Enhanced anti-tumour activity of carmustine (BCNU) with tumour necrosis factor in vitro and in vivo.

The effects on experimental melanoma of a combination of recombinant human tumour necrosis factor alpha (rhTNF alpha) and carmustine (BCNU) were studied in vitro and in vivo. In vitro, BCNU alone was cytotoxic to murine B16 melanoma cells, and at all concentrations of BCNU this toxicity was increased by the addition of TNF. In vivo, BCNU and TNF, when given separately, caused tumour growth delay of B16 melanoma and of human melanoma xenografts in immune-deprived mice. The combination of TNF at low dose 2.5 x 10(5) U kg-1 = 122 ng kg-1) with BCNU (35 mg kg-1) resulted in significant growth delay (compared with either drug alone) in B16 melanoma (P = 0.005). There was no significant increase in toxicity as assessed by weight loss and peripheral blood counts. Experiments with human melanoma xenografts yielded similar results (P = 0.001) but only at higher doses of TNF (1 x 10(6) U kg-1 = 489 ng kg-1). The enhancement of BCNU cytotoxicity by TNF may be important if it can be translated into patients with melanoma. A randomised study is now underway to investigate the clinical potential of this observation

Foam-in-Vein: Rheological Characterisation of Liquid Sclerosing Foams Using a Pipe Viscometer

Sclerotherapy is one of the most common and least-invasive treatment methods for varicose veins. While bench-top properties of sclerosing foams (e.g., bubble size distribution and foam half-life) have been studied previously, their flow behaviour and its relationship to therapeutic efficacy remain largely uncharacterised. To address this research gap, the present study reports on a novel approach for the rheological characterisation of sclerosing foams aimed at obtaining clinically-applicable data. A pipe viscometry apparatus was employed under conditions that mimic the end-point therapeutic application of foams. Polidocanol (1% v/v) foams of various liquid-to-gas volume ratios (1:3, 1:4 and 1:5) were formulated manually using the Tessari and DSS (double syringe system) methods across a clinically-relevant range of shear rates (≈ 7 s^{-1} – 400 s^{-1}), in polytetrafluoroethylene pipes of different diameters (2.48 mm and 4.48 mm). Additionally, end-effect and wall-slip correction methods were utilised to model the nominal rheology of sclerosing foams. The rheological data were fitted into a power-law model to obtain fluid flow index (n) and fluid consistency index (K) of sclerosing foams, followed by an in-depth statistical analysis of the power-law indices. The observed rheological behaviour of sclerosing foams is shown to be dependent on vessel diameter and liquid-to-gas ratio, while the type of manual formulation technique used appears to be statistically insignificant towards foam rheology. Sclerosing foams behaved as shear-thinning fluids with observed flow indices ranging 0.238 < n < 0.445, while the observed consistency indices ranged 2.977 < K < 12.49. The nominal (end-effect corrected) rheology of foams was shown to follow similar trends concerning liquid-to-gas ratio and formulation technique, independent of the tube diameter. The power-law characterisation of sclerosing foam rheology provided evidence of a quasi-static drainage effect that affected foam viscosity during slower injections. Wall-slip correction failed to provide physically meaningful results and statistical analysis suggested that the type of manual formulation technique used has no impact on the outcome of sclerotherapy on larger varicosities. Overall, results suggest a direct correlation between foam dryness and viscosity. Based on the developed rheological model, this work also demonstrates that low injection flowrates could yield higher therapeutic efficacy in dilated varicose veins

INTERGROWTH-21st Gestational Dating and Fetal and Newborn Growth Standards in Peri-Urban Nairobi, Kenya: Quasi-Experimental Implementation Study Protocol.

