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Long-acting injectable (LAI) formulations promise to deliver patient benefits by overcoming issues associated with non-adherence. A preclinical assessment of semi-solid prodrug nanoparticle (SSPN) LAI formulations of emtricitabine (FTC) is reported here. Pharmacokinetics over 28 days were assessed in Wistar rats, New Zealand white rabbits, and Balb/C mice following intramuscular injection. Two lead formulations were assessed for the prevention of an HIV infection in NSG-cmah−/− humanised mice to ensure antiviral activities were as anticipated according to the pharmacokinetics. Cmax was reached by 12, 48, and 24 h in rats, rabbits, and mice, respectively. Plasma concentrations were below the limit of detection (2 ng/mL) by 21 days in rats and rabbits, and 28 days in mice. Mice treated with SSPN formulations demonstrated undetectable viral loads (700 copies/mL detection limit), and HIV RNA remained undetectable 28 days post-infection in plasma, spleen, lung, and liver. The in vivo data presented here demonstrate that the combined prodrug/SSPN approach can provide a dramatically extended pharmacokinetic half-life across multiple preclinical species. Species differences in renal clearance of FTC mean that longer exposures are likely to be achievable in humans than in preclinical models.

COVID-19 has brought to unavoidable prominence what feminist geopolitics has long insisted, namely that the global and the intimate are always, everywhere, already entangled. Drawing on Anglo-American experiences of the pandemic, this paper aims to make two key arguments. The first is that feminist geopolitics is a conceptual approach that is perhaps uniquely placed to make sense of COVID geographies. The second is to propose that this account of COVID speaks back to recent debates about the future of feminist geopolitics. Reflecting on recent debates about possible futures for feminist geopolitics, the paper will make the case for a materially-engaged feminist geopolitics which nevertheless keeps the socially-marked body at the heart of analysis. Publisher PDF

Antiviral interventions are urgently required to support vaccination programmes and reduce the global burden of COVID-19. Prior to initiation of large-scale clinical trials, robust preclinical data in support of candidate plausibility are required. The speed at which preclinical models have been developed during the pandemic are unprecedented but there is a vital need for standardisation and assessment of the Critical Quality Attributes. This work provides cross-validation for the recent report demonstrating potent antiviral activity of probenecid against SARS-CoV-2 in preclinical models (1). Vero E6 cells were pre-incubated with probenecid, across a 7-point concentration range, or control media for 2 hours before infection with SARS-CoV-2 (SARS-CoV-2/Human/Liverpool/REMRQ0001/2020, Pango B; MOI 0.05). Probenecid or control media was then reapplied and plates incubated for 48 hours. Cells were fixed with 4% v/v paraformaldehyde, stained with crystal violet and cytopathic activity quantified by spectrophotometry at 590 nm. Syrian golden hamsters (n=5 per group) were intranasally inoculated with virus (SARS-CoV-2 Delta variant B.1.617.2; 103 PFU/hamster) for 24 hours prior to treatment. Hamsters were treated with probenecid or vehicle for 4 doses. Hamsters were ethically euthanised before quantification of total and sub-genomic pulmonary viral RNAs. No inhibition of cytopathic activity was observed for probenecid at any concentration in Vero E6 cells. Furthermore, no reduction in either total or sub-genomic RNA was observed in terminal lung samples from hamsters on day 3 (P > 0.05). Body weight of uninfected hamsters remained stable throughout the course of the experiment whereas both probenecid- (6 - 9% over 3 days) and vehicle-treated (5 - 10% over 3 days) infected hamsters lost body weight which was comparable in magnitude (P > 0.5). The presented data do not support probenecid as a SARS-CoV-2 antiviral. These data do not support use of probenecid in COVID-19 and further analysis is required prior to initiation of clinical trials to investigate the potential utility of this drug.

