BACKGROUND:We investigated the impact of Drug-Drug Interactions (DDIs) on virologic control among HIV-positive pregnant women initiating antiretroviral therapy while identifying drivers for Traditional Medicine (TM) use and exploring the nature and extent of TM-related DDIs. METHODS:Employing a three-pronged approach, we examined DDIs arising from comedication, including TM, in ART. The DolPHIN-2 trial (NCT03249181) randomized 268 HIV-positive pregnant women in Uganda and South Africa to dolutegravir (DTG)-based (135) or efavirenz-based (133) regimens while systematically recording comedications and screening for DDIs. We used Cox regression models to compare time-to-virologic control between participants with and without DDIs. We conducted in-depth interviews and focus group discussions among 37 and 67 women with and without HIV, respectively, to explore reasons for TM use during pregnancy. Additionally, in-vitro and in-vivo studies evaluated the composition and impact of clay-based TM, mumbwa, on DTG plasma exposure. RESULTS:The baseline prevalence of DDIs was 67.2%, with TM use prevalent in 34% of participants, with mumbwa being the most frequent (76%, 69/91). There was no difference in virologic response between participants with and without DDIs. Fetal health and cultural norms were among the reasons cited for TM use. Analysis of mumbwa rods confirmed significant amounts of aluminium (8.4%-13.9%) and iron (4%-6%). In Balb-C mice, coadministration of mumbwa led to a reduction in DTG exposure observed in the AUC0-24 (-21%; P = 0.0271) and C24 (-53%; P = 0.0028). CONCLUSIONS:The widespread use of clay-based TM may compromise HIV treatment, necessitating medication screening and counselling to manage DDIs in pregnant women.

COVID-19 is a spectrum of clinical symptoms in humans caused by infection with SARS-CoV-2. The coalescence of SARS-CoV-2 with seasonal respiratory viruses, particularly influenza viruses, is a global health concern. To understand this, transgenic mice expressing the human ACE2 receptor (K18-hACE2) were infected with influenza A virus (IAV) followed by SARS-CoV-2 and the host response and effect on virus biology was compared to K18-hACE2 mice infected with IAV or SARS-CoV-2 alone. The sequentially infected mice showed reduced SARS-CoV-2 RNA synthesis, yet exhibited more rapid weight loss, more severe lung damage and a prolongation of the innate response compared to the singly infected or control mice. Sequential infection also exacerbated the extrapulmonary encephalitic manifestations associated with SARS-CoV-2 infection. Conversely, prior infection with a commercially available, multivalent live-attenuated influenza vaccine (Fluenz Tetra) elicited the same reduction in SARS-CoV-2 RNA synthesis, albeit without the associated increase in disease severity. This suggests that the innate immune response stimulated by IAV inhibits SARS-CoV-2. Interestingly, infection with an attenuated, apathogenic influenza vaccine does not result in an aberrant immune response and enhanced disease severity. Taken together, the data suggest coinfection (‘twinfection’) is deleterious and mitigation steps should be instituted as part of the comprehensive public health and management strategy of COVID-19.

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.

COVID-19 has stimulated the rapid development of new antibody and small molecule therapeutics to inhibit SARS-CoV-2 infection. Here we describe a third antiviral modality that combines the drug-like advantages of both. Bicycles are entropically constrained peptides stabilized by a central chemical scaffold into a bi-cyclic structure. Rapid screening of diverse bacteriophage libraries against SARS-CoV-2 Spike yielded unique Bicycle binders across the entire protein. Exploiting Bicycles’ inherent chemical combinability, we converted early micromolar hits into nanomolar viral inhibitors through simple multimerization. We also show how combining Bicycles against different epitopes into a single biparatopic agent allows Spike from diverse variants of concern (VoC) to be targeted (Alpha, Beta, Delta and Omicron). Finally, we demonstrate in both male hACE2-transgenic mice and Syrian golden hamsters that both multimerized and biparatopic Bicycles reduce viraemia and prevent host inflammation. These results introduce Bicycles as a potential antiviral modality to tackle new and rapidly evolving viruses.

