Search

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.

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.

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.

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

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.

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

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

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.

Two techniques that explore how minimising the effects of dynamical interactions can lead to an improved understanding of underlying structural information in real and reciprocal space are reviewed and extended. In this special issue dedicated to David Cockayne, the techniques of dislocation tomography and precession electron diffraction described in this paper echo very strongly David's interests in weak-beam imaging of dislocations and structure determination using kinematic diffraction. The weak-beam dark-field (WBDF) technique has been extended to three dimensions to visualise networks of dislocations in a number of materials systems. Some of the issues that arise from using this technique are explored. It is shown how the overall reconstruction can be improved through careful image processing. Using STEM medium-angle annular dark field (MAADF) imaging many of the artefacts seen in the WBDF technique are minimised, with a significant increase in the ease of acquisition and processing the data. Recent ...

There has recently been much said about the end of public space. In contemporary cities, the public sphere is increasingly been seen as comprised of dead public spaces, privatised shopping malls and gated communities, eroding the essence of city life. However, in this paper it is argued that this particular vision of contemporary public space is skewed by the concentration of research in city centres, and in particular in the recapitalised, flagship spaces associated with urban restructuring. The paper questions the extent that the inclusivity and accessibility of local public spaces is under threat and whether democratic practices unfold to threaten such local public spaces, drawing on the recent experience of two inner-city neighbourhoods in Glasgow.

We have developed a new method of tomographically reconstructing extended three-dimensional dislocation networks using weak-beam dark-field (WBDF) imaging in a TEM. A series of WBDF images is recorded every few degrees over a large tilt range, while ensuring that the dark-field reflection used for imaging maintains a constant deviation parameter. With suitable filtering of the WBDF images prior to tomographic reconstruction, the three-dimensional distribution of dislocations is reproduced with high fidelity and high spatial resolution. The success of this approach is demonstrated for heteroepitaxial Mg-doped GaN films. The fidelity of the tomographic reconstruction varies with the dislocation line-vector and elastic anisotropy of the material.

By combining weak-beam dark-field imaging with tomography, we have been able to reconstruct the three-dimensional structure of dislocation arrays in GaN. With a mixture of both threading and in-plane dislocations, owing to plastic relaxation of the film, we look at how well each dislocation is reconstructed and what limits are imposed by way of dislocation density and material anisotropy.

We review the progress in the electron tomography of dislocation microstructures in the transmission electron microscope (TEM). Dislocation contrast is visible both in conventional TEM and scanning TEM (STEM) modes and, despite the complicated intensity variations, dislocation contrast can be isolated using computational filtering techniques prior to reconstruction. We find that STEM annular dark-field (STEM-ADF) imaging offers significant advantages in terms of dislocation contrast and background artifacts. We present several examples, both in semiconducting and metallic systems, illustrating the properties of 3D dislocations. We present the high-angle triple-axis (HATA) specimen holder where the diffraction condition can be chosen at will and dislocation tomograms of multiple reflections can be combined. 3D dislocations are analyzed in terms of dislocation density and dislocation nodal structures. Several avenues of study are suggested that may exploit the 3D dislocation data.

Electron tomography requires a wide angular range of specimen-tilt for a reliable three-dimensional (3D) reconstruction. Although specimen holders are commercially available for tomography, they have several limitations, including tilting capability in only one or two axes at most, e.g. tilt–rotate. For amorphous specimens, the image contrast depends on mass and thickness only and the single-tilt holder is adequate for most tomographic image acquisitions. On the other hand, for crystalline materials where image contrast is strongly dependent on diffraction conditions, current commercially available tomography holders are inadequate, because they lack tilt capability in all three orthogonal axes needed to maintain a constant diffraction condition over the whole tilt range. We have developed a high-angle triple-axis (HATA) tomography specimen holder capable of high-angle tilting for the primary horizontal axis with tilting capability in the other (orthogonal) horizontal and vertical axes. This allows the user to trim the specimen tilt to obtain the desired diffraction condition over the whole tilt range of the tomography series. To demonstrate its capabilities, we have used this triple-axis tomography holder with a dual-axis tilt series (the specimen was rotated by 90° ex-situ between series) to obtain tomographic reconstructions of dislocation arrangements in plastically deformed austenitic steel foils.

Co50Fe50/(0 1 1)-oriented lead magnesium niobate–lead titanate (PMN–PT) multiferroic (MF) heterostructures were fabricated by RF sputtering magnetic films onto PMN–PT substrates. The effect of magnetic layer thickness (30 nm to 100 nm) on the magnetoelectric (ME) coupling in the heterostructures was studied independently, due to the almost constant magnetostriction constant (λ = 40 ± 5 ppm) and similar as-grown magnetic anisotropies for all studied magnetic layer thicknesses. A record high remanence ratio (M r/M s) tunability of 95% has been demonstrated in the 65 nm Co50Fe50/PMN–PT heterostructure, corresponding to a large ME constant (α) of 2.5 × 10−6 s m−1, when an external electric field (E-field) of 9 kV cm−1 was applied. Such an MF heterostructure provides considerable opportunities for E-field-controlled multifunctional devices.

