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Abstract As the part of a study to develop buparvaquone (BPQ) formulations for the treatment of cutaneous leishmaniasis, the topical delivery of BPQ and one of its prodrugs from a range of formulations was evaluated. In previous studies, BPQ and its prodrugs were shown to be potent antileishmanials in-vitro, with ED50 values in the nanomolar range. 3-Phosphono-oxymethyl-buparvaquone (3-POM-BPQ) was the most potent antileishmanial and was chosen, together with the parent drug, for further investigation. The ability of the parent and prodrug formulations to cross human and murine skin was tested in-vitro using the Franz diffusion cells. Formulations intended for topical application containing either BPQ or 3-POM-BPQ were developed using excipients that were either acceptable for topical use (GRAS or FDA inactive ingredients) or currently going through the regulatory process. BPQ was shown to penetrate both human epidermal membranes and full thickness BALB/c skin from a range of formulations (gels, emulsions). Similarly, 3-POM-BPQ penetrated full-thickness BALB/c skin from several gel formulations. In-vitro binding studies showed that BPQ bound melanin in a dose-dependent manner and preferably bound to delipidized skin over untreated BALB/c skin (on a weight to weight basis). The results confirm that BPQ and its prodrug 3-POM-BPQ can penetrate the skin from several formulations, making them potentially interesting candidates for further investigation of topical formulations using in-vivo models of cutaneous leishmaniasis.

Abstract Techniques for evaluating water management are critical to diagnose the performance of polymer electrolyte membrane fuel cells (PEMFCs). Acoustic emission as a function of polarisation (AEfP) has been recently introduced as a non-invasive, non-destructive method to analyse the water generation and removal inside a PEMFC during polarisation. AEfP was shown to provide unique insight into water management within a conventional PEMFC and correlating it to cell performance. Here, AEfP is used to characterise the performance of fractal PEMFCs by evaluating the hydration conditions inside them. This is achieved by probing the water dynamics inside two different fractal flow-field based PEMFCs, namely 1-way and 2-way fractal PEMFCs, and measuring the corresponding acoustic activity generated from them. AEfP is performed on the fractal PEMFCs under relatively humid (70% RH) and fully humidified (100% RH) reactant relative humidity (RH) conditions. Flooding in the 2-way fractal PEMFC, as opposed to the 1-way fractal PEMFC, is demonstrated under different operating conditions by the relatively higher acoustic activity it generates. Corroborating evidence of flooding in the 2-way fractal flow-field under different conditions is provided by its polarisation curves, impedance tests and galvanostatic (current hold) measurements.

Climate change threatens to undermine the past 50 years of gains in public health. In response, the National Health Service (NHS) in England has been working since 2008 to quantify and reduce its carbon footprint. This Article presents the latest update to its greenhouse gas accounting, identifying interventions for mitigation efforts and describing an approach applicable to other health systems across the world.A hybrid model was used to quantify emissions within Scopes 1, 2, and 3 of the Greenhouse Gas Protocol, as well as patient and visitor travel emissions, from 1990 to 2019. This approach complements the broad coverage of top-down economic modelling with the high accuracy of bottom-up data wherever available. Available data were backcasted or forecasted to cover all years. To enable the identification of measures to reduce carbon emissions, results were disaggregated by organisation type.In 2019, the health service's emissions totalled 25 megatonnes of carbon dioxide equivalent, a reduction of 26% since 1990, and a decrease of 64% in the emissions per inpatient finished admission episode. Of the 2019 footprint, 62% came from the supply chain, 24% from the direct delivery of care, 10% from staff commute and patient and visitor travel, and 4% from private health and care services commissioned by the NHS.This work represents the longest and most comprehensive accounting of national health-care emissions globally, and underscores the importance of incorporating bottom-up data to improve the accuracy of top-down modelling and enabling detailed monitoring of progress as health systems act to reduce emissions.Wellcome Trust.

Resilience is receiving increasing scientific attention, albeit its notion is still in progress and not univocal, especially when it comes to specific sectors such as energy. Energy and resilience policy is detected as a dominant strategy to achieve international development objectives throughout long-term sustainability and wellbeing goals. Energy resilience also crosses major energy policy issues – namely energy vulnerability, security, poverty, and justice. Making use of the Web Of Science 2018 release, this work aims at contributing to a clarification of the concept of energy resilience, proposing a taxonomy. The bibliometric outputs show a sharp increase in scientific publications on the issue. The bibliometric analysis suggests a taxonomy of energy resilience based on 7 approaches or strategies. The results suggest an evolution of the conceptual contributions, that enlarge resilience early use, merely applied to technical and hard sciences. Resilience is today used in different disciplines, including social sciences and sustainability studies, as part of a holistic approach centered on sustainable development.

