater odds of reporting fear of trouble with the police. People reporting drug use that day had lower odds of reporting not knowing where to find help. Men, gender-diverse people and people using drugs that day had greater odds of reporting concern about friends or relatives finding out. Discussion and Conclusions: Our data substantiate concerns regarding policing strategies and their impact on festivals. Initiatives to support conversations about drugs with friends and families may be best targeted to younger people and those from gender-diverse backgrounds

Community pharmacists' interventions with electronic prescriptions in England: an exploratory study

Prescribing errors in primary care are problematic. The electronic prescription service (EPS) is an English electronic system linking prescribing, dispensing and reimbursement, designed to rectify some of the problems associated with paper-based prescribing

Polyornithine-based polyplexes to boost effective gene silencing in CNS disorders.

Gene silencing therapies have successfully suppressed the translation of target proteins, a strategy that holds great promise for the treatment of central nervous system (CNS) disorders. Advances in the current knowledge on multimolecular delivery vehicles are concentrated on overcoming the difficulties in delivery of small interfering (si)RNA to target tissues, which include anatomical accessibility, slow diffusion, safety concerns, and the requirement for specific cell uptake within the unique environment of the CNS. The present work addressed these challenges through the implementation of polyornithine derivatives in the construction of polyplexes used as non-viral siRNA delivery vectors. Physicochemical and biological characterization revealed biodegradability and biocompatibility of our polyornithine-based system and the ability to silence gene expression in primary oligodendrocyte progenitor cells (OPCs) effectively. In summary, the well-defined properties and neurological compatibility of this polypeptide-based platform highlight its potential utility in the treatment of CNS disorders

Fluctuation scaling in complex systems: Taylor's law and beyond

Complex systems consist of many interacting elements which participate in some dynamical process. The activity of various elements is often different and the fluctuation in the activity of an element grows monotonically with the average activity. This relationship is often of the form "$fluctuations \approx const.\times average^\alpha$", where the exponent $\alpha$ is predominantly in the range $[1/2, 1]$. This power law has been observed in a very wide range of disciplines, ranging from population dynamics through the Internet to the stock market and it is often treated under the names \emph{Taylor's law} or \emph{fluctuation scaling}. This review attempts to show how general the above scaling relationship is by surveying the literature, as well as by reporting some new empirical data and model calculations. We also show some basic principles that can underlie the generality of the phenomenon. This is followed by a mean-field framework based on sums of random variables. In this context the emergence of fluctuation scaling is equivalent to some corresponding limit theorems. In certain physical systems fluctuation scaling can be related to finite size scaling.Comment: 33 pages, 20 figures, 2 tables, submitted to Advances in Physic

A Phase I study of the safety, pharmacokinetics and efficacy of navitoclax plus docetaxel in patients with advanced solid tumors

Aim: This Phase I study investigated safety of navitoclax and docetaxel in patients (n = 41) with advanced solid tumors. Patients & methods: Two navitoclax plus docetaxel dosing schedules (21 and 28 days) were evaluated. Maximum tolerated dose, dose-limiting toxicities and preliminary antitumor activity were assessed. Results: Ten (24%) patients experienced dose-limiting toxicities; dose-escalation cohorts: n = 7 (21-day schedule: n = 5; 28-day schedule: n = 2) and 21-day expanded safety cohort: n = 3. Navitoclax 150-mg days 1-5 every 21 days with docetaxel 75 mg/m2 day 1 was the maximum tolerated dose and optimal schedule. Adverse events included thrombocytopenia (63%), fatigue (61%), nausea (59%) and neutropenia (51%). Four confirmed partial responses occurred. Conclusion: Navitoclax 150-mg orally once/day was safely administered with docetaxel. Myelosuppression limited dose escalation; antitumor activity was observed. Clinical trial registration: NCT00888108 (ClinicalTrials.gov)

Development and characterisation of dental composites containing anisotropic fluorapatite bundles and rods

Objectives: To develop dental composites incorporating fluorapatite (FA) crystals as a secondary filler and to characterise degree of conversion, key mechanical properties and fluoride release. Methods: FA rod-like crystals and bundles were hydrothermally synthesised and characterised by scanning electron microscopy/energy dispersive X-ray spectroscopy (SEM/EDS), X-ray diffraction (XRD) and 19F MAS-NMR. Composites were formulated containing BisGMA/TEGDMA/BisEMA and barium-aluminium-silicate glass (0FA). FA crystals were incorporated at 10 (10FA), 20 (20FA), 30 (30FA) and 40 wt% (40FA) maintaining a filler content of 80 wt% (63–67 vol%). Degree of conversion (DC), flexural strength (FS), flexural modulus (FM), fracture toughness (K1C), Vickers hardness (HV) and 2-body wear were measured. Fluoride release was measured in neutral and acidic buffers. Results: XRD and 19F MAS-NMR confirmed that only FA was formed, whilst SEM revealed the presence of single rods and bundles of nano-rods. DC ranged between 56–60% (p > 0.05). FA composites showed lower FM and lower FS (p 0.05) to 0FA. 30FA and 40FA showed similar K1C to 0FA (p > 0.05), with SEM showing evidence of toughening mechanisms, whereas 10FA and 20FA showed lower K1C (p < 0.05). FA containing composites released fluoride that was proportional to the amount of FA incorporated (p < 0.05) but only under acidic conditions. Significance: The addition of FA to the experimental composites reduced strength and stiffness but not the DC, hardness or wear rate. 30FA and 40FA had a higher K1C compared to other FA groups. Fluoride release occurred under an accelerated acidic regime, suggesting potential as a bioactive ‘smart’ composite