Background: Ronapreve demonstrated clinical application in post-exposure prophylaxis, mild/moderate disease and in the treatment of seronegative patients with severe COVID19 prior to the emergence of the Omicron variant in late 2021. Numerous reports have described loss of in vitro neutralisation activity of Ronapreve and other monoclonal antibodies for BA.1 Omicron and subsequent sub-lineages of the Omicron variant. With some exceptions, global policy makers have recommended against the use of existing monoclonal antibodies in COVID19. Gaps in knowledge regarding the mechanism of action of monoclonal antibodies are noted, and further preclinical study will help understand positioning of new monoclonal antibodies under development. Objectives: The purpose of this study was to investigate the impact of Ronapreve on compartmental viral replication as a paradigm for a monoclonal antibody combination. The study also sought to confirm absence of in vivo activity against BA.1 Omicron (B.1.1.529) relative to the Delta (B.1.617.2) variant. Methods: Virological efficacy of Ronapreve was assessed in K18-hACE2 mice inoculated with either the SARS-CoV-2 Delta or Omicron variants. Viral replication in tissues was quantified using qRT-PCR to measure sub-genomic viral RNA to the E gene (sgE) as a proxy. A histological examination in combination with staining for viral antigen served to determine viral spread and associated damage. Results: Ronapreve reduced sub-genomic viral RNA levels in lung and nasal turbinate, 4 and 6 days post infection, for the Delta variant but not the Omicron variant of SARS-CoV-2 at doses 2-fold higher than those shown to be active against previous variants of the virus. It also appeared to block brain infection which is seen with high frequency in K18-hACE2 mice after Delta variant infection. At day 6, the inflammatory response to lung infection with the Delta variant was altered to a mild multifocal granulomatous inflammation in which the virus appeared to be confined. A similar tendency was also observed in Omicron infected, Ronapreve-treated animals. Conclusions: The current study provides evidence of an altered tissue response to the SARS-CoV-2 after treatment with a monoclonal antibody combination that retains neutralization activity. These data also demonstrate that experimental designs that reflect the treatment use case are achievable in animal models for monoclonal antibodies deployed against susceptible variants. Extreme caution should be taken when interpreting prophylactic experimental designs when assessing plausibility of monoclonal antibodies for treatment use cases.

MAX phase composites Ti3SiC2–TiCx and Ti3SiC2–(TiCx + TiC) were synthesized and consolidated via a powder metallurgy spark plasma sintering (SPS) technique. The bulk compositions and micros...

Successful development of a chemoprophylaxis against SARS-CoV-2 could provide a tool for infection prevention implementable alongside vaccination programmes. Camostat and nafamostat are serine protease inhibitors that inhibit SARS-CoV-2 viral entry in vitro but have not been characterised for chemoprophylaxis in animal models. Clinically, nafamostat is limited to intravenous delivery and while camostat is orally available, both drugs have extremely short plasma half-lives. This study sought to determine whether intranasal dosing at 5 mg/kg twice daily was able to prevent airborne transmission of SARS-CoV-2 from infected to uninfected Syrian golden hamsters. SARS-CoV-2 viral RNA was above the limits of quantification in both saline- and camostat-treated hamsters 5 days after cohabitation with a SARS-CoV-2 inoculated hamster. However, intranasal nafamostat-treated hamsters remained RNA negative for the full 7 days of cohabitation. Changes in body weight over the course of the experiment were supportive of a lack of clinical symptomology in nafamostat-treated but not saline- or camostat-treated animals. These data are strongly supportive of the utility of intranasally delivered nafamostat for prevention of SARS-CoV-2 infection and further studies are underway to confirm absence of pulmonary infection and pathological changes.

Currently nitazoxanide is being assessed as a candidate therapeutic for SARS-CoV-2. Unlike many other candidates being investigated, tizoxanide (the active metabolite of nitazoxanide) plasma concentrations achieve antiviral levels after administration of the approved dose, although higher doses are expected to be needed to maintain these concentrations across the dosing interval in the majority of patients. Here an LC-MS/MS assay is described that has been validated in accordance with Food and Drug Administration (FDA) guidelines. Fundamental parameters have been evaluated, and these included accuracy, precision and sensitivity. The assay was validated for human plasma, mouse plasma and Dulbeccos Modified Eagles Medium (DMEM) containing varying concentrations of Foetal Bovine Serum (FBS). Matrix effects are a well-documented source of concern for chromatographic analysis, with the potential to impact various stages of the analytical process, including suppression or enhancement of ionisation. Therefore, a robustly validated LC-MS/MS analytical method is presented capable of quantifying tizoxanide in multiple matrices with minimal impact of matrix effects. The validated assay presented here was linear from 15.6ng/mL to 1000ng/mL. Accuracy and precision ranged between 102.2% and 113.5%, 100.1% and 105.4%, respectively. The presented assay here has applications in both pre-clinical and clinical research and may be used to facilitate further investigations into the application of nitazoxanide against SARS-CoV-2.

The control of COVID-19 across the world requires the formation of a range of interventions including vaccines to elicit an immune response and immunomodulatory or antiviral therapeutics. Here, we demonstrate the nanoparticle formulation of a highly insoluble drug compound, niclosamide, with known anti SARS-CoV-2 activity as a cheap and scalable long-acting injectable antiviral candidate.

Favipiravir (FAV; T-705) has been approved for use as an anti-influenza therapeutic and has reports against a wide range of viruses (e.g., Ebola virus, rabies and norovirus). Most recently FAV has been reported to demonstrate activity against SARS-CoV-2. Repurposing opportunities have been intensively studied with only limited success to date. If successful, repurposing will allow interventions to become more rapidly available than development of new chemical entities. Pre-clinical and clinical investigations of FAV require robust, reproducible and sensitive bioanalytical assay. Here, a liquid chromatography tandem mass spectrometry assay is presented which was linear from 0.78-200 ng/mL Accuracy and precision ranged between 89% and 110%, 101% and 106%, respectively. The presented assay here has applications in both pre-clinical and clinical research and may be used to facilitate further investigations into the application of FAV against SARS-CoV-2.