In the past decade, prescriptions for opioid medicines have been exponentially increasing, instigating opioid abuse as a global health crisis associated with high morbidity and mortality. In particular, diversion from the intended mode of opioid administration, such as injecting and snorting the opioid, is a major problem that contributes to this epidemic. In light of this, novel formulation strategies are needed to support efforts in reducing the prevalence and risks of opioid abuse. Here, modified release tramadol printlets (3D printed tablets) with alcohol-resistant and abuse-deterrent properties were prepared by direct powder extrusion three-dimensional (3D) printing. The printlets were fabricated using two grades of hydroxypropylcellulose (HPC). Both formulations displayed strong ethanol-resistance and had moderate abuse-deterrent properties. Polyethylene oxide (PEO) was subsequently added into the formulations, which improved the printlets' resistance to physical tampering in nasal inhalation tests and delayed their dissolution in solvent extraction tests. Overall, this article reports for the first time the use of direct powder extrusion 3D printing to prepare drug products with both alcohol-resistant and abuse-deterrent properties. These results offer a novel approach for the safe and effective use of opioids that can contribute to the advantages that 3D printing provides in terms of on-demand dose personalisation.

The substrate specificity, pH activity curves, inhibition characteristics and in vitro stabilities of the human ADH isozymes characteristic of the structural loci, ADH1, ADH2 and ADH3, have been investigated using crude tissue extracts and partially purified material. Alcohol substrates: Seventeen different alcohols were tested. The products of the three loci showed differences in their relative activities with the different substrates. Thus ADH1 isozymes were most active with ethanol, allyl alcohol, sec propanol and cyclohexanol; the 'usual' ADH2 were most active with ethanol, butanol, octanol and sec butanol; the 'atypical' ADH2 isozymes were most active with ethanol and octanol, but showed relatively low activity with butanol and Ronicol; the ADH3 isozymes were relatively very active with long straight chain primary alcohols. Aldehyde substrates: Six different aldehydes were tested. No significant differences between the isozyme products of the three loci were detected except in the case of chloral hydrate. The ADH1 and 'usual' ADH2 isozymes showed activity with chloral hydrate but this was a very poor substrate for the ADH3 and 'atypical' ADH2 isozymes. pH activity profiles: With ethanol as substrate the pH optimum for the ADH1, 'usual' ADH2 and the ADH3 isozymes was around pH 11.5 and for the 'atypical' ADH2 isozymes was about pH 8.8. With acetaldehyde as substrate the pH optima for the ADH1, 'usual' ADH2, 'atypical' ADH2 and ADH3 isozymes were about pH 8.8, 6.0, 7.0-7.5 and 6.5, resp. Inhibitors: Trichloroethanol was found to be a potent inhibitor of the ADH1 isozymes; isobutyramide an inhibitor of ADH3; and pyrazole and thiourea were shown to be powerful inhibitors of the 'atypical' ADH2 isozymes. In vitro stability: The ADH1 isozymes appeared to be relatively less stable than the 'usual' ADH2 and ADH3 isozymes. The 'atypical' ADH2 isozymes were found to be relatively very labile and particularly susceptible to freezing and thawing or storage at 10° C. The ADH 1;3 and ADH 2;3 isozymes were not demonstrably different in the properties tested.

The Pan-African Consortium for the Evaluation of Anti-Tuberculosis Antibiotics (PanACEA) was designed to build tuberculosis (TB) trial capacity whilst conducting clinical trials on novel and existing agents to shorten and simplify TB treatment. PanACEA has now established a dynamic network of 11 sub-Saharan clinical trial sites and four European research institutions.In 2011, a capacity development program, funded by the European & Developing Countries Clinical Trials Partnership (EDCTP), was launched with four objectives, aiming at strengthening collaborating TB research sites to reach the ultimate goal of becoming self-sustainable institutions: networking; training; conducting clinical trials; and infrastructure scaling-up of sites.Assessment in six sub-Saharan TB-endemic countries (Gabon, Kenya, South Africa, Tanzania, Uganda and Zambia) were performed through a structured questionnaire, site visits, discussion with the PanACEA consortium, setting of milestones and identification of priorities and followed-up with evaluations of each site. The results of this needs-based assessment was then translated into capacity development measures.In the initial phase, over a four-year period (March 2011 - June 2014), the programme scaled-up six sites; conducted a monitoring training program for 11 participants; funded five MSc and four PhD students, fostering gender balance; conducted four epidemiological studies; supported sites to conduct five Phase II studies and formed a sustainable platform for TB research (panacea-tb.net).Our experience of conducting TB clinical trials within the PanACEA programme environment of mentoring, networking and training has provided a sound platform for establishing future sustainable research centres. Our goal of facilitating emergent clinical TB trial sites to better initiate and lead research activities has been mostly successful.