Foot-and-Mouth Disease Impact on Smallholders - What Do We Know, What Don't We Know and How Can We Find Out More?

Foot-and-mouth disease (FMD) endemic regions contain three-quarters of the world's FMD susceptible livestock and most of the world's poor livestock keepers. Yet FMD impact on smallholders in these regions is poorly understood. Diseases of low mortality can exert a large impact if incidence is high. Modelling and field studies commonly find high FMD incidence in endemic countries. Sero-surveys typically find a third of young cattle are sero-positive, however, the proportion of sero-positive animals that developed disease, and resulting impact, are unknown. The few smallholder FMD impact studies that have been performed assessed different aspects of impact, using different approaches. They find that FMD impact can be high (>10% of annual household income). However, impact is highly variable, being a function of FMD incidence and dependency on activities affected by FMD. FMD restricts investment in productive but less FMD-resilient farming methods, however, other barriers to efficient production may exist, reducing the benefits of FMD control. Applying control measures is costly and can have wide-reaching negative impacts; veterinary-cordon-fences may damage wildlife populations, and livestock movement restrictions and trade bans damage farmer profits and the wider economy. When control measures are ineffective, farmers, society and wildlife may experience the burden of control without reducing disease burden. Foot-and-mouth disease control has benefitted smallholders in South America and elsewhere. Success takes decades of regional cooperation with effective veterinary services and widespread farmer participation. However, both the likelihood of success and the full cost of control measures must be considered. Controlling FMD in smallholder systems is challenging, particularly when movement restrictions are hard to enforce. In parts of Africa this is compounded by endemically infected wildlife and limited vaccine performance. This paper reviews FMD impact on smallholders in endemic countries. Significant evidence gaps exist and guidance on the design of FMD impact studies is provided.

Global Foot-and-Mouth Disease Research Update and Gap Analysis: 2 - Epidemiology, Wildlife and Economics.

We assessed knowledge gaps in foot-and-mouth disease (FMD) research, and in this study, we consider (i) epidemiology, (ii) wildlife and (iii) economics. The study took the form of a literature review (2011-2015) combined with research updates collected in 2014 from 33 institutes from across the world. Findings were used to identify priority areas for future FMD research. During 2011-2015, modelling studies were dominant in the broad field of epidemiology; however, continued efforts are required to develop robust models for use during outbreaks in FMD-free countries, linking epidemiologic and economics models. More guidance is needed for both the evaluation and the setting of targets for vaccine coverage, population immunity and vaccine field efficacy. Similarly, methods for seroprevalence studies need to be improved to obtain more meaningful outputs that allow comparison across studies. To inform control programmes in endemic countries, field trials assessing the effectiveness of vaccination in extensive smallholder systems should be performed to determine whether FMD can be controlled with quality vaccines in settings where implementing effective biosecurity is challenging. Studies need to go beyond measuring only vaccine effects and should extend our knowledge of the impact of FMD and increase our understanding of how to maximize farmer participation in disease control. Where wildlife reservoirs of virus exist, particularly African Buffalo, we need to better understand when and under what circumstances transmission to domestic animals occurs in order to manage this risk appropriately, considering the impact of control measures on livelihoods and wildlife. For settings where FMD eradication is unfeasible, further ground testing of commodity-based trade is recommended. A thorough review of global FMD control programmes, covering successes and failures, would be extremely valuable and could be used to guide other control programmes.

Global Foot-and-Mouth Disease Research Update and Gap Analysis: 1 - Overview of Global Status and Research Needs.