The spread of SARS-CoV-2 across the world requires the formation of a range of interventions that include immunomodulatory or antiviral therapeutics and repurposing of existing drug compounds is an important strategy to rapidly identify possible options. Niclosamide is a cheap and generic drug compound with a proven in vitro ability to inhibit viral replication of SARS-CoV-2; this drug also has known poor oral bioavailability due to very low water solubility. Here, we demonstrate the nanoparticle formulation of niclosamide using a new, cheap and scalable process to enable long-acting injectable administration and show extended circulating drug exposure in vivo over 28 days using a rodent model after depot injection.

BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been declared a global pandemic by the World Health Organisation and urgent treatment and prevention strategies are needed. Many clinical trials have been initiated with existing medications, but assessments of the expected plasma and lung exposures at the selected doses have not featured in the prioritisation process. Although no antiviral data is currently available for the major phenolic circulating metabolite of nitazoxanide (known as tizoxanide), the parent ester drug has been shown to exhibitin vitroactivity against SARS-CoV-2. Nitazoxanide is an anthelmintic drug and its metabolite tizoxanide has been described to have broad antiviral activity against influenza and other coronaviruses. The present study used physiologically-based pharmacokinetic (PBPK) modelling to inform optimal doses of nitazoxanide capable of maintaining plasma and lung tizoxanide exposures above the reported nitazoxanide 90% effective concentration (EC90) against SARS-CoV-2.MethodsA whole-body PBPK model was constructed for oral administration of nitazoxanide and validated against available tizoxanide pharmacokinetic data for healthy individuals receiving single doses between 500 mg – 4000 mg with and without food. Additional validation against multiple-dose pharmacokinetic data when given with food was conducted. The validated model was then used to predict alternative doses expected to maintain tizoxanide plasma and lung concentrations over the reported nitazoxanide EC90in >90% of the simulated population. Optimal design software PopDes was used to estimate an optimal sparse sampling strategy for future clinical trials.ResultsThe PBPK model was validated with AAFE values between 1.01 – 1.58 and a difference less than 2-fold between observed and simulated values for all the reported clinical doses. The model predicted optimal doses of 1200 mg QID, 1600 mg TID, 2900 mg BID in the fasted state and 700 mg QID, 900 mg TID and 1400 mg BID when given with food, to provide tizoxanide plasma and lung concentrations over the reportedin vitroEC90of nitazoxanide against SARS-CoV-2. For BID regimens an optimal sparse sampling strategy of 0.25, 1, 3 and 12h post dose was estimated.ConclusionThe PBPK model predicted that it was possible to achieve plasma and lung tizoxanide concentrations, using proven safe doses of nitazoxanide, that exceed the EC90for SARS-CoV-2. The PBPK model describing tizoxanide plasma pharmacokinetics after oral administration of nitazoxanide was successfully validated against clinical data. This dose prediction assumes that the tizoxanide metabolite has activity against SARS-CoV-2 similar to that reported for nitazoxanide, as has been reported for other viruses. The model and the reported dosing strategies provide a rational basis for the design (optimising plasma and lung exposures) of future clinical trials of nitazoxanide in the treatment or prevention of SARS-CoV-2 infection.

There is a rapidly expanding literature on thein vitroantiviral activity of drugs that may be repurposed for therapy or chemoprophylaxis against SARS-CoV-2. However, this has not been accompanied by a comprehensive evaluation of the ability of these drugs to achieve target plasma and lung concentrations following approved dosing in humans. Moreover, most publications have focussed on 50% maximum effective concentrations (EC50), which may be an insufficiently robust indicator of antiviral activity because of marked differences in the slope of the concentration-response curve between drugs. Accordingly,in vitroanti-SARS-CoV-2 activity data was digitised from all available publications up to 13thApril 2020 and used to recalculate an EC90value for each drug. EC90values were then expressed as a ratio to the achievable maximum plasma concentrations (Cmax) reported for each drug after administration of the approved dose to humans (Cmax/EC90ratio). Only 14 of the 56 analysed drugs achieved a Cmax/EC90ratio above 1 meaning that plasma Cmax concentrations exceeded those necessary to inhibit 90% of SARS-CoV-2 replication. A more in-depth assessment of the putative agents tested demonstrated that only nitazoxanide, nelfinavir, tipranavir (boosted with ritonavir) and sulfadoxine achieved plasma concentrations above their reported anti-SARS-CoV-2 activity across their entire approved dosing interval at their approved human dose. For all drugs reported, the unbound lung to plasma tissue partition coefficient (KpUlung) was also simulated and used along with reported Cmax and fraction unbound in plasma to derive a lung Cmax/EC50as a better indicator of potential human efficacy (lung Cmax/EC90ratio was also calculable for a limited number of drugs). Using this parameter hydroxychloroquine, chloroquine, mefloquine, atazanavir (boosted with ritonavir), tipranavir (boosted with ritonavir), ivermectin, azithromycin and lopinavir (boosted with ritonavir) were all predicted to achieve lung concentrations over 10-fold higher than their reported EC50. This analysis was not possible for nelfinavir because insufficient data were available to calculate KpUlungbut nitozoxanide and sulfadoxine were also predicted to exceed their reported EC50by 3.1- and 1.5-fold in lung, respectively. The antiviral activity data reported to date have been acquired under different laboratory conditions across multiple groups, applying variable levels of stringency. However, this analysis may be used to select potential candidates for further clinical testing, while deprioritising compounds which are unlikely to attain target concentrations for antiviral activity. Future studies should focus on EC90values and discuss findings in the context of achievable exposures in humans, especially within target compartments such as the lung, in order to maximise the potential for success of proposed human clinical trials.