BACKGROUND: The burden of preterm birth, fetal growth impairment, and associated neonatal deaths disproportionately falls on low- and middle-income countries where modern obstetric tools are not available to date pregnancies and monitor fetal growth accurately. The INTERGROWTH-21st gestational dating, fetal growth monitoring, and newborn size at birth standards make this possible. OBJECTIVE: To scale up the INTERGROWTH-21st standards, it is essential to assess the feasibility and acceptability of their implementation and their effect on clinical decision-making in a low-resource clinical setting. METHODS: This study protocol describes a pre-post, quasi-experimental implementation study of the standards at Jacaranda Health, a maternity hospital in peri-urban Nairobi, Kenya. All women with viable fetuses receiving antenatal and delivery services, their resulting newborns, and the clinicians caring for them from March 2016 to March 2018 are included. The study comprises a 12-month preimplementation phase, a 12-month implementation phase, and a 5-month post-implementation phase to be completed in August 2018. Quantitative clinical and qualitative data collected during the preimplementation and implementation phases will be assessed. A clinician survey was administered eight months into the implementation phase, month 20 of the study. Implementation outcomes include quantitative and qualitative analyses of feasibility, acceptability, adoption, appropriateness, fidelity, and penetration of the standards. Clinical outcomes include appropriateness of referral and effect of the standards on clinical care and decision-making. Descriptive analyses will be conducted, and comparisons will be made between pre- and postimplementation outcomes. Qualitative data will be analyzed using thematic coding and compared across time. The study was approved by the Amref Ethics and Scientific Review Committee (Kenya) and the Harvard University Institutional Review Board. Study results will be shared with stakeholders through conferences, seminars, publications, and knowledge management platforms. RESULTS: From October 2016 to February 2017, over 90% of all full-time Jacaranda clinicians (26/28) received at least one of the three aspects of the INTERGROWTH-21st training: gestational dating ultrasound, fetal growth monitoring ultrasound, and neonatal anthropometry standards. Following the training, implementation and evaluation of the standards in Jacaranda Health's clinical workflow will take place from March 2017 through March 5, 2018. Data analysis will be finalized, and results will be shared by August 2018. CONCLUSIONS: The findings of this study will have major implications on the national and global scale up of the INTERGROWTH-21st standards and on the process of scaling up global standards in general, particularly in limited-resource settings. REGISTERED REPORT IDENTIFIER: RR1-10.2196/10293

Scalable, security-oriented solutions for nanoCMOS electronics

The EPSRC pilot project Meeting the Design Challenges of nanoCMOS Electronics (nanoCMOS – www.nanocmos.ac.uk) has been funded to tackle some of the challenges facing the semiconductor electronics industry caused by the progressive scaling of CMOS transistors. As transistor dimensions are now at the nanometer scale with 40nm MOSFETs already in mass production and sub-10 nm transistors scheduled for production by 2018, the intrinsic parameter fluctuations caused by the inherent discreteness of charge and matter at this atomistic scale are now one of the major challenges that the semiconductor electronics industry needs to address. The variability at the device level affects profoundly the circuit/system design process and hence can be regarded a semiconductor industry-wide problem. Fortunately many of the statistical variability related issues can be understood and forecasted through large scale simulation of ensembles of potentially hundreds of thousands of atomistically varying devices. However, one of the main distinguishing features of NanoCMOS when compared to other high performance computing (HPC) simulation domains is the imperative requirements on fine grained security. The data, the designs and even the simulations themselves all potentially have highly sensitive commercial intellectual property (IP) value associated with them, ranging from the IP of device manufacturers and the design houses through to licenses needed to run simulation and design software. This paper outlines the e-Infrastructure that has been developed within the nanoCMOS project with specific focus upon the security capabilities it supports and how these address the IP protection requirements of the industrial and collaborating partners. Our ultimate goal is to provide an environment that addresses security across the board and scales to meet the HPC and data management requirements of nanoCMOS research

Learning to Teach Argumentation: Research and development in the science classroom

The research reported in this study focuses on an investigation into the teaching of argumentation in secondary science classrooms. Over a one-year period, a group of 12 teachers from schools in the greater London area attended a series of workshops to develop materials and strategies to support the teaching of argumentation in scientific contexts. Data were collected at the beginning and end of the year by audio and video recording lessons where the teachers attempted to implement argumentation. To assess the quality of argumentation, analytical tools derived from Toulmin's argument pattern (TAP) were developed and applied to classroom transcripts. Analysis shows there was development in teachers' use of argumentation across the year. Results indicate that the pattern of use of argumentation is teacher-specific, as is the nature of change. To inform future professional development programmes, transcripts of five teachers, three showing a significant change and two no change, were analysed in more detail to identify features of teachers' oral contributions that facilitated and supported argumentation. The analysis showed that all teachers attempted to encourage a variety of processes involved in argumentation and that the teachers whose lessons included the highest quality of argumentation (TAP analysis) also encouraged higher order processes in their teaching. The analysis of teachers' facilitation of argumentation has helped to guide the development of in-service materials and to identify the barriers to learning in the professional development of less experienced teachers

Exploration of the representation of the allied health professions in senior leadership positions in the UK National Health Service