The Global Foot-and-mouth disease (FMD) Research Alliance periodically reviews the state of FMD research to assess progress and to identify new priorities. In this supplement we provide an update of global FMD research, comprising (i) this overview paper, which includes background information with key findings, and papers covering (ii) epidemiology, wildlife and economics, (iii) vaccines, (iv) diagnostics, (v) biotherapeutics and disinfectants, (vi) immunology and (vii) pathogenesis and molecular biology. FMD research publications were reviewed (2011-2015) and activity updates were obtained from 33 FMD research institutes from around the world. Although a continual threat, FMD has been effectively controlled in much of the world using existing tools. However, control remains a challenge in most developing countries, where little has been done to understand the ongoing burden of FMD. More research is needed to support control in endemically infected countries, particularly robust field studies. Traditional FMD vaccines have several limitations including short duration and spectrum of protection, cold chain requirements, and the costs and biosecurity risks associated with vaccine production. Significant progress has been made in the development of novel vaccine candidates, particularly in the use of recombinant vaccines and virus-like particles as an alternative to traditional inactivated whole virus vaccines. Continued investment is needed to turn these developments into improved vaccines produced at scale. Increased knowledge of cellular and mucosal immunity would benefit vaccine development, as would further advances in our ability to enhance vaccine capsid stability. Developments in molecular biology and phylogenetics underlie many of the recent advances in FMD research, including improved vaccines and diagnostics, and improved understanding of FMD epidemiology. Tools for genetic analyses continue to become both more powerful and more affordable enabling them to be used to address an ever-expanding range of questions. This rapidly advancing field potentiates many areas of FMD research and should be prioritized.

Global Foot-and-Mouth Disease Research Update and Gap Analysis: 5 - Biotherapeutics and Disinfectants.

We assessed knowledge gaps in foot-and-mouth disease (FMD) research. Findings are reported in a series of papers, and in this article, we consider biotherapeutics and disinfectants. The study took the form of a literature review (2011-2015) combined with research updates collected in 2014 from 33 institutes from across the world. Findings were used to identify priority areas for future FMD research. While vaccines will remain the key immunological intervention used against FMD virus (FMDV) for the foreseeable future, it takes a few days for the immune system to respond to vaccination. In an outbreak situation, protection could potentially be provided during this period by the application of rapid, short-acting biotherapeutics, aiming either to stimulate a non-specific antiviral state in the animal or to specifically inhibit a part of the viral life cycle. Certain antiviral cytokines have been shown to promote rapid protection against FMD; however, the effects of different immune-modulators appear to vary across species in ways and for reasons that are not yet understood. Major barriers to the effective incorporation of biotherapeutics into control strategies are cost, limited understanding of their effect on subsequent immune responses to vaccines and uncertainty about their potential impact if used for disease containment. Recent research has highlighted the importance of environmental contamination in FMDV transmission. Effective disinfectants for FMDV have long been available, but research is being conducted to further develop methods for quantitatively evaluating their performance under field, or near-field, conditions. During outbreaks in South Korea in 2010 there was public concern about potential environmental contamination after the mass use of disinfectant and mass burial of culled stock; this should be considered during outbreak contingency planning.

Global Foot-and-Mouth Disease Research Update and Gap Analysis: 3 - Vaccines.

This study assessed research knowledge gaps in the field of FMDV (foot-and-mouth disease virus) vaccines. The study took the form of a literature review (2011-15) combined with research updates collected in 2014 from 33 institutes from across the world. Findings were used to identify priority areas for future FMD vaccine research. Vaccines play a vital role in FMD control, used both to limit the spread of the virus during epidemics in FMD-free countries and as the mainstay of disease management in endemic regions, particularly where sanitary controls are difficult to apply. Improvements in the performance or cost-effectiveness of FMD vaccines will allow more widespread and efficient disease control. FMD vaccines have changed little in recent decades, typically produced by inactivation of whole virus, the quantity and stability of the intact viral capsids in the final preparation being key for immunogenicity. However, these are exciting times and several promising novel FMD vaccine candidates have recently been developed. This includes the first FMD vaccine licensed for manufacture and use in the USA; this adenovirus-vectored FMD vaccine causes in vivo expression of viral capsids in vaccinated animals. Another promising vaccine candidate comprises stabilized empty FMDV capsids produced in vitro in a baculovirus expression system. Recombinant technologies are also being developed to improve otherwise conventionally produced inactivated vaccines, for example, by creating a chimeric vaccine virus to increase capsid stability and by inserting sequences into the vaccine virus for desired antigen expression. Other important areas of ongoing research include enhanced adjuvants, vaccine quality control procedures and predicting vaccine protection from immune correlates, thus reducing dependency on animal challenge studies. Globally, the degree of independent vaccine evaluation is highly variable, and this is essential for vaccine quality. Previously neglected, the importance of evaluating vaccination programme effectiveness and impact is increasingly being recognized.

Global Foot-and-Mouth Disease Research Update and Gap Analysis: 6 - Immunology.