Urbanisation is associated with changes in consumption patterns and food production processes. These patterns and processes can increase or decrease the risks of outbreaks of foodborne diseases and are generally accompanied by changes in food safety policies and regulations about food handling. This affects consumers, as well as people economically engaged in the food value chain. This study looks at Tanzania&rsquo, s red meat value chain&mdash, which in its totality involves about one third of the population&mdash, and focuses on the knowledge, attitudes and reported practices of operators of butcheries and eateries with regards to meat safety in an urban and in a rural environment. We interviewed 64 operators about their experiences with foodborne diseases and their explanations and expectations around meat safety, with a particular emphasis on how they understood their own actions regarding food safety risks vis-&agrave, vis regulations. We found operators of eateries emphasising their own agency in keeping meat safe, whereas operators of butcheries&mdash, whose products are more closely inspected&mdash, relied more on official inspections. Looking towards meat safety in the future, interviewees in rural areas were, relative to their urban counterparts, more optimistic, which we attribute to rural operators&rsquo, shorter and relatively unmediated value chains.

Pharmaceutical excipients are no longer considered inert and have been shown to influence the activity of metabolic enzymes and transporters, resulting in altered pharmacokinetics of substrate drugs. In this study, the effect of 25 excipients commonly used in drug formulations were investigated for their effect on P-glycoprotein (P-gp) activity. The effect of excipients on P-gp were assessed by measuring the change in the cellular accumulation of a P-gp substrate, digoxin, in MDCK-MDR1 (Madin Darby canine kidney transfected with multidrug resistance 1 gene) cells. The cells were exposed to low (10 μM) and high (200 μM) concentrations of excipient along with 10 μM digoxin. Excipient concentrations were chosen to span the range of concentrations previously used for investigating activities in vitro. At 10 μM of excipient, an increase in the intracellular digoxin concentration was seen with d-α-tocopherol poly-(ethylene glycol) succinate (Vit-E-PEG; p = 0.002), poly(ethylene oxide)

LiCoMnO4 was made at 550 °C in 2 h using a novel biotemplating synthetic methodology. High temperature heat treatment under flowing N2 was then used to prepare the cation-disordered rock salt, LiCoMnO3. We demonstrate for the first time that both phases can operate as conversion anodes in lithium-ion batteries, operating at ~ 0.7 V with specific capacities of ~ 400 mAh g-1. We also demonstrate that 1,3-propane sultone can be used as an electrolytic additive to provide a modest boost to specific capacity in cells cycled at high potentials with LiCoMnO4 as the cathode.

Titanium alloys are widely used in the field of orthopaedics, however, poor tribological performance arising from the low shear resistance and weak protection of the oxide layer limits their applicability. In this work, the tribocorrosion behaviour of novel β and α + β biomedical titanium alloys were studied in bovine serum solution under open circuit potential. Ti-5Mo-Fe-3Sn and Ti-6Al-4V ELI alloys were found to have the capability to repassivate when testing at a slower sliding speed. Scanning and transmission electron microscopy results revealed that the repassivation was mainly associated with the greater tribofilm formation on the worn surface, rather than an oxide film. The tribolayer performed as a solid lubricating film, which stabilised the coefficient of friction.