Strain-Driven Mn-Reorganization in Overlithiated LixMn2O4 Epitaxial Thin-Film Electrodes

Lithium manganate LixMn2O4 (LMO) is a lithium ion cathode that suffers from the widely observed but poorly understood phenomenon of capacity loss due to Mn dissolution during electrochemical cycling. Here, operando X-ray reflectivity (low- and high-angle) is used to study the structure and morphology of epitaxial LMO (111) thin film cathodes undergoing lithium insertion and extraction to understand the inter-relationships between biaxial strain and Mn-dissolution. The initially strain-relieved LiMn2O4 films generate in-plane tensile and compressive strains for delithiated (x 1) charge states, respectively. The results reveal reversible Li insertion into LMO with no measurable Mn-loss for 0 1) reveals Mn loss from LMO along with dramatic changes in the intensity of the (111) Bragg peak that cannot be explained by Li stoichiometry. These results reveal a partially reversible site reorganization of Mn ions within the LMO film that is not seen in bulk reactions and indicates a transition in Mn-layer stoichiometry from 3:1 to 2:2 in alternating cation planes. Density functional theory calculations confirm that compressive strains (at x = 2) stabilize LMO structures with 2:2 Mn site distributions, therefore providing new insights into the role of lattice strain in the stability of LMO

Spatial ecology of jaguars, pumas, and ocelots: a review of the state of knowledge

Knowledge of the spatial ecology of mammalian carnivores is critical for understanding species’ biology and designing effective conservation and management interventions. We reviewed the available information about the spatial ecology of jaguars Panthera onca, pumas Puma concolor, and ocelots Leopardus pardalis, and we examined how sex and extrinsic variables affect their spatial behaviour. Sixty-one articles addressing home range, home range overlap, daily net displacement (straight-line distance between two locations on consecutive days), and/or distance of dispersal of the three species were included. Meta-analysis, ANOVA, ANCOVA, and beta regression tests were run to analyse differences among species and sexes and to elucidate the influence of other variables, such as latitude and ecoregion, on spatial behaviour. Pumas had on average larger home ranges (mean ± SE: 281.87 ± 35.76 km) than jaguars (128.61 ± 49.5 km) and ocelots (12.46 ± 3.39 km). Intersexual range overlap was higher than intrasexual range overlap in jaguars and pumas. Sex affected the home range size of all three species, but only influenced daily net displacement in ocelots. Ecoregion affected the home range size of all three species but did not significantly affect either the daily net displacement or the dispersal distance of pumas. Latitude affected the home range size of jaguars and pumas. It did not affect daily net displacement or dispersal distance in jaguars and pumas, but did affect daily net displacement in ocelots. Although there was a lack of studies in most countries for the three species, information was particularly lacking in the Neotropics for jaguars and pumas and in North America for ocelots. Researchers usually presented low sample sizes and used different methods to examine the ecological issues considered here. Homogenisation of methods is needed to clarify the ecology of these species and to allow a better understanding of the threats to their populations.Peer Reviewe

The extraordinary evolutionary history of the reticuloendotheliosis viruses

The reticuloendotheliosis viruses (REVs) comprise several closely related amphotropic retroviruses isolated from birds. These viruses exhibit several highly unusual characteristics that have not so far been adequately explained, including their extremely close relationship to mammalian retroviruses, and their presence as endogenous sequences within the genomes of certain large DNA viruses. We present evidence for an iatrogenic origin of REVs that accounts for these phenomena. Firstly, we identify endogenous retroviral fossils in mammalian genomes that share a unique recombinant structure with REVs—unequivocally demonstrating that REVs derive directly from mammalian retroviruses. Secondly, through sequencing of archived REV isolates, we confirm that contaminated Plasmodium lophurae stocks have been the source of multiple REV outbreaks in experimentally infected birds. Finally, we show that both phylogenetic and historical evidence support a scenario wherein REVs originated as mammalian retroviruses that were accidentally introduced into avian hosts in the late 1930s, during experimental studies of P. lophurae, and subsequently integrated into the fowlpox virus (FWPV) and gallid herpesvirus type 2 (GHV-2) genomes, generating recombinant DNA viruses that now circulate in wild birds and poultry. Our findings provide a novel perspective on the origin and evolution of REV, and indicate that horizontal gene transfer between virus families can expand the impact of iatrogenic transmission events