This study assessed gaps and priorities for FMDV (foot-and-mouth disease virus) research in the field of immunology. The study took the form of a literature review (2011-15) combined with research updates collected in 2014 from 33 institutes from across the world. Findings were used to identify priority areas for future FMD research. Improved understanding of FMDV immunology facilitates the development of vaccines, adjuvants and diagnostic tests, and will allow better assessment and prediction of vaccine potency and match, with reduced use of animals, particularly large animals, in experimental studies. Continued characterization of the immune systems of several FMD host species has underpinned substantial advances in knowledge of their interaction with FMDV. Recent studies have shed light on the mechanisms underlying formation of the bovine B- and T-cell response; there is also a greater understanding of the significance of non-neutralizing antibodies during FMDV infection and the interactions of antibody-bound virus with immune cells. This knowledge is directly relevant to vaccine development, as well as understanding protection and cross-protection. Despite ongoing research, significant knowledge gaps remain in the areas of neonatal and mucosal immunity. The impact of maternally derived antibody upon the neonate's ability to respond to FMD vaccination has received some attention, but few firm conclusions can be drawn at this stage, and little is known of the cellular response of young animals in general. The mucosal immune system of FMDV-susceptible species requires continued characterization, especially if the potential of mucosal vaccine-delivery systems is to be realized for FMD immunization.

Global Foot-and-Mouth Disease Research Update and Gap Analysis: 4 - Diagnostics.

This study assessed knowledge gaps in foot-and-mouth disease (FMD) research in the field of diagnostics. The study took the form of a literature review (2011-15) combined with research updates collected in 2014 from 33 institutes from around the world. Findings were used to identify priority areas for future FMD research. Molecular and genetic technologies, including sequencing, are developing at an increasing rate both in terms of capability and affordability. These advances potentiate progress in many other fields of research, from vaccine development to epidemiology. The development of RT-LAMP represents an important breakthrough allowing greater use and access to molecular diagnostics. It is now possible to determine virus serotype using PCR, although only for certain virus pools, continued progress is needed to cover the global spectrum of FMD viruses. Progress has also been made in the development of pen-side rapid diagnostics, some with the ability to determine serotype. However, further advances in pen-side serotype or strain determination would benefit both FMD-free countries and endemic countries with limited access to well-resourced laboratories. Novel sampling methods that show promise include air sampling and baited ropes, the latter may aid sampling in wildlife and swine. Studies of infrared thermography for the early detection of FMD have not been encouraging, although investigations are ongoing. Multiplex tests have been developed that are able to simultaneously screen for multiple pathogens with similar clinical signs. Crucial for assessing FMDV freedom, tests exist to detect animals that have been infected with FMDV regardless of vaccination status; however, limitations exist, particularly when testing previously vaccinated animals. Novel vaccines are being developed with complementary DIVA tests for this purpose. Research is also needed to improve the current imprecise approaches to FMD vaccine matching. The development of simple, affordable tests increases access to FMD diagnostics, greatly benefiting regions with limited laboratory capacity.

Global Foot-and-Mouth Disease Research Update and Gap Analysis: 7 - Pathogenesis and Molecular Biology.

We assessed research knowledge gaps in the fields of FMDV (foot-and-mouth disease virus) pathogenesis and molecular biology by performing a literature review (2011-15) and collecting research updates (2014) from 33 institutes from across the world. Findings were used to identify priority areas for future research. There have been important advances in FMDV pathogenesis; FMDV remains in lymph nodes of many recovered animals that otherwise do not appear persistently infected, even in species previously not associated with the carrier state. Whether virus retention helps maintain host immunity and/or virus survival is not known. Studies of FMDV pathogenesis in wildlife have provided insights into disease epidemiology, in endemic and epidemic settings. Many aspects of FMDV infection and virus entry remain unknown; however, at the cellular level, we know that expression level and availability of integrins (that permit viral entry), rate of clearance of infected cells and strength of anti-viral type I IFN (interferon) response are key determinants of tissue tropism. Extending findings to improved understanding of transmission requires a standardized approach and adoption of natural routes of infection during experimental study. There has been recognition of the importance of autophagosomes for FMDV entry into the cytoplasm following cell surface receptor binding, and that distinct internal cellular membranes are exploited for viral replication and immune evasion. New roles for viral proteins in blocking type I IFN production and downstream signalling have been identified facilitating research in anti-viral therapeutics. We know more about how infection affects cell protein expression, and research into molecular determinants of capsid stability has aided the development of stable vaccines. We have an expanding knowledge of viral and host molecular determinates of virulence and infectiousness, and of how phylogenetics may be used to estimate vaccine match and strain distribution. With ongoing advances, these areas could translate into significantly improved disease control.

