Methodology for the Randomised Injecting Opioid Treatment Trial (RIOTT): evaluating injectable methadone and injectable heroin treatment versus optimised oral methadone treatment in the UK

Whilst unsupervised injectable methadone and diamorphine treatment has been part of the British treatment system for decades, the numbers receiving injectable opioid treatment (IOT) has been steadily diminishing in recent years. In contrast, there has been a recent expansion of supervised injectable diamorphine programs under trial conditions in a number of European and North American cities, although the evidence regarding the safety, efficacy and cost effectiveness of this treatment approach remains equivocal. Recent British clinical guidance indicates that IOT should be a second-line treatment for those patients in high-quality oral methadone treatment who continue to regularly inject heroin, and that treatment be initiated in newly-developed supervised injecting clinics. The Randomised Injectable Opioid Treatment Trial (RIOTT) is a multisite, prospective open-label randomised controlled trial (RCT) examining the role of treatment with injected opioids (methadone and heroin) for the management of heroin dependence in patients not responding to conventional substitution treatment. Specifically, the study examines whether efforts should be made to optimise methadone treatment for such patients (e.g. regular attendance, supervised dosing, high oral doses, access to psychosocial services), or whether such patients should be treated with injected methadone or heroin. Eligible patients (in oral substitution treatment and injecting illicit heroin on a regular basis) are randomised to one of three conditions: (1) optimized oral methadone treatment (Control group); (2) injected methadone treatment; or (3) injected heroin treatment (with access to oral methadone doses). Subjects are followed up for 6-months, with between-group comparisons on an intention-to-treat basis across a range of outcome measures. The primary outcome is the proportion of patients who discontinue regular illicit heroin use (operationalised as providing >50% urine drug screens negative for markers of illicit heroin in months 4 to 6). Secondary outcomes include measures of other drug use, injecting practices, health and psychosocial functioning, criminal activity, patient satisfaction and incremental cost effectiveness. The study aims to recruit 150 subjects, with 50 patients per group, and is to be conducted in supervised injecting clinics across England

Design, synthesis and evaluation of carbamate-linked uridyl-based inhibitors of human ST6Gal I

© 2020 Elsevier Ltd Sialic acid at the terminus of cell surface glycoconjugates is a critical element in cell-cell recognition, receptor binding and immune responses. Sialyltransferases (ST), the enzymes responsible for the biosynthesis of sialylated glycans are highly upregulated in cancer and the resulting hypersialylation of the tumour cell surface correlates strongly with tumour growth, metastasis and drug resistance. Inhibitors of human STs, in particular human ST6Gal I, are thus expected to be valuable chemical tools for the discovery of novel anticancer drugs. Herein, we report on the computationally-guided design and development of uridine-based inhibitors that replace the charged phosphodiester linker of known ST inhibitors with a neutral carbamate to improve pharmacokinetic properties and synthetic accessibility. A series of 24 carbamate-linked uridyl-based compounds were synthesised by coupling aryl and hetaryl α-hydroxyphosphonates with a 5′-amino-5′-deoxyuridine fragment. The inhibitory activities of the newly synthesised compounds against recombinant human ST6Gal I were determined using a luminescent microplate assay, and five promising inhibitors with Ki’s ranging from 1 to 20 µM were identified. These results show that carbamate-linked uridyl-based compounds are a potential new class of readily accessible, non-cytotoxic ST inhibitors to be further explored

Dealing with synthetics: time to reframe the narrative.

Key Points: • Despite adjustments over its lifetime, the contemporary international drug control regime has had an historical emphasis in on ‘narcotic’ drugs, such as opium, heroin and cocaine, rather than on a range of synthetic substances. • Associated policy inertia has resulted in disproportionate attention on counter-narcotic policies and operations in the Global South and in many ways inadequate responses to the synthetic market, including production that is frequently located in the Global North. • Possible explanations for this focus on plant-based drugs are manifold and complex. They include the fact that the control regime began with concerns over opium-smoking in the ‘orient’, a concentration of drug crops in the Global South, the energies of colonialism (which have been intimately tied up with ‘drug wars’), broader geo-political imperatives and the focus of policy metrics on drug crops. • The market for synthetic drugs has grown exponentially in recent years, becoming the second-most illicit drugs consumed after cannabis. In 2014, the UN estimated that there were 35.7 million users of amphetamine type stimulants (including prescription stimulants), and 19.4 million users of ecstasy. These synthetic drugs outstripped the estimated totals of opioids and cocaine combined. • Alongside this consumption is that of New Psychoactive Substances that fall outside the control regime and its schedules, which the regime is now attempting to integrate into national and international controls. • While there was some awareness of the advent of new synthetic drugs in the aftermath of the Second World War and since the 1960s, it is only over recent years, and especially in the wake of the 2016 UNGASS in New York, that a truly serious understanding of the challenges posed by proliferating synthetic drugs has begun to emerge from the international drug control regime. • This is timely since, considering its policy history and contemporary dynamics, it is now time to reframe the narrative surrounding the way the international community deals with synthetic drugs