Abstract Background Food safety will likely be a major policy agenda item as populations and demand for meat grow and livestock intensification progresses in Tanzania and other low- and middle-income countries (LMICs). Meeting this demand comes with considerable meat safety challenges, risks, and opportunities. This paper offers evidence-based reflections on the governance of the Tanzanian red meat value chain, articulating potential policy implications for red meat food safety in Tanzania and other LMICs. Methods This paper synthesizes existing knowledge and data about the food safety dimensions of the Tanzanian red meat value chain, analyzing it through a strengths-weaknesses-opportunities-threats (SWOT) framework. This knowledge and data includes: 1) a review of relevant Tanzanian policy and legislation up to 2020; and 2) published and unpublished multi-disciplinary field and laboratory work conducted under the Hazards Associated with Zoonotic enteric pathogens in Emerging Livestock meat pathways (HAZEL) project in Northern Tanzania. Results Strengths include some enabling policies, legislation, workforce, informal networks and infrastructure supporting meat safety. Weaknesses included confusion over mandates, limited resources and infrastructure for compliance/enforcement, lack of data on meat-borne disease, and limited attention to invisible pathogenic meat contamination. Opportunities include strong in-country training infrastructures and the significant economic potential of boosting meat production systems. Although increased revenue could support meat safety investments, this couples with risks of food safety infrastructure failing to keep up with growth (while envisioned increased centralised production may introduce new forms of meat safety risk), and potential inequalities in economic opportunities, gains and meat safety investments, especially for rural, small scale and/or female meat chain actors and their communities. Conclusions Agricultural intensification and centralized abattoirs may benefit meat safety and spur economic growth but may not alone generate value for Tanzania and has risks. Investments may overlook rural livestock systems and small-scale actors needing critical meat safety improvements. In addition to basic infrastructure investments, context-appropriate innovations encouraging local-level meat safety may provide cost-effective opportunities for Tanzania and other LMICs to strengthen food safety.

Background: There is growing interest in utilizing structured extended periods of simulation as partial replacement for clinical placement (PRCP) due to workforce demands and COVID-19 impact. This project aimed to identify the extent to which stakeholders felt that simulated placements could reduce overall clinical placement time requirement for health care students. Method: Participants included a range of nurses and Allied Health Professionals including managers, clinicians and lecturers. A three-round Delphi study was conducted with a 75% consensus agreement target. Results: Overall, 71 participants engaged with at least one round of the study and identified benefits of PRCP: Safety, learning from mistakes, improved preparation, and reduced placement training burden. Challenges included poor realism, logistics, time, and access to facilities. Conclusions: The consensus opinion indicated that between 11% and 30% of clinical training time could be replaced with simulated placement. Ongoing work will need to identify profession-specific consensus opinion and guidance on the use of simulation as PRCP. (C) 2022 International Nursing Association for Clinical Simulation and Learning. Published by Elsevier Inc.

Securing sufficient practice-based learning opportunities for health care students is long-standing and well documented and not unique to the United Kingdom (Beveridge & Pentland 2020; Martin et al., 2004). Increasing Allied Health Professional learners on healthcare programmes and the COVID-19 pandemic have highlighted the need for radical change and innovative ways of working to address placement capacity. Due to the capacity pressures, blended practice-based placements were implemented in partnership with clinical collaboration across the Cheshire and Merseyside region. As this placement model had not been robustly tested, a decision was made to pilot this across different settings and ethical approval was sought and granted, to fully evaluate this approach. The participants consisted of second-year physiotherapy and first- and second-year occupational therapy learners. The aims of the study were to: ascertain the value and experiences of a newly introduced blended placement-based learning through the anonymous collection of data from an online questionnaire (quantitative) and focus groups (qualitative) in response to challenges relating to placement capacity. Initial findings suggest there are benefits for learners including new skill acquisition, such as organisational and adaptability skills, the ability to influence change in patient care and improved clinical reasoning. Challenges for learners include the type and length of project not being comparable to their peers, reduced clinical time, perceived discrepancies in marking during the placement and opportunities to develop confidence. Alternative placement models are required to meet ongoing capacity demands. This work adds to the growing body of placement related literature.