This research was funded by the Biotechnology and Biological Sciences Research Council, the Department for International Development, the Economic and Social Research Council, the Medical Research Council, the Natural Environment Research Council, and the Defence Science and Technology Laboratory, under the UK Zoonoses and Emerging Livestock Systems Initiative (BB/L017679/1 and BB/L018926/1). BACKGROUND: With increasing demand for red meat in Tanzania comes heightened potential for zoonotic infections in animals and humans that disproportionately affect poor communities. A range of frontline government employees work to protect public health, providing services for people engaged in animal-based livelihoods (livestock owners and butchers), and enforcing meat safety and food premises standards. In contrast to literature which emphasises the inadequacy of extension support and food safety policy implementation in low- and middle-income countries, this paper foregrounds the 'street-level diplomacy' deployed by frontline actors operating in challenging contexts. METHODS: This research is based on semi-structured interviews with 61 government employees, including livestock extension officers/meat inspectors and health officers, across 10 randomly-selected rural and urban wards. RESULTS: Frontline actors combined formal and informal strategies including the leveraging of formal policy texts and relationships with other state employees, remaining flexible and recognising that poverty constrained people's ability to comply with health regulations. They emphasised the need to work with livestock keepers and butchers to build their knowledge to self-regulate and to work collaboratively to ensure meat safety. Remaining adaptive and being hesitant to act punitively unless absolutely necessary cultivated trust and positive relations, making those engaged in animal-based livelihoods more open to learning from and cooperating with extension officers and inspectors. This may result in higher levels of meat safety than might be the case if frontline actors stringently enforced regulations. CONCLUSION: The current tendency to view frontline actors' partial enforcement of meat safety regulations as a failure obscures the creative and proactive ways in which they seek to ensure meat safety in a context of limited resources. Their application of 'street-level diplomacy' enables them to be sensitive to local socio-economic realities, to respect local social norms and expectations and to build support for health safety interventions when necessary. More explicitly acknowledging the role of trust and positive state-society relations and the diplomatic skills deployed by frontline actors as a formal part of their inspection duties offers new perspectives and enhanced understandings on the complicated nature of their work and what might be done to support them. Publisher PDF

The precipitates formed in a new series of Fe Mn maraging steels when aged at 500 °C were identified as the L21-ordered Ni2TiAl phase. The precipitate formed a coherent-coplanar microstructure analogously to γ/γ' Ni-based superalloys and maintained a high number density and homogeneous dispersion within α′-martensite matrix even after aging for 10,080 min. An increase in the Mn content of the alloy led to faster precipitation kinetics and thus rapid hardening kinetics.

Emerging infectious diseases (EIDs) threaten the health of people, animals, and crops globally, but our ability to predict their occurrence is limited. Current public health capacity and ability to detect and respond to EIDs is typically weakest in low- and middle-income countries (LMICs). Many known drivers of EID emergence also converge in LMICs. Strengthening capacity for surveillance of diseases of relevance to local populations can provide a mechanism for building the cross-cutting and flexible capacities needed to tackle both the burden of existing diseases and EID threats. A focus on locally relevant diseases in LMICs and the economic, social, and cultural contexts of surveillance can help address existing inequalities in health systems, improve the capacity to detect and contain EIDs, and contribute to broader global goals for development.

Cold spray (CS) coating technique is being studied as a potential solution for repairing aircraft Ti-6Al-4V components. This work is focused on the restoration of damaged components due to wear induced by vibrations. It is known that Ti-6Al-4V CS deposition shows difficulties to obtain non-porous coatings due to the high strength of this material, that is detrimental for wear resistance. In this sense, performing a post-heat treatment leads to lower porosity CS Ti-6Al-4V coatings and improves their mechanical properties, and thus, a better tribological behaviour is also expected. Therefore, the objective of this study was to determine the effect of a post-heat treatment on the wear resistance of Ti-6Al-4V coatings deposited by the CS technique. Ti-6Al-4V CS coatings were used, which have been sprayed with nitrogen as process gas at a temperature of 1100 °C and a pressure of 50 bar. The coatings were subjected to a solution heat treatment followed by a precipitation heat treatment. Oscillating and unidirectional sliding wear experiments were conducted on the coatings at room temperature and at 450 °C. A pin on disc configuration was used with a bearing steel counterbody. The results were compared to those obtained on the substrate (which represents the material to be repaired) and on the as-sprayed coating, which were derived from a previous work. The heat treated coating presented improved wear behaviour as compared to the substrate as well as to the as-sprayed coating, particularly during the high temperature tests. Wear at high temperature was dominated by material transference from the counterbody to the Ti-6Al-4V coating.

Due to internal processing defects, bulk nanostructured Mg alloys have high strength but extremely poor ductility. A novel and facile process was designed and in-situ powder casting was initiated during spark plasma sintering. This process significantly reduced processing induced defects, enhanced inter-particle bonding and introduced significant precipitation without extra ageing treatment, leading to improvement of the compressive strength and ductility. The compressive strain of bulk sample consisting of pure cryomilled powder was 3.6% with an ultimate strength of 500 MPa, while cryomilled powder mixed with eutectic Mg-Zn alloy powder obtained a compressive strain of 6.6% and ultimate strength of 506 MPa. The ductility of the sample with mixed powder was increased by 83% without any sacrifice of strength compared to the sample consisting of only pure cryomilled powder.