Political brand identity: an examination of the complexities of Conservative brand and internal market engagement during the 2010 UK General Election campaign

This paper seeks to build an understanding of the importance of internal communications when building a strong political brand. Using Kapferer’s brand prism as a conceptual framework, the paper explores UK Conservative Party members’ attitudes towards the development of the Conservative brand as personified by David Cameron. There are clear implications for political strategists as the findings suggest that it is crucial to engage the internal market in the co-creation of the marketing communications strategy for as brand evangelists they interpret the brand promise at the local level

Progress towards a propagation prediction service for HF communications with aircraft on trans-polar routes

Commercial airlines began operations over polar routes in 1999 with a small number of proving flights. By 2014 the number had increased to in excess of 12,000 flights per year, and further increases are expected. For safe operations, the aircraft have to be able to communicate with air traffic control centres at all times. This is achieved by VHF links whilst within range of the widespread network of ground stations, and is by HF radio in remote areas such as the Polar regions, the North Atlantic and Pacific where VHF ground infrastructure does not exist. Furthermore, the Russian side of the pole only has HF capability. Researchers at the University of Leicester and at Lancaster University have developed various models (outlined below) that can be employed in HF radio propagation predictions. It is anticipated that these models will form the basis of an HF forecasting and nowcasting service for the airline industry. Propagation coverage predictions make use of numerical ray tracing to estimate the ray paths through a model ionosphere. Initially, a background ionospheric model is produced, which is then perturbed to include the various ionospheric features prevalent at high latitudes (in particular patches, arcs, auroral zone irregularities and the mid-latitude trough) that significantly affect the propagation of the radio signals. The approach that we are currently adopting is to start with the IRI and to perturb this based on measurements made near to the time and area of interest to form the basis of the background ionospheric model. This is then further perturbed to include features such as the convecting patches, the parameters of which may also be informed by measurements. A significant problem is the high variability of the high latitude ionosphere, and the relative scarcity of real-time measurements over the region. Real time measurements that we will use as the basis for perturbing the IRI include ionosonde soundings from, e.g. the GIRO database, and TEC measurements from the IGS network. Real-time modelling of HF radiowave absorption in the D-region ionosphere is also included. The geostationary GOES satellites provide real-time information on X-ray flux (causing shortwave fadeout during solar flares) and the flux of precipitating energetic protons which correlates strongly with Polar Cap Absorption (PCA). Real-time solar wind and interplanetary magnetic field measurements from the ACE or DSCOVR spacecraft provide geomagnetic index estimates used to model the location of both auroral absorption (on a probabilistic basis) and the proton rigidity cutoff boundary that defines the latitudinal extent of PCA during solar proton events (SPE). Empirical climatological models have been uniquely adapted to assimilate recent measurements of cosmic noise absorption (at 30 MHz) from a large array of riometers in Canada and Scandinavia. The model parameters are continuously optimised and updated to account for regional and temporal variations in ionospheric composition (and hence HF absorption rate (dB/km)) that can change significantly during the course of an SPE, for example. Real-time optimisation during SPE can also improve estimates of the proton rigidity cutoff and improve the modelled ionospheric response function absorption vs. zenith angle) at twilight

Seawater redox variations during the deposition of the Kimmeridge Clay Formation, United Kingdom (Upper Jurassic): evidence from molybdenum isotopes and trace metal ratios

The Kimmeridge Clay Formation (KCF) and its equivalents worldwide represent one of the most prolonged periods of organic carbon accumulation of the Mesozoic. In this study, we use the molybdenum (Mo) stable isotope system in conjunction with a range of trace metal paleoredox proxies to assess how seawater redox varied both locally and globally during the deposition of the KCF. Facies with lower organic carbon contents (TOC 1–7 wt %) were deposited under mildly reducing (suboxic) conditions, while organic-rich facies (TOC >7 wt %) accumulated under more strongly reducing (anoxic or euxinic) local conditions. Trace metal abundances are closely linked to TOC content, suggesting that the intensity of reducing conditions varied repeatedly during the deposition of the KCF and may have been related to orbitally controlled climate changes. Long-term variations in ?98/95Mo are associated with the formation of organic-rich intervals and are related to third-order fluctuations in relative sea level. Differences in the mean ?98/95Mo composition of the organic-rich intervals suggest that the global distribution of reducing conditions was more extensive during the deposition of the Pectinatites wheatleyensis and lower Pectinatites hudlestoni zones than during the deposition of the upper Pectinatites hudlestoni and Pectinatites pectinatus zones. The global extent of reducing conditions during the Kimmerigidan was greater than today but was less widespread than during the Toarcian (Early Jurassic) oceanic anoxic event. This study also demonstrates that the Mo isotope system in Jurassic seawater responded to changes in redox conditions in a manner consistent with its behavior in present-day sedimentary environment