Mass vaccination, immunity and coverage: modelling population protection against foot-and-mouth disease in Turkish cattle.

Foot-and-mouth disease (FMD) in Turkey is controlled using biannual mass vaccination of cattle. However, vaccine protection is undermined by population turnover and declining immunity. A dynamic model of the Turkish cattle population was created. Assuming biannual mass vaccination with a single-dose primary course, vaccine history was calculated for the simulated population (number of doses and time since last vaccination). This was used to estimate population immunity. Six months after the last round of vaccination almost half the cattle aged < 24 months remain unvaccinated. Only 50% of all cattle would have received > 1 vaccine dose in their life with the last dose given ≤ 6 months ago. Five months after the last round of vaccination two-thirds of cattle would have low antibody titres (< 70% protection threshold). Giving a two-dose primary vaccination course reduces the proportion of 6-12 month old cattle with low titres by 20-30%. Biannual mass vaccination of cattle leaves significant immunity gaps and over-reliance on vaccine protection should be avoided. Using more effective vaccines and vaccination strategies will increase population immunity, however, the extent to which FMD can be controlled by vaccination alone without effective biosecurity remains uncertain.

Randomised field trial to evaluate serological response after foot-and-mouth disease vaccination in Turkey.

Despite years of biannual mass vaccination of cattle, foot-and-mouth disease (FMD) remains uncontrolled in Anatolian Turkey. To evaluate protection after mass vaccination we measured post-vaccination antibodies in a cohort of cattle (serotypes O, A and Asia-1). To obtain results reflecting typical field protection, participants were randomly sampled from across Central and Western Turkey after routine vaccination. Giving two-doses one month apart is recommended when cattle are first vaccinated against FMD. However, due to cost and logistics, this is not routinely performed in Turkey, and elsewhere. Nested within the cohort, we conducted a randomised trial comparing post-vaccination antibodies after a single-dose versus a two-dose primary vaccination course. Four to five months after vaccination, only a third of single-vaccinated cattle had antibody levels above a threshold associated with protection. A third never reached this threshold, even at peak response one month after vaccination. It was not until animals had received three vaccine doses in their lifetime, vaccinating every six months, that most (64% to 86% depending on serotype) maintained antibody levels above this threshold. By this time cattle would be >20 months old with almost half the population below this age. Consequently, many vaccinated animals will be unprotected for much of the year. Compared to a single-dose, a primary vaccination course of two-doses greatly improved the level and duration of immunity. We concluded that the FMD vaccination programme in Anatolian Turkey did not produce the high levels of immunity required. Higher potency vaccines are now used throughout Turkey, with a two-dose primary course in certain areas. Monitoring post-vaccination serology is an important component of evaluation for FMD vaccination programmes. However, consideration must be given to which antigens are present in the test, the vaccine and the field virus. Differences between these antigens affect the relationship between antibody titre and protection.

Veterinary and human vaccine evaluation methods.

Despite the universal importance of vaccines, approaches to human and veterinary vaccine evaluation differ markedly. For human vaccines, vaccine efficacy is the proportion of vaccinated individuals protected by the vaccine against a defined outcome under ideal conditions, whereas for veterinary vaccines the term is used for a range of measures of vaccine protection. The evaluation of vaccine effectiveness, vaccine protection assessed under routine programme conditions, is largely limited to human vaccines. Challenge studies under controlled conditions and sero-conversion studies are widely used when evaluating veterinary vaccines, whereas human vaccines are generally evaluated in terms of protection against natural challenge assessed in trials or post-marketing observational studies. Although challenge studies provide a standardized platform on which to compare different vaccines, they do not capture the variation that occurs under field conditions. Field studies of vaccine effectiveness are needed to assess the performance of a vaccination programme. However, if vaccination is performed without central co-ordination, as is often the case for veterinary vaccines, evaluation will be limited. This paper reviews approaches to veterinary vaccine evaluation in comparison to evaluation methods used for human vaccines. Foot-and-mouth disease has been used to illustrate the veterinary approach. Recommendations are made for standardization of terminology and for rigorous evaluation of veterinary vaccines.