The extrinsic size of both crystalline alloys and amorphous metallic alloys strongly affects their mechanical properties at the submicron scale or nanometre scale. For example, Zr-based metallic glass nanopillars exhibit ceramic-like strengths (2.25 GPa) and metal-like ductility (25%) simultaneously when the pillar dimension is reduced to

This research was supported by the UK Biotechnology and Biological Sciences Research Council (BB/J010367/1) and the UK Zoonoses and Emerging Livestock Systems Initiative (BB/L017679/1, BB/L018926/1 and BB/L018845/1) (S.C., J.E.B.H., J.S., J.B., A.D., J.A.C., W.A.d.G., R.R.K., T.K., D.T.H., B.T.M., E.S.S., L.W.). The Wellcome Trust provided supported for K.H. and A.L. (095787/Z/11/Z) and K.J.A. (096400/Z/11/Z). The US National Institutes of Health provided support for J.A.C. (R01AI121378) and M.P.R. (R01AI121378, K23AI116869). Emerging zoonoses with pandemic potential are a stated priority for the global health security agenda, but endemic zoonoses also have a major societal impact in low-resource settings. Although many endemic zoonoses can be treated, timely diagnosis and appropriate clinical management of human cases is often challenging. Preventive ‘One Health’ interventions, e.g. interventions in animal populations that generate human health benefits, may provide a useful approach to overcoming some of these challenges. Effective strategies, such as animal vaccination, already exist for the prevention, control and elimination of many endemic zoonoses, including rabies, and several livestock zoonoses (e.g. brucellosis, leptospirosis, Q fever) that are important causes of human febrile illness and livestock productivity losses in low- and middle-income countries. We make the case that, for these diseases, One Health interventions have the potential to be more effective and generate more equitable benefits for human health and livelihoods, particularly in rural areas, than approaches that rely exclusively on treatment of human cases. We hypothesize that applying One Health interventions to tackle these health challenges will help to build trust, community engagement and cross-sectoral collaboration, which will in turn strengthen the capacity of fragile health systems to respond to the threat of emerging zoonoses and other future health challenges. One Health interventions thus have the potential to align the ongoing needs of disadvantaged communities with the concerns of the broader global community, providing a pragmatic and equitable approach to meeting the global goals for sustainable development and supporting the global health security agenda. Publisher PDF

The image of Scottish National Party (SNP) leader Alex Salmond unfurling the Scottish Saltire behind the bemused UK Prime Minister, David Cameron, moments after Andy Murray won the Wimbledon tennis tournament in July 2013, has come to epitomize the nature of debate around the implications of the Independence Referendum outside of Scotland. Mainstream coverage has rendered “IndyRef” as something of a pantomime politics performed by Salmond and Cameron. The debate has been reduced to a competition between Salmond's idealistic political nationalism and the economic “realities” presented by Cameron, rendered as a chant: “We can afford independence, we will be one of the world's wealthiest countries” versus the response, “Oh no you can't”! In Scotland, on the other hand, debates around the implications of the referendum have gone beyond romanticized notions of tartan, Braveheart and freedom (although these do still exist, of course). Although the political parties themselves have perhaps been rather conservative, debates beyond their official efforts have been much more imaginative, with discussion around the nature of the state, citizenship, and Scotland's role on the international stage, among other issues.

In this work, we report the synthesis, deformation and tribological behaviour of a novel Ti3AlC2 – Ti2AlC MAX phase composite metallo-ceramic. The dual MAX phase composite was synthesized by spark plasma sintering (SPS) under a vacuum environment using Ti, Al, and C precursor powders. The layered composite deformation mechanism and tribological behaviour were studied and analyzed by SEM, TEM, and Raman spectroscopy. The transition in friction and wear as well as the operative wear mechanisms involved were further discussed. Detailed analyses of the worn surface showed that Ti3AlC2 – Ti2AlC dual MAX phase composite is intrinsically self-lubricating.

Critical geopolitics has become one of the most vibrant parts of political geography. However it remains a particularly western way of knowing which has been much less attentive to other traditions of thinking. This paper engages with Pan-Africanism, and specifically the vision of the architect of post-colonial Tanzania, Julius Nyerere, to explore this overlooked contribution to critical engagements with geopolitics. Pan-Africanism sought to forge alternative post-colonial worlds to the binary geopolitics of the Cold War and the geopolitical economy of neo-colonialism. The academic division of labour has meant that these ideas have been consigned to African studies rather than being drawn into wider debates around the definitions of key disciplinary concepts. However Nyerere's continental thinking can be seen as a form of geopolitical imagination that challenges dominant neo-realist projections, and which still has much to offer contemporary political geography.