Weak-beam dark field tomography of dislocations has so far been done in a heuristic way with little theoretical analysis of how to optimise the technique. In this paper a more quantitative analysis of the limits of WBDF tomography is summarised. It can be shown that the object reconstructed from WBDF images by a conventional tomography algorithm is the locus of dislocation images laid down as central slices at the appropriate tilt angles, as would be intuitively expected. By comparison with projections of the displacement field, a reconstruction from dark-field images gives a better indication of the dislocation's path than a projection of the displacement field itself. Reconstruction is performed on a simulated tilt series of stacking fault images; the resulting structure follows the correct plane but is a 3D array of rods, not a flat plane. This is produced by the 'movement' of dynamical fringes in the stacking fault images as the sample is tilted and is an example of WBDF images being suboptimal for tomography. Finally, the influence of misalignment between the tilt axis and systematic row is modelled, and is shown to degrade the reconstruction, especially in the out-of-plane direction. This misalignment changes the excitation error with tilt, which introduces another variable to the reconstruction process and breaks the requirement that the images be a straight-ray projection of a monotonic function of the required parameter.

After previous work producing a successful 3D tomographic reconstruction of dislocations in GaN from conventional weak-beam dark-field (WBDF) images, we have reconstructed a cascade of dislocations in deformed and annealed silicon to a comparable standard using the more experimentally straightforward technique of STEM annular dark-field imaging (STEM ADF). In this mode, image contrast was much more consistent over the specimen tilt range than in conventional weak-beam dark-field imaging. Automatic acquisition software could thus restore the correct dislocation array to the field of view at each tilt angle, though manual focusing was still required. Reconstruction was carried out by sequential iterative reconstruction technique using FEI's Inspect3D software. Dislocations were distributed non-uniformly along cascades, with sparse areas between denser clumps in which individual dislocations of in-plane image width 24 nm could be distinguished in images and reconstruction. Denser areas showed more complicated stacking-fault contrast, hampering tomographic reconstruction. The general three-dimensional form of the denser areas was reproduced well, showing the dislocation array to be planar and not parallel to the foil surfaces.

Dislocations and their interactions govern the properties of many materials, ranging from work hardening in metals to device pathology in semiconductor laser diodes. However, conventional electron micrographs are simply two-dimensional projections of three-dimensional (3D) structures, and even stereo microscopy cannot reveal the true 3D complexity of defect structures. Here, we describe an electron tomographic method that yields 3D reconstructions of dislocation networks with a spatial resolution three orders of magnitude better than previous work. We illustrate the method's success with a study of dislocations in a GaN epilayer, where dislocation densities of 1010 per square centimeter are common.

There is a rapidly expanding literature on the in vitro antiviral activity of drugs that may be repurposed for therapy or chemoprophylaxis against severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). However, this has not been accompanied by a comprehensive evaluation of the target plasma and lung concentrations of these drugs following approved dosing in humans. Accordingly, concentration 90% (EC90 ) values recalculated from in vitro anti-SARS-CoV-2 activity data was expressed as a ratio to the achievable maximum plasma concentration (Cmax ) at an approved dose in humans (Cmax /EC90 ratio). Only 14 of the 56 analyzed drugs achieved a Cmax /EC90 ratio above 1. A more in-depth assessment demonstrated that only nitazoxanide, nelfinavir, tipranavir (ritonavir-boosted), and sulfadoxine achieved plasma concentrations above their reported anti-SARS-CoV-2 activity across their entire approved dosing interval. An unbound lung to plasma tissue partition coefficient (Kp Ulung ) was also simulated to derive a lung Cmax /half-maximal effective concentration (EC50 ) as a better indicator of potential human efficacy. Hydroxychloroquine, chloroquine, mefloquine, atazanavir (ritonavir-boosted), tipranavir (ritonavir-boosted), ivermectin, azithromycin, and lopinavir (ritonavir-boosted) were all predicted to achieve lung concentrations over 10-fold higher than their reported EC50 . Nitazoxanide and sulfadoxine also exceeded their reported EC50 by 7.8-fold and 1.5-fold in lung, respectively. This analysis may be used to select potential candidates for further clinical testing, while deprioritizing compounds unlikely to attain target concentrations for antiviral activity. Future studies should focus on EC90 values and discuss findings in the context of achievable exposures in humans, especially within target compartments, such as the lungs, in order to maximize the potential for success of proposed human clinical trials.

The aim of this paper is to investigate the ways in which changing gender roles in a Bedouin community in Upper Egypt, brought about by settlement over the last 20 years on the shores of Lake Nasser, have impacted on the accumulation and development of indigenous environmental knowledges by Bedouin women. The research was carried out among four groups of Ababda Bedouin in the Eastern Desert of Egypt and involved in-depth monthly conversations carried out over a period of 12 months. The main conclusions of the study are that the women of the study area have had to develop new knowledges which, in some cases, are now different from those held by men because of the different economic circumstances in which many find themselves; that these knowledges are fluid, dynamic and ever-changing with their own internal dynamism; and that socially constructed notions of gender are vital in the development process, notions that are sensitive to both men's and women's interests and their interrelationships.