Background Allied health professionals (AHPs) are an important group within the National Health Service (NHS) in the UK and make up a large portion of the workforce. Investment in AHP leadership is believed to lead to improvements in patient care, resource use, collaboration and innovation. This study aims to assess the current state of AHP strategic leadership within the NHS. Methods A freedom of information (FOI) request was sent to all NHS Trusts and health boards (HBs) within the UK NHS. The questions focused on the AHP workforce, with a particular interest in the chief AHPs (or equivalent roles) working in an NHS setting. Analysis of the FOI used a range of descriptive statistics. Results Of the 217 Trusts/HBs contacted, responses were received from 160 (74%). The majority (81%) reported that they employed a Chief AHP or equivalent role, with only 14% of these having a position on the Trust/HB executive board. There were 50 different job titles reported as the titles for the chief AHP or equivalent roles: with director of AHPs (18.6%), lead AHP (13.9%) and chief AHP (11.6%) being the most reported titles. The results identified an inequity of representation of AHP professions within senior AHP leadership; with most of these roles (70%) held by physiotherapists and occupational therapists. Conclusion Changes in AHP strategic leadership are needed to address the inequities identified in this study. Addressing these issues is required to enable inclusive leadership, which is crucial to improve the contribution of AHPs to healthcare

Kisspeptin Signalling in the Hypothalamic Arcuate Nucleus Regulates GnRH Pulse Generator Frequency in the Rat

Kisspeptin and its G protein-coupled receptor (GPR) 54 are essential for activation of the hypothalamo-pituitary-gonadal axis. In the rat, the kisspeptin neurons critical for gonadotropin secretion are located in the hypothalamic arcuate (ARC) and anteroventral periventricular (AVPV) nuclei. As the ARC is known to be the site of the gonadotropin-releasing hormone (GnRH) pulse generator we explored whether kisspeptin-GPR54 signalling in the ARC regulates GnRH pulses.We examined the effects of kisspeptin-10 or a selective kisspeptin antagonist administration intra-ARC or intra-medial preoptic area (mPOA), (which includes the AVPV), on pulsatile luteinizing hormone (LH) secretion in the rat. Ovariectomized rats with subcutaneous 17β-estradiol capsules were chronically implanted with bilateral intra-ARC or intra-mPOA cannulae, or intra-cerebroventricular (icv) cannulae and intravenous catheters. Blood samples were collected every 5 min for 5–8 h for LH measurement. After 2 h of control blood sampling, kisspeptin-10 or kisspeptin antagonist was administered via pre-implanted cannulae. Intranuclear administration of kisspeptin-10 resulted in a dose-dependent increase in circulating levels of LH lasting approximately 1 h, before recovering to a normal pulsatile pattern of circulating LH. Both icv and intra-ARC administration of kisspeptin antagonist suppressed LH pulse frequency profoundly. However, intra-mPOA administration of kisspeptin antagonist did not affect pulsatile LH secretion.These data are the first to identify the arcuate nucleus as a key site for kisspeptin modulation of LH pulse frequency, supporting the notion that kisspeptin-GPR54 signalling in this region of the mediobasal hypothalamus is a critical neural component of the hypothalamic GnRH pulse generator

Plasmodium knowlesi Genome Sequences from Clinical Isolates Reveal Extensive Genomic Dimorphism.

Plasmodium knowlesi is a newly described zoonosis that causes malaria in the human population that can be severe and fatal. The study of P. knowlesi parasites from human clinical isolates is relatively new and, in order to obtain maximum information from patient sample collections, we explored the possibility of generating P. knowlesi genome sequences from archived clinical isolates. Our patient sample collection consisted of frozen whole blood samples that contained excessive human DNA contamination and, in that form, were not suitable for parasite genome sequencing. We developed a method to reduce the amount of human DNA in the thawed blood samples in preparation for high throughput parasite genome sequencing using Illumina HiSeq and MiSeq sequencing platforms. Seven of fifteen samples processed had sufficiently pure P. knowlesi DNA for whole genome sequencing. The reads were mapped to the P. knowlesi H strain reference genome and an average mapping of 90% was obtained. Genes with low coverage were removed leaving 4623 genes for subsequent analyses. Previously we identified a DNA sequence dimorphism on a small fragment of the P. knowlesi normocyte binding protein xa gene on chromosome 14. We used the genome data to assemble full-length Pknbpxa sequences and discovered that the dimorphism extended along the gene. An in-house algorithm was developed to detect SNP sites co-associating with the dimorphism. More than half of the P. knowlesi genome was dimorphic, involving genes on all chromosomes and suggesting that two distinct types of P. knowlesi infect the human population in Sarawak, Malaysian Borneo. We use P. knowlesi clinical samples to demonstrate that Plasmodium DNA from archived patient samples can produce high quality genome data. We show that analyses, of even small numbers of difficult clinical malaria isolates, can generate comprehensive genomic information that will improve our understanding of malaria parasite diversity and pathobiology