Objective To compare actual and perceived causes of fever in northern Tanzania. Methods In a standardised survey, heads of households in 30 wards in Moshi, Tanzania, were asked to identify the most common cause of fever for children and for adults. Responses were compared to data from a local hospital-based fever aetiology study that used standard diagnostic techniques. Results Of 810 interviewees, the median (range) age was 48 (16, 102) years and 509 (62.8%) were women. Malaria was the most frequently identified cause of fever, cited by 353 (43.6%) and 459 (56.7%) as the most common cause of fever for children and adults, respectively. In contrast, malaria accounted for 8 (2.0%) of adult and 6 (1.3%) of paediatric febrile admissions in the fever aetiology study. Weather was the second most frequently cited cause of fever. Participants who identified a non-biomedical explanation such as weather as the most common cause of fever were more likely to prefer a traditional healer for treatment of febrile adults (OR 2.7, P

In this article we wish to explore the political possibilities of video games. Numerous scholars now take seriously the place of popular culture in the remaking of our geographies, but video games still lag behind. For us, this tendency reflects a general response to them as imaginary spaces that are separate from everyday life and ‘real’ politics. It is this disconnect between abstraction and lived experience that we complicate by defining play as an event of what Brian Massumi calls lived abstraction. We wish to short-circuit the barriers that prevent the aesthetic resonating with the political and argue that through their enactment, video games can animate fantastical futures that require the player to make, and reflect upon, profound ethical decisions that can be antagonistic to prevailing political imaginations. We refer to this as social irrealism to demonstrate that reality can be understood through the impossible and the imagined.

In this paper, the thermal stability of cryomilled nanocrystalline (NC) AZ31 powder was evaluated by annealing at elevated temperature ranging from 350 to 450 °C. The results show the NC AZ31 powder exhibited excellent thermal stability during short anneals at 350–450 °C, and the mechanisms were investigated in detail. There were two separate growth stages with a transition point at around 400 °C. More specifically, between 350 and 400 °C, NC Mg grains were stable at approximately 32 nm, even after 1 h annealing. At 450 °C, the nano grains grew to 37 nm in the first 5 min and grew quickly to approximately 60 nm after 15 min. However, the grain growth was limited when the annealing time was increased to 60 min. The average grain size remained stable less than approximately 60 nm even after long anneals at temperatures as high as 450 °C (0.78 T/TM), indicating an outstanding degree of grain size stability. This excellent thermal stability can be mainly attributed to solute drag and Zener pinning.

A set of Mn-based maraging TRIP steels was designed by Max-Planck-Institut fur Eisenforschung GmbH (MPIE) for light weight and safe automotive applications. According to their research, these Mn-based maraging TRIP steels exhibited a simultaneous increase in both strength and ductility upon aging. They attributed this surprising effect to the combination of precipitation strengthening mechanism and TRIP effect of reverted/retained austenite. This thesis carried out a further study on this type of steels with minor modification of chemical composition (7-12 wt.% Mn, with additional ~ 1 wt.% Al). The unknown precipitates were characterized as L21-ordered Ni2TiAl intermetallic phase for the first time. This type of precipitates is not only coherent but also coplanar with the martensite matrix. Their special orientation relationship together with the small lattice misfit (1.24%) led to the precipitates remaining coherent with the martensite matrix even after a long-term aging for 10080 min. Analyses on precipitate size revealed that the coarsening rate constants follows the diffusion-controlled coarsening kinetics form r ^3~Kt predicted by LSW theory, but the experimental precipitate size distributions (PSDs) is much broader than the theoretical PSD function. In addition, a core/shell structure was observed within the precipitates, but the exact structure of this structure is still not clear. The formation of reverted austenite nanolayers initiated at the onset of aging by a diffusionless shear mechanism since the critical Mn concentration for austenite reversion at the interface is very low. The accumulated Mn segregation at grain boundaries in the following aging led to the austenite nanolayers that grew to lath-like reverted austenite, which means the lateral growth of austenite was supported by the diffusion of Mn. Due to the low diffusion rate of Mn and the thermodynamic resistance to coalescence, the growth rate of lath-like reverted austenite is slow and thus the austenite maintained in the range 70-200 nm for a long time. The segregation of Ti and Mo on grain boundaries in the initial aging stage resulted in the Mn concentration of austenite nanolayers being far from that indicated by the equilibrium Fe-Mn phase diagram. The segregation of Ti and Mo gradually vanished with the enrichment of Mn during the succeeding aging process. The TEM-EDS analyses revealed the Mn concentration of lath-like austenite was at the level of ~24 at.% which is higher than that of retained austenite (8-12 at.%) reported in conventional Mn-based TRIP or Q&P steels. Nanoindentation testing revealed that the high stability of reverted austenite in Mn-based maraging steels was mainly attributed to the high Mn concentration of austenite. The nano-size of reverted austenite was also considered to be responsible for the high stability. Severe embrittlement occurred in samples aged at lower temperatures or for short times. Increasing aging temperatures and duration can significantly improve the embrittlement phenomena. An ultimate tensile strength (UTS) of 1120 MPa with total elongation (TE) of 18.4% was obtained in the 12% Mn alloy by aging at 500 °C for 5760 min. It was demonstrated that the dense precipitates contributed to the increase in yield strength whereas the work hardening of reverted austenite contributed to the enhanced strength and ductility after yielding. The TRIP effect of reverted austenite reported by Raabe et al. does not occur to any significant amount owing to the high stability of reverted austenite in Mn-based maraging steels.