Retrospective evaluation of foot-and-mouth disease vaccine effectiveness in Turkey.

Foot-and-mouth disease (FMD) is present in much of Turkey and its control is largely based on vaccination. The arrival of the FMD Asia-1 serotype in Turkey in 2011 caused particular concern, spreading rapidly westwards across the country towards the FMD free European Union. With no prior natural immunity, control of spread would rely heavily on vaccination. Unlike human vaccines, field protection is rarely evaluated directly for FMD vaccines. Between September 2011 and July 2012 we performed four retrospective outbreak investigations to assess the vaccine effectiveness (VE) of FMD Asia-1 vaccines in Turkey. Vaccine effectiveness is defined as the reduction in risk in vaccinated compared to unvaccinated individuals with similar virus exposure in the field. The four investigations included 12 villages and 1230 cattle >4 months of age. One investigation assessed the FMD Asia-1 Shamir vaccine, the other three evaluated the recently introduced FMD Asia-1 TUR 11 vaccine made using a field isolate of the FMD Asia-1 Sindh-08 lineage that had recently entered Turkey. After adjustment for confounding, the TUR 11 vaccine provided moderate protection against both clinical disease VE=69% [95% CI: 50%-81%] and infection VE=63% [95% CI: 29%-81%]. However, protection was variable with some herds with high vaccine coverage still experiencing high disease incidence. Some of this variability will be the result of the variation in virus challenge and immunity that occurs under field conditions. In the outbreak investigated there was no evidence that the Asia-1 Shamir vaccine provided adequate protection against clinical FMD with an incidence of 89% in single vaccinated cattle and 69% in those vaccinated two to five times. Based on these effectiveness estimates, vaccination alone is unlikely to produce the high levels of herd immunity needed to control FMD without additional control measures.

Risk assessment and cost-effectiveness of animal health certification methods for livestock export in Somalia.

Livestock export is vital to the Somali economy. To protect Somali livestock exports from costly import bans used to control the international spread of disease, better certification of livestock health status is required. We performed quantitative risk assessment and cost-effectiveness analysis on different health certification protocols for Somali livestock exports for six transboundary diseases. Examining stock at regional markets alone without port inspection and quarantine was inexpensive but was ineffective for all but contagious bovine pleuropneumonia, contagious caprine pleuropneumonia and peste des petits ruminants. While extended pre-export quarantine improves detection of infections that cause clinical disease, if biosecurity is suboptimal quarantine provides an opportunity for transmission and increased risk. Clinical examination, laboratory screening and vaccination of animals for key diseases before entry to the quarantine station reduced the risk of an exported animal being infected. If vaccination could be reliably performed weeks before arrival at quarantine its effect would be greatly enhanced. The optimal certification method depends on the disease. Laboratory diagnostic testing was particularly important for detecting infections with limited clinical signs in male animals (only males are exported); for Rift Valley fever (RVF) the probability of detection was 99% or 0% with and without testing. Based on our findings animal inspection and certification at regional markets combined with quarantine inspection and certification would reduce the risk of exporting infected animals and enhance disease control at the regional level. This is especially so for key priority diseases, that is RVF, foot-and-mouth disease and Brucellosis. Increased data collection and testing should be applied at point of production and export.

The economic impacts of foot and mouth disease - what are they, how big are they and where do they occur?

Although a disease of low mortality, the global impact of foot and mouth disease (FMD) is colossal due to the huge numbers of animals affected. This impact can be separated into two components: (1) direct losses due to reduced production and changes in herd structure; and (2) indirect losses caused by costs of FMD control, poor access to markets and limited use of improved production technologies. This paper estimates that annual impact of FMD in terms of visible production losses and vaccination in endemic regions alone amount to between US$6.5 and 21 billion. In addition, outbreaks in FMD free countries and zones cause losses of >US$1.5 billion a year. FMD impacts are not the same throughout the world: FMD is highly contagious and the actions of one farmer affect the risk of FMD occurring on other holdings; thus sizeable externalities are generated. Control therefore requires coordination within and between countries. These externalities imply that FMD control produces a significant amount of public goods, justifying the need for national and international public investment. Equipping poor countries with the tools needed to control FMD will involve the long term development of state veterinary services that in turn will deliver wider benefits to a nation including the control of other livestock diseases.