Preventing SARS-CoV-2 infection by modulating viral host receptors, such as angiotensin-converting enzyme 2 (ACE2) 1 , could represent a new chemoprophylactic approach for COVID-19 that complements vaccination 2,3 . However, the mechanisms that control the expression of ACE2 remain unclear. Here we show that the farnesoid X receptor (FXR) is a direct regulator of ACE2 transcription in several tissues affected by COVID-19, including the gastrointestinal and respiratory systems. We then use the over-the-counter compound z-guggulsterone and the off-patent drug ursodeoxycholic acid (UDCA) to reduce FXR signalling and downregulate ACE2 in human lung, cholangiocyte and intestinal organoids and in the corresponding tissues in mice and hamsters. We show that the UDCA-mediated downregulation of ACE2 reduces susceptibility to SARS-CoV-2 infection in vitro, in vivo and in human lungs and livers perfused ex situ. Furthermore, we reveal that UDCA reduces the expression of ACE2 in the nasal epithelium in humans. Finally, we identify a correlation between UDCA treatment and positive clinical outcomes after SARS-CoV-2 infection using retrospective registry data, and confirm these findings in an independent validation cohort of recipients of liver transplants. In conclusion, we show that FXR has a role in controlling ACE2 expression and provide evidence that modulation of this pathway could be beneficial for reducing SARS-CoV-2 infection, paving the way for future clinical trials.

The ability of acquired immune responses against SARS-CoV-2 to protect after subsequent exposure to emerging variants of concern (VOC) such as B1.1.7 and B1.351 is currently of high significance. Here, we use a hamster model of COVID-19 to show that prior infection with a strain representative of the original circulating lineage B of SARS-CoV-2 induces protection from clinical signs upon subsequent challenge with either B1.1.7 or B1.351 viruses, which recently emerged in the UK and South Africa, respectively. The results indicate that these emergent VOC may be unlikely to cause disease in individuals that are already immune due to prior infection, and this has positive implications for overall levels of infection and COVID-19 disease.

Through a social scientific lens, this paper considers the risk perceptions and “risk-based decision-making” of two key groups in a northern Tanzanian context: (1) frontline government meat inspectors and health officers charged with ensuring that red meat sold commercially is safe for people to consume, and (2) the workers who slaughter and process cattle and red meat prior to its sale in rural butcheries. In contrast to techno-scientific understandings of disease risk and “rational” approaches to its management, this paper foregrounds the role of social, economic and institutional context in shaping the perceptions and practices around meat safety of these actors whose daily, close proximity to meat means they play a significant role in mitigating potential meat-borne disease. We show how limited resources, and a combination of scientific and local knowledge and norms result in “situated expertise” and particular forms of risk perception and practice which both enhance and compromise meat safety in different ways. Actors' shared concerns with what is visible, ensures that visibly unsafe or abnormal meat is excluded from sale, and that infrastructure and meat is kept “clean” and free of certain visible contaminants such as soil or, on occasion, feces. While such contaminants serve as a good proxy for pathogen presence, meat inspectors and especially slaughter workers were much less aware of or concerned with invisible pathogens that may compromise meat safety. The role of process and meat handling did not figure very strongly in their concerns. Microorganisms such as Salmonella and Campylobacter, which can easily be transferred onto meat and persist in slaughter and meat sale environments, went unacknowledged. Although health officers expressed more concern with hygiene and meat handling, their influence over slaughter process and butchery operations was unclear. Ultimately, recognizing the perceptions and practices of frontline actors who engage with meat, and the ways in which social, material and institutional realities shape these, is important for understanding how decisions about risk and meat safety are made in the complexity and context of everyday life, and thus for finding effective ways to support them to further enhance their work.