Bulk nanostructured magnesium alloy AZ31 has been produced by spark plasma sintering at four different temperatures from 350 to 450 °C. The effect of sintering temperature on microstructural evolution and compression behaviour was studied in detail. It was concluded that the sample consolidated at 400 °C exhibited the highest strength. Higher sintering temperature (450 °C) improved the compressive strain of the bulk sample but at the sacrifice of strength. However, samples consolidated at 350 °C displayed brittle behaviour with low strength. All consolidated samples had a bimodal microstructure with nanocrystalline and coarse grains. The nanocrystalline microstructure formed by cryomilling was retained after consolidation and a maximum microhardness was approximately 150 HV. The bulk samples consolidated at 400 °C with an average grain size of 45 nm showed exceptional average true compressive yield strength of 400.7 MPa, true ultimate compressive strength of 499.7 MPa, which was superior to published results for most of conventional magnesium alloys. Although nanostructured materials usually have high strength but poor ductility, the material in this study exhibited high strength and a true compressive strain of 0.036.

Background Zoonoses are common causes of human and livestock illness in Tanzania. Previous studies have shown that brucellosis, leptospirosis, and Q fever account for a large proportion of human febrile illness in northern Tanzania, yet they are infrequently diagnosed. We conducted this study to assess awareness and knowledge regarding selected zoonoses among healthcare providers in Moshi, Tanzania; to determine what diagnostic and treatment protocols are utilized; and obtain insights into contextual factors contributing to the apparent under-diagnosis of zoonoses. Methodology/Results We conducted a questionnaire about zoonoses knowledge, case reporting, and testing with 52 human health practitioners and 10 livestock health providers. Immediately following questionnaire administration, we conducted semi-structured interviews with 60 of these respondents, using the findings of a previous fever etiology study to prompt conversation. Sixty respondents (97%) had heard of brucellosis, 26 (42%) leptospirosis, and 20 (32%) Q fever. Animal sector respondents reported seeing cases of animal brucellosis (4), rabies (4), and anthrax (3) in the previous 12 months. Human sector respondents reported cases of human brucellosis (15, 29%), rabies (9, 18%) and anthrax (6, 12%). None reported leptospirosis or Q fever cases. Nineteen respondents were aware of a local diagnostic test for human brucellosis. Reports of tests for human leptospirosis or Q fever, or for any of the study pathogens in animals, were rare. Many respondents expressed awareness of malaria over-diagnosis and zoonoses under-diagnosis, and many identified low knowledge and testing capacity as reasons for zoonoses under-diagnosis. Conclusions This study revealed differences in knowledge of different zoonoses and low case report frequencies of brucellosis, leptospirosis, and Q fever. There was a lack of known diagnostic services for leptospirosis and Q fever. These findings emphasize a need for improved diagnostic capacity alongside healthcare provider education and improved clinical guidelines for syndrome-based disease management to provoke diagnostic consideration of locally relevant zoonoses in the absence of laboratory confirmation., Author Summary Zoonoses are diseases that are naturally transmitted between animals and humans. In Tanzania, research has shown that several zoonoses, including brucellosis, leptospirosis, and Q fever, are common, but under-diagnosed, causes of human illness. We conducted a mixed methods survey, combining quantitative and qualitative research techniques, of healthcare providers in Moshi, Tanzania. Four (40%) of 10 animal sector respondents and 15 (29%) of 52 human sector respondents reported seeing brucellosis cases in the past 12 months, while none reported cases of leptospirosis or Q fever. Nineteen (31%) respondents reported awareness of a local diagnostic test for human brucellosis, while one reported locally available diagnostic tests for human leptospirosis and Q fever. One (2%) respondent reported a locally available animal brucellosis test, and none reported tests for leptospirosis or Q fever in animals. Many respondents mentioned a lack of diagnostic testing resources during interviews. Our findings suggest that diagnostic testing capacity improvements alongside public health campaigns and healthcare provider education are key steps toward improving recognition and accurate diagnosis of zoonoses in this setting. An improved understanding of healthcare provider awareness, perceptions, and practices regarding zoonoses is critical for the design of effective programs to improve diagnosis and treatment of these diseases.