Aspects of bovine caesarean section associated with calf mortality, dam survival and subsequent fertility.

Bovine caesarean section is a common surgery performed by cattle practitioners yet evidence for justifying many aspects of the surgical procedure is lacking. Between 2001 and 2007, questionnaires were used to gather information on 103 cases of caesarean section performed in one, predominantly dairy, veterinary practice. The results showed that the 14-day cow survival rate was 80.6%, and of those surviving beyond this period, 55.4% carried another calf to term, 27.7% were culled due to infertility and 16.9% were culled due to other reasons. Variables associated with reduced 14-day dam mortality included exteriorising the uterus during surgery (odds ratio [OR] 0.018, 95% confidence interval [CI] 0.0019-0.17, P<0.001), dystocia where fetomaternal disproportion was present (OR 0.090, 95% CI 0.097-0.83, P=0.033), a female calf (OR 0.036, 95% CI 0.0019-0.69, P=0.027), no retained fetal membranes at the first post-operative revisit (OR 0.095, 95% CI 0.013-0.69, P=0.020) and removing abdominal blood clots during surgery (OR 0.10, 95% CI 0.011-0.93, P=0.043). Using a Utrecht suture pattern on the uterus was associated with reduced culling due to infertility (OR 0.12, 95% CI 0.020-0.67, P=0.016). Incision infection was noted in 25.9% of cases where incision status was recorded but this was not associated with the type of local anaesthesia used. Overall calf survival up to the first post-operative visit (24-48 h) was 59.4%, and was associated with shorter duration of surgery, and dystocia due to fetomaternal disproportion. These results offer some evidence-based guidelines to optimise outcomes for this common surgery performed under field conditions.

Assessment of farm-level biosecurity measures after an outbreak of avian influenza in the United Kingdom.

During Avian Influenza outbreaks in England, the 'AI Order' states that a poultry keeper may be required to keep domestic birds separate from wild birds. This study aimed to assess a) how effectively this was done and b) the negative impact this had for bird owners and animal welfare during the November 2007 Highly Pathogenic Avian Influenza (HPAI) outbreak in Suffolk, UK. A voluntary questionnaire was posted to holdings (n=296) that were within 10 km of an infected premises; these holdings were required to separate domestic and wild birds where possible. Holdings were identified during outbreak investigations conducted by the authorities. Holdings of all sizes were included. A sample of holdings received a follow-up visit or telephone call to validate the questionnaire (n=29). From the 38% of eligible holdings that responded, 13% (95% CI 7-22%) left their birds outdoors throughout the outbreak. If game birds were excluded, 9% (CI 4-17%) of holdings did not house their birds. Major cost and welfare problems were rare; however, there were exceptions. Enforced housing was often relaxed before a minor welfare problem deteriorated. Contact between wild and domestic birds was greatly reduced during the outbreak, resulting in a reduced probability of HPAI transmission via wild birds for most, but not all, holdings.

Animal production food safety: priority pathogens for standard setting by the World Organisation for Animal Health.

In this short study, expert opinion and a literature review were used to identify the pathogens that should be prioritised by the World Organisation for Animal Health (OIE) for the development of future standards for animal production food safety. Prioritisation was based on a pathogen's impact on human health and amenability to control using on-farm measures. As the OIE mandate includes alleviation of global poverty, the study focused on developing countries and those with 'in-transition' economies. The regions considered were Eastern Europe, Asia, the Middle East, Africa and South America. Salmonella (from species other than poultry) and pathogenic Escherichia coli were considered to be top priorities. Brucella spp., Echinococcus granulosus and Staphylococcus aureus were also mentioned by experts. As Salmonella, and to a lesser extent pathogenic E. coli, can be controlled by on-farm measures, these pathogens should be considered for prioritisation in future standard setting. On-farm control measures for Brucella spp. will be addressed in 2010-2011 in a review of the OLE Terrestrial Animal/Health Code chapter on brucellosis. In Africa, E. granulosus, the causative agent of hydatidosis, was estimated to have the greatest impact of all pathogens that could potentially be transmitted by food (i.e. via contamination). It was also listed for the Middle East and thought to be of importance by both South American experts consulted. Taenia saginata was thought to be of importance in South America and Africa and by one expert in the Middle East.