Critical geopolitics was established as a poststructural approach, which insists that rather than being an apolitical influence on international politics, as conventional accounts of geopolitics would argue, geographical relationships and entities are specific to historical and cultural circumstances. As the meaning of geography can be made to change, there is a politics to the use of geographical concepts in arguments about international relations. Following Foucault, critical geopolitics analyzes discourses of geography in international relations theory and practice to examine the power relations supported by such representations. Various attempts have been made to apply the critical geopolitics approach to the analysis of political speeches, policy documents, and popular culture. More recently, scholars have sought to go beyond the approach's origins in textual analysis to provide critical accounts of geopolitics which understand the inscription of international politics in the body, take account of the multiple practices that comprise the geopolitical, and offer an extended understanding of agency that takes in a variety of nonhuman actants in the theorization of both the -politics and the geo- in geopolitics.

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’s red meat value chain—which in its totality involves about one third of the population—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-à-vis regulations. We found operators of eateries emphasising their own agency in keeping meat safe, whereas operators of butcheries—whose products are more closely inspected—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’ shorter and relatively unmediated value chains.

The use of Participatory Epidemiology in veterinary research intends to include livestock keepers and other local stakeholders in research processes and the development of solutions to animal health problems, including potentially zoonotic diseases. It can also be an attempt to bring some of the methods and insights of social science into a discipline largely shaped by natural science methods and ways of seeing the world. The introduction of participatory methodologies to veterinary epidemiology and disease surveillance follows a wider movement in development thinking, questioning the top-down nature of much post-second world war development efforts directed from the Global North towards the Global South. In the best cases, participatory methods can help to empower the poor and marginalised to participate in and have some control over research and interventions which affect them. Compiled from experience in multi-disciplinary One Health projects, this paper briefly traces the rise of participatory epidemiology before examining some of the limitations observed in its implementation and steps that might be taken to alleviate the problems observed. The three areas in which the operationalisation of Participatory Epidemiology in veterinary and One Health research could be improved are identified as: broadening the focus of engagement with communities beyond quantitative data extraction; taking note of the wider power structures in which research takes place, and questioning who speaks for a community when participatory methods are used. In particular, the focus falls on how researchers from different disciplines, including veterinary medicine and the social sciences, can work together to ensure that participatory epidemiology is employed in such a way that it improves the quality of life of both people and animals around the world.

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.

In this paper we reflect on the Civil Society and Indigenous Peoples' Mechanism to the UN Committee on World Food Security as a policy convergence space for the global food sovereignty movement. Addressing a gap in the convergence literature around inclusivity, we assess the extent to which the Mechanism is a diverse and inclusive space. More specifically, we analyze whether constituencies and quotas have worked as effective tools to protect diversity while avoiding fragmentation. We further contribute to the growing literature on convergence spaces by highlighting what changes and challenges occur when convergence is situated and managed in relation to a more formal institutional space. Analyzing how it has addressed the two challenges of fragmentation and institutionalization, we show how the Mechanism has moved towards greater inclusivity and diversity by reinforcing weaker constituencies, changing its name, and opening up to new constituencies. At the same time, we identify five issues which require further attention if the Mechanism is to remain an inclusive convergence space: risk of a concentration of power; the role of NGOs; gender equality and generational balance; multiple identities that cut across constituency categories; and, tensions related to sub-regions.

This conclusion presents some closing thoughts on the key concepts discussed in the preceding chapters of this book. The book examines the concepts of demilitarization, security and militarization. It discusses the overall theoretical and principled questions of an assessment of the demilitarization and neutralization of the Aland Islands. The book looks at the legal frameworks of the contingent solutions pertaining to the Aland Islands and shows that the rules are considered still valid and relevant even though many of the circumstances surrounding them have been challenged and reconfirmed over time. It deals with regional and sub-regional forms of security co-operation, that the evolving concept of security has been discussed and grey zones and fusions between peace and war and between civil and military spheres described. The book argues that the demilitarized and neutralized status of the Aland Islands …

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.This article is part of the themed issue 'One Health for a changing world: zoonoses, ecosystems and human well-being'.

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.